Tropical Dermatopathology Manoj Singh
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Mycobacterial Infections1

 
1.1 TUBERCULOSIS OF THE SKIN
 
Tuberculodermas
  1. Primary tuberculosis
  2. Acute, post-primary disease
    • Acute miliary tuberculosis
    • Tuberculosis orificialis
  3. Chronic, secondary disease
    • Lupus vulgaris
    • Tuberculosis verrucosa cutis
    • Scrofuloderma
  4. Tuberculous hypersensitivity reactions
    • Lichen scrofulosorum
    • Papulonecrotic tuberculid
    • Erythema induratum
Mycobacterium tuberculosis is a slender, curved, rod 4-6 µ long and 1 µ in diameter. It is a bacillus, with a cell wall rich in lipids. This gives it a growth advantage in the human system, as it protects against macrophage phagocytosis and killing. This also forms the physiological basis of acid fast staining. When the organism is treated with warm stain, fuchsin penetrates the wall and stains the cytoplasm. The lipid rich wall protects this stain from subsequent washing with acid and/or alcohol (acid and alcohol fastness).
 
Tuberculosis of Skin
Mycobacterium tuberculosis infection of the skin may occur by inoculation of the organism into the skin, contiguous spread from underlying tissue or by hematogenous seeding. The clinical features are largely determined by the host's immunity and previous exposure to the organism. Inoculation of M. tuberculosis into the skin of an uninfected individual (primary tuberculosis) produces a tubercular chancre – an indurated ulcer associated with regional lymphadenopathy. Lupus vulgaris and tuberculosis verrucosa cutis develop, following inoculation in hosts already exposed to the disease and possessing moderate to good immunity. Scrofuloderma follows extension of infection from an underlying focus. Less commonly, hematogenous spread of the bacilli may produce miliary tuberculosis in the non-immune and tubercular gumma in the immune host. Orificial tuberculosis develops by inoculation or hematogenous spread from infection in the lung, intestines or genitourinary tract.
In most cases, the diagnosis is based on the clinical and histopathological appearance in association with the results of skin testing. Organisms may be demonstrated and grown from primary infections or in hosts with low immunity, but this is difficult in the majority of immunocompetent patients with cutaneous tuberculosis.2
Physicians are classifically divided into “lumpers” and “splitters”. Splitters are epitomized by the dermatologists, whose systems of nomenclature have been described as “a colorful cornucopia of concatenating cutaneous classification.”3
Tuberculids are lesions believed to develop as a cutaneous hypersensitivity response to tubercular infection elsewhere. Generally, these lesions develop intermittently in crops and often subside spontaneously. The lesions demonstrate a tubercle on histopathology, the Mantoux test is strongly positive and an active focus of tuberculosis may be demonstrable elsewhere.
 
Isolation of M. Tuberculosis
M.tuberculosis has a long replication time of 15 to 22 hours (other bacteria may replicate in 20 to 30 minutes). This necessitates the use of special techniques for mycobacterial growth. The two media used for mycobacterial cultures are Lowenstein Jensen medium (egg based) and Middlebrook medium (agar based). The growth requires 6 to 8 weeks for typical mycobacteria.
Smear examination requires at least 10,000 AFB/ml for detection.
Radiometry can be used to detect M.tuberculosis. It uses fatty acid substrates like palmitic acid labelled with radioactive carbon. As the mycobacteria grow, radioactive carbon dioxide is released and measured.
