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AIMS: Merkel cell carcinoma (MCC) is frequently caused by the Merkel cell polyomavirus (MCPyV). Characteristic for these virus-positive (VP) MCC is MCPyV integration into the host genome and truncation of the viral oncogene Large T antigen (LT), with full-length LT expression considered as incompatible with MCC growth. Genetic analysis of a VP-MCC/trichoblastoma combined tumour demonstrated that virus-driven MCC can arise from an epithelial cell. Here we describe two further cases of VP-MCC combined with an adnexal tumour, i.e. one trichoblastoma and one poroma. METHODS AND RESULTS: Whole-genome sequencing of MCC/trichoblastoma again provided evidence of a trichoblastoma-derived MCC. Although an MCC-typical LT-truncating mutation was detected, we could not determine an integration site and we additionally detected a wildtype sequence encoding full-length LT. Similarly, Sanger sequencing of the combined MCC/poroma revealed coding sequences for both truncated and full-length LT. Moreover, in situ RNA hybridization demonstrated expression of a late region mRNA encoding the viral capsid protein VP1 in both combined as well as in a few cases of pure MCC. CONCLUSION: The data presented here suggest the presence of wildtype MCPyV genomes and VP1 transcription in a subset of MCC.
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Carcinoma de Células de Merkel , Poliomavirus de Células de Merkel , Infecciones por Polyomavirus , Poroma , Neoplasias Cutáneas , Neoplasias de las Glándulas Sudoríparas , Humanos , Carcinoma de Células de Merkel/metabolismo , Poliomavirus de Células de Merkel/genética , Infecciones por Polyomavirus/complicaciones , Neoplasias Cutáneas/patología , GenómicaRESUMEN
BACKGROUND: Despite its low efficacy, chemotherapy with dacarbazine remains an option in metastatic melanoma patients after failure of immune checkpoint inhibitors (ICI) ± targeted therapy. Some observations suggested an increased efficacy of chemotherapy in melanoma or lung cancer patients previously treated with ICI; we aimed to evaluate the efficacy of dacarbazine in a controlled-group study of patients pre-treated or not with ICI. METHODS: We retrospectively collected data from all consecutive patients treated with dacarbazine for advanced cutaneous melanoma without brain metastasis, in our skin cancer centre between June 2006 and September 2019. The primary endpoint was progression-free survival (PFS); secondary endpoints were overall response rates (ORR), overall survival (OS) and safety of dacarbazine. RESULTS: Among 72 patients, 17 (23.6%) received dacarbazine after ICI and 55 (76.3%) without prior ICI. Despite less favourable prognostic factors in patients ICI-pre-treated, median PFS was 4.27 months (range 0.89-43.69) in this group versus 2.04 months (range 1.25-39.25) P = 0.03 in non-ICI-pre-treated patients; ORR were 35.3% and 12.7%, respectively. The median OS and the occurrence of adverse events were similar in both groups. CONCLUSION: Dacarbazine seems to offer a short-lived benefit in patients with progressive advanced disease despite ICI (±targeted therapy), and could be an alternative before considering best supportive care.
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Antineoplásicos Alquilantes/uso terapéutico , Dacarbazina/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Melanoma/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estudios de Casos y Controles , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Melanoma/inmunología , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Wide local excision constitutes the standard of care for Merkel cell carcinoma, but the optimal margin width remains controversial. OBJECTIVES: To assess whether narrow margins (0.5-1 cm) were associated with outcome. METHODS: Patients were recruited from a retrospective French multicentric cohort and included if they had had excision of primary tumor with minimum lateral margins of 0.5 cm. Factors associated with mortality and recurrence were assessed by multivariate regression. RESULTS: Among the 214 patients included, 58 (27.1%) had undergone excision with narrow margins (0.5-1 cm) versus 156 (72.9%) with wide margins (>1 cm). During a median follow-up of 50.7 months, cancer-specific survival did not differ between groups (5-year specific survival rate 76.8% [95% confidence interval 61.7%-91.9%] and 76.2% [95% confidence interval 68.8%-83.6%], respectively). Overall survival, any recurrence-free survival, and local recurrence-free survival did not significantly differ between groups. Cancer-specific mortality was associated with age, male sex, American Joint Committee on Cancer stage III, and presence of positive margins. LIMITATIONS: Retrospective design, heterogenous baseline characteristics between groups. CONCLUSION: Excision with narrow margins was not associated with outcome in this cohort, in which most patients had clear margins and postoperative radiation therapy. Residual tumor, mostly found on deep surgical margins, was independently associated with prognosis.
