Case 6 -

Merkel Cell Carcinoma with Pagetoid Growth Pattern Steve Billings University of Indiana School of Medicine Indianapolis, IN

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Diagnosis: Merkel cell carcinoma with pagetoid growth pattern Clinical Features Merkel cell carcinoma (MCC) typically occurs on sun-damaged skin of elderly patients, most commonly on the head and neck and extremities. Rare locations include the trunk, genitalia or mucosal sites. Clinically, MCC are not distinctive. Most commonly MCC presents as an erythematous nodule 2 cm or less in diameter, but they may be violaceous, flesh-colored or clinically appear pigmented. Case 6 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 6 - Figure 1 Scanning magnification demonstrated a tumor that involved both the epidermis and dermis. Case 6 - Figure 2 The tumor had a distinctly nested growth pattern. Case 6 - Figure 3 Within the epidermis the tumor showed prominent upward pagetoid spread of tumor nests and individual tumor cells. Case 6 - Figure 4 The tumor cells had uniform round to oval nuclei with a granular chromatin pattern. Microscopic Features MCC is a primary cutaneous neuroendocrine carcinoma characterized by a proliferation of relatively uniform round to oval tumor cells with scant cytoplasm and a stippled chromatin pattern. Mitotic activity is usually prominent and individual apoptotic cells are frequent. MCC has a variety of growth patterns. Most commonly MCC is a dermal tumor arranged in sheets or nests of tumor cells. Rarely, a trabecular pattern as seen in other neuroendocrine tumors may be seen. Involvement of the epidermis may be seen in up to 10% of cases. In rare cases the epidermal involvement has a distinctive pagetoid growth pattern analogous to true Paget's or extramammary Paget's disease. Within the epidermis there are small nests and single tumor cells at various levels of the epidermis that compress adjacent keratinocytes. In nests along the basal layer, there is usually a thin rim of basal cells separating the MCC from the underlying basement membrane. Rarely true junctional nests are present. The majority of MCC with pagetoid growth pattern have a significant dermal component, but the proportion between the dermal and epidermal component can be quite variable with some cases showing predominantly intraepidermal tumor. The intraepidermal pattern can be overemphasized in shallow shave biopsy specimens. A component of actinic keratosis, squamous cell carcinoma, or invasive squamous cell carcinoma may be seen in association with MCC, including pagetoid MCC. These different components may be adjacent to the MCC or be admixed with MCC. Immunohistochemistry Immunohistochemistry is often critical in the diagnosis of MCC. The vast majority of MCC express cytokeratin 20 (CK20). Classically this is manifested in a peri-nuclear dot-like pattern, but many cases will show more diffuse cytoplasmic staining. Rare cases of MCC are negative for CK20. 'Pan-keratin' stains can highlight MCC in a similar pattern as immunohistochemical stains for CK20. As expected, MCC express specific neuroendocrine markers such as chromogranin and synaptophysin in the great majority of cases (>80%). Some cases will only express one of these markers. Neurofilament protein is expressed in greater than 90% of cases, often in a dot-like pattern similar to the pattern of CK20 expression. MCC also expresses neuron specific enolase (NSE), but, with the advent of more specific neuroendocrine markers such as chromogranin, this is largely of historic interest. MCC is negative for S100 protein and TTF-1, as discussed in more detail below. Differential Diagnosis Metastatic Small Cell Carcinoma: The primary entity in the differential diagnosis in the majority of cases of MCC is metastatic small cell carcinoma of the lung. Histologically they can be essentially indistinguishable and immunohistochemical stains are critically important in resolving this question. Both express typical neuroendocrine markers such as synaptophysin, chromogranin, and NSE. MCC express CK20 whereas most metastatic small cell carcinomas are negative for this marker. As a caveat, approximately 1-3% of small cell carcinomas express CK20 and in one series up to 8% of metastatic small cell carcinomas were positive. Expression of thyroid transcription factor-1 (TTF-1) is seen in greater than 80% of metastatic small cell