 
Treatment
Cutaneous tuberculosis is generally treated in the same way as pulmonary tuberculosis though the rationale may not be correct except in scrofuloderma where there is an underlying focus or in cases of lupus vulgaris with systemic involvement or immunosuppression. The suggestion by Prof. V.K. Sharma, Head of Deptt. Dermatology AIIMS to divide treatment of cutaneous TB into two groups is appropriate and recommended. The regular four drug regimen daily (RHZE) for two months followed by two drugs (RH) daily for four months should be given in scrofuloderma, lupus vulgaris with systemic involvement, disseminated TB and lupus vulgaris with HIV. On the other hand, in cases of lupus vulgaris and tuberculosis verrucosa cutis with no systemic involvement an initial three drug regimen (RHZ) daily for two months followed by two drugs (RH) daily for four months should be given.4
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Fig. 1.2a: Lupus vulgaris: Long standing, asymptomatic indurated, scaly, crusted, plaque on the front of the chest
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Fig. 1.2b: Lupus vulgaris: Lesion on back of thigh showing central atrophy and peripheral hyperplasia
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Fig. 1.2c: Lupus vulgaris: Extensive granulomata in the dermis
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Fig. 1.2d: Lupus vulgaris: Dermal granulomas with epidermal hyperplasia mimicking Tuberculosis verrucosa cutis
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1.2 LUPUS VULGARIS
The classic lesion is a gradually enlarging indurated plaque, which heals centrally with atrophy and scarring, while it continues to extend peripherally (Fig. 1.2a). The active, indurated portion of the lesion demonstrates firm, erythematous papules, which have a translucent yellow-brown color on diascopy (‘apple jelly nodules’). The plaques may be crusted, sometimes heavily, and ulcers may be seen. The usual number of plaques in a patient ranges from 1 to 3 but they may occasionally be multiple. In our country, most lesions occur on or around the buttocks (Fig. 1.2b), the face is also commonly affected.
The important factor in diagnosis of Lupus vulgaris is the site of biopsy. Though granulomas may be present in both, but a biopsy from the central, atrophic region will show a flattened epidermis and dermal fibrosis, whereas a biopsy from a peripheral region may show features approaching tuberculosis verrucosa cutis. It is for this reason that we prefer to return a diagnosis of “Tuberculosis, skin”; whatever the given clinical category might be.
This is the prototypic manifestation of tuberculosis of the skin. The dermis, usually in the upper part, contains granulomas with epithelioid cells and giant cells, usually of the Langhans; type (Fig. 1.2c). Caseation necrosis is rarely seen. Lymphocytes are scattered throughout the lesion, and may surround the granulomas to form a collar. Secondary epidermal changes like atrophy, and occasionally ulceration, are common. Hyperplasia with hyperkeratosis, acanthosis and follicular plugs may be seen (Fig. 1.2d), making distinction from tuberculosis verrucosa cutis difficult. Acid-fast bacilli can hardly ever be demonstrated.6
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Fig. 1.3a: Scrofuloderma: Multiple lymph nodes in neck with overlying ulcers and crusts
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Fig. 1.3b: Scrofuloderma: Low power picture showing deep granulomatous inflammation
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Fig. 1.3c: Scrofuloderma: The sinus tract shows granulomas in the wall, and necrosis
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Fig. 1.3d: Scrofuloderma: Langhan's giant cell and epitheloid cells with marked acute inflammation
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1.3 SCROFULODERMA
 
(Syn. Tuberculosis Colliquativa Cutis)
This represents direct extention of tubercular infection from an underlying focus, usually a lymph node, to the skin (Fig. 1.3a) the common sites are the neck, axilla or over an involved bone. It is usually seen as a sinus discharging thin, watery pus, overlying a soft subcutaneous swelling (‘cold’ abscess). The sinus edges are atrophic and bluish. Untreated, the sinuses heal slowly with broad, atrophic scars.
A diagnostic biopsy must remove the entire unit; a small biopsy may result in an incorrect diagnosis. Nowadays, such an extensive biopsy is usually avoidable because of the high diagnostic accuracy of fine needle aspiration cytology.
