Radiotherapy for metastatic merkel cell carcinoma: a review of the literature.

2012

Khan L, Barnes EA.

Source

Princess Margaret Hospital, 610 University Avenue, Toronto, ON, Canada M5G 2M9.

Abstract

Introduction. Merkel cell carcinoma is a rare form of non-melanoma skin cancer of neuroendocrine origin. Optimal management of patients is controversial and the role of radiotherapy is unclear.

Purpose. The purpose of this study was to review the efficacy of RT in the treatment of both local and distant metastatic disease from MCC. Methods. A literature search was conducted in MEDLINE (1946-January Week 1 2012) and Embase (1980-2012 Week 2). Articles of interest analyze the efficacy of radiotherapy for treatment of metastatic MCC and did not exclude case reports.

Results. All articles except one focusing on the role of radiotherapy were of retrospective origin or case series. Significant limitations applied in all studies due to limited sample sizes and the retrospective nature of these studies. Radiotherapy improves locoregional control in the adjuvant setting, and many series suggest an improvement in overall survival. In cases where surgery is not possible, definitive radiotherapy may be an as-efficacious alternative. The radiosensitive nature of MCC coupled with existing reports suggests that treatment via current protocols for other primary tumors is adequate. 

Conclusion. Further studies should be conducted prospectively to clarify the true role of radiotherapy in metastatic MCC.

Journal of Skin Cancer/NLM

Increasing Tumor Thickness is Associated with Recurrence and Poorer Survival in Patients with Merkel Cell Carcinoma.

July 2012

Lim CS, Whalley D, Haydu LE, Murali R, Tippett J, Thompson JF, Hruby G, Scolyer RA.

Source

Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.

Abstract

BACKGROUND:

Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neuroendocrine tumor usually occurring on sun-exposed skin in elderly patients. Clinical and pathologic factors associated with disease progression and mortality in patients with MCC are poorly defined. Recently, it has been reported that p63 expression in primary MCC is strongly associated with clinical outcome.

METHODS:

MCC patients diagnosed between July 1, 1993 and July 31, 2009 were identified from the surgical pathology records of the Sydney South West Area Health Service. Clinical, pathologic, treatment, and survival data were obtained and immunohistochemical analyses for p53, p63, and Ki-67 were performed. The associations of clinical and pathologic features with disease-free and disease-specific survival were analyzed.

RESULTS:

Ninety-five patients were identified (67 males, 28 females; median age at diagnosis of primary MCC 76 [range, 42-93] years). Increasing primary tumor thickness was significantly associated with poorer disease-free survival (5-year survival 18 % in tumors >10 mm thick compared with 69 % for patients with tumors ≤10 mm thick, p = 0.002) and disease-specific survival (5-year survival 74 % in tumors >10 mm thick compared with 97 % for patients with tumors ≤10 mm thick, p = 0.006). There was a strong positive correlation between the Ki-67 index (proportion of Ki-67-positive tumor nuclei) and tumor thickness (r = 0.39, n = 45, p = 0.008). Positive staining for p63 in MCC was infrequent (9 % of primary MCC) and showed no significant association with disease outcome.

CONCLUSIONS:

Tumor thickness is significantly associated with disease-free survival in MCC. We recommend that primary tumor thickness be routinely recorded in the pathology reports of patients with primary MCC.

Springerlink

Entry Tropism of BK and Merkel Cell Polyomaviruses in Cell Culture.

2012

Schowalter RM, Reinhold WC, Buck CB.

Source

Tumor Virus Molecular Biology Section, Laboratory of Cellular Oncology, National Cancer Institute, Bethesda, Maryland, United States of America.