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Carcinoma de Células de Merkel/patología , Márgenes de Escisión , Recurrencia Local de Neoplasia/patología , Neoplasias Cutáneas/patología , Anciano , Carcinoma de Células de Merkel/mortalidad , Carcinoma de Células de Merkel/cirugía , Estudios de Cohortes , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Francia/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/radioterapia , Recurrencia Local de Neoplasia/cirugía , Neoplasia Residual , Modelos de Riesgos Proporcionales , Radioterapia Adyuvante , Estudios Retrospectivos , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/radioterapia , Neoplasias Cutáneas/cirugía , Análisis de SupervivenciaRESUMEN
Advanced melanoma patients who failed anti-PD-1 therapy have limited options. We analyzed a cohort of 133 advanced melanoma patients receiving anti-PD-1 monotherapy in a referral center between April 2015 and December 2017, and included the 26 patients with confirmed progressive (PD) or stable disease who received additional radiotherapy with an unmodified anti-PD-1 mAb regimen. Tumor evaluations were done on radiated and nonradiated (RECIST 1.1) lesions, with abscopal effect defined as a partial (PR) or complete response (CR) outside radiated fields. Primary endpoint was the CR + PR rate in radiated + nonradiated lesions. Secondary endpoints were progression-free survival (PFS), melanoma-specific survival (MSS) and safety. First late radiotherapy, consisting of hypofractionated radiotherapy (3-5 sessions, 20-26 Gy), standard palliative radiotherapy or brain radiosurgery was begun after a median of 6.3 months of anti-PD-1 in 23, 2 and 1 patient(s), respectively. Best response was 8 (31%) CR, 2 (8%) profound PR allowing surgical resection of remaining metastases and 16 (62%) PD. Abscopal effect was seen in 35% of patients. Median PFS and MSS since anti-PD-1 initiation was 15.2 [95% CI: 8.0 not achieved (na)] and 35.3 [95% CI: 18.5 na] months, respectively. PFS curves seemed to achieve a plateau. We discontinued anti-PD-1 therapy in 9/10 of patients with no residual evaluable disease and observed one relapse after a median of 10 months off anti-PD1-therapy. No unusual adverse event was recorded. Limitations of the study include its retrospective nature and limited size. Hypofractionated radiotherapy may enhance anti-PD1 monotherapy efficacy in patients who previously failed anti-PD-1 therapy. Controlled studies are needed.
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Quimioradioterapia/métodos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Melanoma/terapia , Neoplasias Cutáneas/terapia , Adulto , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Melanoma/inmunología , Melanoma/mortalidad , Melanoma/secundario , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Supervivencia sin Progresión , Estudios Prospectivos , Hipofraccionamiento de la Dosis de Radiación , Criterios de Evaluación de Respuesta en Tumores Sólidos , Estudios Retrospectivos , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patologíaAsunto(s)
Antineoplásicos Inmunológicos , Carcinoma de Células de Merkel , Neoplasias Cutáneas , Humanos , Carcinoma de Células de Merkel/tratamiento farmacológico , Carcinoma de Células de Merkel/cirugía , Carcinoma de Células de Merkel/patología , Nivolumab/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/cirugía , Neoplasias Cutáneas/patología , Antineoplásicos Inmunológicos/uso terapéutico , Adyuvantes Inmunológicos/uso terapéuticoRESUMEN
Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous cancer, which is immunogenic, regardless of the presence of MCPyV (80% of cases). The identification of MCC-specific epitopes recognized by CD8 T cells is crucial to expand the arsenal of immunotherapeutic treatments. Until now, most efforts focused on the identification of virus-specific epitopes, whereas immune responses directed against shared cellular tumor-specific antigens have not been evidenced. In this study, we measured T-cell responses against viral (nâ¯=â¯3) and tumor antigens (nâ¯=â¯47) from TILs derived from 21 MCC tumors. Virus-specific CD8 T-cell responses dominated MCC-specific immune responses, and we identified two new HLA-peptide complexes derived from the LT antigen, located in a region encompassing 3 previously identified epitopes. Finally, we show that MAGE-A3 antigen, frequently expressed by MCC tumors, was recognized by CD8 TILs from a virus-negative MCC tumor and thus could be a target for immunotherapy in this setting.
