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We used optimized immunohistochemistry (IHC) with the D5F3 antibody for detection of tumours in a prospective study of 307 pulmonary adenocarcinomas. Cases positive by IHC (1+, 2+, 3+) were further investigated by fluorescent in situ hybridization (FISH). Of 307 cases, 22 (7.2%) were moderately intensely positive (2+/3+); 18 of these (82%) were also positive by FISH. Of the four IHC-positive/FISH-negative cases, one was unsuitable for FISH and three had abnormalities of the ALK gene. All cases with weak reactivity with D5F3 (1+) were FISH-negative. The FISH positive/IHC-positive cases with moderately intense reactivity had the typical clinicopathologic features of ALK-positive patients (younger age, p

Melanocytic differentiation has been described in rare cases of melanin-containing neuroendocrine tumours of the lung [1–5], thyroid [6] and thymus [7]. In some of the cases, neuroendocrine granules and melanosomes were lying free in the cytoplasm of tumour cells, thus indicating true coexpression of melanocytic and neuroendocrine differentiation. On the other hand, neuroendocrine differentiation, consisting in the presence of neuroendocrine granules at ultrastructural level and of intense immunostaining for chromogranin-A and synaptophysin, was described in three cases of cutaneous and mucosal malignant melanomas [8]. Divergent differentiation towards unrelated embryological tissue has been reported in malignant melanoma [9]. So far, cases of neuroendocrine carcinoma with associated melanomatous component in the lung have not been described. There is growing evidence that tumour development may derive from neoplastic transformation of adult stem cells [10]. In a recent publication, it was reported that in the human skin there is a SOX2-positive stem cell capable of differentiation along the neuroendocrine or melanocytic lines [11]. In the present report, we describe the first case of a malignant neoplasm of the lung showing unambiguous differentiation towards neuroendocrine carcinoma and malignant melanoma.