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_FM-fm1SYNOPSIS OF PATHOLOGY_FM-fm2
_FM-fm3SYNOPSIS OF PATHOLOGY
Anoop N Government Medical College Thrissur, Kerala, India
_FM-fm4
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This book has been published in good faith that the contents provided by the author contained herein are original, and is intended for educational purposes only. While every effort is made to ensure accuracy of information, the publisher and the author specifically disclaim any damage, liability, or loss incurred, directly or indirectly, from the use or application of any of the contents of this work. If not specifically stated, all figures and tables are courtesy of the author. Where appropriate, the readers should consult with a specialist or contact the manufacturer of the drug or device.
Synopsis of Pathology
First Edition: 2013
9789350904756
Printed at
_FM-fm5Dedicated to
‘Pratheeksha’, the charity wing of Government Medical College, Thrissur, Kerala, India
_FM-fm6
_FM-fm7Preface
Synopsis of Pathology is a one-of-a-kind book that aims to equip its readers with a comprehensive knowledge of this vast subject from a single read. It is mostly based on Robbins Basic Pathology and other standard textbooks. Synopsis has been presented in a manner that would help its readers to confront the new second MBBS examination pattern with confidence. The simple but precise text has been supplemented with several flow charts, illustrations and essential pictures that expedite understanding of the subject. Clinical pathology notes and a set of 50 clinical essay questions mostly from previous university question papers is also a unique feature to this book.
Although every effort has been made to make the book error free, I acknowledge that some mistakes might have crept in. I request the readers to point out any error—factual or otherwise—that they notice and also to send your feedback and invaluable suggestions towards improving future editions of this book.
Anoop N
_FM-fm8
_FM-fm9Acknowledgments
I wish to express the deepest gratitude to Dr Joy Augustine, Professor and Head, and all the other faculty members of the Department of Pathology, Government Medical College, Thrissur, Kerala, India. Without their guidance and help, the completion of this book could never have been realized. I also thank College Union 2011 to 2012 for their support in publishing this book.
I thank my friend Jithesh R for drawing diagrams in this book. My friends particularly; Achyuth Ajith, Ameesh M, Anto Anand G, Aseel KP, Gautham Rajan, Gokul ED, Habeeb Rehman, Jijo Joseph, Monish Mohan and Rony Mathew of 27th Batch; Ashna KK, Anamika Ummer, Chandini Sundar, Emil Ebin Saji, Harikrishnan AR and Vishnu VM of 29th Batch; Benson Benchamin, Sadhik V and Vineeth of 30th Batch, who gave me selfless support for preparing the manuscript of this book, deserve special mention. I also thank my beloved little sister Navaneetha for her help and support in completion of this book.
I am also thankful to Shri Jitendar P Vij (Group Chairman), Mr Ankit Vij (Managing Director) and Mr Tarun Duneja (Director-Publishing) of M/s Jaypee Brothers Medical Publishers (P) Ltd, New Delhi, India for the efforts they took to publish and bring out the book in its present form.
Last but not least, I thank my parents, my sister, all my teachers, friends and God Almighty, without whose blessings and support this book would still be only a dream.
_FM-fm10Abbreviations AA
Amino acid
AA
Aortic aneurysm
AAA
Abdominal aortic aneurysm
AAH
Atypical adenomatous hyperplasia
AA protein
Amyloid-associated protein
Ab
Antibody
2M
Amyloid β2-microglobulin
Aβ protein
Amyloid β-protein
ACA
Anterior cerebral artery
ACE
Angiotensin-converting enzyme
ACh
Acetylcholine
AD
Autosomal dominant
ADP
Adenosine diphosphate
AF
Atrial fibrillation
AFP
Alpha fetoprotein
Ag
Antigen
AL protein
Amyloid light-chain protein
ANCA
Anti-neutrophil cytoplasmic antibody
ANF
Atrial natriuretic factor
APC
Antigen-presenting cell
APP
Amyloid precursor protein
APTT
Activated partial thromboplastin time
AR
Autosomal recessive
AS
Aortic stenosis
AT2
Angiotensin-2
ATM
Ataxia telangiectasia mutated
ATR
Ataxia telangiectasia and Rad3 related
ATTR
Amyloid transthyretin
AV
Aortic valve
B
Basophils
BC
Bowman's capsule
BCC
Basal cell carcinoma
BF
Blood flow
BI
Bacterial index
BM
Basement membrane
BM
Bone marrow
BMR
Basal metabolic rate
BT
Bleeding time
BV
Blood volume
C
Complement
CA
Carcinoma
CAD
Coronary artery disease
CAM
Cell adhesion molecules
cAMP
Cyclic adenosine monophosphate
CCB
Calcium channel blocker
CCF
Congestive cardiac failure
CD
Crohn disease
CDK
Cyclin-dependent kinase
cDNA
Cytoplasmic deoxyribonucleic acid
CEA
Carcinoembryonic antigen
CF
Cystic fibrosis
CFTR
Cystic fibrosis transconductance factor
CHF
Congestive heart failure
CHO
Carbohydrate
CIN
Cervical intraepithelial neoplasia
CK
Creatine kinase
CMI
Cell-mediated immunity
CMV
Cytomegalovirus
_FM-fm11CO
Cardiac output
COX
Cyclo-oxygenase
CPE
Cytopathic effect
CPZ
Chlorpromazine
CRP
C-reactive protein
CT
Clotting time
CT
Collecting tubule
CTL
Cytotoxic lymphocytes
CV
Cardiovascular
CVD
Cerebrovascular disease
CVP
Central venous pressure
DBP
Diastolic blood pressure
DCIS
Ductal carcinoma in situ
DCT
Distal convoluted tubule
DDS
Denys-Drash syndrome
DHC
Dihydrocalciferol
DHFA
Dihydrofolate
DHT
Dihydrotestosterone
DM
Diabetes mellitus
DMT
Divalent metal transporter
ds DNA
Double-stranded deoxyribonucleic acid
DTH
Delayed-type hereditary sensory neuropathy
DVT
Deep vein thrombosis
E
Eosinophils
EBV
Epstein-Barr virus
EC
Endothelial cells
EC
Extracellular
ECF
Extracellular fluid
ECM
Extracellular matrix
ECP
Eosinophilic cationic protein
EF-2
Elongation factor 2
EGF
Epidermal growth factor
EM
Electron microscopy
EPC
Endothelial precursor cells
ER
Endoplasmic reticulum
FAP
Familial adenomatous polyposis
Fc
Fraction crystallizable of Ig
FDP
Fibrin degraded products
FFA
Free fatty acid
FFP
Fresh frozen plasma
FGF
Fibroblast growth factor
FGFR
Fibroblast growth factor receptor
FIGLU
Formiminoglutamate
FISH
Fluorescent in situ hybridization
FMTC
Familial medullary thyroid carcinoma
GADD
Growth arrest and deoxyribonucleic acid damage
GB
Gallbladder
GBM
Glomerular basement membrane
GCA
Gastric carcinoma
GF
Growth factor
GFR
Glomerular filtration rate
GH
Growth hormone
GN
Glomerulonephritis
GP
Glycoprotein
GS
Glomerular sclerosis
GVHR
Graft-versus-host reaction
Hb
Hemoglobin
HBV, HCV, HDV, HEV
Hepatitis B, C, D, E viruses
HCC
Hepatocellular carcinoma
hCG
Human chorionic gonadotropin
H and E
Hematoxylin and eosin
HF
Heart failure
HGF
Hepatocyte growth factor
HHV 8
Human herpesvirus-8
HL
Hodgkin lymphoma
HLA
Human leukocyte antigen
HNPCC
Hereditary nonpolyposis colon cancer
HP
Hydrostatic pressure
HPOA
Hypertrophic pulmonary osteoarthropathy
HPV
Human papillomavirus
HR
Heart rate
HSN
Hypersensitivity
HTN
Hypertension
IBD
Inflammatory bowel disease
_FM-fm12IC
Immune complex
IC
Intracellular
ICA
Internal carotid artery
ICAM
Intercellular adhesion molecule
ICF
Intracellular fluid
ICP
Intracranial pressure
IDDM
Insulin dependent diabetes mellitus
IE
Infective endocarditis
IF
Intrinsic factor
IFN
Interferon
Ig
Immunoglobulin
IHD
Ischemic heart disease
IL
Interleukin
IMN
Infectious mononucleosis
iNOS
Inducible nitric oxide synthase gene
ITP
Idiopathic thrombocytopenic purpura
IUGR
Intrauterine growth restriction
IVFV
Intravascular fluid volume
IV space
Intravascular space
KS
Kaposi sarcoma
L
Lymphocytes
LA
Left atrium
LAD
Leukocyte adhesion deficiency
LCIS
Lobular carcinoma in situ
LDL
Low-density cholesterol
LM
Light microscopy
LN
Lymph node
LOX
Lipoxygenase
LP
Lipoprotein
LPS
Lipopolysaccharides
LSE
Libman-Sacks endocarditis
LT
Leukotriene
LV
Left ventricle
LVEDP
Left ventricular end-diastolic pressure
LVEDV
Left ventricular end-diastolic volume
LVF
Left ventricular failure
LVH
Left ventricular hypertrophy
M
Monocytes
MAC
Mycobacterium avium complex
MAP
Mitogen-activated protein
MBP
Major basic protein
MC 1R
Melanocortin-1 receptor gene
MCA
Middle cerebral artery
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
M CSF
Macrophage colony-stimulating factor
MCV
Mean corpuscular volume
MEN
Multiple endocrine neoplasia
MHC
Major histocompatibility complex
MI
Myocardial infarction
MM
Multiple myeloma
MMP
Matrix metalloproteinases
MNG
Multinodular goiter
MOA
Mechanism of action
MPO
Myeloperoxidase
MPS
Mucopolysaccharides
MR
Mitral regurgitation
MV
Mitral valve
N
Neutrophils
NA
Noradrenaline
NAD
Nicotinamide dinucleotide
NAP
(N) acid phosphatase
NBTE
Nonbacterial thrombotic endocarditis
NF-κB
Nuclear factor kappa B
NHL
Non-Hodgkin lymphoma
NIDDM
Non-insulin dependent diabetes mellitus
NK cells
Natural killer cells
NO
Nitric oxide
NRAMP
Natural resistance associated macrophage protein
NSCLC
Nonsmall cell lung carcinoma
NSE
Nonspecific esterase
NTRK
Neurotrophic tyrosine receptor kinase
_FM-fm13OCP
Oral contraceptive pills
OP
Osmotic pressure
OPG
Osteoprotegerin
PAF
Platelet-activating factor
PAN
Polyarteritis nodosa
PAS
Periodic acid-schiff
PCA
Posterior cerebral artery
PCT
Proximal convoluted tubule
PDA
Patent ductus arteriosus
PDGF
Platelet-derived growth factor
PECAM
Platelet-endothelial cell adhesion molecule
PG
Prostaglandin
PIH
Pregnancy-induced hypertension
PIN
Prostatic intraepithelial neoplasia
PKC
Protein kinase-C
PL
Phospholipid
PMF
Progressive massive fibrosis
PMN
Polymorphonuclear cell
PND
Paroxysmal nocturnal dyspnea
PPD
Purified protein derivative
PR
Peripheral resistance
PR-3
Proteinase 3
PSA
Prostate-specific antigen
PSGN
Post-streptococcal glomerulonephritis
PT
Prothrombin time
PTH
Parathyroid hormone
PVD
Peripheral vascular disease
RA
Rheumatoid arthritis
RANK
Receptor activator of NF-κB
RBF
Renal blood flow
RB gene
Retinoblastoma gene
RCC
Renal cell carcinoma
RDS
Respiratory distress syndrome
RER
Rough endoplasmic reticulum
RET
Tyrosine kinase receptor gene
RF
Rheumatic fever
RF
Rheumatoid factor
RHD
Rheumatic heart disease
RNP
Ribonucleoproteins
ROS
Reactive oxygen species
RT
Respiratory tract
RT
Reverse transcriptase
RVH
Right ventricular hypertrophy
SAA
Serum amyloid A
SABE
Subacute bacterial endocarditis
SAH
Subarachnoid hemorrhage
SCC
Squamous cell carcinoma
SCD
Sudden cardiac death
SER
Smooth endoplasmic reticulum
SI
Small intestine
SIL
Squamous intraepithelial lesion
SLE
Systemic lupus erythematosus
SMC
Smooth muscle cell
SOD
Superoxide dismutase
SV40
Simian virus-40
TAG
Triglycerides
TGF
Transforming growth factor
THFA
Tetrahydrofolic acid
Th cells
Helper T cells
TIBC
Total iron-binding capacity
TNF
Tumor necrosis factor
TPA
Tissue plasminogen activator
TSH
Thyroid-stimulating hormone
TT
Thromboplastin time
TTP
Thrombotic thrombocytopenia
TXA2
Thromboxane A2
UC
Ulcerative colitis
URTI
Upper respiratory tract infection
VCAM
Vascular cell adhesion molecule
VEGF
Vascular endothelial growth factor
VF
Ventricular fibrillation
VHL
Von Hippel-Lindau
VIP
Vasoactive intestinal peptide
VP
Venous pressure
vWF
von Willebrand factor
ZES
Zollinger-Ellison syndrome
1General Pathology
2

Cell Injury, Cell Death and AdaptationsChapter 1

 
CELLULAR RESPONSE
Cellular response to stress/stimuli is shown in Figure 1.1.
Fig. 1.1: Cellular response
 
CELLULAR ADAPTATIONS
  1. Cellular adaptations are reversible changes in size, number, phenotype, metabolic activity or function of cells in response to changes in the environment.
  2. Physiological:
    1. Response to normal stimulation by hormones or endogenous chemical mediators.
  3. Pathological:
    1. Response to environmental stress, which helps them to escape from injury.
 
Hypertrophy
  1. Increase in size of the cells.
  2. Resulting in increased size of the organ.
  3. Increased amount of structural proteins and organelles.
  4. Physiological:
    1. Uterine enlargement during pregnancy (hypertrophy + hyperplasia).
    2. Breast enlargement during lactation.
  5. Pathological:
    1. Cardiac hypertrophy in HTN and AS.
    2. Cardiac hypertrophy is due to:
      • Mechanical—stress
      • Trophic—α-adrenergic stimulation.
 
Hyperplasia
  1. Increase in number of cells.
  2. Resulting in hypertrophy of the organ.
  3. Physiological:
    1. Breast glands during puberty and pregnancy (hormonal).
    2. Liver regrowth after a part is resected (compensatory).
      4
  4. Pathological:
    1. Endometrial hyperplasia after menstruation (hormonal).
    2. Wound healing (due to growth factors).
 
Atrophy
  1. Decrease in cell size.
  2. Loss of intracellular substance.
  3. Atrophied cells have diminished function.
  4. Sometimes, accompanied by autophagy.
  5. Decreased protein synthesis and increasse protein degradation.
  6. Causes may be:
    1. Decreased work load.
    2. Denervation.
    3. Decreased blood supply.
    4. Malnutrition.
    5. Senility.
    6. Pressure.
    7. Decreased functioning.
  7. Seen in cancer cachexia.
 
Metaplasia
  1. Reversible change of one adult cell type by another.
  2. Metaplasia is in order to withstand certain conditions.
 
Epithelial Metaplasia
  1. Squamous metaplasia:
    1. Columnar epithelium of respiratory tract is replaced by stratified squamous epithelium in cigarette smoking.
  2. Intestinal metaplasia:
    1. Stratified squamous epithelium of esophagus replaced by columnar epithelium in C/c gastric reflux.
 
Mesenchymal Metaplasia
  1. Osseous metaplasia.
    1. Bone in fibrous tissues.
      • In arterial wall
      • Myositis ossificans.
  2. Cartilaginous metaplasia:
    1. Cartilage deposit in fracture healing.
 
SUBCELLULAR ALTERATIONS
  1. Autophagy—self-eating by lysosomal enzymes.
  2. Hypertrophy of SER.
  3. Mitochondrial alterations.
  4. Cytoskeletal abnormalities—loss of integrity, cell mobility, phagocytosis, etc.
 
NECROSIS
  1. Irreversible cell injury.
  2. Resulting from degenerative actions of enzymes.
  3. The enzymes are either from self-lysosomes or from lysosomes of leukocytes.
 
Morphology
  1. Increased eosinophilic staining to the cells.
  2. Cytoplasm become vacuolated and appears moth-eaten.
  3. Large phospholipid masses called myelin figures that are derived from damaged cell membranes.
    5
  4. These myelin figures may get degraded into fatty acids and become calcified to form calcium soaps.
  5. Marked dilatation of mitochondria, damage of cell membrane, lysosomal disruption, etc. can be seen.
  6. Nuclear changes:
    1. Karyolysis—digestion of DNA.
    2. Pyknosis—nuclear shrinkage.
    3. Karyorrhexis—fragmentation of pyknosed nuclei.
 
Classification
 
Coagulative Necrosis
  1. Basic architecture is maintained for some days.
  2. Denaturation of all proteins.
  3. Its own lysosomal enzymes are also denatured.
  4. Later digested by leukocytes.
  5. For example, all infarcts except that in brain.
 
Liquefactive Necrosis
  1. The tissue get converted into liquid viscous mass.
  2. The tissue is digested completely.
  3. Sometimes, the material will be creamy yellow-pus.
  4. Certain bacterial and fungal infections. For example, brain infarcts.
 
Gangrenous Necrosis
  1. Due to ischemia.
  2. Usually lower limb is affected.
  3. Actually this is a type of coagulative necrosis.
  4. Wet gangrene—dry gangrene + bacterial infection.
 
Caseous Necrosis
  1. Friable yellow white (cheesy like) appearance.
  2. Complete distortion of the architecture.
  3. Within a well-defined border (granuloma). For example, TB.
 
Fat Necrosis
  1. Focal areas of fat destruction.
  2. Calcified to produce chalky white areas.
  3. Necrotic fat cells with calcium deposits and surrounded by an inflammatory border. For example, acute pancreatitis.
 
Fibrinoid Necrosis
  1. Commonly seen in immune complex-mediated vasculitis.
  2. These complexes along with fibrin deposits form the fibrinoid necrosis. For example, PAN.
 
MECHANISMS OF CELL INJURY
  1. Adenosine triphosphate ATP depletion (Fig. 1.2).
  2. Mitochondrial damage (Fig. 1.3).
  3. Increased Ca2+ influx (Fig. 1.4).
  4. Defects in membrane permeability (Fig. 1.5).
  5. Accumulation of reactive O2 species (Fig. 1.6).
    6
    1. Antioxidant mechanisms:
  6. Damage to DNA and proteins (Fig. 1.7).
 
APOPTOSIS
Tightly regulated suicide program by activating the degrading enzymes.
 
Causes
 
Physiologic Situations
  1. Programed destruction of cells during embryogenesis.
    Fig. 1.2: ATP depletion
    Fig. 1.3: Mitochondrial damage
    Fig. 1.4: Increased Ca2+ influx
    Fig. 1.5: Defects in membrane permeability
    7
  2. Involution of hormone-dependant tissues upon hormone deprivation.
  3. In proliferating cell populations.
  4. After completion of their work.
  5. Elimination of self-reactive T-cell clones.
  6. Cell death by cytotoxic T cells.
 
Pathologic Situations
  1. DNA damage.
    Fig. 1.6: Accumulation of reactive O2 species
    Fig. 1.7: Damage to DNA proteins
  2. Accumulation of misfolded proteins (results in ER stress).
  3. Certain infections.
  4. Atrophy due to duct obstruction.
  5. Deprivation of GFs.
 
Morphology
  1. Round or oval masses.
  2. Eosinophilic cytoplasm.
  3. Karyorrhexis of nucleus.
  4. Later, those cells get shrinked to form cytoplasmic buds and fragmented into apoptotic bodies.
  5. The cell membrane will be usually intact.
    *FLIP—a caspase antagonist.
 
Mechanisms
  1. Intrinsic/mitochondrial pathway is shown in Figure 1.8.
  2. Extrinsic/death receptor pathway is shown in Figure 1.9.
  3. Final common pathway and clearing mechanism is shown in Figure 1.10.
Fig. 1.8: Intrinsic/mitochondrial pathway
Fig. 1.9: Extrinsic/death receptor pathway
8
Fig. 1.10: Final common pathway and clearing
 
INTRACELLULAR ACCUMULATIONS
 
Pathways
  1. Normal or increased production of a normal substance, but decreased removal. For example, fatty change in liver.
  2. Normal or abnormal substance accumulates due to defect in packaging, transportation, etc. For example, α1-antitrypsin deficiency.
  3. Decreased degrading enzymes. For example, glycogen storage diseases.
  4. Ingestion of indigestible materials. For example, pneumoconiosis, silicosis, etc.
 
Fatty Change (Steatosis)
  1. Accumulation of TAGs in parenchymal organs.
  2. Mostly in liver.
  3. Also in heart, skeletal muscle, kidney, etc.
    1. Fatty liver
      • Alcohol abuse and DM associated obesity are the most important causes
      • Hepatotoxins decrease fatty acid oxidation
      • Decreased fatty acid oxidation, decreased mobilization of fat from liver and increased mobilization of fat from periphery are the important pathways leading to fatty liver.
        Morphology
      • Bright yellow, soft and enlarged
      • Firstly small fat vacuoles around nucleus
      • Then large fat globules and peripheral nucleus
      • At last ruptures and form fatty cysts.
    2. Fat in heart
      • Prolonged moderate hypoxia causes anemia and focal fat droplets
      • Appear as yellow bands within brown colored muscle tissue—thrush breast appearance.
 
Cholesterol Accumulation
  1. Macrophages get filled with membrane bound lipid vacuoles and forms foam cells. For example, in atherosclerosis.
  2. A cluster of foam cells beneath the skin and tendons is called xanthoma.
 
Proteins
  1. Mallory bodies: Eosinophilic hyaline inclusions within the cytoplasm of degenerating hepatocytes in alcoholic liver disease—contains intermediate filaments.
  2. Russell bodies: Round eosinophilic inclusions within the RER of plasma cells and is composed of new Ig.
    9
 
Glycogen
  1. See glycogen storage diseases in the Chapter 7 (Genetic and Pediatric Diseases).
 
Pigments
  1. Lipofuscin.
    1. Wear and tear pigment.
    2. Insoluble brownish yellow granular material.
    3. Intracellularly accumulates in the heart, liver and brain.
    4. Produced after lipid peroxidation of membranes.
    5. Causes brown atrophy of heart.
    6. PAS stain is used and will give a brown color.
  2. Carbon.
    1. Mainly in the lung (anthracosis).
  3. Melanin.
    1. In freckles and in dermal macrophages.
    2. Masson-Fontana stain is used.
  4. Iron.
    1. Hemosiderosis and hemochromatosis.
  5. Human granulocytic anaplasmosis.
    1. In alkaptonuria.
    2. Produces ochronosis.
  6. Bilirubin.
    1. In jaundice.
 
CALCIFICATION
 
Dystrophic Calcification
  1. Occurring in the dead and decaying tissues.
  2. There is no derangements in calcium metabolism.
  3. Normal levels of serum calcium. For example, in atheromas (advanced cases), in aged or damaged heart valves.
  4. Seen as fine white granules felt as gritty deposits.
  5. These are microscopically seen as intracellular or extracellular basophilic deposits.
  6. Sometimes, tuberculous LNs may also get involved.
  7. Occurs as two processes:
    1. Initiation—in mitochondria and in membrane-bound vesicles.
    2. Propagation—depends on other factors too.
  8. The end product is calcium phosphate.
  9. Extracellular initiation in membrane-bound vesicles.
  10. Intracellular initiation in mitochondria.
  11. Propagation depends on Ca2+ and PO4 concentration, mineral inhibitors, collagen content, etc.
 
Metastatic Calcification
  1. Occur in normal tissues.
  2. Derangement in the calcium metabolism.
  3. Causes are:
    1. Increased parathyroid hormone (1° or 2°).
    2. Increased bone destruction.
    3. Vitamin D intoxication and sarcoidosis.
    4. Renal failure—causes 2° hyperparathyroidism.
      10
  4. Usually in vasculature of kidneys, lungs and gastric mucosa.
  5. White granules with gritty feeling.
  6. Nephrocalcinosis is common finding.
 
AGING
  1. Aging is a result of progressive decline in the proliferative capacity and lifespan of cells and continuous exposure to exogenous factors that cause cellular and molecular damage.
  2. The causes are:
    1. DNA damage.
    2. Decreased replication.
    3. Decreased GFs.
    4. Decreased regenerative capacity.
    5. Lifestyle.
    6. Diseases.
 
Mechanism
The mechanism of aging is shown in Figure 1.11.
Fig. 1.11: Mechanism of aging

Acute and Chronic InflammationChapter 2

 
ACUTE INFLAMMATION
Cells involved are polymorphonuclear cells (neutrophils).
 
Stimuli
  1. Infections.
  2. Trauma.
  3. Tissue necrosis.
  4. Foreign bodies.
  5. Immune reactions.
 
Vascular Changes
  1. Changes in vascular caliber and flow are:
    1. Transient vasoconstriction.
    2. Arteriolar dilatation:
      • Increased flow and engorged capillary bed
      • Causes erythema and warmth.
    3. Increased oozing of fluid (transudate).
    4. Increased viscosity and stasis.
    5. Margination.
  2. Increased vascular permeability.
    1. Increased oozing out of protein-rich fluids along with cells (exudate).
    2. The mechanisms leading to increased permeability are:
      • Endothelial cell contraction and retraction.
        • Reversible, transient and immediate
        • Forms intercellular gaps
        • Contraction is by histamine, bradykinin (15–30 min) and leukotrienes
        • Retraction is by TNF and interleukin 1 (IL-1) (4–24 hours).
      • Endothelial injury.
        • Immediate and sustained
        • Cell necrosis and detachment occurs
        • Occur in burns and infections
        • Develop within 2–12 hours and persists longer.
      • Leukocyte-mediated endothelial injury.
        • Due to the release of toxic mediators from accumulated leukocytes
        • Injury or detachment occurs.
      • Increased transcytosis of proteins.
        12
        • Via newly formed channels by VEGF.
      • Leakage from newly formed vessels.
        • Mediated by VEGF.
  3. Responses of lymphatic vessels.
    1. Increased ECF is drained by lymphatics and leads to ↑ lymphatic flow.
    2. Leukocytes and cell debris may also be found in the lymph.
    3. Sometimes, lymphangitis and lymphadenitis can be seen.
    4. Lymph nodes may become enlarged due to hyperplasia.
    5. Lymphangitis is seen as inflamed lymphatic vessels as red streaks near the skin wound.
    6. The enlarged lymph nodes may be tender.
 
Cellular Changes
  1. Leukocyte recruitment.
    1. Margination and rolling.
      • When blood flows from capillaries to venule, the RBCs move faster and leukocytes pushed out of the central cellular column
      • As a result, leukocytes accumulate at the periphery of the vessels and the process is called margination
      • These leukocytes move on the endothelial surface by sticking transiently along the way and is called rolling
      • This weak transient adhesion is mediated via selectins (present on both leukocytes and ECs)
      • Selectins.
        • E on ECs
        • P on ECs and platelets
        • L on leukocytes.
    2. Adhesion and transmigration.
      • Here, firm adhesion to endothelial surface is mediated by the integrins on the leukocytes
      • These intergrins attach onto the ligands only after leukocyte activation by chemokines
      • The main ligands are ICAM-1 and VCAM-1
      • After adhesion, leukocytes migrate into interstitium by moving in between the endothelial cells called transmigration or diapedesis
      • The main adhesion molecule that helps in the diapedesis is CD31 (PECAM-1), which is present on leukocytes, as well as ECs.
    3. Chemotaxis.
      • After extravasating from the blood, leukocytes migrate towards sites of infection or injury along a chemical gradient by a process called chemotaxis
      • The main chemotactic agents are:
        • Bacterial products
        • Chemokines
        • Components of complement system (C5a)
        • Products of LOX pathway (LTB4).
      • Mediated through G-protein coupled receptors
      • Leukocytes move by extending pseudopods
        13
      • Cells:
        • Neutrophils predominate first 6–24 hours
        • Monocytes predominate next 24–48 hours.
      • Reason:
        • Neutrophils are more predominant in blood
        • Respond more rapidly
        • Attach more firmly.
  2. Leukocyte activation.
    1. Stimuli:
      • Microbes
      • Products of necrosis
      • Mediators.
    2. Result:
      • Phagocytosis of particles
      • Production of substances that destroy phagocytosed particles, e.g. lysosomal enzymes, ROS, nitrogen radicals, etc.
      • Production of mediators that increases inflammation, e.g. cytokines, arachidonic acid metabolites.
 
Phagocytosis
Phagocytosis is the process of killing and degradation of a foreign particle by leukocytes (Fig. 2.1).
 
Steps
  1. Recognition and attachment of particle on leukocyte.
    1. Mediators are:
      • Opsonins on microbes or dead cells
      • IgG, C3 breakdown products and collectins are major opsonins.
    2. These opsonins are produced in host cells to coat the microbes (opsonization).
    3. These coated microbes are then attached to leukocytes through special receptors on leukocyte surface.
  2. Engulfment.
    1. Engulfment is triggered after the attachment process.
    2. After attachment, pseudopods are formed around the attached particle and eventually phagosome is formed.
    3. Then the phagosomal and lysosomal membrane fuses to form phagolysosome.
      Fig. 2.1: Phagocytosis
  3. Killing and degradation.
    1. By ROS and lysosome enzymes.
    2. The ROS is produced by oxidative burst in leukocyte.
      14
    3. These ROS and NO kill the bacteria (MOA of ROS mentioned in chapter-1).
    4. These killed particles are degraded by lysosomal acid hydrolases.
    5. Other mediators involved in killing and degradation are lysozyme, MBP, defensins.
 
Defects
  1. Defect in leukocyte adhesion (LAD-1 and LAD-2).
  2. Defect in mitochondrial activity as in chronic granulomatous inflammation.
  3. Defect in phagolysosome formation as in Chediak-Higashi syndrome.
 
Outcomes of Acute Inflammation
  1. Resolution or healing.
  2. Progression to chronic inflammation.
  3. Scarring or fibrosis.
 
Morphological Patterns of Acute Inflammation
  1. Serous.
  2. Fibrinous.
  3. Suppurative.
 
CHEMICAL MEDIATORS OF INFLAMMATION
  1. Chemical mediators are special chemical molecules that mediate the process of acute and chronic inflammation.
  2. The action of these mediators are tightly regulated.
 
Classification
The classification of chemical mediators is illustrated in Figure 2.2.
Fig. 2.2: Classification of mediators
 
Cell-derived Mediators
Tissue macrophages, mast cells, endothelial cells and recruited leukocytes are the main cells capable of producing different mediators.
 
Vasoactive Amines
  1. For example, histamine and serotonin.
  2. These are the first mediators to be released in acute inflammatory reactions.
  3. Mainly produced by mast cells and platelets.
    15
  4. Actions are vasodilatation, ↑ vascular permeability.
 
Arachidonic Acid Metabolites
  1. Arachidonic acid metabolites are PGs, LTs, TXs and lipoxins.
  2. Mainly produced by mast cells, leukocytes and platelets.
  3. Actions:
    1. PGs—vasodilatation, pain, fever.
    2. LTs—vasoconstriction, ↑ vascular permeability, chemotaxis, leukocyte adhesion.
    3. TXs—vasoconstriction.
 
Platelet-activating Factor
  1. Produced from (N), (M), (B), ECs and platelets by the action of phospholipase-A2.
  2. PAF acts via ‘G’ protein-coupled receptor.
  3. Actions: Platelet aggregation and degranulation, vasodilatation, ↑ vascular permeability, chemotaxis, leukocyte adhesion, etc.
 
Cytokines
  1. Cytokines are polypeptide products of many cell types.
    1. Tumor necrosis factor and interleukin 1.
      • Produced by macrophages, mast cells, ECs, etc.
      • Actions: Endothelial activation, systemic acute phase response, fibroblast proliferation, etc.
    2. Chemokines.
      • Produced by macrophages and leukocytes
      • Actions: Chemotaxis, leukocyte activation.
 
Reactive Oxygen Species
  1. Produced by (N) and macrophages via NADPH oxidase pathway (Discussed in detail in Chapter-1).
  2. Response for tissue injury by endothelial damage, ↑ vascular permeability, protease activation and by direct injury.
  3. These ROS are inactivated by various antioxidant mechanisms.
 
Nitric Oxide
  1. Produced by macrophages and ECs by NO synthase enzyme.
  2. Actions: Killing microbes and tumor cells, smooth muscle relaxation, vasodilation, inhibit platelet activation and reduce leukocyte recruitment.
 
Lysosomal Enzymes of Leukocytes
  1. Lysosomal enzymes are acid proteases and neutral proteases.
  2. These are mainly concerned with destruction of proteins like collagen, elastin, etc.
  3. These enzymes are inhibited by antiproteases.
 
Neuropeptides
Mainly produced by nerve fibers (e.g. substance P).
 
Plasma Protein-derived Mediators
 
Complement System
  1. Activated by various stimuli.
  2. Activation occurs through classical pathway, alternate pathway and lectin pathway.
    16
  3. Actions: Opsonization, vasodilatation, ↑ vascular permeability, leukocyte activation, chemotaxis and phagocytosis.
 
Kinin System
  1. Main molecules in this system are bradykinin and kallikrein.
  2. Bradykinin causes vasodilatation, ↑ vascular permeability, bronchial constriction.
  3. Kallikrein causes chemotaxis and activation of Hageman factor.
 
Coagulation/Fibrinolytic System
  1. Factor Xa and thrombin are the main mediators from coagulation system.
  2. Actions: Increased vascular permeability and recruitment of leukocytes.
  3. From fibrinolytic system, the fibrin degradation products ↑ vascular permeability and plasmin causes complement activation.
 
CHRONIC INFLAMMATION
Inflammation of prolonged duration in which active inflammation, tissue injury and healing proceed simultaneously.
Characterized by:
  1. Mononuclear infiltrate (macrophages, plasma cells, etc).
  2. Tissue destruction.
  3. Healing by angiogenesis and fibrosis.
Conditions giving rise to chronic inflammation:
  1. Persistent infections (delayed-type hypersensitivity).
  2. Immune-mediated diseases (hypersensitivity disease) like RA, IBD and asthma.
  3. Prolonged toxic exposure in silicosis and atherosclerosis.
 
Mediators
  1. Macrophages (produce protease, ROS, NO, AA metabolites, cytokines).
  2. Lymphocytes.
  3. Plasma cells.
  4. Eosinophils.
  5. Mast cells.
 
Mechanism
The mechanism of chronic inflammation is shown in Figure 2.3.
Fig. 2.3: Mechanism of chronic inflammation
 
GRANULOMATOUS INFLAMMATION
  1. A pattern of chronic inflammation.
  2. Characterized by aggregates of activated macrophages with epitheliod appearance.
    17
 
Conditions
  1. Tuberculosis: Both caseating and non-caseating granuloma.
  2. Leprosy: Non-caseating granuloma.
  3. Syphilis: Non-caseating granuloma.
  4. Sarcoidosis: Non-caseating granuloma.
  5. Crohn disease: Non-caseating granuloma.
  6. Cat-scratch disease: Rounded stellate granuloma.
 
Morphology
  1. Central caseous necrosis (cheesy like), sometimes, non-caseating as well.
  2. Central necrosis is surrounded by large multinucleated giant cells.
  3. Then aggregates of epithelioid macrophages, which are characteristic.
  4. This is surrounded by a rim of lymphocytic infiltrate, which continually activate macrophages.
  5. In older lesions, a peripheral rim of fibroblast and connective tissue can be seen.
  6. The healing of granuloma is accompanied by extensive fibrosis.
 
SYSTEMIC EFFECTS OF INFLAMMATION
  1. The severe form is called acute phase reaction or systemic inflammatory response syndrome (SIRS).
  2. TNF, IL-1 are the most important mediators.
    1. Fever.
      • Increased in body temperature by 1°C–40°C
      • The substances producing fever are pyrogens
      • Pyrogens act by stimulating PG synthesis in hypothalamus
      • PGs stimulate production of neurotransmitter, which resets the temperature set point to higher level
      • Pyrogens are:
        • Exogenous (bacterial products—LPs)
        • Endogenous (cytokines like IL-1, TNF).
  1. Elevated acute phase proteins.
    1. Most important are CRP, fibrinogen and SAA.
    2. Production of these proteins in liver is mainly induced by IL-6.
  2. Leukocytosis.
    1. Leukemoid reaction may occur.
    2. More immature cells in blood.
  3. Others.
    1. ↑ HR and BP.
    2. ↓ sweating, chills and rigor.
    3. Anorexia, malaise, cachexia, sleep.
  4. Sepsis.
    1. In severe infection.
    2. Disseminated intravascular coagulation DIC, hypoglycemia and hypotension (septic shock).

Tissue Repair, Regeneration, Healing and FibrosisChapter 3

 
CELL CYCLE
Phases of cell cycle are shown in the Figure 3.1.
 
SIGNALING MECHANISMS OF GROWTH FACTOR RECEPTORS
 
Autocrine Signaling
A substance acts predominantly on the tissue that secretes it. For example, T-cell proliferation increased by cytokines.
Compensatory epithelial hyperplasia (liver regeneration).
 
Paracrine Signaling
A substance acts on the cells, which are in the vicinity of the secreting cell. For example, recruiting cells for inflammation wound healing.
 
Endocrine Signaling
A regulatory substance like hormone is released into blood and acts on distant target cells. For example, insulin secretion as a response to hyperglycemia.
 
Receptors
  1. With intrinsic enzyme activity (VEGF, FGF, HGF, EGF).
    Fig. 3.1: Cell cycle
    19
  2. Without intrinsic enzyme activity (IFN, GH, erythropoetin).
  3. G-protein coupled (epinephrine, ADH, serotonin, histamine, glucagon).
 
ANGIOGENESIS
  1. Angiogenesis is the first process in the sequence of repair by connective tissue.
  2. This repair occurs when the injury is severe or chronic and results in parenchymal damage, epithelia or stroma, etc.
  3. Occur in four processes:
    1. Angiogenesis.
    2. Fibroblast proliferation.
    3. Scar formation by ECM.
    4. Remodeling (reorganization of fibrous tissue).
  4. Angiogenesis starts within 24 hours of injury.
  5. Occur by two processes:
    1. Vasculogenesis: Primitive vascular network is assembled from angioblasts.
    2. Angiogenesis: Capillary sprouts from pre-existing vessels and formation of new vessels.
  6. The angioblasts are migrating from BM to the site (Fig. 3.2A).
  7. Important process in healing and tumor growth.
 
Steps
  1. Vasodilatation by NO.
  2. Increased permeability of pre-existing vessels by VEGF (Fig. 3.2B).
    Figs 3.2A and B: Angiogenesis. A. By mobilization of EPCs from BM; B. From pre-existing vessels.
  3. Migration of angioblasts, EPCs to the injury site or migration of ECs and their proliferation.
  4. Increased proliferation and remodeling into capillary tubes.
  5. Recruitment of periendothelial cells.
    1. Pericytes for capillaries (small).
    2. SMCs for larger vessels.
  6. New vessels will be leaky due to incompletely formed endothelial junctions and accounts for edematous granulation tissue.
  7. The leakage is also due to ↑ permeability by VEGF.
  8. Structural ECM participate through integrin receptors.
  9. Non-structural ECM participate by ↑ cell migration, remodeling and ingrowth of vessels.
 
Involvement of Growth Factors
Most importent growth factors are VEGF and FGF-2.
20
 
Vascular Endothelial Growth Factors
  1. VEGF—A, B, C and D.
  2. VEGF receptors—VEGFR 1, 2 and 3.
  3. Most important in angiogenesis is VEGFR-2 (in ECs only).
  4. The inducers for VEGFs are hypoxia, PDGF, TGF-α, TGF-β.
  5. VEGF induces proliferation and motility of ECs and thus ↑ permeability.
  6. VEGFR-2—migration of angioblasts from BM.
 
Fibroblast Growth Factor
  1. FGF-2—increased proliferation of ECM.
    1. ↑ migration of macrophages and fibroblasts.
    2. ↑ migration of epithelial cells.
  2. FGF-7—keratinocyte GF.
    1. Cutaneous wound healing.
    2. Also in oral cavity and gastrointestinal tract (GIT) lesions.
 
Others
  1. Angioprotein 1 and 2—recruit periendothelial cells.
  2. PDGF—recruit smooth-muscle cells (SMCs).
  3. TGF-β—increase in production of ECM.
 
CUTANEOUS WOUND HEALING
Phases of wound healing is shown in the Figure 3.3.
Fig. 3.3: Phases of wound healing
 
Steps
  1. Epithelial proliferation—EGF, HGF.
  2. Monocyte chemotaxis—PDGF, TGF-β, FGF.
  3. Fibroblast migration—PDGF, TGF-β, FGF.
  4. Fibroblast proliferation—PDGF, FGF.
  5. Angiogenesis—VEGF, FGF.
  6. Collagen synthesis—PDGF, TGF-β.
  7. Collagenase secretion ↓ —PDGF, TGF-β, FGF.
 
Phases of Cutaneous Wound Healing
It has mainly three phases, they are:
  1. Inflammation.
  2. Granulation tissue formation.
  3. Collagen (ECM) deposition and remodeling.
 
Healing by First Intention (Healing by 1° Union)
  1. Healing of a clean (Fig. 3.4A) uninfected, incised wound approximated by sutures (surgically).
  2. In incised wound, only less amount of cell death. So, epithelial regeneration predominates over fibrosis.
    21
  3. Small scar and minimum wound contraction.
  4. Within 24 hours—fibrin clot formation and invaded by (N).
    1. Basal cells proliferate and a thin epithelium below scab (24–48 hour).
  5. Within/by 3 days—(N) replaced by macrophages.
    1. Granulation tissue invades into incision space.
    2. Vertical collagen fibers along margins.
  6. By 5th day:
    1. Increased proliferation and thick epithelial layer.
    2. Neovascularization and more granulation tissue.
    3. Bridging of space by collagen fibers.
    4. Epidermis attains normal thickness and keratinization.
  7. By 2nd week:
    1. More collagen and fibroblasts proliferation.
    2. Blanching with regression of ↑ vascular channels.
  8. By 1 month:
    1. Scar comprised of more collagen and falls off.
    2. Normal epithelium and strength ↑ progressively.
 
Healing by Second Intention (Healing by 2° Union)
  1. Occurs when cell (Fig. 3.4B) or tissue loss is more extensive such as in large wounds, abscess formation, ulceration, etc. Here:
    1. Inflammatory reaction is much more intense.
    2. Granulation tissue is abundant.
    3. Wound contracts by the action of myofibroblasts.
    4. Accumulation of ECM and formation of large scar.
  2. Wound contraction occurs by 6 weeks is the main additional feature from first intention healing.
 
Factors Affecting Wound Healing Process
  1. Infection, nutrition, steroids, diabetes, poor perfusion, foreign bodies, etc.
  2. The type of tissue injured—efficient healing with labile cells.
  3. The location of injury—healing becomes prolonged in tissue spaces.
 
Fracture Healing
  1. Depends on whether the fracture is:
    1. Traumatic or pathological.
    2. Complete or incomplete.
    3. Simple, comminuted or compound.
  2. Primary union.
    1. Occurs when the ends of fracture are approximated.
    2. Union takes place by medullary callus formation.
    3. Patient can be made ambulatory early.
    4. Extensive bone necrosis and slow healing.
  3. Secondary union.
    1. More common.
      22
    2. Takes place by procallus formation, osseous callus formation, remodeling.
      1. Procallus formation.
        • Hematoma formation (Fig. 3.5A).
          • Due to bleeding from the torn blood vessels
          • Loose meshwork is formed by blood and fibrin clot, which acts as a framework for subsequent granulation tissue formation.
        • Local inflammation.
          • By PMNs and macro-phages
          • Macrophages clear away the fibrin, red blood cells (RBCs), inflammatory exudate and debris
          • Necrosed bone is lysed by macrophages and osteoclasts.
            Figs 3.4A and B: Wound healing. A. Healing by first intension; B. Healing by second intension
            Figs 3.5A to D: Steps of fracture healing. A. Hematoma (inflammation); B. Soft callus; C. Hard callus; D. Remodeling.
        • Ingrowth of granulation tissue.
          • Begins with neovascularization and mesenchymal cell proliferation from periosteum and endosteum
          • A soft tissue callus (Fig. 3.5B) is thus formed.
        • Procallus formation.
          • This is the callus composed of woven bone and cartilage
          • The cells of inner layer of the periosteum have osteogenic potential and lay down collagen as well as osteoid matrix in the granulation tissue
          • This osteoid undergoes calcification to form woven bone callus (Fig. 3.5C)
          • The woven bone callus bridges the gap and gives rise to a spindle-shaped 23or fusiform appearance
          • In poorly immobilized fracture, the osteoblasts form cartilage at the site.
      2. Osseous callus formation.
        • The woven bone and cartilage get cleared off
        • Newly formed blood vessels and osteoblasts invade and lay down osteoid, which calcified to form lamellar bone.
 
Remodeling
  1. By osteoblastic and osteoclastic activity.
  2. External callus cleared away, cortex is formed in place of intermediate callus and BM develops in internal callus (Fig. 3.5D).
 
Complications
  1. Fibrous union.
  2. Delayed union.
  3. Malunion.
  4. Non-union.

Hemodynamic Disorders, Thrombosis and ShockChapter 4

 
EDEMA
Increased amount of fluid in interstitial tissue spaces.
 
Causes
  1. Increased hydrostatic pressure.
    1. Impaired venous return.
      • CCF
      • Constrictive pericarditis
      • Liver cirrhosis
      • Venous obstruction like DVT.
    2. Arteriolar dilatation.
      • Heat
      • Neurohormonal dysregulation.
  2. Decreased osmotic pressure.
    1. Protein losing glomerulopathies—nephrotic syndrome.
    2. Liver cirrhosis.
    3. Protein losing gastroenteropathy.
    4. Malnutrition.
  3. Lymphatic obstruction.
    1. Inflammatory.
    2. Neoplastic.
    3. Postsurgical and postirradiation.
  4. Sodium and water retention (causes both increased hydrostatic [HP] and decreased plasma OP).
    1. Increased salt intake with renal insufficiency.
    2. Increased tubular reabsorption of sodium.
      • Renal hypoperfusion and increased RAAS activity.
  5. Inflammatory.
    1. Acute inflammation.
    2. Chronic inflammation.
    3. Angiogenesis.
One and two are the main pathologies leading to edema.
 
Mechanism
The formation of edema-mechanism is shown in Figure 4.1.
 
Notes
  1. Heart failure can lead to edema in two ways:
    1. By increasing CVP.
    2. By reducing cardiac output (CD).
  2. Decreased in arterial blood volume can leads to edema in three ways:
    1. By renal hyperperfusion.
    2. By ↑ production of renin.
    3. By ↑ production of ADH.
      25
Fig. 4.1: Mechanism of formation of edema
 
THROMBOSIS
Thrombosis is the process of thrombus formation in our blood circulation.
 
Pathogenesis
Virchow's triad (Fig. 4.2) explains the primary mechanism.
  1. Endothelial injury (Fig. 4.3).
    1. Most important factor.
    2. Important role in heart and arteries.
  2. Abnormal blood flow (Fig. 4.4).
    1. Conditions producing endothelial dysfunction are:
      Fig. 4.2: Virchow's triad
      • Hypercholesterolemia
      • Radiation
      • Cigarette smoking.
        26
        Fig. 4.3: Endothelial injury producing thrombosis
        Fig. 4.4: Abnormal blood flow producing thrombosis
    2. Abnormal blood flow leads to thrombus formation by:
      • Bringing platelets in contact with endothelium
      • Preventing dilution of activated clotting factors
      • Reducing the inflow of clotting factor inhibitors
      • Promoting endothelial cell activation.
    3. Conditions producing abnormal blood flow are:
      • The ulcerated atherosclerotic plaques
      • Aneurysms
      • Mitral stenosis
      • Atrial fibrillation resulting in atrial dilatation
      • Polycythemia and sickle cell anemia.
  3. Hypercoagulability.
    1. Contributes less frequently to thrombosis.
    2. Conditions producing hypercoagulability are:
      1. Primary.
        • Common.
          • Mutation in factor V gene
          • Mutation in prothrombin gene
          • Mutation in methyl THFA gene
        • Rare.
          • Antithrombin-III deficiency
          • Protein C and protein S deficiency
        • Very rare.
          • Defects in fibrinolysis
      2. Secondary (acquired).
        • High risk.
          • Prolonged immobilization
          • MI, AF and DIC
          • Tissue damage
          • Cancer
          • Prosthetic heart valves
          • Heparin-induced thrombocytopenia (HIT) due to use of unfractionated heparin
          • Antiphospholipid antibody syndrome
        • Low risk.
          • Cardiomyopathy
          • Nephrotic syndrome
            27
          • Hyperestrogenic state—pregnancy
          • OCPs
          • Sickle cell anemia
          • Smoking.
 
Morphology
  1. Alternate pale platelets and fibrin rich layer and dark erythrocyte rich layer can be seen macroscopically and microscopically. These are called lines of Zahn. These lines represent antemortem thrombus and which are absent in postmortem clots.
  2. Mural thrombi—cardiac and aortic thrombi.
  3. Arterial thrombi—frequently occlusive.
    1. Grow in a retrograde manner.
    2. Produced by platelets and coagulation activation.
    3. Also called white thrombi.
  4. Venous thrombi—invariably occlusive.
    1. Grow in an anterograde manner.
    2. Produced mainly by coagulation cascade.
    3. Also called red thrombi.
  5. Vegetations—thrombi on heart valves.
    1. Seen in infective IE and NBTE.
 
Fate of Thrombus
  1. Propagation—accumulate more platelets and fibrin, eventually causing vessel obstruction.
  2. Embolization—get dislodged and transported through blood vessels.
  3. Dissolution—by fibrinolytic system.
  4. Organization and recanalization—organized by inflammation and fibrosis.
    1. Recanalized to establish some degree of flow.
 
EMBOLISM
  1. Embolus is a detached intravascular solid, liquid or gaseous mass that is carried by blood to a distant site from its point of origin.
  2. The main embolisms are:
    1. Pulmonary thromboembolism.
      • In pulmonary circulation
      • Originate from deep vein thrombi (mostly).
    2. Systemic thromboembolism.
      • In systemic circulation
      • Originate from arterial or mural thrombi.
    3. Air embolism.
      • Originate from gaseous mass
      • Generally more than 100 mL gas required. For example, decompression sickness characterized by bends and chocks.
    4. Fat embolism (Fig. 4.5).
      • Originate from fat globules
        Fig. 4.5: Effects of fat emboli
        28
      • Occur usually after fracture of long bones or soft tissue trauma
      • Enters the circulation by rupture of vascular sinusoids in marrow or rupture of venules
      • Characterized by:
        • Pulmonary insufficiency
        • Neurologic symptoms
        • Anemia and thrombocytopenia
      • Typically the symptoms appear 1–3 days after injury
      • Symptoms start with tachypnea, dyspnea, tachycardia and can progress to delirium and coma
      • Demonstration of fat emboli requires special methods like frozen sections and fat stains.
    5. Amniotic fluid embolism.
      • Uncommon complication of labor and immediate complication of postpartum period
      • Initial phase—severe dyspnea, cyanosis, hypotensive shock, seizures and coma
      • Late phase—pulmonary edema, alveolar damage and DIC
      • DIC occurs due to release of thrombogenic substances from amniotic fluid
      • Amniotic fluid enters into maternal circulation via a tear in the placental membranes or rupture of uterine veins
      • Pulmonary microcirculation contains:
        • Squamous cells from fetal skin
        • Lanugo hair
        • Fat from vernix caseosa
        • Mucin from fetal respiratory and GI tract.
 
INFARCTION
  1. An infarct is an area of ischemic necrosis caused by occlusion of either the arterial supply or venous drainage in a particular tissue.
  2. Mainly results from thromboembolic phenomenon in arteries.
  3. Other causes include vasospasm, atheroma, external compression, vessel twisting, etc.
  4. Red infarct occurs:
    1. In venous occlusion.
    2. In loose tissues like lung.
    3. In tissues with dual circulation like lung and small intestine.
    4. In tissues that were previously congested.
    5. When flow is previously re-established to a site of previous arterial occlusion.
  5. White infarct occurs:
    1. In arterial occlusion.
    2. In solid organs like heart and kidney.
  6. Septic infarct occurs.
    1. After microbial seeding in an infarct or can occur after embolization of bacterial vegetations.
 
Morphology
  1. Wedge shaped with occluded vessel at the apex and periphery of organ forming the base.
    29
  2. Histologically:
    1. Peripheral inflammatory response.
    2. Central ischemic coagulative necrosis except in brain.
    3. Liquifactive necrosis in brain infarct.
 
Factors Influencing Infarction
  1. Nature of vascular supply (presence of alternate supply).
  2. Rate of development of occlusion.
  3. Vulnerability to hypoxia (neurons are most susceptible).
  4. Oxygen content of the blood.
 
SHOCK
  1. Shock is the final common pathway for a number of potentially lethal events charecterized by systemic hypoperfusion caused either by reduced cardiac output or by reduced effective circulatory blood volume.
  2. The end results are hypotension, impaired tissue perfusion and cellular hypoxia.
  3. Persistent shock can produce irreversible tissue injury and death of the patient.
 
Types of Shock
  1. Cardiogenic shock.
    1. Results from failure of cardiac pump.
    2. Caused by MI, ventricular arrhythmias, cardiac tamponade, pulmonary embolism, etc.
  2. Hypovolemic shock.
    1. Results from loss of blood or plasma volume.
    2. Caused by hemorrhage and fluid loss like vomiting, diarrhea, burns or trauma.
  3. Neurogenic shock.
    1. Results from loss of vascular tone and pooling of blood.
    2. Caused by anesthetic accident or spinal cord injury.
  4. Septic shock.
    1. Results mainly from peripheral vasodilatation and pooling of blood.
    2. Caused by Gram-negative infections (endotoxic shock), Gram-positive infections, fungal infections, super antigens, etc.
  5. Anaphylactic shock
    1. Results from systemic vasodilatation and ↑ vascular permeability.
    2. Caused by IgE hypersensitivity.
 
Stages of Shock
  1. Initial non-progressive stage.
    1. Reflex neurohormonal pathways work and maintain CO and BP and thus perfusion of vital organs.
    2. The neurohormonal pathways activated are baroreceptor reflexes, RAAS, ADH release, sympathetic stimulation and release of catecholamines.
    3. Produces cutaneous vasoconstriction.
    4. Coronary and cerebral vessels are spared.
  2. Progressive stage.
    1. If the underlying causes are not corrected, the shock persists to cause tissue hypoperfusion.
    2. Anaerobic glycolysis occur more and produce lactic acidosis.
      30
    3. This acidic pH blunts the vasomotor response, which causes peripheral pooling of blood.
    4. Later leads to reduced CO, endothelial injury and DIC.
    5. Vital organs are affected and begin to fail.
  3. Irreversible stage.
    1. Widespread cell injury leads to lysosomal enzyme leakage and aggravation of shock.
    2. The CO further worsens.
    3. Ischemic bowel allows intestinal flora to enter into circulation and leads to endotoxic shock.
    4. Complete renal failure due to acute tubular necrosis.
    5. Eventually leads to death.
 
Pathogenesis of Septic Shock
The production of mediators in septic shock is shown in Figure 4.6.
 
Production of Mediators
  1. The LPS in low quantities.
    1. Activation of macrophages, (M) and (N).
    2. Activation of endothelial cell.
    3. Activation of complement.
    4. Production of TNF, IL1, IL6 and IL8.
    5. No secondary mediators.
    6. Local inflammation.
  2. The LPS in moderate amounts.
    1. Production of TNF, IL1, IL6, IL8, NO and PAF.
    2. Fever.
    3. Release of acute phase proteins from liver.
    4. Release of more WBCs from BM.
    5. Systemic effects.
  3. The LPS in high quantities.
    1. Increased TNF, IL1, IL6, IL8, NO and PAF.
    2. Low CO.
    3. Low PR.
    4. Thrombosis and DIC.
    5. ARDS.
    6. Multisystem failure (liver, kidney, CNS and others).
    7. Septic shock.
Fig. 4.6: Production of mediators in septic shock
31
 
Morphology
  1. Fibrin thrombi can be identified at any site.
  2. More evident changes occur in brain, heart, kidney, adrenals and GIT.
  3. Kidney—acute tubular necrosis.
  4. Adrenals—cortical cell lipid depletion, cells become more active to produce steroids.
  5. GIT—focal mucosal hemorrhage and necrosis.
  6. Lung—diffuse alveolar damage (shock lung) in septic shock.

Diseases of the Immune SystemChapter 5

 
HYPERSENSITIVITY
Increased immune responses against an antigen, which can cause tissue injury and diseases.
 
Causes
  1. Autoimmunity—if self-tolerance fails.
  2. Reaction against microbes.
    1. T cell-mediated injury of the affected cell (TB).
    2. Ab to the microbe cross-reacts with host Ag (RHD).
    3. Formation of immune complexes and inflammation (PSGN).
  3. Reaction against environmental Ag.
    1. Shown by only a minor population.
    2. Increase immune response against common Ag (pollen, dust).
 