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Linfocitos T CD8-positivos/inmunología , Carcinoma de Células de Merkel/inmunología , Neoplasias Cutáneas/inmunología , Animales , Antígenos de Neoplasias/inmunología , Antígenos Virales/inmunología , Células COS , Línea Celular Tumoral , Chlorocebus aethiops , Epítopos de Linfocito T/inmunología , Femenino , Antígenos HLA/inmunología , Humanos , Masculino , Proteínas de Neoplasias/inmunologíaAsunto(s)
Antineoplásicos Inmunológicos , Carcinoma de Células de Merkel , Ipilimumab , Neoplasias Renales , Nivolumab , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células de Merkel/tratamiento farmacológico , Carcinoma de Células Renales/tratamiento farmacológico , Humanos , Ipilimumab/uso terapéutico , Neoplasias Renales/patología , Nivolumab/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológicoRESUMEN
BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive skin cancer with a recurrence rate of >40%. Of the 2000 MCC cases per year in the United States, most are caused by the Merkel cell polyomavirus (MCPyV). Antibodies to MCPyV oncoprotein (T-antigens) have been correlated with MCC tumor burden. The present study assesses the clinical utility of MCPyV-oncoprotein antibody titers for MCC prognostication and surveillance. METHODS: MCPyV-oncoprotein antibody detection was optimized in a clinical laboratory. A cohort of 219 patients with newly diagnosed MCC were followed prospectively (median follow-up, 1.9 years). Among the seropositive patients, antibody titer and disease status were serially tracked. RESULTS: Antibodies to MCPyV oncoproteins were rare among healthy individuals (1%) but were present in most patients with MCC (114 of 219 patients [52%]; P < .01). Seropositivity at diagnosis independently predicted decreased recurrence risk (hazard ratio, 0.58; P = .04) in multivariate analyses adjusted for age, sex, stage, and immunosuppression. After initial treatment, seropositive patients whose disease did not recur had rapidly falling titers that became negative by a median of 8.4 months. Among seropositive patients who underwent serial evaluation (71 patients; 282 time points), an increasing oncoprotein titer had a positive predictive value of 66% for clinically evident recurrence, whereas a decreasing titer had a negative predictive value of 97%. CONCLUSIONS: Determination of oncoprotein antibody titer assists in the clinical management of patients with newly diagnosed MCC by stratifying them into a higher risk seronegative cohort, in which radiologic imaging may play a more prominent role, and into a lower risk seropositive cohort, in which disease status can be tracked in part by oncoprotein antibody titer. Cancer 2017;123:1464-1474. © 2016 American Cancer Society.
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Anticuerpos Antivirales/inmunología , Carcinoma de Células de Merkel/diagnóstico , Carcinoma de Células de Merkel/etiología , Proteínas Oncogénicas Virales/inmunología , Anciano , Anciano de 80 o más Años , Anticuerpos Antivirales/sangre , Biomarcadores , Carcinoma de Células de Merkel/epidemiología , Carcinoma de Células de Merkel/mortalidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Vigilancia de la Población , Estudios Prospectivos , Reproducibilidad de los Resultados , Estudios Seroepidemiológicos , Infecciones Tumorales por Virus/complicaciones , Infecciones Tumorales por Virus/inmunología , Infecciones Tumorales por Virus/virologíaRESUMEN
BACKGROUND: Paraneoplastic syndromes (PNS) are commonly associated with neuroendocrine cancers, such as small cell lung cancer. OBJECTIVES: We examined the association of PNS in Merkel cell carcinoma (MCC), a rare neuroendocrine skin cancer. METHODS: We identified PNS associated with MCC based on chart review of a Seattle-based repository and examined the incidence of MCC-associated hyponatremia in an independent cohort within Kaiser Permanente Northern California. RESULTS: Eight PNS cases were identified from the Seattle repository. Three distinct PNS types were observed: cerebellar degeneration (1 case), Lambert-Eaton myasthenic syndrome (2 cases), and malignancy-associated hyponatremia (5 cases). Moreover, the incidence of severe hyponatremia (serum sodium <125 mmol/L) coincident with MCC was identified among 4.3% (9 of 211) patients with MCC in the Kaiser Permanente Northern California cohort. LIMITATIONS: We did not have access to complete medical records on all patients so it was not possible to determine the prevalence of PNS in MCC. CONCLUSIONS: MCC can be associated with PNS similar to those found in other neuroendocrine cancers. Clinicians should be aware of these presentations as PNS often precede the identification of the underlying malignancy and usually resolve with appropriate treatment of the cancer.
