Merkel cell carcinoma

Merkel cell carcinoma is a rare, highly aggressive neuroendocrine cutaneous neoplasm with a variable clinical presentation. Histologically, it is a predominantly dermal-based lesion composed of monotonous small round cells with scanty cytoplasm, often difficult to differentiate from small round cell tumors, metastatic small cell carcinoma, blastic hematologic malignancies, and melanoma. The malignant cells express both epithelial and neuroendocrine immunohistochemical markers, a unique feature that helps differentiate this neoplasm from other entities. The pathogenesis of Merkel cell carcinoma has remained a mystery despite its association with various chromosomal abnormalities and with growth signaling and apoptotic pathways. The discovery of the Merkel cell polyomavirus suggests another clue to its pathogenesis. This virus integrates into band 3p14 and promotes carcinogenesis by altering the activity of tumor suppressor and cell cycle regulatory proteins. This discovery of the Merkel cell polyomavirus may greatly enhance our understanding of this rare aggressive neoplasm and allow further advancements in treatment.     

Cytogenetic study of a Merkel cell carcinoma

Banded karyotypes from two metastatic sites of a Merkel cell carcinoma were analyzed. The results indicate very close similarity between the two specimens including an overall tendency to triploidy and the same five marker chromosomes. One of the markers represented by two copies in most of the karyotyped cells was 1q−.     

Merkel cell carcinoma: a case report

Merkel cell carcinoma is an uncommon, highly malignant, primary cutaneous neuroendocrine tumour mostly occurring as a solitary nodule on the head or on the extremities. It has high recurrence rate. We hereby report a case of Merkel cell carcinoma in a young woman.     

Genetic variability and integration of Merkel cell polyomavirus in Merkel cell carcinoma

Puumala (PUUV) and Hantaan (HTNV) viruses are hantaviruses within the family Bunyaviridae and associated with Hemorrhagic Fever with Renal Syndrome (HFRS) in humans. Little is known about how these viruses interact with host cells, though pathogenic hantaviruses interact with α_vβ₃ integrin. To study host cell interactions and rapidly test the ability of antibodies to prevent infection, we produced HTNV and PUUV pseudovirions on a vesicular stomatitis virus (VSV) core. Similar to replication-competent hantaviruses, infection was low-pH-dependent. Despite broad cell tropism, several human T cell lines were poorly permissive to hantavirus pseudovirions, compared to VSV, indicating a relative block to infection at the level of entry. Stable expression of α_vβ₃ integrin in SupT1 cells did not restore infectivity. Finally, the pseudovirion system provided a rapid, quantitative, and specific method to screen for neutralizing antibodies in immune sera.     

Detection of Merkel cell polyomavirus in Merkel cell carcinoma and Kaposi's sarcoma

Merkel cell carcinoma is a rare malignancy that sometimes occurs in the skin of elderly people. Recently, a new human polyomavirus, Merkel cell polyomavirus (MCPyV) was identified in Merkel cell carcinoma. In the present study, MCPyV‐DNA was detected in 6 of 11 (55%) cases of Merkel cell carcinoma by nested PCR and real‐time PCR. Histologically, MCPyV‐positive cases showed round and vesicular nuclei with a fine granular chromatin and small nucleoli, whereas MCPyV‐negative cases showed polygonal nuclei with diffusely distributed chromatin. Real‐time PCR analysis to detect the MCPyV gene revealed that viral copy numbers ranged 0.04–0.43 per cell in cases of Merkel cell carcinoma. MCPyV was also detected in 3 of 49 (6.1%) cases of Kaposi's sarcoma (KS), but not in 192 DNA samples of other diseases including 142 autopsy samples from 20 immunodeficient patients. The MCPyV copy number in KS was lower than that in Merkel cell carcinoma. PCR successfully amplified a full‐length MCPyV genome from a case of KS. Sequence analysis revealed that the MCPyV isolated from KS had 98% homology to the previously reported MCPyV genomes. These data suggest that the prevalence of MCPyV is low in Japan, and is at least partly associated with the pathogenesis of Merkel cell carcinoma. J. Med. Virol. 81:1951–1958, 2009. © 2009 Wiley‐Liss, Inc.     

