Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: Analysis of 5823 cases as the basis of the first consensus staging system

Lemos, Bianca D.; Storer, Barry E.; Iyer, Jayasri G.; Phillips, Jerri Linn; Bichakjian, Christopher K.; Fang, Lekun; Johnson, Timothy M.; Liegeois-Kwon, Nanette J.; Otley, Clark C.; Paulson, Kelly G.; Ross, Merrick I.; Yu, Siegrid S.; Zeitouni, Nathalie C.; Byrd, David R.; Sondak, Vernon K.; Gershenwald, Jeffrey E.; Sober, Arthur J.; Nghiem, Paul

doi:10.1016/j.jaad.2010.02.056

Cited by 498 publications

(506 citation statements)

References 23 publications

Supporting

Mentioning

457

Contrasting

Unclassified

Order By: Relevance

“…In the 70 cases, multivariate Cox regression analysis assessed p63 expression to be a strong independent prognostic factor (Po0.001) followed by disease stage (P ¼ 0.008). Without unduly dismissing the importance of staging, it should be remarked that the real clinical dilemma is related to localised stage I and II Merkel cell carcinomas, which represent the vast majority at first presentation 4 and where no predictor is available to identify the large number of cases behaving aggressively 4 and to plan therapy accordingly. Indeed, we wish to stress that the utility and importance of data from the current study is that p63 expression was found to be strongly associated with a worse prognosis in patients with low-stage Merkel cell carcinoma and represents a new independent marker of clinical evolution in these patients (Po0.0001) (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

“…4,11 Pathology samples included resection specimens. Haematoxylin and eosin-stained slides (H&E) were available for all cases.…”

Section: Specimensmentioning

confidence: 99%

“…3 Prognosis is related to stage and to the presence of lymph node metastases. 4 However, in low-stage (stage I-II) Merkel cell carcinoma that is the vast majority of cases at presentation, 4 no independent prognostic parameter is available.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Expression of p63 is the sole independent marker of aggressiveness in localised (stage I–II) Merkel cell carcinomas

et al. 2011

View full text Add to dashboard Cite

Merkel cell carcinoma of the skin is a malignant neuroendocrine tumour, whose prognostic criteria are a matter of dispute. Specifically, no predictor is presently available in stage I-II tumours. We collected clinical and follow-up data from 70 Merkel cell carcinomas of the skin. The same cases were studied for p63 expression by immunohistochemistry, by reverse-transcription PCR (RT-PCR) and TP63 gene status by FISH and for presence of Merkel cell polyomavirus by PCR. Stage emerged as a significant prognostic parameter (P ¼ 0.008). p63 expression, detected in 61% (43/70) of cases by immunohistochemistry, was associated with both decreased overall survival (Po0.0001) and disease-free survival (Po0.0001). Variable expression patterns of the different p63 isoforms were found only in cases immunoreactive for p63. In these latter lesions, at least one of the N-terminal p63 isoforms was detected and TAp63a was the most frequently expressed isoform. TP63 gene amplification was observed by FISH in only one case. Presence of Merkel cell polyomavirus DNA sequences was detected in 86% (60/70) of Merkel cell carcinomas and did not emerge as a significant prognostic parameter. Merkel cell carcinoma cases at low stage (stage I-II) represented over half (40/70 cases, 57%) of cases, and the clinical course was uneventful in 25 of 40 cases while 15 cases died of tumour (10/40 cases) within 34 months or were alive with disease (5/40 cases) within 20 months. Interestingly, a very strict correlation was found between evolution and p63 expression (Po0.0001). The present data indicate that p63 expression is associated with a worse prognosis in patients with Merkel cell carcinoma, and in localised tumours it represents the single independent predictor of clinical evolution.

show abstract

Section: Discussionmentioning

confidence: 99%

“…4,11 Pathology samples included resection specimens. Haematoxylin and eosin-stained slides (H&E) were available for all cases.…”

Section: Specimensmentioning

confidence: 99%

See 1 more Smart Citation

Expression of p63 is the sole independent marker of aggressiveness in localised (stage I–II) Merkel cell carcinomas

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Factors recognized as associated with poor prognosis are size of the tumor and presence of metastases according to the AJCC staging (4,47,55,(64)(65)(66)(67)(68), and immunosuppression (65,69,70). Recently, histological and immunochemistry markers have been described as potentially associated with poor outcome like low tumor infiltrating CD8 + T cells (101) and P53 and P63 expression and gen mutations (54, 68, 74) ( Table 2).…”