Type I
  1. Type I is immediate hypersensitivity (Fig. 5.1).
  2. Occurs after the interaction of Ag with IgE, which is bound to the mast cell surface in a previously sensitized host.
Fig. 5.1: Immediate hypersensitivity
33
Fig. 5.2: Type I hypersensitivity mediators
 
Clinical and Pathologic Manifestations
  1. Systemic.
    1. By systemic administration of Ag (bee sting) or drugs (penicillin).
    2. This is called systemic anaphylaxis.
    3. Urticaria and skin erythema; then respiratory difficulty and laryngeal edema; then vasodilatation and hypotension → CV collapse and death (anaphylactic shock).
  2. Localized.
    1. By Ag exposure through skin contact, ingestion or inhalation. For example, skin and food allergy, hay fever, asthma, etc.
    2. If the susceptibility is genetically controlled → atopy.
 
Mediators
The mediators involved in type I hypersensitivity is shown in Figure 5.2.
 
Type II
  1. Type II is antibody-mediated hypersensitivity.
  2. The Ag may be endogenous or exogenous.
 
Opsonization and Phagocytosis (Fig. 5.3)
  1. Autoimmune hemolytic anemia.
  2. Autoimmune thrombocytopenic purpura.
    34
Fig. 5.3: Opsonization and phagocytosis
 
Compliment and FC Receptor-mediated Inflammation (Fig. 5.4)
Fig. 5.4: Compliment-mediated inflammation
  1. Vasculitis by ANCA.
  2. Goodpasture syndrome.
 
Antibody-mediated Cellular Dysfunction
Fig. 5.5: Antibody-mediated cellular dysfunction
  1. Graves disease—Ab-mediated stimulation of thyroid receptors and increased hormone release.
  2. Myasthenia gravis—Ab to Ach receptor inhibits binding of Ach to receptor and cause paralysis. The Antibody-mediated cellular dysfunction is shown in Figure 5.5.
 
Type III
  1. Immune complex mediated (Fig. 5.6).
    Fig. 5.6: Serum sickness
  2. The increased deposition act as pathogenic mechanism.
  3. The immune complexes may formed in circulation and deposit in blood vessels or in specific organs, where the Ag is implanted.
 
Systemic (Serum Sickness—Acute)
  1. First described in persons when large amounts of serum (foreign) is introduced for passive immunization.
  2. Within 5 days → Ab formation.
  3. Within 10 days → inflammatory features.
  4. Very large complexes (Ab excess) → easily phagocytosed.
  5. Small complexes (Ag excess) → harmful (remain in circulation).
  6. Blood vessels, kidney, joints are mostly affected (Fig. 5.7).
  7. Mainly IgG and IgM are involve.
 
Morphology
  1. A/c necrotizing vasculitis.
  2. Microthrombi and fibrinoid necrosis.
  3. Other example is SLE (C/c).
 
Local (Arthus Reaction—Acute)
  1. Cutaneous reaction.
  2. By injecting Ag to a previously sensitized animal.
  3. Immune complexes are formed and deposited at the site of injection.
  4. Results in inflammation and tissue damage.
  5. Other examples are PSGN, PAN, reactive arthritis.
    35
Fig. 5.7: Mechanism of serum sickness
 
Type IV
T cell-mediated hypersensitivity.
 
Delayed-type Hypersensitivity
CD4 T cell-mediated hypersensitivity is shown in Figure 5.8.
Tuberculin test
  1. ID injection of PPD in previously sensitized host.
  2. Local area of erythema and induration reach peak in 24–72 hours (delayed).
  3. TNF and lymphotoxin are cytokines, which causes:
    1. Increased vasodilatation (↑ NO, PGI2).
    2. Increased expression of selectins and integrins.
    3. Secretion of chemokines like IL-8.
  4. Prolonged DTH leads to granuloma formation.
Contact dermatitis type
  1. Exposure of a sensitized host induces inflammation mainly as vesicular dermatitis.
  2. Mechanism similar to that of tuberculin type.
  3. CD4+ T cell-mediated.
  4. Contact to metals, radiations, etc.
Fig. 5.8: Delayed-tuberculin type hypersensitivity
36
 
T cell-mediated Cytotoxicity
  1. CD8+ T cells are causing this type of cytotoxicity.
  2. These cytotoxic cells kill the antigen-bearing target cells.
  3. Recognition is through class I MHC receptors.
  4. Typical role in viral infections and some tumors.
  5. Killing is by perforin and granzyme system.
  6. Perforin binds to cell membrane and allows the granzyme (protease) to enter the cell.
 
GRAFT REJECTION
 
Immune Recognition of Allograft
  1. Rejection is a response to MHC molecules.
  2. No two individuals (except identical twins) have same MHC.
    1. Direct recognition.
      • The host T cells directly recognize the foreign MHC
      • Through MHC class II → DTH (CD4+ T cells)
      • Through MHC class I → cytotoxicity (CD8+ T cells)
      • Violation of MHC restriction rule.
    2. Indirect recognition.
      • The host T cells identify the foreign Ag and MHC after processing and presentation by host's APCs
      • According to MHC restriction rule
      • Mainly DTH and Ab to foreign Ag are involved in rejection.
 
Mechanisms
  1. T cell-mediated rejection.
    1. Cytotoxic T cells → killing of graft cells.
    2. CD4+ T cells → DTH → damage and destruction of graft due to ischemia (mediated by macrophages and cytokines).
  2. Ab-mediated rejection (Fig. 5.9).
 
Types of Rejection
 
Hyperacute Rejection
  1. In those conditions, where preformed antidonor antibodies are present in the host. For example, prior blood transfusions (Ab to platelets and WBCs) previous organ rejection.
  2. Immediate rejection (within minute to hour).
  3. Morphology.
    1. Cyanotic, mottled and flaccid.
    2. A/c arteritis, thrombosis.
    3. Fibrinoid necrosis.
    4. Narrowing or complete occlusion of vessel lumen.
 
Acute Rejection
  1. Within days to weeks.
  2. In a non-immunosuppressed host.
Types of acute rejection
  1. Acute cellular rejection.
    1. First months.
    2. Extensive CD4 and CD8 T cell infiltration.
    3. Edema and hemorrhage.
    4. Necrosis and arthritis.
    5. Not much response to immunosuppressive therapy.
      37
      Fig. 5.9: Antibody-mediated graft rejection
  2. Acute humoral rejection.
    1. Rejection vasculitis.
    2. Antidonor Ab may present.
    3. Necrotizing vasculitis and cell necrosis.
    4. N, deposition of complement, Ab and fibrin.
    5. Vasculitis and ischemic necrosis and atrophy.
    6. Mimics arteriosclerotic thickening.
 
Chronic Rejection
  1. Months to years.
  2. Progressive deterioration.
  3. Vascular changes, fibrosis, atrophy, etc.
  4. (L) infiltrate.
  5. SMC proliferation of arteries and arterioles.
  6. Increased ECM synthesis.
  7. Not respond to standard immunosuppressive therapy.
 
Graft-versus-host Reaction
  1. Occurs when immunologically competent T cells are transplanted into an immunocompromised host.
  2. Occurs usually with BM transplantation.
  3. Also with some solid organs rich in lymphoid cells (e.g. liver) with irradiated blood.
  4. Here the host cannot reject the transplant.
  5. Graft will induce DTH and CTL responses against host.
  6. A/c → epithelial cell necrosis mainly in liver, gut and skin.
  7. C/c → mainly skin, like in systemic sclerosis.
  8. GVHR decreased by HLA matching and T cell suppression → increased chance of failure.
 
IMMUNOLOGICAL TOLERANCE
  1. Unresponsiveness to an antigen that is induced by exposure of specific lymphocytes to that Ag.
  2. Self-tolerance means lack of immune responsiveness to one's own tissue antigens.
  3. There will be specific receptors on lymphocytes for self-antigens for recognition.
 
Central Tolerance Mechanism
 
In Thymus
The central tolerance mechanism in thymus is given in Figure 5.10.
Fig. 5.10: Central tolerance mechanism in thymus
38
Fig. 5.11: Central tolerance mechanism in bone marrow
 
In Bone Marrow
The central tolerance mechanism in bone marrow is given in Figure 5.11.
 
Peripheral Tolerance Mechanism
The peripheral tolerance mechanism is shown in Figure 5.12.
 
MECHANISMS OF AUTOIMMUNITY
 
Genetic Susceptibility
The active immunity by genetic susceptibility is given in Figure 5.13.
 
Infections and Tissue Injury
The autoimmunity by infections and tissue injury is given in Figure 5.14.
  1. A single autoimmune can leads to further attack by epitope spreading.
  2. Epitopes (specific by determining sites) are present on every self-Ag.
  3. This epitope will stimulate self-reactive clones.
  4. These self-reactive clones spread immune responses to other epitopes, which are not recognized initially.
 
SYSTEMIC LUPUS ERYTHEMATOSUS
  1. Multisystem autoimmune system disease.
  2. Remitting and relapsing disease. May be A/c or insidious.
  3. Has a female preponderance (20–40).
 
Etiopathogenesis
Defect in maintenance of self-tolerance.
 
Immunologic Variables
  1. Increased generation of nuclear Ag by apoptosis.
  2. Decreased clearance of nuclear Ag from apoptotic cells.
  3. Failure of self-tolerance.
  4. C/c B cell hyperactivity.
 
Genetic Variables
  1. Increased incidence rate in monozygotic twins.
  2. Familial inheritance.
  3. Association with HLA class II genes.
  4. Association with complement defect.
    39
Fig. 5.12: Peripheral tolerance mechanism
Fig. 5.13: Autoimmunity by genetic susceptibility
 
Non-genetic variables
  1. Ultraviolet (UV) exposure.
  2. Drugs like hydralazine and procainamide.
  3. Sex hormones.
 
Autoantibodies in Systemic Lupus Erythematosus
  1. Antinuclear Ab.
    1. To DNA.
    2. To histones.
    3. To non-histone proteins attached to RNA (RNPs).
    4. To nucleolar Ag.
  2. Anticytoplasmic Ab.
  3. Antiblood cell Ab.
    1. To red cells.
    2. To platelets.
    3. To lymphocytes.
  4. Antiphospholipid Ab.
 
Morphology
  1. Blood vessels.
    1. A/c necrotizing vasculitis.
    2. Fibrinoid necrosis with lumen narrowing.
    3. Deposits of immune complex (IC), C, fibrin and leukocytes.
  2. Skin.
    1. Erythematous maculopapular lesions.
    2. Malar rashes (butterfly pattern) and discoid rashes.
    3. Photosensitivity.
    4. Degeneration of basal layer with infiltrate.
      40
      Fig. 5.14: Autoimmunity by infections and tissue injury
    5. IC deposition at the dermo-epidermal junction.
  3. Joints.
    1. Swelling with infiltrate.
    2. Arthritis, even destruction of articular cartilage (rare).
  4. Central nervous system (CNS).
    1. Focal neurologic deficits.
    2. Neuropsychiatric illness.
    3. Due to ischemia and cerebral microinfarcts.
  5. Kidney.
    1. Most important.
    2. Mainly glomerular pathology.
    3. Interstitial and tubal lesions also seen (Fig. 5.15).
Fig. 5.15: Pathogenesis of systemic lupus erythematosus
41
 
Grades
 
Grade I
  1. Almost normal by LM and EM (5%).
 
Grade II
  1. Mesangial lupus GN (10%–25%).
  2. Mild symptoms with IC in mesangium.
 
Grade III
  1. Focal proliferative GN (20%–35%).
  2. Proliferation of endothelial and mesangial cells.
  3. (N) and fibrinoid deposits and microthrombi.
  4. Mild microscopic hematuria and proteinuria.
 
Grade IV
  1. Diffuse proliferative GN (35%–60%).
  2. Most serious in SLE and most common.
  3. Diffuse proliferation of cells.
  4. Some crescents in Bowman's capsule.
  5. Capillary wall thickening → wire-loop appearance.
  6. Proteinuria, HTN and renal insufficiency.
 
Grade V
  1. Membranous GN (10%–15%).
  2. Capillary wall thickening.
  3. Severe proteinuria and nephrotic syndrome.
    • Heart
      • Pericarditis
      • Myocarditis with non-specific infiltrate
      • Libman-Sacks endocarditis (valvular lesions)
      • Non-bacterial verrucous endocarditis
      • Increased CAD due to atherosclerosis.
    • Spleen
      • Enlarged and capsular fibrous thickening
      • Follicular hyperplasia with plasma cells
      • Arteries—onion like lesions.
    • Serosa
      • Pleuritis, pericarditis
      • Fibrinous exudates and fibrosis.
    • Liver
      • Enlarged.
 
Clinical Course
  1. Butterfly rashes on face.
  2. Fever, arthritis, pleuritic chest pain.
  3. Neuropsychiatric illness.
  4. Hematuria, proteinuria.
 
Diagnosis
The code is ‘SOAP BRAIN MD’.
  1. Any four features out of 11.
    1. Serositis.
    2. Oral ulcers.
    3. Arthritis.
    4. Photosensitivity.
    5. Blood related disorder.
    6. Renal disorder.
    7. Antinuclear Ab.
    8. Immunologic disorder.
    9. Neurologic disorders.
    10. Malar rash.
    11. Discoid rash.
      42
  2. Specific Ab in SLE diagnosis.
    1. Ab to dsDNA.
    2. Ab to Smith Ag.
 
Treatment
The systemic lupus erythematosus is treated with corticosteroids.
 
RHEUMATOID ARTHRITIS
  1. Systemic C/c inflammatory disease.
  2. Principally affecting joints.
  3. Non-suppurative progressive and proliferative synovitis that frequently results in destruction of articular cartilage and underlying bone and ultimately disabling arthritis.
  4. Common in women than in men.
 
Clinical Course
  1. Fever, malaise, weakness.
  2. Joint-ache, stiffness and swelling.
  3. Raynaud phenomenon and C/c leg ulcers (vascular).
 
Pathogenesis
Pathogenesis of rheumatoid arthritis is shown in Figure 5.16.
 
Morphology
  1. Systemic arthritis—mainly affecting small joints.
  2. Mainly proximal interphalangeal and metacarpophalangeal joints.
  3. Axial skeletal involvements—mainly cervical vertebrae.
  4. C/c synovitis.
    1. Synovial cell hyperplasia and proliferation.
    2. Inflammatory infiltrate—mainly (L), plasma cells, macrophages.
    3. Increased vascularity due to angiogenesis.
    4. (N) and fibrin aggregates in synovial membrane.
    5. Bone erosion.
  5. Appearance of pannus formed by:
    1. Synovial cells.
    2. Inflammatory cells.
    3. Granulation tissue.
    4. Fibrous connective tissue.
  6. C/c → thinning of synovial membrane.
  7. Continuous pannus deposition leads to permanent ankylosis by fibrosis and calcification.
  8. Destruction of articular cartilage.
  9. Destruction of tendons and ligaments → swan neck deformity of fingers.
  10. Rheumatoid S/c nodules.
    1. Extensor aspect of fore arm mainly (also in many organs).
    2. Central fibrinoid necrosis.
    3. Macrophage palisading.
    4. Rimmed by granulation tissue.
  11. Heart, lung, bloodvessels, skin and muscles also affected.
 
Diagnosis
  1. Characteristic radiographic features.
  2. Sterile, turbid and thin synovial fluid.
  3. RA factor.
 
AMYLODOSIS
Amylodosis is a condition of systemic inflammation caused by abnormal extracellular deposition of fibrillar proteins.
43
Fig. 5.16: Pathogenesis of rheumatoid arthritis
 
Classification
 
Systemic Amyloidosis
  1. Primary amyloidosis.
    1. Associated with multiple myeloma and other conditions of monoclonal B cell proliferation.
    2. AL protein accumulated.
  2. Secondary amyloidosis.
    1. C/c inflammatory conditions (AA protein increases).
  3. Dialysis induced.
    1. C/c renal failure (Aβ2m protein increases).
 
Hereditary Amyloidosis
  1. Familial Mediterranean fever.
    1. AA protein increases.
  2. Familial amyloidotic neuropathies.
    1. ATTR proteins increases.
  3. Senile amyloidosis.
    1. ATTR protein ↑.
      44
 
Localized Amyloidosis
  1. Senile cerebral.
    1. Assosiated with Aizheimer's.
    2. Aβ protein increases.
  2. Endocrine.
    1. Medullary CA thyroid associated—a cal protein ↑ (calcitonin).
    2. Type II DM–AIAPP ↑ (islet amyloid peptide—IAP).
  3. Atrial amyloidosis.
    1. AANF ↑ (ANF precursor).
 
Pathogenesis
The pathogenesis of amyloidosis is shown in Figure 5.17.
  1. Amyloid associated protein and AL proteins are accumulated due to limited proteolysis.
  2. Aβ2M is deposited due to limited excretion.
 
Morphology
  1. Many organs are affected (grey pale waxy).
  2. Deposition of amyloid proteins (extracellular).
  3. Stains.
    • Brown with I2 and sulfuric acid (H2SO4)
    • Red green with congo red.
  4. Kidney.
    1. Most common and most serious.
    2. Enlarged, pale green and firm.
      Fig. 5.17: Pathogenesis of amyloidosis
      45
    3. Amyloid deposits mainly in glomeruli.
    4. Also in interstitium, blood vessels and tubules.
  5. Spleen.
    1. Moderate or marked enlargement.
    2. Sago spleen—tapioca-like granules (deposit in follicles).
    3. Lardaceous spleen—sheet-like deposits (in sinuses and pulp).
  6. Liver.
    1. Massive hepatomegaly.
    2. First deposit in space of Disse and then progress.
  7. Heart.
    1. Subendocardial elevations, myocardial deposits and atrophy.
 
Clinical Course
  1. Multiorgan damage.
  2. Macroglossia (deposition on tongue).
  3. Carpal tunnel syndrome (deposition on carpal ligament).
  4. Poor prognosis.
 
SCLERODERMA
  1. Better described as systemic sclerosis.
  2. Excessive fibrosis throughout the body.
  3. Mainly involves skin.
  4. Lungs, kidneys, heart, GIT and skeletal muscles also affected.
 
Types of Scleroderma
 
Diffuse Scleroderma
  1. Initial skin involvement (wide spread).
  2. Rapid progression with early visceral involvement.
 
Limited Scleroderma
  1. Limited skin involvement.
  2. Visceral involvement occurs only late.
  3. Also called CREST syndrome.
    1. Calcinosis.
    2. Raynaud phenomenon.
    3. Esophageal dysmotility.
    4. Sclerodactyly.
    5. Telangiectasia.
 
Etiopathogenesis
  1. B-cell activation also occurs and so two Abs are specific for SS diagnosis.
    1. Ab to DNA topoisomerase-I.
    2. Ab to centromere.
  2. B-cell activation → not much role in pathogenesis (Fig. 5.18).
 
Morphology
  1. Skin (100%).
    1. Sclerotic atrophy (begins from fingers).
    2. Edema and infiltrate containing CD4 + T cells.
    3. Small vessels show wall thickening.
    4. Increased collagen and fibrosis.
    5. Later calcification, ulceration and atrophy.
      Fig. 5.18: Pathogenesis of scleroderma
      46
      Fig. 5.19: Entry of the virus into the cell
      Fig. 5.20: Viral replication in the host cell
  2. Gastrointestinal tract.
    1. In 90% patients.
    2. At any part (more severe in esophagus).
    3. Mucosa is thinned and ulcerated.
    4. Collagen deposition and fibrosis of lamina propria, submucosa and muscularis.
  3. Musculoskeletal.
    1. Synovial hyperplasia and inflammation (10%).
    2. Later fibrosis and joint destruction.
    3. Polymyositis may develop.
  4. Lungs.
    1. Pulmonary fibrosis and pulmonary HTN.
  5. Kidneys (60%).
    1. Fibrinoid necrosis, thrombosis and infarction.
    2. Thickening of blood vessels.
    3. Malignant HTN may occur.
  6. Heart.
    1. Myocardial fibrosis.
    2. Ischemia (cardiac Raynaud).
 
Clinical Course
  1. More in women than in men.
  2. Overlapped with RA, SLE, etc.
  3. Raynaud phenomenon.
  4. CREST syndrome.
  5. Features of multiorgan damage.
    47
Fig. 5.21: Progression of disease
 
PATHOGENESIS OF HUMAN IMMUNODEFICIENCY VIRUS
  1. Involves five steps:
    1. Entry of virus into cells.
    2. Viral replication.
    3. Progression of infection.
    4. Depletion of T cells.
    5. Alteration in other cell types.
  2. HIV principally affect CD4+ T cells, macrophages and dendritic cells.
 
Entry of Virus into Cell (Fig. 5.19)
Requires CD4 and chemokine receptors.
 
Viral replication
The viral replication in the host cell is given in Figure 5.20.
 
Progression of infection
The progression of infection in the body is given in Figure 5.21.
 
Depletion of T cells
  1. Infected CD4+ T cells.
    • Death by CPE of virus.
  2. Uninfected CD4+ T cells.
    • Activation and activation-induced cell death.
  3. Expression of HIV peptides on infected CD4+ T cells and killing by virus specific cytotoxic T cells.
 
Other Alterations
  1. Decreased T cell functioning.
  2. Defective monocyte or macrophage and dendritic cell functioning.
  3. Polyclonal B cell proliferation.

NeoplasiaChapter 6

 
NEOPLASM
Neoplasm is defined as an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner after the cessation of the stimuli, which evoked the change.
 
Features of Tumors
Features of tumors, both benign and malignat are listed in Table 6.1.
 
ANAPLASIA
  1. Anaplasia is lack of differentiation.
  2. This is characteristic of many malignant tumors.
  3. The features of anaplasia are:
    Microscopic features of malignant tumors is given in Table 6.1.
 
METASTASIS
  1. Metastasis is the spread of malignant tumor by invasion in such a way that discontinuous secondary tumor masses are formed at the site of lodgement.
  2. This is a major characteristic feature of most of malignant tumors with a few exceptions like:
    • Gliomas of CNS
    • Basal cell carcinoma of skin.
 
Routes of Metastasis
 
Lymphatic Spread
  1. In general, carcinomas metastasize by lymphatic route, while sarcomas favor hematogenous routes.
  2. Two forms of involvement of lymphatics are given below.
    1. Lymphatic permeation: The walls of lymphatics are invaded and form a continuous growth in the lymphatic channels.
    2. Lymphatic emboli: The detached tumor emboli get carried along the lymph to lymph node. The tumor cells start growing in lymph node and later lymph node may replaced by enlarged metastatic tumor.
  3. Generally regional lymph nodes draining the tumor site are invariably involved producing regional nodal metastasis. For example, CA breast to axillary nodes. CA thyroid to lateral cervical nodes.
  4. Sometimes, metastases do not develop first in the regional lymph nodes, but affect distant nodes due to venous-lymphatic anastomoses or due to obliteration of lymphatics by inflammation and is called skip metastasis.
    49
  5. Some other times, due to obstruction of lymphatics by tumor cells spread against the flow of lymph causing retrograde metastases. For example, CA prostate to supraclavicular lymph nodes. CA lung to axillary lymph nodes.
  6. Regional lymphadenitis is not always due to nodal metastasis and is also produced by sinus histiocytosis induced by tumor cells.
 
Hematogenous Spread
  1. Hematogenous spread is the common route of spread for sarcomas, but also for certain carcinomas like carcinoma of lungs, breasts, thyroid, kidneys, liver, prostate and ovary.
    50
  2. The sites mainly involved by hematogenous spread are: Liver, lungs, brain, bones, kidneys and adrenals.
  3. The sites like spleen, heart and skeletal muscles are rarely involved.
  4. Cancers of limbs, head, neck and pelvis are more often metastasis to lungs through systemic veins.
  5. Cancers of bowel, spleen and pancreas usually spread to liver through portal veins.
  6. Systemic arterial spread is rare because they are thick walled and resistant to invasion.
  7. Cancers of lung may metastasis to kidneys, adrenals, bones, brain, etc. through pulmonary artery.
  8. Retrograde spread may occur due to venous obstructions. For example, CA thyroid and CA prostate to vertebral column.
 
Spread Along BodyCavities and Others
  1. Transcoelomic spread, e.g. CA stomach to ovaries (Krukenberg tumor).
    1. Carcinoma ovary to peritoneal cavity, pseudomyxoma peritonei (from CA ovary and appendix). CA lung and breast to pleura and pericardium.
  2. Along epithelial lined surfaces (rare), e.g. through fallopian tube from endometrium to ovary and vice versa.
    Through bronchus to alveoli. Through ureter to lower urinary tract from kidneys.
  3. Via CSF, e.g. malignancy of ependyma and leptomeninges.
  4. Direct implantation. By surgeon's scalpel, needles, sutures of direct contact.
 
Mechanism of Metastasis
  1. Aggressive clonal proliferation and angiogenesis.
    1. Aggressive clonal proliferation of a subgroup of monoclonal tumor cells is the first step in metastasis.
    2. This nature of tumor cells that subpopulation can involve completely in the development of metastasis is on the basis of tumor heterogeneity.
    3. Tumor angiogenicity plays a major role, because the new vessels formed are more vulnerable to invasion.
  2. Tumor cell loosening.
    1. Normal cells are held together by CAMs.
    2. In tumors, these adhesion molecules get inactivated and this results in loosening.
  3. Tumor cell/ECM interaction.
    1. Loosened tumor cells are then attached to ECM proteins mainly laminin and fibronectin through the receptors on the cancer cells.
    2. Facilitated by lose of integrins.
  4. Degradation of ECM.
    1. Tumor cells induce proteases and metalloproteinases like gelatinase and collagenase.
    2. Also the metalloproteinase inhibitors are decreased.
    3. All these results in dissolution of ECM (BM of tumor cells, interstitial matrix and BM of vessel wall).
  5. Entry of tumor cells into capillary lumen.
    1. A cytokine AMF stimulates receptormediated motility of tumor cells into the lumen.
      51
    2. Matrix degradation products have properties of chemotaxis, growth promotion and angiogenesis.
  6. Thrombus formation.
    1. Tumor cells in the lumen get transformed into a thrombus.
    2. The thrombus provides nutrition and protects tumor cells from immune attack.
  7. Extravasation of tumor cells.
    1. This occurs at the site of metastasis.
    2. Just reversal of steps of tumor cell entry into lumen.
  8. Survival of growth of metastatic deposit.
    1. The main growth factors acting here are PDGF, FGF, TGF and VEGF.
    2. These deposits can further metastasize also.
 
PRENEOPLASTIC DISORDERS
Preneoplastic disorders are group of conditions, which predispose to the subsequent development of cancer. Many of these conditions are characterized by features like increased nuclear-cytoplasmic ratio, pleomorphism, increased mitotic activity, etc. The major types are:
  1. Carcinoma in situ
    1. Here the cytological features of malignancy are present, but the malignant cells are confined to epithelium without invasion across BM.
    2. The common sites are:
      • Uterine cervix at the junction of ecto- and endocervix
      • Bowens disease of skin
      • Oral leukoplakia
      • LCIS and DCIS of breast.
  2. Benign lesions.
    1. For example, multiple villous adenoma of large intestine may develop into adenocarcinoma.
      • Neurofibromatosis may develop into sarcoma.
  3. Miscellaneous.
    1. Certain inflammatory and hyperplastic conditions predispose to cancer.
      • Long-standing ulcerative colitis to colorectal ulcer
      • Cirrhosis liver to hepatocellular carcinoma
      • Chronic bronchitis to carcinoma bronchus
      • Chronic irritation from jagged tooth may lead to oral cancer
      • Old burn scar (Marjolin's ulcer) to squamous cell carcinoma
      • Chronic atrophic gastritis to CA stomach
      • A typical endometrial hyperplasia to endometrial cancer.
 
CARCINOGENESIS: MOLECULAR BASIS ORGENETIC MECHANISM
  1. Carcinogenesis or oncogenesis is the mechanism by which the tumor develops from a normal tissue by the action of carcinogens.
  2. The major non-lethal mutations account for cancer are on the following targets:
    1. Growth promoting proto-oncogenes.
    2. Growth inhibiting tumor suppressor genes.
    3. Genes that regulate apoptosis.
    4. Genes involved in DNA repair.
      52
  3. The major mechanisms by which a cancer develops are:
    1. Self-sufficiency in growth signals and excessive growth.
      • By the action of oncogenes, e.g. RAS, BCR-ABL, MYC, CDK4, etc.
    2. Insensitivity to growth inhibitory signals.
      • By mutation of tumor suppressor genes, e.g. mutation of RB gene, p53 gene, etc.
    3. Evasion of apoptosis.
      • By mutation of genes like BCL2, CD95, etc.
    4. Avoiding cellular ageing and increased replicative potential.
      • By the action of increased telomerase.
    5. Tumor angiogenesis.
      • Due to increased angiogenic factors (VEGF and FGF) and decreased antiangiogenic factors (thrombospondin and angiostatin).
    6. Invasion and distant metastasis.
      • By a series of events (already discussed).
    7. Genetic instability.
      • Mainly by DNA damage due to defective repair, e.g. HNPCC, xeroderma pigmentosum, CA breast.
    8. Clonal aggressiveness.
      • By cancer progression and heterogenicity.
    9. Multistep molecular phenomenon.
      • Mutation at different genes together.
    10. Oncomirs.
      • These are microRNAs in certain cancers
      • These leads to certain mutations.
 
Mechanism
The genetic mechanism is given in the Figure 6.1.
 
RB GENE
  1. Located on long arm of chromosome 13.
  2. This is the first tumor suppressor gene discovered.
  3. The RB gene product is a DNA binding protein expressed in two forms:
    1. A hypophosphorylated active form.
    2. A hyperphosphorylated inactive form.
 
Mechanism of Functioning
  1. The active form blocks E2F mediated transcription in two ways (Fig. 6.2).
    • Sequesters E2F and prevent it from interacting with other transcriptional factors
    • Recruits chromatin remodeling proteins which bind to promoters of E2F responsive genes.
  2. During M-phase, the phosphate groups are removed by phosphatases and make RB gene active.
  3. In tumors, the mutations inactivate RB gene and leads to increased cell growth, e.g. retinoblastoma, osteosarcoma, CA lung, CA colon and CA breast.
    53
Fig. 6.1: Genetic mechanism
 
Knudson's Two-hit Hypothesis
  1. RB gene functioning, is a classical example for Knudson's two-hit hypothesis, which states that “a tumor suppressor gene transforms to a cancer producing oncogene usually after two different mutations”.
  2. Other examples are neurofibromin gene in neurofibromatosis and APC gene in FAP.
  3. p53 gene is an exception for this hypothesis.
 
p53 GENE
  1. p53 gene is one of the most commonly mutated genes in human cancers and is called ‘protector of the genome’.
  2. p53 induces neoplastic transformation by three interlocking mechanisms:
    54
    Fig. 6.2: Mechanism of RB gene functioning
    1. Activation of temporary cell cycle arrest (quiescence).
    2. Induction of permanent cell cycle arrest (senescence).
    3. Triggering of programmed cell death (apoptosis).
  3. The p53 is triggered by anoxia, inappropriate oncogene expression and damage to integrity of DNA.
  4. The p53 gene is located on the short arm of chromosome 17.
 
Mechanism of Functioning
  1. The key initiators of DNA damage are the ATM and ATR genes, those are seen in ataxia telengectasia patients and that patients have an increased risk of malignancy due to p53 mutation.
  2. p53 brings about the G1 arrest through p21 (CDK inhibitor) and the DNA repair GADD 45.
  3. The p53 is normally seen in association with MDM2, which targets the destruction of p53.
  4. On stress, p53 undergo certain post-transcriptional modifications and get released from MDM2.
  5. On release from MDM2, p53 induce DNA repair.
  6. After DNA repair, p53 upregulates the transcription of MDM2 leading to destruction of p53 and relief of cell cycle block.
  7. Many tumor show p53 mutation, e.g. sarcomas, CA breast, leukemia, brain tumor, etc.
  8. Patients with Li-Fraumeni syndrome has inherited p53 mutation and has 25-fold increased risk for cancer.
  9. p53 is inactivated by certain DNA viruses like HPV, HBV, EBV, etc.
    55
Fig. 6.3: Effect of carcinogens on cells
 
CHEMICAL CARCINOGENS
Chemicals, which induces cancer.
 
Initiator Carcinogens
Carcinogens (Fig. 6.3), which can initiate the process of carcinogenesis.
 
Directly Acting
  1. Directly acting agents do not need metabolic activation to become carcinogenic.
    1. Alkylating agents.
      • Anticancer drugs (cyclophoshphamide, busulfan, melphalan, etc.)
      • β-propionolactone
      • Epoxides
      • These are weakly carcinogenic
      • Causes lymphomas and leukemias.
    2. Acylating agents.
      • Acetylimidazole
      • Dimethylcarbamoyl chloride.
 
Indirectly Acting
  1. Indirectly acting agents require prior metabolic activation to become carcinogenic.
  2. Also called procarcinogens.
    1. Poly cyclic aromatic hydrocarbons.
      • Anthracenes
        56
      • Benzpyrene
      • Methylcholanthrene
      • Largest group
      • Causes skin cancer by topical application, sarcomas by subcutaneous injections and lung cancer by inhalation
      • The sources are tobacco, smoke, fossil fuel, soot, tar, mineral oil, smoked animal foods, industrial and atmospheric pollutants, etc.
    2. Aromatic amines and azo dyes.
      • β-naphthalene: Bladder cancer
      • Benzidine: Bladder cancer
      • Azo-dyes (margarine, scarlet red): Hepatocellular carcinoma.
    3. Naturally occurring products.
      • Aflatoxin-B1, actinomycin-D, mitomycin-C, safrol and batel nuts
      • All these are known to cause hepatocellular carcinoma.
    4. Miscellaneous.
      • Nitrosamines and nitrosamides: CA stomach
      • Vinyl chloride monomer: Hemangiosarcoma of liver
      • Asbestos: Bronchogenic carcinoma, mesothelioma
      • Arsenical compounds: Basal cell carcinoma of skin
      • Metals like nickel, cobalt: Lung cancer
      • Insecticides and fungicides: Cancer in experimental animals
      • Saccharin and cyclamates: Cancer in experimental animals.
 
Promoter Carcinogens
  1. Promoter carcinogen agents lack the intrinsic carcinogenic potential.
  2. But their exposure subsequent to initiator helps the initiated cell to proliferate further, e.g. phorbol esters, phenols, certain hormones and drugs, dietary fat, etc.
  3. Hormones include.
    1. Estrogen: Carcinoma endometrium, CA breast.
    2. Diethyl stillbestrol: Postmenopausal CA endometrium.
    3. Adolescent vaginal cancer in female child if mother exposed during pregnancy.
  4. Dietary fat causes CA colon.
 
CHEMICAL CARCINOGENESIS
  1. Chemical carcinogenesis is the process by which carcinogens induce the cancer.
  2. The factors influencing are:
    1. Dose and mode of administration of carcinogens.
    2. Individual susceptibility.
    3. Various predisposing factors.
  3. Following are the stages.
 
Initiation
  1. Initiation is the first stage and induced by initiators.
  2. The induced change is sudden, irreversible and permanent.
  3. Initiation is brought about by both direct and indirect acting carcinogens.
  4. The steps involved are given below.
 
Metabolic Activation
  1. Metabolic activation step is only required for indirect-acting carcinogens 57and not required for direct-acting carcinogens.
  2. Activation occurs in ER of liver by mono-oxygenases of cyt-p450 system.
  3. Sometimes the procarcinogen get inactivated.
  4. The carcinogenic potential is determined by.
    1. Balance between activation and inactivation.
    2. Genes that code for cyt-p450 dependent enzymes.
    3. Age, sex and nutritional status of the host.
 
Reactive Electrophiles Formation
  1. Direct acting agents are intrinsically electrophilic and indirect acting agents become electrophilic after activation.
  2. These reactive electrophiles bind to electron-rich portions of DNA, RNA and other proteins.
 
Target Molecule Attack
  1. The primary target molecules are DNA.
  2. Several genes are affected.
  3. The commonly affected growth promoter oncogene is RAS gene and anti-oncogene is p53 gene.
  4. RNA and proteins are also targets.
 
Formation of Initiated Cells
  1. The cells with sudden, irreversible, permanent DNA damage is called initiated cell.
  2. These are vulnerable to the action of promoters.
 
Promotion
  1. The main promoter carcinogens are phorbol esters, phenols, hormones, artificial sweetners and certain drugs.
  2. The promoters differ from initiators in the following aspects:
    1. Do not produce sudden change.
    2. Require application or administration in sufficient time and dose.
    3. The induced change may be reversible.
    4. Do not damage DNA as such, but enhance the damage caused by initiators.
    5. Act by further proliferation of initiated cell.
  3. Initiator alone can also result in cancer, but promoter alone cannot cause cancer.
 
Progression
  1. This is the stage in which the mutated proliferated cell shows phenotypic features of malignancy.
  2. Features pertain to morphology, biochemical composition and molecular features.
  3. Throughout this process, the cells accumulate more and more mutations.
 
Tests for Carcinogenicity
  1. Experimental induction.
    1. Expose experimental animals to specific chemicals.
    2. Prolonged and expensive.
  2. Ames' test.
    1. Evaluates the carcinogenetic potential of a chemical in the mutant 58strain of Salmonella typhimurium, which cannot produce histidine.
    2. The mutant strains are incubated with carcinogen and liver homogenate.
    3. Liver homogenate is to activate carcinogen.
    4. If the carcinogen is potent, that will cause mutation in Salmonella strains and thus those strains can produce histidine.
    5. So these strains can grow in histidine free medium.
 
Sequential Stagesin Chemical Carcinogenesis
The Sequential stages in chemical carcinogenesis is shown in Figure 6.4.
 
DNA VIRAL ONCOGENESIS
The DNA viral oncogenesis steps is shown in Figure 6.5.
  1. DNA oncogenesis viruses have three special genes:
    1. gag’ gene—codes for group antigen.
    2. pol’ gene—codes for polymerase enzyme.
    3. env’ gene—codes for envelope protein.
  2. Persistence of DNA virus in the host cell act as one step in the multistep process of cancer development.
  3. These viruses induce clonal proliferation of cells by:
    Fig. 6.4: Chemical carcinogenesis
    59
    Fig. 6.5: Steps in DNA virus oncogenesis
    1. Activation of growth promoting pathways.
    2. Inhibition of tumor suppressor genes.
  4. This oncogenetic mechanism involves two steps:
    1. Replication of virus in the host cells and release of virions.
    2. Integration of viral DNA with host cell DNA.
  5. The replication leads to host cell death, but no neoplastic transformation.
  6. Integration induces mutation and thus leads to neoplastic transformation.
 
Specific DNA Oncogenic Viruses
  1. Papovaviruses
    1. HPV (humans) → cervical cancer, SCC at other sites, skin cancer and papillomas (warts).
      • Cervical → HPV 16, 18, 31 and 33
      • Warts → HPV 6 and 11
      • Skin → HPV 5 and 8.
    2. Papilloma virus (animals) → papillomas, alimentary tract cancer.
    3. Polyoma virus (mice) → various carcinomas and sarcomas.
    4. SV-40
      • Animals → sarcoma
      • Humans → mesothelioma.
  2. Herpes virus
    1. EBV (humans) → Burkitt's lymphoma.
    2. HHV-8 (humans) → Kaposi sarcoma, pleural effusion, lymphoma.
    3. Lucke frog virus (frog) → RCC.
    4. Marek's disease virus (chicken) → T cell leukemia, lymphoma.
  3. Adenoviruses.
    1. Animals → sarcomas.
  4. Poxviruses.
    1. Rabbits → myxomatosis.
    2. Humans → molluscum contagiosum.
  5. Hepadna viruses.
    1. Hepatitis B virus (humans) → hepatocellular carcinoma.
 
Mechanism in four ImportantDNA Viral Oncogenesis
  1. Human papilloma virus.
    1. Refer pathogenesis of CIN given in the chapter 19, the FGS and breast.
      60
      Fig. 6.6: Steps in EBV oncogenesis
  2. Epstein-barr virus (EBV) (Fig. 6.6).
    1. Causes Burkitt's lymphoma, nasopharyngeal carcinoma, a subset of Hodgkin lymphoma and B cell lymphomas in AIDS.
  3. Human herpes virus-8 (HHV-8)(Fig. 6.7).
  4. Hepatitis virus (Fig. 6.8).
    Fig. 6.7: Steps in HHV oncogenesis
 
RNA VIRAL ONCOGENESIS
  1. These viruses also have three typical genes (gag, pol and env) as DNA oncogenic viruses.
  2. The RNA oncogenic viruses are mainly retroviruses that having reverse transcriptase enzyme.
  3. This enzyme (RT) helps the viral RNA to synthesize viral DNA.
 
Specific RNA Oncogenic Viruses
  1. Acute transforming viruses (rapidly acting) (by viral oncogenes).
    1. Rous sarcoma virus (animals) → sarcomas.
    2. Leukemia sarcoma virus (animals) → leukemia, sarcomas.
  2. Slow transforming viruses (slowing acting) (by mutagenesis).
    1. Mouse mammary tumor virus (animals) → leukemia, lymphomas and breast cancer.
  3. Human T cell lymphotropic virus (HTLV) (Fig. 6.9):
    61
    Fig. 6.8: Steps in hepatitis virus oncogenesis
    1. HTLV-I (humans) → adult T-cell leukemia lymphoma (ATLL).
    2. HTLV-II (humans) → T-cell variant of hairy cell leukemia.
  4. Hepatitis–C (HCV) (humans) → hepatocellular carcinoma.
 
HTLV Oncogenesis
Human T cell lymphotropic virus does not have viral oncogenes and have no fixed site for interstitial mutagenesis.
 
TUMOR ANTIGENS
  1. Tumor are certain surface antigens on tumor cells.
  2. Tumor specific antigens are those, which are seen only on tumor, but not on normal cells. These are specific antigens for particular tumor.
  3. Tumor associated antigens are those, which are present both on tumor cells and normal cell from which the tumor originated.
    Fig. 6.9: Steps in HTLV oncogenesis
    62
    63
    1. Oncoproteins from mutated oncogene.
      • Oncoproteins express certain cell surface antigens, e.g. RAS, BCR/ABL, CDK4.
    2. Products of tumor suppressor genes.
      • Mutated tumor suppressor genes also express tumor antigens, e.g. p53, β-catenin.
    3. Products of other mutated genes.
      • Various random mutations elaborate tumor antigens and protein products which are targeted by cytotoxic T cells.
    4. Overexpressed cellular proteins.
      • Here the cellular proteins are normal, but overexpressed and elaborate tumor antigens, e.g. HER/NEU protein in breast cancer, melanoma specific protein in melanoma.
    5. Abnormally expressed cellular proteins.
      • Her abnormal proteins are seen on tumor cells, e.g. MAGE gene in CA lungs, CA liver and CA stomach.
    6. Tumor antigens from viral oncoproteins.
      • For example, oncoproteins of HPV in cervical cancer, EBNA protein of EBV in Burkitt's lymphoma.
    7. Cell specific differentiation antigens.
      • Tumor cells express antigens due to varying degree of differentiation
      • For example, CD markers in lymphoma, PSA in CA prostate.
    8. Oncofetal antigens.
      • These are normal in embryonic life, but later appear as tumor antigens, e.g. AFP in liver cancer, CEA in colon cancer.
    9. Abnormal cell surface molecules.
      • For example, abnormal expression of mucin in CA ovary (CA-125), abnormal mucin (MUC-1) in breast cancer.
 
PARANEOPLASTIC SYNDROMES
  1. Paraneoplastic syndromes (Table 6.2) are a group of conditions that occur in patients with advanced cancer, which are neither explained by direct or distant spread of tumor nor by the usual hormone elaboration by the tissue of origin of tumor.
  2. These represent significant clinical problems, sometimes occult neoplasm and may mimic metastases.

Genetic and Pediatric DiseasesChapter 7

 
MUTATIONS
Mutations are the permanent changes in DNA, which may be inherited if affect the germ cells. Point mutation is the change in a single nucleotide.
 
Types of Mutation
 
Substitution
Resulting from the substitution of a single nucleotide base by a different base, resulting in the replacement of one amino acid by another in the protein structure.
For example, sickle cell anemia—glutamic acid in the 6th position of β-globin chain is replaced by valine.
  1. Transition—substitution of purine by another purine (A and G) or pyrimidine by another pyrimidine (T and C).
  2. Transversion—substitution of a purine by a pyrimidine or vice versa.
 
Deletion
  • Deletion of a single nucleotide or
  • Deletion of a codon (cystic fibrosis) or
  • Deletion of a large gene (hemophilia).
 
Insertion
  • Insertion of a single nucleotide or
  • Trinucleotide expansion (Huntington's chorea) or
  • Duplication (Duchenne muscular dystrophy).
 
Effects of Mutation
 
Silent Mutation
Silent mutation has no effect.
 
Mis-sense Mutation
An abnormal amino acid or protein is formed.
  1. Acceptable (functionally normal).
  2. Partially acceptable (partial loss of function).
  3. Unacceptable (non-functional).
 
Nonsense/Terminator Codon Mutation
  1. Leads to premature termination of proteins.
 
Frame Shift Mutation
  1. Due to deletion or insertion of nucleotides.
  2. A completely irrelevant protein is formed.
    65
 
Conditional Mutation
  1. Become manifested under certain circumstances only.
 
Manifestations
  1. Lethal—alteration is incompatible with life.
  2. Silent—no functional effect.
  3. Beneficial—beneficial to life.
  4. Carcinogenic—results in neoplasms.
 
Mutagens
The substances, which produce mutations are called mutagens.
For example, X-ray, ultraviolet (UV) ray, γ-ray, acridine orange dye, etc.
 
MARFAN SYNDROME
  1. An autosomal dominant disorder of connective tissues.
  2. Basically affect fibrillin-1.
  3. Fibrillin-1 is a glycoprotein secreted by fibroblasts, which is a major component of myofibrils in ECM.
  4. Myofibrils are integral part of elastin and elastic fibers.
  5. Fibrillin-1 is encoded by FBN-1 gene on chromosome 15q21.
  6. Marfan syndrome is almost always associated with FBN-1 mutations, but FBN-1 mutations are not always associated with Marfan syndrome.
  7. Recently an additional dysregulation of transforming growth factor-beta (TGF-β) production, which leads to increased TGF-β production and connective tissue overgrowth.
 
Morphology
Morphological features mainly confined to three systems, they are skeleton, CVS and eyes.
 
Skeletal Abnormalities
  1. These are the most obvious features.
  2. Slender elongated habitus.
  3. Abnormally long legs, arms and fingers (arachnodactyly).
  4. High arched palate.
  5. Hyper extensibility of joints.
  6. Spinal deformities-like kyphoscoliosis.
  7. Pectus excavatum or pigeon chest deformity.
 
Ocular Features
  1. Bilateral dislocation or subluxation of lens.
  2. Ciliary zonule is devoid of elastin.
 
Cardiovascular Features
  1. Most serious.
  2. Predisposition to aortic aneurysm and dissection.
  3. Aortic valve incompetence.
  4. Mitral and tricuspid regurgitation (floppy valve syndrome).
  5. Leads to congestive cardiac failure (CCF).
  6. Most common cause of death in Marfan syndrome is aortic rupture.
 
LYSOSOMAL STORAGE DISEASE
  1. Resulting from the inherited lack of lysosomal enzymes, which leads to accumulation of partly degraded insoluble 66metabolites within the lysosomes.
  2. An autosomal recessive condition.
  3. Commonly affects infants and young children.
  4. Usually this produce hepatosplenomegaly.
  5. Frequent CNS involvement is seen.
 
Main Types
 
Tay-Sachs Disease
  1. Resulting from the accumulation of gangliosides.
  2. Due to deficiency of hexosaminidase-A.
  3. Mainly GM2 gangliosides are accumulated in the neurons and glial cells of CNS, autonomic nervous system (ANS) and peripheral nerves.
  4. Sometimes retina also involved.
  5. C/f—motor weakness, mental retardation, blindness, etc.
 
Niemann-Pick Disease Type A and B
  1. Accumulation of sphingomyelin.
  2. Due to deficiency of acid sphingomyelinase.
  3. Accumulation mainly in the phagocytic cells and neurons.
  4. Spleen, liver, BM, LNs and lungs are severely affected.
  5. C/f—massive visceromegaly and neurologic deterioration.
 
Niemann-Pick disease Type C
  1. Accumulation of cholesterol and gangliosides (GM1 and GM2).
  2. C/f-ataxia, dystonia, dysarthria and psychomotor regression.
 
Gaucher Disease
  1. Accumulation of glucosylceramide in phagocytic cell.
  2. Due to deficiency of glucosylceramidase.
  3. C/f—hepatosplenomegaly, bone erosion due to deposition in BM and neuronal involvement.
  4. Accumulation leads to the formation of large phagocytic cells (Gaucher cells) with pathognomonic wrinkled tissue paper appearance of cytoplasm.
  5. High levels of IL-2, IL-6 and TNF can be seen.
  6. Type I non-neuropathic form is characterized by hepatosplenomegaly and bone erosion.
  7. Type II and III forms predominantly shows neuronal involvement.
 
Mucopolysaccharides
  1. Accumulation of mucopolysaccharides (MPS) in liver, spleen, heart, brain, blood vessels, cornea, joints, etc.
  2. Several types (I–VII) are reported and each due to deficiency of one specific lysosomal degrading enzyme.
  3. The MPS accumulated are dermatan sulfate, heparan sulfate and chondroitin sulfate.
  4. C/f—coarse facial features, joint stiffness, clouding of cornea and mental retardation.
  5. Hurler syndrome (type I) is severe and Hunter syndrome (type II) has a milder course.
  6. Six types are AR except hunter syndrome, which is X-linked recessive.
  7. Death is commonly due to cardiac complications.
    67
 
GLYCOGEN STORAGE DISEASES (GLYCOGENOSIS)
  1. Due to inherited deficiency of any one enzyme involved in glycogen synthesis or degradation, glycogen accumulates in excessive amount or in abnormal form.
  2. Most glycogen storage diseases are autosomal recessive (AR).
  3. One of the glycogen storage disease, i.e. Pompe disease is not only a glycogenosis, but also a lysosomal storage disease, because the enzyme deficient is a lysosomal enzyme and is involved in glycogen metabolism.
 
Hepatic Form
  1. Also called von Gierke disease (type I).
  2. Deficient enzyme is glucose-6-phosphatase.
  3. C/f—Hepatomegaly and renomegaly.
    1. Hypoglycemia due to failure of glucose mobilization.
    2. Hyperlipidemia and hyperuricemia.
    3. Bleeding tendency due to platelet dysfunction.
 
Myopathic Form
  1. Also called McArdle syndrome (type V).
  2. Deficient enzyme is muscle phosphorylase.
  3. C/f—painful cramps with exercise, myoglobinuria, failure of increased lactate level in exercise.
 
Generalized Form
  1. Also called Pompe disease (type II).
  2. Deficient enzyme is lysosomal glucosidase or acid maltase.
  3. C/f—mild hepatomegaly with ballooning of lysosomes.
  4. Cardiomegaly, cardiorespiratory failure.
  5. Muscle hypertonia and chronic myopathy.
 
AUTOSOMAL GENETIC DISORDERS
 
Autosomal Trisomies
 
Down Syndrome
  1. Most common chromosomal disorder.
  2. This is the trisomy of chromosome 21.
  3. The chromosome count will be 47.
  4. It occurs due to meiotic non-disjunction of chromosomes.
  5. Maternal age has a strong influence on the incidence of Down syndrome.
  6. 95%—trisomy 21.
  7. 4%—extrachromosome is seen as a translocation of the long arm of chromosome 21 to chromosome 22 or 14.
  8. 1%—mosaics mixture of cells with 47 and 46 chromosomes.
 
Clinical features
  1. Mental retardation and dementia.
  2. Epicanthic folds.
  3. Flat facial profile.
  4. Abundant neck skin.
  5. Simian crease.
  6. Cardiac defects.
  7. Intestinal stenosis.
  8. Umbilical hernia.
  9. Hypotonia.
  10. Increased gap between 1st and 2nd toe.
    68
  11. Predisposition to leukemia and serious infections.
Diagnosis—demonstration by FISH technique.
 
Edward Syndrome
Edward syndrome is trisomy 18.
Clinical features:
  1. Prominent occiput.
  2. Mental retardation.
  3. Low set ears.
  4. Micrognathia.
  5. Short neck.
  6. Overlapping fingers.
  7. Cardiac defects.
  8. Renal malformations.
  9. Limited hip abduction.
  10. Rocker-bottom feet.
 
Patau Syndrome
This is trisomy 13.
Clinical features:
  1. Microcephaly.
  2. Mental retardation.
  3. Microphthalmia.
  4. Cleft palate and lip.
  5. Polydactyly.
  6. Cardiac defects.
  7. Umbilical hernia.
  8. Renal defects.
  9. Rocker-bottom feet.
 
Deletion Syndromes
 
Chromosome 22q 11.2 Syndrome
Due to small interstitial deletion of band 11 on the long arm of chromosome 22.
Clinical features:
  1. Facial dimorphism.
  2. Palatal abnormalities.
  3. Thymic hypoplasia and impaired CMI.
  4. Parathyroid hyperplasia and hypocalcemia.
  5. Heart defects.
 
Cri du Chat Syndrome
Due to partial deletion of short arm of chromosome 5.
 
SEX CHROMOSOMAL DISORDERS
Even a large variation in the sex chromosomal pattern is compatiable with life because:
  1. Lyonization of X chromosomes.
    1. All the X chromosomes except one are inactivated in the developmental period.
    2. Only a small amount of genetic information is carried by Y chromosomes.
 
Klinefelter Syndrome
  1. Best defined as male hypogonadism.
  2. Develops when there are at least two X chromosomes and one or more Y chromosomes.
  3. Most patients are 47 XXY.
  4. Results from non-disjunction of sex chromosome during meiosis.
  5. The extra X chromosome may be maternal or paternal.
  6. Advanced maternal age of irradiation may contribute to this anomaly.
    69
  7. This is the most common cause of hypogonadism in males.
  8. Mosaics have a less severity of the disease.
 
Clinical Features
  1. Increased length between soles and pubic bones.
  2. Decreased facial, body and pubic hair.
  3. Gynecomastia.
  4. Testicular atrophy and decrease in size.
  5. Decreased testosterone levels.
  6. Impaired spermatogenesis.
  7. Mild mental retardation.
  8. Increased predisposition to breast cancers, extragonadal germ cell tumors, autoimmune diseases like SLE.
 
Turner Syndrome
  1. Primary hypogonadism in phenotypic females.
  2. Results from partial or complete monosomy of short arm of X chromosome.
  3. Commonly 45-XO genotype.
  4. Mosaics are also seen and have a less severe course of the disease.
 
Clinical Features
  1. Growth retardation (short stature).
  2. High-arched palate.
  3. Low-posterior hairline.
  4. Webbed neck.
  5. Hypothyroidism.
  6. Cubitus valgus.
  7. Shield-like chest with widely spaced nipple.
  8. Bicuspid aortic valve.
  9. Coarctation of the aorta.
  10. Horseshoe kidney.
  11. Pigmented nevi all over the body.
  12. Subnormal secondary sexual characters:
    1. Genitalia remain infantile.
    2. Minimal breast development.
    3. Little pubic hair.
    4. Primary amenorrhea.
    5. Transformation of ovaries to white fibrous streaks.
    6. Ovaries are devoid of follicles.
 
RESPIRATORY DISTRESS SYNDROME OF THE NEWBORN
 
Etiology of Respiratory Distress
  1. Excessive sedation of the mother.
  2. Fetal head injury during delivery.
  3. Aspiration of blood or amniotic fluid.
  4. Intrauterine hypoxia.
  5. Respiratory distress syndrome (RDS) or hyaline membrane disease.
 
Pathogenesis
  1. Basically RDS is a disease of premature infants (Fig. 7.1).
  2. Other contributing factors are maternal diabetes, cesarian section before the onset of labor and twin gestation.
  3. Fundamental defect is the inability of type II pneumocytes of immature lung to produce surfactant.
  4. Function of surfactant is to coat the alveolar surface to reduce the surface tension and thus decrease the pressure required to keep alveoli open.
    70
  5. The surfactant production is stimulated by steroids. So RDS is less likely to develop in intrauterine fetal stress and IUGR.
 
Morphology
  1. Lungs are of normal size, but are heavy and airless.
  2. Have a mottled purple color.
  3. Collapsed alveoli (atelectasis).
  4. Necrotic cellular debris in alveoli (early phase).
  5. Eosinophilic hyaline membranes (late phase) in the respiratory bronchioles, alveolar ducts and alveoli.
  6. (N) infiltration also seen.
 
Clinical Features
  1. Respiratory distress.
  2. Retrolental fibroplasia or retinopathy of prematurity due to angiogenic factors like VEGF.
  3. Bronchopulmonary dysplasia (BPD) is a disease in mature alveoli and due to several cytokines.
  4. Increased risk for PDA, intraventricular hemorrhage and necrotizing enterocolitis.
 
CYSTIC FIBROSIS
  1. An AR condition.
  2. This is a disorder of epithelial transport affecting the fluid secretion in exocrine glands and the epithelial lining of the respiratory, GI and reproductive tracts.
  3. Most important manifestations are chronic pulmonary infections and pancreatic insufficiency.
  4. We can see a high level of NaCl in the sweat.
Fig. 7.1: Pathogenesis of respiratory distress syndrome
 
Pathogenesis
  1. The primary defect is abnormal functioning of an epithelial chloride channel protein encoded by CFTR gene.
  2. CFTR gene is located on chromosome 7q 31.2 and is get mutated in cystic fibrosis.
    71
 
In Sweat Gland
  1. Normally CFTR protein reabsorb chloride ions and augment reabsorption of Na ions from lumen to cells.
  2. In CF, the reabsorption of Na+ and Cl get reduced and hypertonic sweat is produced.
 