carcinomas of the lung. TTF-1 expression has not been described in MCC. Neurofilament protein expression, present in MCC, is not seen in metastatic small cell carcinoma. Merkel cell carcinoma vs. metastatic small cell carcinoma Immunohistochemical Stain Merkel Cell Carcinoma Metastatic Small Cell Carcinoma CK20 + -/+ (rare positive cases) TTF-1 - + Neurofilament Protein + - Chromogranin + + Synaptophysin + + Melanoma: In MCC with pagetoid spread, melanoma needs to be considered in the differential diagnosis. There are subtle differences in the growth pattern. Pagetoid MCC does not typically have areas with a prominent single cell growth pattern along the basal layer, and the epidermal nests are usually separated from the basement membrane by compressed keratinocytes. Cytologically, MCC lack the prominent nucleoli and intranuclear cytoplasmic inclusions often seen in melanoma. Melanin pigment, when present, also helps distinguish melanoma from MCC. In equivocal cases immunoreactivity for S100 protein or melanocytic specific markers (e.g. HMB45) will distinguish melanoma from MCC. Pagetoid Squamous Cell Carcinoma in Situ/poorly Differentiated Squamous Cell Carcinoma: Squamous cell carcinoma (SCC) can have a pagetoid growth pattern in the epidermis characterized by small nests and single atypical squamous cells. The tumor cells have more abundant eosinophilic cytoplasm and intercellular bridges can usually be seen with careful examination under high magnification. The tumor cells do not have the stippled chromatin pattern of MCC. It is important to keep in mind that MCC can have an associated SCC in situ or invasive SCC component. The MCC component will likely drive the behavior of the neoplasm and therefore management strategies may be significantly different with consideration of sentinel lymph node biopsy and possibly adjuvant radiation therapy. In tumors with mixed patterns, it is probably prudent to confirm the diagnosis of MCC with immunohistochemical stains (i.e. CK20, neuroendocrine markers, neurofilament protein). Paget's/Extramammary Paget's disease: The distinction of pagetoid MCC from mammary or extramammary Paget's disease is usually not difficult owing to their distinctly different clinical settings. Mammary Paget's disease presents on the nipple and extramammary Paget's usually presents in the anogenital region. Rare cases of Merkel cell carcinoma have been described in these areas, however. Mammary and extramammary Paget's disease are essentially identical from the histologic standpoint. Both have an intraepidermal proliferation of neoplastic cells arranged in nests or individual cells within the dermis. Either may show an underlying invasive carcinoma, but this is more common in mammary Paget's disease. The growth pattern is similar to pagetoid MCC, but the cytologic features are distinct from MCC. The tumor cells in Paget's disease have relatively abundant, lightly eosinophilic cytoplasm. The nuclei are large and often have prominent nucleoli. Some tumor cells have intracytoplasmic vacuoles imparting signet-ring morphology. In questionable cases, histochemical and immunohistochemical stains can distinguish mammary or extramammary Paget's disease from pagetoid MCC. Mucicarmine stains can highlight mucin production in the tumor cells of Paget's disease. By immunohistochemistry, Paget's disease is usually immunoreactive for cytokeratin 7 (CK7) but negative for CK20. An exception is perianal extramammary Paget's disease associated with underlying rectal carcinoma. In this setting the Paget cells typically express CK20 and may or may not express CK7. MCC does not express CK7, but normal Merkel cells may express this marker. Therefore it is not inconceivable that MCC could rarely express CK7. CDX-2, a homeobox gene expressed by nuclei of gastrointestinal epithelium and neoplasms, is positive in perianal Paget's disease associated with rectal carcinoma. CEA and EMA are expressed by Paget cells, but expression of these markers is also seen in MCC and is therefore not useful in the differential diagnosis. Diffuse Large Cell B-cell lymphoma: Diffuse large cell B-cell lymphoma (DLCBCL) can sometimes be considered in the differential diagnosis of MCC. The nuclei often have a vesicular chromatin pattern and large nucleoli. DLCBCL lack CK20 expression and do not express neuroendocrine markers while they are positive for lymphoid markers (e.g. LCA, CD20). Mycosis Fungoides: In rare cases of pagetoid MCC, mycosis fungoides could be considered. The tumor cells in mycosis fungoides have more cerebriform nuclei, surrounding clear halos and lack the cohesion of the pagetoid nests of MCC. Immunoreactivity for lymphocytic markers easily allows distinction if necessary. Prognosis and Treatment: MCC is well known for the risk of local recurrence and relatively high risk of metastasis. The most comprehensive outcome study was from Memorial Sloan-Kettering Cancer center by Allen, et al in 2005. Disease stage was the single independent predictor of survival. Stage I disease, defined as tumor <2 cm without lymph node involvement, had a 5-year survival rate of 81%. Stage II disease, defined as tumor ≥ 2 cm without lymph node involvement was 67%. Stage III disease, defined as any lymph node involvement, had a survival rate of 52%. Stage IV disease, defined as the presence of distant metastasis, had a very poor outcome with a 5-year survival rate of 11%. Sentinel lymph node biopsy significantly improved staging and should be considered in all patients with MCC. Surgery is the mainstay of therapy. Adjuvant radiation has been utilized with differing results. Some have shown a decreased risk of local recurrence while others have demonstrated no such value when negative surgical margins were achieved. Chemotherapy has not been shown to offer a survival advantage. Selected References LeBoit PE. Crutcher WA. Shapiro PE. Pagetoid intraepidermal spread in Merkel cell (primary neuroendocrine) carcinoma of the skin. American Journal of Surgical Pathology. 16(6):584-92, 1992 Jun. Bobos M. Hytiroglou P. Kostopoulos I. Karkavelas G. Papadimitriou CS. Immunohistochemical distinction between Merkel cell carcinoma and small cell carcinoma of the lung. American Journal of Dermatopathology. 28(2):99-104, 2006 Apr. Best TJ. Metcalfe JB. Moore RB. Nguyen GK. Merkel cell carcinoma of the scrotum. Annals of Plastic Surgery. 33(1):83-5, 1994 Jul. Asioli S. Dorji T. Lorenzini P. Eusebi V. Primary neuroendocrine (Merkel cell) carcinoma of the nipple. Virchows Archiv. 440(4):443-4, 2002 Apr. Lewis KG. Weinstock MA. Weaver AL. Otley CC. Adjuvant local irradiation for Merkel cell carcinoma. Archives of Dermatology. 142(6):693-700, 2006 Jun. Gupta SG. Wang LC. Penas PF. Gellenthin M. Lee SJ. Nghiem P. Sentinel lymph node biopsy for evaluation and treatment of patients with Merkel cell carcinoma: The Dana-Farber experience and meta-analysis of the literature. Archives of Dermatology. 142(6):685-90, 2006 Jun. Poulsen MG. Rischin D. Porter I. Walpole E. Harvey J. Hamilton C. Keller J. Tripcony L. Does chemotherapy improve survival in high-risk stage I and II Merkel cell carcinoma of the skin? International Journal of Radiation Oncology, Biology, Physics. 64(1):114-9, 2006 Jan 1. Allen PJ. Bowne WB. Jaques DP. Brennan MF. Busam K. Coit DG. Merkel cell carcinoma: prognosis and treatment of patients from a single institution. Journal of Clinical Oncology. 23(10):2300-9, 2005 Apr 1. Al-Ahmadie HA. Mutasim DF. Mutema GK. A case of intraepidermal Merkel cell carcinoma within squamous cell carcinoma in-situ: Merkel cell carcinoma in-situ? American Journal of Dermatopathology. 26(3):230-3, 2004 Jun. Scott MP. Helm KF. Cytokeratin 20: a marker for diagnosing Merkel cell carcinoma. American Journal of Dermatopathology. 21(1):16-20, 1999 Feb. Schmidt U. Muller U. Metz KA. Leder LD. Cytokeratin and neurofilament protein staining in Merkel cell carcinoma of the small cell type and small cell carcinoma of the lung. American Journal of Dermatopathology. 20(4):346-51, 1998 Aug. Chan JK. Suster S. Wenig BM. Tsang WY. Chan JB. Lau AL. Cytokeratin 20 immunoreactivity distinguishes Merkel cell (primary cutaneous neuroendocrine) carcinomas and salivary gland small cell carcinomas from small cell carcinomas of various sites. American Journal of Surgical Pathology. 21(2):226-34, 1997 Feb. Leech SN. Kolar AJ. Barrett PD. Sinclair SA. Leonard N. Merkel cell carcinoma can be distinguished from metastatic small cell carcinoma using antibodies to cytokeratin 20 and thyroid transcription factor 1. Journal of Clinical Pathology. 54(9):727-9, 2001 Sep. Iacocca MV. Abernethy JL. Stefanato CM. Allan AE. Bhawan J. Mixed Merkel cell carcinoma and squamous cell carcinoma of the skin. Journal of the American Academy of Dermatology. 39(5 Pt 2):882-7, 1998 Nov.