Sections usually show an ulcerated lesion with extensive necrosis in the base, pseudoepitheliomatous hyperplasia at the margins, and a non-specific inflammatory infiltrate extending into the deep dermis and subcutaneous tissues beneath the ulcer base. ¹⁴ In the series from South Africa, referred to above, two fairly distinctive histopathological patterns were observed. About a third of cases were characterized by superficial lesions with the ulceration and inflammation confined to the upper dermis, while the remaining cases had deep lesions extending into subcutis with extensive ‘liquefactive’ necrosis with karyorrhectic debris, numerous trophozoites, and sometimes suppurative foci. ⁷ The deep variant was associated with visceral disease. ⁷ Sometimes there is extensive pseudoepitheliomatous hyperplasia involving much of the lesion, with only small punctate areas of ulceration (Fig. 27.1). This may resemble a verrucous carcinoma. E. histolytica may be found, singly and in clusters, in the overlying exudate (Fig. 27.2). They differ from histiocytes by the presence of a single eccentric nucleus with a prominent central karyosome and occasional phagocytosed red blood cells in the cytoplasm. ⁹ The term hematophagous amebic trophozoites (HATS) has been used for these amebae. ⁷ In sections of fixed tissue their diameters are usually within the range 12–20 µm, but larger forms up to 50 µm may be seen. ³ They are basophilic. Viable amebae can be highlighted in the necrotic debris by the PAS stain. Degenerate amebae are not enhanced by this stain. ⁷

Sections have shown tuberculoid granulomatous lesions in the deep dermis and subcutaneous tissue, often with accompanying vasculitis.^{17. and 20.} In patients with AIDS, granulomas are not always present. There may be a diffuse neutrophilic infiltrate with numerous organisms, and abscess formation. A suppurative panniculitis has also been described.^{21.22. and 24.} Amebae, 15–40 µm in width, can often be seen lying free in the tissues; ²⁹ they may take the form of trophozoites or cysts. ²² Organisms are not invariably present in immunocompetent individuals with granulomas.

Of the two cases of Balamuthia that presented with cutaneous lesions, one was misinterpreted by experts from around the world, ²⁸ and the other was initially misdiagnosed, although a subsequent biopsy showed a suppurative and granulomatous process with multinucleated giant cells and pseudoepitheliomatous hyperplasia. ²⁷ There was extensive tissue necrosis. Amebic trophozoites were identified in the necrotic tissue and in the walls of small blood vessels. ²⁷

Sections of the chancre show a superficial and deep, predominantly perivascular infiltrate with lymphocytes and many plasma cells, with some resemblance to the lesions of secondary syphilis. ³² Organisms can be seen in Giemsa-stained smears taken from the exudate of a chancre, but they are not usually seen in tissue sections. ³² In the secondary stage the trypanids show mild spongiosis with exocytosis of lymphocytes, a superficial perivascular infiltrate of lymphocytes, and a mild diffuse infiltrate of neutrophils with some leukocytoclasis. ³⁴ Amastigotes of T. cruzi may be present in the epidermis, in walls of blood vessels, in arrector pili muscles, and in the cytoplasm of inflammatory cells in cutaneous lesions of Chagas’ disease. A variable inflammatory cell infiltrate is also present.

In acute lesions there is a massive dermal infiltrate of lymphocytes, parasitized macrophages, epithelioid cells and occasional giant cells, plasma cells, and sometimes a few eosinophils (Fig. 27.3).^{162. and 163.} Both CD4⁺ and CD8⁺ lymphocytes are present. ⁹¹ Variable numbers of neutrophils are present in the upper dermis. Granulated calcific Michaelis–Gutmann bodies have been reported in the cytoplasm of macrophages in two cases. ¹⁶⁴ Rarely, the inflammatory infiltrate extends around small nerves in the deep dermis in a manner similar to leprosy. ¹⁶⁵ The parasites are round to oval basophilic structures, 2–4 µm in size. They have an eccentrically located kinetoplast. Their lack of a capsule is helpful in distinguishing them from Histoplasma capsulatum. Although organisms can be seen in macrophages in hematoxylin and eosin-stained sections (Fig. 27.4), the morphological details are better seen on a Giemsa stain, preferably of a slit-skin smear. ¹⁶⁶ Organisms tend to localize at the periphery of the macrophages, the so-called ‘marquee’ sign. The epidermis shows hyperkeratosis and acanthosis, but sometimes atrophy, ulceration, or intraepidermal abscesses (Fig. 27.5).^{132. and 167.} Pseudoepitheliomatous hyperplasia is present in some long-standing lesions.

