ASO Author Reflections: Merkel Cell Carcinoma and Nodal Staging with SLNB.

Merkel cell carcinoma in a patient with noninvasive vulvar Paget's disease

Merkel's cell carcinoma rarely arises in the vulva. It is unclear whether those cases arising in the vulva behave differently from the usual Merkel's cell carcinomas. A Merkel's cell carcinoma of the vulva was studied by light microscopy, immunohistochemistry, and electron microscopy. The clinical data of this case and of other reported cases are summarized and compared with those of Merkel's cell carcinoma in general. This tumor showed the characteristic trabecular pattern of Merkel's cell carcinoma. The tumor cells were immunoreactive to low-molecular-weight cytokeratin and neuron-specific enolase. This patient was treated initially with local excision. She died 17 months later with progressive metastatic disease unresponsive to chemotherapy. This case study and the review of six other cases indicate that Merkel's cell carcinoma of the vulva is universally metastatic, both to the regional lymph nodes and distant sites, and that it invariably follows a rapidly fatal course. Merkel's cell carcinoma of the vulva appears to have a biologic behavior more aggressive than that of Merkel's cell carcinoma in general. An initial modality combining chemotherapy, with or without irradiation, with aggressive surgery should be tried in future cases.

Cytokeratin 20 (CK20) is a low-molecular-weight cytokeratin (CK) that shows restricted expression in the gastrointestinal epithelium, urothelium, and Merkel cell. Recent studies have suggested that since Merkel cell (primary cutaneous neuroendocrine) carcinomas are consistently CK20-positive, this feature may help to distinguish it from pulmonary small cell carcinomas. However, only limited numbers of these tumors have been studied, and the pattern of CK20 expression in other small cell carcinomas has not been established. Therefore, we studied CK20 expression in small cell carcinomas from a wide variety of sites. Immunohistochemical study was performed on paraffin sections using CK20 antibody, coupled with antigen retrieval by pressure cooking in citrate buffer. The cases included 34 Merkel cell carcinomas and 89 small cell carcinomas from various sites (pulmonary, 37; gastrointestinal tract, nine; pharynx and tongue, two; sinonasal tract, three; salivary gland, five; larynx, nine; breast, two; thymus, three; uterine cervix and corpus, 12, prostate, three; urinary bladder, two; kidney, one; pancreas, one). In addition, all cases were immunostained with pan-CK (MNF-116) and low-molecular-weight CK (CAM5.2) antibodies to ascertain their epithelial nature. With the exception of one case, all Merkel cell carcinomas were CK20-positive; and 30 of the 33 cases showed a punctate pattern. Almost 100% of tumor cells were positive, except for two cases that showed staining of 10% and 30% of tumor cells, respectively. Among the other small cell carcinomas, only five cases were CK20-positive, including one of 37 pulmonary (40% cells positive in punctate pattern), one of 11 cervical (10% cells positive), and three of five salivary gland (100% cells positive). We conclude that CK20-positivity in a small cell carcinoma of uncertain origin strongly predicts a diagnosis of Merkel cell carcinoma, especially if the majority of tumor cells are positive. A negative CK20 reaction can practically rule out Merkel cell carcinoma, provided that an effective antigen retrieval technique is used and appropriate staining is obtained with other cytokeratin antibodies. The frequent CK20 positivity observed in salivary gland small cell carcinomas in this series suggests that at least some of them may be more closely related biologically to Merkel cell carcinoma than to pulmonary-type small cell carcinoma. This may explain why they are far less clinically aggressive than other small cell carcinomas.

Multiple Merkel cell carcinomas: Late metastasis or multiple primary tumors? A molecular study

The spectrum of Merkel cell polyomavirus expression in Merkel cell carcinoma, in a variety of cutaneous neoplasms, and in neuroendocrine carcinomas from different anatomical sites

Factors associated with time to treatment for Merkel cell carcinoma

Cutaneous squamous and neuroendocrine carcinoma: genetically and immunohistochemically different from Merkel cell carcinoma

Two developmentally highly divergent nonmelanoma skin cancers, the epidermal squamous cell carcinomas (SCC) and the neuroendocrine Merkel cell carcinomas (MCC), occur late in life at sun-exposed body sites. To determine whether these similarities may indicate common genetic alterations, we studied the genetic profile of 10 MCCs and analyzed 6 derived cell lines and 5 skin SCC lines by comparative genomic hybridization (CGH) and molecular genetic analyses. Although the MCCs were highly divergent-only 3 of the 10 tumors exhibited common gains and losses-they shared gain of 8q21-q22 and loss of 4p15-pter with the genetically much more homogeneous SCC lines. In addition, 2 of 5 SCC and 2 of 6 MCC lines exhibited UV-B-type-specific mutations in the p53 tumor-suppressor gene and a high frequency (9/11) of CC-->TT double base changes in codon 27 of the Harvey (Ha)-ras gene. Since 45% of the tumor lines were homozygous for this nucleotide substitution compared to 14% of the controls and in 1 MCC patient the wild-type allele was lost in the tumor, this novel polymorphism may contribute to tumor development. On the other hand, loss of 3p, characteristic for SCCs, was rare in MCCs. Although in 2 of 3 SCC lines 3p loss was correlated with reduced expression of the FHIT (fragile histidine triad) gene, the potential tumor suppressor mapped to 3p14.2 and 2 MCC lines with normal 3p showed aberrant or no FHIT transcripts. Taken together, in addition to the common UV-B-specific mutations in the p53 and Ha-ras gene, MCCs and SCCs also share chromosomal imbalances that may point to a common environmental-derived (e.g., UV-A) oxidative damage.

