A new in situ hybridization and immunohistochemistry with a novel antibody to detect small T-antigen expressions of Merkel cell polyomavirus (MCPyV)

Matsushita, Michiko; Nonaka, Daisuke; Iwasaki, Takeshi; Kuwamoto, Satoshi; Murakami, Ichiro; Kato, Masako; Nagata, Kazuhiro; Kitamura, Yukisato; Hayashi, Kazuhiko

doi:10.1186/1746-1596-9-65

Cited by 16 publications

(13 citation statements)

References 22 publications

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“…Alternatively, it is also possible that this case represents a CK20 negative MCC and that the unclear pathobiology of MCPyV‐negative MCC may correlate with INSM1 expression (or lack thereof). Up to 20% of MCC lack detectable Merkel cell polyoma virus, and are instead associated with a spectrum of genomic changes possibly related to solar damage …”

Section: Discussionmentioning

confidence: 99%

Insulinoma‐associated 1: A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma)

et al. 2017

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Merkel cell carcinoma (MCC) is a rare, clinically aggressive, cutaneous neuroendocrine (NE) neoplasm. As a tumor with small, round, blue cells, the histologic differential diagnosis for MCC can include melanoma, metastatic small cell carcinoma (SCC), nodular hematopoietic tumors, basal cell carcinoma (BCC), atypical variants of squamous carcinoma and the uncommon occurrence of primary cutaneous Ewing sarcoma. In cases with atypical histology or without the classic immunophenotype, the diagnosis can be challenging. Ultimately, immunohistochemistry (IHC) is essential to the definitive diagnosis of MCC and in difficult cases, the diagnosis may hinge entirely on the immunophenotype of the tumor cells. Insulinoma-associated 1 (INSM1) is a transcription factor expressed in tissues undergoing terminal NE differentiation. As a nuclear protein tied to both differentiation and the cell cycle, INSM1 may offer additional utility in comparison to traditional, cytoplasmic markers of NE differentiation.

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Section: Discussionmentioning

confidence: 99%

Insulinoma‐associated 1: A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma)

et al. 2017

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“…However, CM2B4 has been shown to have limited sensitivity relative to qPCR (14,31). Other methods that have also been reported in the literature include fluorescence in situ hybridization (FISH) and IsHyb ISH (32)(33)(34). However, the interpretation/reporting of FISH results can be challenging.…”

Section: Discussionmentioning

confidence: 99%

Age and Gender Associations of Virus Positivity in Merkel Cell Carcinoma Characterized Using a Novel RNA In Situ Hybridization Assay

Wang

Harms

Palanisamy

et al. 2017

Clinical Cancer Research

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Purpose-Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine tumor of the skin. Merkel cell polyomavirus (MCPyV) plays an oncogenic role in the majority of MCCs. Detection of MCPyV in MCCs has diagnostic utility and prognostic potential. We investigated whether RNAscope, an RNA in situ hybridization (ISH) assay for detection of RNA transcripts in tissues, is useful for MCPyV detection.Experimental Design-We applied an RNAscope probe targeting MCPyV T antigen transcripts on tissue microarrays (TMAs) and whole tissue sections encompassing 87 MCCs from 75 patients, 14 carcinomas of other types, and benign tissues. For comparison, quantitative PCR (qPCR) was performed on 57 cases of MCC from 52 patients.Results-RNA-ISH demonstrated the presence of MCPyV in 37/75 (49.3%) cases. Notably, tumors from younger patients (< 73 years) had a significantly higher virus positivity than those from elderly patients (≥ 73 years) (64.9% vs. 34.2%, P =0.011). Female patients had a higher positive rate of MCPyV than male patients (66.7% vs. 39.6%, P =0.032). Data from both RNA- HHMI Author Manuscript HHMI Author Manuscript HHMI Author Manuscriptdetermining MCPyV status, RNAscope had 100% sensitivity and 100% specificity. There was a strong correlation between qPCR copy number and RNA-ISH product score (Spearman's correlation coefficient R 2 = 0.932, P < 0.0001).Conclusions-RNA-ISH is comparably sensitive to qPCR for detection of MCPyV and allows for correlation with tissue morphology. This study also reveals a significant association between age, gender, and MCPyV positivity.

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“…A study using Ab3, a novel LTAg antibody purported to be more sensitive than other antibodies, reported MCV positivity in an unexpected 97 % of MCC tumors [27]; however, these findings have not been replicated by other laboratories. Newer methods have recently been developed for MCV detection, including in situ hybridization and an antibody to sTAg, which may be more sensitive than CM2B4 staining alone [28]. With many test options having varying claims of sensitivity and specificity, comparative studies and establishing a gold standard for MCV detection are needed to more accurately stratify patients for clinical investigations.…”

Section: Diagnosis and Work-upmentioning

confidence: 99%

Merkel Cell Carcinoma Therapeutic Update

Cassler

Merrill

Bichakjian

et al. 2016

Curr. Treat. Options in Oncol.

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Opinion statement Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine tumor of the skin. Early-stage disease can be cured with surgical resection and radiotherapy (RT). Sentinel lymph node biopsy (SLNB) is an important staging tool, as a microscopic MCC is frequently identified. Adjuvant RT to the primary excision site and regional lymph node bed may improve locoregional control. However, newer studies confirm that patients with biopsy-negative sentinel lymph nodes may not benefit from regional RT. Advanced MCC currently lacks a highly effective treatment as responses to chemotherapy are not durable. Recent work suggests that immunotherapy targeting the programmed cell death receptor 1/programmed cell death ligand 1 (PD-1/PD-L1) checkpoint holds great promise in treating advanced MCC and may provide durable responses in a portion of patients. At the same time, high-throughput sequencing studies have demonstrated significant differences in the mutational profiles of tumors with and without the Merkel cell polyomavirus (MCV). An important secondary endpoint in the ongoing immunotherapy trials for MCC will be determining if there is a response difference between the virus-positive MCC tumors that typically lack a large mutational burden and the virus-negative tumors that have a large number of somatic mutations and predicted tumor neoantigens. Interestingly, sequencing studies have failed to identify a highly recurrent activated driver pathway in the majority of MCC tumors. This may explain why targeted therapies can demonstrate exceptional responses in case reports but fail when treating all comers with MCC. Ultimately, a precision medicine approach may be more appropriate for treating MCC, where identified driver mutations are used to direct targeted therapies. At a minimum, stratifying patients in future clinical trials based on tumor viral status should be considered as virus-negative tumors are more likely to harbor activating driver mutations.

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A new in situ hybridization and immunohistochemistry with a novel antibody to detect small T-antigen expressions of Merkel cell polyomavirus (MCPyV)

Cited by 16 publications

References 22 publications

Insulinoma‐associated 1: A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma)

Insulinoma‐associated 1: A novel nuclear marker in Merkel cell carcinoma (cutaneous neuroendocrine carcinoma)

Age and Gender Associations of Virus Positivity in Merkel Cell Carcinoma Characterized Using a Novel RNA In Situ Hybridization Assay

Merkel Cell Carcinoma Therapeutic Update

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