In Respiratory Tract and Pancreas
  1. Active luminal secretion of Cl ions reduced and luminal Na+ ions absorption increased.
  2. This leads to increased passive water reabsorption from lumen into epithelial cells.
  3. As a result, mucous become dehydrated and impairs the mucociliary clearance.
  4. This also leads to obstruction of air passages by viscid secretions and predispose to recurrent pulmonary infections.
  5. In pancreas, mucus obstructs the ducts.
 
Morphology
  1. Pancreas:
    1. Accumulation of mucus and dilatation of glands.
    2. Later the ducts become totally plugged and leads to atrophy and fibrosis.
    3. Impaired fat absorption and avitaminosis A leads to squamous metaplasia.
  2. Pulmonary:
    1. Obstruction of air passages.
    2. Hyperplasia and hypertrophy of mucous secreting cells.
    3. Bronchitis and bronchiectasis.
  3. Liver:
    1. Bile canaliculi are plugged with mucus.
    2. Ductular proliferation and portal inflammation.
    3. Hepatic steatosis in biopsy.
    4. Cirrhosis in late stages.
  4. Small intertine
    1. Small bowel obstruction and meconium ileus.
  5. Genital system:
    1. Azoospermia and infertility.
    2. Bilateral absence of vas deferens.
 
Clinical Features
  1. Malabsorption of protein, fat and fat-soluble vitamins.
  2. Persistent diarrhea.
  3. Chronic pancreatitis.
  4. C/c cough, lung infections, obstructive pulmonary diseases, cor pulmonale, liver disease, etc.
 
NEUROBLASTOMA
  1. Affecting the sympathetic ganglia and adrenal medulla, which are derived from the primordial neural crest cells.
  2. This is a malignant neoplasm, which is a second most common solid malignancy of childhood after brain tumors.
  3. Mainly sporadic, but familial also (AD).
  4. Demonstrate certain unique features in history including spontaneous regression and spontaneous maturation.
 
Morphology
Most commonly occcurs in adrenal medulla (40%), paravertebral sympathetic 72chain of abdomen (25%) and sympathetic chain in posterior mediastinum (15%).
 
Gross
  1. Size varies from minute nodules to large masses.
  2. Some are well-encapsulated and some others are extensively infiltrative.
  3. They are composed of soft, grey tan, brain-like tissue.
  4. Some large tumors show areas of necrosis, cystic softening and hemorrhage.
 
Microscopy
  1. Small, primitive appearing cells with dark nucleus and scanty cytoplasm.
  2. Cells are arranged as rosettes (Homer-Wright pseudorosettes) in which cells are seen concentrically around a central space filled with neurofibrillary material.
  3. Mitotic activity, karyorrhexis and pleomorphism are prominent.
  4. Neuron specific enolase can be demonstrated.
  5. Some neoplasms show signs of maturation, which are the larger cells with abundant cytoplasm and large vesicular nucleus with a prominent nucleolus.
  6. These large cells are called ganglion cells.
  7. In some tumors (ganglioneuroblastomas), these ganglion cells are seen admixed with primitive cells and in some others (ganglioneuroma), these large cells are seen alone.
  8. The maturation usually accompanied by the appearance of Schwann cells.
 
Clinical Features
  1. Protuberant abdomen with mass, fever and weight loss.
  2. Metastasis leads to hepatomegaly, ascites and bone pain.
  3. In infants, deep blue discoloration of skin due to metastasis (blueberry muffin baby).
 
Prognosis
Most important factors influencing prognosis are:
  1. Stage of tumor.
  2. Age of patient.
  3. Metastasis worsens the prognosis.
  4. Younger age group will have a good prognosis.
  5. Amplification of MYCN oncogene again worsens the prognosis.
  6. Expression of TrKA (a receptor for nerve growth factor) favors the prognosis.
  7. Over expression of telomerase worsens the prognosis.
 
RETINOBLASTOMA
  1. Most common malignant eye tumor of childhood.
  2. Usually develop as a congenital tumor.
  3. Usually undergo spontaneous regression.
  4. Familial cases are mostly multifocal and bilateral, where as sporadic cases are mostly unilateral and unifocal.
  5. Almost always results from RB-1 gene mutation.
    73
 
Morphology
  1. Usually in the posterior retina, from a cell of neuroepithelial origin.
  2. Composed of small round cells with hyperchromatic nuclei and scanty cytoplasm resembling undifferentiated retinoblasts.
  3. Characteristic true rosette (Flexner-Wintersteiner rosette) in which cells are arranged around a central lumen are seen.
 
Clinical Features
  1. Poor vision and strabismus.
  2. A whitish hue to pupil (cats eye reflex).
  3. Pain and tenderness in the eye.
  4. Increased risk for developing osteosarcoma.

Environmental and Nutritional DiseasesChapter 8

 
PROTEIN-ENERGY MALNUTRITION
Inadequate consumption of protein and energy as a result of primary dietary deficiency or conditioned deficiency that leads to loss of body mass (protein and adipose tissue).
 
Primary
  1. Occurs in children due to dietary deficiency or increased loss.
    1. Kwashiorkor (between 6 months and 3 years of age).
      • Protein deficiency with sufficient calorie intake
      • Can occur due to dietary deficiency of proteins or due to protein-losing enteropathies, severe nephrotic syndrome, etc.
      • Here, severe loss of protein from the visceral protein compartment and hence, reduced level of serum albumin (hypoalbuminemia)
      • This hypoalbuminemia leads to generalized and dependant edema
      • The muscle proteins and subcutaneous fat are relatively spared
      • Their minute loss is marked by edema
      • Flaky paint skin lesions → alternate bands of hyperpigmentation, desquamation and hypopigmentation
      • Flag sign → alternate bands of light and dark hair
      • Growth is retarded
      • Liver is fatty and enlarged (↑ LPs)
      • Small bowel shows mucosal atrophy and loss of villi, 7 microvilli
      • BM will be hypoplastic
      • Anemia is present (usually microcytic hypochromic)
      • Brain and lymphoid organs show atrophy
      • Deficiency of other vitamins and minimal muscle wasting
      • Decreased immunity and increased infections.
    2. Marasmus (< 1 year age)
      • Starvation in infants with overall lack of calories
        75
      • Muscle protein and adipose tissue are extensively reduced
      • Severe muscle wasting, emaciation and thinning of skin are present
      • Growth is retarded
      • Edema and hepatic involvement are absent
      • Reduction in serum protein level is minimal
      • Decreased immunity (T cell) and increased infections
      • Lipolysis is due to ↓ leptin and thus ↑ cortisol
      • Monkey-like face, abdominal protuberance and anemia are present
      • Hypoplastic BM, atrophy of brain and lymphoid organs.
 
Secondary
  1. Secondary to certain diseases.
  2. Commonly in advanced cancers.
  3. Severe form is called cachexia.
 
VITAMIN A DEFICIENCY
  1. Vitamin A is available in two forms:
    1. Retinol.
    2. Retinoid (precursor).
  2. Normal functions:
    1. Normal vision in dim light.
    2. Maintenance of structure and function of epithelium.
    3. Maintenance of cartilaginous and bone growth.
    4. Antioxidant action.
  3. Lesions in deficiency.
    1. Ocular.
      • Night blindness (1st sign)
      • Xerophthalmia (dry and scaly conjunctiva)
      • Corneal ulcers
      • Keratomalacia (infected corneal ulcers—keratinization)
      • Bitot spots (small opaque plaques on cornea)
      • Blindness.
    2. Cutaneous.
      • Xeroderma (due to hyperkeratosis papules).
    3. Epithelial.
      • Squamous metaplasia of:
        • Respiratory epithelium (↑ infections)
        • Pancreatic ductal epithelium (obstruction)
        • Urothelium (stones and pyelonephritis).
    4. Decreased bone and cartilaginous growth.
 
VITAMIN D DEFICIENCY
 
 
Rickets and Osteomalacia
Refer Chapter 21, Musculoskeletal System.
 
EFFECTS OF TOBACCO
  1. Carcinoma (CA) of oral cavity.
  2. Carcinoma of larynx.
    76
  3. Carcinoma of esophagus.
  4. Lung carcinoma.
  5. C/c bronchitis and emphysema.
  6. MI and systemic atherosclerosis.
  7. Peptic ulcer.
  8. Pancreatic carcinoma.
  9. Carcinoma of bladder.
 
Toxic Componentsof Tobacco Smoke
  1. Tar.
  2. Nicotine.
  3. Phenol.
  4. CO.
  5. Formaldehyde.
  6. N2 oxides.
  7. Nitrosamine.
  8. Benzopyrine.
 
EFFECTS OF ALCOHOL
  1. Fatty liver, hepatitis, cirrhosis, HCC.
  2. Portal HTN and systemic HTN.
  3. Metabolic acidosis.
  4. Gastric ulcers and C/c gastritis.
  5. Peripheral neuropathy and Wernicke-Korsakoff syndrome (↓ pyridoxine).
  6. A/c and C/c pancreatitis.
  7. Atherosclerosis and cardiomyopathy.
  8. Fetal alcoholic syndrome.
  9. CA of oral cavity, pharynx, larynx, esophagus, etc.
 
EFFECTS OF OBESITY
  1. Hyperlipidemia, HTN, DM.
  2. Atherosclerosis, CAD, stroke.
  3. Hyperventilation syndrome.
  4. Fatty liver and cholelithiasis.
  5. Osteoarthritis.

General Pathology of Infectious DiseasesChapter 9

 
MECHANISMS OF VIRAL INJURY
The predilection of virus to infect certain cells and not others (tissue tropism) is determined by:
  1. Host cell receptors for a particular virus, e.g. human immunodefeciency virus (HIV) gp120 binds to CD4 cells.
  2. Cell type specific transcription factors that recognize viral enhancer and promoter sequences, e.g. John cunningham (JC) virus active only in oligodendroglia due to presence of specific transcription factors in glial cells.
  3. Physical barriers, e.g. enterovirus replicate in intestine, because they can resist acidic pH, bile, enzymes, etc.
 
Mechanism
After entry into host cells, virus injure the cells by:
  1. Lysis of host cells. For example, influenza virus kills the respiratory epithelium, rabies virus kills the neurons.
  2. Immune cell-mediated killing—by stimulation of cytotoxic T cells. For example, HBV destroys hepatocytes.
  3. Alteration of apoptosis pathway. For example, apoptosis induced by gp 120 of HIV, apoptosis inhibited by Bcl-2 homologous.
  4. Introduction of cell proliferation and transformation—resulting in cancer. For example, EBV, HPV, HBV, HCV.
  5. Inhibition of host cell DNA, RNA or protein synthesis. For example, poliovirus inhibits translation of host's mRNA.
  6. Damage to plasma membranes. For example, HIV, measles virus, herpes virus.
  7. Damage to cells involved in antimicrobial defense. For example, influenza damages respiratory epithelium and leads to bacterial pneumonia, HIV damages CD4+ TH2 cells and leads to opportunistic infections.
 
MECHANISMS OF BACTERIAL INJURY
The bacterial injury on a cell depends on:
  1. Adherence to host cells—with the help of adhesins on bacterial surface. For example, fibrillae on Streptococcus 78pyogenes are composed of lipoteichoic acids and M-protein, which help in adherence as well as resistance against host immune response.
  2. Virulence is the ability of a bacteria to cause a disease and is depending upon:
    1. Entry into cells.
      For example, Mycobacterium tuberculosis enters into macrophages by inducing an alternate compliment pathway.
    2. Intracellular survival.
      For example, Escherichia coli and Shigella survive by inhibiting host protein synthesis.
      M. tuberculosis survives by blocking the phagosome formation.
  3. Bacterial endotoxins.
    1. This is a LPS, which forms a major component of outer cell wall of gram-negative bacteria.
    2. The LPS attaches to LPS binding protein and then the complex binds to CD14 on macrophages, (M), (N).
    3. CD14 causes signaling through tall-like receptor 4 (TLR-4) and leads to production of various cytokines.
    4. Effects of LPS (Refer Pathogenesis of Septic Shock).
  4. Bacterial exotoxins: These are secreted proteins.
    1. Directly acting
      For example, proteases of Staphylococcus aureus helps in cutaneous invasion, lecithinase of Clostridium perfringens disrupt plasma membrane.
    2. Altering the regulatory pathways. For example,
      • Diphtheria toxin: Inactivating protein synthesis by transferring ADP-ribose to EF-2
      • Cholera toxin: Generates excess of cAMP by transfer of ADP-ribose from NAD.
    3. Inhibiting the release of neurotransmitters. For example, C. tetani, C. botulinum.
    4. Stimulating T lymphocytes—results in a cytokine storm. For example, superantigens by S. aureus and S. pyogenes.
      • Superantigens bind with MHC-class I
      • Then binds with T-cell receptors
      • Thus activates T cells.
 
TUBERCULOSIS
Refer Chapter 13, Lungs.
 
LEPROSY (HANSEN DISEASE)
Leprosy is a chronic non-fatal granulomatous infectious diseases principally affecting the skin and nerves.
 
Causative Organism
By M. leprae.
 
Mode of Transmission
  1. Direct contact—commonest.
  2. Transplacental.
  3. Through breast milk.
 
Pathogenesis
  1. The main pathogenesis is by cell-mediated delayed hypersensitivity reaction (type IV).
    79
  2. The determinants of immune reaction are:
    1. Antigens of lepra bacilli.
      • Specific phenolic glycolipid (PGL-1) and lipoarabinomannan (LAMN) determine the host immune response
      • Trisaccharide Ag helps to invade nerves by binding with basal lamina of Schwann cells.
    2. Genotype of the host.
      • Major histocompatibility complex (MHC) class in host determines the immune response in different hosts.
    3. T cell response.
      • Activation of both CD4+ T cells and CD8+ T cells
      • CD4+ T cells elaborate promoter as well as cytotoxic functions
      • CD4+ TH1 and CD4+ TH2 cells produce different types of cytokines
      • In TT, the response is largely by CD4+ T cells and in LL, the response is mainly by CD4+ T cells.
    4. Humoral response.
      • Mainly in LL
      • High levels of IgG, IgM and IgA can be seen
      • But no protective role.
 
Classification
  1. Types.
    1. Lepromatous type (low resistance).
    2. Tuberculoid type (high resistance).
    3. Borderline type.
    4. Indeterminate type.
  2. Modified Ridley and Jopling classification.
    1. TT → tuberculoid polar.
    2. BT → borderline tuberculoid.
    3. BB → mid borderline.
    4. BL → borderline lepromatous.
    5. LL → lepromatous polar.
  3. Lepromin test is mainly used to classify the clinic-pathologic groups of leprosy.
 
Lepromin Test
  1. Intradermal injection of lepromin (an antigenic extract of M. leprae) reveals delayed HSN reaction in patients with TT.
  2. Fernandez reaction—early positive reaction (24–48 h).
  3. Mitsuda reaction—delayed reaction with granulomatous lesion (3–4 weeks).
  4. This shows that CMI is suppressed in LL and good CMI response in TT.
Difference between lepromatous leprosy and tuberculoid leprosy is given in Table 9.1.
 
Lepra Reaction
  1. Type I (reversal reaction).
    1. This is shown by patients with borderline leprosy.
    2. Upgrading reaction.
      • In BL type on treatment
      • Increase in CMI
      • Shows ↑ (L), edema and ↓ bacterial index (BI).
    3. Downgrading reaction.
  2. Type II (erythema nodosum leprosum—ENL).
    1. ENL occurs in lepromatous patients after treatment.
    2. Characterized by tender cutaneous nodules, fever, iridocyclitis, synovitis and LN involvement.
    3. Lesions show infiltration by (N) and (E) and vasculitis.
    4. Inflammation extends to subcutaneous fat.
    5. Bacillary load is increased.
    6. Repeated attacks of ENL can lead to 2° amyloidosis.
 
Histopathology
  1. Lepromatous leprosy.
    1. Foamy macrophages (lepra cells) in the dermis.
    2. Lepra bacilli are seen in lepra cells as globi or cigarettes in packappearance.
    3. The collection of lepra cells separated from the epidermis by a clear zone.
    4. The epidermis is thinned out and may ulcerate.
  2. Tuberculoid leprosy.
    1. Granulomas made of epitheloid cells, giant cells and (L) in the dermis.
    2. Lepra bacilli are few and seen in destroyed nerves.
    3. Dermal nerves are infiltrated by epitheloid cells and lymphocytes.
    4. Tubercles erode into epidermis and no clear zone.
  3. Borderline leprosy.
    1. BT form.
      • Epitheloid cells and numerous (L)
      • A narrow clear zone
      • Scanty bacilli in nerves.
    2. BL form.
      • Predominant histiocytes
      • A few epithelioid cells and (L)
      • Numerous lepra bacilli.
    3. BB form.
      • Epithelioid cells and some (L)
        81
      • No giant cells
      • Lepra bacilli present mainly in nerves.
    4. Indeterminate leprosy.
      • Features are non-specific
      • (L) infiltration particularly around hair follicles, sweat glands, blood vessels, etc.
      • Nerve involvement may be seen
      • Lepra bacilli can be demon-strated.
 
Clinical Types
  1. Multibacillary.
    1. More than five lesions.
    2. Lepromatous and borderlineleprosy.
  2. Paucibacillary.
    1. Less than or equal to five lesions.
    2. Tuberculoid and indeterminate leprosy.
 
SYPHILIS
Refer Chapter 18, Male Genital System.
82
Clinical Pathology
 
EXFOLIATIVE CYTOLOGY
  1. Exfoliative cytology is the branch of diagnostic medicine, which deals with the study of cells that shed off.
  2. The material is obtained by scraping, brushing or washing (lavage).
  3. The various sites commonly studied under this technique are:
    1. Uterine cervix.
      • Smear is taken by using bifid end of Ayre spatula
      • Smear is called Pap smear
      • To assess dysplasia and neoplasia.
    2. Vaginal mucosa.
      • Taken by using round end of Ayre spatula
      • This smear is also called Pap smear
      • To diagnose infections and neoplasia.
    3. Sputum.
      • Usually, early morning samples are taken in clean wide-mouthed bottles
      • Sputum expectoration increased by steam inhalation
      • Taken in suspected conditions of TB, Ca lung.
    4. Buccal mucosa.
      • By using glass slide, scrape the mucosa
      • For Barr body (sex chromatin) examination.
 
Fixation
  1. The commonly used fixatives are:
    1. Equal parts of ether and 95% alcohol.
    2. 95% ethanol.
    3. 85% isopropyl alcohol.
  2. Fixation time is usually 30 min.
  3. For long transport, we will use Carbowax spray.
  4. If there is a delay, use refrigerator.
  5. Some specimens are air dried and some others are wet fixed.
  6. For body fluids, we will use 10% formal or 50% ethanol. Then centrifuge and concentrate is used for smear preparation.
  7. Body fluids like urine, spinal fluid, etc. are coated with Mayer's egg albumin on slide.
    83
 
Staining
  1. For wet-dried specimens, we use Papanicolaou stain H and E stain.
  2. For air-dried specimens, we use Leishman and Giemsa stains.
  3. After staining mount on DPX.
 
FINE-NEEDLEASPIRATION CYTOLOGY
  1. Fine-needle aspiration cytology (FNAC) is one of the invasive techniques in diagnostic cytology.
  2. Commonly aspirated organs are thyroid, breast, soft tissue swellings and LNs.
 
Advantages
  1. One of the cheapest and easiest tools.
  2. Any superficial or deep structures (with image guidance) can be aspirated.
  3. This is an OP procedure and can be done without anesthesia.
  4. Quick, safe and less painful.
  5. Repeated aspirations are possible.
  6. Complications are rare.
 
Limitations
  1. Cannot depend completely for confirmation of diagnosis.
  2. Difficulty in reaching lesion.
  3. Absence of imaging facilities.
  4. Inadequate confidence of physician.
 
Equipments
  1. Disposable 20–25 G needle with 5– 10 mL syringe.
  2. 21 G needle gives better and adequate material.
  3. clean glass slides about 4–6.
  4. Spirit as skin disinfectant.
  5. Coplin jar with 85% isopropyl alcohol.
  6. Papanicolaou and Romanowsky stains.
 
Biopsy Procedure
  1. Clean the skin with spirit.
  2. Immobilize the area to be aspirated.
  3. Insert needle and take aspirate (if blood is present, discard the sample).
  4. Blow the aspirate on to the slide.
  5. Deep-seated lesions are aspirated with the help of USG or CT.
 
Fixation and Staining
  1. After transferring on to the slide, crush the thick portion.
  2. Then fix it rapidly by wet fixing or air drying.
  3. Air-dried specimens are stained by Leishmania-giemsa staining.
  4. Wet fixes are stained by Pap H and E stains.
  5. Morphologic details are seen better in wet-fixed Pap smears.
 
Complications
  1. Hematoma (thyroid, breast).
  2. Infection.
  3. Pneumothorax (lung).
  4. Dissemination of malignancy.
 
Contraindication
Coagulopathies like hemophilia.
84
 
HISTOPATHOLOGY
Histopathology is the study of tissues after a series of processes.
 
Fixation
  1. Most important step.
  2. Should be fixed as soon as the material is removed from the body.
  3. This process will prevent putrefaction and autolysis.
  4. Preserve the cell architecture by coagulating the proteins.
  5. Routinely, we use 10% formalin for 12–24 hours.
  6. The best thickness is 3–5 mm.
  7. For complete fixation, we inject formol saline in addition to the immersion.
  8. Other fixatives are:
    1. Bouin fluid (BM and testicular biopsy, skin, gastric).
    2. Helly fluid (hematopoietic tissue).
    3. Formol HNO3, Gooding and Stewart fluid (bone).
    4. Formol saline, Zenker fluid, etc.
 
Paraffin Embedding
  1. Before the proper procedure, do the fixation.
  2. Then dehydration by serial passage through 70%, 90% and absolute alcohol for 2–4 hours or 12–24 hours.
  3. Then clearing with xylol for half an hour to 1 hour or 2–4 hours.
  4. After that do impregnation with paraffin for 2–3 hours at 58°C–60°C in two changes.
  5. Then casting or blocking in molten wax and cool.
  6. At last, do section cutting in microtome and then place in warm water at 45°C.
  7. Then coating the section with egg albumin and glycerine and kept for overnight incubation.
 
Staining
The steps for staining are:
  1. Deparaffinization with xylol and hydrate with descending grades of alcohol.
  2. Then wash in running water.
  3. Staining with H and E stain.
  4. Bluing in ammonia water—pink color changes to blue.
  5. Counterstaining with 1% aqueous eosin.
  6. Differentiation by treating with acid alcohol.
  7. Dehydration and clearing with ascending grades of alcohol and xylol.
  8. Mounting in Canada balsam or DPX.
 
Frozen Section Technique
  1. Cryostat or a freezing microtome is used.
  2. This is used for rapid preparation of special tissue parts.
  3. Used for the demonstration of fats and lipids.
  4. Fixation is done in 10% formol saline at 60°C for 10–20 minutes.
  5. Then put in gum syrup and then cut by freezing microtome (CO2 cooling system type).
  6. Staining.
    85
 
URINE EXAMINATION
 
Physical Examination
  1. Color:
    1. Straw colored normally (due to urochrome).
    2. Colorless in polyuria.
    3. Dark brown in oliguria.
  2. Transparency:
    1. Normally clear.
    2. Turbid if pus, blood or bacteria.
  3. Odor:
    1. No smell or aromatic smell normally.
    2. Ammoniacal smell—decomposed urine.
    3. Acetone smell—ketonuria.
  4. pH reaction:
    1. Normally litmus blue to red (pH around 6).
    2. Alkaline pH—vegetarian diet, citrate, bicarbonates.
    3. Highly acidic—high-protein diet, ketonuria.
  5. Specific gravity:
    1. Normal is around 1.025.
    2. Temperature variation is ± 0.001 for every 3°C.
 
Urine Dipstick Test
 
For Nitrite
  1. Significance.
    1. Gram-negative bacteriuria.
    2. Dependant on the conversion of dietary nitrate to nitrite by gram-negative bacteria.
  2. Limitations.
    1. Interference: Bacterial overgrowth.
    2. Only able to detect bacteria that reduce nitrate to nitrite.
  3. Other tests.
    1. Correlate with leukocyte esterase.
    2. Urine microscopic examination (bacteria).
    3. Urine culture.
  4. Inference.
    1. Negative or positive.
 
For Leukocyte Esterase
  1. Significance.
    1. Pyuria.
    2. Acute inflammation.
    3. Renal calculus.
  2. Limitations.
    1. Interference: Oxidizing agents, menstrual contamination.
  3. Other tests.
    1. Urine microscopic examination (WBCs and bacteria).
    2. Urine culture.
  4. Inference.
    1. Negative/trace/mild positive/moderate positive/strong positive.
 
Chemical Examination
 
Proteinuria
  1. Seen in CCF, cystitis, prostatitis, nephrotic syndrome, etc.
  2. Laboratory tests are based on precipitation of protein by chemical agents or coagulation by heat.
  3. The commonly used tests are:
    1. Heat and acetic acid test.
      • Precipitate increases on adding acetic acid in proteinuria
      • Precipitate disappear on adding acetic acid in phosphaturia.
        86
    2. Sulphosalicylic acid test.
    3. Esbach test—quantitative test.
  1. In multiple myeloma—Bence-Jones proteinuria.
    1. These are light chain of Ig precipitated at 50°C–60°C.
 
Glycosuria
  1. Seen in diabetes mellitus.
  2. Based on reduction of CuSO4 to yellow or red cuprous oxide.
  3. The main test is Benedict test (semiquantitative).
    1. False positive in alkaptonuria, urine with uric acid and creatinine.
 
Ketonuria
  1. Seen in diabetes mellitus.
  2. The ketone bodies are acetoacetic acid, acetone and β-hydroxybutyric acid.
  3. The main test is Rothera test will get a purple ring in ketonuria.
 
Bilirubinuria
  1. In hepatocellular and obstructive jaundice.
  2. The tests are:
    1. Fouchet test.
      • Green color for biliverdin
      • Blue color for bilicyanin.
    2. Ehrlich test:
      • For urobilinogen—pink color from top, if positive.
 
Bile Salt
  1. In obstructive jaundice.
  2. The test is Hay's sulfur test.
  3. The sulfur powder sinks, if positive.
 
Hematuria
  1. The test is benzidine test.
  2. It will give a blue color in hematuria.
  3. False positive results by myoglobin, iron and peroxidase.
 
Microscopic Examination
  1. Done in proteinuria, suspected UTI, etc.
  2. Fresh morning sample of urine is examined within 6 hours of voiding.
  3. The urine sample is centrifuged for 3,000 rpm for 5 minutes and sediment is obtained.
  4. Place a drop of sediment on a glass slide and cover it with a coverslip.
  5. First look under low power and then in high power.
  6. At least look 10 high power fields.
  7. Examination without staining is enough, but if needed, we can do staining also.
 
Organized Sediments
Organized sediments include various cells and urinary casts.
Cells
  1. Red blood cells: Appear as pale discs and may show crenated margins.
  2. Pus cells: These are neutrophils, which appear as round, granular spheres larger than RBCs.
  3. Epithelial cells: Have a single round nucleus.
    1. Renal tubular epithelial cells.
    2. Bladder epithelial cells.
    3. Squamous epithelial cells.
  4. Bacteria: Usually seen better in gram-stained smear.
    87
  5. Fungus: Yeast cells can be seen in UTI in DM.
  6. Parasites: Like Schistosoma, Trichomonas, etc.
  7. Spermatozoa and foreign bodies.
Urinary casts: These are formed by coagulation of albuminous material and cells in renal tubules (Fig. 1).
  1. Hyaline casts.
    1. Colorless, homogenous and transparent.
    2. Most common and seen in many renal diseases, diabetic retinopathy and CCF.
  2. Granular casts.
    1. Fine and coarse granular casts.
    2. Seen in chronic GN, nephrotic syndrome, pyelonephritis, lead toxicity, etc.
  3. Fatty casts.
    1. Contain highly refractile globules.
    2. Have epithelial cells and fat.
  4. Waxy casts.
    1. Yellow and homogenous with irregular margins seen in tubular degeneration, renal failure or transplant rejection.
  5. Tubular epithelial casts.
    1. Two rows of cells in a narrow cast.
    2. Seen in acute GN, tubular necrosis, CMV infection and transplant rejection.
  6. RBC casts.
    1. Yellow to orange.
    2. Seen as bundle of coins.
    3. Adherent to hyaline or granular casts.
    4. Seen in acute GN, SABE, renal infarction and lupus nephritis.
  7. WBC casts
    1. Small granular casts in a clear matrix.
    2. Admixed with RBCs and epithelial cells.
    3. These are also adherent to hyaline or granular casts.
    4. Seen in acute GN, acute pyelonephritis and lupus nephritis.
 
Unorganized Sediments
  1. Unorganized sediments have little diagnostic and prognostic value.
  2. May be crystalline or amorphous (Fig. 2).
Fig. 1: Different types of urinary casts
88
Fig. 2: Different unorganized sediments
In normal acidic urine:
  1. Sodium and potassium urates: Amorphous yellow-red granules.
  2. Uric acid crystals: Yellow or red brown and irregular.
  3. Calcium oxalate crystals: Refractile and octahedral.
In normal alkaline urine:
  1. Amorphous phosphate: Fine precipitate.
  2. Triple phosphate: Ammonium magnesium phosphate.
  3. Calcium phosphate: Stellate prisms.
  4. Calcium carbonate: Colorless spheres or dumbbells.
  5. Ammonium biurate: Yellow brown spheres like thornapple.
In abnormal urine:
  1. Cysteine: Colorless and refractile.
  2. Tyrosine: Yellow fine needles.
  3. Leucine: Yellow oily spheres.
  4. Sulfonamide: Yellow brown and asymmetrical.
  5. Cholesterol: Flat, notched plates.
 
PACKED CELL VOLUME
  1. Also called hematocrit.
  2. This is the volume of red cells expressed as a percentage of the volume of the whole blood in the sample.
  3. Dried heparin, EDTA or double oxalate are satisfactory anticoagulants.
  4. Double oxalate mixture containing ammonium and potassium oxalates in the ratio 3:2 is commonly used. This mixture does not alter the cell morphology, because ammonium oxalate causes swelling and potassium oxalate causes shrinkage of RBCs.
  5. The common methods employed are:
    1. Wintrobe tube.
      • Fill up to 10 mark by using a Pasteur pipette without any air bubbles
      • Then centrifuge for 30 minute at 3,000 rpm
      • Measure the length of RBC column and expressed as percentage
      • Errors are due to inadequate mixing and incomplete packing.
        89
    2. Microhematocrit.
      • By using capillary tubes coated with heparin
      • Take capillary blood and centrifuge at high rates for 3 min.
 
Values
  1. Normal.
    1. Men: 42%–52% (47%).
    2. Women: 37%–47% (42%).
  2. Abnormal values.
    1. High PCV.
      • Newborns, high altitude, exercise (physiological)
      • Dehydration, polycythemia, burns (pathological).
    2. Low PCV—pregnancy (physiological).
      • Anemias (pathological).
 
Plasma Column
  1. Normally straw colored.
  2. Yellow color—jaundice.
  3. Pink or reddish—hemolysis.
  4. Creamy white—hyperlipidemia.
  5. Brown—methemoglolbinemia.
 
Buffy Coat
  1. Buffy coat is the thin middle zone between RBC column and plasma column.
  2. Normal thickness is about 0.5–1 mm.
  3. Used for estimation of WBC and platelets.
  4. Increased thickness—leukocytosis and thrombocytosis.
  5. Decreased thickness—leukopenia and thrombocytopenia.
 
ERYTHROCYTE SEDIMENTATION RATE
  1. Erythrocyte sedimentation rate (ESR) is the rate at which RBCs sediment on their own weight, when anticoagulated blood is held in vertical column.
  2. It is expressed as the fall of RBCs in mm at the end of 1 hour.
  3. The whole process occurs in three stages.
    1. Stage 1 of aggregation (rouleaux formation)—first 10 minutes.
    2. Stage 2 of elimination (falling of cells)—next 40 minutes.
    3. Stage 3 of packing—last 10 minutes.
  4. ESR is measured as the length of the plasma column above the red cell column at the end of 1 hour.
  5. ESR is mainly determined by rouleaux formation; which inturn is influenced by fibrinogen (main), globulin, albumin and lipid content of plasma.
 
Method
 
Westergren Method
  1. Tube is 30 cm long and 2.5 mm bore diameter. Both ends are open.
  2. Lower 20 cm is marked from 0 to 200 and will have 2 mL blood.
  3. The anticoagulant used is 0.4 mL 3.8% sodium citrate for 1–6 mL of venous blood.
  4. Fill upto zero mark and keep it vertical.
  5. Take reading at the end of 1 hour.
  6. Normal value:
    1. Male: 1–5 mm at the end of 1 hour.
    2. Female: 1–7 mm at the end of 1 hour.
      90
 
Wintrobe Method
  1. Wintrobe method is 11 cm long with 2.5 mm bore diameter.
  2. Fill anticoagulated blood (with double oxalate mixture) up to zero mark and keep it undisturbed for 1 hour.
  3. Normal value:
    1. Male: 1–9 mm at the end of 1 hour.
    2. Female: 1–20 mm at the end of 1 hour.
 
Esrite Method
  1. This ESR pipette has a volume of 1.25 mL with 0.25 mL sodium citrate and 1 mL blood.
  2. The pipette is not graduated, but an aluminium sheet with marking is kept as background.
  3. This is better because easy to use, elimination of risk of infection, more accurate and highly convenient.
  4. Normal values same as Westergren method.
 
Sources of Error
  1. Improper anticoagulant.
  2. Inclination of tube.
  3. Dirty tube.
  4. Air bubble.
  5. Prolonged blood storage.
 
Factors Influencing Erythrocyte Sedimentation Rate
  1. Plasma factors:
    1. Fibrinogen and globulin (increase ESR).
    2. Plasma lipid content (decrease ESR).
    3. Albumin (decrease ESR).
  2. Red cell factors:
    1. Anemia (decrease ESR).
    2. Shape and size of RBC's.
  3. Anticoagulants:
    1. Oxalates and heparin may affect.
  4. Products of tissue destruction and inflammation.
 
Variations in Erythrocyte Sedimentation Rate
  1. Rapid ESR.
    1. Pregnancy, menstruation (physiological).
    2. Anemia (except sickle cell), infection (pathological).
    3. Septicemia, RF, RA less than TB, MI, shock, etc.
  2. Slow ESR.
    1. Newborn (physiological).
    2. Sickle cell anemia, polycythemia, allergy, CCF (pathological).
91Systemic Pathology
92

Blood VesselsChapter 10

 
RESPONSE TO INJURY
 
Functions of Endothelial Cells
  1. Maintenance of permeability.
  2. Elaboration of anticoagulants, antithrombotic and fibrinolytic regulators.
    1. Thrombomodulin, PGI2, TPA.
    2. Heparin-like molecules.
  3. Elaboration of prothrombotic molecules.
    1. Tissue factor, VWF, TPA inhibitor.
  4. Production of ECM.
  5. Modulation BF and reactivity.
    1. Vasoconstrictors—endothelins, ACE.
    2. Vasodilators—NO, PGI2.
  6. Regulation of inflammation and immunity.
    1. Chemokines, IL-1, IL-6.
    2. Selectins, VCAM-1, ICAM.
    3. Histocompatibility Ag.
  7. Regulation of cell growth.
    1. Stimulators—PDGF, FGF.
    2. Inhibitors—heparin, TGF-β.
  8. Oxidation of LDL.
 
Responses
  1. Thrombosis, atherosclerosis, hypertensive vascular disorders.
  2. Release of several molecules.
  3. Vasodilatation, hypercoagulable states, leukocyte adhesion.
  4. Stimulation of smooth muscle cell proliferation.
    1. Increased ECM collagen, elastin, etc.
    2. Proteoglycans, GFs, cytokines.
  5. Intimal thickening.
 
Intimal Thickening (Stereotyped)
  1. Vascular injury → EC loss and EC dysfunction → SMC proliferation and matrix production.
  2. Injury → SMCs or their precursors move into intima → proliferate → increase ECM production.
    1. The various stimuli are infection, inflammation, immuneinjury, physical trauma, toxic exposure, etc.
    2. Neointimal SMCs → cannot contract. Capacity to divide. Organelles for protein synthesis—more.
    3. Repeat injury → lumen narrowing as in atherosclerosis.
 
ATHEROSCLEROSIS
  1. Presence of intimal lesions—atheromas/atheromatous plaques/atherosclerotic plaques.
    94
  2. Protrude into vascular lumen.
  3. Atheroma—raised, soft and yellow with lipid core. It is made up of four layers.
    • Lipid core (IC/EC)
    • Cell debris
    • Macrophages, SMCs, foam cells, lymphocytes, etc.
    • Outer fibrous cap—collagen, proteoglycans, elastin, etc (Fig. 10.1).
 
Risk Factors
  1. Major.
    1. Non-modifiable.
      • Increased age
      • Male
      • Genetic abnormalities
      • Postmenopausal and family history.
    2. Modifiable.
      • Hyperlipidemia (hypercholestrolemia)
      • Hypertension (HTN)
      • Cigarette smoking
      • Diabetes mellitus (DM)
      • C-reactive proteins
      • Increased inflammation.
  2. Minor.
    1. Homocyteinemia.
      • Increased LP-a
      • Thrombotic factors
      • Obesity
      • Physical inactivity and stress
      • Chlamydia pneumonia infection
      • Increased CHO diet and increased saturated fat in body.
Fig. 10.1: Steps in atherosclerosis
 
Pathogenesis
  1. Chronic (C/c) endotheFlial injury due to:
    1. Hyperlipidemia.
    2. HTN.
    3. Smoking.
    4. Hemodynamic factors.
    5. Infections, immune response and toxins.
      95
  2. Endothelial dysfunction.
    1. Increased permeability and accumulation of LPs.
    2. Leukocyte adhesion.
    3. Monocyte adhesion.
  3. Macrophage activation, foam cell formation and platelet adhesion.
  4. Release of factors and SMC recruitment.
  5. Smooth muscle cells engulf lipids and also foam cells.
  6. Smooth muscle cell proliferation and ECM production, collagen and EC lipid deposition.
    1. Early stages → plaques are aggregates of SMCs, foam cells, macrophages and EC lipids.
    2. Late stages → more connective tissue (collagen and proteoglycans). Calcification also.
 
Morphology
  1. Fatty streaks.
    1. Composed of lipid filled foam cells.
    2. Not much raised.
    3. Multiple minute yellow flat spots can coalesce.
    4. Acts as precursors for atheroma.
  2. Atheromas (fibro-fatty plaques).
    1. Abdominal aorta is more involved.
    2. Preference of involvement.
      • Lower abdominal aorta > coronaries > popliteal artery (A) > ICA > circle of Willis.
    3. At the periphery—neurovascularization.
    4. Can undergo calcification and necrosis.
    5. Rupture, ulceration or erosion can occur.
    6. Hemorrhage and thrombosis.
    7. Can produce atheroembolism and occlusion.
    8. Can leads to aneurysm and fissuring.
 
Consequences
Myocardial infarction (MI), cerebral strokes, aortic aneurysm, PVDs.
 
Prevention
  1. Primary.
    1. Delaying atheroma formation.
    2. Regressing established lesions.
    3. Risk factor identification and elimination.
  2. Secondary.
    1. Prevention of recurrent consequences.
    2. Use of aspirin (antiplatelets).
    3. Statins (hypocholesterolemic).
    4. Beta blockers (anti-HTN).
    5. Surgeries (bypass).
 
HYPERTENSION
 
Causes
  1. Essential HTN (90%–95%)—idiopathic.
  2. Secondary HTN.
    1. Renal—A/c GN, C/c renal disease, polycystic kidney, renal A stenosis and renin producing tumors.
    2. Endocrine—adrenal hyperfunction (Cushing syndrome and 1° aldosteronism), exogenous hormones (glucocorticoids, OCPs), pheochromocytoma, acromegaly, myxedema and thyrotoxicosis.
      96
    3. Cardiovascular—coarctation of aorta, PAN, increased IVFV and increased CO.
    4. Neurological—psychogenic, increased ICT and A/c stress.
 
Pathogenesis
  1. Reduced renal Na+ excretion → increased BV → increased CO → increased BP.
  2. Vasoconstriction → increased peripheral resistance (PR) → increased BP.
  3. Defects in vascular SM growth → increased vessel thickness → increased PR → increased BP.
 
Regulation of Blood Pressure
Mechanism Regulation of BP is given in Fig. 10.2.
 
Morphology
  1. Hyaline arteriosclerosis.
    1. Pink, homogenous, hyaline thickening.
    2. Loss of underlying structure.
    3. Narrowing of lumen.
    4. More generalized.
    5. Due to leakage of plasma components and increased ECM.
    6. In benign HTN.
  2. Hyperplastic arteriosclerosis.
    1. In malignant HTN DBP > 120 mm Hg with cerebral or renal injury).
    2. Onion skin like concentric laminated thickening.
    3. Narrowing of lumen.
      Fig. 10.2: Mechanism of regulation of BP
      97
    4. Increased SCMs and duplicated basement membrane (BM).
    5. Fibrinoid deposits and wall necrosis (necrotizing arteriolitis)—prominent in kidney.
 
ANEURISMS
  1. Localized abnormal dilatation of blood vessel or heart.
  2. True → involves all the layers. For example, atherosclerotic, syphylitic, congenital and ventricular that follow MI.
  3. False → breach in vessel wall leads extravascular hematoma, which communicates with IV space pulsating hematoma. For example, ventricular rupture after MI and leak at the junction of vascular graft.
 
Classification
  1. Saccular—spherical outpouchings involves small portion and contain thrombi.
  2. Fusiform—diffuse circumferential dilatation, involves long vascular segment.
 
Etiology
  1. Atherosclerosis.
  2. Cystic degeneration of tunica media.
  3. Trauma.
  4. Congenital defects (Berry aneurysm).
  5. Infections (mycotic and syphilitic).
  6. Mycotic infection through,
    1. Embolization of septic thrombi. Extension of adjacent suppuration. Circulating pathogens.
 
Aortic Aneurysm
  1. Causes are atherosclerosis and tunica media degeneration.
  2. Commonly abdominal aorta is invoved.
 
Pathogenesis
Thoracic AA produces—encroachment of mediastinum, respiratory difficulty, dysphagia, persistent cough (laryngeal nerve), pain due to bone erosion, cardiac problems and aortic rupture. Pathogenesis of atherosclerosis in given in Fig. 10.3.
 
Morphology
  1. Usual position is below renal artery and above aortic bifurcation.
  2. Inflammatory AA—dense periaortic fibrosis, abundant L, plasmacytes and macrophages, giant cells also.
  3. Mycotic AA—Bacteria primarily from Salmonella gastroenteritis, suppuration and destruction of media.
 
Clinical Consequences
  1. Rupture into peritoneal cavity and retroperitoneum and leads to fatal hemorrhage.
  2. Obstruction of a branch and causes ischemic tissue injury.
    1. Iliac artery—leg.
    2. Renal artery—kidney.
    3. Mesenteric artery—GIT.
    4. Vertebral artery—spinal cord.
  3. Embolism from atheroma or mural thrombus.
  4. Compression on adjacent structures.
    98
    Fig. 10.3: Pathogensis of aortic aneurism
  5. Abdominal mass, which can stimulate a tumor.
 
Syphilitic Aneurysm
  1. In 3° syphilis—obliterative endarteritis of vasa vasorum.
  2. Ischemic injury of tunica media—leads to AA.
 
Morphology
  1. Obliteration and lumen narrowing.
  2. Scarring of wall.
  3. Inflammatory infiltrate of (L) and plasma cells, which extending to media—syphilitic endarteritis.
  4. Patchy loss of medial fibers and muscle cells.
  5. Wrinkling of aortic intima—tree bark appearance
  6. Leads to valvular insufficiency and volume overload and hypertrophy of left ventricle
  7. This dilated heart is called cor bovinum (cow heart).
 
DISSECTION
  1. Often aneurysmal and can rupture.
  2. Tearing of wall and extravasation of blood into wall.
 
Aortic Dissection
  1. Blood filled channel within the aortic wall.
  2. Can rupture through adventitia.
  3. Can cause massive hemorrhage or cardiac tamponade.
  4. Commonly in males (40–60) with severe HTN and younger patients with connective tissue disorders (Marfan).
 
Morphology
  1. Intimal tear usually in ascending aorta with sharp edges.
  2. Tear progress towards heart or distally.
  3. Hematoma usually spreads along laminar plane (B/n middle and outer thirds).
  4. Sometimes hematoma into the lumen double-barreled aorta.
    99
    Fig. 10.4: Pathogensis of aortic dissection
  5. Cystic medial degeneration without inflammation.
 
Pathogenesis
Pathogensis of aortic dissection is given as Fig. 10.4.
 
Classification
  1. Type A—common and dangerous (DeBakey—I and II).
    1. Ascending only or both ascending and descending.
  2. Type B—Not involving ascending (DeBakey III) (Fig. 10.5).
Fig. 10.5: Classification of aortic dissection
 
Clinical Course
  1. Sudden excruciating pain.
  2. Begin in anterior chest and radiates to back.
  3. Cause of death—hemorrhage into pericardial/pleural/peritoneal cavities.
  4. Retrograde progression leads to cardiac tamponade, aortic insufficiency and MI.
  5. Involvement of other arteries also.
 
VASCULITIS
Inflammation of blood vessel walls.
 
Infectious Vasculitis
  1. By Aspergillus, Mucor, bacterial pneumonia.
  2. Syphilitic endarteritis.
  3. Mycotic arteries and aneurysm.
 
Non-infectious Vasculitis
  1. Immune-complex associated (Both local and circulating complex).
    1. In SLE (DNA –anti-DNA complex).
    2. Associated with drug hypersensitivity (e.g. penicillin).
      100
    3. Associated secondarily with viral infections (e.g. Hep.B).
  2. Anti-neutrophil cytoplasmic Ab (ANCAs).
    1. Cytoplasmic localization.
      • Target Ag is proteinase 3 (PRs)
      • Wegener granulomatosis.
    2. Perinuclear localization
      • Target is myeloperoxidase (MPO)
      • Microscopic polyangitis.
    3. Circulating Ab might not be present.
  3. Anti-endothelial cell Ab (AECAs).
    1. Kawasaki disease.
 
Types of Non-infectious Vasculitis
  1. Large vessel vasculitis.
  2. Medium vessel vasculitis.
  3. Small vessel vasculitis.
Large vessel vasculitis—giant cell arteritis.
  1. C/c granulomatous inflammation (Not affect < 50 age).
  2. Affect mainly the cranial vessels, especially temporal.
  3. Also affect vertibral, ophthalmic and aorta.
Pathogenesis
  1. T cell-mediated.
  2. Immune response against a vessel wall Ag.
  3. Associated with helper T cells and MHC.
  4. Responds to steroids (Fig. 10.6).
Morphology
  1. Nodular intimal thickening with thrombosis.
  2. Granulomatous inflammation in inner media.
  3. Fragmentation of internal elastic lamina.
  4. Heal by collagenous thickening and become fibrous cord.
Clinical features
  1. Fever, fatigue, weight loss.
  2. Facial pain or head ache, along with polymyalgia rheumatica.
  3. Tender temporal artery.
  4. Diplopia and loss of vision.
Treatment
Corticosteroids.
Medium vessel vasculitis—PAN.
  1. Systemic vasculitis (Younger age group).
  2. Typically involves renal and visceral arteries.
  3. Not involving pulmonary circulation.
Pathogenesis
  1. Immune transmural necrotizing inflammation.
    Fig. 10.6: Pathogenesis of non-infections vasculitis
    101
  2. Only one part of vessel circumference involved.
  3. Aneurysmal dilatation.
  4. Ulceration, infarct, ischemia and hemorrhage of those areas supplied by affected vessels.
  5. Fibrinoid necrosis + (N), (E), (M), etc.
  6. Later fibrosis.
Clinical features
  1. Fever, malaise, weight loss, HTN.
  2. Abdominal pain, melena, neurotic pain.
Treatment
Cyclophosphamide and corticosteroids.
Small vessel vasculitis—Wegener granulomatosis.
  1. Necrotizing vasculitis.
  2. Triad of:
    1. A/c necrotizing granulomas of RT.
    2. Necrotizing/granulomatous vasculitis of RT.
    3. Necrotizing vasculitis of renal A and GN.
Pathogenesis
C-ANCAs associated.
Morphology
  1. Inflammatory sinusitis with granulomas.
  2. Ulcerative lesions of nose, palate, pharynx rimmed by granulomas with central necrosis.
  3. Parenchymal granuloma and alveolar hemorrhage.
  4. Segmental necrotizing GN and cresentic GN.
Clinical features
  1. Males—more affected, age around 40.
  2. Persistent pneumonitis, C/c sinusitis and ulcerations.
  3. Renal disease.
  4. Fever, rashes, muscle and joint pain, neuritic pain.
 
TUMORS
 
Hemangioma
  1. Increased number of normal or abnormal vessels with blood.
  2. Most are present from birth.
  3. Most are localized and superficial.
  4. Extensive angiomatosis.
 
Capillary Hemangioma
  1. In skin, s/c tissue, mucos membrane of oral cavities, lips, liver, spleen and kidneys.
  2. Very common at birth and usually regress by age 7.
  3. Strawberry type/juvenile hemangioma.
Morphology
  1. Bright red to blue, raised with intact epithelium.
  2. Aggregates of thin walled capillaries.
  3. Blood filled and lined by flat EC.
  4. Stroma is only scanty.
  5. Focal scarring and hemosiderin pigment due to rupture.
  6. Pyogenic granuloma—a form of capillary HA, which occur usually after trauma and with edema and inflammation.
 
Cavernous Hemangioma
  1. Large dialated vascular channels.
  2. Less circumscribed and deeper than capillary HA.
    102
Morphology
  1. Red-blue, soft spongy masses.
  2. Large blood filled cavernous spaces.
  3. Moderate amount of stroma.
  4. Thrombosis and dystrophic calcification.
  5. Vulnerable to traumatic ulceration and bleeding.
  6. Component of Von-Hippel-Lindau disease (neoplasm of pancreas, liver and kidney).
 
KAPOSI SARCOMA
  1. Boderline or low grade malignant tumors.
  2. Common in AIDS patients.
 
Types of Kaposi Sarcoma
 
Chronic Kaposi sarcoma (KS) (Classic KS)
  1. Associated with underlying malignancy/altered immunity.
  2. Multiple red to purple plaques or nodules.
  3. In distal lower extremities and gradually progress.
 
Lymphadenopathic KS (Endemic KS)
  1. Skin and lymph node (LN) involvement.
  2. Sometimes viscera also.
  3. Aggressive.
 
Transplant-associated KS
  1. Due to associate immunosuppressive therapy.
  2. Mucosal, nodal and visceral involvement.
 
AIDS-associated KS (Epidemic KS)
  1. Particularly male homosexuals with HIV.
  2. Involves nodes and viscera.
  3. Wide spread.
 
RAYNAUD PHENOMENON
  1. Increased vasoconstriction of digital arteries and arterioles.
  2. Digits, toes, nose, ear lobes and lips are involved.
  3. Show red, white and blue from proximal to distal.
  4. Due to vasodilatation, constriction and cyanosis respectively.
  5. Primary.
    1. Increased vasomotor response (central/local).
    2. Cold or emotion.
  6. Secondary.
    1. Vascular insufficiency.
    2. Due to SLE, Buerger disease and atherosclerosis.

HeartChapter 11

 
HEART FAILURE
  1. Heart failure (HF) also called congestive heart failure (CHF).
  2. Commonly due to systolic dysfunction (contractility). It can also be due to diastolic dysfunction.
  3. Causes are IHD, HTN, DM, valve failure, overload, etc.
  4. Cannot pump blood to meet the needs of body.
  5. Heart cannot pump the blood that delivered to it by venous circulation → forward failure and is accompanied by venous congestion → backward failure.
  6. Increased LVEDV → increased LVEDP → increased (VP).
 
Pathogenesis
 
Pathways
  1. Activation of neurohormonal systems.
    1. Increased release of NA.
    2. Increased RAAS working.
    3. Increased ANF.
  2. Frank-Starling mechanism.
    1. Early → increased fiber length → increased force → increased CO → compensated HF.
    2. Late → increased O2 demand → myocardial failure → decompensated HF.
  3. Myocardial structural changes like hypertrophy.
    1. Concentric.
      • In pressure overload (HTN, stenosis)
      • Increased diameter of muscle fibers
      • Increase in wall thickness without chamber size.
    2. Eccentric.
      • In volume overload (regurgitation, shunts)
      • Increased length
      • Increased wall thickness and chamber size.
    3. Increased O2 demand and tension.
    4. Myocardium becomes vulnerable to ischemic injury.
 
Left-sided Heart Failure
Left-sided heart failure is due to damming of blood in pulmonary circulation.
 
Causes
  1. Ischemic heart disease.
  2. Hypertension.
    104
  3. Mitral or aortic valve disease.
  4. Primary (1°) disease of myocardium.
 
Morphology
  1. Myocardial infraction and valvular deformities.
  2. Usually LV is dilated and hypertrophied.
  3. Hypertrophy and fibrosis of myocardium.
  4. Secondary (2°) enlargement of LA and AF → thrombosis.
  5. Increased pressure in pulmonary veins → pulmonary congestion and edema.
  6. Lungs are heavy and boggy with transudate, alveolar septal edema and alveolar edema.
  7. Hemosiderin-laden macrophages in alveoli (heart failure cells).
 
Clinical Features
  1. Dyspnea, cough, orthopnea, PND, tachycardia.
  2. Systolic murmer, MR, S3, AF, cardiomegaly.
 
Right-sided Heart Failure
Right-sided heart failure (RSHF) alone is very rare.
 
Causes
  1. Left ventricular failure—increased pressure in pulmonary circulation.
  2. Tricuspid valve disease, left (L) to right (R) shunt (chronic pressure and volume overload).
  3. Intrinsic lung parenchymal disease (cor pulmonale).
 
Morphology
  1. Congestive hepatomegaly with nutmeg appearance.
  2. Congested red centers of liver lobules surrounded by pallor.
  3. With LVF—centrilobular necrosis.
  4. Long standing—cardiac cirrhosis.
  5. Congestive splenomegaly (increased pressure in portal system).
  6. Sinusoidal dilatation of spleen.
  7. Edema of bowel wall and ascites.
  8. Pleural and pericardial effusions.
  9. Ankle and pretibial edema (also anasarca).
 
Clinical Features
  1. Hepatomegaly.
  2. Splenomegaly.
  3. Ascites.
  4. Pleural and pericardial effusions.
  5. Edema.
 
ISCHEMIC HEART DISEASES
Ischemic heart diseases (IHD) are caused due to imbalance between cardiac perfusion and myocardial oxygen demand.
 
Causes
  1. Increased demand—increased HR and HTN.
  2. Decreased O2 carrying capacity—anemia, CO poisoning.
  3. Decreased O2 of coronary blood flow BF—atherosclerosis.
  4. Acute coronary syndrome—unstable angina, acute MI, SCD.
    105
 
Pathogenesis
The followings plays an important role in pathogenesis:
  1. Acute changes in plaque.
  2. Inflammation.
  3. Thrombosis and emboli.
  4. Vasoconstriction (Fig. 11.1).
 
Plaque Disruption
  1. By intraplaque hemorrhage, erosion, ulceration, rupture, fissuring, etc.
  2. Platelets release 2° molecules—TX-A2, ADP, serotonin.
 
Acute Coronary Syndromes
Evolution of coronary artery disease is shown in Figure 11.2.
 
Angina Pectoris
Intermittent chest pain caused by transient reversible myocardial ischemia.
  1. Typical or stable angina.
    1. Episodic chest pain due to increased myocardial O2 demand.
    2. Squeezing/crushing retrosternal pain radiates to left arm or left jaw or to back.
    3. Due to fixed coronary obstruction.
    4. Treatment is adequate rest or nitroglycerine.
  2. Prinzmetal or variant angina.
    1. Occurring at rest due to coronary vasospasm.
    2. Responds to nitroglycerine or CCBs.
  3. Unstable angina or crescendo angina.
    1. Increasing frequency of pain with less exertion progressively.
    2. Episode will be more intense and long lasting.
    3. Mural thrombus with variable obstruction/vasospasm.
    4. Also called preinfarction angina.
Fig. 11.1: Pathogenesis of coronary artery disease
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Fig. 11.2: Diagram showing evolution of coronary artery disease
 
Myocardial Infarction
  1. Necrosis of myocardium due to ischemia.
  2. Caused by acute coronary thrombosis from atherosclerosis.
  3. Vasospasm and platelet aggression can contribute.
Response to ischemia
Response to ischemia is shown in Figure 11.3.
Morphology
Mophological features of MI is listed in Table 11.1.
Clinical features
  1. Severe crushing retrosternal pain radiates to neck, jaw, left arm epigastrium, etc.
  2. Long lasting (20 min) and not relived by nitroglycerine.
  3. Sometimes asymptomatic.
    107
    Fig. 11.3: Response of myocardium to ischemia
  4. Rapid and weak pulse.
  5. Dyspnea, pulmonary congestion and edema.
  6. Cardiogenic shock in massive MIs.
  7. Q and ST abnormalities and T-wave inversion.
** Markers are the cardiac troponins T and I and creatine kinase-MB (CK-MB).
Complications
  1. Contractile dysfunction.
  2. Arrhythmias.
    108
  3. Myocardial rupture.
  4. Pericarditis.
  5. Infarct expansion.
  6. Mural thrombus and thromboembolism.
  7. Ventricular aneurysm.
  8. Papillary muscle dysfunction.
  9. Progressive late HF.
Reperfusion
  1. Achieved by:
    1. Thrombolysis (streptokinase, TPA).
    2. Balloon angioplasty.
    3. Coronary artery bypass graft.
  2. Reperfusion injury can occur due to O2 free radicals liberated by leukocytes. This injury even occlude the vessel → no reflow.
  3. Reperfusion site shows hemorrhage and contraction band necrosis.
  4. In the absence of ATP, contraction persists.
  5. Do not affect on stunned myocardium (the myocardium failed to contract due to injury of cells).
 