With increasing chronicity there is a reduction in the number of parasitized macrophages, and the appearance of small tuberculoid granulomas which consist predominantly of epithelioid cells and histiocytes with occasional giant cells. ¹⁶⁷ Central necrosis is rare. ¹⁶⁸ There is an intervening mild to moderate mononuclear cell infiltrate. Langerhans cells in the epidermis also decrease with chronicity of the lesions. ¹⁶⁹

Cutaneous leishmaniasis is frequently misdiagnosed in countries where it is not endemic, particularly if organisms are not seen. ¹⁷⁰ It may be misinterpreted as sarcoidosis, foreign body reaction, granulomatous rosacea, and even granuloma annulare. ¹⁷⁰

In the recidivous form the appearances resemble those seen in lupus vulgaris, with tubercles surrounded by lymphocytes and histiocytes with some giant cells.^{66. and 167.} However, there is no necrosis and only sparse plasma cells. Occasional organisms may be found on careful search. The polymerase chain reaction can be used to demonstrate the presence of DNA of Leishmania amastigotes in tissue sections⁶⁶ or lesional scrapings. ⁴⁸ It is the most sensitive method for diagnosis.^{48.74.171. and 172.} An immunohistochemical method using a monoclonal anti-Leishmania (G2D10) antibody has been developed. ¹⁷³ It has only marginally greater sensitivity and specificity than the routine H & E stain.

In the disseminated anergic lesions the infiltrate is almost entirely composed of parasitized macrophages, with scant lymphocytes. ¹⁷⁴ Eosinophils were abundant in one reported case. ¹⁷⁵

The appearances resemble those seen in the acute cutaneous form, although the number of organisms is considerably smaller and occasional tuberculoid granulomas may be seen. Suppurative granulomas have been described. ¹⁷⁶ The mucosal lesions show non-specific chronic inflammation, with only a few parasitized macrophages. Pseudoepitheliomatous hyperplasia may be prominent in some lesions, particularly at the periphery. ¹⁸⁴ There may be fibrosis in the dermis in cicatricial lesions. ¹⁸⁴ A favorable prognostic feature is the presence of necrosis with a reactive response. ¹⁸⁸

There is usually a dense infiltrate of inflammatory cells in the upper dermis beneath an atrophic epidermis. ¹⁹⁴ Acanthosis is sometimes present. ²¹⁵ The infiltrate is composed of a variable admixture of macrophages, lymphocytes, plasma cells, and epithelioid cells. ²¹⁶ Occasional eosinophils can usually be found. Neutrophils are present in a few cases. ¹⁹⁷ There may be an occasional tuberculoid granuloma. In nodular lesions the infiltrate may occupy the entire thickness of the dermis. ¹⁹⁷ In patients with a neuropathy, the inflammatory cell infiltrate shows perineural accentuation. ²¹⁷ Follicular plugging is often present, particularly in lesions from the face. ¹⁹⁴ Organisms (Leishman–Donovan bodies) are nearly always present, but their number varies from case to case and from lesion to lesion. They may be visualized better in sections stained with Weigert iron hematoxylin than in those stained with hematoxylin and eosin or the Giemsa stain. ¹⁹⁷ An immunohistochemical method, using G2D10 antibody is a more sensitive method of detecting Leishman–Donovan bodies than H & E section. ²¹⁸ Immunohistochemistry shows a preponderance of CD3⁺ T cells. There are few B cells. ²¹⁵ There are conflicting reports on whether CD4⁺ cells or CD8⁺ cells predominate.^{215. and 219.}

There is a superficial and mid-dermal perivascular lymphohistiocytic infiltrate. In about half the cases parasites can be seen in the cytoplasm of macrophages, in the form of pseudocysts, or lying free in the dermis, ²²⁸ or rarely the epidermis, ²²⁴ in the form of trophozoites. Pseudoepitheliomatous hyperplasia may develop in a few cases. ²²⁸ The histology has resembled dermatomyositis in those cases presenting with a dermatomyositis-like syndrome. Some of the rare histological expressions of the disease have recently been reviewed. ²³³

The patient with the annular erythema referred to above had histopathological features said to be compatible with necrolytic migratory erythema. There was subcorneal pustulation with adjacent parakeratosis, but the vacuolated keratinocytes reported were difficult to see in the published photomicrograph. ²³⁴ Dermal inflammatory changes were superficial and mild.

Sections show perivascular mantles of amphophilic, foamy to finely stippled material similar to that seen in pulmonary pneumocystosis. ²³⁶ The methenamine silver stain may show large numbers of small cysts typical of Pneumocystis jiroveci. The other two structural forms of P. jiroveci, the intracystic sporozoite and the trophozoite (the encysted form), may be seen with polychrome stains such as the Giemsa or Wright stain. ²³⁷