Next generation sequencing of Cytokeratin 20-negative Merkel cell carcinoma reveals ultraviolet-signature mutations and recurrent TP53 and RB1 inactivation
Abstract:Merkel cell carcinoma is a rare but highly aggressive cutaneous neuroendocrine carcinoma. Cytokeratin-20 (CK20) is expressed in approximately 95% of Merkel cell carcinomas and is useful for distinction from morphologically similar entities including metastatic small cell lung carcinoma. Lack of CK20 expression may make diagnosis of Merkel cell carcinoma more challenging, and has unknown biological significance. Approximately 80% of CK20-positive Merkel cell carcinomas are associated with the oncogenic Merkel c… Show more
“…Mutational load was not examined in this case. However, based on recent genomic findings in MCPyV-negative tumors, we would predict this MCPyV-negative case to display a high mutational burden with associated neoantigens that may result in susceptibility to immunotherapy [11, 19]. Fig.…”
Section: Discussionmentioning
confidence: 99%
“…Pathology demonstrated morphologic and immunohistochemical (strongly cytokeratin-20, neuron specific enolase and CD56 positive and thyroid transcription factor-1 negative) findings in both lesions consistent with MCC. Polymerase chain reaction performed on deoxyribonucleic acid extracted from formalin-fixed, paraffin-embedded tumor tissue alongside appropriate controls using a previously described protocol demonstrated that the tumor lacked detectable Merkel cell polyomavirus (MCPyV) large T antigen and small T antigen [10, 11]. Staging fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) revealed lesions in right upper lung, right upper back, right axilla and right adrenal gland consistent with metastatic disease (Fig.…”
BackgroundMerkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine malignancy with limited treatment options. Several lines of evidence support the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) axis as a likely contributor to immune evasion in MCC.Case presentationWe report a case of a patient with metastatic MCC with a significant and durable response to nivolumab, a humanized IgG4 monoclonal anti-PD-1 antibody.ConclusionImmunotherapy with PD-1/PD-L1 inhibitors has become a rational and promising treatment option for MCC in the advanced or metastatic disease. Clinical trials are currently in progress to further evaluate these novel therapeutic agents.
“…Mutational load was not examined in this case. However, based on recent genomic findings in MCPyV-negative tumors, we would predict this MCPyV-negative case to display a high mutational burden with associated neoantigens that may result in susceptibility to immunotherapy [11, 19]. Fig.…”
Section: Discussionmentioning
confidence: 99%
“…Pathology demonstrated morphologic and immunohistochemical (strongly cytokeratin-20, neuron specific enolase and CD56 positive and thyroid transcription factor-1 negative) findings in both lesions consistent with MCC. Polymerase chain reaction performed on deoxyribonucleic acid extracted from formalin-fixed, paraffin-embedded tumor tissue alongside appropriate controls using a previously described protocol demonstrated that the tumor lacked detectable Merkel cell polyomavirus (MCPyV) large T antigen and small T antigen [10, 11]. Staging fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) revealed lesions in right upper lung, right upper back, right axilla and right adrenal gland consistent with metastatic disease (Fig.…”
BackgroundMerkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine malignancy with limited treatment options. Several lines of evidence support the programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) axis as a likely contributor to immune evasion in MCC.Case presentationWe report a case of a patient with metastatic MCC with a significant and durable response to nivolumab, a humanized IgG4 monoclonal anti-PD-1 antibody.ConclusionImmunotherapy with PD-1/PD-L1 inhibitors has become a rational and promising treatment option for MCC in the advanced or metastatic disease. Clinical trials are currently in progress to further evaluate these novel therapeutic agents.
“…For 22 MCC cases from 14 unique patients, the results of MCPyV immunohistochemistry previously performed for other studies were available. 2,35,36 The SmCC cohort consisted of 61 tumours from 60 unique patients, with primary sites including lung (27), bladder (18), cervix (3), gastrointestinal tract (3), sinonasal tract (2), ovary (3), breast (1), prostate (1), thymus (1) and larynx (1). Five negative lymph nodes from non-MCC cases served as negative controls.…”
Section: Materials and Methods C A S E C O H O R Tmentioning
Aim
Primary cutaneous neuroendocrine carcinoma, or Merkel cell carcinoma (MCC), cannot be distinguished morphologically from small‐cell neuroendocrine carcinomas (SmCC) from other sites. Immunohistochemistry is required to confirm cutaneous origin, and is also used for detection of sentinel lymph node (SLN) metastases of MCC. Cytokeratin 20 (CK20) expression is commonly used for these purposes, but is negative in some MCC cases, and has unclear specificity. We evaluated immunohistochemistry for neurofilament and CK20 in MCC compared with SmCC from other sites.
Methods and results
We evaluated neurofilament expression in 55 MCC specimens from 39 unique patients, including nine CK20‐negative MCC tumours. Neurofilament expression was observed in 42 of 55 (76.4%) MCC cases, including seven of nine (77.8%) CK20‐negative MCC cases. Neurofilament was expressed in nine of 12 (75%) Merkel cell polyomavirus‐positive tumours and five of 10 (50%) virus‐negative tumours. Compared to a standard immunohistochemical panel (cytokeratin cocktail and CK20), neurofilament was 87.5% sensitive for detecting SLN metastases. Neurofilament and CK20 expression was also assessed in 61 extracutaneous SmCC from 60 unique patients, with primary sites including lung (27), bladder (18), cervix (3), gastrointestinal tract (3), sinonasal tract (2) and other sites (7). The specificity of neurofilament and CK20 for MCC versus non‐cutaneous SmCC was 96.7% and 59.0%, respectively.
Conclusions
Neurofilament has superior specificity to CK20 in distinguishing MCC from non‐cutaneous SmCC. Neurofilament is frequently expressed in CK20‐ and virus‐negative MCC tumours. Limitations of neurofilament immunohistochemistry include lower sensitivity than CK20 and subtle staining in some tumours. However, our findings indicate that neurofilament is useful for excluding non‐cutaneous SmCC.
“…Harms et al reported that 80% of CK20-positive MCC patients were associated with MCPyV oncogenes. Next-generation sequencing techniques were used to show the presence of virus-independent mechanisms such as BAP1, or TP53 and RB1 inactivation in CK20-negative MCC patients, and were able to interpret these as findings of CK20 negativity in MCC to date [10].…”
Merkel cell carcinoma (MCC) is a rare neuroendocrine tumor that is highly aggressive in nature and indolent in progression. The common risk factors for MCC are senility, prolonged exposure to sunlight, and immune deficient states. Moreover, Merkel cell polyomavirus has recently been characterized to be significantly associated with pathogenesis of MCC, including the expression of Cytokeratin 20 (CK20). Diagnosis is often difficult since histopathological results require a number of differential diagnoses through immunohistochemical (IHC) stains with other cutaneous malignancies. A 67-year-old man presented with a solitary domeshaped erythematous round mass on the left upper arm for 2 months. Biopsy and IHC studies revealed findings consistent with Merkel Cell Carcinoma of neuroendocrine origin. Common IHC stains usually confirm positive findings for CK20, which is also recognized as the key component in making the diagnosis. We present a CK20 negative MCC in light of expanding the knowledge of unusually stained IHC results in MCC.
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