Chronic Ischemic Heart Disease
  1. Can be with or without previous infarction.
  2. Enlarged heart with LV dilatation and hypertrophy.
  3. Grey-white healed scar can be seen.
  4. Fibrous thickening and mural thrombi.
 
Sudden Cardiac Death
  1. Within 24 hours of symptom onset.
  2. Causes are:
    1. Congenital coronary artery abnormalities.
    2. Aortic valve (AV), stenosis (AS).
    3. Mital valve (MV) prolapse.
    4. Myocarditis.
    5. Dilated or hypertrophic cardiac myopathy.
    6. Pulmonary HTN.
    7. Abnormalities of conducting system.
    8. Myocardial hypertrophy.
    9. Cause of death is VF.
 
HYPERTENSIVE HEART DISEASES
 
Cardiac Hypertrophy
  1. Increased muscle mass.
  2. HTN → pressure overload → concentric hypertrophy.
  3. AS, MR → volume overload → eccentric hypertrophy.
  4. Hypertrophy → increased O2 demand → ischemia → HF.
 
Systemic Hypertensive Heart Disease
Left ventricular hypertrophy (LVH) (concentric) with h/o HTN, impairs diastolic filling.
 
Morphology
  1. Left ventricular hypertrophy and LA enlargement.
  2. Increased interstitial fibrosis.
  3. Irregular, enlarged and prominent nuclei with hyperchromasia → boxcar nuclei.
 
Clinical Features
  1. AF and CHF and IHD.
  2. Renal damage and stroke.
    109
 
Pulmonary Hypertensive Heart Disease (Cor Pulmonale)
  1. Right ventricular hypertrophy (RVH) and dilatation due to pulmonary HTN caused by primary disease of lung parenchyma or pulmonary vasculature.
  2. Acute → from massive pulmonary embolism.
  3. Chronic → RVH and dilatation.
 
Morphology
  1. Acute → may not show RVH, but show dilatation.
  2. Chronic → RVH and dilatation.
 
Predisposing Diseases for Cor Pulmonale
  1. Lung parenchymal diseases → COPD, fibrosis, pneumoconiosis, bronchiectasis.
  2. Pulmonary vessel diseases → thromboembolism, primary pulmonary HTN, arteritis.
  3. Chest movement diseases → kyphoscoliosis, neuromuscular disease.
  4. Diseases inducing pulmonary artery constriction → metabolic acidosis, hypoxemia, C/c altitude sickness, idiopathic.
 
RHEUMATIC VALVULAR DISEASE OR RHEUMATIC HEART DISEASE
  1. Rheumatic heart disease (RHD) is the cardiac manifestation of RF.
  2. RF is a multisystem disease sequelae of poststreptococcal pharyngitis.
  3. RHD—inflammation of pericardium, myocardium and valves.
  4. Chronic valvular deformities are most important consequences.
  5. Diffuse and dense scarring of valves (most common mitral stenosis [MS]).
 
Morphology
  1. Discrete inflammatory lesions—Aschoff bodies are present.
    1. Aschoff bodies—central degenerating ECM, infiltrate of (L), (P) and plump activated macrophages (Anitschkow cells).
    2. Anitschkow cells—abundant cytoplasm and central nucleus, wavy ribbon like chromatin (caterpillar cells).
  2. Pancarditis with exudates.
  3. Valve.
    1. Fibrinoid necrosis along lines of closure.
    2. Verrucae formation (due to fibrin precipitate).
    3. Inflammation and collagen degradation.
  4. C/c.
    1. Fibrosis and scarring.
    2. Thickening of leaflets and chordae tendineae.
    3. Fibrous bridging and calcification → fish mouth or buttonhole stenosis.
    4. Obliteration of normal leaflet architecture.
  5. Valvular stenosis and regurgitation.
    1. Involvement—mitral—aortic —tricuspid—tricuspid—pulmonary.
  6. MS.
    1. LA dilates with mural thrombi inside.
    2. Chronic → RVH.
      110
 
Pathogenesis
  1. Streptococcal antigen (Ag) induces antistreptococcal antibody (Ab).
  2. This antibody reacts with glycopeptide (GP) Ag in heart, joint and other sites.
 
Clinical Features
  1. Occur 3 weeks after streptococcal pharyngitis.
  2. Arthritis and carditis.
  3. Swollen and painful joint.
  4. Pericardial exudates and arrhythmias.
  5. Cardiac dilatation and MS and CHF.
  6. Stenosis, murmers, hypertrophy, etc.
 
Jone's Major Criteria
  1. Carditis.
  2. Polyarthritis.
  3. Subcutaneous nodules.
  4. Erythema marginatum of skin.
  5. Sydenham chorea.
 
Jone's Minor Criteria
  1. Fever.
  2. Arthralgia.
  3. Increased A/c phase reactants.
  4. Leukocytosis.
  5. Previous RF.
  6. First degree AV block.
 
Diagnosis
Two major manifestations/one major and two minor manifestations with evidence of preceding streptococcal infection.
 
INFECTIVE ENDOCARDITIS
  1. Microbial invasion into valves and mural endocardium.
  2. Destruction of cardiac tissue and form vegetations composed of necrotic debris, thrombosis and organisms.
  3. Mainly caused by bacteria.
 
Acute Endocarditis
  1. By highly virulent organisms affecting normal heart.
  2. Fatal within 2–3 weeks.
 
Subacute Endocarditis
  1. By low virulent organisms affecting abnormal heart.
  2. Most will recover after antibiotic therapy.
 
Etiopathogenesis
  1. Heart lesions like RHD and indwelling catheters predispose to this by seeding of bacteria and platelet aggregation induction (prosthetic valves also).
  2. Mainly by Streptococcus viridans.
  3. Also by Staphylococcus aureus, Haemophilus, etc.
 
Clinical Features
  1. Fever (most consistent).
  2. Fatigue, weight loss and flu-like syndrome.
  3. Splenomegaly subacute bacterial endocarditis (SABE) and murmers.
    111
 
Complications
  1. Glomerulonephritis.
  2. Septicemia.
  3. Arrhythmias.
  4. Systemic embolization.
 
Libman-Sacks Endocarditis
  1. Usually affect normal valves.
  2. Sterile vegetation.
  3. On both sides of valves.
  4. As a part of SLE.
 
Non-bacterial Thrombotic Endocarditis
  1. Sterile vegetations.
  2. Caused by hypercoagulable states, endocardial trauma, etc.
  3. Also called marantic endocarditis.
 
Major Forms of Vegetative Endocarditis
Forms of vegetative endocardities are shown in Figure 11.4.
 
CARDIOMYOPATHIES
  1. Intrinsic myocardial dysfunction.
  2. Includes (causes):
    1. Inflammatory → myocarditis (1°).
    2. Immunologic → sarcoidosis (2°).
    3. Systemic metabolic diseases → hemochromatosis (2°).
    4. Muscular dystrophies.
    5. Idiopathic.
  3. Primary—involves heart muscle only.
  4. Secondary—involves heart muscle as a part of another disease.
 
Dilated Cardiomyopathies
  1. Most common.
  2. Progressive cardiac dilatation and systolic dysfunction.
  3. Usually with hypertrophy.
 
Pathogenesis
  1. Viral.
    1. Virus → infection → myocarditis → dilated cardiomyopathy (DCM).
      Fig. 11.4: Major forms of vegetative endocarditis
      112
  2. Alcohol and other toxic exposure.
    1. Alcohol → acetaldehyde → DCM.
    2. Alcohol → thiamine deficiency→ DCM.
    3. Doxorubicin → DCM.
  3. Genetic and familial.
    1. AD inheritance (X-linked and AR also seen).
    2. X-linked—dystrophin gene
      defective cytoskeleton due to defective dystrophin gene → DCM.
    3. Mitochondrial—decreased ATP → DCM.
  4. Peripartum.
    1. Volume increase, PIH, nutritional deficiency and immunologic reactions leads to DCM.
 
Morphology
  1. Enlarged, flabby heart with dilatation of all chambers.
  2. Mural thrombi and valvular damage.
  3. Myocytes are hypertrophied and enlarged nuclei.
  4. Fibrosis and scarring.
 
Clinical Features
Dyspnea on exertion, murmers.
 
Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) involves myocardial hypertrophy, diastolic dysfunction and ventricular outflow obstruction.
 
Pathogenesis
  1. Mutations (missense point mutations) of several genes encoding for sarcomere proteins.
  2. Usually autosomal dominant (AD) inheritance.
  3. Beta-myosin heavy chain is commonly affected.
  4. Myosin binding protein-C and troponin-T are also affected.
  5. Mutation → defective contractility
    compensatory hypertrophy and fibrosis later.
 
Morphology
  1. Thick walled, heavy and hypercontracting heart.
  2. Without ventricular dilatation.
  3. Disproportionate increase in thickness of septal wall with respect to free wall. It is called asymmetrical septal hypertrophy.
  4. Concentric hypertrophy of walls.
  5. MS and plaque in the LV outflow.
  6. Severe myocyte hypertrophy and interstitial fibrosis.
 
Clinical Features
  1. Dyspnea, harsh systolic ejection murmer.
  2. Thrombus, IE, CHF, arrythmias.
 
Restrictive Cardiomyopathy
  1. Diastolic dysfunction and impaired ventricular filling.
  2. Causes are idiopathic, fibrosis, amyloidosis, sarcoidosis, etc.
  3. Genetic involvement is less defined.
 
Morphology
  1. Ventricles usually normal in size and cavities not enlarged.
  2. Interstitial fibrosis are two forms.
    113
    1. Endomyocardial fibrosis (common).
      • Fibrosis of endocardium and subendocardium
      • Decreased volume and compliance.
    2. Loeffler endomyocarditis.
      • Endocardial fibrosis and with mural thrombi
      • ↑ (E) → (E) degranulation → ↑ MBP release → endocardial damage necrosis → scarring and fibrosis.

Hematopoietic and Lymphoid SystemsChapter 12

 
CLASSIFICATION OF ANEMIA
 
Etiological
 
Blood Loss
  1. Acute—trauma.
  2. Chronic—GIT lesions, gynecological disturbances.
 
Increased Destruction of RBCs
  1. Intrinsic abnormalities.
    1. Hereditary.
      • Membrane abnormalities—spherocytosis, elliptocytosis, etc.
      • Enzyme deficiencies—deficiency of pyruvate kinase, G6PD, etc.
      • Disorders of Hb synthesis
        • Deficient globin—thalassemia
        • Abnormal globin—sickle cell anemia.
    2. Acquired.
      • Membrane defect—PNH.
  2. Extrinsic abnormalities.
    1. Antibody mediated.
      • Isohemagglutinins—transfusion reactions, erythroblastosis fetalis
      • Autoantibodies—idiopathic, drug induced, SLE.
    2. Mechanical trauma to red cells.
      • Microangiopathic hemolytic anemias—TTP, DIC
      • Infections—malaria.
 
Impaired Red Blood Cell Production
  1. Disturbance of stem cell proliferation and differentiation.
    1. Aplastic anemia, pure red cell aplasia, anemia due to renal and endocrine disorder.
  2. Disturbance of proliferation and maturation of erythroblasts.
    1. Defective DNA synthesis.
      • Vitamin B12 and folate deficiency.
    2. Defective Hb synthesis.
      • Deficient heme—iron-deficiency anemia
      • Deficient globin—thalassemia
      • Anemia of renal failure.
    3. Unknown or multiple factors.
      • Myelodysplastic syndrome and anemia of chronic inflammation.
 
Morphological
  1. Normochromic normocytic.
  2. Hypochromic microcytic.
    115
  3. Macrocytic.
  4. Others—spherocytosis, elliptocytosis, sickle cell anemia.
 
HEREDITARY SPHEROCYTOSIS
  1. Inherited disorder characterized by an intrinsic defect in the RBC membrane.
  2. Autosomal dominant (75%) or autosomal recessive (25%) inheritance.
 
Pathogenesis
  1. The basic abnormality is with the major membrane protein spectrin.
  2. The spectrin is attached to membrane at two points.
    1. Through ankyrin and band 4.2 to band 3.
    2. Through band 4.1 to glycophorin.
  3. The normal membrane stability is maintained by spectrin—spectrin as well as spectrin-intrinsic membrane protein interactions.
  4. In HS, mainly the spectrin-intrinsic membrane protein interactions are affected due to mutation of ankyrin, band 3 or spectrin genes.
  5. As a result, the integrity of RBC membrane is lost and certain fragments are separated off without much loss in volume.
  6. Thus, RBCs assume a spherical shape to maintain the maximum volume.
  7. These spherical RBCs because of their limited deformability get sequestrated in the splenic cords and eventually destroyed by macrophages.
 
Morphology
  1. In smear—RBCs lack central pallor.
  2. Spherocytes are seen, but not diagnostic.
  3. Hyperplasia of marrow red cell progenitors.
  4. Reticulocytosis in peripheral blood.
  5. Splenomegaly is very common.
  6. Congestion of cords of Billroth in spleen.
  7. Increased phagocytes in spleen.
  8. Later cases—hemosiderosis due to increased hemolysis.
  9. Cholelithiasis may be also seen due to increased hemolysis.
 
Clinical Features
  1. Anemia, splenomegaly and jaundice.
  2. Increased osmotic fragility.
  3. Splenectomy can correct anemia to a major extent, because the RBC destruction mainly occurs in spleen.
 
SICKLE CELL ANEMIA
Sickle cell anemia is one of the majorhemoglobinopathies characterized by the presence of structurally abnormal hemoglobins.
 
Etiopathogenesis
  1. Caused by a mutation in the betaglobin chain.
  2. Results in the substitution of valine for glutamic acid at the 6th position in the β-chain.
  3. Thus, the normal HbA is replaced by HbS completely in homozygous and half in heterozygous individuals.
  4. These HbS molecules undergo polymerization on deoxygenation and these polymers distort the red cells, which assume a cresentic or sickle shape.
    116
  5. The sickling is initially reversible by reoxygenation.
  6. Later the cells accumulate calcium, lose K+ and water and become irreversibly sickled.
  7. The determinants of sickling are:
    1. Presence of other Hb.
      • HbA and HbF reduce sickling
      • HbC increases sickling.
    2. Concentration of HbS in the cell.
      • HbS concentration increases sickling.
    3. The duration of hypoxia.
  8. These sickled RBCs are recognized and destroyed by mononuclear phagocytes.
  9. Thus, produces a chronic extravascular hemolytic anemia.
  10. Also produces microvascular obstruction and leads to tissue damage and pain crisis.
 
Morphology
  1. Chronic hemolytic anemia and peripheral reticulocytosis.
  2. Increased bilirubin.
  3. Microvascular obstruction.
  4. Sickled cells are seen in peripheral smear.
  5. Fatty changes in heart, liver and renal tubules.
  6. Hyperplasia of marrow erythroid progenitors.
  7. Bone resorption and new bone formation may occur and leads to prominent cheek bones and skull changes.
  8. Extramedullary hematopoiesis in liver and spleen.
  9. Splenomegaly and congestion of red pulp.
  10. Later, spleen undergoes hypoxic tissue damage and eventually become a useless fibrous tissue. This process is called autosplenectomy.
  11. Many organs are affected by vascular congestion, thrombosis and infarction.
  12. Bone marrow and penis are more vulnerable to ischemic injury.
  13. Hemosiderosis and gallstones are common.
 
Clinical Features
  1. Anemia, jaundice.
  2. Vaso-occlusive pain crisis.
  3. Acute chest syndrome.
    1. Due to fat emboli from necrotic marrow.
    2. Worsening of pulmonary and systemic hypoxemia.
  4. CNS stroke.
  5. Aplastic crisis.
  6. Prone to infections.
 
G6PD DEFICIENCY
  1. X-linked disorder.
  2. G6PD deficiency leads to decreased production of reduced glutathione (GSH).
  3. This GSH is essential for RBCs to get protected from endogenous and exogenous oxidants.
  4. G6PD deficiency becomes manifested when the patient is exposed to increased oxidant stress by infections and drugs like antimalarials, sulfonamides, nitrofurantoin, aspirin, etc.
    117
  5. Infections and certain drugs induce phagocytes to produce oxidants like hydrogen peroxide.
  6. This peroxide and other free radicals attack the sulfhydryl group of Hb.
  7. These oxidized Hb get denatured and precipitated to form intracellular inclusions called Heinz bodies, which will damage the RBC membrane to cause intravascular hemolysis.
  8. The affected RBCs again get damaged in spleen, when the splenic phagocytes pluck out the Heinz bodies. As a result, deformed RBCs are called bite cells, are formed.
  9. These bite cells are destroyed by splenic phagocytes and produce extravascular hemolysis.
  10. Thus, produces anemia and a compensatory reticulocytosis.
 
PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
  1. Paroxysmal nocturnal hemoglobinuria is the only hemolytic anemia resulting from an acquired membrane defect secondary to a mutation that affects myeloid stem cells.
  2. An X-linked disorder, which is rare in community.
  3. In this, PIGA gene which is responsible for an intramembranous glycolipid anchor—PIG, is get mutated.
  4. As a result, the PIG deficient RBCs get lysed by the activated complement system.
  5. Here, the hemolysis occurs nocturnally because the blood becomes acidic during sleep due to carbon dioxide retention and an acidic pH promotes hemolysis.
  6. Increased susceptibility to infections and intravascular thrombosis.
  7. The term paroxysmal is not explained.
 
THALASSEMIA
  1. A group of disorders that resulting from mutations that decrease the rate of synthesis of α or β-globin chains.
  2. So, there is a deficiency of normal Hb with secondary red cell abnormalities caused by relative excess of the unaffected globin chains.
 
Etiopathogenesis
  1. HbA is a tetramer composed of 2α and 2β chains.
  2. Each α-chain is encoded by 2α- globin genes on chromosome 11 and each β-chain is encoded by a single β-globin gene on chromosome 16.
 
β-thalassemia
Here, the defects can be in:
  • Transcription of beta-globin gene (β+)
  • Translation of beta-globin mRNA (β°)
  • Processing of mRNA (β+ or β0).
  1. β-thalassemia major.
    1. β°/β° or β°/β+ (homozygous or compound heterozygous).
    2. Severe symptoms.
  2. β-thalassemia intermedia.
    1. β++.
    2. Moderately severe course.
  3. β-thalassemia minor (trait).
    1. β/β+ or β/β0 (Box 12.1).
    2. Asymptomatic or mildly anemic.
      118
      • β—normal β-globin chain
      • β+—reduced β-globin synthesis
      • β0—no β-globin synthesis.
  4. The anemia in β-thalassemia is due to:
    1. Reduced β-globin and inadequate HbA. Thus, MCHC decreases and cells become microcytic and hypochromic.
    2. Excess of α-chains stand as unpaired and form insoluble precipitates, which damage RBC membrane and induce extravascular hemolysis in spleen.
  5. Also leads to destruction of erythroblasts in bone marrow and this ineffective erythropoiesis leads to:
    1. Increased iron absorption and secondary hemochromatosis.
    2. Increased erythropoietin levels and BM expansion, which ultimately results in skeletal abnormalities.
 
α-thalassemia
α-thalassemia results from deletions of α-globin genes.
  1. Hydrops fetalis.
    1. --/-- (all the 4 genes deleted).
    2. Fetus die in utero.
  2. HbH disease.
    1. --/-α (3 genes deleted).
    2. Moderately severe anemia due to ineffective oxygen delivery.
  3. Alpha thalassemia trait.
    1. --/αα or -α/-α (2 genes deleted).
    2. Asymptomatic or mild symptoms.
  4. Silent carrier.
    1. -α/αα (only 1 gene deleted).
    2. Asymptomatic, normal RBCs.
Here, the abnormal Hb produces less damage to RBC membrane, so that anemia is less when compared to β-thalassemia.
 
Morphology
  1. β-thalassemia minor.
    1. Features confined to peripheral blood.
      • Microcytic and hypochromic RBCs
      • Normal shape
      • Target cells may be seen.
  2. β-thalassemia major.
    1. Peripheral smear.
      • Microcytosis and hypochromia
      • Anisopoikilocytosis
      • Reticulocytosis.
    2. Bone marrow.
      • Hyperplasia of erythroid progenitors
      • BM expansion.
        119
    3. Others.
      • Skeletal deformities
      • Hepatosplenomegaly
      • Lymphadenopathy
      • Hemochromatosis
      • Growth retardation and cachexia.
 
IRON DEFICIENCY ANEMIA
Iron deficiency anemia is most common form of anemia.
 
Etiology
  1. Low dietary intake—poor economy, anorexia.
  2. Malabsorption syndromes—sprue, celiac disease, etc.
  3. Increased demand not met by normal intake.
    1. Pregnancy and infancy.
  4. Chronic blood loss.
    1. GIT bleeds.
    2. Female genital tract bleeding.
 
Pathogenesis
Decreased iron leads to decreased heme synthesis, decreased Hb and anemia.
 
Morphology
  1. Red blood cells are microcytic and hypochromic.
  2. Decreased MCV, MCH and MCHC.
  3. Increased erythropoietin levels and decreased Hb.
  4. Marrow response is blunted due to Fe deficiency, so that marrow cellularity is only slightly elevated.
  5. Reticulocyte count is usually normal. Iron metabolism is given in Figure 12.1.
 
Clinical Features
  1. Weakness, restlessness and pallor.
  2. Thinning, flattening and eventually spooning of fingernails (koilonychia).
  3. Pica—a neurobehavioral problem characterized by consumption of non-foodstuffs like dirt or clay.
 
Biochemistry
  1. Low serum ferritin and low serum iron levels.
  2. Low transferrin saturation.
  3. Increased TIBC.
    Fig. 12.1: Iron metabolism
    120
  4. Response to iron therapy.
  5. Decreased marrow iron.
 
Treatment (Rx)
  1. Correction of the disorder.
  2. Correction of the deficiency—oral and parenteral therapy.
 
MEGALOBLASTIC ANEMIA
 
Etiology
 
Folate Deficiency
  1. Inadequate dietary intake.
    1. Alcoholics, infants, old age.
  2. Malabsorption.
    1. Tropical sprue, Crohn disease, celiac disease, gastrectomy.
  3. Excess demand.
    1. Pregnancy, lactation, infancy.
    2. Malignancy, tuberculosis, RA.
  4. Excess urinary loss.
    1. Alcoholic liver disease, CCF.
  5. Drugs.
    1. Phenytoin and methotrexate.
 
Vitamin B12 deficiency
  1. Inadequate dietary intake.
    1. Strict vegetarians, breastfed infants.
  2. Malabsorption.
    1. Gastric causes—pernicious anemia, gastrectomy.
    2. Intestinal causes—topical sprue, Crohn disease.
 
Pathogenesis
  1. Folate and vitamin B12 deficiencies leads to impaired DNA synthesis and thus results in a delay in nuclear maturation and cell division.
  2. But the cytoplasm and RNA synthesis occurs normally, which leads to nuclear-cytoplasmic asynchrony.
  3. This leads to anemia by:
    1. Destruction of megaloblasts in marrow.
    2. Decreased number of macrocytes (RBCs) in blood.
 
Morphology
  1. Peripheral blood.
    1. Hypersegmented neutrophils (early changes).
    2. Macrocytic RBCs.
    3. Giant metamyelocytes.
    4. Anemia, thrombocytopenia and granulocytopenia.
  2. BM.
    1. Hypercellular.
    2. Megaloblasts (large RBC precursors).
      • Fine chromatin and abundant basophilic cytoplasm.
    3. Giant metamyelocytes.
    4. Giant megakaryocytes with bizarre multilobed nuclei.
 
Vitamin B12 Metabolism
  1. Vitamin B12 combines with IF in stomach and reaches distal ileum.
  2. Then vitamin B12-IF complex is taken to the mucosal cells and there the IF get destroyed.
  3. Later the vitamin B12 complex is coupled with a transporter protein transcobalamin-2.
    121
  4. Then the vitamin B12-TC2 complex transported to liver, BM and other cells by circulation.
 
Folate Metabolism
Absorbed directly from small intestine (Fig. 12.2).
Fig. 12.2: Folate metabolism
 
Lab Diagnosis
 
Tests for Vitamin B12 Deficiency
  1. Serum vitamin B12 assay.
    1. Microbiological.
    2. Radioassay.
  2. Schilling test.
    1. 24 hour urinary excretion test.
  3. Enzyme levels.
    1. These enzymes with vitamin B12 as cofactor are estimated.
 
Tests for Folate Deficiency
  1. Urinary excretion of FIGLU.
  2. Serum folate assay.
    1. Microbiological.
    2. Radioasssay.
  3. Red cell folate assay.
 
Treatment (Rx)
  1. Hydroxocobalamin injection and folic acid tablets.
  2. Blood transfusion should be avoided.
 
PERNICIOUS ANEMIA
Anemia due to vitamin B12 deficiency resulting from inadequate gastric production or defective functioning of IF.
 
Etiology
  1. Circulating autoantibodies like antiparietal cell Ab and anti-IF Ab are seen.
  2. Increased occurrence in autoimmune diseases like Grave disease, thyroiditis, vitiligo, DM, etc.
  3. Increased incidence in families.
  4. Corticosteroids are found to be useful in treatment.
 
Pathogenesis
  1. Vitamin B12 metabolism and role of IF is mentioned previously.
  2. So when the IF becomes defective, the absorption of vitamin B12 willnot occur properly and which leads to a vitamin B12 deficient state.
 
Morphology
  1. Blood and BM similar as megaloblastic anemia.
  2. Gastric atrophy of acid and pepsin secreting portion.
  3. Cellular atypia of gastric secretion.
    122
  4. Peripheral neuropathy and spinal cord damage.
 
Diagnostic Criteria
  1. Major criteria.
    1. Low serum B12 level.
    2. Megaloblastic anemia.
    3. Presence of IF Ab.
  2. Minor lab criteria.
    1. Anemia and macrocytosis.
    2. Hypergastrinemia.
    3. Presence of parietal cell Ab.
    4. Gastric pH above 6.
  3. Minor clinical criteria.
    1. Neuropathy.
    2. Hypothyroidism.
    3. Family history.
  4. Reference standard criteria.
    1. Schilling test showing malabsorption of oral vitamin B12, which is corrected by IF administration.
 
Clinical Features
  1. Anemia, glossitis, gastric atrophy.
  2. Peripheral neuropathy and retrobulbar neuritis.
  3. Spinal cord degeneration.
  4. Hepatosplenomegaly, CCF, hemorrhages, etc.
 
Treatment (Rx)
  1. Parenteral vitamin B12 supplementation.
  2. Corticosteroids for autoantibodies.
  3. Treatment of neuropathy and gastric atrophy.
 
APLASTIC ANEMIA
In aplastic anemia, the multipotent myeloid stem cells are suppressed, leading to marrow failure and pancytopenia.
 
Etiopathogenesis
  1. Primary aplastic anemia.
    1. Fanconi's anemia—congenital and AR inheritance.
    2. Immune causes—acquired.
  2. Secondary aplastic anemia.
    1. Drugs.
      • Dose related.
        • Antimetabolites (methotrexate)
        • Mitotic inhibitors (daunorubicin)
        • Alkylating agents (busulfan)
        • Anthracyclines.
      • Idiosyncratic.
        • Chloramphenicol
        • Phenylbutazone
        • Chlorpromazine
        • Sulpha drugs.
    2. Toxic chemicals—benzene derivatives, arsenic compounds.
    3. Infections—hepatitis, EBV, AIDS.
    4. Others associated with SLE and X-ray medications.
 
Clinical Features
Anemia, hemorrhage and infections.
 
Morphology
  1. Peripheral blood.
    1. Normochromic normocytic anemia.
    2. Reticulocyte count is highly reduced.
    3. Decreased WBC count (leukopenia).
      123
    4. Decreased platelet count (thrombocytopenia).
  2. BM.
    1. Hypocellular.
    2. Pancytopenia.
    3. Stem cells also decrease.
    4. Increased amount of fat.
 
Treatment (Rx)
  1. Elimination of cause.
  2. Blood transfusion.
  3. Prevent infections.
  4. BM stimulators.
  5. Immunosuppressive therapy.
  6. BM transplantation.
 
MICROCYTIC HYPOCHROMIC ANEMIAS
The different types of microcytic hypochromic anemias are explained in Table 12.1.
 
POLYCYTHEMIA
  1. Also called erythrocytosis.
  2. Denotes an increase in the blood concentration of red cells.
  3. Hb concentration also increases.
 
Types
  1. Relative.
    1. Due to hemoconcentration—in prolonged dehydration.
  2. Absolute.
    1. Primary—polycythemia vera.
      • Mutations in erythropoietin receptor.
    2. Secondary—increased erythropoietin levels.
      • Appropriate—lung diseases, high altitude, cyanotic heart disease, etc.
      • Inappropriate—erythropoietin secreting tumors (RCC, hepatoma).
        • Increased erythropoietin use (athletes).
 
Polycythemia Vera
  1. Due to excessive neoplastic proliferation and maturation of myeloid elements (erythroid, granulocytic and megakaryocytic) and producing a panmyelosis.
  2. Low erythropoietin level is a characteristic feature.
  3. Have a mutation in JAK2.
    124
 
Morphology
  1. Increased blood volume and viscosity.
  2. Plethoric congestion of all organs.
  3. Thrombosis and infarctions can be seen mainly in heart, spleen and kidneys.
  4. Hepatosplenomegaly can be seen.
  5. Hemorrhages usually from GIT, oropharynx and brain.
  6. Basophilia can be seen in peripheral blood.
  7. Hypercellular BM.
  8. Some degree of marrow fibrosis can also be seen.
 
Clinical Features
  1. Patients will be plethoric and often cyanotic.
  2. Pruritis and peptic ulcer due to histamine from basophils.
  3. Headache, dizziness, hematemesis, melena.
  4. Hyperuricemia.
  5. Spent phase—myelofibrosis occurs.
  6. Blast crisis may occur.
 
Treatment (Rx)
  1. Phlebotomy.
  2. Anticoagulants.
  3. Chemotherapy.
  4. Interferon-alpha.
 
LEUKEMOID REACTION
  1. Leukemoid reaction is defined as a reactive excessive leukocytosis in the peripheral blood resembling that of leukemia in a subject, who does not have leukemia.
  2. The clinical features of leukemia like splenomegaly, lymphadenopathy and hemorrhages are usually absent.
 
Myeloid Leukemoid Reaction
Much more common.
 
Etiology
  1. Infections—Staphylococcus pneumonia, disseminated TB, sepsis, meningitis, endocarditis, etc.
  2. Intoxications—eclampsia, mercurypoisoning, severe hemolysis, etc.
 
Morphology
  1. Leukocytosis (not exceeding 1,00,000/μL).
  2. Increased immature cells (meta-myelocytes, myelocytes, blasts).
  3. Similar to CML.
  4. Toxic granulation and Dohle bodies in (N) cytoplasm.
  5. Anemia and thrombocytosis.
 
Lymphoid Leukemoid Reaction
 
Etiology
  1. Infections—IMN, CMV infection, chickenpox, measles, TB.
  2. Malignancies like bone metastasis.
 
Morphology
  1. Leukocytosis not exceeding 1,00,000/μL.
  2. Increased mature lymphocytes.
  3. Similar to CLL.
    125
Fig. 12.3: Etiopathogenesis of IMN
 
Myeloid Leukemoid Reaction vs CML
  1. NAP score is high in leukemoid reaction.
  2. Philadelphia chromosome is absent in leukemoid reaction.
 
INFECTIOUS MONONUCLEOSIS
  1. Acute self-limiting disease.
  2. Mainly affecting the adolescents and young adults.
  3. Caused by B-lymphotropic EBV.
  4. Characterized by:
    1. Fever, sore throat and generalized lymphadenopathy.
    2. Atypical lymphocytes.
    3. Ab and T-cell response to EBV.
 
Pathogenesis
Usually, transmitted by direct oral contact and so it is also called kissing cousin syndrome. Etiopathogenesis of IMN is shown in Figure 12.3.
 
Morphology
  1. Peripheral blood leukocytosis.
  2. More than half of WBCs will be atypical lymphocytes, which are large cells with abundant cytoplasm containing azurophilic granules and folded nucleus.
  3. Generalized lymphadenopathy.
  4. Cells resembling RS cells may be seen.
  5. Enlarged spleen infiltrated with atypical lymphocytes.
  6. Liver is enlarged and with parenchymal necrosis.
  7. Abundant atypical lymphocytes are seen in liver also.
 
Clinical Features
  1. Prodromal period (3–5 days).
    1. Mild symtoms.
    2. Malaise, myalgia, headache, fatigue.
  2. Frank clinical features (7–21 days).
    1. Fever, sorethroat, generalized lymphadenopathy.
    2. Hepatosplenomegaly and splenitis.
      126
    3. Erythematous and maculopapular skin eruptions.
    4. Neurologic manifestations (meningitis, encephalitis).
    5. Pneumonia and cardiac involvement.
  3. Can progress to Burkitt lymphoma and B cell NHL.
 
ACUTE MYELOGENOUS LEUKEMIA
Primarily, affects older adults with the median age being 50 years.
 
Pathophysiology
  1. Arise from myeloid stem cells and give rise to monoclonal proliferations that replace the normal BM cells.
  2. Basic defect is acquired mutations in transcription factors that inhibit normal myeloid differentiation and lead to accumulation of cells at early stages. For example, (15:17) translocation in acute promyelocytic leukemia. Classification of acute myelogenous leukemia is shown in Table 12.2.
 
Morphology
 
Peripheral Blood
  1. Anemia.
  2. Thrombocytopenia (< 50,000/μL).
  3. WBC—may be subnormal or highly elevated.
  4. Increase myeloblasts and promyelocytes.
Table 12.2   Classification of acute myelogenous leukemia
FAB class
Morphology
Cytochemistry
M0—minimally differentiated
Blasts without differentiation. Have myeloid lineage antigens.
MPO –ve
M1—AML without maturation
Myeloblasts predominate. Auer rods are seen.
MPO +ve
M2—AML with maturation
Promyelocyte predominate. Auer rods may be seen.
MPO+++
M3—acute promyelocytic leukemia
Hypergranular promyelocytes. Multiple Auer rods per cell.
MPO+++
M4—acute myelomonocytic leukemia
Both myeloid and monocytic series in peripheral blood.
MPO++ Non-specific esterace +ve
M5—acute monocytic leukemia
M5A—poorly differentiated monoblasts M5b—differenciated promonocytes and monocytes
Non-specific esterace++
M6—acute erythrocytic leukemia
Erythroblast predominant. Myeloblasts and promyelocytes also seen
PAS +ve MPO +ve
M7—acute megakaryocytic leukemia
Undifferentiated blasts react with antiplatelet Ab.
Platelet peroxidase +ve
127
 
BM
  1. Marrow is hypercellular.
  2. BM tightly packed with leukemic blast cell.
  3. Myeloblasts are large cells with delicate chromatin, 3–5 nucleoli and azurophilic granules in cytoplasm.
  4. Distinctive red staining rod-like structures called Auer rods can be seen in myeloblasts.
  5. Decreased erythropoiesis.
  6. Decreased megakaryocytes.
 
Immunophenotype
Most express some combination of myeloid associated antigens like CD13, CD14, CD15, CD64, CD117 and CD33.
 
Histochemistry
  1. Positive for enzyme myeloperoxidase.
  2. Auer rods are positive for peroxidase.
  3. Monocytic differentiation is demonstrated by staining for lysosomal non-specific esterase (NSC).
  4. Positive for Sudan black.
  5. PAS positive in M6 and acid phosphatase positive in M4 and M5.
 
Clinical Features
  1. Pallor, fatigue, lethargy.
  2. Petechiae, bleeding gums.
  3. Infections and fever.
  4. Bone pain and tenderness.
  5. Lymphadenopathy.
  6. Hepatosplenomegaly.
  7. Leukemic infiltration of kidney.
  8. Gum hypertrophy.
  9. Chloroma.
  10. Meningeal involvement.
 
Treatment (Rx)
  1. Treatment of anemia and hemorrhage.
  2. Treatment of infection.
  3. Cytotoxic drug therapy.
    1. Combination of cytosine arbinoside, anthracycline and 6-thioguanine.
    2. Amsacrine can be added.
  4. BM transplantation.
 
Prognosis
  1. AML is most malignant of all leukemias with a median survival with treatment is 12–18 months.
  2. Remission rate is low and shorter duration of remission.
 
CHRONIC MYELOGENOUS LEUKEMIA
  1. Primarily affect adults between 25 and 60 years of age with peak incidence in the 4th and 6th decades of life.
  2. Marked by hyperproliferation of neoplastic myeloid progenitors that retain the capacity for terminal differentiation.
 
Pathophysiology
  1. Caused by the effect of reciprocal translocation between chromosomes 9 and 22 forming the Philadelphia chromosomes (t9;22).
  2. Involves the fusion of BCR gene with the ABL gene.
    128
  3. BCR/ABL fusion brings about the following changes.
    1. ABL protein activates some kinases, which inhibits apoptosis.
    2. Ability of ABL protein to act as a DNA binding protein is altered.
    3. Binding of ABL to actin filaments is increased.
  4. Mechanisms leading to blast phase are:
    1. Structural alterations in p53 gene.
    2. Structural alterations RB gene.
    3. Alterations in RAS oncogene.
    4. Alterations in MYC oncogene.
    5. Release of cytokine IL-1β.
    6. Inactivation of tumor suppressor—phosphatase A2.
 
Morphology
  1. Blood.
    1. Anemia (normocytic normochromic).
    2. Marked leukocytosis (2,00,000/μL).
    3. Promyelocytes, myelocytes, metamyelocytes and band forms can be seen.
    4. Platelets: Normal or raised (thrombocytosis).
      • Chronic phase—myelocytes and metamyelocytes
      • Accelerated phase—increased basophils and thrombocytopenia
      • Blastic phase—basophilia.
  2. BM.
    1. Hypercellular.
    2. Predominantly myeloid cells.
    3. Decreased erythropoiesis.
    4. Megakaryocytes usually normal.
 
Cytochemistry
  1. Reduced NAP score.
  2. Elevated serum B12 and B12 binding capacity.
  3. Hyperuricemia.
 
Clinical Features
  1. Weakness, pallor, tachycardia (anemia).
  2. Weight loss, anorexia, night sweats (increase BMR).
  3. Splenomegaly.
  4. Bleeding tendencies like easy bruising, epistaxis.
  5. Gout, visual disturbances and lymphadenopathy.
 
Treatment (Rx)
  1. Removal of all clones with BCR/ABL fusion protein.
    1. Imatinib oral therapy.
    2. BM transplantation.
    3. IFN-alpha.
    4. Chemotherapy.
    5. Splenectomy, splenic radiation, etc.
 
Prognosis
Better than AML, but worse than CLL.
 
ACUTE LYMPHOBLASTIC LEUKEMIA
  1. Also called precursor (immature) B and T cell leukemia.
  2. Most common malignancy of children under 4 years of age.
  3. B-cell acute lymphoblastic leukemia (ALL) is more common (80%) than T-cell ALL (20%).
    129
    Classification of acute lymphoblastic leukemia is shown in Table 12.3 and subtypes of ALL is shown in Table 12.4.
 
Pathophysiology
Block in differentiation and accumulation of blasts in BM and peripheral blood.
 
Morphology
  1. Peripheral blood.
    1. Anemia.
    2. Thrombocytopenia.
    3. WBC—variable.
    4. Increased lymphoblasts.
  2. BM.
    1. Malignant undifferentiated precursors of B or T cells.
    2. Megakaryocytes reduced or absent.
 
Cytochemistry
  1. Positive for:
    1. PAS.
    2. Acid phosphatase.
  2. Negative for:
    1. MPO.
    2. Sudan black.
    3. NSE.
 
Immunophenotype
  1. Express TdT.
  2. B-cell ALL—positive for CD19, CD10 and CD9a.
  3. T-cell ALL—positive for CD1, CD2, CD3, CD5 and CD7.
  4. Pre B-cell ALL shows Philadelphia chromosome.
    130
 
Clinical Features
  1. B-cell ALL.
    1. In children.
    2. Lymphadenopathy, hepatosplenomegaly.
    3. CNS infiltration.
    4. Testicular and cutaneous involvement.
  2. T-cell ALL.
    1. In adults.
    2. Mediastinal mass or pleural effusion.
    3. Anemia, neutropenia, thrombocytopenia.
    4. Lymphadenopathy, hepatosplenomegaly and CNS infiltration.
 
Treatment (Rx)
  1. Chemotherapy.
    1. Combination of vincristine, prednisolone, anthracyclines and L-asparaginase.
  2. BM transplantation.
 
Prognosis
  1. High remission rate and prolonged duration of remission.
  2. Survival.
    1. Adults: 12–18 months.
    2. Children: 33 months (if CNS involved) or 60 months (if CNS not involved).
 
CHRONIC LYMPHOCYTIC LEUKEMIA
  1. Also called B-cell chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma.
  2. More commonly in middle and older age groups with a male preponderance.
 
Pathophysiology
  1. Suppression of normal B cell function.
  2. Later normal marrow elements are replaced by neoplastic B cells.
 
Morphology
  1. Peripheral blood:
    1. Anemia and mild reticulocytosis.
    2. Marked leukocytosis (50,000–2,00,000/μL).
    3. About 90% of WBCs are mature small lymphocytes.
    4. Smudge or basket cells may be present.
    5. Later neutropenia.
    6. Thrombocytopenia.
  2. BM:
    1. Increased lymphocyte count.
    2. Decreased myeloid and erythroid precursors.
  3. LNs:
    1. Certain foci of mitotically active cells-proliferation center.
    2. Increased number of small lymphocytes.
 
Cytochemistry
  1. Coomb's test +ve.
  2. Decreased serum Ig levels.
 
Immunophenotype
  1. Typically +ve for CD5.
  2. Trisomy 12 can be seen.
  3. Also CD19, CD20 and CD23.
    131
 
Clinical Features
  1. Weakness, fatigue.
  2. Lymphadenopathy, hepatosplenomegaly.
  3. Hemorrhagic manifestations, increased infections.
 
Treatment (Rx)
  1. Palliative and symptomatic.
  2. Cyclophosphamide, steroids, radiotherapy and splenectomy.
 
Prognosis
  1. Stage A: Lymphocytosis alone—10 years.
  2. Stage B: Lymphocytosis, LNs, hepatosplenomegaly—5 years.
  3. Stage C: Lymphocytosis, anemia, thrombocytopenia—less than 2 years.
 
BURKITT LYMPHOMA
  1. Although this is a rare tumor, this comprises about 30% of childhood NLHs.
  2. Burkitt lymphoma corresponds to L3-ALL.
 
Types
  1. African endemic Burkitt lymphoma.
    1. Some relation to EBV.
    2. Usually present as a jaw tumor.
    3. Extranodal sites like BM and meninges are involved.
  2. Sporadic Burkitt lymphoma.
    1. More aggressive.
    2. Infiltrate CNS.
  3. Immunodeficiency associated.
    1. Usually in association with HIV.
 
Morphology
  1. Cells are round and uniform with round or oval nuclei containing two to five prominent nucleoli and moderate amount of basophilic cytoplasm with lipid vacuolation.
  2. High mitotic rate.
  3. Numerous macrophages containing nuclear debris are often surrounded by a clear space to produce a starry sky pattern.
 
Immunophenotype
  1. Positive for CD10, CD19 and CD20.
  2. Express surface IgM.
  3. Traslocations of MYC gene on chromosome-8.
  4. t(8;14) and t(8;22) are seen.
 
Clinical Features
  1. Jaw, bowel, retroperitoneum, ovaries are involved.
  2. LNs, BM and CNS are involved.
  3. Most of the patients can be cured.
 
MULTIPLE MYELOMA
  1. Originates from a single clone of B cells (monoclonal) that differentiate into plasma cells.
  2. Also called monoclonal gammopathy due to increased serum Ig.
  3. Usually affects the elderly.
 
Etiopathogenesis
  1. Radiation exposure and epidemiological factors have an influence on the occurrence of multiple myeloma.
  2. Karyotypic abnormalities like:
    132
    1. Translocations-t (11;14) (q13;q32) and t(4;14) (p16;q32).
    2. Deletion of 13q.
  3. Oncogene-antioncogene mutations.
    1. Over expression of MYC and RAS oncogenes.
    2. Mutation of P53 and RB genes.
 
Molecular Pathogenesis
  1. Plasma cells bind with BM stromal cells and ECM proteins with the help of adhesion molecules.
  2. This adhesion leads to production of cytokines.
  3. The cytokines like IL-1, lymphotoxin, RANK ligand and TNF-α leads to osteoclast activation and bone destruction.
  4. The cytokine IL-6 leads to proliferation of tumor cells through its anti-apoptotic effects.
  5. All these again lead to drug resistance and migration of tumor cells.
 
Immunochemistry
  1. The Ig in multiple myeloma is referred to as ‘M’ component.
  2. The ‘M’ component is commonly IgG (60%), followed by IgA (20%–25%) and rarely IgM, IgD or IgE.
  3. In some cases, there is only kappa or lambda light chains and these are excreted through urine and are called Bence-Jones proteins.
 
Morphology
  1. Osseous (BM) lesions.
    1. Most commonly involved bones are skull, spine, ribs and pelvis.
    2. Lesions erode the medullary cavity and ultimately destroys the cortex and radiographically appear as punched out round defects.
    3. The normal marrow is replaced by soft, gelatinous reddish-grey tumors.
    4. Often leads to pathological fractures.
    5. Microscopy.
      • Marrow is hypercellular with myeloma cells greater than or equal to 10%
      • Myeloma cells are usually large oval cells with a rounded nucleus and slightly basophilic cytoplasm with vacuolation. Usually have a cartwheel chromatin pattern.
  2. Extraosseous lesions.
    1. Peripheral blood.
      • Anemia and ↑ ESR
      • Atypical plasma cells can be seen.
    2. Myeloma kidney.
      • The Bence-Jones proteins are precipitated in DCT along with Tamm-Horsfall proteins.
    3. Myeloma neuropathy.
      • Tumor cells infiltrate the nerve trunks to produce non-specific polyneuropathy.
    4. Systemic amyloidosis.
      • AL amyloid get deposited.
    5. Hepatosplenomegaly.
 
Clinical Features
  1. Bone pain and multifocal destructive bone lesions.
  2. Increased susceptibility to infections (pyelonephritis, pneumonia).
  3. Renal failure.
  4. Anemia.
    133
  5. Bleeding tendencies.
  6. Hyperviscosity syndrome.
  7. Neurologic symptoms.
  8. Hypercalcemia, hyperuricemia.
  9. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, multiple myeloma and skin changes).
 
Diagnosis
  1. Triad of:
    1. Marrow plasmacytosis greater than 10%.
    2. Radiological evidence of lytic bony lesions.
    3. Demonstration of serum and urine ‘M’ component.
 
Treatment (Rx)
  1. Chemotherapy—alkylating agents.
  2. Symptomatic treatment.
  3. Stem cell transplantation.
  4. IFN-α.
 
Prognosis
  1. Poor prognosis, if there is:
    1. Secretion of lambda light chain.
    2. Increased cytogenic abnormalities.
    3. Increased β2 microglobulin.
 
HODGKIN LYMPHOMA
  1. Hodgkin lymphoma is a group of neoplasms that arise almost invariably in a single lymph node or chain of LNs and spread characteristically in a stepwise pattern to the anatomically contiguous nodes.
  2. This is characterized by the presence of RS cells.
 
Reed-Sternberg Cells or RS Cells
 
Classic RS Cell
  1. A large cell with bilobed nucleus.
  2. Each lobe is a mirror image of the other.
  3. Each lobe is a prominent, eosinophilic nucleolus.
  4. A clear halo around the nucleolus, giving an owl eye appearance.
  5. Abundant amphophilic cytoplasm.
 
Lacunar Type RS Cell
  1. Smaller than classic RS cell.
  2. Similar to classic RS cell except that these lie in a pericellular space or lacuna.
 
Popcorn RS Cell
  1. Larger with lobulated nucleus.
  2. Have a popcorn shape.
 
Pleomorphic RS Cell
Pleomorphic atypical nucleus.
(Refer Fig. 14.16, Harshmohan 6th edition).
 
Etiopathogenesis
  1. Arising from germinal center of B cells (Fig. 12.3)
  2. A close association with EBV.
  3. The RS cells contain high levels of activated NF-κB, which stimulates B cell proliferation and protect B cells from apoptosis.
  4. The EBV protein activates this NF-κB.
  5. Certain cytokines like IL-5, IL-13 and TGF-β have a role in pathogenesis of Hodgkin lymphoma.
    134
    These cytokines are produced by RS cells.
 
Classification
 
Rye Classification
  1. (L) predominance type.
  2. Nodular sclerosing type.
  3. Mixed cellularity type.
  4. (L) depletion type.
 
WHO Classification
The WHO classification is shown in the Table 12.5.
 
Morphology
 
(L) Predominance Type
  1. Proliferation of small (L) admixed with histiocytes.
  2. Increased number of classic RS cells.
  3. Popcorn RS cells can also be seen.
  4. Nodular form—replacement of nodal architecture by numerous neoplastic nodules.
  5. Diffuse form—diffuse proliferation of cells and number of nodules.
 
Nodular Sclerosing Type
  1. Presence of lacunar type of RS cells.
  2. Presence of collagen bands.
  3. Classic RS cells are infrequent.
  4. Some (L), (E) and histiocytes are seen.
 
Mixed Cellularity Type
  1. Typical RS cells are frequent.
  2. Presence of infiltrate, which includes (L), (E), (N), histiocytes and plasma cells.
 
(L) Depletion Type
  1. Diffuse fibrotic variant.
    1. Hypocellular and diffuse fibrosis.
    2. Numerous classic and pleomorphic RS cells.
    3. Some (L) and atypical histiocytes (Hodgkin cells).
  2. Reticular variant.
    1. More cellular.
    2. Few classic RS cells.
    3. Large number of atypical histiocytes and some (L).
      135
 
Nodular (L) Predominant Type
  1. Have a nodular growth pattern.
  2. Predominance of small (L) and a few RS cells.
 
Immunophenotype
Refer the classification.
 
Clinical Features
  1. Lymphadenopathy (mainly cervical and mediastinal).
  2. Splenomegaly and sometimes hepatomegaly.
  3. Constitutional symptoms.
 
Diagnosis
  1. Clinical features.
  2. Demonstration of RS cells.
  3. In Hodgkin lymphoma, the neoplastic cells are RS cells, but these are only less than 5% of total cellularity.
  4. Anemia.
  5. Serum iron and TIBC are low.
  6. Marrow infiltration.
  7. Moderate leukemoid reaction.
  8. Increased ESR.
  9. Decreased CMI, but humeral immunity is normal.
  10. Immunophenotyping.
 
Staging
  • Stage 1: Involvement of a single LN region
  • Stage 1E: A single extralymphatic site
  • Stage 2: Two or more LN region on the same side of the diaphragm
  • Stage 2E: Stage 2 with contiguous extranodal site
  • Stage 3: LN regions on the both sides of the diaphragm
  • Stage 3E: Stage 3 with contiguous extranodal site
  • Stage 3S: Stage 3 with spleen involvement
  • Stage 3ES: Stage 3E + stage 3S
  • Stage 4: Multiple disseminated involvement of extranodal sites.
Table 12.6   Hodgkin lymphoma (HL) VS non-Hodgkin lymphoma (NHL)
Features
HL
NHL
Cells
Mostly B cells
90% B cell, 10% T cell
LN involvement
Localized
Disseminated
Extranodal involvement
Uncommon
Common
BM involvement
Uncommon
Common
Constitutional symptoms
Common
Uncommon
Chromosomal defect
Aneuploidy
Translocation, deletion
Spill-over
Never
May spread to blood
Prognosis
Better (75%–85%)
Bad (30%–40%)
136
 
Prognosis
  1. Stage 1 and 2 have 100%, 5 year survival.
  2. Advanced stages have 50%, 5 year survival.
  3. Refer classification.
The Hodgkin lymphoma vs non-Hodgkin lymphoma is given in Table 12.6.
 
DISSEMINATED INTRAVASCULAR COAGULATION
  1. Also called defibrillation syndrome or consumption coagulopathy.
  2. As the name indicates DIC is characterized by formation of thrombi throughout the microvasculature.
 
Etiology
 
Obstructive Complications
  1. Abruption placenta.
  2. Septic abortion.
  3. Amniotic fluid embolism.
  4. Retained dead fetus.
  5. Toxemia.
 
Infections
  1. Sepsis (gram −ve and gram +ve).
  2. Meningococcemia.
  3. Histoplasmosis.
  4. Aspergillosis.
  5. Malaria.
 
Neoplasms
  1. CA pancreas, CA prostate, CA lung, CA stomach.
  2. Acute promyelocytic leukemia.
 
Massive Tissue Injury
  1. Trauma.
  2. Burns.
 
Miscellaneous
Snakebite, shock, heat stroke, vasculitis, aortic aneurysm, liver disease, etc.
 
Pathogenesis
  1. The two major mechanisms, which starts the DIC process are:
    1. Release of thromboplastic substances.
    2. Widespread endothelial damage.
  2. The steps of pathogenesis of DIC are:
    1. Coagulation activation by the two mechanism mentioned above.
    2. Thrombotic phase.
      • The activation of coagulation leads to formation of platelet aggregates and thus deposition of thrombi.
    3. Consumption phase.
      • The thrombus consumes coagulation factors and platelets.
    4. Secondary fibrinolysis.
      • As a protective mechanism, the fibrinolysis get activated and FDPs are formed in circulation.
  3. As a result of thrombus formation, there occurs microvascular occlusion, which in turn leads to ischemic tissue injury and microangiopathic hemolytic anemia.
  4. Severe bleeding occurs as a result consumption of coagulation factors and platelets and inhibition of platelet aggregation. Pathogenesis of DIC is given in Figure 12.4.
    137
Fig. 12.4: Pathogenesis of DIC
 
Morphology
  1. Microthrombi in arterioles and capillaries.
  2. Kidneys, adrenals, brain and heart are mostly affected.
  3. A focal glomerulitis.
  4. Renal cortical infarcts.
  5. Sometimes, renal cortical necrosis.
  6. Adrenals—Waterhouse-Friderichsen syndrome.
  7. Contributes to Sheehan postpartum pituitary necrosis.
  8. Hemorrhages, petechiae and ecchymoses.
 
Clinical Features
  1. Bleeding and organ damage.
  2. Shock, acute renal failure, dyspnea, cyanosis, convulsion and coma.
 
Lab Findings
  1. Thrombocytopenia.
  2. Microangiopathic hemolytic anemia.
  3. PT, TT, APTT are prolonged.
    138
  4. Decreased fibrinogen levels.
  5. Increased FDPs.
 
Treatment (Rx)
  1. Treat the cause.
  2. Treat with anticoagulants or coagulants in FFP.
 
IDIOPATHIC OR IMMUNE THROMBOCYTOPENIC PURPURA
Idiopathic or immune thrombocytopenic purpura (ITP) is characterized by immunologic destruction of platelets and normal or increased megakaryocytes in BM.
 
Etiology
An autoimmune condition.
 
Pathogenesis
 
Acute ITP
  1. Self-limiting condition usually affects children after a viral illness (hepatitis C, IMN, CMV, HIV) or a URTI.
  2. In this, immune complexes are formed (viral Ag and Ab) and they crossreact with platelets leading to their destruction.
  3. Usually have a severe thrombocytopenia.
  4. Recovery within a few weeks to 6 months.
 
Chronic ITP
  1. More commonly in young females (20–40 years).
  2. Here, antiplatelet autoantibodies are found.
  3. These antibodies are mainly produced in spleen.
  4. Ab are targeted against platelet glycoproteins 2b-3a and 1b-9 complexes.
  5. Ab to platelet surface antigens are also seen.
  6. The antibodies are of IgG type.
  7. The Ab-mediated platelet destruction mainly in spleen.
 
Clinical Features
  1. Petechial hemorrhages, early bruising, mucosal bleeding.
  2. Melena and hematuria.
  3. Hepatosplenomegaly.
  4. Lymphadenopathy.
 
Lab Findings
  1. Thrombocytopenia (10,000–50,000/μL).
  2. Increased megakaryocytes in BM.
  3. Antiplatelet IgG Ab can be detected.
  4. Increased bleeding time.
 
Treatment (Rx)
  1. Shows 90% spontaneous recovery.
  2. Steroids and immune suppressants.
  3. Splenectomy.
  4. Platelet transfusions.
 
THROMBOTIC THROMBOCYTOPENIC PURPURA
Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy characterized by the pentad of:
  1. Fever.
  2. Thrombocytopenia.
    139
  3. Microangiopathic hemolytic anemia.
  4. Transient neurologic deficits.
  5. Renal failure.
 
