Ivan Damjanov MD PhD
Professor Department of Pathology The University of Kansas School of Medicine Kansas City
Kansas, USA
Semir Vranic
Assistant Professor Department of Pathology Clinical Center and School of Medicine, University of Sarajevo
Sarajevo, Bosnia and Herzegovina
Faruk Skenderi
Senior Teaching Assistant Department of Pathology Clinical Center and Faculty of Health Sciences, University of Sarajevo
Sarajevo, Bosnia and Herzegovina
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Review of Gynecologic and Breast Pathology
First Edition: 2017
9789352700479
fm5Preface
This book of questions and answers deals with common and not so common pathologic entities encountered in the female genital organs and the breast. We have written this book primarily for pathologists and their trainees and suggest that it can be used as a review text, for continuing medical education (CME), a study guide, or as ancillary material during their studies of major textbooks. However, we also hope that it might be used by senior students, trainees in gynecology, surgery or oncology, and even as a CME book by their attendings.
We envisioned the book primarily as a brief review for specialists or advanced trainees who have a solid background in pathology. The book contains over 350 questions and we estimate that a serious student could finish it in 5 to 10 hours. However, the book could be used in many other ways. For example, for those who prefer to study a certain topic by first reading the questions, this compilation of questions and brief answers could serve as an introduction to further studies from more comprehensive and voluminous gynecologic pathology or breast pathology textbooks. The textbooks that we have used as reference points and also for possible further studies are listed of the end of this book. Some readers could also use our book as a source of key words and common abbreviations, and even less common data that can be found only in recent publications. Such data are usually from journals referenced next to the answers, included typically for more demanding readers who want to pursue the problem even further. For teachers of pathology and gynecology, the books could serve as a source of test questions and topics for discussions and seminars.
Most of the questions and answers are textual, but some questions are based on microphotographs of important pathologic entities. Accordingly, we have included in the book over 115 color microphotographs including immunohistochemical and in situ hybridization images.
In addition to basic pathology of the vulva, vagina, cervix, endometrium and myometrium, fallopian tubes, ovary, placenta and trophoblastic tumor, as well as breast pathology, at the end of the book we have included a separate chapter on immuno-histochemistry and molecular biology/cytogenetics of tumors in these organs. For readers who are pathologists, such data are already essential components of their diagnostic workload. For gynecologists, surgeons and oncologists, these topics are becoming more and more important because in many instances new genetic data may critically direct the modalities of treatment of their patients. For some of our clinical colleagues, this chapter might be a good review; and for those less experienced in modern applied molecular and cell biology, these data might be a stimulus for further studies. Your impressions, comments and critical remarks may be sent to us by email to: semir.vranic@gmail.com.
Ivan Damjanov
Semir Vranic
fm7Abbreviations
ACC
– Adenoid cystic carcinoma
ADH
– Atypical ductal hyperplasia
AFP (αFP)
– Alpha fetoprotein, serum protein found in fetal and neonatal blood. It is normally secreted by yolk sac cells and fetal liver cells; also secreted by yolk sac tumors in mixed germ cell tumors or yolk sac carcinoma, and hepatocellular carcinoma.
ALDH1
– Aldehyde dehydrogenase 1, a protein preferentially expressed in endometrioid carcinomas of the ovary.
AR
– Androgen receptor
β-hCG
– Beta human chorionic gonadotropin, normally secreted by trophoblastic cells; also secreted by gestational and nongestational choriocarcinoma or choriocarcinoma cells in mixed germ cell tumors.
BMT
– Borderline mucinous tumor of the ovary
BRCA genes
– Include BRCA1 and BRCA2 tumor suppressor genes that are involved in repair of damaged DNA. Germline mutations of both genes are responsible for the majority of familial breast and ovarian cancers.
BST
– Borderline serous tumor of the ovary
CHM
– Complete hydatidiform mole
CHEK2
– Checkpoint kinase 2; it is a tumor suppressor gene, involved in signaling processes related to DNA damage.
CD
– Cluster of differentiation, a designation followed by a specific numbers, given to group of proteins used as markers for lymphoid and hematopoietic cells and the molecular biologic/immunohistochemical classification of lymphomas and several other tumors.
CDH1
– E-cadherin gene, encoding a cell adhesion molecule that is typically mutated in lobular breast cancer and diffuse gastric cancer. Germline mutations of CDH1 gene cause familial cancer syndrome called hereditary diffuse gastric cancer (HDGC).
CDKN1
– Cyclin-dependent kinase inhibitor 1C, a protein encoded by the maternally imprinted CDKN1C gene. Also known as p57kip2.
