Merkel cell carcinoma and HIV infection

Engels, Eric A.; Frisch, Mørten; Goedert, James J.; Biggar, Robert J.; Miller, Robert W.

doi:10.1016/s0140-6736(02)07668-7

Cited by 486 publications

(334 citation statements)

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“…Development of cutaneous Merkel cell carcinoma may be related to ultraviolet light irradiation and immunosupression. [45][46][47][48] In our study, 8 of 22 (36%) patients had a history of other aggressive or systemic tumors prior to the diagnosis of nodal Merkel cell carcinoma, and 3 of them had chronic lymphocytic leukemia/small lymphocytic lymphoma. Approximately 27% of patients with cutaneous Merkel cell carcinoma had other invasive non-Merkel cell carcinoma malignancies, with chronic lymphocytic leukemia/small lymphocytic lymphoma the most common one, accounting for 45% of all tumors.…”

Section: Possible Histogenesis Of Nodal Merkel Cell Carcinomamentioning

confidence: 52%

Merkel cell carcinoma of lymph node with unknown primary has a significantly lower association with Merkel cell polyomavirus than its cutaneous counterpart

Pan

Chen

et al. 2014

Modern Pathology

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Rare cases of Merkel cell carcinoma have been encountered in lymph nodes with unknown extranodal primary, which exhibit similar morphologic and immunophenotypic features to those in primary cutaneous Merkel cell carcinomas. However, it is uncertain whether the nodal Merkel cell carcinoma is a primary tumor of the lymph node or represents a metastasis from an occult or regressed extranodal lesion. To establish an accurate diagnosis of the nodal Merkel cell carcinoma can be challenging because of significant morphologic mimics, including lymphoblastic lymphoma and metastatic small cell carcinoma. Moreover, there is no consensus for a diagnostic term, and many different terms have been used, which can be confusing and may not fully reflect the nature of nodal Merkel cell carcinoma. In this study, we investigated the detailed clinicopathologic features of 22 nodal Merkel cell carcinomas, with comparison to 763 primary cutaneous cases retrieved from the literature. Overall, the nodal and cutaneous Merkel cell carcinomas shared similar clinical presentations, morphologic spectrum, and immunophenotype; both were mostly seen in elderly male with a typical neuroendocrine morphology. Most of cases expressed CK20, synaptophysin, and chromogranin A; and PAX5 and TdT were also positive in majority of cases. However, nodal Merkel cell carcinomas had a significantly lower association with Merkel cell polyomavirus than cutaneous cases (31% vs 76%, P ¼ 0.001). Therefore, these two entities may arise from overlapping but not identical biological pathways. We also recommend the use of the diagnostic term 'Merkel cell carcinoma of lymph node' to replace many other names used.

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Section: Possible Histogenesis Of Nodal Merkel Cell Carcinomamentioning

confidence: 52%

Merkel cell carcinoma of lymph node with unknown primary has a significantly lower association with Merkel cell polyomavirus than its cutaneous counterpart

Pan

Chen

et al. 2014

Modern Pathology

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“…M erkel cell carcinoma (MCC) is an aggressive skin cancer associated with sun exposure and immunosuppression (1,2). Using digital transcriptome subtraction, we recently identified Merkel cell polyomavirus (MCV) as a novel polyomavirus integrated into the genome of MCC tumors (3,4).…”