Pathogenesis
  1. Deficiency of a metalloprotease ADAMTS-13 is the underlying cause of TTP.
  2. Either this can be congenital or acquired due to an autoantibody against the metalloprotease.
  3. This enzyme is essential for the degradation of very high molecular weight multimers of vWF.
  4. So the enzyme deficiency leads to accumulation of vWF multimers in plasma, which in turn stimulates the formation of platelet aggregates.
  5. These platelet aggregates and later get surrounded by fibrin to form microthrombi.
  6. These microthrombi consume platelets and leads to thrombocytopenia.
  7. An endothelial injury can trigger the process.
 
Clinical Features
  1. Pentad of symptoms—mentioned.
  2. Spleen may be palpable.
 
Lab Findings
  1. Thrombocytopenia and increased bleeding time.
  2. Negative Coomb's test.
  3. Leukocytes.
  4. Increased megakaryocytes in BM.
  5. Slight myeloid hyperplasia in BM.
  6. Microthrombi in capillaries, arterioles and venules.
 
HEMOPHILIA
 
Hemophilia-A
  1. Also called classic hemophilia.
  2. Due to deficiency or reduced activity of factor-VIII (antihemophilic factor).
  3. This is an X-linked recessive disorder.
  4. Clinically affected are mainly males.
  5. Females are usually asymptomatic carriers, but sometimes become symptomatic if factor VIII is less than 50% of normal.
 
Pathogenesis
  1. About 90% due to reduced level of factor-VIII and other 10% due to reduced activity of factor-VIII.
  2. Factor-VIII is essential for activation of factor-X in intrinsic coagulation pathway.
  3. So in hemophilia-A, the intrinsic coagulation pathway becomes defective.
  4. At least 25% factor-VIII activity is needed for normal coagulation.
  5. In symptomatic patients, the factor-VIII concentration will be less than 5%.
 
Clinical Features
  1. Petechiae are absent.
  2. Prolonged bleeding after injury.
  3. Increased TT, but normal PT.
  4. Decreased factor-VIII level.
 
Treatment (Rx)
  1. Factor-VIII replacement therapy.
  2. Factor-VIII concentrates or cryoprecipitates.
    140
 
Hemophilia-B
  1. Also called Christmas disease.
  2. Due to factor-IX deficiency.
  3. Inheritance and C/F are similar to hemophilia-A.
  4. BT is normal and APTT is prolonged.
 
Treatment (Rx)
Infusion of FFP or plasma enriched in factor-IX.
 
VON WILLEBRAND DISEASE
  1. Most common inherited coagulation disorder.
  2. Due to qualitative or quantitative defect in vWF.
  3. The vWF circulates in blood as a complex of factor-VIII-vWF.
  4. An autosomal dominant inheritance.
  5. Mutation of gene for vWF on chromosome-12 is responsible for this disease.
  6. The main function of vWF is to facilitate the adhesion of platelets to subendothelial collagen and thus to induce coagulation.
 
Clinical Features
  1. Bleeding from mucous membrane.
  2. Excessive bleeding from injuries.
  3. Type I.
    1. Most common.
    2. Mild-to-moderate.
    3. Synthesis of vWF is normal release of its multimers get inhibited.
  4. Type II.
    1. Less common.
    2. vWF is functionally defective.
  5. Type III.
    1. Rare and most severe.
    2. Low activity and reduced activity of vWF.
 
Lab Findings
  1. Prolonged BT, TT and APTT.
  2. Normal platelet count.
  3. Decreased vWF level.
  4. Reduced factor-VIII activity.
  5. Defective platelet aggregation.
 
Treatment (Rx)
Cryoprecipitates or factor-VIII concentrates are used to treat the bleedingepisodes.

LungsChapter 13

 
ACUTE RESTRICTIVE LUNG DISEASE
Acute restrictive lung disease is caused by diffuse alveolar capillary and epithelial damage.
 
Causes
 
Direct Lung Injury
  1. Common:
    1. Pneumonia.
    2. Aspiration of gastric content.
  2. Uncommon:
    1. Pulmonary contusion.
    2. Fat embolism.
    3. Near drowning.
    4. Inhalational injury.
 
Indirect Lung Injury
  1. Common:
    1. Sepsis.
    2. Shock (trauma).
  2. Uncommon:
    1. Cardiopulmonary bypass.
    2. A/c pancreatitis.
    3. Blood transfusion.
    4. Drug overdose and uremia.
 
Pathogenesis
  1. The main events are:
    1. Epithelial damage.
    2. Necrosis of type I pneumocytes.
    3. ↑ edema fluid.
    4. ↓ surfactant → due to damage of type II pneumocytes.
    5. Hyaline membrane formation.
  2. Basically results from the imbalance between protective and destructive molecules.
 
ALVEOLI IN ACUTE RESPIRATORY DISTRESS SYNDROME
The pathogenesis of ARDS is shown in Figure 13.1.
 
Morphology
  1. Dark red, firm, airless and heavy.
  2. Alveolar edema, hemorrhage and necrotic cells.
  3. Hyaline membrane lining the distended alveolar ducts.
  4. Organizing stage → ↑ proliferation of pneumocytes.
  5. Healing by alveolar fibrosis due to collagen deposition.
    142
Fig. 13.1: Pathogenesis of ARDS
 
Clinical Course
  1. Respiratory insufficiency and cyanosis.
  2. Poor prognosis—if increased age, sepsis and multisystem failure.
  3. If healed by alveolar fibrosis, the lung function gets compromised.
 
EMPHYSEMA
Emphysema is a abnormal permanent dilation of air spaces distal to terminal bronchioles (alveoli) along with destruction of their walls without much fibrosis.
 
Pathogenesis
  1. Protease—antiprotease imbalance (α-1 antitrypsin deficiency).
  2. Oxidant—antioxidant imbalance (smoking related).
  3. α-1 antitrypsin—encoded by genes on Pi locus on chromosome-14.
  4. Smoking—functional α-1 antitrypsin deficiency (Fig. 13.2).
 
Centriacinar (Centrilobular)
  1. Central or proximal part of the acini are involved.
  2. Distal alveoli are spared.
  3. More common and significant in apical segments.
  4. Mainly occur as a consequence of smoking in people who do not have α-1 antitrypsin deficiency.
  5. Most significant obstruction clinically.
 
Panacinar (Panlobular)
  1. Whole acini are involved.
  2. Common in lower lobe.
  3. Common in α-1 antitrypsin deficiency.
    143
Fig. 13.2: Pathogenesis of emphysema
 
Distal Acinar (Paraseptal)
  1. Distal acini are involved.
  2. Commonly adjacent to pleura, septa and margins.
  3. More severe in the upper half.
  4. Cyst-like structures (bullae) can be seen.
 
Irregular
Most common type.
 
Morphology
  1. Panacinar—lungs will be pale and voluminous.
  2. Centriacinar—lungs will be pink and less voluminous.
 
Histology
  1. Thinning and destruction of alveolar walls.
  2. Terminal and respiratory bronchioles are deformed.
  3. Loss of elastic tissue from alveolar septae.
  4. ↓ alveolar capillaries.
 
Clinical Course
  1. Dyspnea, cough, wheezing.
  2. Barrel-shaped chest and prolonged expiration.
  3. Sitting preferably in leaning forward position.
  4. Sometimes weight loss.
  5. Pink puffers (emphysema only).
  6. Blue blotters (emphysema + bronchitis → cyanosis).
  7. Death due to:
    1. Pulmonary failure → acidosis, hypoxia and coma.
    2. Right heart failure (cor pulmonale).
144
 
Conditions Related to Emphysema
  1. Compensatory overinflation.
  2. Obstructive overinflation.
  3. Bullous emphysema.
  4. Mediastinal emphysema.
 
CHRONIC BRONCHITIS
 
Definition
Persistent productive cough for at least 3 consecutive months in at least 2 consecutive years.
 
Types
  1. Simple chronic (C/c) bronchitis.
    • Mucoid sputum, but airflow is not obstructed.
  2. C/c asthmatic bronchitis.
    • Sputum, bronchospasm and wheezing intermittently.
  3. C/c obstructive bronchitis.
    • Sputum, outflow obstruction (in heavy smokers).
 
Pathogenesis
The pathogenesis of chronic bronchitis is shown in Figure 13.3.
 
Morphology
  1. Hyperemic and swollen mucosa.
  2. Mucoid or mucopurulent discharge.
  3. Hypertrophy of mucous glands.
  4. ↑ inflammatory infiltrate.
  5. ↑ goblet cells and obliteration of lumen.
 
Clinical Course
  1. Cough and sputum, recurrent infection.
  2. Blue blotters (severe cases).
 
ASTHMA
  1. Asthma is a chronic inflammatory disorder of the airway that causes recurrent episode of wheezing, breathlessness, chest tightness and cough (at night and early morning).
    Fig. 13.3: Pathogenesis of chronic bronchities
    145
  2. Characterized by triad of:
    1. Intermittent and reversible airway obstruction.
    2. C/c bronchial inflammation with eosinophilia.
    3. Bronchial smooth muscle hypertrophy and hyper-reactivity.
 
Main Mediators of Bronchoconstriction and Increased Permeability
  1. LTC4, LTD4, LTE4.
  2. Ach.
  3. Histamine.
  4. PG-D2.
  5. PAF → ↑ histamine.
 
Pathogenesis
  1. Non-atopic asthma (Fig. 13.4).
    Fig. 13.4: Pathogenesis of non-atopic asthma
  2. Drug-induced asthma (Fig. 13.5).
  3. Atopic (allergic) asthma (Fig. 13.6).
 
Morphology
  1. Overinflated lung with areas of atelectasis.
  2. Occlusion of bronchi and bronchioles with mucus plugs.
  3. Curschmann spirals—whorls of epithelial cells in mucus plugs.
  4. Charcot-leyden crystals—eosinophilic crystalloids.
  5. Airway remodeling—thickening of basement membrane, edema and inflammatory infiltrate, hypertrophy of glands and smooth muscles.
 
Clinical Course
  1. Dyspnea and wheezing.
  2. More difficulty in expiration.
  3. Intermittent attacks respond to corticosteroids and bronchodilators.
  4. Status asthmaticus—persistent and not respond to treatment.
  5. The disease is disabling than lethal.
 
BRONCHIECTASIS
Bronchiectasis abnormal permanent dilatation of bronchi and bronchioles caused by destruction of muscle and elastic supporting tissue due to C/c necrotizing infections.
Fig. 13.5: Pathogenesis of drug-induced asthma
146
Fig. 13.6: Pathogenesis of atopic (allergic) asthma
147
 
Causes
  1. Bronchial obstruction.
    1. Tumors, foreign body, mucous plug, etc.
  2. Congenital or hereditary condition.
    1. Cystic fibrosis—obstruction and infections.
    2. Ig deficiencies—infections.
    3. Kartagener syndrome—infections.
  3. Necrotizing or the suppurative pneumonia.
 
Pathogenesis
The pathogenesis of bronchiectasis is shown in Figure 13.7.
 
Morphology
  1. Usually bilateral lower lobes are affected.
  2. Mostly affect vertical air passages.
  3. Dilated bronchioles and distal bronchi (4 times).
  4. A/c and C/c inflammatory infiltrate (exudate).
  5. Desquamation and ulceration.
  6. Bacterial infections usually increased.
  7. Fibrosis of walls and peribronchiolar fibrosis (C/c).
  8. Sometimes necrosis and abscess.
Fig. 13.7: Pathogenesis of bronchiectasis
 
Clinical Course
  1. Severe persistent cough.
  2. Copious amount of mucopurulent sputum.
  3. Hemoptysis and clubbing.
  4. Respiratory failure and cor pulmonale.
 
PNEUMOCONIOSIS
  1. Pneumoconiosis is a chronic restrictive lung disease.
  2. This is a non-neoplastic lung reaction to inhalation of mineral dust particles.
 
Pathogenesis (Fig. 13.8)
  1. Depending on size, shape, solubility, reactivity, etc.
    Fig. 13.8: Pathogenesis of pneumoconiosis
    148
  2. More than 5 μm—cannot reach distal airway.
  3. Less than 0.5 μm—reach distal airway without much effect.
  4. 1–5 μm—dangerous and lodged at the bifurcation of distal airways.
  5. Coal dust—inert and need large amount.
  6. Silica and asbestos—relatively reactive.
 
Coal Worker's Pneumonia
  1. Asymptomatic anthracosis.
    • Pigment deposition only.
  2. Simple coal worker's pneumoconiosis (CWP).
    • Macrophage accumulation, but no pulmonary dysfunction.
  3. Complicated CWP or PMF.
    • Pulmonary function compromised.
 
Morphology
  1. Pulmonary anthracosis—carbon particles are engulfed by macrophages and deposited in connective tissues.
  2. CWP—coal macules and coal nodules:
    1. Coal macules—dust laden macrophages.
    2. Coal nodules—coal macules + collagen fibers.
  3. Upper lobe and upper part of lower lobe involved.
  4. Centriacinar emphysema can be seen.
  5. PMF—coal nodules coalesce to form larger lesions.
    1. Dense collagen fiber bundles are seen.
 
Clinical Course
  1. Coal worker's pneumoconiosis—benign black lungs.
  2. PMF—pulmonary dysfunction, pulmonary hypertension, cor pulmonale.
 
SILICOSIS
  1. Currently most prevalent C/c occupational disease.
  2. By inhalation of crystalline silica (mainly quartz).
  3. Release of TNF is very important in silicosis.
  4. Anti-TNF, Ab can reduce collagen accumulation in silicosis.
  5. Quartz with other minerals → decreases fibrogenic effect.
 
Morphology
  1. Silicotic nodules.
    1. Pale to black in upper zone.
    2. Concentric collagen bundles.
    3. Central amorphous area (birefringent silica particles).
  2. May coalesce to form hard collagen scar.
  3. Fibrotic lesion in pleura and hilar LNs.
  4. Eggshell calcification in lymph node—Ca surrounding a zone without calcification.
 
Clinical Course
  1. Fine nodularity in radiographs.
  2. PMF—dyspnea, pulmonary HTN, cor pulmonale.
  3. ↑ incidence of TB.
 
ASBESTOSIS AND RELATED DISEASES
  1. Asbestosis—parenchymal interstitial fibrosis.
    149
  2. Localized fibrotic plaques, pleural effusion, mesothelioma, bronchogenic carcinoma and laryngeal carcinoma.
  3. Two forms of asbestos fibers—serpentine and amphibole fibers.
  4. Amphibole is more pathogenic (straight fibers).
  5. Beyond its fibrogenic effect, it induces carcinogenesis by:
    1. Reactive free radicals—initiator and promoter.
    2. Adsorbing toxins onto its surface.
 
Morphology
  1. Diffuse parenchymal interstitial fibrosis with asbestos bodies.
  2. Asbestos bodies are:
    1. Golden brown bodies with translucent center.
    2. Its fibers coated with iron containing proteinaceous material.
  3. Begins in lower lobe.
  4. Distortion of normal architecture with enlarged air spaces.
  5. Thickening of visceral pleura and adhesion with chest wall.
  6. Pleural plaque of collagen and Ca on partial pleura.
 
Clinical Course
  1. Dyspnea, cough with sputum, bloody effusion.
  2. Cor pulmonale and CHF.
 
SARCOIDOSIS
  1. C/c restrictive lung disease.
  2. Multisystem disease of unknown etiology characterized by non-caseating granuloma in many tissues.
  3. More in age group of less than 40 and non-smokers.
 
Pathogenesis
  1. Mainly due to dysregulation of immune system.
  2. Genetic predisposition with certain HLA are also seen.
  3. Intra-alveolar and interstitial accumulation of CD4 TH1 cells (Fig. 13.9).
 
Morphology
  1. Non-caseating epithelioid granuloma—discrete collection of epithelioid cells and gaint cells rimmed by CD4 TH1 cells and outer fibroblast.
  2. Schaumann bodies—laminated bodies of Ca and proteins.
  3. Asteroid bodies—stellate inclusions within gaint cells.
  4. Sometimes central necrosis suggestive of infection.
    Fig. 13.9: Pathogenesis of sarcoidosis
    150
  5. Lungs.
    1. Granulomas mainly in interstitium.
    2. Later diffuse interstitial fibrosis.
    3. Hilar and parenchymal LNs involved.
    4. Sometimes peripheral lymphadenopathy (non-matted).
  6. Skin.
    1. Erythema nodosum (hallmark of A/c sarcoidosis).
      • Red tender nodules on anterior aspect of legs.
    2. Lupus pernio.
      • Indurated plaques with violaceous discoloration in the region of nose, lip and cheeks.
  7. Eyes and lacrimal glands.
    1. Iritis or iridocyclitis.
    2. Choroiditis, retinitis and optic nerve involvement.
    3. Sicca syndrome—lacrimal gland inflammation and suppression of lacrimation.
  8. Painful enlargement of parotids (xerostomia).
  9. Combined uveoparotid involvement— Mikulicz syndrome.
  10. Spleen—enlarged and granulomas can be seen.
  11. Liver—sometimes enlarged and granulomas often seen.
  12. Bone marrow is involved sometimes:
    1. Hypercalcemia and hypercalciuria due to ↑ calcium absorption (not due to bone destruction).
 
Clinical Course
  1. Skin lesions, hepatosplenomegaly, lymphadenopathy, etc.
  2. Dyspnea and dry cough.
  3. Fever, fatigue, weight loss, anorexia, etc.
 
PNEUMONIA
  1. Community acquired acute pneumonia.
  2. Community acquired atypical pneumonia.
  3. Nosocomial pneumonia (Klebsiella, Escherichia coli, Pseudomonas).
  4. Aspiration pneumonia (necrotizing).
  5. Chronic pneumonia (Nocardia, Actinomycetes, Histoplasma, Mycobacterium).
  6. Necrotizing pneumonia (mainly anaerobic bacteria).
  7. Pneumonia in immunocompromised (CMV, MAC, Aspergillus, Cryptococcus).
 
Acute Pneumonia
  1. Abrupt onset, high fever, shaking chills, pleuritic chest pain, cough with mucopurulent sputum and occasional hemoptysis.
  2. Streptococcus pneumoniae is most common cause.
  3. Examination of gram stained sputum for diagnosis.
  4. Numerous (N) and bacteria in sputum.
  5. Also caused by Haemophilus influenza, Moraxella, Staphylococcus aureus (abscess), Klebsiella (in C/c alcoholics), Legionella, Pseudomonas, etc.
 
Morphology
The lower lobes or right middle lobes are mostly affected.
151
 
Stage of Congestion (1–2 Day)
  1. Affected lobe is heavy, red and boggy.
  2. Exudate of bloody frothy fluid (CS).
  3. Vascular congestion and dilatation.
  4. Proteinaceous fluid, (N) and bacteria in alveoli.
 
Stage of Red Hepatization (2–4 Day, Early Consolidation)
  1. Liver-like consistency, firm and red.
  2. (N), red cells and fibrin in alveoli.
  3. (N) shows ingested RBCs.
 
Stage of Grey Hepatization (5–7 Day, Late Consolidation)
  1. Dry, grey and firm.
  2. Granular and liver-like consistency.
  3. Red cells are lysed and ↓ bacteria.
  4. ↓ (N) and macrophage appear.
  5. More dense fibrin strands.
 
Stage of Resolution (8–20 Day)
  1. The exudate (fibrinous) in alveoli is enzymatically lysed to produce granular semi fluid debris, which is ingested by macrophages.
  2. Dirty brown creamy fluid on presenting.
  3. ↑ macrophages, ↓ (N).
  4. Fragmented fibrin strands.
  5. Engorged alveolar capillaries.
 
Complications
  1. Lung abscess.
  2. Empysema.
  3. Fibrosis.
  4. Meningitis, arthritis and infective endocarditis (due to bacterial dissemination).
 
Atypical Pneumonia
  1. A/c febrile respiratory disease with patchy inflammatory lesions in the lungs confined to septa and interstitium.
  2. Most common causative organism is Mycoplasma pneumoniae.
  3. Also by Chlamydia, Coxiella burnetii and some viruses.
 
Morphology
  1. Red-blue and congested lobes.
  2. Confined within alveolar walls.
  3. Septa are widened and edematous.
  4. Infiltrate of (L) and plasma cells.
  5. Lack of alveolar exudates and consolidation findings.
  6. Moderate amount of sputum.
 
Clinical Course
  1. Upper respiretory tract infection (URTI).
  2. Fever, headache, malaise and cough.
 
Nosocomial Pneumonia
Most common by Enterobacteriaceae, Pseudomonas, S. aureus, etc.
 
TUBERCULOSIS
Tuberculosis (TB) is communicable chronic granulomatous disease caused by Mycobacterium tuberculosis.
152
 
Epidemiology
 
Risk Factors
  1. Diabetes mellitus (DM).
  2. Hodgkin disease.
  3. C/c lung disease (silicosis).
  4. C/c renal failure.
  5. Malnutrition.
  6. Alcoholism.
  7. Immunosuppression (HIV).
 
Etiology
  1. Mycobacterium tuberculosis, Mycoplasma hominis (mainly).
  2. Mycobacterium bovis and M. avium-intracellulare (rarely).
  3. Transmission is air borne.
 
Clinical Course
  1. Low grade fever (evening rise of temperature), malaise, anorexia, weight loss, night sweats.
  2. Hemoptysis, pleuritic chest pain.
  3. Consolidation and cavitation (X-ray).
 
Primary Tuberculosis
  1. Occur in unsensitized person.
  2. Fate of primary TB.
    1. Induces hypersensitivity and increases resistance.
    2. Reactivation and cause secondary TB.
    3. Progressive primary TB (without interruption—mainly in HIV).
  3. Complication—TB meningitis, miliary TB.
 
Pathogenesis
  1. An example for cell-mediated (delayed) hypersensitivity.
  2. Figures 13.10 and 13.11 gives the schematic representation of delayed hypersensitivity at the age of ‘0’–3 weeks and more than 3 weeks respectively.
 
Morphology
  1. Mainly lower part of upper lobe and upper part of lower lobe is affected.
  2. Grey white inflammatory consolidation (granuloma of 1–1.5 cm)—Ghon focus.
    Fig. 13.10: Pathogenesis of primary pulmonary TB (0–3 week)
    153
    Fig. 13.11: Pathogenesis of primary pulmonary TB (> 3week)
  3. Spread to LNs and the combination of parenchymal and nodular lesion —Ghon complex.
  4. Granuloma.
    1. Central caseous necrosis.
    2. Epithelioid and gaint cells.
    3. Few fibroblasts and inflammatory cells (L).
  5. Later Ghon complex regresses and fibrosed, which is followed by calcification—Ranke complex.
 
Secondary Tuberculosis
  1. Occur in previously sensitized host.
  2. Occur usually by reactivation.
  3. More localized to apex of upper lobes (↑ O2 tension).
  4. Regional LNs are less involved.
  5. Decreases bacilli in sputum HIV patients.
 
Pathogenesis
  1. Occur in re-exposure or previously sensitized host.
  2. The mechanism is same.
  3. But the defensive reaction is more and hence, the necrosis will be more intense and rapid.
  4. There will be false negative for tuberculin test due to loss of hypersensitivity.
 
Morphology
The initial small granuloma can regress by fibrosis and leaving only fibrotic scars at different sites.
 
Later (Disseminated) Stages of Secondary Tuberculosis
Progressive pulmonary TB
  1. Enlargement of the apical lesion with ↑ caseation.
    154
  2. Erosion into bronchus and an irregular cavity lined by caseous material can be seen.
  3. Erosion into blood vessels leads to hemoptysis.
  4. With adequate treatment—healing by fibrosis.
  5. Inadequate treatment—dissemination.
Miliary TB
  1. Organism → lymphatics → venacava → right heart → pulmonary arteries → lungs.
  2. Multiple small (2 mm) yellow white consolidation spots in lung parenchyma.
Endobronchial, endotracheal and laryngeal TB
  1. Occur when spreads through lymphatics or expectorated material.
Systemic miliary TB
  1. Organism → pulmonary veins → left heart → other tissues.
  2. Mainly in liver, BM, spleen, adrenals, kidney, meninges, epididymis and fallopian tube.
 
Isolated Organ TB
  1. Hematogenous spread.
  2. Meninges, kidney, adrenals and bones are mainly involved.
  3. TB of vertebrae—Pott disease (leads to cold abscess).
Lymph nodes
  1. Lymphadenitis—most frequent extrapulmonary TB.
  2. Cervical LNs—scrofula (commonest).
Intestinal TB
  1. By intake of contaminated milk or other products.
  2. Inflammatory enlargement and ulceration.
Pleural involvement
  1. Effusion, tuberculosis, empyema, fibrous pleuritis, etc.
 
LUNG CARCINOMAS
  1. Small cell lung carcinoma (SCLC).
  1. Mixed → adenosquamous carcinoma, squamous-small cell carcinoma.
  2. Most commonest—squamous cell carcinoma (smokers).
  3. Most commonest in non-smokers—adenocarcinoma.
  4. SCLC:
    1. Metastasized by the time of diagnosis.
    2. Better treated by chemotherapy.
    3. RB gene mutations are usually seen.
  5. Non-small cell lung carcinoma (NSCLC):
    1. Better treated by surgery.
    2. p16 gene mutation is usually seen.
 
Etiopathogenesis
The etiopathogenesis of CA lungs is shown in Figure 13.12.
 
Morphology
  1. Begins as a small grey white mucosal lesion.
  2. Later enlarges and invade bronchi and air spaces.
  3. Large masses push adjacent lung parenchyma.
    155
    Fig. 13.12: Etiopthogenesis of CA lung
  4. May lead to cavitation and hemorrhage.
  5. May undergo necrosis.
  6. May invade pleura and chest wall.
  7. Distant spread through hematogenous and lymphatic route.
 
Squamous Cell Carcinoma
  1. Arise centrally in major bronchus.
  2. Dissemination is more.
  3. This is usually preceded by metaplasia and dysplasia. Later transform into carcinoma in situ.
  4. Well differentiated—with keratin pearls and intercellular bridges with well-defined squamous cell features.
  5. Poorly differentiated—with minimal squamous cell features.
 
Adenocarcinoma
  1. Usually more peripherally located near the scars.
  2. Grow slowly, but metastasize at an early stage.
  3. Precursor lesions are atypical adenomatous hyperplasia (AAH).
  4. AAH—hyperplasia of epithelial cells resembling type II pneumocytes with ↑ atypia (hyperchromasia, pleomorphism and prominent nucleoli).
  5. Three types—acinar (gland forming), papillary and solid.
 
Bronchioalveolar Carcinoma
  1. Bronchioalveolar carcinoma (BAC) is a subtype of adenocarcinoma.
  2. Growth along pre-existing structures without altering the alveolar structure.
  3. Pneumonia-like consolidation.
  4. Mucinous and non-mucinous type.
  5. The ↑ proliferation of BA stem cells leads to BAC.
  6. Sometimes the sequence will be, AAH → BAC → invasive adenocarcinoma.
 
Large Cell Carcinoma
Undifferentiated and cells have large nuclei and prominent nucleoli.
 
Small Cell Lung Carcinoma
  1. Pale grey central masses invade into parenchyma and nodes.
    156
  2. Small cells with scanty cytoplasm and granular chromatin.
  3. Mitotic figures can be seen.
  4. Extensive necrosis.
  5. Shows cellular fragmentation and nuclear molding.
  6. Derived from neuroendocrine cells of lung and show neuroendocrine markers.
 
Clinical Course
  1. The chain of spread involves nodes in the order of:
    1. Hilar nodes → mediastinal → neck (scalene) → clavicular (Virchow) → distant metastasis.
  2. Pancoast tumor—apical tumors compress on:
    1. Brachial plexus—pain along ulnar nerve distribution.
    2. Cervical sympathetic plexus —Horner syndrome (endopthalmos, ptosis, miosis, anhydrosis).
  3. Often accompanied by destruction of first and second ribs and sometimes thoracic vertebrae also.
  4. C/c cough with expectoration and hemoptysis.
  5. Hoarseness of voice, chest pain, effusion, atelectasis.
  6. Superior venacaval syndrome due to compression.
  7. Metastasis to bone liver and bones.
  8. SCLC has less prognosis compared to NSCLC.
 
Paraneoplastic Syndromes in Carcinoma Lung
  1. Hypercalcemia due to parathormone-like peptide.
  2. Cushing syndrome due to ↑ ACTH-like peptide.
  3. Syndrome of inappropriate secretion of ADH.
  4. Neuromuscular syndrome (myasthenia gravis, peripheral neuropathy).
  5. Hypertrophic pulmonary osteoarthropathy (HPOA).
  6. Hematologic—like DIC, NBTE, etc.
 
MALIGNANT MESOTHELIOMA
  1. Carcinoma of mesothelial cells arising from pleura.
  2. Also occur rarely from pericardium and peritoneum.
  3. Close relation with asbestosis:
    1. Asbestos accumulate mainly near the pleura.
    2. Release reactive O2 species → DNA damage and oncogenic mutation.
    3. Mutation of p16 and NF2.
 
Morphology
  1. Preceded by extensive pleural fibrosis and plaque formation.
  2. Lung is en-sheathed by a yellow -white gelatinous layer of tumor.
  3. Distant metastasis is rare.
  4. Spreads to parenchyma of chest wall.
  5. Epithelial pattern.
    1. Lining of cuboidal cells.
    2. Small papillary projections.
  6. Sarcomatoid pattern.
    1. Fibroblast like spindle cells.
  7. Biphasic.
    1. Both pattern mixed.

Kidney and its Collecting SystemChapter 14

 
NEPHROTIC SYNDROME
  1. Nephrotic syndrome is a clinical complex including:
    1. Massive proteinuria (> 3.5 g/day).
    2. Hypoalbuminemia (< 3 g/dL).
    3. Generalized edema.
    4. Hyperlipidemia and lipiduria.
  2. The principal derangement is in the capillaries of glomeruli, which leads to ↑ permeability → proteinuria and lipiduria.
  3. Hypoalbuminemia → edema.
  4. Fluid escapes from vascular compartment into tissue → ↓ plasma volume → ↑ aldosterone → ↓ GFR and ↓ ANF → salt and water retention → aggregation of edema → anasarca.
 
Causes of Nephrotic Syndrome
 
Primary Causes (Glomerular Diseases)
  1. The membranous glomerulonephritis (GN).
  2. Minimal change disease (lipoid nephrosis).
  3. Focal segmental glomerulosclerosis (FSAS).
  4. Membranoproliferative GN.
  5. Immunoglobulin (IgA) nephropathy.
 
Secondary Causes (Systemic Diseases)
  1. Diabetes.
  2. Amyloidosis.
  3. Systemic lupus erythematosus (SLE).
  4. Drugs (gold, penicillamine).
  5. Infections (malaria, HIV, hepatitis-B).
  6. Malignancy (carcinoma, melanoma).
  7. Others (bee sting, allergy, hereditary).
 
Membranous Glomerulonephritis
Membranous glomerulonephritis is common in adults.
  1. Characterized by the presence of subepithelial Ig containing deposits along GBM.
  2. Diffuse thickening of capillary wall in late stage.
  3. It is usually idiopathic and sometimes secondary.
 
Pathogenesis
  1. C/c immune complex-mediated nephritis.
  2. Antibodies against endogenous or planted glomerular Ag (Fig. 14.1).
158
Fig. 14.1: Pathogenesis of membranous GN
 
Morphology
  1. Diffuse thickening of GBM.
  2. Subepithelial complex deposits and GBM spikes for separating these deposits (spikes and dome pattern).
  3. Granular deposits on GBM.
  4. With progression, sclerosing of GBM and ↑ thickening.
  5. Effacement of foot processes of podocytes.
 
Clinical Course
Non-selective and less proteinuria; bad prognosis.
 
Minimal Change Disease (Lipoid Nephrosis)
Minimal change disease is most commonly seen in children.
 
Pathogenesis
Injury to podocytes and effacement of foot processes caused by T cell derived factors.
 
Morphology
  1. Glomeruli appears normal in light microscopy.
  2. Proximal convoluted tubule (PCT)—cells laden with protein droplets and lipids.
  3. Uniform and diffuse effacement of podocyte foot processes in electron microscopy.
  4. Microvillus formation and focal derangements may be seen.
 
Clinical Course
  1. Selective proteinuria (mainly albumin).
  2. Prognosis is good with corticosteroids.
 
Focal Segmental Glomerulosclerosis
  1. Focal segmental glomerulosclerosis (FSGS) is most common in adults.
  2. Sclerosis of some glomeruli (focal).
  3. Only some segments in each glomeruli are affected (segmental).
  4. Primary or secondary to some other diseases like HIV, IgA nephropathy.
 
Pathogenesis
  1. Clearly not known.
  2. Believed to be resulting from MCD.
  3. Podocyte injury is the initiating event.
 
Morphology
  1. Focal and segmental involvement of glomeruli.
    159
  2. Affected glomeruli have increased matrix, capillary lumen obliteration and deposition of hyaline masses and lipids.
  3. Global sclerosis → completely sclerosed glomeruli (late).
  4. Effacement of foot processes and IgM deposition.
  5. Tubular atrophy and interstitial fibrosis.
  6. Collapsing glomerulopathy → severe manifestation of FSGS.
 
Clinical Course
  1. Hematuria, HTN, non-selective proteinuria.
  2. Prognosis with corticosteroid—poor.
 
Membranoproliferative Glomerulonephritis
  1. Hematuria, HTN, non-selective proteinuria.
  2. Proliferation of glomerular cells.
 
Pathogenesis
  1. Membranoproliferative glomerulonephritis-1 (MPGN-1).
    1. Caused by circulating immune complex.
  2. MPGN-2.
    1. Not much clear.
    2. Due to ↑ complement activation.
    3. Ab against C3 convertase → activation of alternate complement pathway.
 
Morphology
  1. Large glomeruli of lobular appearance.
  2. Proliferation of glomerular cells and ↑ leukocytes.
  3. Thickening and splitting of GBM.
  4. Type I—subendothelial deposition of C3 and IgG.
  5. Type II—subendothelial deposition of C3, but not IgG.
 
Clinical Course
  1. Hematuria and protenuria.
  2. Poor prognosis.
 
IgA Nephropathy (Berger Disease)
Immunoglobulin A (IgA) deposition in mesangium.
 
Pathogenesis
  1. Increased IgA production and decreased clearance.
  2. Abnormal glycosylation of IgA leads to decreased clearance.
  3. Increased deposition of IgA and IgA immune complexes in the mesangium trigger alternate complement pathway leads to glomerular injury.
 
Morphology
  1. Mesangial widening (deposits of IgA, IgG, IgM and C3).
  2. Focal segmental inflammation.
  3. Diffuse mesangial proliferation (MPGN).
  4. Subendothelial deposits.
 
Clinical Course
  1. Gross hematuria usually after some systemic infection.
  2. With or without proteinuria.
160
 
NEPHRITIC SYNDROME
  1. Clinical complex of acute onset characterized by:
    1. Hematuria with RBC and RBC casts.
    2. Oliguria and azotemia (↑ N2 containing compound).
    3. Hypertension (HTN).
    4. Some proteinuria and edema.
  2. Proliferation of glomerular cells followed by leukocyte infiltrate.
  3. Inflammatory reaction injuries the capillaries and leads to hematuria and ↑ GFR (oliguria and azotemia).
  1. As a result, Na+ and water retention → HTN.
 
Acute Postinfectious Glomerulonephritis (Poststreptococcal glomerulonephritis or PSGN)
  1. Glomerular deposits of immune complexes.
  2. Glomerular proliferation and (N) infiltrate.
  3. Exogenous antigen → streptococcal, pneumococcal, staphylococcal, etc.
  4. Endogenous antigen → in SLE.
  5. PSGN occurs 4–8 weeks after recovery from infection.
 
Pathogenesis
Accumulation of immune complex, IgG, C3 complement on GBM and leads to glomerular injury.
 
Morphology
  1. Uniformly ↑ cellularity of all glomeruli (diffuse).
  2. ↑ (N) and (M) infiltrate.
  3. Necrosis of capillary wall.
  4. Crescents may be seen in glomeruli.
  5. Subepithelial humps (immune complexes) on GBM.
  6. Granular deposits of IgG and C3 complement.
 
Clinical Course
  1. Abrupt onset fever, malaise.
  2. Oliguria, azotemia, hematuria and HTN.
  3. Smoky brown urine.
 
Hereditary Nephritis
  1. Caused by mutations in GBM protein genes.
  2. Alport syndrome → nephritis + nerve deafness + eye disorders.
 
Pathogenesis
  1. Type IV collagen is made of heterotrimers of α3, α4 and α5.
  2. Mutation in any one α-chain → defective type IV collagen → alport syndrome.
 
Morphology
  1. Glomerular basement membrane (GBM), lens, cochlea are affected.
  2. Interstitial cells accumulate fats cells to form foam cells.
  3. With progress → glomerular sclerosis, tubular atrophy and fibrosis.
  4. GBM—thinned, attenuated and splitted.
  5. Later GBM—basket weave appearance.
161
 
Clinical Course
  1. X-linked (α5) mainly.
  2. α3 and α4 → AR/AD.
    • Familial hematuria/thin BM lesions.
 
IgA Nephropathy
Already discussed.
 
RAPIDLY PROGRESSIVE GN (CRESENTIC GN)
  1. Characterized by rapid loss of renal function with features nephritic syndrome (severe oliguria) and death due to renal failure, if untreated.
  2. Presence of crescents in the glomeruli.
  3. Proliferation of parietal epithelial cells of Bowman's capsule and (M) and macrophage infiltrate and exudates of plasma protein → formation of crescents.
 
Etiopathogenesis
Type I
  1. Anti-GBM Ab-mediated.
  2. Idiopathic.
  3. Good pasture syndrome.
Type II
  1. Immune complex mediated.
  2. Postinfectious.
  3. IgA nephropathy.
  4. Systemic lupus erythematosus (SLE).
Type III
  1. Pauci-immune, ANCA associated.
  2. Idiopathic.
  3. Wegener's granulomatosis.
  4. Microscopic angiitis.
 
Type I RPGN
  1. IgA and C3 deposits on GBM.
  2. Idiopathic → renal involvement only.
  3. Goodpasture syndrome →
    1. Renal failure + pulmonary hemorrhage.
    2. Anti-GBM Ab react with pulmonary alveolar capillary membrane.
Morphology
  1. Enlarged and pale kidneys.
  2. Petechial hemorrhages on cortical surface.
  3. Segmental necrosis and crescents in Bowman's capsule.
  4. IgA and C3 deposit on GBM.
 
Type II RPGN
  1. Deposition of immune complex on GBM.
  2. Lumpy bumpy appearance of GBM.
Morphology
  1. Segmental necrosis and GBM breaks.
  2. Crescents in BC.
  3. Granular pattern of immune complex.
 
Type III RPGN
  1. Lack of anti-GBM Ab and immune complex.
  2. ANCAs in serum.
Morphology
  1. Segmental necrosis and crescents.
  2. No detectable deposits.
Clinical Course
  1. Rapid onset.
  2. More severe oliguria and azotemia.
  3. Death due to renal failure, if untreated.
    162
  4. Prognosis becomes worse with increase in crescents.
 
ACUTE PYELONEPHRITIS
  1. Suppurative inflammation of kidney and renal pelvis caused by bacterial infection.
  2. Majority are associated with lower UTI.
 
Pathogenesis
  1. Hematogenous infection (Staphylococcus, Escherichia coli).
    1. Bacteria in blood → reach kidneys → acutepyelonephritis (APN).
  2. Ascending infection (E. coli, Klebsiella, Proteus, Enterobacter) (Fig. 14.2).
 
Risk Factors
  1. Genetic factors.
    1. Abnormal urinary tract, immunodeficiency.
  2. Instrumentation.
    1. Cystoscopy, catheterization.
  3. Female urethra.
    1. Short urethra, proximity to rectum.
  4. Urinary tract obstruction (easy bacterial multiplication).
    1. BPH, uterine prolapse in pregnancy.
  5. Diabetes.
    1. ↑ susceptibility infections, neurogenic bladder.
  6. Incompetence of vesicourethral valve and previous renal lesions.
 
Morphology
  1. Yellowish discrete raised abscess on the surface.
  2. Suppurative necrosis within the parenchyma.
  3. Intratubular (N) infiltrate and WBC casts in urine.
  4. Sometimes pyelonephrosis → pus in pelvis, calyces and ureter.
  5. Renal papillary necrosis (in DM, analgesic abuse) and coagulative necrosis with (N).
    Fig. 14.2: Pathogenesis of acute pyelonephritis
    163
  6. Cystitis → urine obstruction → hypertrophic bladder.
 
Clinical Course
  1. Sudden onset chill, fever, malaise.
  2. Pain at costovertebral angle.
  3. Pyuria and bacteriuria.
  4. Dysuria and ↑ frequency and urgency of micturition.
  5. Better treated with antibiotic.
  6. Papillary necrosis → poor prognosis.
 
C/c PYELONEPHRITIS
  1. Interstitial inflammation and parenchymal scarring.
  2. Visible scarring and deformity of calyces.
  3. Important cause of C/c renal failure.
 
Types
 
C/c Obstructive Pyelonephritis
  1. C/c obstructive lesions and recurrent infection.
  2. C/c inflammation and scarring → C/c pyelonephritis.
 
C/c Reflex Associated Pyelonephritis
  1. More common form.
  2. UTI + vesicoureteral reflux and intrarenal reflex.
  3. Leads to scarring and C/c renal insufficiency.
 
Morphology
  1. Uneven scarring of kidney.
  2. Scarring of pelvis and calyces.
  3. Uneven scarring of interstitium.
  4. Infiltrate of (L) and plasma cells.
  5. Dilation or contraction of tubules.
  6. Epithelial atrophy and fibrosis.
  7. Vascular changes.
  8. Glomerulosclerosis.
 
Clinical Course
  1. Gradual onset.
  2. HTN and renal failure.
  3. Kidneys are asymmetrically contracted.
  4. Secondary FSGS → Proteinuria.
 
DRUG INDUCED NEPHRITIS
  1. Penicillin (ampicillin, methicillin).
  2. Other antibiotics (Rifampin).
  3. Diuretics (Thiazides).
  4. Analgesics (aspirin, paracetamol, caffeine, codeine).
  5. Others (phenindione, cimetidine).
 
A/c TUBULAR NECROSIS
  1. Damaged tubular epithelial cells.
  2. A/c suppression of tubular function.
  3. Most common cause of A/c renal failure.
  4. A/c renal failure → oliguria (< 400 mL/day) within 24 hours of onset of disease.
    1. Ischemic ATN → associated with shock and hypotension.
    2. Nephrotic ATN → caused by poions like Hg, CCl4, drugs (gentamicin).
 
Clinical Course
  1. Initiation phase.
    1. 0–36 hours.
      164
    2. ↓ urine output.
    3. ↑ Serum creatinine.
  2. Maintenance phase.
    1. 2–6 days.
    2. Oliguria (50–400 mL/day).
    3. Uremia and fluid overload.
  3. Recovery phase.
    1. ↑ urine output.
    2. Serious electrolyte imbalances.
    3. ↑ vulnerability to infections.
    4. Later urine output comes to normal.
 
Pathogenesis
Pathogenesis of ATN in shown in Fig. 14.3.
 
MORPHOLOGY
  1. Necrosis of short segments of tubules.
  2. Tubular injury with cell detachment leads to formation of casts.
  3. Proteinaceous casts,
    1. Tamm-Horsfall protein + Hb + plasma protein.
    2. Sometimes myoglobin.
    Fig. 14.3: Pathogenesis of ATN
    165
  4. Edema and inflammation infiltrate in interstitium.
  5. But in toxic ATN,
    1. The tubular BM is generally spared.
    2. Necrosis prominent in PCT.
 
BENIGN NEPHROSCLEROSIS
Hyaline arteriosclerosis in kidney that occurs in benign HTN.
 
Pathogenesis
  1. Clear pathogenesis is not known.
  2. HTN is associated with renal vascular changes, which together induces sclerosis.
 
Morphology
  1. Kidneys are symmetrically atrophied.
  2. Fine granularity on surface.
  3. Hyaline arteriolosclerosis.
    1. Hyaline thickening of walls of small arteries and arterioles.
    2. Homogenous pink hyaline thickening of walls with the loss of underlying cellular details.
  4. ↓ lumen width → ↓ blood flow → ischemia → sclerosis.
  5. Diffuse tubular atrophy and interstitial fibrosis.
  6. Larger arteries show reduplication of elastic lamina along with fibrous thickening of media → fibroelastic hyperplasia.
 
Clinical Course
  1. Impairment of kidney function.
  2. ↓ GFR → ↓ urine output.
 
MALIGNANT NEPHROSCLEROSIS
Kidney changes in malignant HTN (hyperplastic arteriosclerosis).
 
Morphology
  1. Small pinpoint petechial hemorrhages on cortical surface → flea-bitten appearance.
  2. Fibrinoid necrosis and thrombi in glomerular capillaries.
  3. Homogeneous eosinophilic granular appearance of vessels.
  4. Hyperplastic arteriosclerosis.
  5. Some vessel wall → onion skin appearance.
 
Pathogenesis
Pathogenesis of malignant nephrosclerosis in shown in Fig. 14.4.
 
Clinical Course
  1. DBP is > 120 mm Hg.
  2. Papilledema, encephalopathy, CV abnormalities, renal failure.
  3. ↑ ICP → headache, nausea, vomiting, visual impairment.
  4. Microscopic hematuria.
  5. Mainly death is due to uremia.
 
POLYCYSTIC KIDNEY DISEASE
 
Adult Polycystic Kidney Disease
  1. Multiple expanding cyst, which ultimately destroy the intervening parenchyma.
  2. Leads to C/c renal failure.
166
Fig. 14.4: Pathogenesis of malignant nephrosclerosis
 
Pathogenesis
  1. Autosomal dominant.
  2. Usually the defective gene is PKD-1 (on chromosome-16).
  3. Adult polycystic kidney disease (APKD) develops usually by loss of 2 alleles of PKD-1 gene.
  4. PKD-2 mutation is minor.
  5. PKD-2 is on chromosome-4.
  6. Polycystin-2 → Ca permeable membrane channel (Figs 14.5 and 14.6).
 
Morphology
  1. Enlarged kidneys, readily palpable abdominally.
  2. Multiple cyst with destruction of intervening parenchyma.
  3. Cyst are filled with clear/turbid/hemorrhagic fluid.
  4. Pressure atrophy of surrounding parenchyma.
  5. Superimposed HTN or infection is common.
  6. Liver cysts are also seen (asymptomatic).
167
Fig. 14.5: Pathogenesis of adult PKD-1
Fig. 14.6: Pathogenesis of adult PKD-2
 
Clinical Course
  1. Does not produce symptoms until 4th decade.
  2. Flank pain (usually), intermittent gross hematuria.
  3. HTN and urinary infection.
  4. Death due to uremia and hypertensive complications.
 
Childhood Polycystic Kidney Disease
  1. Autosomal recessive.
  2. Mutation in the PKHD-1 gene (chromosome-6p) → defective receptor protein-fibrocystin → defective function of cilia in tubular epithelial cells.
  3. Subcategories—perinatal, neonatal, infantile and juvenile.
 
Morphology
  1. Numerous small cysts.
  2. Sponge like appearance.
  3. Cuboidal lining of the cysts (origin from CT).
  4. Invariably bilateral.
  5. Cyst in liver—symptomatic.
 
Clinical Course
  1. Perinatal and neonatal forms are common.
  2. Dies in infancy due to hepatic and renal failure.
  3. If survive infancy—develop liver cirrhosis later.
 
RENAL STONES
The important cause is increased urine concentration of constituents, so that it exceeds their solubility in urine (supersaturation) and leads to precipitation.
  1. Calcium stones (75%) → alkaline pH.
  2. Struvite stones (15%) → urea splitting organism, alkaline pH.
  3. Uric acid stones (6%) → acidic urine.
  4. Cysteine stones (2%) → cystinuria.
  5. Others (2%) → xanthinuria.
 
Etiopathogenesis
Calcium stones (phosphate and oxalates)
  1. Idiopathic hypercalciuria without hypercalcemia (↑ absorption).
  2. Hypercalciuria with hypercalcemia (hyperparathyroidism, ↑ vitamin D).
  3. Hyperoxaluria.
    168
  4. Hyperuricosuria.
  5. Without any known metabolic abnormality.
Struvite stones
  1. UTI (due to alkaline urine).
Uric acid stone
  1. With hyperurecemia (gout, leukemia).
  2. With hyperuricosuria (gout, leukemia).
  3. Idiopathic.
Cysteine stone
  1. Inborn error of metabolism.
    1. Staghorn calculi → branching structures on calculi.
 
Inhibitors of CrystalFormation in Urine
  1. Tamm-horsfall proteins.
  2. Osteopontins.
  3. Pyrophosphate.
  4. Diphosphonates.
  5. Mucopolysaccharides.
  6. Nephrocalcin (GP).
 
Clinical Course
  1. Intense pain (renal or ureteric colic) → Flank pain radiating to groin (loin to groin).
  2. Hematuria.
  3. Ulceration and bleeding.
  4. ↑ urinary infection.
  5. Renal failure at later stage.
 
HYDRONEPHROSIS
  1. Dilatation of pelvis and calyces with accompanying parenchymal atrophy caused by obstruction to urine outflow.
  2. Obstruction may be sudden or insidious.
  3. Obstruction can occur at any level from urethra upto pelvis.
 
Causes
  1. Congenital:
    1. Atresia of urethra.
    2. Valve formations.
    3. Renal ptosis with torsion.
    4. Kinking of ureter.
  2. Acquired:
    1. Foreign bodies (calculi, necrotic papillae).
    2. Tumors (BPH, CA prostrate, CA bladder)
    3. Inflammation (prostatitis, urethritis, ureteritis).
    4. Neurogenic—spinal cord damage with bladder palsy.
    5. Normal pregnancy—due to mild compression.
 
Pathogenesis
Pathogenesis of hydronephrosis is shown in Fig. 14.7.
 
Morphology
  1. Dilated pelvis and calyces.
  2. Parenchymal atrophy.
  3. ↓ GFR and renal function impairment.
  4. Sometimes hydroureter (dilatation of ureter).
  5. Tubular dilatation followed by atrophy and fibrosis.
  6. Sometimes coagulation necrosis also.
169
Fig. 14.7: Pathogenesis of hydronephrosis
 
Clinical Course
  1. Bilateral—if the obstruction is below ureter.
  2. Unilateral—if the obstruction is in ureter or above.
  3. Oliguria and anuria.
  4. Decreased GFR and renal function impairment.
 
RENAL CELL CARCINOMA
  1. Derived from the renal tubular epithelium.
  2. Located predominantly in the cortex.
 
 
Risk Factors
  1. Smoking.
  2. HTN and obesity.
  3. Cadmium exposure (occupation).
  4. APKD as a result of dialysis.
 
Clear Cell Carcinoma
  1. Renal cell carcinoma (RCC).
  2. Occur sporadically and familial.
  3. Occur in association with von-Hippel-Lindau disease.
  4. Mutation of VHL gene (tumor suppressor gene)—clear cell RCC (chromosome-3p25).
 
Morphology
  1. Usually solitary and large.
  2. CS—yellow to grey-white with cystic softening or hemorrhage.
  3. Well defined margins.
  4. Aggressive and surrounding parenchyma affected.
  5. Tumor invades pelvis, calyses, ureter and renal vein.
  6. Invasion into perinephric fat and adrenals.
  7. Tumor cells appear vacuolated (lipid-laden) or solid with granular or clear cytoplasm.
  8. Sometimes anaplasia (mitotic figures, hyperchromasia, pleomorphism).
  9. Scanty, but vascularized stroma.
 
Papillary Renal Cell Carcinoma
  1. Second most common type of RCC.
  2. Papillary growth pattern.
  3. Usually multifocal and bilateral.
  4. Both sporadic and familial.
  5. No mutation.
  6. Duplication of MET proto-oncogene on chromosome-7q31.
  7. Associated with trisomy 7.
170
 
Morphology
  1. Numerous papillae with fibrovascular core.
  2. Necrosis, hemorrhage and cystic degeneration.
  3. Orange-yellow color due to less lipid content.
  4. Tumor cells have pink cytoplasm.
 
Chromophobe RenalCell Carcinoma
  1. Least common type of RCC.
  2. Arise from intercalated cells of collecting duct.
  3. Multiple losses of entire chromosomes—1, 2, 6, 10, 13, 17 and 21.
  4. Have good prognosis.
 
Morphology
  1. Grossly tan brown.
  2. Darkly stained tumor cells.
  3. Distinct cell membrane.
  4. Perinuclear hallow.
  5. Microvesicles are seen.
 
Clinical Course of Renal Cell Carcinoma
  1. Hematuria (most frequent)
  2. Large tumor—flank pain with palpable mass.
  3. Fever and polycythemia.
  4. Hypercalcemia, HTN, Cushing syndrome (paraneoplastic syndromes).
  5. Metastasis to bone and lungs.
  6. Triad of:
    1. Painless hematuria.
    2. Palpable abdominal mass.
    3. Dull flank pain.
 
WILMS TUMOR
  1. One of the major cancers in children (2–5 year).
  2. Derived from mesoderm.
  3. Also called nephroblastoma.
  4. Sporadic and familial occurrence.
  5. Patients with WAGR and DDS show ↑ occurrence of Wilms tumor.
  6. Associated with the abnormality of WT1 gene (chromosome-11p13).
  7. WAGR—deletion of WT1.
  8. DDS—mutation of WT1.
  9. BWS also predispose to Wilms tumor—mutation of WT2 locus (chromosome-11).
 
Morphology
  1. Large, solitary, well circumscribed mass.
  2. CS—homogenous, soft, tan grey colored.
    1. Cystic degeneration, hemorrhage and necrosis are seen.
  3. Triphasic combination.
    1. Blastemal (sheets of blue cells) cells.
    2. Stromal (fibrocystic or myxoid) cells.
    3. Epithelial (tubules or glomeruli) cells.
  4. Rarely heterogenous—SMCs, epithelial cells, adipose tissue, cartilage, osteoid, etc.
  5. Rarely shows anaplasia.
  6. Nephrogenic rests.
    1. Precussor lesions of Wilms tumor.
    2. Hyperplastic or sclerotic.
 
Clinical Course
  1. Palpable abdominal mass.
  2. Fever, abdominal pain with hematuria.
  3. Good prognosis with nephrectomy and chemotherapy.

Oral Cavity and Gastrointestinal TractChapter 15

 
LEUKOPLAKIA
  1. Whitish well-defined mucosal patch or plaque by epidermal thickening or hyperkeratosis.
  2. Cannot be scraped off easily.
  3. Commonly seen on the vermilion border of lower lip, buccal mucosa, hard and soft palate.
  4. Localized, smooth or roughened, leathery, white discrete areas.
  5. May be without epithelial dysplasia or with severe dysplasia (carcinoma in situ).
  6. Close association with tobacco abuse.
  7. More seen in older men.
  8. Can be transformed to squamous cell carcinoma.
  9. Lip and tongue lesions—more chance of transformation.
  10. Hairy leukoplakia (only in AIDS) and verrucous leukoplakia are different from classical leukoplakia.
 
ERYTHROPLAKIA
  1. Red, velvety, granular, circumscribed areas of irregular borders.
  2. May be elevated or hot.
  3. Marked dysplasia.
  4. Chance of transformation to carcinoma.
 
BARRETT ESOPHAGUS
  1. Replacement of normal distal stratified squamous mucosa by metaplastic columnar epithelium containing goblet cells.
  2. Occurring as a complication of long-standing gastroesophageal reflux disease (GERD).
  3. More common in males than in females (4:1).
  4. More common in white race.
  5. The re-epithelialization by columnar epithelium is due to the induction by low pH.
  6. This metaplastic columnar epithelium is more resistant acidic pH (not typical intestinal variety).
  7. Complications are ulceration and strictures.
  8. More risk of developing adenocarcinoma.
    172
    Fig. 15.1: Schematic representation of various diseases affecting esophagus
  9. Due to high grade dysplasia. The schematic representation of various diseases affecting esophagus is shown in the Figure 15.1.
 
Morphology
  1. Salmon-pink velvety mucosa.
  2. Exist as tongue extending into the junction.
  3. Metaplastic columnar epithelium with globlet cells.
  4. Dysplastic changes may be present.
  5. Repeated endoscopy and biopsy is needed for definitive diagnosis. The sequence of events in Barrett esophagitis is shown in the Figure 15.2.
    Fig. 15.2: Sequence of events in Barret esophagitis
 
ESOPHAGEAL CARCINOMA
  1. Arise from both mucosa and underlying mesenchyme.
 
Squamous Cell Carcinoma
  1. Common (90% of esophageal cancers).
  2. Mutation of tumor suppressor gene p16 and p53.
  3. Mutation of EGFR, KRAS and APC also seen.
 
Risk Factors
  1. Esophageal disorders—esophagitis, achalasia, Plummer-Vinson syndrome.
  2. Habits—alcoholism and tobacco abuse.
  3. Dietary.
    1. Deficiencies of vitamins (A, C), trace metals (Zn, Mb).
    2. Fungal contamination.
    3. Increased nitrites and nitrosamines.
  4. Genetic predisposition.
    1. Familial, associated with tylosis.
 
Morphology
  1. Epithelial dysplasia → CA in situ → invasive CA.
  2. At first: Grey-white small thickenings (plaque like).
  3. Later transformed to one of three forms.
    173
    1. Polypoid masses.
    2. Ulcerations into depth (sometimes erode outside structures).
    3. Diffuse infiltrative—wall thickening and lumen narrowing.
 