CEP17
– Chromosome 17 centromere; its probe is usually used by in-situ hybridization assays (Fluorescent or chromogenic/FISH/CISH) to evaluate the HER-2/neu gene copy number in patients with breast cancer (HER2/CEP17 ratio).
CHM
– Complete hydatiform mole
cKIT
– Receptor tyrosine kinase encoded by KIT gene, a proto-oncogene discovered as human equivalent of viral oncogene v-kit. It is also known as stem cell growth factor receptor (SCFR) or tyrosine-protein kinase kit.
CMV
– Cytomegalovirus
CTNNB1
– β-catenin gene that is essential part of the WNT signaling pathway. It is mutated in desmoid tumors (fibromatosis) as well as in a subset of colorectal, thyroid, liver, ovarian, endometrial and skin cancers.
DCIS
– Ductal carcinoma in situ
D2.40 (podoplanin)
– Marker of lymphatic endothelium, but also expressed in dysgerminoma
DICER
– A highly conserved enzyme belonging to the RNase III family of nucleases that specifically cleave double-stranded RNAs, and removes toxic RNAs.fm8
EMA
– Epithelial membrane antigen; EMA is glycoprotein on cell surface and is expressed by most glandular and ductal epithelial cells.
ER
– Estrogen receptor
ESS
– Endometrial stromal sarcoma, a tumor composed of cells that resemble endometrial stromal cells.
FEA
– Flat epithelial atypia
FOXL2
– A forkhead transcription factor with a DNA binding domain. It plays a critical role in the development of the ovary. FOXL2 gene is mutated in over 90% of all adult granulosa cell tumors, and is thus considered to be important for the pathogenesis of these tumors.
FSH
– Follicle-stimulating hormone
GCDFP-15
– Gross cystic disease fluid protein 15
HELLP
– Syndrome including hemolysis, elevated liver enzymes, low platelet count.
HER-2/neu
– Human epidermal growth factor receptor 2; a member of the family of epidermal growth factor receptors; amplified in ~15–20% of all breast cancers.
HGSC
– High-grade serous carcinoma of the ovary
HIV
– Human immunodeficiency virus
HM
– Hydatidiform mole
HMG1 and 2
– High mobility group of nuclear non-histone proteins containing HMG-box domain, expressed in leiomyomas
HNPCC
– Hereditary nonpolyposis colorectal carcinoma
HPV
– Human papillomavirus
HSV
– Herpes simplex virus
IHC
– Immunohistochemistry
ISH
– In situ hybridization assay including fluorescent (FISH) or chromogenic (CISH) techniques.
JGCT
– Juvenile granulosa cell tumor
JAZF1/SUZ12
– Fusion gene of JAZF1, acronym for Juxtaposed with another zinc finger gene, and SUZ12 (suppressor of zeste-12 protein). Typically found in 50% high-grade endometrial stromal sarcomas.
Ki-67
– A protein that is encoded by the MKI67 gene. A sensitive marker of proliferation. Ki-67 has diagnostic and prognostic utility in many cancers. Other markers that are used for the evaluation of tumor cell proliferation include proliferating cell nuclear antigen (PCNA), topoisomerase IIα (Topo2α), and phosphohistone H3 (PPH3).
KRAS
– Oncogene, human equivalent of Kirsten Rous sarcoma virus (v-ras)
LCIS
– Lobular carcinoma in situ
LH
– Luteinizing hormone
MALT
– Mucosa-associated lymphoid tissue lymphoma
MED12
– A subunit of the multiprotein complex mediator, an evolutionary-conserved regulator of transcription, mutated in most uterine leiomyomas and mammary fibroadenomas.
MGA
– Microglandular adenosis
MLH1
– MutL homolog 1 gene inactivated in hereditary nonpolyposis colorectal carcinoma and 10% endometrioid carcinoma of the uterus caused by this germline mutation
MYB
– A gene, which is a member of the MYB family of transcription factors.
NCB
– Needle core biopsy
NFIB
– Nuclear factor 1 B-type
NGS
– Next-generation sequencing assay, a new high-throughput technique, which may sequence thousands or millions of sequences in one reaction.
NLRP7
– NACHT, leucine rich repeat, and PYD containing protein 7, a gene mutated in hereditary hydatidiform mole.
