Immunohistochemical Distinction Between Merkel Cell Carcinoma and Small Cell Carcinoma of the Lung Mattheos Bobos, MD, Prodromos Hytiroglou, MD, Ioannis Kostopoulos, MD, Georgios Karkavelas, MD, and Constantine S. Papadimitriou, MD Abstract: We assessed the usefulness of several immunohisto- chemical stains in distinguishing these two neoplasms, including cytokeratin 7, cytokeratin 20 (CK20), neuron-specific enolase, chromogranin, synaptophysin, neurofilaments (NF), thyroid- transcription factor-1 (TTF-1), CD56 antigen, S-100 protein, vimentin, c-erbB-2 oncoprotein, and CD117 antigen. All 13 cases of Merkel cell carcinoma evaluated were positive for CK20, and negative for TTF-1. Twelve of 13 Merkel cell carcinoma cases were positive for NF. Eleven of 13 cases of small cell lung carcinoma were positive for TTF-1. All small cell lung carcinoma cases were negative for NF, and all but one were negative for CK20. In terms of the remaining antigens, there were no differences of significance between the two neoplasms. These findings suggest that a set of three immunohistochemical stains, including CK20, NF, and TTF-1, is useful in affording a distinction between Merkel cell carcinoma and small cell lung carcinoma. Key Words: cytokeratin 20, Merkel cell carcinoma, neurofila- ments, small cell lung carcinoma, thyroid transcription factor-1 (Am J Dermatopathol 2006;28:99–104) M erkel cell carcinoma (MCC) is a rare primary neuroendocrine tumor of the skin, usually occur- ring in elderly patients, and characterized by an aggres- sive biologic behavior. 1–4 This neoplasm histologically resembles other more common neuroendocrine tumors originating in various organs, most notably the lung. Therefore, issues of differential diagnosis often arise when a pathologist encounters a tumor with neuroendocrine features in the skin (MCC versus metastatic neuroendo- crine carcinoma) or a neuroendocrine tumor with features suggestive of MCC in internal organs. Merkel cell carcinoma is derived from Merkel cell, a unique epidermal cell that was first described as a tactile cell (Tastzelle) by Friedrich Merkel in 1875. This tumor was named ‘‘Merkel cell carcinoma’’ by De Wolf-Peeters et al in 1980. 5 Merkel cells are believed to be of neuroectodermal origin, 2 and are found in the basal layer of the epidermis as single cells. They also form aggregates in the tactile hair discs of Pinkus where they function as slowly adapting type I mechanoreceptors. 2 The first description of a neoplasm composed of these cells was made by Toker in 1972, as a malignant skin tumor with trabecular architecture, presumably originating from sweat glands. 6 In 1978, Tang and Toker 7 demonstrated ultrastructurally the presence of dense core granules in 3 cases of MCC. The histogenesis of this tumor from Merkel cells has been supported by the recently described intraepidermal development of MCC lacking a dermal component, 8–10 as well as by the detection of intraepi- dermal spread in various cases of MCC. 3 On immunohistochemical assessment, Merkel cells have been found to express a variety of neuroendo- crine markers, including neurofilaments, 11,12 neuron specific enolase, 13 chromogranin A, 14 neural cell adhesion molecule (NCAM/CD56), 14,15 synaptophysin, 16,17 soma- tostatin, 17 bombesin, and vasoactive intestinal peptide. 13 MCCs have been reported to express all the above markers, as well as other neuropeptides, such as ACTH, leu-enkephalin, gastrin, 13 secretogranin II, 3 and chromo- granin B. 18,19 Differential diagnosis between MCC and metastatic small cell lung carcinoma (SCLC) has significant prog- nostic and therapeutic implications. Recent reports indicate that immunohistochemistry can be useful in affording a distinction. 20–27 In the present study, we have assessed the usefulness of a variety of antibodies in the differential diagnosis between MCC and SCLC. MATERIALS AND METHODS We used 13 archival cases of MCC and 13 cases of SCLC from the Department of Pathology of the Aristotle University Medical School. Patient demographics and exact anatomic location of each tumor are shown in Table 1. The diagnosis was based on tumor location, clinical and radiologic information, as well as routine histologic and immunohistochemical findings. All patients with MCC had skin tumors, whereas the SCLC patients either had lung and mediastinal tumors, or lymph node metastases plus radiologic evidence of lung tumor. The SCLC cases were classified as either classic type, or mixed small cell/large cell type, according to the WHO classification. 28 Copyright r 2006 by Lippincott Williams & Wilkins From the Department of Pathology, Aristotle University Medical School, Thessaloniki, Greece. Reprints: Prodromos Hytiroglou, Department of Pathology, Aristotle University Medical School, 540 06 Thessaloniki, Greece (e-mail: phitir@med.auth.gr). ORIGINAL ARTICLE Am J Dermatopathol  Volume 28, Number 2, April 2006 99