Biopsy may be non-diagnostic, showing granulation tissue (Fig. 1.3b); granulomas may be identified only in a deeper biopsy (Fig. 1.3c). Necrosis is often present, and stain for AFB will frequently be positive. Scrofuloderma is the variant where AFB are most frequently demonstrated. The reason for this is that M. tuberculosis is a highly aerophilic organism, optimal growth being at 142 mmHg of oxygen. In a manner analogous to a lung cavity connecting via brouchi to the outside air where the pO2 is mm, in scrofuloderma, as there is expesure to atmospheric oxygen, the organism gets a significant growth advantage, and is present in large numbers. Eosinophils are often present in sizeable numbers, mixed with the chronic inflammation and granulomas, (Fig. 1.3d) making scrofuloderma the one exception to the dictum “when you see eosinophils, move away from a diagnosis of tuberculosis”.8
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Fig. 1.4a: Tuberculosis verrucosa cutis: Verrucous, indurated plaque on the sole
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Fig. 1.4b: Tuberculosis verrucosa cutis: Massive hypertrophy of epidermis with granulomatous inflammation in the dermis
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Fig. 1.4c: Tuberculosis verrucosa cutis: Extensive chronic inflammation in the dermis with granulomas
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Fig. 1.4d: Tuberculosis verrucosa cutis: High power of figure 1.4c, showing epidermal hyperplasia, chronic inflammation and granulomas
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1.4 TUBERCULOSIS VERRUCOSA CUTIS
The characteristic lesion is a long standing verrucous, hyperkeratotic indurated plaque on the extremities, usually the lower limbs (Fig. 1.4a). The size of the lesion and the degree of hyperkeratosis usually varies with the duration of the lesion. Some plaques involve the entire foot and verrucosity may be severe enough to produce cutaneous horns. Fissuring and secondary infection of the hyperkeratotic surface may cause a purulent discharge and crusting.
Epidermal hypertrophy is marked. There is hyperkeratosis, acanthosis, and papillomatosis (Fig. 1.4b). The upper dermis has a varying amount of chronic inflammation, and granulomas may have to be searched for in multiple sections (Fig. 1.4c). Frequently, biopsies may show only, or chiefly, hyperkeratotic epidermis. A carefully taken, deep biopsy is essential to provide adequate material for diagnosis (Fig. 1.4d).10
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Fig. 1.5a: Lichen scrofulosorum: Grouped erythematous crusted papules in a patient with tuberculosis of the lymph nodes
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Fig. 1.5b: Lichen scrofulosorum: Small aggregates of non-caseating granulomas in the upper dermis
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1.5 TUBERCULIDES
 
(Papulonecrotic Tuberculid, Lichen Scrofulosorum, Erythema Induratum)
The tuberculids are considered to be an immunological response to systemic tuberculosis. Whether the organisms actually exist in the lesion at some stage, or the tuberculid is caused by a response to circulating tubercular antigens, is not clear.
Papulonecrotic tuberculid: Multiple necrotizing papules occur in crops, usually on the extensor surfaces of the forearms. They heal, leaving behind atorphic scars.
Lichen scrofulosorum: Crops of small, grouped, lichenoid and crusted papules develop, mainly on the trunk, and resolve spontaneously with no sequelae (Fig. 1.5a).
Erythema induratum: Painful, tender nodules develop, especially on the calves in females. The nodules may break down and form stubborn, indolent ulcers.
Papulonecrotic tuberculid represents leukocytoclastic or lymphocytic vasculitis of a medium-sized blood vessel, with thrombus formation, and wedge shaped infarction of the overlying skin.
Lichen scrofulosorum: consists of a mass of epithelioid granulomas, usually superficial. Necorsis is infrequent. Bacilli have not been demonstrated in these granulomas (Fig. 1.5b).
Erythema induratum is a medium vessel vasculitis present deep in the subcutaneous fat. There is extensive surrounding panniculitis.12
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Fig. 1.6a: Hansen's disease: Focal perineural inflammation in the dermis may at time be the only histologically detectable sign of leprosy
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Fig. 1.6b: Hansen's disease: Perineural inflammation with necrosis
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1.6 LEPROSY—GENERAL ASPECTS
Leprosy is an ancient disease. It has been documented in India since 600 B.C. and from China and Japan since 400 B.C. The extent of disease caused by M. leprae depends almost entirely on the host response, as the organism itself does not secrete toxins. The most common sequel of infection is a sub-clinical episode, which is seen in the vast majority of infected individuals. Persons with a low or absent cell-mediated immunity develop a widespread infection involving many organs (lepromatous leprosy). When the immune response is good, the infection gets localized to skin and nerves, and granuloma formation results in extensive tissue destruction (tuberculoid leprosy). Cases with moderate immunity develop infection of varying extent (borderline leprosy): Localized, ill defined disease is referred to as indeterminate leprosy. At times, the infection may affect the nerves alone (neuritic leprosy), and this may be the prominent, or only histological change (Fig. 1.6a to c).
