Trichilemmal carcinoma with neuroendocrine differentiation

We report a 12‐mm nodular, cream‐coloured skin lesion that appeared on the left nasal ala in an 81‐year‐old man. This trabecular infiltrative tumour showed keratin microcysts, stromal hyalization, cytoarchitectural malignancy features, colonizing melanocytes, and immunoexpression of epithelial membrane antigen, cytokeratin 15/20, chromogranin, synaptophysin and CD56. To our knowledge, this is the first documented case of a trichilemmal carcinoma with neuroendocrine differentiation and melanocyte colonization, which is suggested by the trabecular growth pattern and requires immunohistochemical confirmation. The colonization of the epithelial nests by nonatypical dendritic or spindle melanocytes is a clue to morphological recognition of pilar neoplasms, along with the presence of stromal induction (CD34‐positive peritumoral spindle cells), catagen‐like apoptotic bodies, calcifications, keratin microcysts and cell balls.

Skin adnexal tumours are rare entities causing diagnostic dilemmas in histopathological practice, for which the pattern recognition is diagnostically essential. 1 Helpful clues include the presence of intracellular and intercellular lumina containing diastase-resistant, periodicacid-Schiff (PAS)-positive material (ductal tumours), vacuolated epithelial cells with nuclear indentations (sebaceous tumours) and pilar elements (tumours with hair follicle differentiation). Adnexal neoplasms with pilar differentiation are the most elusive, often diagnosed as basal cell, squamous cell or undifferentiated carcinomas. The pilar differentiation is suggested by the presence of PAS-positive hyalinized stromal changes around the epithelial nests, keratinous microcysts and ⁄ or cell 'balls' with or without peripheral nuclear palisading, and changes in the eosinophils and clear cytoplasm. 1,2 Features suggestive of pilar differentiation and malignancy criteria have been reviewed in detail elsewhere. [3][4][5][6] The presence of melanocytes within various tumours has been reported, but they are almost always present in tumours with pilar differentiation. 2 The terms 'pigmented' or 'melanocyte-containing' tumours have been used to describe 'new' entities or variants that occur when the number of melanocytes is increased in an otherwise conventional and well-recognized entity. 7 We present a trichilemmal carcinoma with neuroendocrine differentiation and melanocyte colonization, discussing useful features to recognize its differentiation. Features helpful to diagnosis of skin adnexal tumours with epithelial pilar differentiation are outlined, in particular for cases with other lines of differentiation that may cause further diagnostic difficulties.

Report
The patient was an 81-year old man, who presented with a 12-mm nodular, cream-coloured skin lesion on the left ala of nose of unknown duration. The clinical diagnosis was of basal cell carcinoma. The specimen was routinely processed, inking the margins and serially sectioning the 20-mm area containing the lesion, which was 5 mm from the closest lateral margin.
The tumour showed infiltrative growth in trabeculae and strands, and contained keratin cysts and hyalinized stroma ( Fig. 1). Cytologically, there was marked nuclear pleomorphism, small but distinct nucleoli and focal clear-cell changes. Numerous mitotic figures including abnormal forms were evident as were focal areas of necrosis. Another sparse population of spindle-shaped melanocytes was also noted within the tumour islands.
The tumour had an infiltrative pattern with foci of necrosis, pleomorphic cells and atypical mitoses, suggesting a malignant neoplasm, and showed evidence of pilar differentiation, i.e. keratin cysts, peritumoral hyalinized stroma with CD34+ spindle cells, and tumour cells positive for CK15, CK20 and EMA (the latter previously reported occurring focally). 3 Tumour cells were focally positive for neuroendocrine markers (chromogranin, synaptophysin and CD56). The diagnosis was trichilemmal carcinoma with neuroendocrine differentiation.
Neuroendocrine differentiation has not previously been reported in pilar neoplasms, with the exception of trichogerminoma. 8 This neuroendocrine differentiation has been correlated with vascular endothelial growth factor and transforming growth factor-a immunoexpression in carcinomas. These two angiogenic factors may aid the neovascularization of carcinomas, and their increased expression in tumour-associated neuroendocrine cells may contribute to a more aggressive phenotype in several types of tumour. 9 Primary cutaneous neuroendocrine (Merkel cell) carcinomas mainly present as dermal and subcutaneous masses in the sun-exposed skin of elderly patients. They show generally monomorphic cells with foci of pronounced pleomorphism. These tumours are heterogeneous and can occur in intimate association with carcinomas (particularly squamous and eccrine types). 10 Merkel cell carcinomas have also been reported associated with a trichilemmal cyst, showing pagetoid spread into the trichilemmal epithelium and other cutaneous malignancies. 11 The association of Merkel cell carcinomas with other adnexal lesions and their dermal location strengthen the hypothesis of an origin   from pluripotent stem cells of adnexal epithelium. 11 In the case reported here, malignant cells showed a predominant pilar differentiation with only focal neuroendocrine features (Table 1). Abnormal differentiation has been inversely correlated with malignancy and precancerous lesions; progressive undifferentiation is often associated with advanced tumour stages and divergent differentiation is not unusual in a variety of poorly differentiated malignant tumours (e.g. breast ductal carcinoma, gastrointestinal adenocarcinomas or desmoplastic small round cell tumour). The neuroendocrine differentiation is important, because these tumours have been reported to be resistant to chemotherapy.
The presence of melanocytes in epithelial tumours is relatively rare in cutaneous or extracutaneous neoplasms. The systematic presence of nonatypical spindle melanocytes in pilar neoplasms questions the separation of pigmented pilar neoplasms as independent entities. 2,7 These conditions probably represent extreme forms of melanocyte colonization of epithelial pilar tumours and do not merit creation of 'new' entities such as 'pigmented' or 'melanocyte-containing' tumours. 2 The most important issue is to determine if the melanocytic component shows evidence of dysplasia or malignancy using standard criteria. 12,13 Dysplastic and malignant changes may occur in the melanocytic component of epithelial pilar neoplasms and would explain the description 'biphasic neoplasms'. 7,14 Melanocytes are found within the epithelial nests of epithelial pilar tumours (both benign and malignant), 2 and can be used as a clue to the recognition of this differentiation in the absence of clinical pigmentation or epithelial cell melanin during histological examination. 2 Melanocytes are rarely identified in other cutaneous epithelial tumours, and are normally associated with clinical and or histological pigmentation.
In conclusion, neuroendocrine differentiation in trichilemmal carcinomas is suggested by a trabecular growth pattern and requires immunohistochemical confirmation. The colonization of the epithelial nests by nonatypical dendritic ⁄ spindle melanocytes is a clue to the morphological recognition of pilar neoplasms, along with the presence of stromal induction, catagenlike apoptotic bodies, calcification, keratin microcysts and cell balls. This feature lends the tumours a heterogeneous appearance, containing tumour cells and dendritic cells that may be pigmented.