Diagnostic accuracy of a panel of immunohistochemical and molecular markers to distinguish Merkel cell carcinoma from other neuroendocrine carcinomas

Kervarrec, Thibault; Tallet, Anne; Miquelestorena-Standley, Élodie; Houben, Roland; Schrama, David; Gambichler, Thilo; Berthon, Patricia; Corre, Y. Le; Hainaut-Wierzbicka, Ewa; Aubin, F.; Bens, Guido; Tabareau-Delalande, Flore; Bénéton, N.; Fromont, Gaëlle; Arbion, Flavie; Leteurtre, Emmanuelle; Touzé, Antoine; Samimi, Mahtab; Guyétant, Serge

doi:10.1038/s41379-018-0155-y

Cited by 82 publications

(101 citation statements)

References 45 publications

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“…While in TB a mixture of cells with either epithelial progenitor or MC phenotype is present, almost all MCC tumor cells display a phenotype of mature MC. Indeed, in a previous study we observed 100, 99, and 92% of MCC cases with widespread positivity for the MC markers KRT8, 18, and 20, respectively [33,34]. Accordingly, in the present work, diffuse and strong nuclear positivity for SOX2 was detected in almost all analyzed MCC tumors (98%).…”

Section: Mc-progenitor and MC Markers Are Expressed In Trichoblastomasupporting

confidence: 76%

Merkel Cell Polyomavirus T Antigens Induce Merkel Cell-Like Differentiation in GLI1-Expressing Epithelial Cells

Kervarrec

Samimi

Hesbacher

et al. 2020

Cancers

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Merkel cell carcinoma (MCC) is an aggressive skin cancer frequently caused by the Merkel cell polyomavirus (MCPyV). It is still under discussion, in which cells viral integration and MCC development occurs. Recently, we demonstrated that a virus-positive MCC derived from a trichoblastoma, an epithelial neoplasia bearing Merkel cell (MC) differentiation potential. Accordingly, we hypothesized that MC progenitors may represent an origin of MCPyV-positive MCC. To sustain this hypothesis, phenotypic comparison of trichoblastomas and physiologic human MC progenitors was conducted revealing GLI family zinc finger 1 (GLI1), Keratin 17 (KRT 17), and SRY-box transcription factor 9 (SOX9) expressions in both subsets. Furthermore, GLI1 expression in keratinocytes induced transcription of the MC marker SOX2 supporting a role of GLI1 in human MC differentiation. To assess a possible contribution of the MCPyV T antigens (TA) to the development of an MC-like phenotype, human keratinocytes were transduced with TA. While this led only to induction of KRT8, an early MC marker, combined GLI1 and TA expression gave rise to a more advanced MC phenotype with SOX2, KRT8, and KRT20 expression. Finally, we demonstrated MCPyV-large T antigens’ capacity to inhibit the degradation of the MC master regulator Atonal bHLH transcription factor 1 (ATOH1). In conclusion, our report suggests that MCPyV TA contribute to the acquisition of an MC-like phenotype in epithelial cells.

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Section: Mc-progenitor and MC Markers Are Expressed In Trichoblastomasupporting

confidence: 76%

Merkel Cell Polyomavirus T Antigens Induce Merkel Cell-Like Differentiation in GLI1-Expressing Epithelial Cells

Kervarrec

Samimi

Hesbacher

et al. 2020

Cancers

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“…reported a detailed evaluation of a set of 10 immunohistochemical markers that had previously shown promise in assigning NEC site of origin. When positive was thresholded as ‘diffuse, strong, and homogeneous staining identified by low magnification (×5)’, SATB2 was one of the best‐performing markers [along with neurofilament, Merkel cell polyomavirus (by polymerase chain reaction), and CK20], with a sensitivity of 64%, specificity of 98% and positive likelihood ratio of 36.6 for Merkel cell carcinoma . These results caused me to re‐examine SATB2 expression in NECs by using H‐scores.…”

Section: Discussionmentioning

confidence: 99%

“…Most recently, Kervarrec et al . reported neurofilament (clone 2F11) expression in 75% of 97 Merkel cell carcinomas, and in only 5% of 59 visceral NECs . Given that SATB2 is expressed in the brain and spinal cord, its (along with neurofilament's) preferential expression in Merkel cell carcinoma may reflect a neuronal phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…When positive was thresholded as 'diffuse, strong, and homogeneous staining identified by low magnification (95)', SATB2 was one of the best-performing markers [along with neurofilament, Merkel cell polyomavirus (by polymerase chain reaction), and CK20], with a sensitivity of 64%, specificity of 98% and positive likelihood ratio of 36.6 for Merkel cell carcinoma. 26 These results caused me to re-examine SATB2 expression in NECs by using H-scores. At an H-score threshold of ≥150 (analogous to the qualitative threshold used by Kervarrec et al), SATB2 was 69% sensitive and 90% specific for Merkel cell carcinoma.…”

Section: Discussionmentioning

confidence: 99%

“…1 Most recently, Kervarrec et al reported neurofilament (clone 2F11) expression in 75% of 97 Merkel cell carcinomas, and in only 5% of 59 visceral NECs. 26 Given that SATB2 is expressed in the brain and spinal cord, its (along with neurofilament's) preferential expression in Merkel cell carcinoma may reflect a neuronal phenotype. Supporting the conclusion that SATB2 is functioning as a neuronal marker in this context, SATB2 expression has also been described in sudomotor cholinergic neurons, and our group has observed it in ganglion cells of the enteric nervous system (the latter is an unpublished observation).…”

Section: Discussionmentioning

confidence: 99%

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SATB2 in neuroendocrine neoplasms: strong expression is restricted to well‐differentiated tumours of lower gastrointestinal tract origin and is most frequent in Merkel cell carcinoma among poorly differentiated carcinomas