The Ridley Jopling Classification divides leprosy into five subtypes, TT, BT, BB, BL, and LL, based on four criteria-clinical appearance, bacillary load, histopathology and lepromin test (Mitsuda).
 
 
Immunopathogenesis
Tuberculoid leprosy is a persistent, delayed type hypersensitivity (DTH) response to M.leprae antigens. Its histological features resemble those of a Mitsuda reaction site. There is a very high level of CMI. In a granuloma of tuberculoid leprosy, the peripheral cuff of lymphocytes is usually CD8 + cells (T cytotoxic/suppressor) and, scattered amongst the epithelioid cells, many CD4+(T helper) cells are seen.
Lepromatous leprosy appears to be the result of a specific diminished T cell response to M.leprae antigens; the response to other antigens may be normal. CD8 + cells are sprinkled all over the lesions, and CD4 + cells are diminished.
T memory cells (UCHL-1) are many more in tuberculoid than in lepromatous leprosy.
 
Reactions
Reactions in leprosy represent sudden, immune mediated changes in the clinical and histological course of the disease.
Type 1 reactions (Reversal) represent a sudden change in the CMI response to M.leprae, and are a feature of borderline leprosy. Usually, the CMI upgrades, but may diminish in some cases.
Type II or ENL represents an immune complex disease. This is usually seen in lepromatous leprosy, where the mycobacterial antigen and circulating antibody levels are high.
Bacillary index (B.I.) is expressed as bacilli counted per oil immersion field (OIF). The stages are:
0
(negative)
no bacilli seen
I
(rare)
1-10 bacilli / 100 OIF
II
(very few)
1-10 bacilli / 10 OIF
III
(few)
1-10 bacilli / 1 OIF
IV
(moderate)
10-100 bacilli /1 OIF
V
(numerous)
100-1000 bacilli / 1 OIF
VI
(very numerous)
>1000 bacilli / 1 OIF
Morphological Index (MI) is the percentage of undamaged bacilli of normal size and shape, staining uniformly (solid staining).
 
Cultivation
M leprae for a long time has not been grown on artificial media although many attempts have been made to grow it. Classically inoculation into the footpads of BalB/C mice, nude mice or into the 9-banded armadillo has been classically used for growing M. leprae.
 
Criteria for Successful Culture of M. leprae
A purported isolate should satisfy the following criteria
  1. Pyridine extractable acid fastness
  2. +DOPA oxidase test14
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    Fig. 1.6c: Hansen's disease: S-100 stain showing nerve damage
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  3. +Mitsuda component
  4. Inoculation causing LL in 9-banded armadillo
For a long time, the 9-banded armadillo was the only animal apart from human where M. leprae could be grown. M. leprae is now also known to grow experimentally in:
  1. Mouse foot pad (BalB/C and nude)
  2. 9–banded armadillo
  3. Lewis rats
  4. Ant eater (Mauis crassicaudatus)
  5. Malaysian white headed gibbon (Hylobatus)
  6. European hedgehog
  7. Korean chipmunk
 
Slit Smear
The most productive areas are the cooler parts of the skin. Ear lobes, forehead, and a nodular lesion are the usual sites. After cleaning and disinfecting the skin, an area is pinched, so that the skin blanches. With a scalpel, a (5 mm long and 2 mm deep) slit is made, and before blood seeps through, the walls of this slit are scraped, the serous material smeared on a glass slide, and stained.