Immunological detection of viral large T antigen identifies a subset of Merkel cell carcinoma tumors with higher viral abundance and better clinical outcome

Beta Human Papillomavirus and Merkel Cell Polyomavirus in Skin Neoplasms

Four new patients with trabecular (Merkel cell) carcinoma of the skin are described, and an additional 76 patients from the literature are reviewed. The mean age of the combined group of patients was 68; 84% were 60 years or older. Primary tumors appeared most frequently on the head and neck (44%), leg (28%), arm (16%), or buttock (9%). No primary tumor appeared on the trunk. The rate of local recurrence was 36%, regional metastatic disease, 53%; distant metastases, 28%; and death due to metastatic tumor (minimally), 25%. It appears that trabecular carcinoma of the skin is more aggressive and lethal than previously thought. The authors recommend that patients with this tumor undergo wide resection of the primary site and, in healthy patients, prophylactic regional node dissection. Both radiation therapy and chemotherapy are effective in palliating unresectable disease.

The majority of small-cell lung cancers (SCLCs) express p16 but not pRb. Given our previous study showing loss of pRb in Merkel cell carcinoma (MCC)/neuroendocrine carcinoma of the skin and the clinicopathological similarities between SCLC and MCC, we wished to determine if this was also the case in MCC. Twenty-nine MCC specimens from 23 patients were examined for deletions at 10 loci on 9p and 1 on 9q. No loss of heterozygosity (LOH) was seen in 9 patients including 2 for which tumour and cell line DNAs were examined. Four patients had LOH for all informative loci on 9p. Ten tumours showed more limited regions of loss on 9p, and from these 2 common regions of deletion were determined. Half of all informative cases had LOH at D9S168, the most telomeric marker examined, and 3 specimens showed loss of only D9S168. A second region (IFNA-D9S126) showed LOH in 10 (44%) cases, and case MCC26 showed LOH for only D9S126, implicating genes centromeric of the CDKN2A locus. No mutations in the coding regions of p16 were seen in 7 cell lines tested, and reactivity to anti-p16 antibody was seen in all 11 tumour specimens examined and in 6 of 7 cell lines from 6 patients. Furthermore, all cell lines examined reacted with anti-p14(ARF) antibody. These results suggest that neither transcript of the CDKN2A locus is the target of deletions on 9p in MCC and imply the existence of tumour-suppressor genes mapping both centromeric and telomeric of this locus.

The aim of the present study was to assess a possible role of the tumour suppressor gene p53 in neuroendocrine (Merkel cell) carcinoma of the skin with regard to tumour development and tumour progression. p53 was investigated in a series of routinely processed Merkel cell carcinomas, with application of four different p53 antibodies (CM-1, PAb1801, DO7, and PAb240) to 25 carcinomas and screening for p53 mutations of exons 4-8 by single-strand conformation polymorphism (SSCP) analysis in 9 cases. All 25 tumours in the present series showed the characteristic microscopic and immunohistochemical features of Merkel cell carcinoma of the skin. In 5 of the 25 Merkel cell carcinomas investigated 5-10% of tumour cell nuclei showed a positive p53 reaction with at least one anti-p53 antibody. A few scattered p53 positive nuclei were found in an additional 9 cases. The remaining 11 cases completely lacked p53 immunostaining. SSCP analysis of exons 4-8 revealed no significant alterations in the mobility shift of the single strand DNAs in the five cases with 5-10% p53-immunoreactive tumour nuclei or in five cases lacking p53 accumulation significant. Our results suggest that alterations of the p53 gene play only a minor part in the development or progression of Merkel cell carcinoma of the skin.

Merkel cell (primary cutaneous neuroendocrine) carcinoma is a rare neoplasm of the skin. Its occurrence has been reported in association with other cutaneous neoplasms (Bowen disease, squamous cell carcinoma) in cases regarded as collision tumors. It has recently been described in association with cysts of the follicle apparatus. We present a unique case of rapidly growing nodular tumor on the left forearm of an 84-year-old woman, which proved to be a Merkel cell carcinoma located within a cystic trichoblastoma. The malignant component located in the center of the lesion had typical histopathological and immunohistochemical features of Merkel cell carcinoma. It was surrounded by an epithelial proliferation, made of K17-positive basaloid cells, whose aspects where those of trichoblastoma in a retiform pattern. Both lesions were intertwined, suggesting that the Merkel cell carcinoma had developed within a previously existing trichoblastoma and that it derived from the follicular Merkel cells present in the trichoblastoma. The unique features of this case, together with the reported cases of Merkel cell carcinoma arising within follicular lesions, and the fact that numerous Merkel cells are normally localized in the adult hair follicle, further support the hypothesis of a histogenetic link between normal follicular Merkel cells and Merkel cell carcinoma.

A case of combined Merkel cell carcinoma and squamous cell carcinoma: Molecular insights and diagnostic pitfalls