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confidence: 99%

T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus

Shuda

Feng

Kwun

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

629

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Merkel cell polyomavirus (MCV) is a virus discovered in our laboMerkel cell carcinoma ͉ pRB interaction ͉ viral integration ͉ virus replication ͉ helicase M erkel cell carcinoma (MCC) is an aggressive skin cancer associated with sun exposure and immunosuppression (1, 2). Using digital transcriptome subtraction, we recently identified Merkel cell polyomavirus (MCV) as a novel polyomavirus integrated into the genome of MCC tumors (3, 4). The close association between MCV and MCC has been confirmed by others (5). Polyomaviruses are small circular DNA viruses encoding a T antigen oncoprotein locus. T antigens are expressed from variably spliced viral transcripts that target tumor suppressor and cell cycle regulatory proteins, including retinoblastoma tumor suppressor protein (Rb) (6), p53 (7, 8), protein phosphatase 2A (9), and Bub1 (10). Murine polyomavirus (MuPyV) middle T (MT) antigen, a membrane-bound protein, is particularly potent in initiating cell transformation through interactions with phosphatidylinositol 3-kinase, protein phosphatase 2A, Src, and Shc proteins (11,12). MCV large T (LT) antigen retains conserved domains, such as pocket Rb binding LXCXE and DnaJ motifs, present across virus species (13). LT not only encodes tumor suppressor targeting domains but also origin binding and helicase/ATPase functions required for viral genome replication. MCV integration in MCC tumors is incompatible with transmissible virus and likely represents a rare biological accident in which the tumor cell is a dead-end host. The monoclonal pattern of MCV integration into MCC tumors suggests that virus integration occurs before tumor cell expansion and that MCV is a contributing factor in a portion of MCC (3).We have isolated MCV T antigen sequences from both tumor cases and nontumor cases to characterize their abilities to act as a viral DNA replicase. Sequence analysis demonstrates that LT protein is prematurely truncated in all MCC cases, whereas the Rb-interacting domain is preserved. Viruses from nontumor sources do not possess these mutations. We also describe here an MCC cell line stably harboring MCV and an origin replication assay to assess MCV replication. We show that wild type (WT) LT from nontumorous sources activates MCV replication of integrated tumor virus, suggesting that MCV-associated MCC arises from a two-step process in which viral genome integrates into the host genome and develops T antigen mutations to prevent autonomous viral genome replication. Failure to truncate the viral T antigen may lead to DNA damage responses or immune recognition that hinders nascent tumor cell survival.

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“…The majority of MCCs are associated with the Merkel cell polyomavirus (MCPyV) MCC occurs more frequently in patients with immunodeficiency, including AIDS, suggesting that MCC may have an infectious etiology similar to Kaposi's sarcoma and EBV-induced Burkitt's lymphoma [7][8][9][10]. This was confirmed in 2008 when MCPyV was discovered in eight of ten MCC tumors using Digital Transcriptome Subtraction, a high-throughput cDNA sequencing platform that aligned MCC tumor Rationale for immune-based therapies in Merkel polyomavirus-positive and -negative Merkel cell carcinomas future science group Review Vandeven & Nghiem transcripts against reference human sequences [6].…”

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confidence: 99%

Rationale For Immune-Based Therapies in Merkel Polyomavirus-Positive and -Negative Merkel Cell Carcinomas

Vandeven

Nghiem

2016

Immunotherapy

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Merkel cell carcinoma (MCC) is a rare but often deadly skin cancer that is typically caused by the Merkel cell polyomavirus (MCPyV). Polyomavirus T-antigen oncoproteins are persistently expressed in virus-positive MCCs (∼80% of cases), while remarkably high numbers of tumor-associated neoantigens are detected in virusnegative MCCs, suggesting that both MCC subsets may be immunogenic. Here we review mechanisms by which these immunogenic tumors evade multiple levels of host immunity. Additionally, we summarize the exciting potential of diverse immunebased approaches to treat MCC. In particular, agents blocking the PD-1 axis have yielded strikingly high response rates in MCC as compared with other solid tumors, highlighting the potential for immune-mediated treatment of this disease.

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Merkel cell carcinoma and HIV infection

Cited by 486 publications

References 3 publications

Merkel cell carcinoma of lymph node with unknown primary has a significantly lower association with Merkel cell polyomavirus than its cutaneous counterpart

Merkel cell carcinoma of lymph node with unknown primary has a significantly lower association with Merkel cell polyomavirus than its cutaneous counterpart

T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus

Rationale For Immune-Based Therapies in Merkel Polyomavirus-Positive and -Negative Merkel Cell Carcinomas

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