1: Med Mol Morphol. 2006 Sep;39(3):164-8.

Immunohistochemical and ultrastructural investigation on cutaneous
neuroendocrine carcinoma: report of a case and review of the literature.

Ishii H, Joshita T, Matsuyama N, Uchida T, Ishikawa A, Ebihara Y.

Department of Pathology, Tokyo Medical University, 6-1-1 Shinjuku, Tokyo,
160-8402, Japan, hhishii@tokyo-med.ac.jp.

We report a tumor in an 80-year-old man that was difficult to distinguish from other tumors, i.e., small cell carcinoma of the lung, PNET/Ewing tumor, malignant lymphoma, or malignant melanoma (amelanotic), and which was finallynidentified as cutaneous neuroendocrine carcinoma using immunohistochemical and ultrastructural methods. Autopsy did not show any tumors in the lungs, excluding the possibility of small cell carcinoma of the lung. Immunohistochemistry tests gave negative results for LCA, UCHL-1, CD3, and CD20, thereby excluding malignant lymphoma, and the negative results for S-100 protein and HMB-45 ruled out malignant melanoma. The possibility of PNET/Ewing sarcoma was also excluded because of negativity for CD99. In addition, the ultramicrostructure showed intercellular junctional complexes and neuroendocrine granules, indicating that the tumor had characteristics of both epithelial and neuroendocrine tissues. We therefore diagnosed the primary carcinoma of the skin as cutaneous neuroendocrine carcinoma.

2: Arch Dermatol. 2006 Jun;142(6):685-90.

Sentinel lymph node biopsy for evaluation and treatment of patients with Merkel cell carcinoma: The Dana-Farber experience and meta-analysis of the literature.

Gupta SG, Wang LC, Penas PF, Gellenthin M, Lee SJ, Nghiem P.

Cutaneous Oncology Disease Center, Dana-Farber/Brigham and Women's Cancer Center, Boston, Mass., USA.

OBJECTIVE: To determine the diagnostic accuracy and usefulness of sentinel lymph node biopsy (SLNB) and computed tomographic scans in the initial evaluation and treatment of patients with Merkel cell carcinoma (MCC). DESIGN: Single-institution case series and literature-based case-level meta-analysis.
SETTING: Academic cutaneous oncology clinic.Patients Sixty-one adults with biopsy-proven MCC (30 who had undergone SLNB) plus 92 cases from the literature of patients who had undergone SLNB.
MAIN OUTCOME MEASURES: Relapse-free survival.
RESULTS: In 122 patients with no nodal disease found by physical examination, SLNB findings revealed nodal involvement in 39 cases (32%). At 3 years, the recurrence rate for those with a positive SLNB was 3 times (60%) higher than for those with a negative SLNB (20%; P = .03). Patients with a
positive SLNB who received adjuvant nodal therapy had a relapse-free survival rate of 51% at 3 years (n = 26) compared with 0% for patients who did not receive nodal therapy (n = 3; P < .01). In contrast, among patients with a negative SLNB there was no significant difference in 3-year relapse-free
survival rates for those who did (90%; n = 24) or did not (70%; n = 19; P = .26) receive adjuvant nodal therapy. Using SLNB plus clinical follow-up as a gold standard, computed tomographic scans had low sensitivity (20%) for detecting MCC that had spread to the lymph node basin and low specificity for distant disease (only 4 of 21 "positive" scans were confirmed during 6 months of follow-up).
CONCLUSIONS: Sentinel lymph node biopsy detects MCC spread in one third of patients whose tumors would have otherwise been clinically and radiologically understaged and who may not have received treatment to the involved node bed. There was a significant benefit of adjuvant nodal therapy, but only when the SLNB was positive. Thus, SLNB is important for both prognosis and therapy and should be performed routinely for patients with MCC. In contrast, computed tomographic scans have poor sensitivity in detecting nodal disease as well as poor specificity in detecting distant disease.

3: Laryngoscope. 2006 May;116(5):791-5.

Merkel cell carcinoma: does tumor size or depth of invasion correlate with recurrence, metastasis, or patient survival?

Sandel HD 4th, Day T, Richardson MS, Scarlett M, Gutman KA.