 
Morphology, Structure and Staining
M leprae is an acid alcohol fast, weakly curved bacillus which is 2 to 7 µ long and 0.3 µ wide. It may have, on AFB stain, a solid or beaded appearance, and especially in reactional states, a fragmented appearance.
Staining. Ziehl-Neelsen stain is classically used for demonstrating mycobacteria. This entails staining with carbol fuchsin solution, and later decolorization with weak acid, or acid alcohol. The wall lipids contain Phthiocerol demycocerosate (described as being a passive protector) and phenolic glycolipid (OPGL-1), which is serologically active, evokes immunity, and is not described in any other mycobacteria.
 
Treatment of Leprosy
Multibacillary leprosy: Dapsone, 100 mg daily, clofazimine 50 mg daily and 300 mg once a month, supervised, and rifampicin 600 mg once a month for 1 year.
Paucibacillary leprosy: Dapsone, 100 mg daily, and rifampicin 600 mg once a month for 6 months.
Single lesion paucibacillary leprosy: Single dose of rifampicin 600 mg, ofloxacin 400 mg and minocycline 100 mg.16
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Fig. 1.7a: Lepromatous leprosy: Multiple, ill defined, hypopigmented macules all over the trunk; macules show minimal loss of sensation
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Fig. 1.7b: Lepromatous leprosy: Infiltration and thickening of facial skin
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Fig. 1.7c: Lepromatous leprosy: H and E stained slide showing foam cells and intracytoplasmic aggregates of bacilli, called globi, which stain with Hematoxylin
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Fig. 1.7d: Lepromatous leprosy: AFB stain showing Mycobacteria in the cytoplasm of histiocytes and lying free
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Fig. 1.7e: Lepromatous leprosy: Auramine rhodamine stain showing bundles of Mycobacterium leprae in the phagocytes
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1.7 LEPROMATOUS LEPROSY (LL)
The cutaneous manifestations may be in three distinct or overlapping forms. There may be diffuse thickening (infiltration) of the skin, beginning on the ears and the face (Fig. 1.7a), but spreading to involve the rest of the body or skin colored, soft variably sized nodules may develop on involved skin. Some patients develop numerous, small, hypopigmented, ill-defined, shiny macules distributed symmetrically all over the body with slight or no loss of sensation (Fig. 1.7b). Nerve thickening is not prominent, but fibrosis is a feature of long-standing disease, producing ‘glove and stocking’ anesthesia and peripheral motor weakness.
The causative organism, Mycobacterium leprae, grows best in vivo at a temperature of 32°C. It therefore prefers to grow in the cooler parts of the body, like the skin of the face, specially the ear lobes, the nose, and the forehead. Thickening of skin in these areas gives rise to the typical ‘leonine’ facies of lepromatous leprosy.
Sheets of histiocytes with foamy cytoplasm are seen in the dermis in a perivascular and periappendageal distribution (Fig. 1.7c). Some cells may contain a bluish-gray vacuole called a globus in their cytoplasm. These globi represent huge intracellular aggregates of bacilli. Organisms may be seen inside nerves, in the cytoplasm of Schwann cells, or inside arrectore pili muscles, though inflammation and consequent damage to these structures is not marked. The organisms are well demonstrated on Z-N stain (Fig. 1.7d) or Auramine Rhodamine stain (Fig. 1.7e)18
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Fig. 1.8a: Borderline lepromatous leprosy: Multiple hypoesthetic, variably sized plaques on the trunk and back
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Fig. 1.8b: Borderline lepromatous leprosy: Perivascular aggregates of foamy histiocytes and lymphocytes
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Fig. 1.8c: Borderline lepromations leprosy: Moderate AFB positivity
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1.8 BORDERLINE LEPROMATOUS LEPROSY (BL)
Borderline lepromatous leprosy (BL) manifests with a large number of variably-sized macules and plaques which tend to be symmetrical (Fig. 1.8a). The larger lesions may show some features of BT lesions, being dry, atrophic, hairless, and hypoaesthetic with satellite lesions. Smaller lesions are shiny, and not anesthetic or only mildly so. The skin of the ear lobes and face is infiltrated, but patchily involved. There is widespread, usually symmetrical involvement of nerve trunks which are moderately thickened and palpable.