Tenascin-C in primary Merkel cell carcinoma

BACKGROUND/AIMS: Merkel cell carcinoma (MCC) is a rare malignant cutaneous neuroendocrine tumour that mostly affects the elderly. It shows rapid progression of the primary tumour, together with a vertical growth pattern into the underlying subcutaneous tissue. Metastatic dissemination to regional lymph nodes is early and frequent. Tenascin-C (Tn-C) is a large extracellular matrix glycoprotein that is expressed in various benign and malignant processes. Expression of Tn-C is also associated with invasion and cellular proliferation, and is often downregulated in fully evolved advanced carcinomas. In previous studies, Tn-C expression correlated with prognosis in tumours of different origin. METHODS: Immunohistochemistry was used to investigate the expression of Tn-C in 25 MCC specimens and to evaluate the prognostic importance of this glycoprotein. RESULTS: Seventeen samples expressed Tn-C. Staining was mainly seen in the invasion borders and within the connective tissue septae inside the tumours. The expression of Tn-C correlated significantly with large tumour size. There was also frequent expression of Tn-C in primary tumours with metastatic dissemination. Most of the Tn-C negative samples were of small size. CONCLUSIONS: Tn-C expression seems to increase with tumour size and malignant behaviour. Expression was slightly enhanced in tumours with high proliferative indices. Expression is seen mainly in areas of invasive growth and, in this respect, resembles that of other invasive tumours.     

Merkel cell carcinosarcoma: Merkel cell carcinoma with embryonal rhabdomyosarcoma-like component

Merkel cell carcinoma is an uncommon primary neuroendocrine neoplasm of the skin that may exhibit divergent differentiation. However, rhabdomyosarcomatous differentiation has only been rarely described and takes the form of isolated rhabdomyoblasts. We describe a case of cutaneous Merkel cell carcinoma with biphasic morphology imparted by discrete patches of embryonal rhabdomyosarcoma-like spindle cells alternating with islands of neuroendocrine small round cells, justifying a designation of "Merkel cell carcinosarcoma." The former component showed positive immunostaining for desmin and myogenin; and the later component, pan-cytokeratin, cytokeratin 20, synaptophysin, and chromogranin. The patient was an elderly man who presented with a temporal skin mass, and the biphasic morphology was evident in the recurrence and metastasis that developed 2 months after incomplete excision of the skin lesion.     

Association of Merkel cell polyomavirus infection with morphologic differences in Merkel cell carcinoma

Recently, it has been shown that approximately 80% of Merkel cell carcinomas harbor a novel polyomavirus named Merkel cell polyomavirus, thought to be a carcinogenic agent. However, it is not fully elucidated whether Merkel cell carcinomas differ with regard to the presence or absence of Merkel cell polyomavirus. To address this, we investigated morphologic differences between Merkel cell polyomavirus-positive and -negative Merkel cell carcinomas by morphometry. Using polymerase chain reaction and real-time quantitative polymerase chain reaction, Merkel cell polyomavirus was detected in 20 (77%) of 26 Merkel cell carcinoma cases, including 4 Merkel cell carcinomas combined with squamous cell carcinomas. Interestingly, Merkel cell polyomavirus was detected only in ordinary (pure) Merkel cell carcinomas; none of the 4 combined Merkel cell carcinomas + squamous cell carcinomas was positive for Merkel cell polyomavirus (P = .001). Morphometric analyses revealed that Merkel cell polyomavirus-negative Merkel cell carcinomas had more irregular nuclei (P < .001) and more abundant cytoplasm (P = .001) than Merkel cell polyomavirus-positive Merkel cell carcinomas, which had uniform round nuclei and scant cytoplasm. Reliability of the morphometry was confirmed using intraobserver and interobserver reliability tests. These results demonstrated statistically significant differences in tumor cell morphology between Merkel cell polyomavirus-positive and -negative Merkel cell carcinomas and reconfirmed the absence of Merkel cell polyomavirus in combined tumors. Furthermore, the results strongly suggest fundamental biological differences between Merkel cell polyomavirus-positive and -negative Merkel cell carcinomas, supporting that Merkel cell polyomavirus plays an important role in the pathogenesis of Merkel cell polyomavirus-positive Merkel cell carcinoma.     

Nuclear localization of Merkel cell polyomavirus large T antigen in Merkel cell carcinoma

To clarify whether mutations in the large T gene encoded by Merkel cell polyomavirus affect the expression and function of large T antigen in Merkel cell carcinoma cases, we investigated the expression of large T antigen in vitro and in vivo. Immunohistochemistry using a rabbit polyclonal antibody revealed that large T antigen was expressed in the nuclei of Merkel cell carcinoma cells with Merkel cell polyomavirus infection. Deletion mutant analyses identified an Arg-Lys-Arg-Lys sequence (amino acids 277-280) as a nuclear localization signal in large T antigen. Sequence analyses revealed that there were no mutations in the nuclear localization signal in any of the eleven Merkel cell polyomavirus strains examined. Furthermore, stop codons were not observed in the upstream of the nuclear localization signal in any of the Merkel cell carcinoma cases examined. These data suggest that the nuclear localization signal is highly conserved and functional in Merkel cell carcinoma cases.     