Abstract

Merkel Cell Polyomavirus (MCV or MCPyV) was recently discovered in an aggressive form of skin cancer known as Merkel cell carcinoma (MCC). Integration of MCV DNA into the host genome likely contributes to the development of MCC in humans. MCV infection is common and many healthy people shed MCV virions from the surface of their skin. MCV DNA has also been detected in samples from a variety of other tissues. Although MCC tumors serve as a record that MCV can infect the Merkel cell lineage, the true tissue tropism and natural reservoirs of MCV infection in the host are not known. In an effort to gain insight into the tissue tropism of MCV, and to possibly identify cellular factors responsible for mediating infectious entry of the virus, the infection potential of human cells derived from a variety of tissues was evaluated. MCV gene transfer vectors (pseudoviruses) carrying reporter plasmid DNA encoding GFP or luciferase genes were used to transduce keratinocytes and melanocytes, as well as lines derived from MCC tumors and the NCI-60 panel of human tumor cell lines. MCV transduction was compared to transduction with pseudoviruses based on the better-studied human BK polyomavirus (BKV). The efficiency of MCV and BKV transduction of various cell types occasionally overlapped, but often differed greatly, and no clear tissue type preference emerged. Application of native MCV virions to a subset of highly transducible cell types suggested that the lines do not support robust replication of MCV, consistent with recent proposals that the MCV late phase may be governed by cellular differentiation in vivo. The availability of carefully curated gene expression data for the NCI-60 panel should make the MCV and BKV transduction data for these lines a useful reference for future studies aimed at elucidation of the infectious entry pathways of these viruses.

Full text article:

PLOS

Immunohistochemical prognostication of Merkel cell carcinoma: p63 expression but not polyomavirus status correlates with outcome.

July 2012

Hall BJ, Pincus LB, Yu SS, Oh DH, Wilson AR, McCalmont TH.

Source

Department of Pathology, University of Utah, Salt Lake City, UT, USA.

Abstract

Merkel cell carcinoma (MCC) represents a cutaneous malignancy with high associated mortality. Numerous studies have attempted to define characteristics to more accurately predict outcome. Two recent studies have demonstrated that Merkelcell polyomavirus (MCPyV) seropositivity correlated with a better prognosis, while a third study revealed no difference. Expression of p63 by tumor cell nuclei has been shown to be associated with a worse prognosis in a European cohort. To better understand the relationship between prognosis and MCPyV or p63 status, we used immunohistochemistry to evaluate both attributes in 36 US patients with MCC. Our results show that when considered as a binary variable, p63 expression represents a strong risk factor (p < 0.0001, hazards ratio (HR) = ∞) for shortened survival. In addition, our results show that MCPyV status does not correlate with survival (p = 0.6067, HR = 1.27). Our study corroborates the European observation that p63 immunoexpression is useful as a prognostic tool. Larger studies will need to be performed in order to determine whether p63 status should be included in MCC staging, since our study is limited by its relative small size.

Wiley OnLine

Structures of Merkel Cell Polyomavirus VP1 Complexes Define a Sialic Acid Binding Site Required for Infection.

July 2012

Neu U, Hengel H, Blaum BS, Schowalter RM, Macejak D, Gilbert M, Wakarchuk WW, Imamura A, Ando H, Kiso M, Arnberg N, Garcea RL, Peters T, Buck CB, Stehle T.

Source

Interfaculty Institute of Biochemistry, University of Tuebingen, Tuebingen, Germany.

Abstract

The recently discovered human Merkel cell polyomavirus (MCPyV or MCV) causes the aggressive Merkel cell carcinoma(MCC) in the skin of immunocompromised individuals. Conflicting reports suggest that cellular glycans containing sialic acid (Neu5Ac) may play a role in MCPyV infectious entry. To address this question, we solved X-ray structures of the MCPyV major capsid protein VP1 both alone and in complex with several sialylated oligosaccharides. A shallow binding site on the apical surface of the VP1 capsomer recognizes the disaccharide Neu5Ac-α2,3-Gal through a complex network of interactions. MCPyV engages Neu5Ac in an orientation and with contacts that differ markedly from those observed in other polyomavirus complexes with sialylated receptors. Mutations in the Neu5Ac binding site abolish MCPyV infection, highlighting the relevance of the Neu5Ac interaction for MCPyV entry. Our study thus provides a powerful platform for the development of MCPyV-specific vaccines and antivirals. Interestingly, engagement of sialic acid does not interfere with initial attachment of MCPyV to cells, consistent with a previous proposal that attachment is mediated by a class of non-sialylated carbohydrates called glycosaminoglycans. Our results therefore suggest a model in which sialylated glycans serve as secondary, post-attachment co-receptors during MCPyV infectious entry. Since cell-surface glycans typically serve as primary attachment receptors for many viruses, we identify here a new role for glycans in mediating, and perhaps even modulating, post-attachment entry processes.

