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Leishmaniasis is a protozoan disease with a prevalence of 12 million cases and an incidence of almost 2 million new cases worldwide, making it, together with malaria, helminthic infestations of the gastrointestinal tract, and HIV infection, one of the most common infectious diseases worldwide . The inciting organism belongs to the order Trypanosomatida, which comprises two genera pathogenic to humans: Trypanosoma and Leishmania .
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Leishmania species primarily affect cells of monocyte-macrophage lineage and exist in two forms during their life cycle: a flagellar (promastigote) and an aflagellar (amastigote) stage. The former is found in the intestines of sandflies, which function as the arthropod vector to Leishmania species. In the Old World the sand flies belong to the genus Phlebotomus, and in the New World to the genera Lutzomia and Psychodopygus . After the promastigotes enter the skin of the human host via the bite of infected sandflies, they transform into amastigotes within histiocytes. If the histiocytic response to Leishmania species remains confined to the skin, cutaneous lesions develop; if dissemination of the protozoa occurs, internal organs become involved.
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At the center stage of all of the different forms of leishmaniasis is a disruption of macrophage activation with the subsequent avoidance of intracellular killing mechanisms . The parasites do so by inhibiting lysosomal phosphatases and protein kinase C. Substrates of protein kinase C are involved in cytoskeletal rearrangements and vacuolar trafficking and are thus important in cellular signaling. Leishmania species also inhibit the synthesis of proinflammatory and increase the production of antiinflammatory cytokines, thereby preventing their elimination from the human host.
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Classification of Leishmaniasis
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The former simplistic classification dividing leishmaniasis into cutaneous, mucocutaneous, and visceral forms has been abandoned in favor of a classification that recognizes the overlap in the clinical spectrum of the different types of leishmaniasis ;
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• Localized (acute) cutaneous leishmaniasis
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• Diffuse (acute) cutaneous leishmaniasis (= disseminated anergic cutaneous leishmaniasis)
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• Chronic cutaneous leishmaniasis (including leishmaniasis recidivans or lupoid leishmaniasis)
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• Post-kala-azar dermal leishmaniasis
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• Mucocutaneous leishmaniasis
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• Viscerotropic leishmaniasis
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Each form of leishmaniasis is associated with a different type of Leishmania species and has a specific predilection for a geographic location .
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Localized (Acute) Cutaneous Leishmaniasis
Representing the most common form of skin involvement, localized acute cutaneous leishmaniasis affects primarily the exposed parts of the body, such as face, scalp, and arms . It appears initially as a painless, erythematous papule that enlarges over a period of 4 to 12 weeks to a nodule or a plaque measuring up to 2 em in diameter (Fig. 24-1A). Ulceration is common. After several months the lesion spontaneously regresses, starting from the center and progressing outward. The end stage is represented by a scar accompanied by hypo- or hyperpigmentation . New World leishmaniasis commonly presents with a single lesion and Old World leishmaniasis with multiple ones .
Histopathology.
The characteristic changes are noted throughout the dermis and consist of a dense, diffuse infiltrate of histiocytes admixed with lymphocytes and few plasma cells . Eosinophils and neutrophils are rare;
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the latter are more numerous if the lesion is ulcerated . The cytoplasm of the histiocytes is filled with numerous dull blue-gray, round to oval bodies measuring 2 to 4 IJm in diameter and exhibiting a round basophilic nucleus and a rod-shaped paranuclear kinetoplast, a specialized mitochondrial structure containing extracellular DNA . These intracellular bodies stain red or dark blue with Giemsa but not with periodic acid-schiff (PAS) and Grocott's methenamine silver (GMS) because of a lack of a capsule and represent amastigotes, known as Leishman-Donovan bodies. When numerous, they can also be seen extracellularly. The number of leishmania organisms decreases with time and is often inversely related to the amount of plasma cells.
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Differential Diagnosis.
The organisms of histoplasmosis do not exhibit a kinetoplast and do stain with (PAS) and (GMS) stains. Klebsiella rhinoscleromatis, the inciting agent of rhinoscleroma, also resides in macro phages and measures 2 to 3IJm in diameter. In contrast to leishmaniasis, rhinoscleroma reveals a large number of plasma cells with formation of Russell bodies. Granuloma inguinale, caused by Calymmatobacterium granulomatis, displays numerous small abscesses throughout the inflammatory infiltrate .
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Diffuse (Acute) Cutaneous Leishmaniasis
Diffuse acute cutaneous leishmaniasis, also known as disseminated anergic cutaneous leishmaniasis, is a rare variant of localized cutaneous leishmaniasis and is due to a lack of a Leishmania-specific cellular immune response . It begins as a single lesion and then spreads diffusely all over the body, characteristically as nonulcerated nodules, often involving upper and lower extremities, buttocks, and face . In atypical cases ulceration of the nodules is noted .
Histopathology.
The histopathologic changes of the individual lesions are the same as those seen in localized acute cutaneous leishmaniasis except for a larger number of Leishman-Donovan bodies and a relative lack of accompanying lymphocytes
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. In the rare ulcerated lesions of diffuse cutaneous leishmaniasis, eosinophils are predominant within the inflammatory infiltrate and reveal ultrastructural characteristics of parasitocidal activity .
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In reactivated, previously dormant leishmaniasis in a kidney transplant recipient, a subcutaneous inflammatory infiltrate with numerous intracellular amastigotes was seen; the dermis was not involved .