There is dense to moderate dermal inflammation consisting of histiocytes, lymphocytes, and plasma cells (Fig. 1.8b). Epithelioid cells are infrequent. Bacilli are seen in sizeable numbers inside the histiocytes, and also extracellularly (Fig. 1.8c). Careful search reveals bacilli in the nerves and in the cytoplasm of Schwann cells, though damage to nerves is much less than that seen in tuberculoid leprosy.20
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Fig. 1.9a: Mid-borderline leprosy (BB): Typical, erythematous annular plaque with central, normal appearing skin
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Fig. 1.9b: Mid-borderline leprosy (BB): Moderate perivascular and periappendageal inflammation
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Fig. 1.9c: Mid-borderline leprosy (BB): AFB are present in the infiltrate
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Fig. 1.9d: Mid-borderline leprosy (BB): High magnification showing focal AFB positivity
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1.9 MID-BORDERLINE LEPROSY (BB)
Mid-borderline leprosy is characterized by annular plaques with skin colored centers. The plaques are often erythematous, and have significant hypoesthesia in the peripheral ring (Fig. 1.9a). Lesions vary in diameter from a few centimeters across to large plaques that may cover the entire back, and vary in number from few to many. Regional nerve trunks show asymmetrical thickening involving multiple nerves.
The usually seen picture is one of reaction, and a pure, static BB may be rarely, if ever seen.
Histological features are variable, and the picture is so variable that a classic picture can be rarely, if ever defined. Lymphocytes and histiocytes are present in variable numbers (Fig. 1.9b). Nerve involvement is common. Epithelioid cells are extremely scanty, if at all seen. AFB can be seen in almost all cases (Fig. 1.9c) though they may have to be carefully searched for (Fig. 1.9d).22
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Fig. 1.10a: Borderline tuberculoid leprosy (BT): Hypopigmented, anesthetic plaque with a dry atrophic surface and margin that is ill-defined in part. Notice the satellite lesions adjacent to the main plaque
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Fig. 1.10b: Borderline tuberculoid leprosy (BT): Granulomas consisting of epithelioid cells and lymphocytes. The Grenz zone is not involved
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Fig. 1.10c: Borderline tuberculoid leprosy (BT): Perineural appendageal inflammation and granulomata
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Fig. 1.10d: Borderline tuberculoid leprosy (BT): Perineural appendageal inflammation and granulomata
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1.10 BORDERLINE TUBERCULOID LEPROSY (BT)
Tuberculoid leprosy manifests with well defined macules and/or plaques. The macules are dry, hairless, atrophic and anesthetic. Plaques have a sharp, raised margin with a relatively depressed and at times atrophic center. The lesion may be erythematous. Both types show satellites – smaller, morphologically similar lesions around the periphery of the larger lesion (Fig. 1.10a). The cutaneous nerves supplying the area may be thickened, as is the regional nerve trunk.
The histological features resemble those of TT. Well-defined granulomas are less prominent, and the number of lymphocytes is more than that in any other form of leprosy except, possibly BL. The Grenz zone is spared (Fig. 1.10b). Cutaneous nerves are frequently inflamed although this may have to be searched for in several serial sections (Fig. 1.10c). Appendages are involved (Fig. 1.10d).24
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Fig. 1.11a: Tuberculoid leprosy (TT): Single anesthetic, erythematous plaque with well-defined margin
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Fig. 1.11b: Tuberculoid leprosy (TT): A granuloma composed of epithelioid cells is present in the upper dermis and extends into and erodes the epidermis. There is a large foreign body giant cell at the lower pole of the granuloma, and lymphocytes at the periphery
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Fig. 1.11c: Tuberculoid leprosy (TT): Grenz zone involvement, overlying epidermal atrophy and well-defined granuloma
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1.11 TUBERCULOID LEPROSY (TT)
Clinically, the differences between TT and BT are relative. TT lesions are better defined, fewer than in BT, and usually do not have satellites (Fig. 1.11a). There is more extensive nerve involvement, and loss of sensation.