Department of Otolaryngology, Head and Neck Surgery, Georgetown University
Hospital, Washington, DC 20007, USA. dansandel@hotmail.com

OBJECTIVE: The objective of this retrospective study and literature review was to compare the clinical and histologic criteria including tumor size and depth of invasion with outcomes in patients with Merkel cell carcinoma. METHODS: The state cancer registry provided patients (n = 46) diagnosed with Merkel cell carcinoma from 1992 through 2002. Pathology slides were reviewed by the author for tumor size, depth of invasion, Clark level, and margin status. Further clinical information and survival data were gathered from patient records. Statistical analysis was performed using t tests and Kaplan-Meier survival curves. Patients were excluded from specific analysis based on misdiagnosis, unavailability of pathology slides, absent medical records, or those lost to follow up. RESULTS: Disease-free survival rates were 52%, 39%, and 9% at 1, 2, and 5 years, respectively. The average disease-free interval was 18.4 months (range, 1-80 months). No correlation was found between tumor size (P = .49), depth (P = .41), or Clark level (P = .82) to overall survival. A trend was found comparing tumor size or depth of invasion with local recurrence (P = .07) but with no correlation to regional recurrence (P = .93 and P = .60) or distant metastasis (P = .16 and P = .24). Overall recurrence was found in 60.7% of patients with local recurrence occurring in 18.1%, regional recurrence 40.9%, and distant recurrence 47.8%. Comparing patients with positive versus negative margins at initial excision, local recurrence was found in 33.3% versus 9.09% (P= .19), regional recurrence 66.6% versus 27.2% (P = .08), and distant metastasis 66.6% versus 45.4% (P = .36), respectively. CONCLUSIONS: No correlation was found between tumor size or depth of invasion to patient survival or metastasis. However, there was a trend toward increased local and regional recurrence rates when comparing size and depth and in specimens with positive tumor margins. These outcomes are consistent with those reported in recent literature and further characterize the unpredictable nature of this disease. An aggressive approach should be taken, including wide local excision with negative tumor margins and lymph node dissection; however, larger multistate reviews are needed for additional support.

4: Am J Dermatopathol. 2006 Apr;28(2):99-104.

Immunohistochemical distinction between merkel cell carcinoma and small cell carcinoma of the lung.

Bobos M, Hytiroglou P, Kostopoulos I, Karkavelas G, Papadimitriou CS.

Department of Pathology, Aristotle University Medical School, Thessaloniki,
Greece.

We assessed the usefulness of several immunohistochemical 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.

5: Eur J Nucl Med Mol Imaging. 2006 Apr;33(4):433-40. Epub 2006 Jan 24.

Impact of sentinel lymph node biopsy in patients with Merkel cell carcinoma: results of a prospective study and review of the literature.

Maza S, Trefzer U, Hofmann M, Schneider S, Voit C, Krossin T, Zander A, Audring H, Sterry W, Munz DL.

Clinic for Nuclear Medicine, Charite, Universitatsmedizin Berlin, Schumannstrasse 20-21, 10117, Berlin, Germany. sofianem@web.de

PURPOSE: Merkel cell carcinoma (MCC) is the most aggressive of the cutaneous malignancies, showing a propensity to spread to regional lymph nodes (LNs). The aim of this prospective study was to examine the feasibility and clinical impact of sentinel lymph node biopsy (SLNB) in this cutaneous malignancy. METHODS: The study population comprised 23 patients with stage I MCC (median age 70 years, range 50-85 years). Lymphoscintigraphic mapping with( 99 m)Tc-nanocolloid was performed in all patients. Sentinel lymph nodes (SLNs) were identified, excised and analysed in serial sections by conventional histopathology and cytokeratin-20 immunohistochemistry. RESULTS: Metastatic disease was determined in the SLNs of 11 patients (47.8%). Elective lymph node dissection (ELND) was performed in eight of these 11 patients, four of whom had additional positive LNs. During follow-up (median 36.1 months, range 3-79 months), seven of the 23 patients (30%) relapsed: four had a local recurrence and three, in-transit metastases. Recurrence developed in two SLN-negative patients with local LN metastases and in one SLN-positive patient with distant metastases. This patient died, representing the only tumour-related death in our sample. Median survival was 49.1 and 35.5 months for SLN-negative and SLN-positive patients, respectively. This difference was not statistically significant (p=0.3452). CONCLUSION: SLNB allows for exact nodal staging in patients with MCC. Whether additional ELND is of further benefit remains unclear.

6: Am J Dermatopathol. 2006 Apr;28(2):99-104.

7: Am J Surg Pathol. 2006 Mar;30(3):405-10.

Primary neuroendocrine carcinoma of the vagina with Merkel cell carcinoma phenotype.

Coleman NM, Smith-Zagone MJ, Tanyi J, Anderson ML, Coleman RL, Dyson SW, Reed JA.

Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA. ncoleman@bcm.tmc.edu

We describe a case of primary neuroendocrine carcinoma arising from the anterior vaginal wall of a 67-year-old woman. Primary neuroendocrine carcinoma of the vagina is a rare entity with only 25 previously reported cases in the literature. In previous reports, these tumors have not been distinguished from primary neuroendocrine carcinoma of the skin (Merkel cell carcinoma). The tumor was composed of cells that showed neuroendocrine-type nuclear features with hyperchromasia, nuclear molding, occasional small nucleoli, and a chromatin pattern that was finely granular. The tumor cells were positive for cytokeratin 20 (CK20), neuron specific enolase, pancytokeratin, epithelial membrane antigen, and chromogranin A expression. Ki-67, a marker of proliferation, was also positive in>90% of cells. The tumor cells showed intense expression of Bcl-2 oncoprotein and mild to moderate expression of c-KIT. Synaptophysin, neurofilament, CD45, CD56, CD10, S-100, HMB-45, cytokeratin 7, and thyroid transcription factor 1 were negative. This pattern of staining is consistent with a Merkel cell carcinoma. This is the first report of a primary neuroendocrine carcinoma of the vagina with a Merkel cell phenotype. Previous studies have not distinguished primary neuroendocrine carcinoma of the vagina from Merkel cell carcinoma of the skin. Positive expression of CK20 in primary small cell carcinoma of the vagina might represent a Merkel cell carcinoma subtype of this tumor.

8: Ultrastruct Pathol. 2005 May-Aug;29(3-4):287-94

Merkel cells, normal and neoplastic: an update.

Sidhu GS, Chandra P, Cassai ND.

The New York Harbor Healthcare System and New York University School of Medicine, New York, New York 10010, USA. deepsidhu@optoline.net

Merkel cells (MC) occur in the basal epidermal layer, hair follicles, and oral mucosa, as complexes with sensory axons. The axons transduce slowly adapting type I mechanoreception, and MC modulate their sensitivity. MC also determine and maintain the 3-dimensional epidermal structure. They have neuroendocrine granules, rigid spinous processes, and desmosomal junctions with each other and with keratinocytes. Rare MC are dermaWl. Current evidence supports a basal cell origin. Merkel cell carcinomas (MCC) occur mostly in sun-exposed skin in old age. Trabecular, intermediate, or small cell in pattern, MCC have neuroendocrine granules, intercellular junctions, rigid spinous processes, and a paranuclear collection of intermediate filaments staining for cytokeratin 20. Most MCC behave indolently, but those with the small cell pattern, and some with the intermediate pattern, are aggressive and rapidly fatal.

9: J Eur Acad Dermatol Venereol. 2005 Sep;19(5):546-51.

Merkel cell carcinoma: a clinicopathological study of 11 cases.

Acebo E, Vidaurrazaga N, Varas C, Burgos-Bretones JJ, Diaz-Perez JL.

Department of Dermatology, Hospital de Cruces, Barcaldo, Vizcaya, Spain.
eacebo@aedv.es

OBJECTIVE: To report our 12-year experience with Merkel cell carcinomas (MCCs) from a clinical and pathological point of view. SUBJECTS AND SETTING: Eleven MCCs were diagnosed at our institution between 1991 and 2002. METHODS: A retrospective clinical, histopathological and immunohistochemical study was performed. Age, gender, location, size, stage, treatment and follow-up data were collected. Histopathological pattern and immunohistochemical study with CAM 5.2, cytokeratin 20 (CK20), CK7, Ber EP4, neurofilaments, synaptophysin, chromogranin, S100 protein, p53 protein, CD117, leucocyte common antigen (LCA) and Ki-67 were accomplished. RESULTS: Six females and five males with a mean age
of 82 years were identified. Tumours were located on the face (n = 6), extremities (n = 3) and trunk (n = 1). At diagnosis, one patient was in stage Ia, six in stage Ib, three in stage II and one in stage III. All but one patient experienced wide surgical excision of the tumour. Additional treatment consisted of lymph node dissection in two patients, radiotherapy in four patients andsystemic chemotherapy in one patient. Local recurrence developed in five patients. Three patients died because of MCC after 14 months of follow-up. Intermediate-size round cell proliferation was found in all cases. Additional small-size cell pattern and trabecular pattern were observed in seven and sixcases, respectively. Eccrine and squamous cell differentiation were found in three cases. A dot-like paranuclear pattern was observed in all cases with CAM 5.2 and neurofilaments, and in 89% of cases with CK20. Seventy-five per cent ofcases reacted with Ber EP4, chromogranin and synaptophysin, 70% with p53, 22% with S100 protein, 55% with CD117 and none with LCA. Ki-67 was found in 75% of tumoral cells on average. Fifty per cent of MCCs reacted with CK7 and showedeccrine differentiation areas. CONCLUSIONS: MCC is an aggressive neuroendocrine tumour of the elderly. Wide surgical excision is the recommended treatment. Lymph node dissection, adjuvant radiotherapy and chemotherapy decrease regional recurrences but have not been demonstrated to increase survival. Immunohistochemically, MCC is an epithelial tumour with neuroendocrine features.