NOS
– Not otherwise specified
OHSS
– Ovarian hyperstimulation syndrome
p16
– Cyclin-dependent kinase 2A inhibitor p16INK4, a protein encoded by tumor suppressor gene CDKN2A gene; it is used in IHC for the diagnosis of cervical intraepithelial neoplasia.
p53
– Protein encoded by TP53 tumor suppressor gene. It is the most commonly mutated gene across the all cancer subtypes. Germline mutations of the TP53 gene cause Li-Fraumeni syndrome.fm9
p63
– Protein encoded by the gene of the same name, belonging to the TP53 gene family. It is involved in the stratification of squamous epithelium (positive in basal and parabasal cell of normal squamous epithelium) and a marker for myoepithelial cells; a good IHC marker for differentiating intraepithelial and invasive squamous carcinoma, but expressed in other tumors as well.
p57kip2
– Officially known as CDKN1 (cyclin-dependent kinase inhibitor 1C), a protein encoded by the maternal imprinted CDKN1C gene.
pCR
– Pathologic complete response; related to the evaluation of the breast cancer patients treated with neoadjuvant (preoperative) chemotherapy. There are many evaluation tools of which MD Anderson Residual Burden calculator (RBC) has been shown to have the best reproducibility.
PASH
– Pseudoangiomatous stromal hyperplasia.
PAX
– Paired-box containing genes, which play important roles in the development and proliferation of multiple cell lines and development of several organs. Antibodies to PAX2 and PAX8 have a diagnostic utility in histopathologic diagnosis of tumors.
PEComa
– Perivascular epithelioid cell tumor. It is a family of mesenchymal neoplasms composed of perivascular epithelioid cells. The neoplastic cells are typically positive for melanocytic and myogenic markers.
PHM
– Partial hydatidiform mole
PIK3CA
– Phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha; PIK3CA is involved in various cell processes including cell proliferation and death and represents one of the most commonly mutated and amplified genes across the cancers.
PNET
– Primitive neuroectodermal tumor
POC
– Product of conception
POF
– Premature ovarian failure
PCOS
– Polycystic ovary syndrome
PR
– Progesterone receptor
PTCH1
– Protein patched homolog 1, the member of the patched family.
PTEN
– Phosphatase and tensin homolog gene, which encodes the phosphatase and tensin protein, inactivated by mutation or deleted in most endometrioid endometrial carcinomas of the uterus and ovary; germline mutations of the PTEN gene cause Cowden syndrome that predisposes to multiple hamartomas and an increased risk of certain cancers (breast cancer, thyroid cancer, and endometrial cancer).
SALL4
– Sal-like protein 4, a transcription factor encoded by a member of the Spalt-like (SALL) gene family, SALL4 also known as key embryonic stem cells factor.
SBT
– Serous borderline tumor of the ovary
SCOUT
– Secretory cell outgrowths, also known as benign epithelial hyperplasia. They consists of hyperplastic foci composed of secretory cells, which may be ciliated, or show pseudostratification resembling endometrial epithelium, and are p53 negative.
SET
– Solid endometrioid transitional pattern of high-grade serous carcinoma often found in women with germline BRCA mutations.
SIN
– Salpingitis isthmica nodosa
SLCT
– Sertoli-Leydig cell tumor of the ovary
SMA
– Smooth muscle actin; a protein that is encoded by the ACTA2 gene. It is a marker of smooth muscle differentiation. Similar function has smooth muscle myosin heavy chain marker (SMM-HC). Both proteins have diagnostic utility by immunohistochemistry.
SMARC4
– SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4; a gene that it mutated in small cell undifferentiated carcinoma, hypercalcemic type, and is considered to be a molecular signature of this malignancy.
STIC
– Serous tubal intraepithelial carcinoma, the precursor of invasive high-grade serous carcinoma.
STIL
– Serous tubal intraepithelial lesion; a term used by some pathologists for the same lesions as STIN.
STIN
– Serous tubal intraepithelial neoplasia (low-grade) a p53 positive multilayered lesions which shows pseudo-stratification but only mild atypia and no loss of polarityfm10
STK11
– Serine threonine kinase, also known as liver kinase B1, LKB; gene encoding this protein is mutated in Peutz-Jeghers syndrome.
TDLU
– Terminal duct lobular unit, the functional unit of the breast gland.
TP53
– Tumor suppressor gene encoding p53
TSC2
– Tuberous sclerosis 2 gene encoding the protein tuberin is inactivated in most perivascular epithelioid cell tumors.
UDH
– Usual ductal hyperplasia
VUE
– Villitis of unknown etiology
WT1
– Wilms tumor suppressor gene 1
YWHAE-FAM22
– A fusion gene found in high-grade endometrial stromal sarcomas, but not in low-grade ESS and endometrioid stromal nodules. YWHAE gene also known as 14-3-3ε, belongs to the family of 14-3-3 proteins—a gene encoding for a protein that belongs to the family of 14-3-3 proteins. It regulates signal transduction and has many cellular functions. By forming a fusion gene with FAM22 it becomes oncogenic.