Epithelioid cell granulomas are present in the dermis. A thin rim of lymphocytes surround each granuloma, and lymphocytes may be scattered throughout the lesion. Some authors have highlighted the involvement of the Grenz zone, and consequent erosion of the basement zone, as a diagnostic feature of TT, and an important distinctive feature from BT (Fig. 1.11b). This feature is not seen in other forms of leprosy. In some cases the perineural arrangement of the granulomas gives them an elongated, oblong shape to the granulomas (Fig. 1.11c). At times there may be extensive caseation necrosis. This necrosis may represent a severly damaged nerve twig or a reactional state in leprosy. On AFB staining, although bacilli are extremely infrequently seen in TT, degenerated bacilli may be seen in these necrotic areas.26
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Fig. 1.12a: Histoid leprosy: Firm, shiny nodules on the back, with many smaller nodules
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Fig. 1.12b: Histoid leprosy: The presence of histoid nodules on the face and earlobes in brothers suggest a familial predilection for developing this variant of lepromatous leprosy
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Fig. 1.12c: Histoid leprosy: The infiltrate consists of closely packed spindle cells and foam cells, histologically resembling a dermatofibroma
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Fig. 1.12d: Histoid leprosy: High power view of 1.12c
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Fig. 1.12e: Histoid leprosy: Ziehl-Neelsen stain reveals a large number of M.leprae occurring in aggregates known as globi and also discretely. The bacilli appear longer and more slender than in other types of leprosy
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Fig. 1.12f: Histoid leprosy: Auramine-Rhodamine stain showing the same features as the Ziehl-Neelsen stain
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1.12 HISTOID LEPROSY
This is a variant of lepromatous leprosy originally described in cases of dapsone resistence but since then has also been seen in untreated patients. It is characterized by firm, yellowish nodules occurring in any part of the body (Fig. 1.12a). The nodules may develop on normal or infiltrated skin (Fig. 1.12b). Nerve trunks are diffusely and symmetrically involved, but nerve function is preserved till fibrosis sets in, manifesting itself as firm, cord-like thickening of nerve trunks.
The histoid nodules represent rapidly expanding lepromas, and, especially when they occur without any other sign of leprosy, may cause diagnostic confusion with xanthomas, fibromas, and other dermal tumors.
The dermis is occupied by a sheet of spindle cell shaped histiocytes (Fig. 1.12c). These cells may encircle appendages and encroach on the subcutis. The nodule may push the surrounding collagen into a pseudocapsule. The cytoplasm of these cells is homogenous, though some vacuolated cells may be seen. On AFB staining, these cell are packed with bundles of intact solid staining bacilli (Figs 1.12d and e), these bacilli appear to be larger than those seen in other forms of leprosy. Auramine-Rhodamine stain demonstrates AFB letter (Fig. 1.12f).28
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Fig. 1.13a: ENL: Multiple, coalescent plaques on the back, with erythematous border and swelling
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Fig. 1.13b: Type I reaction: Erythema and edema developed in these plaques of BL leprosy two months after treatment was started
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Fig. 1.13c: Type II reaction: Showing many fragmented acid-fast bacilli due to reaction
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Fig. 1.13d: BT with vasculitis: A dense perivascular collection of neutrophils with histiocytes and lymphocytes. Other areas of the slide showed typical feature of BT
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1.13 REACTIONAL LEPROSY
Reactions are acute episodes in the chronic course of infection with Mycobacterium leprae. They can be broadly divided into two types based on the clinical and immunological features.