Full text article:

PLOS/Pathogens

Chronic lymphocytic leukemia, lymphoma, merkel cell carcinoma

Increased incidence of chronic lymphocytic leukaemia and lymphomas in patients with Merkel cell carcinoma - a population based study of 335 cases with neuroendocrine skin tumour.

Mar 2012

Tadmor T, Liphshitz I, Aviv A, Landgren O, Barchana M, Polliack A.

Source

Haematology, Oncology Unit, Bnai-Zion Medical Centre, Haifa, Israel.

Abstract

Merkel cell carcinoma (MCC) is a rare aggressive skin tumour that appears to be associated with a large number of other tumours. We collected all reported cases in Israel and estimated its association with other tumours, including haematological malignancies. The population based Israel Cancer Registry identified 335 patients with MCC diagnosed between1989 and 2010. Ninety-seven percent were in the Jewish population; median age at diagnosis for Jewish patients was 73·4 and 55·6 years for the Arab population. Other associated malignancies were encountered in 92 patients (27·4%) with MCC (90 Jews, two Arabs). Of the Jewish cases, 66 presented with an associated malignancy before, and 24 after, the diagnosis of MCC. Solid tumours were not significantly increased among patients with MCC. Thirty-one of these associated cancers (34·4%) were haemato-oncological malignancies, 24 were detected before and seven after the diagnosis of MCC. The standardized incidence ratio (SIR) for haematological malignancy was 3·67 for males and 3·62 for females, and the most frequent haemato-oncological neoplasias recorded were chronic lymphocytic leukaemia (45%) and lymphomas (29%). Although MCC is rare, clinicians should be aware of the possible association with B-cell lymphoproliferative disorders when evaluating patients with neuroendocrine skin tumours.

Wiley OnLine

Significant overexpression of the Merkel cell polyomavirus (MCPyV) large T antigen in Merkel cell carcinoma.

Feb 2012

Erovic BM, Al Habeeb A, Harris L, Goldstein DP, Ghazarian D, Irish JC.

Source

Department of Otolaryngology-Head and Neck Surgery/Surgical Oncology, University Health Network, Princess Margaret Hospital, Toronto, Ontario, Canada.

Abstract

BACKGROUND:

The purpose of this study was to determine the expression pattern of the Merkel cell polyomavirus (MCPyV) large T-protein antigen in patients with Merkel cell carcinoma.

METHODS:

A tissue microarray (TMA) containing 30 specimens was constructed and stained for the MCPyV large T protein. Immunohistochemical expression was determined semiquantitively and was compared to patients' outcome.

RESULTS:

Nuclear expression of MCPyV large T protein was detected in 29 of 30 specimens (97%). In particular, 60% to 100%, 30% to 60%, and 10% to 30% of tumor cells were positive in 27 specimens (90%), 1 (3%), and 1 (3%), respectively. There was no difference in positivity between primary and metastatic lesions. Clinical data could not be correlated to MCPyV large T-protein expression.

CONCLUSION:

MCPyV large T protein was significantly overexpressed in 97% of all specimens. Although we could not demonstrate a predictive effect, MCPyV large T protein may represent a molecular marker with utility in pathological diagnosis as well as a potential new therapeutic target in patients with Merkel cell carcinoma. .

Wiley Online