Cytogenetic study in a bone marrow metastatic Merkel cell carcinoma

We report an additional cytogenetic study of a metastatic Merkel cell carcinoma. Even though the cells analyzed were from a metastatic lesion, chromosomal abnormalities were not complex. Similarities between cytogenetic findings described in small-cell lung carcinoma and the present case are observed. However, further studies are needed to define the relationship between these two neuroendocrine small-cell malignancies.     

Trisomy 6 in Merkel cell carcinoma: a recurrent chromosomal aberration

We retrospectively investigated 17 cases of primary and metastasizing Merkel cell carcinomas (MCC) from 14 patients using chromosomal in-situ hybridization (CISH) to study the occurrence of trisomy 6 in these lesions. METHODS AND RESULTS: Histological diagnosis on all tumour samples was obtained on haematoxylin and eosin stained sections. Immunohistochemistry was performed with antibodies against pancytokeratin (CAM 5.2), cytokeratin 20 (CK20), MIC2 antigen (CD99), neuron-specific enolase (NSE), and chromogranin A (chrA). Sections (4 microm) of the paraffin-embedded tumours were analysed with alpha-satellite centromeric probes for chromosome 6 or 17 using CISH. The signal was amplified by the Tyramide Signal Amplification (TSA) assay. Immunohistochemically, the tumours showed the same general epithelial neuro-endocrine pattern: 11/13 expressed cytokeratin 20, and 47% exhibited trisomy 6, with no significant difference between primary and metastatic lesions. Incomplete follow-up data did not allow us to establish a prognostic value of trisomy 6, however, this aberration might be an additional diagnostic tool in distinguishing MCC from other small round blue cell tumours. CONCLUSIONS: CISH seems to be a promising adjunctive method to diagnose Merkel cell carcinoma. Trisomy 6 should be investigated more closely in these cases, as has been done for chromosomes 1 and 11. Of particular interest would be identification of modifications in proto-oncogene(s) located on chromosome 6.     

Expression of cyclin A in Merkel cell carcinoma

Merkel cell carcinoma (MCC) is a rare and aggressive primary neuroendocrine carcinoma of the skin. Large tumours, in particular, show rapid progression and metastatic dissemination, while smaller tumours show less aggressive behaviour. Cyclin A is considered to play a central role in cell cycle control. Its overexpression has been found to correlate with prognosis in many types of carcinomas and sarcomas. Twenty-six MCC patients with complete clinical data were selected. Formalin-fixed paraffin-embedded primary tumour samples were immunohistochemically stained for cyclin A. Correlation between expression of cyclin A and primary tumour size, invasion of subcutaneous tissue, local recurrence, metastasis and survival was statistically analysed. Twenty-five samples expressed cyclin A, and the mean value of positive cells was 25%. Our findings demonstrate that even small and superficial MCC show overexpression of cyclin A. There was no statistical correlation between cyclin A expression and the above-mentioned variables. Cyclin A does not seem to be useful as a prognostic tool. Consequently, size of the primary tumour (>/=2 cm) remains the primary prognostic tool. As a result every tumour, even those small in size, should be considered aggressive and treated radically and rapidly.     

Merkel cell carcinoma arising in the ear canal

A case of rare tumor, Merkel cell carcinoma, located in the ear canal of a 25-year-old woman is presented. A polypoid tumor mass was extirpated, and tympanoplasty was done at the first operation, whereas at the second operation, all the bones of the ear canal were removed. Epitympanum and cavum were filled with tumor, and the tumor mass was removed in toto. The histopathology and immunohistochemical staining characteristics of tumor confirmed the presence of Merkel cell tumor. Postoperatively, radiation therapy to the tumor bed was completed. There was no clinical or radiographic evidence of recurrence or metastasis of Merkel cell tumor for 3 years.     

Merkel cell carcinoma with pagetoid spread.

A case of Merkel cell carcinoma showing epidermotropism is presented. The neoplastic cells displayed dotlike immunoreactivity for cytokeratins and strong immunoreactivity for neuron-specific enolase. Although no neuroendocrine granules were found, characteristic paranuclear fibrous bodies were present.