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Chronic Cutaneous Leishmaniasis
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If the lesions do not resolve within 1 to 2 years, the condition is termed chronic cutaneous leishmaniasis . Two subtypes are noted: nonhealing chronic cutaneous leishmaniasis and leishmaniasis recidivans (the latter is also called lupoid leishmaniasis, relapsing chronic cutaneous leishmaniasis, or recurrent cutaneous leishmaniasis) . In the former the original lesion of localized (acute) cutaneous leishmaniasis persists, clinically presenting as an erythematous plaque of several years' duration and no evidence of healing (18). Leishmaniasis recidivans refers to the appearance of new lesions in the center or at the periphery of an atrophic scar derived from a previous lesion of localized (acute) cutaneous leishmaniasis . It carries great clinical resemblance to lupus vulgaris and presents with erythematous papules, often coalescing into crust-covered plaques, in association with a scar. The face is the area of predilection . It is either due to reactivation of persistent organisms or exogenous reinfection .
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Histopathology.
Both subtypes of chronic cutaneous leishmaniasis reveal essentially the same histopathologic changes, except for the presence of scar tissue in leishmaniasis
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recidivans in contrast to nonhealing chronic cutaneous leishmaniasis .
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The histopathologic hallmark of chronic cutaneous leishmaniasis is a dense, diffuse, or nodular infiltrate composed of epithelioid cell granulomas within the superficial and deep dermis . The granulomas are tuberculoid in nature, made up of epithelioid histiocytes and Langhans giant cells surrounded by lymphocytes and plasma cells. Necrosis at the center of the granulomas is exceedingly rare , although it is occasionally documented (20). Leishman-Donovan bodies are either absent or very small in number. There is an inverse relationship between the number of organisms and the age of the lesion (23). The epidermal changes are nonspecific.
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Differential Diagnosis.
Other granulomatous dermatitides, especially lupus vulgaris, have to be differentiated from chronic cutaneous leishmaniasis . This may require the use of ancillary techniques such as immunohistochemistry with Leishmania-specific antibodies or the polymerase chain reaction .
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Post-Kala-azar Dermal Leishmaniasis
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Post-kala-azar dermal leishmaniasis occurs 1 to 5 years after successful treatment of visceral leishmaniasis . It presents initially as hypopigmented macules over the trunk and extremities. The macules become progressively erythematous and evolve into nonulcerated papules and nodules with marked involvement of the face, clinically resembling lepromatous leprosy . The human host is apparently able to confine Leishmania to the skin but cannot eradicate the organisms from the body .
Histopathology. Reports on the histopathology of post-kala-azar dermal leishmaniasis are sparse. Hypopigmented macules display a superficial perivascular lymphocytic infiltrate with admixed plasma cells without evidence of granuloma formation . The amount of epidermal melanin is decreased .
The nonulcerated papules and nodules show a dense, diffuse infiltrate composed of histiocytes, lymphocytes, and plasma cells within the dermis with sharply defined margins and a narrow grenz zone . Granulomas are not reported, and organisms are sparse. This is in contrast to earlier studies, which described the presence of well-
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formed epithelioid cell granulomas in nodular lesions of post-kala-azar dermal leishmaniasis . The overlying epidermis is often atrophic, and the hair follicles show prominent keratotic plugging .
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Mucocutaneous Leishmaniasis
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Mucocutaneous leishmaniasis, most commonly seen in South America, affects the upper respiratory tract and usually develops subsequently to healed localized (acute) cutaneous leishmaniasis . The mucosal lesions usually appear within 2 years of the initial skin involvement but may take as long as 30 years to develop . They often begin in the nasal septum, which becomes inflamed and later perforates. The lips (especially the upper lip), oral cavity, the pharynx, and even the trachea and bronchi can become involved, imposing a severe lifethreatening condition. South American mucocutaneous leishmaniasis probably develops secondary to hematogenous or lymphatic dissemination from primary cutaneous lesions or occasionally from direct extension of nearby skin lesions .
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Histopathology.
The histopathologic changes of mucocutaneous leishmaniasis are subdivided into an edematous, a granulomatous proliferative, and a granulomatous necrotizing stage (3D). In the early edematous stage parasites are scanty, a Iymphohistiocytic infiltrate with admixed plasma cells in the superficial and deep dermis is noted, and the overlying epidermis is thin. When the patient develops proliferative lesions, parasites become obvious, tuberculoid granulomas can be seen, and pseudocarcinomatous epidermal hyperplasia develops. These changes characterize the granulomatous proliferative phase. In clinically destructive lesions areas of necrosis with numerous neutrophils and abundant Leishman-Donovan bodies constitute the granulomatous necrotizing phase.
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Visceral leishmaniasis
Visceral leishmaniasis is a systemic disease characterized by fever, lymphadenopathy, hepatosplenomegaly, ascites, pancytopenia, and emaciation . The Indian name kala-azar
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(meaning "black fever") refers to the diffuse darkening of the skin, most pronounced on the face, hands, and feet, which is seen, however, only in a small proportion of patients and peculiarly confined to those from the Indian subcontinent (18). The initial cutaneous lesion of visceral leishmaniasis-the leishmanioma-is rarely seen. Although generally being devoid of cutaneous involvement during the course of the active visceral disease, patients coinfected with HIV can present with skin lesions. The lesions comprise erythematous papules, often confluent to plaques, and, less often, hypo- and hyperpigmented macules with a tendency to localize symmetrically on acral zones . These lesions have to be differentiated from those seen in post-kala-azar dermal leishmaniasis, which appear after the patient has been successfully treated for visceral leishmaniasis.
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Histopathology.
The cutaneous lesions in HIV-infected patients consist of a perivascular infiltrate within the superficial dermis composed of lymphocytes and histiocytes with numerous intracytoplasmic organisms within the latter . Leishman-Donovan bodies are also found extracellularly and, in one case in eccrine sweat glands, suggesting transepithelial elimination . Parasitization of Kaposi's sarcoma by Leishmania species and a leishmanial cutaneous spindle cell pseudotumor have also been reported.
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