Bellizzi

2019

Histopathology

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Aims Special AT‐rich sequence‐binding protein 2 (SATB2) is a transcriptional regulator with critical roles in brain, craniofacial and skeletal development. It has emerged as a key marker of lower gastrointestinal (GI) tract columnar epithelial and osteoblastic differentiation. Transcription factor immunohistochemistry is useful in assigning site of origin in well‐differentiated neuroendocrine tumours (NETs), and has had a limited role in poorly differentiated neuroendocrine carcinomas (NECs). This study sought to evaluate the role of SATB2 in assigning site of origin in neuroendocrine epithelial neoplasms. Methods and results Tissue microarrays were constructed from the following: 317 NETs (37 thyroid, 46 lung, 16 stomach, 12 duodenum, 70 pancreas, 106 jejunoileum, 24 appendix, and six rectosigmoid), 44 phaeochromocytomas/paragangliomas, and 79 NECs (29 Merkel cell, 30 lung, and 20 extrapulmonary visceral); nine appendiceal and 19 rectal NETs were examined in whole sections. SATB2 immunohistochemistry was scored for extent (%) and intensity (0–3+), with an H‐score being calculated. SATB2 was expressed by 96% of rectosigmoid NETs, 79% of appendiceal NETs, and only 7% of other well‐differentiated neoplasms (P < 0.0001). Expression in lower GI tract NETs (median H‐score of 255) was stronger than in other positive tumours (median H‐score of 7) (P < 0.0001). Any SATB2 expression was 86% sensitive/93% specific for lower GI tract origin. SATB2 was expressed by 79% of Merkel cell carcinomas (median H‐score of 300), 33% of lung NECs (median H‐score of 23), and 60% of extrapulmonary visceral NECs (median H‐score of 110), with stronger expression in Merkel cell carcinoma (P < 0.001). At an H‐score cutoff of ≥150, SATB2 was 69% sensitive/90% specific for Merkel cell carcinoma. Conclusions SATB2 is frequently and strongly expressed by lower GI tract NETs; we have adopted it as our rectal NET marker. Relatively frequent and strong expression in Merkel cell carcinoma may have value in assigning NEC site of origin.

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Assessment of Age, Period, and Birth Cohort Effects and Trends in Merkel Cell Carcinoma Incidence in the United States

Jacobs

Huang²,

Olino

et al. 2021

JAMA Dermatol

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IMPORTANCE Merkel cell carcinoma is an aggressive, cutaneous, neuroendocrine cancer that is increasing in incidence. Understanding why the incidence of Merkel cell carcinoma is increasing through underlying factors, such as age effects, calendar period of diagnosis effects, and birth cohort effects, can help guide resource allocation and design of screening programs.OBJECTIVES To evaluate the associations of patient age, calendar period of diagnosis, and birth cohort with the increasing incidence of Merkel cell carcinoma and to provide new incidence projections to 2030. DESIGN, SETTING, AND PARTICIPANTSA cross-sectional retrospective study with age-period-cohort analysis and incidence projection modeling using data from the Surveillance, Epidemiology, and End Results Program database of 9 registries from 1987 to 2016 was conducted among 3720 patients with Merkel cell carcinoma. Statistical analysis was conducted from October 20, 2019, to July 29, 2020.EXPOSURES Age effects (ie, physiology), period of diagnosis effects (ie, changes in diagnostics and clinical awareness), and birth cohort effects (ie, environmental risk factors) over time were assessed. MAIN OUTCOMES AND MEASURESIncidence rates of Merkel cell carcinoma. RESULTS Among the 3720 patients in the study (2200 male patients [59.1%]; median age, 77 years [interquartile range, 68-84 years]), during the period from 2012 to 2016, the age-adjusted Merkel cell carcinoma incidence rate was 0.66 per 100 000 (95% CI, 0.62-0.70), which represented a 3.5-times (95% CI, 3.0-4.2) increase from 1987 to 1991. The incidence of Merkel cell carcinoma increased with patient age across calendar periods and birth cohorts; the highest incidence rate was observed for those aged 85 years or older, with an age-adjusted rate from 2012 to 2016 of 14.6 per 100 000 for men and 5.5 per 100 000 for women. Although the birth cohort effect has continued to increase over time, the calendar period of diagnosis effect has started to plateau. It is projected that there will be 3023 new cases of Merkel cell carcinoma in 2020 and 5130 new cases in 2030, increased from an estimated 1933 cases in 2010. CONCLUSIONS AND RELEVANCEThe slowing down of the period effect (ie, changes in diagnostics and awareness) found in this longitudinal cohort study suggests that part of the initial increased incidence of Merkel cell carcinoma was associated with increased detection. However, the projected increase in incidence rate is likely associated with the aging population and increasing risk factor exposure in more recent birth cohorts.

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Diagnostic accuracy of a panel of immunohistochemical and molecular markers to distinguish Merkel cell carcinoma from other neuroendocrine carcinomas

Cited by 82 publications

References 45 publications

Merkel Cell Polyomavirus T Antigens Induce Merkel Cell-Like Differentiation in GLI1-Expressing Epithelial Cells

Merkel Cell Polyomavirus T Antigens Induce Merkel Cell-Like Differentiation in GLI1-Expressing Epithelial Cells

SATB2 in neuroendocrine neoplasms: strong expression is restricted to well‐differentiated tumours of lower gastrointestinal tract origin and is most frequent in Merkel cell carcinoma among poorly differentiated carcinomas

Assessment of Age, Period, and Birth Cohort Effects and Trends in Merkel Cell Carcinoma Incidence in the United States

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