Section: Mcpyv Status and MCC Prognosismentioning

confidence: 99%

Human Merkel cell polyomavirus: virological background and clinical implications

Coursaget

Samimi

Nicol

et al. 2013

APMIS

View full text Add to dashboard Cite

The Merkel cell polyomavirus (MCPyV), identified in humans in 2008, is associated with a relatively rare but aggressive neuroendocrine skin cancer, the Merkel cell carcinoma (MCC). MCC incidence is increasing due to the advancing age of the population, the increase in damaging sun exposure and in the number of immunocompromised individuals. MCPyV must be considered as the etiological agent of MCC and thus is the first example of a human oncogenic polyomavirus. MCPyV infection is common, and seroprevalence studies indicate that widespread exposure begins early in life. The majority of adults have anti-MCPyV antibodies and there is a growing body of evidence that healthy human skin harbors resident or transient MCPyV suggesting that MCPyV infection persists throughout life. However, the mode of transmission, the host cells, and the latency characteristics of this virus remain to be elucidated. In addition, it is still not clear whether MCPyV is associated with diseases or lesions other than Merkel cell carcinoma. The etiologic role of MCPyV in MCC opens up opportunities to improve the understanding of this cancer and to potentially improve its treatment.

show abstract

“…3 There is an overall 5-year survival rate of 40%, with stage being a significant prognosticator. 3,4 Merkel cell polyomavirus was discovered in Merkel cell carcinoma and found to be clonally integrated in B80% of cases. [5][6][7] Merkel cell polyomavirus has a high seroprevalence in the general population and asymptomatic infection begins in childhood.…”

mentioning

confidence: 99%

Retinoblastoma gene mutations detected by whole exome sequencing of Merkel cell carcinoma

et al. 2014

View full text Add to dashboard Cite

Merkel cell carcinoma is a highly aggressive cutaneous neuroendocrine tumor that has been associated with Merkel cell polyomavirus in up to 80% of cases. Merkel cell polyomavirus is believed to influence pathogenesis, at least in part, through expression of the large T antigen, which includes a retinoblastoma protein-binding domain. However, there appears to be significant clinical and morphological overlap between polyomaviruspositive and polyomavirus-negative Merkel cell carcinoma cases. Although much of the recent focus of Merkel cell carcinoma pathogenesis has been on polyomavirus, the pathogenesis of polyomavirus-negative cases is still poorly understood. We hypothesized that there are underlying human somatic mutations that unify Merkel cell carcinoma pathogenesis across polyomavirus status, and to investigate we performed whole exome sequencing on five polyomavirus-positive cases and three polyomavirus-negative cases. We found that there were no significant differences in the overall number of single-nucleotide variations, copy number variations, insertion/deletions, and chromosomal rearrangements when comparing polyomavirus-positive to polyomavirus-negative cases. However, we did find that the retinoblastoma pathway genes harbored a high number of mutations in Merkel cell carcinoma. Furthermore, the retinoblastoma gene (RB1) was found to have nonsense truncating protein mutations in all three polyomavirus-negative cases; no such mutations were found in the polyomavirus-positive cases. In all eight cases, the retinoblastoma pathway dysregulation was confirmed by immunohistochemistry. Although polyomavirus-positive Merkel cell carcinoma is believed to undergo retinoblastoma dysregulation through viral large T antigen expression, our findings demonstrate that somatic mutations in polyomavirus-negative Merkel cell carcinoma lead to retinoblastoma dysregulation through an alternative pathway. This novel finding suggests that the retinoblastoma pathway dysregulation leads to an overlapping Merkel cell carcinoma phenotype and that oncogenesis occurs through either a polyomavirusdependent (viral large T antigen expression) or polyomavirus-independent (host somatic mutation) mechanism. Modern Pathology (2014) 27, 1073-1087; doi:10.1038/modpathol.2013.235; published online 10 January 2014Keywords: Merkel cell carcinoma; retinoblastoma; whole exome sequencing; polyomavirus Merkel cell carcinoma is a rare neuroendocrine tumor of the skin with an aggressive clinical course and an increased prevalence in the elderly and immunosuppressed. 1 The incidence of Merkel cell carcinoma has increased in the last several decades, and the United States has an estimated incidence rate of 0.32 per 100 000 persons per year. 2 Merkel cell carcinoma has a predilection for sun exposed areas, most often occurring in the head and neck region. 3 There is an overall 5-year survival rate of 40%, with stage being a significant prognosticator. 3,4 Merkel cell polyomavirus was discovered in Merkel cell carcinoma and found to be clonally integ...

show abstract

Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: Analysis of 5823 cases as the basis of the first consensus staging system

Cited by 498 publications

References 23 publications

Expression of p63 is the sole independent marker of aggressiveness in localised (stage I–II) Merkel cell carcinomas

Expression of p63 is the sole independent marker of aggressiveness in localised (stage I–II) Merkel cell carcinomas

Human Merkel cell polyomavirus: virological background and clinical implications

Retinoblastoma gene mutations detected by whole exome sequencing of Merkel cell carcinoma

Contact Info

Product

Resources

About