Adenocarcinoma
  1. Complication of Barrett esophagus.
  2. High grade dysplasia easily leads to adenocarcinoma.
  3. Aneuploidy and p53 mutation is commonly associated.
 
Morphology
  1. Usually located in distal one-third and may invade into stomach.
  2. Large nodular masses/ulcerative/diffuse infiltrative.
  3. Mostly these are mucin-producing glandular tumors.
 
Clinical Course
  1. Dysphagia, weight loss, anorexia, fatigue, weakness, etc.
  2. Often pain and obstruction also.
 
PEPTIC ULCER
  1. Discontinuity in the epithelial lining.
  2. Most common sites are first part of duodenum and lesser curvature of stomach (4:1).
  3. Duodenal ulcer—male is more affected than female (3:1).
  4. Remitting and relapsing disease.
 
Definition
Lesions or defects in the mucosa that penetrate at least into the submcucosa and often to muscularis propria or deeper.
 
Etiology
  1. Increased damage to mucosa.
    1. Helicobacter pylori infection (Fig. 15.3).
    2. NSAIDS (Fig. 15.4).
    3. Cigarette smoking (Fig. 15.5).
    4. Alcoholism.
    5. Hyperacidity.
  2. Decreased defence mechanisms.
    1. Ischemia.
    2. Shock.
    3. Delayed gastric emptying.
    4. Host factors.
 
Normal Defence Mechainsms
  1. Surface mucus secretion.
  2. Bicarbonate secretion.
  3. Mucosal blood flow.
  4. Apical surface membrane transport.
  5. Epithelial regenerative capacity.
  6. Elaboration of PGs.
Fig. 15.3: Helicobactor pylori leading onto peptic ulcer
Fig. 15.4: NSAIDs leading onto peptic ulcer
174
 
Pathogenesis
  1. Helicobacter pylori infection is the major etiology of peptic ulcer.
    1. H. pylori strains producing (vacuolating toxin) and CagA (cytotoxin associated gene-A) are more virulent.
  2. NSAIDs are the second most important etiological factor.
  3. Cigarette smoking.
 
Morphology
  1. Round, sharply punched out lesions (2–4 cm diameter).
  2. Usually, sites are anterior and posterior walls of first part of duodenum and lesser curvature of stomach.
  3. Associated with antral gastritis.
  4. Duodenal—smaller lesions.
  5. Gastric—larger lesions.
  6. The edges of the craters are perpendicular to the surface.
  7. Mild edema of adjacent mucosa.
  8. There is no significant elevation.
  9. Surrounding mucosal folds may be flat or radiating like spokes of wheel.
  10. The base of the lesion is clean due to peptic digestion.
  11. Perforation can leads to peritonitis.
  12. Healing—granulation tissue and re-epithelialization.
  13. C/c gastritis is common. The microscopy of peptic ulcer is shown in the Figure 15.6.
 
Histology (Superficial to Deep)
  1. N—base and margins have thin layer of necrotic debris.
  2. I—inflammatory infiltrate, mainly (N).
    Fig. 15.5: Smoking leading onto peptic ulcer
    Fig. 15.6: Microscopy of peptic ulcer
  3. G—granulation tissue.
  4. S—fibrous, collagenous material.
The microscopy of peptic ulcer is shown in the Figure 15.6.
 
Clinical Course
  1. Epigastric pain (burning sensation).
  2. Hemorrhage and perforation (complication).
  3. Nausea, vomiting, bloating, belching, etc.
  4. Can be transformed to malignancy.
  5. Usually pain worsens at night.
  6. Usually pain.
    1. Relieved on taking food—gastric ulcer.
    2. Aggravating on taking food—duodenal ulcer.
 
GASTRIC CARCINOMA
 
Intestinal Type Adenocarcinoma
  1. Arise from gastric mucous cells that have undergone intestinal metaplasia after long-term C/c gastritis.
    175
  2. Better differentiated.
  3. Occur more in older males.
 
Risk Factors
  1. C/c gastritis with intestinal metaplasia.
  2. H. pylori infection.
  3. Nitrites and nitrosamines in food.
  4. Reduced intake of vegetables and fruits.
  5. Partial gastrectomy.
  6. Pernicious anemia.
 
Pathogenesis
Pathogenesis of gastric carcinoma is shown in the Figure 15.7.
Fig. 15.7: Pathogenesis of gastric carcinoma
 
Diffuse Type Adenocarcinoma
  1. Arise from gastric mucous cells not with C/c gastritis.
  2. Poorly differentiated.
  3. Occur more in younger females.
 
Risk Factors
  1. Undefined.
  2. H. pylori infection and C/c gastritis often absent.
 
Pathogenesis
  1. Mutation of E-cadherin in 50% individuals.
  2. Some other mutations are also present.
  3. FGFR2 mutation.
  4. Expression of MMPs.
 
Morphology
  1. More in pylorus and antrum.
  2. Followed by cardia, body, fundus, lesser and greater curvature.
  3. The most favored site is lesser curvature of antropyloric region.
  4. Early GCA.
    1. Confined to mucosa and submucosa.
    2. Perigastric LNS may or may not involved.
  5. Advanced GCA.
    1. Extend into muscularis.
    2. Had spread more widely.
  6. Dysplasia is the precursor lesion.
  7. Three growth patterns.
    1. Exophytic (polyp-like and contain adenoma).
    2. Flat or depressed.
    3. Excavated (shallow or deep crater)—mimic peptic ulcer.
  8. If the entire stomach is involved, then the stomach become rigid and thickened—leather bottle stomach (linitis plastica).
  9. Intestinal—gastric cells and intestinal type glands.
    176
  10. Diffused—only gastric cells, but no glands.
  11. Spread to LNs—commonly left supraclavicular LN (Virchow's node).
  12. Spread intraperitoneally to ovaries—Krukenberg tumor.
 
Clinical Course
  1. Asymptomatic early stages.
  2. Abdominal discomfort and weight loss later.
  3. Fatigue and anorexia.
  4. Dysphagia rarely.
 
COLONIC DIVERTICULOSIS
  1. A diverticulum means a blind pouch that communicates with the gut lumen.
  2. All the three layers of gut wall are present.
  3. Congenital.
    1. Distinctly three layers.
    2. Most common site is Meckel diverticulum.
  4. Acquired.
    1. Muscularis propria is attenuated.
    2. Most common site is colon (due to Taenia).
  5. Focal defects are created in the muscle wall.
  6. Nerves and arteries penetrate the muscle coat through the defects.
  7. The connective tissue sheath accompanying these nerves and arteries provide potential sites for herniation.
  8. Low fiber diet predisposes to diverticulosis.
  9. Exaggerated peristaltic contractions (segmentation) also lead to herniation through anatomical site of weakness.
 
Morphology
  1. Small, flask-like or spherical out-pouchings.
  2. Most commonly in sigmoid colon.
  3. Isolated cecal diverticula are also seen.
  4. Muscular hypertrophy and prominent Taenia.
  5. Frequently dissecting into appendices epiploicae.
  6. Uninflamed state—thin walls.
  7. Perforation leads to peritonitis and abscesses.
  8. Later—lumen narrowing and fibrosis.
 
Clinical Features
  1. Mostly asymptomatic.
  2. Feeling of incompleteness of rectum.
  3. Bleeding, peritonitis, abscesses, etc.
 
MALABSORPTION SYNDROMES
  1. Defective absorption of fats, CHO, proteins, vitamins, minerals, electrolytes and water.
  2. Most common presentation is C/c diarrhea.
  3. Hallmark is steatorrhea.
 
Pathogenesis
 
Defective Intraluminal Digestion
  1. Defective digestion of fats and proteins.
    1. Pancreatic insufficiency (C/c alcoholism, Crohn disease).
    2. ZES.
  2. Defective solubilization of fat (due to ↓ bile secretion).
    177
    1. Ileac dysfunction.
    2. Biliary obstruction.
  3. Total or subtotal gastrectomy.
 
Defective Mucosal Absorption
  1. Primary mucosal cell abnormalities.
    1. Defective terminal digestion (lactose intolerance, bacterial overgrowth).
    2. Defective transepithelial transport (abetalipoproteinemia).
  2. Reduced SI surface area.
    1. Celiac disease (gluten sensitive enteropathy)—destruction of villi.
    2. Crohn disease.
    3. Surgical resections.
  3. Infections.
    1. A/c infectious enteritis, parasitic infestation, tropical sprue, Whipple disease.
 
Defective Nutritional Delivery
Lymphatic obstruction
  1. Lymphoma.
  2. TB and tuberculous lymphadenitis.
 
Clinical Course
  1. Bulky, frothy, greasy, yellow-gray stools.
  2. Weight loss, anorexia, abdominal distension, flatus, muscle wasting.
  3. Hematopoietic system—vitamin B12 and vitamin K deficiency.
  4. Musculoskeletal—osteopenia, tetany, muscle wasting.
  5. Endocrine—amenorrhea, impotence, hyperparathyroidism.
  6. Skin—purpura, petichia, edema, dermatitis.
  7. Nervous system—peripheral neuropathy.
 
INFLAMMATORY BOWEL DISEASE
  1. Crohn disease (CD).
  2. Ulcerative colitis (UC).
 
Etiopathogenesis
  1. Mainly idiopathic.
  2. Result from abnormal local immune responses against normal flora of gut and probably against some self-antigens.
 
Genetic Predisposition
  1. Related to MHC-II alleles.
  2. CD—HLA-DR7, HLA-DQ4, NOD2, IL-23R genes.
  3. UC—HLA-DRB1, IL-23R genes.
 
Immunologic Factors
  1. Mainly CD4+ TH cells associated.
  2. CD—IFN producing TH1 cells are associated.
  3. Recently TH17 subset is seems to be associated, which produces IL-17.
  4. CD—association with TNF.
 
Microbial Factors
  1. Triggers the immune response and inflammation.
  2. The final common pathway in IBD pathogenesis is inflammation.
  3. Mucosal destruction with loss of integrity of epithelial barrier and absorptive function.
178
 
Crohn Disease
  1. May affect any level of the alimentary tract from mouth to anus, but most commonly the terminal ileum.
  2. This is a systemic inflammatory disease with predominant gastrointestinal involvement.
  3. Occur at any age.
  4. Characterized by the triad of:
    1. Mucosal damage and transmural involvement.
    2. Non-caseating granulomas.
    3. Fistula formation.
 
Morphology
  1. SI alone—30%.
  2. Colon alone—30%.
  3. SI and colon—40%.
    1. Triad—already mentioned.
    2. Intestinal wall will be rubbery and thick due to edema, inflammation, fibrosis and hypertrophy.
    3. Narrow lumen—string sign radiographically.
    4. Serosal extension into mesentric fat—creeping fat.
    5. Sharp demarcation between involved and non-involved areas.
    6. Presence of skip lesions.
    7. Small ulcers
      large ulcers
      fissuring
      fistula.
    8. (N) infiltrate and granulomas.
    9. Crypt abscesses, ulceration and C/c mucosal damage.
    10. Mucosal metaplasia and dysplasia may occur.
 
Clinical Course
  1. Diarrhea, abdominal pain, fever, melena.
  2. Uveitis, polyarthritis, erythema nodosum, obstructive uropathy.
  3. Relapses are very common.
  4. Complications are fistulae, abscesses, strictures, carcinoma.
 
Ulcerative Colitis
  1. Ulceroinflammatory disease of colon, usually limited to mucosa and submucosa.
  2. A systemic disease, primarily involving the colon.
  3. A non-granulomatous disease.
  4. No skip lesions.
  5. Usually not extending beyond submucosa.
  6. Mural thickening usually absent.
  7. Risk of carcinoma development.
  8. Start in rectum and extending proximally to involve entire colon.
  9. Peak incidence between 20 and 25 years of age.
 
Morphology
  1. Continuous colonic lesion.
  2. Mucosal destruction with hyperemia, edema, etc.
  3. Easy bleeding and presence of ulcerations.
  4. Pseudopolyps are present—extending upwards.
  5. Rarely perforation, abscesses and peritonitis.
  6. Sometimes expose muscularis propria and neural plexus to fecal matter, which leads to complete arrest of neuromuscular junction. This results in swelling and gangrene of colon—toxic megacolon.
    179
  7. Healing leads to fibrosis and atrophy (granulation).
  8. (L) infiltrate in lamina propria.
  9. (N) and crypt abscesses may present.
  10. Most serious complication is carcinoma colon.
 
Clinical Course
  1. Bloody diarrhea, abdominal cramps, tenesmus, colicky abdominal pain.
  2. Relapse is common.
  3. Uveitis, polyarthritis, erythema nodosum, etc.
  4. Mucosal metaplasia and dysplasia.
 
ADENOMAS
  1. Neoplastic polyps.
  2. Small pedunculated or large sessile lesions.
  3. Lesser in SI and more in large intestine.
  4. Resulting from epithelial proliferation and dysplasia.
  5. Shows genetic and familial predisposition.
  6. Four subtypes. They are:
    1. Tubular adenomas (mostly tubular glands—pedunculated).
    2. Villous adenomas (villous projections—sessile).
    3. Tubulovillous adenomas (mixed type).
    4. Sessile serrated adenomas (lining of serrated epithelium).
  7. Carcinoma incidence is:
    1. Lesser in small pedunculated tubular adenomas.
    2. Greater in large sessile villous adenomas.
    3. Greater with dysplasia.
    4. Greater with diameter.
 
Morphology
  1. Tubular adenomas.
    1. Usually in rectosigmoid junction.
    2. Has usually a slender stalk and a head.
    3. Stalk—normal epithelium.
    4. Head—Neoplastic cells.
    5. Shows slight dysplasia and atypia.
    6. Leads to intramucosal or invasive carcinoma.
  2. Villous adenomas.
    1. Commonly in rectum and rectosigmoid junction.
    2. Generally sessile cauliflower-like masses.
    3. High degree of dysplasia.
 
Clinical Course
  1. Bleeding and anemia.
  2. Smaller ones are asymptomatic.
 
COLORECTAL CARCINOMA
  1. About 98% is constituted by adenocarcinomas.
  2. Adenomas are the precursor lesions.
  3. Males are more affected than females.
 
Pathogenesis
Pathogenesis of colorectal carcinoma is shown in the Figure 15.8. The NSAIDs vs colorectal carcinoma are shown in the Figure 15.9.
 
Carcinogenesis
  1. Adenoma—carcinoma sequence (Fig. 15.10) or APC/β-catenin pathway or chromosomal instability pathway.
    180
    Fig. 15.8: Pathogenesis of colorectal carcinoma
    Fig. 15.9: NSAIDs vs colorectal carcinoma
    Fig. 15.10: Adenoma-carcinoma sequence
    Fig. 15.11: Mismatch repair pathway
    181
  2. Mismatch repair pathway as shown in the Figure 15.11 (microsatellite instability [MSI]).
    1. Apoptosis regulating genes.
      • TGF-β, BAX, IGF2R, etc.
    2. DNA repair genes.
      • MLH1, MSH2 (main)
      • MSH6, PMS1, PMS2.
    3. Adenoma-carcinoma sequence.
      • Hereditary—FAP
      • Sporadic—left-sided predominant cancers.
    4. Mismatch repair pathway.
      • Hereditary—HNPCC
      • Sporadic—right-sided predominant cancers.
 
Morphology
  1. Mostly single.
  2. Proximal tumor.
    1. Occur as polypoid masses.
    2. Not much obstructive.
  3. Distal tumor.
    1. Occur as encircling lesions (napkin ring).
    2. Narrowing of lumen.
  4. Adenomatous change.
  5. May be well differentiated or anaplastic.
  6. Many tumors secrete mucin.
  7. Mucin facilitate extension and thus ↓ prognosis.
 
Clinical Course
  1. Right sided—fatigue, iron-deficiency anemia.
  2. Left sided—bleeding, changes in bowel habit.
  3. Metastasis.
    1. Regional LNS, liver, lungs and bones.
 
TNM Staging
  1. Tumor.
    1. T0—none evident.
    2. Tis—in situ.
    3. T1—invasion into lamina propria or submucosa.
    4. T2—invasion into muscularis propria.
    5. T3—invasion into subserosa and serosa.
    6. T4—invasion into other structures or organs.
  2. Lymph nodes.
    1. L0—none evident.
    2. L1—1 to 3 pericolic LNs.
    3. L2—greater than four pericolic LNs.
    4. L3—any positive node along a named blood vessel.
  3. Metastasis.
    1. M0—none evident.
    2. M1—any distant metastasis.
 
FAMILIAL POLYPOSIS SYNDROMES
  1. Autosomal dominant.
  2. Can transform into malignancy.
  3. Peutz-Jeghers (PJ) polyposis and familial adenomatous polyposis.
 
Peutz-Jeghers Polyposis
  1. Uncommon hamartomatous polyps.
  2. Autosomal dominant.
  3. As a part of PJ syndrome.
  4. Germ line mutations in PTEN are associated.
182
 
Familial Adenomatous Polyposis
  1. Defect in APC gene.
  2. 500–2,500 colonic adenomas.
  3. Minimum 100 number is required for diagnosis.
  4. Mostly tubular.
  5. Usually become evident in early childhood and adolescence.
  6. There is 100% chance for malignant transformation unless colonectomy has done.

Liver, Gallbladder and Biliary TractChapter 16

 
HEPATIC FAILURE
 
Complications
  1. Coagulopathy.
  2. Hepatic encephalopathy.
  3. Hepatorenal syndrome.
 
Hepatic Encephalopathy
  1. Disturbances in brain functioning.
  2. Symptoms ranging from subtle behavior abnormalities to marked confusion and stupor to coma and death.
  3. Rigidity, hyper reflexia, non-specific EEG changes and rarely seizure are also seen.
  4. Characteristics asterixis (flapping tremor).
  5. Non-rhythmic rapid flexion—extension movements of head and extremities; best elicited when the arms are held in extension with dorsiflexion of wrist.
Pathogenesis
  1. Severe loss of hepatocellular function.
  2. Shunting of blood from portal to systemic circulation.
    1. This leads to exposure of brain to NH3 (A/c) and neuronal dysfunction and brain edema.
    2. C/c—disturbance in AA metabolism in brain.
 
Hepatorenal Syndrome
  1. Renal failure without primary renal disease and associated with hepatic failure.
  2. Kidney function will improve, if the liver failure reversed.
  3. Oliguria, ↑ blood urea, ↑ blood N2, ↑ serum creatinine.
  4. Hyperosmolar urine with ↓ Na+ and no proteins.
Pathogenesis
Splanchnic vasodilatation and systemic vasoconstriction leads to decreased RBF and renal failure.
 
CIRRHOSIS
 
Definition
A diffuse process characterized by fibrosis and convertion of normal liver architecture into abnormal structure characterized by:
  1. Bridging fibrous septae.
    184
  2. Parenchymal nodules.
  3. Disruption of the architecture.
 
Causes
  1. Alcoholism.
  2. Chronic infection.
  3. Autoimmune hepatitis.
  4. Biliary disease.
  5. Iron overload.
 
Vascular Changes in Cirrhosis
  1. Hepatic artery to portal vein and portal vein to hepatic vein shunts.
  2. Loss of fenestration between EC.
 
Pathogenesis
Figure 16.1 shows the pathogenesis of cirrhosis.
 
Fibrogenesis
The fibrogenesis is shown in Figure 16.2.
 
Clinical Course
  1. Progressive liver failure.
  2. Leads to portal HTN.
  3. Lead to HCC.
 
PORTAL HYPERTENSION
  1. Increased resistance to portal blood flow.
    1. Intrahepatic causes—cirrhosis, fatty liver, sarcoidosis, etc.
    2. Prehepatic causes.
    3. Posthepatic causes.
  2. The main consequences are detailed below.
 
Ascites
  1. Collection of excess fluid in the peritoneal cavity (Fig. 16.3).
  2. Clinically detectable if volume more than 500 mL.
  3. The fluid is usually serous with low proteins, glucose, Na+ and K+.
  4. Some mesothelial cells and leukocytes are also seen.
 
Portosystemic Shunt
  1. Due to ↑ pressure, there will be portosystemic shunt and manifests as:
    1. Hemorrhoids (rectum).
    2. Esophageal varices (esophagus).
    3. Caput medusa (umbilicus).
 
Congestive Splenomegaly
Due to long-standing congestion.
Fig. 16.1: Schematic representation of pathogenesis of cirrhosis
185
Fig. 16.2: Fibrogenesis (*Ito cells are normally vitamin A or fat storing cells)
 
Hepatic Encephalopathy
Described earlier.
 
VIRAL HEPATITIS
 
Hepatitis A Virus
  1. Benign self-limited disease.
  2. ssRNA virus of incubation period 15–50 days.
  3. Feco-oral route of transmission.
  4. Largest potential of causing epidemics.
  5. Does not cause C/c hepatitis or a carrier state.
  6. Seems to be results from T cell-mediated injury of infected hepatocytes.
 
Diagnosis
Diagnosis is by detection of IgM Ab.
 
Prevention
  1. Hygiene.
  2. Passive immunization.
  3. Pre-exposure prophylaxis with HAV vaccine.
Fig. 16.3: Mechanism of formation of ascites in portal hypertension
186
 
Hepatitis B Virus
  1. Double-stranded DNA virus.
  2. Transmission through sexual contact, parenteral and perinatal.
  3. High rate of producing chronic illness.
  4. Incubation period is 1–4 months.
  5. CD4+ T cells and CD8+ T cells act on the affected hepatocytes and cause hepatocellular injury. The outcomes of hepatitis B is shown in the Figure 16.4.
 
Diagnosis and Prevention
  1. Diagnosis is by detection of HBSAg and Ab to HBcAg.
  2. Prevention is by screening and vaccination.
 
Hepatitis C Virus
  1. Single-stranded RNA virus.
  2. Parenterally transmitted.
  3. Intranasal use of cocaine is a risk factor.
  4. Incubation period is 6–12 weeks.
  5. Persistent infection is the hallmark. The outcomes of hepatitis C virus is shown in Figure 16.5.
 
Diagnosis
  1. Diagnosis
    1. PCR for HCV RNA.
    2. ELISA for Ab.
 
Hepatitis D Virus
  1. Single-stranded RNA virus with multiplication defect.
  2. Become infective when multiplication defects.
  3. Always dependent on HBV infection.
  4. Can cause A/c coinfection or superinfection.
  5. Parenterally transmitted.
 
Diagnosis
  1. Detection of IgG and IgM.
  2. Detection of HDV RNA in blood.
  3. Detection of HDV Ag in liver.
 
Hepatitis E Virus
  1. Enterically transmitted, waterborne disease.
  2. ssRNA virus.
    Fig. 16.4: Outcomes of hepatitis B infection
    187
    Fig. 16.5: Outcomes of hepatitis C infection
  3. Not producing C/c infection or persistent viremia.
 
Diagnosis
  1. HEV PCR for RNA.
  2. IgM and IgG Abs.
 
Clinical Outcomes
  1. HAV, HCV, HEV—no carrier state.
  2. HAV, HEV—no C/c hepatitis.
  1. Asymptomatic
    1. No external symptoms, but infection is there.
  2. A/c viral hepatitis
    1. Caused by all hepatitis viruses.
    2. Four phases.
      • Incubation period
      • Symptomatic preicteric phase
      • Symptomatic icteric phase
      • Convalescence.
    3. Peak infectivity is noticed during last days of incubation period and early days of preicteric phase.
  3. Carrier state
    1. Caused by HBV and HDV only.
    2. Can transmit the disease, but no symptoms.
  4. Fulminant hepatitis.
    1. A/c liver failure (only a small proportion).
    2. Massive hepatic necrosis.
    3. Massive necrosis and regenerative hyperplasia.
  5. Chronic hepatitis.
    1. Hepatocyte injury, apoptosis, cytolysis, regeneration, etc.
    2. Portal tract inflammation and interphase hepatitis.
    3. Bridging inflammation and necrosis.
    4. Fibrous collagen deposition in portal tracts.
    5. Later bridging fibrosis (p-p, c-c, p-c).
    6. At last—endstage cirrhosis.
    7. Occurs when persistent more than 6 months.
    8. Many causes are there like viral, autoimmune, drugs, Wilson disease, α1-AT deficiency, alcoholism, etc.
 
Morphology
  1. Liver is enlarged, red or green.
  2. Hepatocytes undergo swelling—ballooning degeneration.
    188
  3. Hepatocytes undergo fatty changes—ground-glass cell.
  4. Hepatocyte injury and necrosis.
  5. Cytolysis or apoptosis of hepatocytes.
  6. Sometimes bridging necrosis (p-p, c-c, p-c).
  7. Lobular disarray (loss of architecture).
  8. Hepatocyte proliferation.
  9. Hypertrophy and hyperplasia of Kupffer cells.
  10. Mononuclear infiltrate (mainly in portal tracts).
  11. Interphase hepatitis—inflammation spill over to adjacent parenchyma.
 
Diagnosis of Hepatitis with Reference to Ag and Ab
Hepatitis A: The hepatitis A serology is shown in Figure 16.6.
Hepatitis B: The hepatitis B serology is shown in Figure 16.7.
Fig. 16.6: Hepatitis A serology
Hepatitis C: The hepatitis C serology is shown in Figure 16.8.
 
ALCOHOLIC LIVER DISEASE
  1. Three diseases are coexisting with alcohol abuse.
    1. Fatty liver.
    2. Alcoholic hepatitis.
    3. Alcoholic cirrhosis.
 
Pathogenesis
The pathogenesis of alcoholic liver disease is shown in Figure 16.9.
Fig. 16.7: Hepatitis B Serology
189
Fig. 16.8: Hepatitis C serology
 
Morphology
 
Fatty Liver
  1. Moderate alcohol intake—microvesicular fat droplets (Fig. 16.10).
  2. C/c intake—macrovesicular fat droplets.
  3. First centrilobular change, then entire lobule.
  4. Grossly the liver is enlarged, soft, yellow and greasy.
  5. No fibrosis, if not progressing.
 
Alcoholic Hepatitis
  1. Hepatocyte swelling and necrosis (ballooning degeneration).
  2. Mallory bodies—tangled intermediate filaments and some proteins together form eosinophillic inclusion bodies in the degenerating hepatocytes.
  3. (N) infiltration; also (L) and macrophages.
    Fig. 16.9: Pathogenesis of alcoholic liver disease
    190
    Fig. 16.10: Sequence of liver changes in alcoholism (*AE-Alcohol exposure; **AA-Alcohol abstinence)
  4. Fibrosis—sinusoidal and perivenular fibrosis.
  5. Sometimes hemosiderin deposits also.
 
Alcoholic Cirrhosis
  1. Enlarged liver with yellow–tan color.
  2. Micronodules are formed (micronodular cirrhosis).
  3. Hobnail appearance—nodularity on the surface.
  4. Progressive necrosis and fibrosis (bridging fibrosis).
  5. Bile stasis and loss of architecture.
  6. Nodules are formed by aggregation of degenerating hepatocytes.
 
Clinical Course
  1. Mild to severe hepatomegaly.
  2. Progressive anorexia and weight loss.
  3. Progressive impairment of liver function.
  4. May progress to complications like,
    1. Liver failure.
    2. Hepatic encephalopathy.
    3. Hepatorenal syndrome.
    4. Massive GI bleeding.
    5. HCC.
 
DRUG-INDUCED LIVER DISEASE
 
Intrinsic (Predictable)
  1. Occur in anyone who accumulates a large dose.
  2. Examples for these drugs are paracetamol, tetracycline, antineoplastic drugs, amanitin toxin, etc.
 
Idiosyncratic (Unpredictable)
  1. Depend upon the host's immune response, metabolic capacity, etc.
  2. Drugs like CPZ, halothane, sulphonamide, allopurinol, α-methyl dopa, etc. causes this type of reaction.
 
Mechanism
  1. Direct
    1. Acetaminophan, CCl4, mushroom toxins, etc.
  2. Mediated through several inflammatory reactions and immune-mediated destruction.
    191
    1. Halothane, sulfonamide.
    2. A/c liver failure—acetaminophen, CCl4 and halothane.
 
Morphology
  1. Massive hepatic necrosis.
  2. Liver may get shrinked.
  3. Capsule may get wrinkled.
  4. Complete destruction of hepatocytes.
  5. Only a little inflammatory reaction.
  6. Shows some regeneration.
  7. Macronodular cirrhosis (similar to viral hepatitis).
 
Pattern of Injury
  1. Cholestasic and cholestatic hepatitis.
  2. Hepatocellular necrosis (mainly by acetaminophen).
  3. Steatosis and steatonecrosis.
  4. Fibrosis and cirrhosis.
  5. Granulomas and vascular lesions.
  6. Neoplasms.
 
HEMOCHROMATOSIS
  1. Excessive accumulation of body iron most of which is deposited in parenchymal organs like liver and pancreas.
  2. Hereditary and acquired are there.
  3. Most common among hereditary is an AR disease.
    1. Adult onset.
    2. Caused by mutation in HFE gene.
  4. Acquired form is 2° to repeated transfusions, ↑ Fe intake, infective erythropoiesis, C/c liver disease, etc.
 
Pathogenesis (Hereditary)
  1. Net iron accumulation of 0.5–1 g/year.
  2. Total iron content will become > 50 g over years (normal is 2–6 g).
  3. Hereditary hemochromatosis—atleast 20 g Fe.
  4. Excess Fe causes toxicity by:
    1. Lipid peroxidation.
    2. Collagen formation.
    3. Direct DNA damage (Fig. 16.11).
 
Morphology
  1. Deposit of hemosiderin in liver, pancreas, myocardium, etc.
    1. Triad.
      • Cirrhosis (micronodular), inflammation is absent
      • Pancreatic fibrosis and DM
      • Skin pigmentation (due to ↑ melanin production).
  2. Heart is enlarged and with brown discoloration.
  3. A/c synovitis with hemosiderin deposition.
  4. Testes may get atrophied.
 
Clinical Course
  1. Male predominance.
  2. Hepatomegaly, abdominal pain and skin pigmentation.
  3. Atypical arthritis, DM.
  4. May leads to HCC due to DNA damage.
Fig. 16.11: Pathogenesis of hemochromatosis
192
 
WILSON'S DISEASE
  1. AR disease.
  2. Increased copper accumulation in many organs and tissues; principally in liver, brain and eye.
  3. Due to mutation in ATP7B gene on chromosome 13.
  4. This leads to defective ATPase metalion transporter in liver.
  5. Thus, the cooperation of Cu into ceruloplasmin and ceruloplasmin secretion into plasma gets arrested, which in turn leads to defective excretion of Cu into bile.
  1. So Cu gets accumulated primarily in liver and later in brain, eyes, etc.
  2. The accumulated Cu exerts toxicity through.
    1. Free radical generation.
    2. Binding to cellular proteins.
    3. Replacing metals from hepatic metalloenzymes.
 
Morphology
  1. Fatty change.
  2. A/c hepatitis.
  3. C/c hepatitis.
  4. Massive liver necrosis.
  5. Fibrosis and cirrhosis.
  6. Cholestasis.
  7. Brain—mainly the basal ganglia (putamen) is affected.
    1. Atrophy and even cavitation.
  8. Eyes—Kayser-Fleischer rings.
    1. Green-brown Cu deposits in Descemet membrane of cornea.
 
Clinical Course
  1. Younger age.
  2. A/c or C/c hepatitis.
  3. Neuropsychiatric illness.
  4. Kayser-Fleischer ring.
 
Diagnosis
  1. Decreased serum ceruloplasmin level.
  2. Increased urinary Cu.
  3. Increased hepatic Cu.
 
Treatment
D-penicillamine.
 
ALPHA1-ANTITRYPSIN DEFICIENCY
  1. Autosomal recessive disease.
  2. Decreased levels of AAT (antiprotease).
  3. AAT is predominantly synthesized by hepatocytes.
  4. Due to mutation of AAT gene on chromosome 14.
  5. Increased lysosomal destruction of liver parenchyma.
 
Morphology
  1. Globular inclusion in hepatocytes (+ve with PAS stain).
  2. Cholestasis and hepatocyte necrosis in newborn.
  3. Childhood cirrhosis.
 
Clinical Course
  1. Presenting with hepatic failure or pulmonary disease.
  2. Closely associated with pathogenesis of emphysema.
193
 
HEPATOCELLULAR CARCINOMA
 
Risk Factors
  1. Sex (male predominance).
  2. HBV and HCV infection.
  3. Aflatoxin and C/c alcoholism.
  4. Cirrhosis.
 
Pathogenesis
  1. Most of cases arise from high-grade dysplasa nodules (Fig. 16.12).
    Fig. 16.12: Pathogenesis of hepatocellular carcinoma
  2. Tumor may arise from mature hepatocytes or progenitor cells.
  3. Characterized by numerical or structural chromosomal abnormalities.
 
Morphology
  1. Three patterns.
    1. Unifocal (usually massive).
    2. Multifocal.
    3. Diffusely infiltrative.
  2. Areas of hemorrhage and necrosis.
  3. Increases tendency for invasion of vascular channels.
  4. Well differentiated and with bile globules.
  5. Large multinucleated anaplastic tumor cells.
  6. Mallory bodies-like inclusions.
  7. Another form—fibrolamellar carcinoma (no association with cirrhosis).
 
Clinical Course
  1. Hepatomegaly.
  2. Increases ascites and even with blood.
  3. Fever.
  4. Cirrhotic features.
  5. Poor prognosis.
  6. Death by.
    1. Profound cachexia.
    2. GI bleed.
    3. Liver failure and hepatic coma.
    4. Rupture of tumor with hemorrhage.
 
CHOLELITHIASIS (GALLSTONES)
 
Risk Factors
  1. Cholesterol stones.
    1. Demography and advancing age.
    2. Female sex hormones.
    3. Obesity.
    4. Gallbladder stasis.
    5. Hyperlipidemia.
  2. Pigment stones.
    1. Demography.
    2. C/c hemolytic syndromes.
    3. Biliary infection.
    4. GI disorders like Crohn's disease.
 
Pathogenesis
  1. Cholesterol stones are four conditions are predisposing:
    1. Supersaturation of bile with cholesterol.
    2. Microprecipitates of calcium.
    3. Gallbladder stasis.
    4. Mucus hypersecretion—trap the crystals.
    194
  2. Pigment stones.
    1. Bilirubin in biliary tree get usually precipitated as calcium salts.
 
Morphology
  1. Cholesterol stones.
    1. Mainly in gallbladder.
    2. Pure-pale yellow, mostly radiolucent.
    3. Mixed with other substances—gray-white.
    4. Usually multiple, firm and faceted.
  2. Pigment stones—anywhere in the biliary tree.
    1. Black—mainly in gallbladder small, firm and radio-opaque.
    2. Brown—in biliary ducts soft, soap like and mostly radiolucent.
 
Clinical Course
  1. Colicky pain.
  2. Complication—empyema, perforation, fistulae, etc.
 
CHOLECYSTITIS
  1. Inflammation of gallbladder.
  2. Can be A/c, C/c or A/c superimposed on C/c.
  3. Almost always associated with cholelithiasis.
 
Morphology
 
Acute
  1. Gallbladder sometimes violaceous or green colored.
  2. It is 90% associated with stones.
  3. Obstruction of neck or cystic duct usually.
  4. GB contains turbid bile even with pus or blood.
  5. If the exudate is purely pus—empyema of GB.
  6. GB wall may get edematous and hyperemic.
  7. Sometimes gangrenous cholecystitis.
 
Chronic
  1. GB may be shrinked/normal/enlarged.
  2. GB wall is often thickened by fibrosis.
  3. (L) infiltrate—less amount.
A/c calculus cholecystitis
  1. Commonly seen.
  2. Most common indication for emergency cholecystectomy.
  3. Due to chemical irritation and inflammation.
  4. Lecithin
    lysolecithin (toxic to GB mucosa).
  5. PGs are produced and accounts for inflammation.
  6. May leads to ↓ blood flow and later bacterial infection.
A/c non-calculus cholecystitis
  1. Postoperatively, severe trauma, severe burns and sepsis.
  2. GB stasis, dehydration, vascular compromise also contributes.
C/c cholecystitis
  1. Usually associated with GB stones.
  2. Symptoms are similar to A/c.
  3. Not usually associated with obstruction.
  4. Not much inflammation.
 
Clinical Course
  1. Colicky pain.
  2. Tender distended GB.
  3. Nausea, vomiting, less tenderness (chronic stage).

PancreasChapter 17

 
ACUTE PANCREATITIS
  1. A group of reversible lesions characterized by inflammation of the pancreas.
  2. Can range from focal edema and fat necrosis to parenchymal necrosis and hemorrhage. Pathogenesis of acute pancreatitis is shown in Figure 17.1.
 
Etiology
  1. Metabolic.
    1. Alcoholism.
    2. Hypercalcemia and hyperlipoproteinemia.
    3. Genetic (hereditary pancreatitis—AD).
    4. Drugs like thiazide, furosemide, methyldopa.
  2. Mechanical.
    1. Trauma, gallstones and iatrogenic injury.
  3. Vascular.
    1. Shock, arterioembolism and PAN.
  4. Infection.
    1. Mumps.
    2. Coxsackie virus.
    3. Mycoplasma pneumoniae.
 
Morpholgy
  1. Microvascular leakage and edema.
  2. Fat necrosis and acute inflammation.
  3. Necrosis and destruction of pancreatic parenchyma.
  4. Hemorrhage due to destruction of blood vessels.
  5. Red black hemorrhagic spots.
  6. Yellow-white chalky fat necrosis.
  7. Fat globules in peritoneal fluid.
  8. Necrotizing pancreatitis (moderately severe).
    1. Hemorrhagic pancreatitis (severe).
 
Clinical Course
  1. Abdominal pain (cardinal symptom).
  2. Explosive inflammatory reaction (ARDS and even shock).
  3. Markedly elevated serum amylase.
  4. DDS.
    1. Ruptured A/c appendicitis.
    2. Ruptured A/c cholecystitis.
      196
      Fig. 17.1: Pathogenesis of acute pancreatitis
    3. Perforated peptic ulcer.
    4. Occlusion of mesenteric vessels.
  5. Complication/sequelae is pancreatic pseudocyst.
 
CHRONIC PANCREATITIS
  1. Long-standing inflammation with irreversible lesion.
  2. Destruction of exocrine parenchyma followed by destruction of endocrine parenchyma later.
  3. Results from recurrent bouts of A/c pancreatitis.
 
Etiology
  1. Long-term alcohol abuse.
    197
  2. Long-term standing pancreatic duct obstruction.
  3. Tropical pancreatitis due to malnutrition.
  4. Hereditary pancreatitis.
  5. Cystic fibrosis (CFTR gene mutation).
 
Pathogenesis
  1. Similar to that of A/c pancreatitis.
  2. Can result from:
    1. Ductal obstruction and acinar cell injury.
    2. Direct acinar cell injury by toxins.
    3. Acinar cell injury by oxidative stress.
    4. Necrosis, fibrosis—due to repeated A/c pancreatitis.
 
Morphology
  1. Parenchymal fibrosis.
  2. Acinar atrophy and loss.
  3. Dilatation of pancreatic ducts.
  4. Epithelium may be hyperplastic or show squamous metaplasia.
  5. First exocrine sclerosis.
  6. Later endocrine sclerosis and loss of islets.
 
Clinical Course
  1. Persistent abdominal or back pain.
  2. Recurrent jaundice and indigestion.
  3. Pancreatic insufficiency and DM only later.
  4. Can lead to chronic malabsorption.
  5. Predisposing to pancreatic carcinoma.

Male Genital SystemChapter 18

 
TESTICULAR NEOPLASMS
Most common cause of painless enlargement of the testes.
 
Risk Factors
The risk factors of testicular neoplasms are:
  1. Cryptorchidism.
  2. Gonadal dysgenesis.
  3. CA of other testis.
  4. Isochromosome of short arm of chromosome 12.
 
Classification
  1. Seminomatous germ cell tumor.
    1. Seminoma.
  2. Non-seminomatous germ cell tumors.
    1. Embryonal carcinoma.
    2. Yolk sac tumor (extraembryonic).
    3. Choriocarcinoma (extraembryonic).
    4. Teratoma (somatic cell line).
  3. Sex cord/stromal tumors (rare).
 
Seminoma (Only hCG Elevated)
  1. The commonest form is referred to as classical.
  2. Counter part of ovarian dysgerminoma.
  3. Also related to germinomas of extragonadal sites (CNS).
  4. Large soft well-demarcated homogenous gray-white tumors that bulge from the cut surface.
  5. Typically confined to the testes by an intact tunica albuginea.
  6. Foci of coagulation necrosis usually without hemorrhage.
  7. If hemorrhage, there will be a component of non-seminomatous tumor.
  8. Large cells with distinct borders, glycogen-rich clear cytoplasm and round nuclei with conspicuous nucleoli.
  9. Intratubular neoplasia is seen.
  10. Tumor cells are arranged in separate lobules.
  11. (L) infiltrate and granulomatous inflammation.
  12. Cells staining positive for hCG.
Spermatocytic seminoma
  1. A less frequent morphologic variant of seminoma.
  2. Occur usually in older patients.
  3. Small, medium and large cells are seen.
    199
  4. May be uninucleate or multinucleate.
  5. The relation with intratubular metaplasia is less.
  6. Less metastatic potential.
 
Embryonal Carcinomas (Both hCG and AFP Elevated)
  1. Ill-defined invasive masses.
  2. Foci of necrosis and hemorrhage are seen.
  3. Larger lesions may invade spermatic cord and epididymis.
  4. Large cells with ill-defined borders, basophilic cytoplasm with large nuclei and prominent nucleoli.
  5. Usually undifferentiated.
  6. Intratubular neoplasia is seen.
 
Yolk Sac Tumors (Only AFP Elevated)
  1. Also called endodermal sinus tumors.
  2. Usually affect children with less than 3 years of age.
  3. Large and well demarcated.
  4. Differentiated towards endodermal sinus.
  5. Tumor cells arranged in different patterns.
  6. Characteristic presence of primitive glomeruli-like structures called Schiller-Duval bodies.
  7. Alpha-fetoprotein (AFP) with tumor cell cytoplasm.
 
Choriocarcinomas (Only hCG Elevated)
  1. Differentiation of stem cells towards trophoblastic cells.
  2. Small, but extensive metastatic potential.
  3. Tumor cells—eosinophilic cytoplasm and pleomorphic nuclei.
  4. Well-formed placental villi are not seen.
  5. Increased hCG can be demonstrated.
 
Teratoma (Both hCG and AFP Elevated)
  1. Differentiation towards somatic cell line.
  2. Mature teratoma—fully differentiated tissues seen.
  3. Immature somatic elements are seen.
  4. With malignant somatic elements—frank malignancies arise in pre-existing teratoma.
  5. For example, adenocarcinoma, squamous cell carcinoma.
  6. Main somatic elements are cyst, cartilage, bone, epithelium, fat, neural tissue, glands, etc.
  7. Mixed germ cell tumors are also seen.
 
Clinical Course
  1. Painless enlargement of testes.
  2. Metastasis commonly to iliac and para-aortic LNs.
  3. Both lymphatic and hematogenous route.
  4. hCG and AFP are markers for diagnosis.
 
NODULAR HYPERPLASIA OF THE PROSTATE
  1. Also called benign prostatic hypertrophy (BPH) as misnomer.
  2. BPH is more in central and transitional zones.
    200
  3. Carcinomas are more in peripheral zone.
  4. Both stromal and glandular hyperplasia occurs.
  5. Males are affected after the age of 40.
  6. Risk increases with increase in age.
  7. Androgens (specific DHT) have a central role in BPH.
    1. DHT → increased DNA, RNA, GFs, cellular proteins → hyperplasia.
 
Clinical Course
  1. Lower urinary tract obstruction.
  2. Difficulty in starting urination and also intermittently get arrested.
  3. Painful distension of bladder and sometimes hydronephrosis.
  4. Urinary, urgency, frequency and nocturia.
  5. Increased chance of UTI.
 
Morphology
  1. Nodularity, mainly in inner zone.
  2. Enlarged prostate.
  3. Nodules bulge out from cut surface.
  4. Nodules may be cystic or solid appearance.
  5. May produce compressive obstruction or ball-valve type of obstruction (projecting into the bladder).
  6. Proliferating stroma and glandular elements.
  7. Glands are lined by columnar epithelium and the lumen contains proteinaceous secretory material—corpora amylacea.
  8. Some glands show squamous metaplasia.
 
PROSTATIC CARCINOMA
  1. Most common visceral cancer in males.
  2. Peak incidence between the ages of 65 and 75.
  3. Does not occur before puberty.
 
Etiology
  1. Hormonal, genetic and environmental factors contributed.
  2. Androgen increases the risk and estrogen decreases the risk.
  3. Genetic.
    1. Susceptible foci in chromosome 1 is identified.
    2. Certain mutations and telomere shortening.
 
Morphology
  1. Mainly in the peripheral zones.
  2. Palpable by rectal examination.
  3. Not much urethral obstruction in the initial stages.
  4. Grey white masses infiltrating the adjacent glands and ill defined.
  5. Early metastasis to regional lymph nodes.
  6. May invade into seminal vesicle, bladder, adjacent soft tissues and rectum.
  7. Most of these are adenocarcinomas.
  8. Variable degree of differentiation and anaplasia.
  9. Neoplastic glands are lined by cuboidal cells.
  10. Gland adjacent to cancer shows atypia (PIN).
    201
  11. This PIN acts as a precursor for carcinoma.
  12. There is a high-grade and low-grade PIN (according to degree of atypia).
 
Clinical Course
  1. Early lesions—usually asymptomatic.
  2. Late—metastasis.
  3. Bone metastasis—both osteoclastic and osteoblastic lesions.
  4. Diagnosis by assay of PSA and imaging techniques.
  5. Treated with surgery and chemotherapy.
 
Anatomical Staging
 
Tumor Extent
  1. T1: Clinically apparent (T1a, T1b, T1c).
  2. T2: Palpable or visible imaging and cancer confined to prostate (T2a, T2b, T2c).
  3. T3: Local extraprostatic invasion (T3a, T3b).
  4. T4: Invasion of contagious organs (bladder, rectum).
 
Regional Lymph Nodes
  1. N0: No metastasis to regional LNs.
  2. N1: Metastasis to regional LNs.
 
Distant Metastasis
  1. M0: No distant metastasis.
  2. M1: Distant metastasis.
    • M1a: Distant LNs metastasis
    • M1b: Bone metastasis (more osteoblastic lesion)
    • M1c: Other organs.
 
SYPHILIS (LUES)
  1. C/c veneral infection caused by Treponema pallidum.
  2. Sexually transmitted disease through the cutaneous mucosal lesions.
  3. Transmission mainly occurs at the primary and secondary stages.
  4. Congenital syphilis—transmission through placenta.
  5. Rapid dissemination of the organism occurs through lymphatics and bloodstream.
  6. Incubation period is 9–90 days (mean 21 days).
  7. Primary lesion is a chancre at the site of entry.
  8. Two antibodies are developed.
    1. Ab to non-treponemal Ag.
    2. Ab to specific treponemal Ag.
 
Morphology
  1. Macroscopic lesions vary with stages.
  2. Microscopic lesions are common fundamentally.
    1. Proliferative endarteritis.
    2. Inflammatory infiltrate rich in plasma cells.
  3. Hypertrophy and proliferation of ECs.
  4. Lumen narrowing.
  5. Local ischemia, cell death and fibrosis.
 
Primary Syphilis
  1. Chancre/hard chancre at the point of entry.
  2. The chancre develops usually on the penis (on vagina and cervix in females).
  3. Begins as a firm papule.
    202
  4. Progress into painless ulcer with indurated well-defined edges and clear base.
  5. Regional LNs usually enlarged, but painless.
  6. Infiltrate of (L) and plasma cells with arteritis.
  7. Usually resolves without any treatment leaving a scar.
 
Secondary Syphilis
  1. Occur within 2 months of resolution of chancre (25%).
  2. Combination of generalized lymphadenopathy and various mucocutaneous lesions.
  3. Lesions may be maculopapular, scaly or pustular.
  4. Mainly palms and soles are involved.
  5. Condyloma lata.
    1. Broad based elevated lesions in moist skin areas like anogenital region, thighs and axilla.
  6. Mucosal lesions are common in oral cavity, pharynx and external genitalia.
  7. Endarteritis and plasma-lymphocytic infiltrate.
  8. LNs enlargement mainly in neck and inguinal region.
    1. Non-specific hyperplasia of germinal centers with increased plasma cells.
  9. Hepatitis, renal involvement and iritis are also seen.
  10. Then 2° syphilis resolves as 1° at which the patient enters early latent phase.
  11. Most infective stage.
 
Tertiary Syphilis
  1. In about one-third of untreated patients.
  2. Usually after a latent period of 5 days. These are three forms that are given as.
 
Cardiovascular Syphilis
  1. Syphilitic aortitis (common).
  2. Endarteritis of vasa vasorum of aorta.
  3. Occlusion of vasa vasorum leads to scarring of media.
  4. So aortic insufficiency and aneurysms occurs.
  5. Mainly the proximal aorta is involved.
  6. Sometimes, coronary artery occlusion also.
 
Neurosyphilis
  1. Chronic meningovascular disease and tabes dorsalis.
  2. General paresis (parenchyma affected).
  3. Increased frequency in HIV patients.
 
Benign Tertiary syphilis
  1. Uncommon.
  2. Deposition of gumma at various sites—commonly in bones and mucocutaneous areas.
  3. This results from delayed type of hypersensitivity.
Gumma
  1. Irregular firm mass of necrotic tissue.
  2. Surrounded by connective tissue.
    203
  3. Central coagulation necrosis.
    1. Surrounded by infiltrate of (L), plasma cells, macrophages and giant cells.
    2. Peripheral zone of fibrous tissue.
 
Congenital Syphilis
  1. Stillbirth with syphilis.
    1. Hepatomegaly, bone abnormalities, pneumonitis and pancreatic fibrosis.
    2. Liver shows extramedullary hematopoiesis and portal tract inflammation.
  2. Infantile syphilis.
    1. Clinically manifests at birth or within a few months after birth.
    2. Chronic rhinitis and mucocutaneous lesions.
  3. Late/tardive syphilis.
    1. Untreated congenital syphilis of more than 2 years duration.
    2. Hutchinson triad.
      • Notched central incisors
      • Keratitis with blindness
      • Nerve injury (8th) and deafness.
    3. Saber shin deformity.
    4. Mulberry molars.
    5. Saddle nose deformity.
    6. Chronic meningitis.
    7. Chorioretinitis.
 
Diagnosis
  1. Primary syphilis.
    1. Dark ground microscopy of T. pallidum.
  2. Secondary syphilis.
    1. Dark ground microscopy of T. pallidum.
    2. Non-treponemal and antitreponemal Ab detection.
  3. Tertiary syphilis.
    1. Antitreponemal Ab detection.
  4. VDRL and RPR are done for Ab detection.

Female Genital System and BreastChapter 19

 
CERVICAL INTRAEPITHELIAL NEOPLASIA
  1. Precursor of invasive cervical carcinoma.
  2. All cervical intraepithelial neoplasia (CIN) does not progress to CA cervix.
  3. But all CA cervix develop from CIN.
  4. Peak age is 30 years.
  5. High grade SIL.
    1. CIN-I: Mild dysplasia (low grade SIL).
    2. CIN-II: Moderate dysplasia.
    3. CIN-III: Severe dysplasia and carcinoma in situ.
 
Risk Factors
  1. Early age of first intercourse.
  2. Multiple sexual partners.
  3. Men have multiple sexual partners.
  4. Persistent infection with high risk HPV (high risk HPV—HPV 16, 18, 31 and 45).
  5. Cigarette smoking.
  6. Immunodeficiency.
 
Pathogenesis
The pathogenesis of cervical intraepithelial neoplasia is shown in the Figure 19.1.
 
Morphology
  1. CIN-I.
    1. Mild dysplasia (flat condyloma).
    2. Koilocytosis.
      • Nuclear hyperchromasia
      • Angulation with perinuclear vacuolization due to cytopathic effect of HPV.
        Fig. 19.1: Pathogenesis of cervical intraepithelial neoplasia
    205
  2. CIN-II.
    1. Moderate dysplasia.
    2. Variation in nuclear and cell size.
    3. Heterogenicity of nuclear chromatin.
    4. Superficial cells show differentiation and koilocytosis.
    5. Increased mitosis.
  3. CIN-III.
    1. Marked severe dysplasia.
    2. Marked size variation and marked heterogenecity.
    3. Normal or abnormal mitosis.
    4. Loss of maturation and differentiation.
    5. Loss of koilocytosis.
    6. Confined to epithelium and its glands, so called carcinoma in situ.
 
INVASIVE CARCINOMA OF CERVIX
  1. Squamous cell CA (75%).
  2. Adenocarcinoma (20%).
  3. Small cell neuroendocrine CA (5%).
  4. Always arise from CIN.
  5. Peak age is 45 years.
 
Morphology
  1. Usually occurring in the squamocolumnar junction.
  2. Begin as early stromal invasion.
  3. Late stage tumor—encircling the overall survival (OS).
  4. Late stage tumor penetrates into underlying stroma and produce barrel cervix.
  5. Extension to parametrium—fixes the uterus.
  6. Nodal and distant metastasis as progresses.
  7. Grades (1–3) based on cellular differentiation.
  8. Stages (1–4) based on clinical spread.
 
Clinical Course
  1. Vaginal bleeding, leukorrhea, painful coitus.
  2. Dysuria.
  3. Pap smear is for diagnosis.
  4. Treated with chemotherapy.
 
ENDOMETRIAL CARCINOMA
Mostly seen in peak age of 60 (55–65).
 
Risk Factors
  1. Obesity (↑ estrogen synthesis).
  2. DM, HTM.
  3. Infertility.
  4. Increased exposure to estrogen.
 
Endometrioid Carcinoma
  1. Usually seen in perimenopausal women with excess estrogen.
  2. Usually arise in the background of endometrial hyperplasia and is highly glandular.
  3. These tumors are usually associated with breast carcinoma.
  4. Close association with HNPCC (mismatch repair) and also microsatellite instability.
  5. Seen in association with Cowden syndrome (hematoma of breast, thyroid and endometrium) in which mutation of PTEN is seen (suppressor gene).
    206
  6. This tumor closely resembles normal endometrium.
  7. May be exophytic or infiltrative.
  8. They show mucinous, tubal and squamous patterns.
  9. Arise in the mucosa of uterus.
  10. Sometimes arises simultaneously in uterus and ovary.
  11. Grading (1–3) according to local invasion.
  12. Staging:
    • Stage I—limited to corpus.
    • Stage II—extending to cervix.
    • Stage III—beyond uterus, but within true pelvis.
    • Stage IV—distant metastasis.
 
Serous Carcinoma
  1. Usually arise in the background of endometrial atrophy in an old age women.
  2. p53 mutations are usually seen.
  3. This forms small tufts or papillae, rather than glands.
  4. Much greater cytological atypia.
  5. These are poorly differentiated and aggressive.
  6. Glandular element is less.
 
Clinical Course
  1. Marked leukorrhea and irregular bleeding.
  2. With progression, the uterus will enlarge.
  3. Local invasion also seen.
 
OVARIAN TUMORS
 
Classification
  1. Surface epithelial-stromal tumors (70%) (> 20 years).
    1. Serous tumor.
    2. Mucinous tumor.
    3. Endometrioid tumor.
    4. Clear cell tumor.
    5. Brenner tumor.
    6. Cystadenofibroma.
  2. Germ cell tumors (20%) (0–30 years arise from totipotent germ cells).
    1. Teratoma.
    2. Dysgerminoma.
    3. Endodermal sinus tumor.
    4. Choriocarcinoma.
  3. Sex cord-stromal tumors (10%) (any age arise from multipotent cells).
    1. Fibroma-thecoma.
    2. Granulosa-theca cell tumor.
    3. Sertoli-Leydig cell tumor.
  4. Metastasis to ovary (< 5%) (older age).
 
Serous Tumors
  1. Most frequent ovarian tumors.
  2. Benign, low malignant and malignant tumors.
  3. Benign: 30–40 years (60%).
  4. Malignant: 45–60 years.
  5. Can be unilateral or bilateral.
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  6. Serosal covering will be smooth and glistening for benign and nodular for malignant tumors.
  7. Contains cystic spaces usually filled with clear serous fluid.
  8. Benign.
    1. Lined by ciliated columnar epithelium.
    2. Psammoma bodies in papillae.
  9. Low malignant.
    1. Mild cellular atypia.
    2. Usually non-invasive.
  10. Malignant.
    1. Anaplastic and undifferentiated cells.
    2. Locally invasive and regional LN metastasis.
    3. Distant metastasis is rare.
    4. Poor prognosis.
 
Mucinous Tumors
  1. Consisting of mucin secreting cells.
  2. Benign (80%), low malignant and malignant tumors.
  3. Can be unilateral (major) and bilateral.
  4. Cystic spaces are filled with mucinous material.
  5. Most of these are larger and multiocular.
  6. Papillary formations are less.
  7. Psammoma bodies are not seen.
  8. Endocervical, intestinal and endometrial type of lining epithelia are seen.
  9. The rupture of mucinous cyst results in release of mucin into peritoneum and mucin production in the peritoneum by mucinous cells leads to pseudomyxoma peritonei.
  10. Prognosis is better than serous tumor.
 