Type I reactions represent in a sudden change in the cell-mediated immune response of Mycobacterium leprae. This type of reaction is a feature of borderline leprosy. Usually, there is an improvement in the CMI but it may be impossible to distinguish, clinically and histopathologically, between an upgrading or downgrading reaction. Most type I reactons develop a few months after anti-leprosy therapy is begun, but reactions may develop in untreated individuals and those who have completed therapy. Clinically, the reaction manifests with an inflammatory exacerbation of pre-existing skin and nerve lesions accompanied by the development of new lesions. Histopathologically, there is evidence of acute inflammation. Bacilli may be absent, or fragmented (Figs 1.13b and c).
Type II or ENL reactions probably represent an immune complex disease. They occur in lepromatous and borderline lepromatous leprosy where the mycobacterial antigen load is high. The features are reminiscent of serum sickness syndrome with fever, arthritis, tender red nodules (Fig. 1.13a) and constitutional symptoms and vasculitis on histopathology (Fig. 1.13d). Reactions may be precipitated by anti-leprosy therapy, infections, physical and mental stress, pregnancy, vaccinations or may occur without apparent cause.
Histologically, a biopsy from ENL shows dermal edema, and acute inflammation (Fig. 1.13b). T helper cells may be increased. Vasculitis may be present, and there may be associated panniculitis.
Note: Histologically, it is very important to distinguish a reactional state from a relapse.30
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Fig. 1.14a: Indeterminate Hansen's: An ill-defined hypopigmented hypoesthetic macule on the forearm
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Fig. 1.14b: Indeterminate Hansen's disease showing scant perivascular inflammation
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Fig. 1.14c: Indeterminate Hansen's disease: At times perineural inflammation and/or neuritis may be the only indicator towards leprosy (see also Figs 1.14a and b)
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1.14 INDETERMINATE LEPROSY
Usually this is an ill-defined hypopigmented macule (Fig. 1.14a) with slight hypoesthesia and is more common in children. The condition can be diagnosed more confidently if the patient belongs to an area endemic for leprosy. Indeterminate leprosy may evolve into tuberculoid, borderline or lepromatous leprosy, its course being determined by host immunity to M.leprae.
Biopsy from a hypopigmented lesion usually shows nonspecific changes. There is focal perivascular inflammation (Fig. 1.14b). Diagnosis depends on detecting nerve twigs, usually found by locating vascular bundles, and searching carefully for evidence of inflammation, which is often minimal. Numerous serial sections may need to be cut, and a nerve twig followed through several step sections. AFB stain may be similary unhelpful, though small numbers are usually identified, at times after carefull searching (Fig. 1.14c).32
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Fig. 1.15a: Neuritic leprosy: Greater auricular nerve is thickened and palpable
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Fig. 1.15b: Neuritic leprosy: Chronic inflammation and granulomas destroying a nerve
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Fig. 1.15c: Neuritic leprosy showing a central large area of necrosis
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Fig. 1.15d: Z-N stain showing bacilli inside Schwann cells of a nerve
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1.15 NEURITIC LEPROSY
Leprosy may be confined to the nerves for the entire duration of the infection or for long periods before the skin and other tissues are involved. Neuritic leprosy presents as a peripheral neuropathy whose pattern is determined by the number and extent of nerves involved. This may range from a mononeuritis to a symmetrical peripheral neuritis. The nerve trunks are characteristically thickened and/or tender (Fig. 1.15a). However, a clinically normal nerve may show evidence of infection on histopathological examination. In fact, smaller, purely sensory nerves, usually the radial cutaneous or sural nerve, are biopsied even if they appear to be unaffected, while the clinically affected larger nerve trunks are hardly ever biopsied.
In lepromatous leprosy, nerves may appear to be histologically unremarkable. This is fallacious; a Z-N stain may reveal a large number of bacilli in the cells, specially in the Schwann cells (Fig. 1.15c). In tuberculoid leprosy, there is increasing destruction of the nerves consequent to the inflammatory reaction. In some cases, an extensive granuloma may be seen destroying the nerve (Fig. 1.15b). Often, especially in reactional states, large areas of necrosis may be seen (Fig. 1.15d).