Krukenberg Tumors
  1. Metastasis of mucinous tumor from GIT mimics the primary mucinous ovarian tumor.
  2. Usually bilateral involvement.
  3. Infiltration of stroma.
  4. Dirty necrosis (necrosis with cellular debris).
 
Endometrioid Tumors
  1. May be solid or cystic.
  2. Cyst contains chocolate-colored fluid.
  3. Tubular glands similar to those in endometrium.
  4. Mostly malignant.
  5. PTEN mutation is usually observed.
 
Brenner Tumors
  1. Usually unilateral and uncommon.
  2. Consisting of abundant stroma.
  3. Nests of transitional-like epithelium.
  4. Cysts are lined by columnar mucin secreting cells.
  5. Usually smooth and encapsulated.
 
Teratoma
  1. Differentiation towards somatic cell line.
  2. Younger the age of the patient, more chances to be malignant.
    1. Benign mature cystic teratoma.
      • Most common (90%)
      • Mature somatic elements are formed
      • Cysts are lined by epidermis (dermoid cyst)
      • Mostly unilateral (more often in right ovary)
        208
      • Filed with sebaceous secretion.
      • Hair, teeth, bone, cartilage and epithelium are seen.
      • Can produce infertility.
      • Can produce torsion.
      • Rarely malignant transformation of somatic element can occur (usually SCC).
    2. Immature malignant teratoma.
      • Found early in life (18 years)
      • Bulky and predominantly solid
      • The somatic elements are immature
      • Areas of necrosis
      • Foci of neuroepithelial lesions—metastatic
      • Late stages—poor prognosis.
    3. Specialized teratoma.
      • Only certain specialized tissues are seen
      • Struma ovarii → thyroid tissue (hyperthyroidism)
      • Ovarian carcinoid → carcnoid syndrome.
 
Dysgerminoma
  1. Usually unilateral and malignant.
  2. Counterpart of testicular seminoma.
  3. Grey-white masses and has less amount of stroma.
  4. (L) infiltration and granuloma can be seen.
 
Choriocarcinoma
  1. Unilateral and identical to placental tumor.
  2. Small and foci of hemorrhage.
  3. Cytotrophoblastic and syncytiotrophoblastic differentiation.
  4. Metastasize widely and resistant to chemotherapy.
 
Granulosa-theca Cell Tumors
  1. Usually postmenopausal, unilateral and cystic.
  2. Cuboidal granulosa cells → usually malignant.
  3. Lipid-laden thecal cells → secrete estrogen and induce endometrial and breast Ca.
 
Thecoma-fibroma Tumors
  1. Solid grey fibrous cells and lipid-laden thecal cells.
  2. Produce hydrothorax and ascites (Meigs syndrome).
  3. Rarely malignant and elaborate estrogen.
 
Sertoli-Leydig Cell Tumors
  1. Grey to yellow masses and usually solid.
  2. Masculinizing or defeminizing effect.
  3. Rarely malignant.
 
HYDATIDIFORM MOLE
  1. One of gestational trophoblastic disease.
  2. This is a voluminous mass of swollen chorionic villi appearing as grape-like structures.
  3. These swollen chorionic villi are covered by atypical chorionic epithelium.
 
Complete Mole
  1. Diploid (46 XX/46 XY).
  2. All villi are edematous.
    209
  3. Does not produce embryogenesis (no fetal parts).
  4. Diffuse trophoblastic proliferation.
  5. Highly elevated β-hCG levels.
  6. Atypia is often present.
  7. Some progresses to choriocarcinoma.
  8. In this, an empty egg is fertilized by two spermatozoa or a diploid spermatozoon.
  9. Delicate friable mass of translucent cystic structure.
  10. Absence of vascularization of villi.
  11. Myxomatous and edematous stroma.
  12. Can be removed by curettage.
 
Partial Mole
  1. Triploid (69 XXY).
  2. In this, a normal egg is fertilized by two spermatozoa or a diploid spermatozoon.
  3. Allows some embryogenesis (fetal parts present).
  4. Only focal trophoblastic proliferation (mild).
  5. β-hCG is less elevated.
  6. Only some villi are affected.
  7. Atypia is absent.
  8. Rarely progresses to choriocarcinoma.
  9. Villi have an irregular scalloped margin.
  10. Fetal parts are seen in villi.
  11. Can be removed by curettage.
 
Invasive Mole
  1. Invasive mole is a complete mole, which is more invasive locally, but do not have the aggressive metastatic potential as that of choriocarcinoma.
  2. The enlarged villi penetrate the uterine wall and sometimes cause rupture and hemorrhage.
  3. Local invasion to broad ligament and vagina also.
  4. The villi epithelium will be hyperplastic.
  5. The villi can embolize and reach lungs or brain.
  6. Not possible to remove completely by curettage.
  7. Possible to cure by chemotherapy.
 
Choriocarcinoma
  1. Another gestational trophoblastic disease.
  2. Aggressive malignant tumor.
  3. Arises usually from chorionic epithelium.
  4. 50% from complete mole, 25% arise after abortion, 25% arise after normal pregnancy.
  5. Bloody brownish discharge (hemorrhagic and necrotic).
  6. Elevated HCG level (β-subunit) in blood and urine.
  7. Originates due to abnormal ovum.
  8. Hematogenous spread mainly to lungs (50%).
  9. Also spreads to vagina, brain, liver and kidneys.
  10. Hemorrhagic and necrotic mass.
  11. No chorionic villi.
  12. Purely epithelial.
  13. Cuboidal cytotrophoblast and syncytiotrophoblast, which are anaplastic.
  14. Lymphatic spread is uncommon.
    210
 
BENIGN TUMORS OF BREAST
 
Fibroadenoma
  1. Most common benign neoplasm of breast.
  2. Almost always benign.
  3. Usually in young women (20–30 years).
  4. Due to ↑ estrogen activity.
  5. Usually small, solitary, discrete and freely movable within the breast.
  6. Rarely may be multiple or giant fibroadenoma.
  7. Can easily shell out.
  8. Glandular elements are seen.
  9. Loose fibroblastic stroma and ductal spaces.
  10. Pericanalicular pattern—the ducts may be open, regular, round/oval.
  11. Intracanalicular pattern—the ducts are compressed, slit like and irregular.
  12. The stromal cells secrete GFs for epithelium.
 
Phyllodes Tumor
  1. Arise from periductal stroma.
  2. Usually massive and distending the breast.
  3. Some become lobulated, cystic or leaf like.
  4. Increased stromal cellularity with anaplasia and increased mitosis.
  5. Rapid increased in size and leads to carcinoma.
  6. Most are cured by excision.
 
Intraductal Papilloma
  1. Always benign.
  2. Neoplastic papillary growth within the duct.
  3. Clinically.
    1. Serous or bloody nipple discharge.
    2. Small subareolar tumor.
    3. Nipple retraction rarely.
  4. Solitary or multiple papillae.
  5. Papillae have a connective tissue axis and epithelial lining.
  6. Multiple.
    1. Intraductal papillomatosis.
    2. Can leads to carcinoma.
 
CARCINOMA OF BREAST
Usually occur in women after 50 years.
 
Risk Factors
 
Well-established
  1. Geographic factors.
  2. Age.
    1. Usually after 50 years.
    2. Uncommon before 30 years.
  3. Family history.
    1. First degree relative with breast carcinoma.
    2. Mutation of BRCA 1 and BRCA 2 genes.
  4. Menstrual history.
    1. Menarche before 12.
    2. Menopause after 55.
  5. Pregnancy.
    1. Risk for late pregnancy and nullipara.
  6. Benign breast disease.
 
Less Well-established
  1. Exogenous estrogens.
    1. Estrogen replacement therapy.
  2. Oral contraceptives.
    211
  3. Obesity.
  4. High fat diet.
  5. Alcoholism.
  6. Cigarette smoking.
  7. Ionizing radiation.
 
Pathogenesis
 
Genetic Changes
  1. Mutation in BRCA 1 and 2 (Familial).
  2. Overexpression of RAS and MYC genes and HER2/NEU.
  3. Inhibition of p53 and RB genes.
 
Hormonal Factors
  1. Estrogen stimulates production of GFs like TGF-α, FGF, PDGF.
  2. Autocrine mechanism.
 
Environmental Factors
Ionizing radiation.
 
Classification
 
Non-invasive
  1. Ductal carcinoma in situ (DCIS).
  2. Lobular carcinoma in situ (LCIS).
 
Invasive
  1. Invasive ductal carcinoma.
  2. Invasive lobular carcinoma.
  3. Medullary carcinoma.
  4. Colloid carcinoma.
  5. Tubular carcinoma.
  6. Other types.
 
Sites
  1. Upper outer quadrant—50%.
  2. Upper inner quadrant—10%.
  3. Lower outer quadrant—10%.
  4. Lower inner quadrant—10%.
  5. Central portion—20%.
 
Ductal Carcinoma in Situ
  1. Does not invade beyond basement membrane.
  2. Arises within the ducts.
  3. Involve distorted duct like space.
  4. Many patterns like solid, cribriform, papillary, etc.
  5. Necrosis may be present.
  6. Nuclei may be monotonous or pleomorphic.
  7. Comedo subtype has toothpaste-like necrosis.
  8. Calcifications are seen.
  9. Late stage—palpable masses or nipple discharge.
  10. Express estrogen and progesterone receptors.
  11. Very good prognosis with mastectomy.
 
Paget Disease of the Nipple
  1. Due to expression of DCIS into lactiferous duct and into skin and nipple.
  2. Exudate is coming out due to disruption of epidermal barrier by tumor cells.
  3. Prognosis depends upon underlying DCIS.
 
Lobular Carcinoma in Situ
  1. Uniform appearance with monomorphic nuclei.
  2. Signet ring cells are seen (intracellular mucin).
  3. Calcification is rare.
    212
  4. Expanded ducts, but does not disrupt the architecture.
  5. This is a marker of ↑ risk of CA in either breast.
  6. Radiologic follow-up of both breasts and prophylactic bilateral mastectomy.
  7. Does not extend beyond the basement membrane.
 
Invasive Ductal Carcinoma (Scirrhous Carcinoma)
  1. These are carcinomas of no special type.
  2. Not essentially arising from ducts.
  3. Majority of breast carcinomas (70%–80%).
  4. Usually associated with DCIS, but rarely with LCIS.
  5. Desmoplastic and replacing the normal breast fat.
  6. May be well differentiated or poorly differentiated.
  7. Invasion of lymphovascular spaces and along nerves.
  8. Express estrogen and progesterone receptors.
  9. Advanced cancers show dimpling of skin, nipple, retraction and fixation of chest wall.
 
Invasive Lobular Carcinoma
  1. Associated with LCIS.
  2. The cells surrounding the acini or ducts to form Bull's eye pattern.
  3. Express hormone receptors and more metastatic power.
 
Medullary Carcinoma
  1. Rare subtype, which will clinically mistaken for fibroadenoma.
  2. Large anaplastic cells.
  3. Increased lymphoplasmacystic infiltrates.
  4. Increased BRAC 1 mutations and no hormone receptors.
 
Colloid (Mucinous) Carcinoma
  1. Rare subtype with ↑ mucin production.
  2. Well circumscribed and express hormone receptors.
 
Tubular Carcinoma
  1. Well-formed tubules with low grade nuclei.
  2. Express hormone receptors and good prognosis.
 
Inflammatory Carcinoma
  1. Enlarged swollen erythematous breast with palpable mass.
  2. Poorly differentiated and diffusely infiltrating.
  3. True inflammation is absent.
  4. Poor prognosis.
  5. Blockade of dermal lymphatics leads to the clinical picture.
 
Spread
  1. Outer quadrant and central lesions—axillary lymph nodes.
  2. Inner quadrant lesions—lymph nodes along internal mammary artery.
  3. Supra clavicular lymph nodes are also involved.
  4. Metastasis to lungs, bone, liver, brain, adrenals, spleen and pituitary.
    213
 
Prognosis
Depends on:
  1. Size of primary carcinoma (< 1 cm— good prognosis).
  2. Nodal involvement and number of lymph nodes involved.
  3. Distant metastasis.
  4. Grade of the carcinoma (well differentiated → good prognosis).
  5. The histologic type of carcinoma → specialized types have good prognosis than non-specialized types.
  6. Hormone receptors → presence of receptors—slightly better prognosis.
  7. Proliferative rate of cancer.
  8. Aneuploidy—worsens the prognosis.
  9. Overexpression of HER2/NEU—worsens the prognosis.
 
Stages
Stage 0: DCIS or LCIS.
Stage I: Invasive CA ≥ 2 cm without nodal involvement.
Stage II:
  1. Invasive CA ≥ 5 cm with 3 axillary LNs or.
  2. Invasive CA > 5 cm without nodes.
Stage III:
  1. ≥ 5 cm with 4 or more axillary nodes.
  2. > 5 cm with axillary nodes.
  3. Invasive CA with mammary lymph nodes.
  4. With skin involvement or chest wall fixation.
Stage IV: Invasive CA with distant metastasis.
 
FIBROCYSTIC CHANGES
 
Non-proliferative Changes
  1. Cysts and fibrosis.
  2. Without epithelial cell hyperplasia.
  3. Also called simple fibrocystic change.
  4. Very common.
  5. Increase in fibrous stroma and dilatation of ducts with formation of cysts.
  6. Usually multifocal and bilateral.
  7. The cysts are brown to blue color and contains serous/turbid fluid.
  8. Small areas of calcification can be seen.
  9. Smaller cysts are lined by polygonal cells with abundant granular eosinophilic cytoplasm and small, round, hyperchromatic nuclei → apocrine metaplasia.
  10. Virtually always benign.
  11. Cysts are surrounded by compressed fibrous tissue, which had lost its myxomatous appearance.
  12. Stromal lymphocytic infiltrate is seen.
 
Proliferative Changes
  1. Epithelial hyperplasia
    1. Some are only mild hyperplasia.
    2. On the other extent, some are severe hyperplasia with ↑ atypia.
    3. Often accompanied by other fibrocystic changes.
    4. The ductules or lobules are filled with hyperplastic cuboidal cells.
    5. Some glandular patterns can be seen—fenestrations.
    6. Sometimes papillary projections into ductal lumen—ductal papillomatosis.
      214
    7. Atypical ductal hyperplasia— similar to DCIS.
    8. Atypical lobular hyperplasia—similar to LCIS.
    9. Usually do not produce palpable breast mass.
    10. Microcalcifications can be seen.
  2. Sclerosing adenosis.
    1. Similar to carcinoma.
    2. Produce intralobular fibrosis and ductular proliferation.
    3. Hard and rubbery mass.
    4. Proliferation of epithelial and myoepithelial cells.
    5. Small glandular elements in markedly fibrosed stroma.
    6. Compression of acini and ductules leads to the appearance of solid cords of cells.
    7. Not much risk of progressing to carcinoma.
 
Fibrocystic Changes and Breast Carcinoma
  1. Minimal or no risk of carcinoma.
    1. Cysts and fibrosis.
    2. Apocrine metaplasia.
    3. Mild hyperplasia.
    4. Fibroadenoma.
  2. Slightly higher risk of carcinoma.
    1. Moderate to severe hyperplasia without atypia.
    2. Ductal papillomatosis.
    3. Sclerosing adenosis.
  3. Significantly higher risk of carcinoma.
    1. Atypical hyperplasia (ductular or lobular).
*A family history of breast carcinoma increases the risk in all cases.

Endocrine SystemChapter 20

 
HASHIMOTO'S THYROIDITIS
  1. A common cause of hypothyroidism.
  2. An autoimmune disease.
  3. Common in women than men.
 
Pathogenesis
  1. Autoimmune destruction of thyrocytes and replaced by mononuclear inflammatory infiltrate and fibrosis.
    1. Activation of CD+ T cells against thyroid Ag.
      • Release of IFN-ϒ and activation of macrophages.
      • Inflammation, tissue injury and phagocytosis.
    2. Activation of CD8+ T cells and direct killing of thyrocytes.
    3. Ab against thyroid Ag produced by B cells.
      • Ab-dependant cell-mediated cytotoxicity by natural killer (NK) cells.
  2. Association with HLA-DR3 and HLA-DR5 mutations.
  3. Three antibodies are detected:
    1. Ab to TSH receptor.
    2. Ab to thyroglobulin.
    3. Ab to thyroid peroxisome.
 
Morphology
  1. Diffuse enlargement of thyroid.
  2. The capsule is intact.
  3. Cut surface is pale and firm.
  4. Mononuclear inflammatory infiltrate (lymphocytes and plasma cells)
  5. Well-developed germinal centers.
  6. Thyroid follicles are atrophied.
  7. Some follicles lined by cells with abundant eosinophilic granular cytoplasm—Hürthle/oxyphilic cells.
  8. Hurthle cells have numerous mitochondria in them.
  9. Interstitial fibrous tissue is increased.
  10. Fibrosing variant—sometimes atrophic due to increased fibrosis.
 
Clinical Course
  1. Painless enlargement of the thyroid.
  2. Features of hypothyroidism (sometimes preceded by transient toxicosis).
  3. Increased risk for B cell NHL.
 
GRAVES' DISEASE
  1. Most common cause of endogenous hyperthyroidism.
    216
  2. Characterized by:
    1. Hyperthyroidism—diffuse the enlargement and hyperfunctional.
    2. Ophthalmopathy—exophthalmos.
    3. Dermopathy—pretibial myxedema.
  3. Women more affected than men.
 
Pathogenesis
  1. Autoimmune disease with mainly three Abs.
    1. Ab to TSH receptor.
    2. Ab to thyroglobulin.
    3. Ab to thyroid peroxisome.
  2. The Ab to TSH receptor is central to pathogenesis.
    1. Thyroid stimulating Ig.
      • Binds to TSH receptor and stimulates it.
    2. Thyroid growth stimulating Ig.
      • Binds to TSH receptor and increases proliferation.
    3. TSH–binding inhibitor Ig (TBII).
      • Actually these are inhibitors of thyroid
      • Some TBII mimics TSH and induce thyroid.
 
Ophthalmopathy
  1. T cell-mediated autoimmunity.
  2. Volume of retro-orbital connective tissue and extraocular muscles is increased by:
    1. Marked infiltration by mononuclear cells.
    2. Inflammatory edema and swelling.
    3. Accumulation of ECM components.
    4. Increased adipocytes.
 
Morphology
  1. Diffusely enlarged due to hypertrophy and hyperplasia.
  2. Smooth and soft with intact capsule.
  3. Crowded columnar cells lining the follicles.
  4. Small papillae formation and project into follicular lumen.
  5. These papillae lack fibrovascular core.
  6. Infiltrate of T cells (mainly), B cells and plasma cells.
  7. Well-developed germinal centers.
  8. Generalized lymphoid hyperplasia.
  9. Orbital tissues will be edematous.
  10. Thickening of dermis in dermopathy (increased infiltrate).
 
Clinical Course
  1. Hyperthyroidism, exophthalmos, dermopathy.
  2. Diffuse enlargement of the gland.
 
DIFFUSE AND MULTINODULAR GOITER
Most commonly caused by I2 deficiency.
 
Types
 
Endemic Goiter
  1. In geographic areas, where the soil, water and food supply has little I2, especially in mountain areas.
  2. Declined by increasing I2 availability.
 
Sporadic Goiter
  1. There is an increase demand for T4.
  2. Occur by ingestion of certain substances, which interferes with thyroid hormone synthesis, like increased Ca and vegetables like cabbage, cauliflower, etc.
    217
    Fig. 20.1: Pathogenesis of goiter
  3. Occur more in younger females.
 
Dyshormonogenetic Goiter
Hereditary enzyme defects.
 
Pathogenesis
  1. Goiter with euthyroid—here the hormone deficiency is overcome by increase in thyroid mass.
  2. Goitrous hypothyroidism—here the hormone deficiency is severe and cannot be overcome by increased thyroid mass (Fig. 20.1).
 
Morphology
  1. Mostly the hypertrophy and hyperplasia of follicles result in diffuse enlargement initially.
  2. There will be papillary projection of crowded columnar epithelium.
  3. If I2 increases and hormone demand decreases, the follicles become colloid rich and enlarged to form colloid goiter.
  4. Now the epithelium will be cuboidal (involution).
  5. With recurrent hyperplasia and involution, the gland becomes irregularly enlarged to form multinodular goiter (MNG).
  6. This may be non-toxic or produce thyrotoxicosis (toxic MNG).
  7. Colloid will be brown and gelatinous.
  8. Long-standing MNG necrosis, hemorrhage, cystic change, fibrosis, calcification, etc. can be seen.
  9. The nodules will be similar to those in follicular adenoma.
 
Clinical Course
  1. Airway obstruction, dysphagia, compression of neck vessels.
  2. Sometimes hyperthyroidism (Plummer syndrome).
    1. Not associated with ophthalmopathy or dermopathy.
  3. Less commonly hypothyroidism.
 
ADENOMA OF THYROID (FOLLICULAR ADENOMA)
  1. Benign neoplasm derived from follicular epithelium.
  2. Nodularity is usually observed.
  3. Nodules will be usually neoplastic if:
    1. Solitary nodule (usually benign).
    2. Nodules in younger patients.
    3. Nodules in males.
    4. Nodules after radiation exposure.
    5. Nodules taking radioactive I2, which are usually benign (hot nodules).
      218
 
Pathogenesis
  1. The mutations in TSH receptor signalling pathway.
  2. Activating mutation in:
    1. TSH receptor (common).
    2. Alpha-subunit of stimulatory G (GS) protein leads to increased production of cAMP (chronic).
  3. This results in clonal expansion of epithelial cells of follicles and increased thyroid hormone production.
  4. Point mutations in RAS family of oncogenes are also observed.
 
Morphology
  1. Usually solitary and well-encapsulated nodule often compressing adjacent non-neoplastic thyroid.
  2. The neoplastic cells are uniform round cells.
  3. Some cells will be like oxyphil cells.
  4. Some follicular adenoma shows atypia, pleomorphism and prominent nucleoli.
 
Clinical Course
  1. Toxic nodules—if features of thyrotoxicosis.
  2. Cold or hot nodules—in radioactive I2 imaging.
 
PAPILLARY CARCINOMA OF THYROID
  1. Most common thyroid carcinoma (75%–85%).
  2. Derived from follicular epithelium.
 
Pathogenesis
 
Genetic Variables
  1. Chromosomal rearrangements in RET gene (tyrosine kinase receptor gene) and NTRK 1 gene (neurotropic tyrosine kinase receptor gene).
  2. Point mutations BRAF proto-oncogene.
  3. Leads to activation of MAP kinase signalling pathway and ultimately to papillary carcinoma.
 
Environmental Variables
Exposure to ionising radiations.
 
Morphology
  1. Can be solitary of multifocal.
  2. May be well-encapsulated or with ill-defined margins.
  3. Foci of cystic change, fibrosis and calcification are seen.
  4. Papillary projections with fibrovascular core.
  5. The cells have nuclei with finely dispersed chromatin—ground glass nuclei/Orphan Annie eye nuclei.
  6. Cytoplasmic invaginations look like nuclear inclusions in CS and called pseudoinclusions.
  7. Concentrically calcified structures—psammoma bodies are seen often within the papillae.
 
Clinical Course
  1. Painless mass in the neck with cervical lymph node (LN) metastasis.
  2. Rarely hematogenous spread to lungs.
  3. Good prognosis.
 
FOLLICULAR CARCINOMA OF THYOROID
  1. Second most common (10%–20%) and arising from follicular epithelium.
  2. Usually in older age.
    219
 
Pathogenesis
  1. Mutation in RAS family of proto-oncogene (HRAS, KRAS, NRAS).
  2. Translocation between PAX-8 and PPAR-ϒ-1.
  3. Associated with dietary I2 deficiency and follicular adenomas.
 
Morphology
  1. Uniform cells forming small follicles.
  2. Well demarcated—minimally invasive.
  3. Infiltrating—show infiltration of capsules and vessels.
  4. The early stage resembles normal thyroid or follicular adenoma.
 
Clinical Course
  1. Usually solitary and cold nodules.
  2. Regional LN metastasis is rare.
  3. Hematogenously metastasize to liver, lungs and bones.
 
MEDULLARY CARCINOMA
  1. Five percent of thyroid carcinoma.
  2. This is a neuroendocrine neoplasm derived from parafollicular cells or ‘C’ cells.
 
Pathogenesis
  1. Mutation in RET proto-oncogene and leads to activation of TSH receptor.
  2. Occur sporadically in 80%.
  3. Familial 20%.
    1. Associated with MEN 2A or 2B or FMTC without MEN.
 
Morphology
  1. Solitary or multiple nodules.
  2. Multiple is common in familial variety.
  3. C-cell hyperplasia in the surrounding thyroid is also seen in familial cases.
  4. These hyperplastic zones are the precursor lesions.
  5. Polygonal to spindle-shaped cells form nests, trabeculae or follicles.
  6. Acellular amyloid deposits derived from calcitonin.
  7. Calcitonin can be demonstrated in tumor cells and in amyloid bodies.
  8. This tumor also secretes somatostatin, serotonin and VIP.
 
Clinical Course
  1. Mass in the neck, sometimes producing dysphagia.
  2. VIP causes diarrhea, but calcitonin does not cause hypocalcemia.
 
ANAPLASTIC CARCINOMA
  1. Only less than 5%.
  2. Aggressive tumor arising in older age.
 
Pathogenesis
  1. Usually arise by dedifferentiation of well-differentiated papillary or follicular carcinoma.
  2. As a result of one or more genetic alterations.
  3. p53 mutation is usually observed.
 
Morphology
  1. Bulky masses invade the capsule to reach neck structures.
  2. Highly anaplastic cells and shows four patterns:
    220
    1. Pleomorphic giant cells.
    2. Spindle cells.
    3. Mixed giant cells and spindle cells.
    4. Small cells as in small cell carcinoma.
  3. Foci of papillae or follicles some times.
 
Clinical Features
Highly aggressive and metastasize rapidly (death in 1 year).
 
HYPERPARATHYROIDISM
Refer Chapter 21 (Musculoskeletal System).
 
DIABETES MELLITUS
 
Pathogenesis of Type I DM (IDDM)
  1. An autoimmune disease.
  2. T cell-mediated destruction of islets (β cells) and results in reduction of beta-cell mass.
  3. There is absolute insulin deficiency.
  4. Genetic predisposition and environmental factors play a role in pathogenesis.
  5. Commonly develops in childhood, manifests at puberty and progressive with age.
  6. Responds to exogenous insulin.
  7. The mechanisms of destruction are:
    1. CD4+ T cells activate macrophages.
    2. Release of IL-1, IL-6 and TNF by macrophages.
    3. Results in inflammation and tissue injury.
    4. CD8+ T cells causes direct cytotoxicity.
    5. Ab-mediated beta-cell destruction.
  8. The susceptibility locus is HLA–D on chromosome-6, which is encoding for class-2 MHC molecules.
 
Pathogenesis of Type II DM (NIDDM)
  1. Insulin resistance and progressive beta-cell dysfunctioning.
  2. Here relative insulin deficiency only (Fig. 20.2).
 
Insulin Resistance
  1. This is the resistance to the effects of insulin on glucose uptake, metabolism or storage.
  2. Caused by:
    1. Genetic defects of insulin receptor and insulin signalling pathways.
    2. Obesity:
      • Increased free fatty acid (FFAs)—decreased sensitivity to insulin
      • Adipocytokines.
        • ↓ leptin
        • ↓ adiponectin
        • ↑ resisitin.
      • Decreased activity of thiazolidinediones (TZD) and loss of activation of PPAR-ϒ (insulin resistance)
      • Decreased sirtuins (a family of proteins)
      • Insulin resistance.
        • Decreased beta-cell stimulation.
        • Decreased adiponectin insulin resistance.
 
Beta-cell Dysfuncion
  1. Develops after several years of hyperactivity to compensate insulin resistance.
  2. May be due to:
    1. Lipotoxicty by ↑ FFAs.
    2. Glucotoxicity by chronic hyperglycemia.
      221
      Fig. 20.2: Pathogenesis of type II DM
  3. Qualitative β-cell dysfunction.
  4. Quantitative β-cell dysfunction.
    1. Decrease in β-cell mass.
    2. Islet degeneration.
    3. Deposition of amyloid in islet.
 
Pathogenesis of DM Complications
  1. Non-enzymatic glycosylation.
    1. This is the process by which glucose is attached to free amino acids of proteins without the aid of enzymes.
    2. This results in the formation of advanced glycosylation end products (AGEs).
    3. The AGEs of collagen in vascular wall leads to accumulation of cholesterol (atherosclerosis).
    4. AGEs modify the plasma proteins and these modified proteins get attached to AGE receptor and induce:
      • Release of cytokines
      • Proliferation of ECM
      • Increased membrane permeability, etc.
    5. All these contributes to complications.
  2. Activation of protein kinase-C (Fig. 20.3).
  3. IC hyperglycemia with disturbance in polyol pathway.
    1. By this, accumulation of sorbitol and fructose get increased, which in turn increases the susceptibility of cells towards oxidative stress.
    2. This is due to decrease in antioxidants (IC) by sorbitol metabolism.
 
Morphology
 
Pancreas
  1. Reduction in number and size of islets.
  2. Leukocytic infiltration of islets (insulitis).
  3. Amyloid replacement of islets in long-standing type II DM.
  4. Increase in number and size of islets in non-diabetic newborn of a diabetic mother.
 
Diabetic Macrovascular Disease
  1. Atherosclerosis.
  2. If coronaries involved—(1st cause of death in DM).
  3. Gangrene of lower extremities can occur.
  4. Severe hyaline arteriosclerosis of HTN.
 
Diabetic Microangiopathy
  1. Thickening of basement membrane (BM) due to deposition of AGEs and proliferation of fibroblasts.
    222
  2. Occur in skin, skeletal muscle, retina, renal glomeruli, renal medulla and cerebrum.
 
Diabetic Nephropathy
  1. Second cause of death in DM.
    1. Capillary BM thickening (glomerular lesion).
    2. Diffuse mesangial sclerosis (glomerular lesion).
      • Increased mesangial matrix and BM thickening
      • Can manifest as nephrotic syndrome.
    3. Nodular glomerulosclerosis.
      • Increased deposition of matrix
      • Leads to renal ischemia.
    4. Renal atherosclerosis and arteriosclerosis.
      • Both afferent and efferent arterioles are affected.
    5. Pyelonephritis.
      • More severe and with necrotizing papillitis.
 
Ocular Complications
  1. Diabetic retinopathy.
    1. Non-proliferative.
      • Retinal hemorrhages and exudates
      • Microaneurysms
      • Retinal edema
      • Microangiopathy (BM thickening).
    2. Proliferative.
      • Neovascularization and fibrosis
      • Vitreous hemorrhages from new vessels
      • Retinal detachment.
  2. Cataract.
  3. Glaucoma.
 
Diabetic Neuropathy
  1. Peripheral neuropathy of extremities mainly affecting the sensory function.
  2. Autonomic neuropathy affecting bowel and bladder functioning.
  3. This is due to microangiopathy, increased capillary permeability and direct axonal damage caused by sorbitol accumulation.
 
Clinical Course
  1. Hyperglycemia.
  2. Polyuria, polyphagia, polydipsia.
  3. Diabetic ketoacidosis and diabetic coma.
  4. Hyperosmolar non-ketotic coma.
 
CUSHING SYNDROME
  1. Also called hypercortisolism.
  2. Caused by any condition that produces elevation in glucocorticoids level.
 
Etiology
  1. Primary hypothalamic-pituitary diseases, which increases ACTH secretion.
    1. Cushing disease (50%).
    Fig. 20.3: Pathogenesis of DM complications (activation of protein kinase-C)
    223
  2. Primary adrenocortical hyperplasia or neoplasia.
  3. Secretion of ectopic ACTH by non-endocrine tumors (paraneoplastic).
    1. Small cell carcinoma of lung.
    2. Carcinoid tumors.
    3. Medullary carcinoma of thyroid.
    4. Islet cell tumors of pancreas.
  4. Exogenous glucocorticoids (clinically most common).
 
Morphology
 
Pituitary
  1. Crooke hyaline change.
    1. The normal basophilic granular cytoplasm of ACTH producing cells is replaced by homogenous hyaline material.
    2. Due to deposition of keratin filaments.
 
Adrenal Gland
  1. Depends on the cause:
    1. Cortical atrophy—in exogenous hypercortisolism.
      • Atrophy of zona fasciculata and reticularis
      • Zona glomerulosa will be normal.
    2. Diffuse hyperplasia—in endogenous hypercortisolism.
    3. Nodular hyperplasia—an extension of diffuse hyperplasia.
    4. Adrenocortical neoplasms.
      • Adenoma—benign and well encapsulated
      • Carcinoma—malignant and unencapsulated.
 
Clinical Course
  1. Hypertension (HTN) and weight gain.
  2. Moon facies and buffalo hump.
  3. Osteoporosis and decrease muscle mass.
  4. Hyperglycemia, glycosuria, polydipsia.
  5. Purple abdominal striae.
  6. Hirsutism and menstrual disturbances.
  7. Mental problems.
 
HYPERALDOSTERONISM
 
Primary
  1. Overproduction of aldosterone autonomously and there will be:
    1. Suppression of RAAS.
    2. Increased plasma renin activity.
  2. By primary adrenocortical hyperplasia or adrenocortical neoplasms.
 
Secondary
  1. Extra-adrenal cause and there will be stimulation of RAAS and increased plasma renin activity.
  2. Caused by:
    1. Decreased renal perfusion (renal artery stenosis).
    2. Arterial hypovolemia and edema (CCF, cirrhosis).
    3. Pregnancy (induced by estrogen).
 
Morphology
  1. The 80% of primary hyperaldosteronism is by aldosterone secreting adenoma (Conn syndrome).
  2. There will be cortical hyperplasia also.
    224
  3. Eosinophilic lamellated cytoplasmic inclusions called aldosterone bodies are seen.
  4. In most cases, adrenocortical hyperplasia will be there.
 
Clinical Course
  1. Na+ retention and K+ excretion—HTN and hypokalemia.
  2. Primary—treated with spironolactone or surgery.
  3. Secondary—treated according to the course.
 
ADRENAL INSUFFICIENCY
 
Primary Acute
  1. Waterhouse-Friderichsen syndrome.
  2. Sudden withdrawal of long-term corticosteroid therapy.
  3. Stress in patients with underlying C/c insufficiency.
  4. Massive adrenal hemorrhage.
 
Primary Chronic (Addison Disease)
  1. Due to progressive destruction of adrenal cortex:
    1. Autoimmune adrenalitis (60%–70%).
      • Isolated autoimmune Addison disease or
      • Autoimmune polyendocrinopathy syndrome.
    2. Infections such as:
      • Tuberculosis.
      • Fungal infections also.
    3. AIDS:
      • Infections (CMV, MAC).
      • Non-infectious (Kaposi sarcoma).
    4. Metastatic neoplasms:
      • CA breast and CA lung commonly.
 
Secondary Insufficiency
  1. Disease of pituitary and hypothalamus.
  2. Decreased ACTH level.
 
Morphology
  1. Depending upon cause.
  2. Primary autoimmune adrenalitis—irregularly shrunken.
  3. Secondary—small and atrophic.
  4. Tuberculous—granulomatous inflammation.
 
PHEOCHROMOCYTOMA
  1. Neoplasms composed of chromaffin cells capable of synthesizing and releasing catecholamines and sometimes other peptide hormones also.
  2. Neoplasm of adrenal medulla and is surgically correctable.
  3. Rule of 10:
    1. 10% occur in association with Familial syndromes like MEN-2A, MEN-2B, VHL and neurofibromatosis.
    2. 10% occur extra-adrenal in sites like carotid body (paraganglioma).
    3. 10% adrenal pheochromocytoma are bilateral.
    4. 10% adrenal pheochromocytoma are malignant.
      225
 
Morphology
  1. Can be small circumscribed or large hemorrhagic.
  2. Incubation with potassium dichromate produces dark brown color.
  3. Polygonal or spindle-shaped chromaffin cells and supporting cells form nests.
  4. Chromaffin cells have granules containing CAs and highlighted by silver stains.
  5. Pleomorphic nuclei.
  6. Invasion and mitotic figures are present in both benign and malignant lesions.
  7. Malignancy is identified by metastasis.
 
Clinical Course
  1. Sudden onset of HTN (episodes) with tachycardia, palpitation, headache, sweating, tremor, etc.
  2. Sense of apprehension.
  3. Chronic sustained HTN also.
  4. Increased risk of MI, cardiac failure, renal failure, CVD, etc.
 
MULTIPLE ENDOCRINE NEOPLASIA SYNDROMES
  1. A group of inherited diseases resulting in proliferative lesions of multiple endocrine organs.
  2. Usually in younger age with Increased aggressiveness and more chance of recurrence.
  3. Usually multifocal and may arise simultaneously or one by one.
  4. Usually preceded by asymptomatic endocrine hyperplasia.
 
MEN1
  1. Autosomal dominant (AD) involving MEN1 gene on chromosome 11q 13.
  2. Affected organs are:
    1. Parathyroid—primary hyperparathyroidism due to hyperplasia.
    2. Pancreas—leading cause of death in MEN1, ZES, gastrinomas, hypoglycemia (insulinoma).
    3. Pituitary—prolactinoma (mainly), GH secreting tumors also.
 
MEN2
Mutation of RET proto-oncogene on 10q 11.
 
MEN2A
  1. Thyroid:
    1. Medullary carcinoma.
  2. Adrenal medulla:
    1. Pheochromocytoma.
  3. Parathyroid:
    1. Hyperplasia with primary hyperparathyroidism.
 
MEN2B
  1. Thyroid and adrenal medulla are involved as in MEN2A.
  2. Do not develop primary hyperparathyroidism.
  3. Develop extraendocrine manifestations like ganglioneuromas of mucosa and Marfan syndrome.

Musculoskeletal SystemChapter 21

 
CONGENITAL DISEASES OF BONE
The defect is in migration of mesenchymal cells during development leads to the formation of condensations—dysostosis. For example,
  1. Aplasia—absence of a digit.
  2. Formation of extra digit.
  3. Fusion of two bones.
 
Osteogenesis Imperfecta
  1. Osteogenesis imperfecta is also called brittle bone disease.
  2. Due to defective formation of type I collagen.
  3. Autosomal dominant.
  4. Mutations in genes for α-1 or α-2 subunit of collagen 1 leads to defective extracellular matrix (ECM) production and its early degradation.
  5. Too little bone resulting in extreme fragility.
  6. Type I: Normal lifespan with ↑ fractures, blue sclera, hearing loss, misshapen teeth.
  7. Type II: Fatal due to fractures in utero.
 
Achondroplasia
  1. Autosomal dominant and a major cause of dwarfism.
  2. Point mutation in FGFR-3 leads to its activation.
  3. Activated FGFR-3 inhibits chondrocyte proliferation.
  4. So normal epiphyseal growth plate expansion is suppressed and long bone growth is severely stunted.
  5. In homozygous condition, abnormalities in chest leads to respiratory arrest and death.
  6. Features are shortening of extremities, bowing of legs and a lordotic posture.
  7. Thanatotropic dwarfism severe and also FGFR-3 mutation:
    1. Shortening of limbs.
    2. Bossing of forehead.
    3. Extremely small thorax.
 
Osteopetrosis
  1. Rare.
  2. Reduced osteoclast-mediated resorption and thus defective bone remodeling.
    227
  3. Affected bone is dense and stone like.
  4. Readily leads to fractures as a chalk piece.
  5. The decalcification and digestion of bone matrix get affected.
  6. The decalcification needs an acidic environment and so the associated deficiency of (CA-II) also contributes to pathogenesis.
  7. Easy fracture, cranial nerve problems and increased infections.
  8. Hepatosplenomegaly due to extra medullary hematopoiesis.
 
Osteoporosis
  1. Characterized by increased porosity of bones due to reduced bone mass.
  2. This is an acquired disease of bone.
  3. Increased bone fragility and susceptibility to fractures.
  4. Localized: Disuse osteoporosis of a limb.
  5. Generalized: Metabolic bone diseases (primary or secondary).
 
Causes
  1. Primary: Senile and postmenopausal (common).
  2. Secondary:
    1. Endocrine disorders—hyperparathyroidism, hypogonadism, pituitary tumors.
    2. Neoplasia—multiple myeloma, carcinomatosis.
    3. Gastrointestinal (GI) disorders—malnutrition, malabsorption.
    4. Drugs—anticoagulants, anticonvulsants, alcohol, corticosteroids and cancer chemotherapy.
    5. Others—immobilization, pulmonary disease, homocystinuria, anemia.
 
Pathogenesis
Due to loss of balance between bone formation and resorption (Fig. 21.1).
 
Determinants
  1. Increased age.
    1. Decreased replication of osteoprogenitor cells.
    2. Decreased synthetic activity of osteoblasts.
    3. Decreased activity of GFs.
    4. Decreased physical activity.
  2. Menopause as shown in the Figure 21.2 (hormonal).
  3. Physical activity.
    Fig. 21.1: Pathogenesis of osteoporosis
    228
  4. Genetic factors.
  5. Nutrition (especially Ca2+).
 
Morphology
  1. Vertebrae and femoral neck is more affected, because there is increased resorption rate in our body.
  2. Loss of bone is more conspicuous, where there is abundant trabecular bone.
  3. Thinning of trabeculae and widening of Haversian canals.
 
Treatment
  1. Vitamin D3 and Ca.
  2. Bisphosphonates.
  3. Selective estrogen receptor agonists.
  4. Parathyroid hormone (in ineffective estrogen therapy).
 
PAGET DISEASE (OSTEITIS DEFORMANS)
  1. Paget disease is characterized by:
    1. Osteolytic stage.
      • Regional osteoclastic activity and bone resorption.
    2. Mixed osteoclastic.
      • Osteoblastic stage—exuberant bone formation.
    3. Osteosclerotic stage.
      • Exhaustion of cellular activity.
  2. There will be a net gain in bone mass, which lacks strength.
 
Pathogenesis
Occur as a result of hyper-responsiveness to vitamin D and RANK ligand (Fig. 21.3).
 
Morphology
  1. May be unifocal or multifocal.
  2. Lytic phase.
    1. Increased osteoclasts and of increased size.
  3. Mixed phase.
    1. Both osteoclasts and osteoblasts.
    2. Marrow contains increased connective tissue and vessels.
    3. Mosaic pattern of lamellar bone.
  4. Sclerotic phase.
    1. Normal marrow, but increased fragile bone mass.
Fig. 21.2: Menopause leading onto osteoporosis
Fig. 21.3: Pathogenesis of Paget disease
229
 
Clinical Course
  1. Can be mono-ostotic or polyostotic.
  2. Symptoms depend on the site.
  3. Back pain, cranial nerve involvement.
  4. Special chalk-stick fractures of long bones.
  5. Treatment by calcitonin and bisphosphonates.
 
RICKETS AND OSTEOMALACIA
  1. Rickets—affects growing children.
  2. Osteomalacia—adult counterpart.
  3. Both results from diet deficient in Ca and vitamin D.
  4. Decreased sunlight exposure, renal disorders (decreased 1, 25-DHC).
  5. Phosphate depletion and malabsorption are also leading to rickets and osteomalacia.
 
Pathogenesis of Rickets
  1. Overgrowth of epiphyseal cartilage due to inadequate calcification.
  2. Failure of maturation of cartilage cells.
  3. Persistence of distorted irregular masses of cartilage.
  4. Deposition of osteoid matrix and replacement of cartilage with lateral expansion of osteochondral junction.
  5. Abnormal overgrowth of capillaries and fibroblast.
  6. Deformed skeleton due to loss of rigidity.
  7. Occipital bone flattening and buckling of parietal bones due to pressure and regains normal, if pressure is removed.
  8. Frontal bossing.
  9. Rachitic rosary—prominent costochondral junction.
  10. Pigeon chest—anterior protrusion of sternum.
  11. Harrison's groove—due to inward pull by diaphragm.
  12. Lumbar lordosis.
  13. Bowing of legs.
 
Pathogenesis of Osteomalacia
  1. Inadequately mineralized excess osteoid.
  2. Defective remodeling.
The Figure 21.4 shows the pathogenesis of both rickets and osteomalacia.
Fig. 21.4: Pathogenesis of rickets and osteomalacia
230
 
HYPERPARATHYROIDISM
  1. Parathyroid hormone (PTH) causes hypercalcemia and increased bone resorption.
  2. PTH acts on bone metabolism through:
    Increasing
    1. RANKL production by osteoblasts.
    2. Osteoclasts and bone resorption.
    3. Ca mobilization from bones.
    4. Ca reabsorption from kidney.
    5. 1,25-DHC production in kidney.
    Decreasing
    1. Ca excretion.
    2. Phosphate excretion.
  3. Primary—increased autonomous parathyroid secretion.
  4. Secondary—due to C/c renal diseases (Fig. 21.5).
 
Morphology
  1. Increased osteoclastic activity.
  2. Cortical and trabecular bone are lost and replaced by loose connective tissue.
  3. Bone resorption mainly in the subperiosteal region.
  4. Marrow contain fibrovascular tissue and hemosiderin.
  5. The mass of osteoclasts, giant cells and hemorrhagic debris is called brown tumor of hyperparathyroidism.
  6. Contain cystic spaces and so called osteitis fibrosa cystica.
 
OSTEOMYELITIS
Inflammation of bone and bone marrow.
 
Pyogenic Osteomyelitis
  1. Pyogenic osteomyelitis caused by bacteria.
  2. The infection occurs through three routes:
    1. The hematogenous dissemination (common).
    2. Extension from adjacent site.
    3. Traumatic implantation (compound fracture, orthopedic surgeries).
  3. Staphylococcus aureus is the most common organism.
  4. Escherichia coli, Group-B Streptococcus, Salmonella are also common.
 
Morphology
  1. Depend on the stage—acute, subacute or chronic.
  2. The affected bone undergoes necrosis and the dead bone is called sequestrum.
  3. Subperiosteal abscess in children due to loosely attached periosteum.
    Fig. 21.5: Events in secondary hyperthyroidism
    231
  4. Rupture of periosteum leads to abscess formation in surrounding soft tissue—draining sinus.
  5. Usually in infants, the epiphyseal infection spreads to adjacent joint to produce suppurative arthritis.
  6. After the 1st week, chronic inflammatory cells will get deposited.
  7. The cytokines induce bone resorption, fibrous tissue ingrowth and new bone formation.
  8. This reactive new bone surrounded by the dead bone is called involucrum.
 
Clinical course
  1. Fever, malaise, leukocytosis.
  2. Throbbing pain.
  3. Typical radiological features.
  4. Treatment with draining and antibiotics.
 
Tuberculous Osteomyelitis
  1. Tuberculous osteomyelitis is caused by Mycobacterium tuberculosis.
  2. Occur mainly by hematogenous spread and also by direct extension.
  3. Hematogenously spreads mainly to long bones and vertebrae.
  4. Granulomatous inflammation with caseous necrosis and extensive bone destruction.
  5. Tuberculosis of vertebral bodies (Pott disease) leads to:
    1. Compression fractures.
    2. Psoas abscess.
 
Bone Tumors
Primary bone tumors are less compared to bone metastasis.
The classificaton of bone tumors (Table 21.1) are as given below:
 
Osteosarcoma
  1. A bone producing malignant mesenchymal tumor.
  2. Primary—younger age group (< 20).
  3. Secondary—older age group (> 40).
    1. Secondary to Paget disease, bone infarcts, etc.
  4. Usually affects metaphysis of distal femur, proximal tibia, humerus, pelvis, jaw, etc.
 
Pathogenesis
Mutations in RB gene and p53 are associated.
 
Morphology
  1. Gritty and grey-white tumors.
  2. Hemorrhage and cystic degeneration.
  3. Destroy the surrounding cortex and produce soft tissue masses.
  4. They invade through the medullary canal and replace the marrow.
  5. Involvement of joint space is rare.
  6. Large bizarre tumor giant cells have hyperchromatic nuclei.
  7. Increased unmineralized osteoid production.
  8. Cartilage and fibrous tissue are also seen.
  9. If there is increased amount of cartilage—chondroblastic osteosarcoma.
  10. There will be spontaneous necrosis of tumor.
  11. Can go outward to periosteum or go inward to medullary cavity.
 
Clinical course
  1. Painful enlarging mass.
  2. Pathologic fractures.
  3. Periosteal new bone formation.
  4. A triangular shadow in X-ray between cortex and raised periosteum —Codman's triangle.
    232
  5. Typically spread hematogenously.
  6. Amputation and chemotherapy is the treatment.
 
Chondrosarcoma
  1. These are cartilage producing malignant tumor (mainly in 40–60 age group).
  2. According to site they are intramedullary and juxtacortical.
 
Morphology
  1. Conventional.
    1. Expansile glistening mass.
    2. Arise in the medullary cavity and erodes the cortex.
    3. Exhibit malignant hyaline and myxoid cartilage.
  2. Myxoid.
    1. Viscous and gelatinous.
      233
    2. Spotty calcifications.
    3. Necrosis and cystic degeneration.
  3. Dedifferentiated.
    1. High grade poorly-differentiated variety.
    2. Foci of fibrosis or osteosarcomas.
  4. Clear cell chondrosarcoma.
  5. Mesenchymal chondrosarcoma.
    1. Low grade—cartilage will be normal.
    2. High grade—pleomorphic chondrocytes with mitotic figures.
 
Clinical course
  1. Mainly in shoulder, pelvis, ribs and femur.
  2. Metastasize hematogenously to lungs and other bones.
  3. Surgical excision and chemotherapy as treatment.
 
Ewing Sarcoma
  1. Primary malignant small round cell tumors of bone and soft tissue.
  2. Undifferentiated tumor and usually affect below 20 year of age group.
  3. Second most common pediatric bone tumor after osteosarcoma.
  4. The chromosomal abnormality is fusion of EWS gene on ETS family of transcription factors (FL1 and ERG).
  5. The resultant gene induces cell proliferation.
 
Morphology
  1. Arise in the medullary cavity.
  2. Erodes cortex and periosteum to form soft-tissue mass.
  3. Hemorrhage, necrosis and periosteal reaction.
  4. Small round tumor cells with glycogen-rich cytoplasm.
  5. Homer-Wright rosettes.
    1. Tumor cells circled around a central fibrillary space—neural differentiation.
  6. Mainly seen in diaphysis as a mass.
  7. Mainly in femur and pelvis.
 
Giant Cell Tumor (Osteoclastoma)
  1. Mainly affect epiphysis of long bone (especially around knee).
  2. Multinucleated osteoclast-like giant cells (reactive cells).
  3. Usually benign, but locally aggressive.
  4. Frequently cystic degeneration, hemorrhage and necrosis.
  5. Small round, spindle-shaped mononuclear cells are seen (neoplastic cells).
  6. Bulging soft-tissue mass and reactive bone formation are seen.
 
OSTEOARTHRITIS
  1. Degenerative joint disease.
  2. The fundamental feature is degeneration of articular cartilage.
  3. Primary:
    1. Occurs insidiously with age.
    2. Oligoarticular (affecting a few joints).
  4. Secondary:
    1. In youth due to predisposing conditions like:
      • Trauma
      • Developmental deformity
      • Obesity
      • Systemic diseases like DM, hemochromatosis
      • Affecting the predisposed joints.
        234
  5. Female—mainly knees and hands are affected.
  6. Male—mainly hip.
 
Pathogenesis
The pathogenesis of osteoarthritis is shown in the Figure 21.6.
 
Morphology
  1. Proliferation and disorganization of chondrocytes in the superficial part of articular cartilage (as a response to increased chondrocyte apoptosis).
  2. Increased water content and ↓ proteoglycans in the matrix.
  3. Cracking of matrix.
  4. Soft-granular articular cartilage.
  5. The bone surface get exposed and due to friction, polished surfaces are formed—bone eburnation.
  6. The underlying cancellous bone get thickened and becomes sclerotic (subchondral sclerosis).
  7. Fractures lead to dislodging small pieces of cartilage and bone into joint space—loose bodies.
  8. The synovial fluid forced into subchondral region to form fibrous walled cysts.
  9. Osteophytes (bone outgrowths) develop at the margins of articular surface.
  10. Severe cases—pannus formation also.
  11. No ankylosis as in RA.
 
Clinical Course
  1. Deep aching pain.
  2. Morning stiffness.
  3. Crepitus.
  4. Neurological symptoms due to compression by osteophyte.
  5. Heberden nodes on distal interphalangeal joints.
 
GOUT
  1. Gout is caused by tissue accumulation of uric acid crystals.
    Fig. 21.6: Pathogenesis of osteoarthritis
    235
  2. Monosodium urate crystals are accumulated.
  3. Primary:
    1. Due to inborn errors in uric acid metabolism.
    2. ↑ production with normal or ↑ excretion.
    3. Normal production with ↓ excretion.
    4. Constitutes 90% and this is idiopathic.
  4. Secondary:
    1. Constitutes 10%.
    2. ↑ nucleic acid turn over—↑ production and ↑ excretion.
    3. Chronic renal disease—normal production and ↓ excretion.
 
Pathogenesis
  1. Increased uric acid synthesis (HGPRTase deficiency).
    1. Abnormal ‘de novo’ pathway.
    2. Abnormal ‘salvage’ pathway.
  2. Decreased uric acid excretion.
    1. Renal disorder (by thiazide diuretic).
The pathogenesis of gout is shown in the Figure 21.7.
Fig. 21.7: Pathogenesis of gout
236
 
Morphology
  1. Acute arthritis.
    1. Dense (N) infiltrate.
    2. Long needle-shaped monosodium urate crystals in the cytoplasm.
    3. The synovium is congested and edematous.
  2. Chronic tophaceous arthritis.
    1. Repeated precipitation of urate crystals leads to the formation of visible deposits—tophi.
    2. Synovium becomes hyperplastic, fibrotic and thickened with increased inflammatory cells.
    3. Forms a pannus, which destroys the cartilage.
    4. Bone erosions and ankylosis may occur.
  3. Tophi at various sites.
    1. Tophi are large aggregations of urate crystals surrounded by (L), macrophages and foreign body giant cells.
    2. Deposit in joints, ligaments, tendons, soft tissues like ear lobes, nasal cartilage, finger tips, etc.
    3. Tophi can lead to draining ulcerations.
  4. Gouty nephropathy.
    1. Medullary tophi, intra tubular tophi and renal calculi.
    2. Can leads to obstruction and pyelonephritis.
 
Clinical Course
  1. More in men after 30 years.
  2. Four stages.
    1. Asymptomatic hyperuricemia.
    2. Acute gouty arthritis.
    3. Intercritical gout (resolved stage without treatment).
    4. Chronic tophaceous gout.
 
Pseudogout
  1. Pseudogout is also called chondrocalcinosis.
  2. Deposition of calcium pyrophosphate crystals in various joints.
  3. Produce inflammation and joint destruction.
 
FATTY TUMORS
 
Lipoma
  1. Benign tumors of fat.
  2. Commonest soft-tissue tumor in adults.
  3. Mostly are unifocal.
  4. Types.
    1. Conventional lipoma—only fat.
    2. Myolipoma—fat + muscle.
    3. Neurolipoma—fat + neural tissue.
    4. Myelolipoma—fat + marrow elements.
    5. Angiolipoma—fat + blood vessels.
    6. Fibrolipoma—fat + fibrous tissue.
    7. Pleomorphic lipoma—mixed variety.
  5. Conventional lipomas are soft, yellow, well-encapsulated masses of mature adipocytes.
 
Liposarcoma
  1. Malignant neoplasms of adipocytes (mainly in old age).
  2. Arise in deep soft tissues or in visceral sites.
    237
  3. Well-differentiated and myxoid varieties—good prognosis.
  4. Aggressive round cell and pleomorphic types—bad prognosis.
  5. MDM2 gene mutation and p53 suppression are seen.
  6. t(12,16) translocation also seen.
  7. Well-circumscribed lesions.
  8. Abundant mucoid ECM.
  9. Lipoblasts are seen.
    1. Adipocytes precursors.
    2. Lipid vacuoles in cytoplasm.
 
SMOOTH-MUSCLE TUMORS
 
Leiomyoma
  1. Benign smooth-muscle tumor.
  2. Well-circumscribed lesions (grey white masses).
  3. Occurs anywhere in the body.
  4. Mostly in the uterus (fibroid uterus).
  5. Most common benign tumor in females.
  6. Estrogen and oral contraceptives (OCP) induces the growth.
  7. They shrink postmenopausally.
  8. The cut surface is typically whorled.
  9. Usually solitary.
  10. Types.
    1. Intramural, submucosal and subserosal.
  11. Some are attached to adjacent structures—parasitic fibroids.
  12. Foci of hemorrhage, necrosis, cystic change, fibrosis and calcification can be seen.
  13. Manifest as menorrhagia with or without metrorrhagia.
 
Leiomyosarcoma
  1. Most commonly in uterus (retroperitoneal).
  2. Arise from the mesenchymal cells of myometrium and not from pre-existing leiomyoma.
  3. Can form bulky masses infiltrating myometrium or form polyps protruding into uterine cavity.
  4. Usually solitary, soft, hemorrhagic and necrotic.
  5. Range from well-differentiated to highly anaplastic.
  6. Cytologic atypia and increased mitosis are observed.
  7. Metastasize typically to lungs.
  8. Occurs also in skin and deep soft tissue.
  9. The cutaneous lesions are easy to excise.
  10. The retroperitoneal lesions cannot be excised completely.

SkinChapter 22

 
SQUAMOUS CELL CARCINOMA
  1. Squamous cell carcinoma (SCC) is a common skin tumor arising mainly on sun-exposed areas in older people.
  2. Predisposing factors include sunlight, industrial carcinogen, chronic ulcers, old burn scars, arsenic, ionizing radiation, immunosuppression, etc.
 
Pathogenesis
The pathogensis of squamous cell carcinoma is shown in Figure 22.1.
Fig. 22.1: Pathogenesis of squamous cell carcinoma
 
Morphology
  1. Highly atypical cells.
  2. Squamous dysplasia.
  3. Carcinoma in situ → well demarcated, red plaques.
  4. Invasive SCC.
    1. Invade through BM.
    2. Highly anaplastic cells and ulcerations.
    3. Foci of necrosis seen.
  5. Keratin horn pearls typically seen.
 
Clinical Course
  1. Metastasis is uncommon for cutaneous SCC.
  2. Mucosal SCC is aggressive.
 
BASAL CELL CARCINOMA
  1. Most common human cancer.
  2. Slow growing tumor that rarely metastasizes.
  3. Occur at chronically sun exposed sites and in lightly pigmented people.
  4. Risk increases in immunosuppression and in persons with inherited DNA repair defect.
 
Pathogenesis
  1. Dysregulation of sonic hedgehog pathway (PTCH pathway) due to mutation in PTCH gene.
  2. p53 muptation also seen.
    239
 
Morphology
  1. Tumor cell resemble normal epidermal basal cells.
  2. Not seen in mucous cell surfaces.
  3. Two patterns:
    1. Multifocal → superficial type.
    2. Nodular.
      • Goes deep into dermis as special tumor islands
      • The tumor cells are basophilic with hyperchromatic nuclei
      • The peripheral tumor cells in the islands are in a palisading arrangement.
 
Clinical Course
  1. Present as pearly papules containing prominent dilated subepidermal blood vessels (telangiectasia).
  2. Some contain melanin pigment.
  3. Advanced lesions may ulcerate or invade the underlining tissue extensively (often bone).
  4. When ulcerate, it is called rodent ulcer.
 
MALIGNANT MELANOMA
Less common, but much more deadly than SCC.
 
Pathogenesis
  1. Sunlight exposure plays an important role.
  2. Previous nevi and heredity are also risk factors.
  3. Occur mostly sporadically.
  4. Mutation in CDKN2A gene—this regulates the G1-S transition.
  5. Activating mutations of NRAS or BRAF are also seen.
  6. Suppression of PTEN gene.
  7. Polymorphism of MC1R gene (melanocortin receptor gene).
  8. All these leads to increased melanocyte production.
 
Morphology
  1. Radial growth.
    1. Grow horizontally within the epidermis and superficial layers of dermis.
    2. Initial stage.
    3. No ability to metastasize.
    4. No angiogenesis observed.
  2. Vertical.
    1. Grows into the depth of dermis.
    2. As an expansile mass (angiogenesis).
    3. Lack cellular maturation.
    4. Have metastatic potential.
    5. Metastasize to LNs and hematogenously to lungs, liver, brain, etc.
  3. Malignant cells are larger.
  4. The nuclei have clumped chromatin at periphery and eosinophilic nucleoli (cherry red).
  5. May arranged as nests or nodules in radial and vertical growth respectively.
  6. Melanin pigment can be seen.
 
Clinical Course
  1. Occur mostly in skin.
  2. Also in mucosa of mouth, anogenital region, esophagus, meninges and even eye.
    240
  3. May be itching or painful.
  4. Suggestive of MM.
    1. Increase in size of lesion.
    2. Change on color of the lesion.
  5. The borders are irregular.
  6. ABCDEs of melanoma.
    1. Asymmetry.
    2. Border—irregular.
    3. Color—change.
    4. Diameter—increase.
    5. Evolution of new nevus during adulthood.

Nervous SystemChapter 23

 
BERRY ANEURYSM
  1. Also called saccular aneurysm.
  2. The rupture of this aneurysm is the most common cause of SAH. Sites of berry aneurysms is shown in Figure 23.1.
  3. The rupture can occur at any time, but particularly during increased ICT with straining stools and sexual orgasm.
  4. The blood then rapidly leaks into subarachnoid space and the patients will be having sudden excruciating headache (described as the worst headache that I have ever had) and loss of consciousness.
  5. The aneurysm means abnormal dilatation of blood vessel due to the defect in tunica media.
  6. Sites → occuring typically around the circle of Willis.
  7. Berry aneurysm is the most common intracranial aneurysm.
  8. The unruptured saccular aneurysm is a thin walled outpouching.
  9. The sac is composed of hyalinized intima.
  10. The media and elastic lamina are absent.
  11. Rupture usually occurs at the apex.
 
MENINGITIS
  1. Inflammation of leptomeninges and CSF within the subarachnoid space.
  2. If both meninges and underlying brain parenchyma are involved—that is called meningoencephalitis.
  3. Meningitis will be usually infectious.
 
Acute Pyogenic Meningitis
  1. Also called bacterial meningitis.
  2. Neonates—Escherichia coli, group B-streptococci.
  3. Adolescent and young adults—Neisseria, Haemophilus.
  4. Older age—Streptococcus pneumoniae, Listeria monocytogenes.
    Fig. 23.1: Sites of berry aneurysm
    242
  5. Meningeal irritation and neurological impairment
  6. Symptoms are headache, photophobia, irritability, cloudiness, neck stiffness, etc.
  7. CSF studies show increased in ICT, N, protein and decreased glucose.
  8. Bacteria demonstrated by CSF smear.
  9. Pyogenic (purulent) exudate is seen within the leptomeninges and brain parenchyma.
  10. In Fulminant meningitis: (N) increased in CSF and may spreads to brain producing focal cerebritis.
  11. Sometimes, produces ventriculitis.
  12. Bacterial meningitis may be associated with brain abscess too.
  13. Phlebitis may be produced and can leads to venous occlusion and hemorrhagic infarction of brain.
 
Aseptic Meningitis
  1. Also called viral meningitis.
  2. Signs of meningeal irritation, fever, alteration of consciousness, etc. without recognizable organisms and of acute onset.
  3. Usually self-limiting.
  4. CSF study shows increased (L), moderate elevation of proteins and nearly normal glucose level.
  5. Some swelling of the site can be seen.
  6. Not much other finding.
 
Chronic Meningitis
A paranchymal component is also present.
 
Tuberculous Meningitis
  1. Usually presents with headache, malaise, vomiting and mental confusion.
  2. Highly purulant and thick exudate—gelatinous or fibrinoid.
  3. Increased CSF cellularity (pleocytosis) either (L) alone or (L) and (N) together.
  4. Increased protein level and decreased glucose level.
  5. A well-circumscribed intraparnchymal granulomatous lesion (tuberculoma) is present.
  6. Arteries in the subarachnoid space shows obliterating endarteritis.
  7. May spreads to choroid plexus or ependymal surface.
  8. Well-developed granulomas on meninges with central caseous necrosis, macrophages, plasma cells and giant cells.
  9. Can lead to arachnoid fibrosis and hydrocephalous.
 
Neurosyphilis
  1. Tertiary stage of syphilis in untreated patients.
  2. One of the manifestation is meningitis and is called meningovascular neurosyphilis.
  3. Parenchymal involvement due to invasion of Treponema pallidum leads to progressive loss of mental and physical function and terminating in severe dementia (paretic neurosyphilis).
  4. If the meninges of spinal cord is involved it can invade into sensory nerves in the dorsal root, which leads to tabes dorsalis. This develops due to pallor and atrophy of axons and myelin sheath.
  5. HIV is predisposing to neurosyphilis.
    243
  6. Usually involves the base of brain.
  7. Obliterating endarteritis with perivascular infiltrate of (L) and plasma cells.
  8. Cerebral gummas are also seen.
  9. Paretic neurosyphilis mainly involves the frontal lobe and gliosis is observed along with loss of neurons.
 
Neuroborreliosis
  1. By Borrelia burgdorferi.
  2. Aseptic meningitis is caused.
  3. Facial nerve palsy and encephalopathy are also observed.
 
BRAIN TUMORS
  1. Histologic distinction between benign and malignant is more subtle than in other sites.
  2. Even low grade tumors can infiltrate large areas.
  3. Even benign lesions can be life threatening by compression at various sites.
  4. The metastasis outside CNS is rare and the main route is through CSF.
 
Classification
  1. Gliomas—tumors of brain parenchyma.
    1. Astrocytoma.
    2. Oligodendroglioma.
    3. Ependymoma.
  2. Neuronal tumors.
    1. Central neurocytoma.
    2. Ganglioglioma.
    3. Dysembryoplastic neuroepithelial tumors.
  3. Poorly differentiated.
    1. Medulloblastoma.
  4. Other parenchymal tumors.
    1. Primary CNS lymphoma.
    2. Germ cell tumors.
  5. Meningiomas.
  6. Metastatic tumors.
    1. Five common primary sites for brain metastasis are lung, breast, skin, kidney and GIT.
    2. Usually at the grey-white matter junction and surrounded by gliosis.
    3. Paraneoplastic syndromes may involve CNS also.
    4. Subacute cerebellar degeneration (ataxia).
    5. Limbic encephalitis (dementia).
    6. Subacute sensory neuropathy (altered pain).
 
Astrocytoma
Fibrillary astrocytoma
  1. About 80% of adult primary brain tumors.
  2. Usually found in cerebral hemispheres.
  3. Seizures, headache, focal neurological deficit, etc. occurs.
  4. These are three types.
    1. Well differentiated (mild pleomorphism).
    2. Anaplastic (highly pleomorphic).
    3. Glioblastoma multiforme (highest grade).
Morphology
  1. Poorly defined gray, infiltrative tumor.
    244
  2. Firm or soft gelatinous mass.
  3. Cystic change and necrosis may be seen.
  4. Glioblastoma shows highly anaplastic cells with additional features of necrosis and vascular or EC proliferation and pseudopalisading nuclei.
  5. High-grade tumors have leaky vessels.
Pilocytic astrocytoma
  1. Benign tumors usually affecting children.
  2. Usually located in cerebellum.
  3. Also appear in third ventricle, optic nerves and cerebrum.
  4. Tumors extending into hypothalamic region have more complicated clinical course.
  5. Usually cystic tumors.
  6. Bipolar cells with long hair-like processes (rosenthal fibers), eosinophilic granules and microcytes are present.
  7. Necrosis and mitosis are absent.
 
Oligodendroglioma
  1. Several years of neurologic complaints including seizures.
  2. Usually seen in cerebral hemispheres predominantly white matter.
  3. Better prognosis than astrocytoma.
Morphology
  1. Gelatinous grey infiltrative masses.
  2. May show cystic changes, hemorrhage and calcification.
  3. Tumor cells are similar to normal oligodendrocytes with finally granular chromatin.
  4. High grade—anaplastic oligodendroglioma.
 
Ependymoma
  1. Usually arise in ependyma lined ventricles and spinal central canal.
  2. Early age—fourth ventricle.
  3. Adults—central canal of spinal cord.
  4. CSF dissemination is common.
  5. Relatively good prognosis with complete excision.
Morphology
  1. Usually small cells with round-oval nuclei containing finely granular chromatin.
  2. The tumor in fourth ventricle usually arises from the floor as a solid mass or papille.
  3. The tumor cell arrange to form rosette or canal with projecting delicate process into lumen.
  4. Sometimes pseudorosettes by arrange around the blood vessels.
  5. Anaplastic—increased mitosis, necrosis and decreased differentiation.
 
Medulloblastoma
  1. Predominantly in children.
  2. Exclusively in cerebellum (midline).
  3. Often undifferentiated and highly malignant.
  4. Origin from neuroectodermal cells.
Morphology
  1. Often well-circumscribed gray masses.
  2. Infiltrate into leptomeninges.
  3. Small blue cells, which are highly anaplastic and with hyperchromatic nuclei.
  4. Abundant mitoses.
  5. Laterally occurring tumors are more in adults.
    245
 
Meningioma
  1. Predominantly benign tumors of adults.
  2. Arising from the meningothelial cells of arachanoid space and usually attached to dura.
  3. Usually producing symptoms of brain compression.
Morphology
  1. Well-defined masses on dura may extend into over lying bone also.
  2. Differential types.
    1. Syncitial clusters → of cells in tight groups.
    2. Fibroblastic → elongated cells and abundant collagen in between.
    3. Transitional → features of both syncitial and fibroblastic.
    4. Psammomatous → with numerous psammoma bodies.
    5. Secretory → with PAS positive intracytoplasmic droplets.
    6. Microcystic → loose spongy appearance.
  3. Atypical → highly infiltrative and highly mitotic.
  4. Anaplastic → highly aggressive and malignant, high metastatic potential.
Fig. 23.2: Pathogenesis of Alzheimer disease
246
 
ALZHEIMER DISEASE
  1. Most common cause of dementia in elderly.
  2. Insidious impairment of intellectual function with alteration in mood and behavior.
  3. Later progressive disorientation, memory loss and aphasia.
  4. Finally become disabled, mute and immobile.
  5. Mostly sporadic and rarely familial.
 
Pathogenesis
The pathogenesis alzheimer disease is shown in Figure 23.2.
 
Predisposition
  1. Trisomy 21.
  2. Mutation of Apo E4 gene.
  3. Mutation in SORL1 gene.
  4. Mutations in APP or enzymes involved.
 
Morphology
  1. Cortical atrophy and compensatory ventricular enlargement.
  2. Widening of sulci—more in frontal, temporal and pariteal.
  3. Plaques (EC) and neurofibrillary tangles (IC).
  4. First seen in entorhinal cortex, then in isocortex and finally in neocortex.
  5. Neuritic plaques.
    1. Collections of neuritic processes (dystrophic).
    2. Central amyloid core.
    3. Peripheral astrocytes and glial cells.
    4. Seen in cortex, amygdale, hippocampus, cerebellum, basal ganglia, etc.
  6. Neurofibrillary tangles.
    1. Bundles of paired helical filaments.
    2. Seen as basophilic fibrillary structures.
    3. Especially seen in entorhinal cortex.
    4. The major component is abnormally hyperphosphorylated forms of Tau protein.
 
NEUROBLASTOMA
Refer Chapter 7, Genetic and Pediatric Diseases.

Essays

CLINICAL QUESTIONS
  1. A 29-year-old man hospitalized for AIDS is found to have bilateral patchy pulmonary lesions. He had fever with evening rise of temperature. Liver also showed multiple lesions with central necrosis.
    1. What is your complete diagnosis?
    2. Which type of tissue reaction is expected in the lung?
    3. Which type of necrosis is seen in these lesions?
    4. Indicate the special stains useful in confirming the diagnosis.
    5. Name the commonest lung pathology seen in AIDS.
  2. A 74-year-old diabetic man presented with fever with chills, pallor and dimness of vision. Investigations revealed Hb was 4 g%, reticulocyte count was 0.5%. Urine showed—sugar ++, protein +++ with plenty of hyaline casts and pus cells. O/E pedal edema was present. His BP was 200/110 mm of Hg. Blood glucose was 350 mg%, blood urea was 109 mg% and serum creatinine was 3.4 mg%.
    1. What is your complete diagnosis?
    2. Explain the reason for his:
      • Anemia
      • Proteinuria
      • Fever.
    3. How are urinary casts formed?
    4. Describe the pathogenesis of edema in this patient.
    5. Enumerate the etiology of edema.
  3. A 25-year-old man from leprosy sanatorium presented with severe edema. O/E proteinuria, hyperlipidemia and lipiduria.
    1. What is your diagnosis?
    2. Name the dye used to diagnose the condition in biopsy section.
    3. Pathology of kidney in this condition.
    4. Other organs involved.
  4. A 60-year-old man presented with bone pain, pallor and backache. O/E he had localized tenderness in L1, L2 and L3 levels and paraparesis. Investigations revealed Hb was 8 g% and ESR was 140 mm/1st hour. X-ray revealed destructive bony lesions.
    1. What is your diagnosis?
    2. Explain the reason for his anemia and paraplegia.
      248
    3. Name the two investigations, which will be diagnostic in this patient.
    4. Describe the blood picture in this condition.
  5. A 40-year-old woman died after a long history of an illness characterized by dyspnea, orthopnea, hepatomegaly, distended neck veins and peripheral edema. The cut surface of the liver showed alternating dark and yellowish appearance.
    1. What is the most likely diagnosis?
    2. What is the appearance of the liver?
    3. What is the most likely appearance of her heart?
    4. Describe the pathogenesis of the condition.
  6. A 26-year-old man developed dyspnea and cough with blood-tinged sputum. On enquiry, he indicated that he had right-sided chest pain 2 days before and was intermittent and varying with respiration. O/E he was febrile and had a pulse rate of 102/min.
    1. What is your diagnosis?
    2. What is the significance of his chest pain?
    3. Explain the pathogenesis and natural history of his disease.
    4. What would his chest X-ray show?
    5. What are the complications of this condition?
  7. A 22-year-old woman presented with intermittent fever, weight loss, sweating and painless supraclavicular lymph nodes. A biopsy of one of the lymph nodes showed binucleated giant cells with prominent nucleoli. Some of the atypical cells are seen, surrounded by a clear space.
    1. What is your diagnosis?
    2. What are her symptoms described?
    3. What is the name of the two type of cells described?
    4. What would the histopathology in addition to the above cells?
    5. What is the natural history of this disease?
  8. A 55-year-old strict vegetarian presented with weakness and easy fatigue. O/E he was having pallor. His Hb was 8.5 g%. He had undergone surgery for CA stomach 2 years back.
    1. What is the probable diagnosis?
    2. What is the etiology?
    3. What will be the morphology?
    4. How will you diagnose?
    5. How will you treat?
  9. Within minutes of a bee sting, a 23-year-old woman develops generalized pruritus and hyperemia of the skin, followed shortly by swelling of the face and eyelids and stridor.
    1. What is your diagnosis?
    2. What is the pathogenesis of this condition?
    3. What are the other diseases with the same pathology?
    4. Name one inherited disorder that could cause a similar reaction.
    5. Will this problem recur?
  10. A 59-year-old patient received chemotherapy with the anthracycline—Adriamycin for breast carcinoma. 2 years later, she developed severe refractory heart failure. No specific 249cause could be immediately identified for the cardiac failure. The patient died 3 days later. An autopsy was performed. Her heart was found to be flabby and dilated.
    • What is your diagnosis?
    • What is the pathogenesis of this condition?
    • What is the diagnostic test?
    • Describe the histopathology of the heart in this condition.
  11. A 23-year-old African-American man with a history of severe lifelong anemia requiring many transfusions. He has non-healing leg ulcers and recurrent episodes of joint, abdominal and chest pain.
    1. What is your diagnosis?
    2. How will you confirm the diagnosis?
    3. What will the peripheral smear show?
    4. Name two other diseases with the similar pathology?
    5. What is the significance of his abdominal and chest pain?
  12. A 5-year-old boy developed a massive hemarthrosis. The platelet count is normal. The PT and bleeding time are normal, but the APTT is prolonged.
    1. What is your diagnosis?
    2. How will you confirm the diagnosis?
    3. Name one other disease with a similar pathology?
    4. What is the significance of clinical history in this patient?
  13. Two weeks after recovery from a severe bout of pharyngitis, a 11-year-old girl is seen because of the acute onset of periorbital edema, hematuria, malaise, nausea and headache. ASO titer was 700 Todd units. Urine was positive for blood, blood cell casts and protein.
    1. What is your complete diagnosis?
    2. Explain the reason for her.
      • Hematuria
      • Proteinuria
      • Casts.
    3. Indicate the probable cause for her headache and nausea.
    4. How are urinary casts formed?
    5. What type of cast will be diagnostic in this patient?
    6. Describe the pathogenesis of edema in this patient.
  14. A 60-year-old man presented in a dermatology OP with a hypopigmented anesthetic patch on his face. O/E peripheral nerves are thickened.
    1. What is your diagnosis?
    2. What are the investigations you want to do in this case?
    3. What is the pathology of the disease?
    4. What are the morphological types?
    5. How can you identify the disease according to immunological status?
  15. A 24-year-old man came to STD clinic with complaints of low grade fever, malaise and mucocutaneous rash. He gives a past history of sexual contact following which he developed a painless ulcer over glans. O/E he has generalized lymphadenopathy.
    1. What is your diagnosis?
    2. What are the modes of transmission?
      250
    3. Describe the various stages of disease.
  16. A 14-year-old boy presented with yellowish discoloration of the eyes and abdominal pain. Investigation revealed Hb was 6 g%, reticulocyte count was 11%. O/E splenomegaly was present, patient was jaundiced and USG revealed gallstones. Maternal uncle gave history of similar complaints.
    1. What is your diagnosis?
    2. Name two investigations to confirm your diagnosis (other than blood picture).
    3. Describe the blood picture in this condition.
    4. Mention three similar diseases.
    5. What is the likely cause of the gallstones?
  17. A 48-year-old male was admitted to hospital because of hematemesis. O/E he has jaundice, ascites, splenomegaly and a nodular hepatomegaly. USG showed multiple nodules. One nodule was larger with central necrosis.
    1. What is the most likely diagnosis?
    2. Indicate four investigations you will do in this patient.
    3. Describe the pathogenesis of his problem.
    FNAC was unsuccessful from the large nodule. Hence, finally a liver biopsy was done.
    1. Mention why this was done?
    2. What is the histopathology likely to be, in this patient?
  18. A 25-year-old female presented with fever, joint pain and edema since 4 weeks. On examination, butterfly rash on face and oral ulcer. No joint deformity. Bilateral pleural effusion was present. Urine: Albumin +++, granular casts are present.
    1. What is your provisional diagnosis?
    2. What is the etiology?
    3. What is the pathogenesis?
    4. Enumerate two relevant investigations for confirmation.
    5. Mention the most serious renal lesion in this condition.
    6. What are the cardiac lesions seen in this disease?
  19. A 5-year-old male presented with pain and swelling of right thigh. History of rapid increase in size. On examination, X-ray revealed an ‘onion peel’ appearance in the shaft of femur.
    1. What is your diagnosis?
    2. Mention two relevant investigations.
    3. What is the reason for the radiological appearance of this lesion?
    4. What is the histopathology of this lesion?
    5. Name any two conditions with similar histology.
  20. A 40-year-old male presented with pallor, ecchymotic patches and hepatosplenomegaly. O/E he was found to have gum hypertrophy and cervical lymph node enlargement.
    1. What is the clinical diagnosis?
    2. Describe the blood smear in this patient.
    3. Mention one important investigation for diagnosis.
    4. How will you confirm the diagnosis?
    5. What serum test can be done to confirm the diagnosis?
    6. How will you classify this disease?
      251
  21. A 15-year-old boy presented with painful swelling above knee. X-ray revealed a metaphyseal lesion with characteristic sunray spicules.
    1. What is your diagnosis?
    2. Radiographic and histological features.
    3. Common site and age group.
    4. Most common malignancy of bone?
    5. Most common site of metastasis?
  22. A 2-year-old child presented with high fever, prostration and vomiting. His pulse is rapid and thready. BP is recorded at 60/40. A diffuse generalized hemorrhagic rash is noted.
    1. What is your diagnosis?
    2. Mention one important investigation and its diagnostic features.
    3. What immediate test should you do?
    4. Mention two etiological factors.
  23. A 24-year-old man has shortness of breath and ascites. USG revealed cirrhosis of liver. A sister and several close relatives also have had similar findings.
    1. What is the clinical diagnosis?
    2. How will you confirm the diagnosis?
    3. What is the cause of his shortness of breath?
    4. How will you classify his lung condition?
  24. A 60-year-old woman seeks medical attention for soreness and oozing from the nipple of her left breast. She denies trauma to the breast. O/E, there is fissuring and ulceration of the areola and nipple. A lump 1.5 × 1.5 cm was palpable below the areola.
    1. What is the most likely diagnosis?
    2. What is the clinical significance of this finding?
    3. Indicate two tests you would do to confirm the diagnosis.
    4. What are the features to assess the prognosis of this condition?
  25. A 35-year-old woman complains of shortness of breath and cough for the last 2 months. She also has had fatigue and mild fever. A chest radiograph shows bilateral hilar lymphadenopathy. O/E two cervical nodes were palpable. She also had hypercalcemia.
    1. What is your provisional diagnosis?
    2. What would her cervical node biopsy show?
    3. What type of pathology is likely to explain her shortness of breath?
    4. What serum blood test can help to confirm the diagnosis?
  26. A 60-year-old woman has pain in her lower back upon bending over in her kitchen. A radiograph of the spine shows a compression fracture of the lumbar vertebrae at L2–L3. Further evaluation reveals normocytic anemia, hypercalcemia and a high ESR.
    1. What is the diagnosis?
    2. Indicate one test you would do to confirm the diagnosis
    3. What would you expect to find in her urine?
    4. What other tests might be contributory to her diagnosis and follow-up?
    5. In the context of this patient, what would the term ‘CRAB’ mean?
  27. A 55-year-old man complaining of gross hematuria and right loin pain. 252Physical examination reveals a flank mass. The complete blood count (CBC) reveals a Hb level of 21 g/dL. Ultrasound shows a 6 cm mass at the upper pole of the right kidney.
    1. What is the most likely diagnosis?
    2. What is the brain lesion associated with this condition?
    3. What is the most likely explanation for this patient's polycythemia?
    4. What is the likely microscopy of this lesion?
  28. A 48-year-old man complains of weakness, fatigue and bleeding from the gums when he brushes his teeth. O/E no organomegaly was present. His WBC—1000/mm3, Hb—8 g/dL and platelets—30,000/mm3. Reticulocyte count was less than 0.5%.
    1. What is the most likely diagnosis?
    2. If the patient had hepatosplenomegaly, what differential diagnosis would you entertain?
    3. What test need to be done to confirm the diagnosis?
    4. Indicate three etiological factors.
  29. A 57-year-old man complains of fatigue, weakness and weight gain, particularly around the abdomen. O/E, he is found to have hypertension, fullness over the upper back and abdominal striae. Laboratory studies include an elevated serum cortisol level that is not suppressed with dexamethasone. Imaging studies reveal no pituitary or adrenal masses, but a CT scan of the chest shows a right lung mass arising near the hilum.
    1. What is the most likely diagnosis?
    2. What test would be useful in confirming the diagnosis?
    3. What are the underlying mechanisms involved?
    4. What other disorders may cause similar clinical findings?
  30. A 4-year-old boy is seen by his pediatrician for easy bruising, joint pain and leg pain; red dots on the skin that do not blanch and hepatosplenomegaly. CBC reveals an elevated white blood cell count of 50,000/mm3, Hb of 4 g% and thrombocytopenia. Peripheral smear showed numerous cells with a high nuclear to cytoplasmic ratio and fine chromatin.
    1. What is the most likely diagnosis?
    2. What other investigations need to be done to confirm it?
    3. How do you classify this condition?
    4. What is the prognosis?
  31. A 45-year-old lady with a history of fracture shaft of femur 2 days back, had a sudden onset of tachypnea, tachycardia and petechial skin rashes. She was restless and irritable.
    1. What is your provisional diagnosis?
    2. How will you confirm your diagnosis?
    3. Pathogenesis of symptom complex.
  32. A 25-year-old lady suddenly developed profound respiratory difficulty with deep cyanosis immediately after delivery.
    1. What is your provisional diagnosis?
    2. Mention two important causes of death in this condition.
    3. What will be the microscopic picture of lung in this condition?
    4. Describe the pathogenesis of this condition.
  33. A 42-year-old male was admitted with history of head injury following 253RTA. On the 3rd day, he developed progressive dyspnea with tachypnea and hypoxia refractory to therapy. X-ray showed diffuse bilateral pulmonary infiltrates. He became comatose and died on 6th day.
    1. Give the most possible cause of death.
    2. Describe the microscopy of lung in this condition.
    3. Mention two important events in pathogenesis.
    4. State two other causes, which can lead to this event.
  34. A 35-year-old woman was admitted due to snakebite in MCH. She later developed bleeding from gums, purpuric and ecchymotic patches over the body. Her BP was 90/60 mm Hg. Renal O/P for first 24 hours was 75 mL.
    1. What is your diagnosis?
    2. What lab investigation would you suggest?
    3. What are the major disorders associated with this condition?
    4. Is it true that in hospital, snakebite is the commonest cause of this condition?
  35. A 10-year-old boy presented in the OP with features suggestive of meningitis. CSF culture yielded Haemophilus influenzae. Doctor prescribed a course of chloramphenicol. Later the boy developed pallor and dyspnea. Petechiae and ecchymosis appeared on his trunk. There was also high grade fever. Blood investigation revealed Hb was 4.5 g%.
    1. What is your diagnosis?
    2. How will you confirm your diagnosis?
    3. Is splenomegaly possible in this case?
    4. What are the causes of this condition and what is the commonest cause?
    5. What is the treatment ideally?
    6. What are the causes of pancytopenia?
  36. A 80-year-old man presented with pathological fracture. X-ray revealed osteoblastic metastatic deposits in the bones.
    1. What will be the most likely primary malignancy is?
    2. What type of clinical manifestations will you do to confirm the diagnosis?
    3. Tumor marker associated with malignancy and its importance in clinical evaluation?
    4. What is the staging system for this malignancy?
    5. Describe the gross and microscopy?
    6. What are hormonal, genetic and environmental factors?
  37. A 60-year-old man presented with fever with chills. Routine blood examination revealed neutrophilic leukocytosis. Urine analysis revealed pyuria and bacteriuria. Patient gives history of urinary hesitancy, urgency and increased frequency for months.
    1. Which condition was the predisposing factor to the present illness?
    2. How the commonly used term for this condition is a misnomer?
    3. What is the role of hormone in this condition?
    4. Why is it most commonly in elderly?
    5. Microscopic features of the lesion.
      254
  38. A 56-year-old woman came with complains of irregular vaginal bleeding, leukorrhea, painful coitus and dysuria. On examination a fungating mass at cevix.
    1. Give your diagnosis.
    2. Explain the cytological grading.
    3. Staging of the disease.
    4. What are macroscopic forms?
    5. Describe the risk factors and pathogenesis.
  39. A 45-year-old women presented with a painless movable mass on the upper outer quadrant of her right breast. Axillary LNs are enlarged. Mammography revealed microcalcification in the lesion.
    1. What is your diagnosis?
    2. What other lesions can produce calcification in the mammogram?
    3. What are the factors that determine the prognosis?
    4. Explain the staging system?
    5. Genetic factors involved in the pathogenesis?
    6. Hormonal and environmental influence?
  40. A 55-year-old man with a habit of heavy cigar smoking came to OP with a history of cough and blood stained sputum and loss of weight. X-ray reveals Hilar shadows.
    1. What is your diagnosis?
    2. What are the etiological factors of this condition?
    3. Microscopic picture of this condition.
  41. A 50-year-old man came to OP with distension of abdomen and weight loss. O/E he was having ascitis, gynecomastia, increased SGPT and reversal of S/G ratio.
    1. What is your diagnosis?
    2. Give gross and microscopy of affected organ.
    3. What is the pathogenesis of ascitis?
  42. A 55-year-old male presenting with dry cough, hemoptysis and chest pain. X-ray chest showed a well-circumscribed round opacity in the right middle lobe.
    1. What is your diagnosis?
    2. Give five investigations that will confirm diagnosis.
    3. What are the histological types?
    4. What are the risk factors associated?
  43. A 48-year-old male presenting with dyspepsia, hard palpable mass in the epigastrium. A hard fixed palpable supraclavicular node also.
    1. What is your diagnosis?
    2. How will you confirm?
    3. Gross and microscopy of this condition.
    4. Two predisposing factors of this condition.
  44. A 40-year-old male presented with history of fatigue and weight loss for the last 6 months. O/E large spleen was present. On lab investigations, Hb—9 g%, TC—95,000/cm with shift to left and platelet count—6 lakhs/cm.
    1. What is your diagnosis?
    2. What is the common genetic and cytogenetic abnormality expected?
    3. Describe the blood and bone marrow findings.
    4. What is the outcome and prognosis?
  45. A 32-year-old female from Wayanad admitted with fever, dyspnea and 255abdominal pain. O/E she has pallor and mild icterus. No hepatosplenomegaly. No lymphadenopathy. There is a scar of a healed ulcer on leg. Hb —4.8 g% TC—26000, ESR—30 mm and reticulocyte count—6%. Urine albumin—nil, sugar—nil and urobilinogen ++.
    1. What is your diagnosis? Give reasons.
    2. What will be the blood picture?
    3. Name two investigations to confirm and explain.
    4. Name two common complications that can occur here.
  46. A 42-year-old male taken to casualty with acute onset of left-sided chest pain radiating to left arm, dyspnea and died after 2 hours.
    1. What is your probable diagnosis?
    2. What is the cause of death in this case?
    3. Outline the complication of this case.
    4. Name two serum enzymes useful in the diagnosis of this condition.
  47. A 55-year-old male presented with retrosternal chest pain. Coronary angiogram shows narrowing of descending branch of left coronary artery. Serum cholesterol elevated.
    1. What is your diagnosis?
    2. What will be the likely outcome?
    3. Enumerate the risk factors and complications.
  48. A mother came to OP with the compliant that her child is eating non-food stuffs like dirt. The child was restless and pale. O/E the child was found to have koilonychia.
    1. What is your diagnosis?
    2. What will be the morphology of peripheral blood?
    3. What are the etiological factors?
    4. How will you treat this condition?
    5. DDs of microcytic hypochromic anemia.
  49. A male patient presented with convulsions and vomiting. CT scan shows a well-circumscribed mass in parasagittal sinus arising from meninges.
    1. What is your diagnosis?
    2. Describe the gross and microscopic features.
  50. A 12-year-old male child presented with fever, sore throat and cervical lymphadenopathy. O/E mild hepatosplenomegaly, Hb—13 g% and TC—20000/cm with lymphocytosis.
    1. What is your diagnosis?
    2. Name one investigation to confirm diagnosis.
    3. Describe the blood picture.
    4. What is the etiology of this condition?
    5. Name the special type of cells seen in peripheral smear.

256Diagnosis

  1. Tuberculosis.
  2. DM nephropathy, UTI, anemia of CRF.
  3. 2° Amyloidosis.
  4. Multiple myeloma.
  5. COPD and CCF.
  6. Lobar pneumonia.
  7. Hodgkin disease—nodular sclerosis.
  8. Megaloblastic anemia.
  9. Anaphylactic reaction.
  10. Adriamycin cardiomyopathy.
  11. Sickle cell anemia.
  12. Hemophilia A.
  13. Acute poststreptococcal glomerulonephritis.
  14. Leprosy.
  15. Syphilis.
  16. Hereditary spherocytosus.
  17. Cirrhosis with hepatocellular carcinoma.
  18. Systemic lupus erythematosus.
  19. Ewing sarcoma.
  20. Acute myeloid leukemia.
  21. Primary osteosarcoma.
  22. Acute pyogenic meningitis.
  23. α-1 antitrypsin deficiency.
  24. Breast carcinoma with Paget disease.
  25. Sarcoidosis.
  26. Multiple myeloma.
  27. Renal cell carcinoma.
  28. Aplastic anemia.
  29. Small cell lung carcinoma.
  30. Acute lymphatic leukemia.
  31. Fat embolism.
  32. Amniotic fluid embolism.
  33. ARDS.
  34. DIC.
  35. Aplastic anemia.
  36. CA prostate.
  37. Nodular hyperplasia of prostate.
  38. Cervical carcinoma.
  39. Breast carcinoma.
  40. Bronchogenic carcinoma.
  41. Chronic hepatic failure due to cirrhosis.
  42. Bronchogenic carcinoma.
  43. Stomach carcinoma.
  44. Chronic myeloid leukemia.
  45. Sickle cell anemia.
  46. MI.
  47. Angina.
  48. Iron deficiency anemia.
  49. Meningioma.
  50. IMN.

257Most Important Topics

 
 
General Pathology
  1. Necrosis, free radical-mediated cell injury, apoptosis, pathologic calcification.
  2. Acute inflammation, phagocytosis, chemical mediators, granulomatous inflammation.
  3. Angiogenesis, cutaneous wound healing.
  4. Edema, thrombosis, shock.
  5. CMI, HSN reactions (all types), SLE, pathogenesis of HIV, amyloidosis.
  6. Metastasis, molecular basis of carcinogenesis, RB gene, p53 gene, chemical carcinogens and carcinogenesis, viral oncogenesis, paraneoplastic syndromes.
  7. Down, Klinefelter and Turner syndromes, RDS of newborn, Wilm's tumor.
  8. Vitamin D defeciency.
  9. Mechanism of viral and bacterial injury.
Clinical pathology
FNAC, histopathology, urine sediments, ESR, PCV.
 
Systemic Pathology
  1. Atherosclerosis, aneurysm, dissection, PAN.
  2. Angina, MI, IE, cardiomyopathy.
  3. Classification of anemia, hereditary spherocytosis, sickle cell anemia, thalassemia, PNH, iron deficiency anemia, megaloblastic anemia, aplastic anemia, polycythemia, IMN, leukemoid reaction, HL, multiple myeloma, AML, ALL, CML, DIC, ITP, hemophilia.
  4. ARDS, emphysema, asthma, pneumonia, pneumoconioses, sarcoidosis, TB, CA lung.
  5. Nephrotic and nephritic syndrome, crescentic GN, A/C pyelonephritis, PKD, renal stones, RCC.
  6. Barrett esophagus, CA esophagus, peptic ulcer, CA stomach, CD, UC, CA colon, FAP.
  7. Cirrhosis, viral hepatitis, ALD, hemochromatosis, Wilson disease, α1-AT deficiency, HCC, cholelithiasis, cholecystitis.
  8. Acute pancreatitis.
  9. Testicular neoplasms, seminoma, BPH, CA prostate, syphilis.
    258
  10. CIN, CA cervix, tumors of ovary, teratoma, hydatidiform mole, fibrocystic changes of breast, fibroadenoma, CA breast.
  11. Hashimoto's thyroiditis, Graves disease, goiter, papillary and follicular carcinoma, hyperparathyroidism, cushing syndrome, pheochromocytoma, MEN.
  12. Osteoporosis, osteomyelitis, osteosarcoma, ewing sarcoma, gout, duchene dystrophy rickets, osteomalacia.
  13. SCC, BCC and malignant melanoma of skin.
  14. Meningitis, astrocytoma, meningioma.

259Important Laboratory Values

Test Name
Values
Blood routine
Hb
• Male
• Female
TC
DC
• Neutrophils
• Bands
• Lymphocytes
• Monocytes
• Eosinophils
• Basophils
ESR
• Male
• Female
13.3–16.2 g/dL
12–15.8 g/dL
4–11 × 103
40%–70%
0%–5%
20%–50%
4%–8%
0%–6%
0%–2%
0–15 mm/h
0–20 mm/h
Platelet count
165–415 × 109/mm3
Erythrocyte count
• Male
• Female
4.30–5.60 × 106 mm3
4.00–5.20 × 106 mm3
PCV
• Male
• Female
38.8–46.4 mm
35.4–44.4 mm
Erythrocyte life-span
120 day
Bleeding time
2–7 min
Clotting time
5–8 min
Prothrombin time
12.7–15.4 s
Erythropoietin
4–27 U/L
MCH
MCHC
MCV
26.7–31.9 pg
32.3–35.9 g/dL
78–98 fl
Osmotic fragility
0.35%–0.45%
Red cell distribution width
< 14.5%
Reticulocyte count
• Male
• Female
0.8%–2.3% red cells
0.8%–2.0% red cells
LFT
Bilirubin
• Total
• Direct
• Indirect
SGOT
SGPT
GGT
0.3–1.3 mg/dL
0.1–0.4 mg/dL
0.2–0.9 mg/dL
12–38 U/L
7–41 U/L
9–58 U/L
Albumin
• Male
• Female
4.1–5.3 g/dL
4.0–5.0 g/L
Total protein
6.7–8.6 g/dL
Amylase
20–96 IU/L
RFT
S urea
S uric acid
• Male
• Female
S creatinine
• Male
• Female
15–40 mg/dL
3.1–7.0 mg/dL
2.5–5.6 mg/dL
0.6–1.2 ng/mL
0.5–0.9 ng/mL
260
S electrolytes
S Na
S K
S Ca
S Cl
136–146 mEq/L
3.5–5.0 mEq/L
8.7–10.2 mg/dL
102–109 mEq/L
Glucose
Fasting
• Normal
• Impaired tolerance
• Diabetes mellitus
2 h postprandial
75–110 mg/dL
111–125 mg/dL
> 125
70–120 mg/dL
Total cholesterol
• Desirable
• Borderline high
• High
< 200 mg/dL
200–239 mg/dL
> 240 mg/dL
LDL
• Optimum
• Near optimum
< 100 mg/dL
100–129 mg/dL
• Borderline high
• High
• Very high
130–159 mg/dL
160–189 mg/dL
> 190 mg/dL
HDL
• Low
• High
< 40 mg/dL
> 60 mg/dL
TFT
TSH
T4
• Free
• Total
T3
• Free
• Total
0.3–3.3 mU/mL
0.8–1.7 ng/dL
5.4–11.7 ug/dL
2.4–4.2 pg/dL
77–135 ng/dL
Rheumatoid factor
< 30 IU/mL
Urine albumin
• Normal
• Microalbuminuria
• Nephrotic range
< 0.03 g/24 h
0–30 mg/24 h
> 3.5 g/24 h

261Bibliography

  1. Colledge, Walker, Ralston. Davidson's Principles and Practices of Medicine, 21st edition. Churchill-Livingstone, Elsevier;  UK: 2010.
  1. Dr Vasudevan DM, Dr Sreekumari S, Dr Kannan Vaidyanathan. Textbook of Biochemistry, 5th edition. Jaypee Brothers Medical Publishers (P) Ltd;  New Delhi:  2007.
  1. Dr Ramnik Sood. Medical Laboratory Technology, 5th edition. Jaypee Brothers Medical Publishers (P) Ltd;  New Delhi:  1999.
  1. Dr Varma RN. Diagnostic Manual of Fine-needle Aspiration Cytology, 1st edition. Banik Traders;  Culcutta:  1992.
  1. Fauci, Braunwald, Kasper, et al. Harrison's Principles of Internal Medicine, 18th edition. Mcgraw-Hill companies;  USA:  2012.
  1. Kumar, Abbas, Fausto, et al. Robbin's Basic Pathology, 8th edition. Saunders-Elsevier;  Philadelphia:  2007.
  1. Prof Harshmohan. Textbook of Pathology, 6th edition. Jaypee Brothers Medical Publishers (P) Ltd;  New Delhi:  2010.
Index
Page numbers followed by f refer to figure and t refer to table, respectively.
A Abnormal cell surface molecules Abnormally expressed cellular proteins Abruption placenta Abundant neck skin Acanthosis nigricans Achondroplasia Acute and chronic inflammation arthritis cellular rejection coronary syndromes endocarditis humoral rejection inflammation , ITP lymphoblastic leukemia myelogenous leukemia pancreatitis pneumonia postinfectious glomerulonephritis pyelonephritis pyogenic meningitis respiratory distress syndrome restrictive lung disease Addison disease Adenocarcinoma , , Adenoma of thyroid Adrenal gland insufficiency Adult polycystic kidney disease Aggressive clonal proliferation and angiogenesis Alcoholic cirrhosis , hepatitis , liver disease Alpha1-antitrypsin deficiency Alzheimer disease Amniotic fluid embolism Amylodosis Anaphylactic shock Anaplasia Anaplastic carcinoma Anemia Angiogenesis Antibody-mediated cellular dysfunction , graft rejection Aortic aneurysm dissection Aplastic anemia Apoptosis Arachidonic acid metabolites Aromatic amines Arteriolar dilatation Arthralgia Arthus reaction Ascites Aseptic meningitis Aspergillosis Aspiration of blood gastric content Asthma Atherosclerosis , , Atresia of urethra Atrial amyloidosis Atrophy Atypical pneumonia Autocrine signaling Autosomal dominant genetic disorders trisomies B Bacterial endotoxins exotoxins Barrett esophagus Basal cell carcinoma Benign and malignant tumor nephrosclerosis tertiary syphilis tumors of breast Berger disease Berry aneurysm Beta-cell dysfunction Bicuspid aortic valve Bilirubin Bitot spots Blindness Blood loss transfusion vessels , Bone tumors Borrelia burgdorferi Brain tumors Brenner tumors Bronchiectasis Bronchioalveolar carcinoma Burkitt lymphoma C Calcinosis Calcium stones Calculus cholecystitis Capillary hemangioma Carcinogenesis , Carcinoid syndrome Carcinoma of bladder breast esophagus Cardiac defects , hypertrophy Cardiogenic shock Cardiopulmonary bypass Cardiovascular syphilis Carditis Cartilaginous metaplasia Caseous necrosis Causes of nephrotic syndrome Cavernous hemangioma Cell cycle , derived mediators Cellular adaptations Central tolerance mechanism in bone marrow in thymus Centriacinar Cervical intraepithelial neoplasia Chemokines Chemotaxis Childhood polycystic kidney disease Cholecystitis Cholelithiasis Cholesterol accumulation Chondrosarcoma Choriocarcinoma , , Chromophobe renal cell carcinoma Chronic bronchitis endothelial injury hepatitis inflammation ischemic heart disease ITP Kaposi sarcoma lymphocytic leukemia meningitis myelogenous leukemia pancreatitis rejection tophaceous arthritis Cirrhosis Classification of acute lymphoblastic leukemia myelogenous leukemia anemia aortic dissection bone tumors mediators Clear cell carcinoma Cleft palate and lip Clonal aggressiveness Clostridium perfringens Coagulative necrosis Coal worker's pneumonia Coarctation of aorta Colloid carcinoma Colonic diverticulosis Colorectal carcinoma Complement system Complete destruction of hepatocytes mole Compliment and FC receptor-mediated inflammation Congenital diseases of bone syphilis Corneal ulcers Coronary artery disease Cri Du Chat syndrome Crohn disease , Cubitus valgus Cushing syndrome , Cutaneous wound healing Cystic fibrosis D Defective intraluminal digestion mucosal absorption nutritional delivery Degradation of ECM Deletion syndromes Depletion of T cells Dermatomyositis Diabetes mellitus Diabetic macrovascular disease nephropathy neuropathy Diffuse scleroderma type adenocarcinoma Dilated cardiomyopathies Diphosphonates Direct lung injury Diseases of immune system Disseminated intravascular coagulation Distal acinar Distant metastasis Down syndrome Drug induced liver disease Dry and scaly conjunctiva Ductal carcinoma in situ Dysgerminoma Dyshormonogenetic goiter Dystrophic calcification E Edema Edward syndrome Elevated acute phase proteins Embryonal carcinomas Emphysema , Endemic goiter Endocrine syndrome system Endometrial carcinoma Endometrioid carcinoma tumors Endothelial dysfunction injury producing thrombosis Eosinophils Ependymoma Epicanthic folds Epithelial metaplasia Epstein-Barr virus Erythema marginatum of skin Erythroplakia Escherichia coli , , , Esophageal carcinoma dysmotility Evasion of apoptosis Ewing sarcoma Excessive sedation of mother Exfoliative dermatitis Extravasation of tumor cells Eyes and lacrimal glands F Facial dimorphism Familial adenomatous polyposis , amyloidotic neuropathies mediterranean fever polyposis syndromes Fat necrosis Fate of thrombus Fatty liver , , tumors Female genital system and breast Fetal head injury during delivery Fever Fibrillary astrocytoma Fibrinoid necrosis Fibrinolytic system Fibroadenoma Fibroblast growth factor Fibrogenesis Fibrosis Flat facial profile Focal segmental glomerulosclerosis Folate deficiency , metabolism Follicular adenoma carcinoma of thyoroid Formation of initiated cells Fracture healing Frame shift mutation Fulminant hepatitis Functions of endothelial cells G Gallstones Gangrenous necrosis Gastric carcinoma Gastrointestinal tract Gaucher disease General pathology of infectious diseases Genitalia remain infantile Genotype of host Giant cell arteritis tumor Glomerular diseases Glycogen storage diseases Glycogenosis Gout Gouty nephropathy Graft rejection versus-host reaction Granulomatous inflammation Granulosa-theca cell tumors Graves' disease Growth retardation H Haemophilus influenzae Hansen disease Hashimoto's thyroiditis Heart failure Helicobacter pylori , Hemangioma , Hematoma Hemochromatosis Hemodynamic disorders Hemophilia A B Heparin-induced thrombocytopenia Hepatic encephalopathy , failure Hepatitis A serology virus B serology virus C serology virus E virus virus Hepatocellular carcinoma Hepatorenal syndrome Hereditary amyloidosis nephritis spherocytosis Herpes virus High-arched palate Histoplasmosis Hodgkin lymphoma , Horseshoe kidney Human granulocytic anaplasmosis herpesvirus papilloma virus T cell lymphotropic virus Hyaline arteriosclerosis membrane disease Hydatidiform mole Hydronephrosis Hyperacute rejection Hypercalcemia Hyperkeratosis papules Hyperparathyroidism , Hyperplasia Hyperplastic arteriosclerosis Hypertension Hypertensive heart diseases Hypertrophic cardiomyopathy Hypertrophy Hypoalbuminemia Hypoglycemia Hypotonia Hypovolemic shock I IgA nephropathy , Immature malignant teratoma Immune recognition of allograft thrombocytopenic purpura Impaired red blood cell production Indeterminate leprosy Indirect lung injury Infarct expansion Infected corneal ulcers Infectious mononucleosis vasculitis Infective endocarditis Inflammatory bowel disease carcinoma Ingrowth of granulation tissue Inhalational injury Inhibitors of crystal formation in urine Intestinal metaplasia stenosis TB type adenocarcinoma Intracellular accumulations Intraductal papilloma Intrauterine hypoxia Invasive carcinoma of cervix ductal carcinoma lobular carcinoma mole Involvement of growth factors Iron deficiency anemia Ischemic heart diseases Isolated organ TB J Jone's major criteria K Kaposi sarcoma Keratinization Keratomalacia Kinin system Kinking of ureter Klinefelter syndrome Knudson's two-hit hypothesis Krukenberg tumors L Large cell carcinoma , vessel vasculitis Later stages of secondary tuberculosis Leiomyoma Leiomyosarcoma Lepra reaction Lepromatous leprosy Lepromin test , Leprosy Leukemia sarcoma virus Leukemoid reaction Leukocyte activation mediated endothelial injury recruitment Leukocytosis , Leukoplakia Libman-Sacks endocarditis Limited hip abduction Lipofuscin Lipoid nephrosis Lipoma Liposarcoma Liquefactive necrosis Listeria monocytogenes Little pubic hair Lobular carcinoma in situ Low-posterior hairline Lung abscess carcinoma , Lymph nodes Lymphadenopathic KS Lymphatic spread Lymphocytes Lymphoid leukemoid reaction systems Lymphoma of small bowel Lysosomal enzymes of leukocytes storage disease M Malabsorption syndromes Malaria Male genital system Malignant melanoma mesothelioma nephrosclerosis Mallory bodies Marasmus Marfan syndrome Massive hepatic necrosis tissue injury Mast cells Mechanisms of autoimmunity bacterial injury cell injury chronic inflammation formation of ascites in portal hypertension edema metastasis serum sickness viral injury Medium vessel vasculitis Medullary carcinoma , Medulloblastoma Megaloblastic anemia Membranoproliferative glomerulonephritis Membranous glomerulonephritis Meningioma Meningitis Meningococcemia Mental retardation and dementia Mesenchymal metaplasia Metaplasia Metastatic calcification Microcytic hypochromic anemias , Micrognathia Microphthalmia Microscopy of peptic ulcer Miliary TB Minimal breast development Mitochondrial damage Mucinous tumors Mucopolysaccharides , Multiple endocrine neoplasia syndromes myeloma , Multistep molecular phenomenon Musculoskeletal system Myasthenia gravis Mycobacterium bovis tuberculosis , , Mycoplasma hominis pneumoniae , Myeloid leukemoid reaction , Myocardial infarction rupture N Necrosis Neoplasm Nephritic syndrome Nephrocalcin Nervous system Neuroblastoma , Neuroborreliosis Neurogenic shock Neuromuscular disorders Neuropeptides Neurosyphilis , Niemann-Pick disease Night blindness Nitric oxide Nodular hyperplasia of prostate Non-bacterial thrombotic endocarditis Non-calculus cholecystitis Non-Hodgkin lymphoma Non-infectious vasculitis Nosocomial pneumonia O Obstructive pyelonephritis Oligodendroglioma Oncofetal antigens Oral cavity and GIT Osseous callus formation metaplasia Osteitis deformans Osteoarthritis Osteoblastoma Osteogenesis imperfecta Osteoid osteoma Osteoma Osteomalacia , Osteomyelitis Osteopetrosis Osteopontins Osteoporosis Osteosarcoma Outcomes of acute inflammation hepatitis B infection C infection Ovarian tumors Overlapping fingers P Paget disease of nipple Pancreas Pancreatic carcinoma Pancreatitis Papillary carcinoma of thyroid muscle dysfunction renal cell carcinoma Papilloma virus Papovaviruses Paracrine signaling Paraneoplastic syndromes , in carcinoma lung Parathyroid hyperplasia and hypocalcemia Paroxysmal nocturnal hemoglobinuria Partial mole Patau syndrome Pathogenesis of acute pancreatitis pyelonephritis alcoholic liver disease Alzheimer disease amyloidosis aortic aneurism dissection ARDS ATN atopic asthma bronchiectasis cervical intraepithelial neoplasia chronic bronchitis cirrhosis colorectal carcinoma coronary artery disease DIC DM complications emphysema gastric carcinoma goiter gout hemochromatosis hepatocellular carcinoma human immunodeficiency virus hydronephrosis malignant nephrosclerosis non-atopic asthma non-infections vasculitis osteoarthritis osteomalacia osteoporosis Paget disease pneumoconiosis primary pulmonary TB respiratory distress syndrome rheumatoid arthritis rickets and osteomalacia sarcoidosis scleroderma septic shock squamous cell carcinoma systemic lupus erythematosus Paucibacillary Pediatric diseases Peptic ulcer , , Pericarditis Peripheral blood tolerance mechanism , Pernicious anemia Peutz-Jeghers polyposis Phagocytosis , Pheochromocytoma Phyllodes tumor Pigmented nevi Pilocytic astrocytoma Plasma cells protein-derived mediators Pneumoconiosis Pneumonia , Polyarthritis Polycystic kidney disease Polycythemia , vera Polyoma virus Popcorn RS cell Portal hypertension Portosystemic shunt Poststreptococcal glomerulonephritis Preneoplastic disorders Primary amenorrhea amyloidosis aplastic anemia syphilis tuberculosis Production of mediators in septic shock Products of tumor suppressor genes Progression of disease infection Prostatic carcinoma Protein energy malnutrition Pseudogout Pulmonary hypertensive heart disease Pyelonephritis Pyogenic osteomyelitis Pyrophosphate R Rapidly progressive GN Raynaud phenomenon , Reactive electrophiles formation Reed-Sternberg cells Reflex associated pyelonephritis Regional lymph nodes Regulation of blood pressure Renal cell carcinoma , defects malformations ptosis with torsion stones vein thrombosis Respiratory distress syndrome tract and pancreas Restrictive cardiomyopathy Retained dead fetus Retinoblastoma Rheumatic heart disease valvular disease Rickets , RNA viral oncogenesis Rocker-bottom feet Rous sarcoma virus Russell bodies Rye classification S Salmonella typhimurium Sarcoidosis Scleroderma Seborrheic dermatitis Secondary amyloidosis aplastic anemia insufficiency syphilis tuberculosis Seminoma Senile amyloidosis Sepsis , Septic abortion shock Serous carcinoma tumors Sertoli-Leydig cell tumors Serum sickness Sex chromosomal disorders Shock Sickle cell anemia Silicosis Simian crease Slow transforming viruses Small cell lung carcinoma , vessel vasculitis Smooth muscle tumors Spermatocytic seminoma Sporadic goiter Squamous cell carcinoma , , , metaplasia , Stage of congestion gray hepatization red hepatization resolution shock Staphylococcus aureus , , Steps in DNA virus oncogenesis EBV oncogenesis HHV oncogenesis HTLV oncogenesis Streptococcus pneumoniae , Subacute endocarditis Subcellular alterations Subcutaneous nodules Subtypes of ALL Sudden cardiac death Sweat gland Sydenham chorea Syphilis , Syphilitic aneurysm Systemic amyloidosis diseases hypertensive heart disease inflammatory response syndrome lupus erythematosus , miliary TB T T cell-mediated cytotoxicity rejection Tamm-Horsfall proteins Tay-Sachs disease Telangiectasia Teratoma Tertiary syphilis Testicular neoplasms Thalassemia Thrombophlebitis Thrombotic thrombocytopenic purpura Thymic hypoplasia Toxemia Transformation of ovaries Treponema pallidum , Tuberculin test Tuberculoid leprosy Tuberculosis , Tuberculous meningitis osteomyelitis Tubular carcinoma necrosis Tumor angiogenesis antigens cell loosening Turner syndrome Types of acute rejection Kaposi sarcoma mutation non-infectious vasculitis rejection scleroderma shock U Ulcerative colitis , Umbilical hernia , Underlying cancer V Valve formations Vascular endothelial growth factors Vasoactive amines Ventricular aneurysm Viral hepatitis , oncoproteins replication in host cell Virchow's triad Vitamin A deficiency B12 deficiency metabolism D deficiency von Willebrand disease W Webbed neck Wegener granulomatosis White fibrous streaks WHO classification of acute leukemia Wilms tumor Wilsons disease Wound healing X Xeroderma Xerophthalmia Y Yolk sac tumors