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Carcinoma de Células de Merkel/diagnóstico , Síndromes Paraneoplásicos/diagnóstico , Síndromes Paraneoplásicos/epidemiología , Neoplasias Cutáneas/diagnóstico , Distribución por Edad , Anciano , Anciano de 80 o más Años , Carcinoma de Células de Merkel/epidemiología , Carcinoma de Células de Merkel/cirugía , Comorbilidad , Supervivencia sin Enfermedad , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Síndromes Paraneoplásicos/terapia , Pronóstico , Sistema de Registros , Medición de Riesgo , Muestreo , Distribución por Sexo , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/terapia , Análisis de SupervivenciaRESUMEN
OBJECTIVES: The participation rate in the Danish National Health Survey (DNHS) 2010 was significantly lower among ethnic minorities than ethnic Danes. The purpose was to characterize nonresponse among ethnic minorities in DNHS, analyze variations in item nonresponse, and investigate barriers and incentives to participation. DESIGN: This was a mixed-method study. Logistic regression was used to analyze nonresponse using data from DNHS (N = 177,639 and chi-square tests in item nonresponse analyses. We explored barriers and incentives regarding participation through focus groups and cognitive interviews. Informants included immigrants and their descendants of both sexes, with and without higher education. RESULTS: The highest nonresponse rate was for non-Western descendants (80.0%) and immigrants 25 (72.3%) with basic education. Immigrants and descendants had higher odds ratios (OR = 3.07 and OR = 3.35, respectively) for nonresponse than ethnic Danes when adjusted for sex, age, marital status, and education. Non-Western immigrants had higher item nonresponse in several question categories. Barriers to non-participation related to the content, language, format, and layout of both the questionnaire and the cover letter. The sender and setting in which to receive the questionnaire also influenced answering incentives. We observed differences in barriers and incentives between immigrants and descendants. CONCLUSIONS: Nonresponse appears related to linguistic and/or educational limitations, to alienation generated by the questions' focus on disease and cultural assumptions, or mistrust regarding anonymity. Ethnic minorities seem particularly affected by such barriers. To increase survey participation, questions could be sensitized to reflect multicultural traditions, and the impact of sender and setting considered.
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Participación de la Comunidad , Etnicidad , Encuestas Epidemiológicas , Grupos Minoritarios , Adolescente , Adulto , Dinamarca , Emigrantes e Inmigrantes/psicología , Femenino , Estado de Salud , Humanos , Lenguaje , Masculino , Clase Social , Encuestas y Cuestionarios , Adulto JovenAsunto(s)
Carcinoma de Células de Merkel/secundario , Neoplasias Hepáticas/secundario , Fosfatidilinositol 3-Quinasas/genética , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/uso terapéutico , Purinas/uso terapéutico , Quinazolinonas/uso terapéutico , Neoplasias Cutáneas/patología , Femenino , HumanosRESUMEN
BACKGROUND: Quantitation of circulating tumor cells (CTCs) has utility in managing breast, colon, and prostate carcinomas. OBJECTIVE: We sought to determine whether a commercially available CTC assay provides prognostic information in Merkel cell carcinoma (MCC), insight into treatment responses, or both. METHODS: We analyzed CTCs in 52 specimens from 34 patients with MCC. RESULTS: The presence of CTCs correlated with extent of disease at blood draw (P = .004). Among 15 patients with regional nodal disease, CTC-negative patients had 80% disease-specific survival at 2 years after the test, versus 29% for CTC-positive patients (P = .015). Among the entire cohort, those without CTCs had 72% MCC-specific survival whereas CTC-positive patients had 25% survival (n = 34, median follow-up 19 months, P = .0003). Fifty seven percent of patients with MCC had a cytokeratin "dot" visible in 20% or more of CTCs, a feature that was absent among CTCs from other carcinomas (0 of 13 cases). LIMITATIONS: CTC assay was performed at variable times after diagnosis and heterogeneity in extent of disease affects interpretability of the data. CONCLUSION: CTC detection in MCC is feasible and appears to add prognostic information, particularly in patients with regional nodal disease. It may also assist clinical management in certain situations, including differentiating metastatic MCC cells from those of other carcinomas.
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Carcinoma de Células de Merkel/mortalidad , Carcinoma de Células de Merkel/patología , Recurrencia Local de Neoplasia/mortalidad , Células Neoplásicas Circulantes/patología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Biomarcadores , Carcinoma de Células de Merkel/sangre , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Queratinas/análisis , Queratinas/metabolismo , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Pronóstico , Medición de Riesgo , Neoplasias Cutáneas/sangre , Estadísticas no Paramétricas , Análisis de SupervivenciaRESUMEN
Nature-based Solutions (NbS) are actions that harness nature to help address major societal challenges. The assessment frameworks for NbS proposed in the literature differ in scope and intended use. In 2020, the International Union for Conservation of Nature (IUCN) introduced their Global Standard for NbS as a framework that can be used by anyone working on different types of NbS. Since research on the applicability of the IUCN Standard remains limited, the aim of this paper is to analyse whether the IUCN Standard may be used as an overarching assessment framework for NbS in river flood management applications and to identify the main differences in content with other NbS-frameworks. This was achieved through a comparison with 29 assessment frameworks for NbS, that are applicable to physical interventions for riverine flood risk reduction. The comparisons showed that the IUCN Standard has the largest breadth in scope of application and may therefore be used as an overarching framework. In addition, we identified a distinction between frameworks for the assessment of project processes (process-oriented) and project results (results-oriented), where the IUCN Standard can be characterized as process-oriented. This implies that the IUCN Standard may be used to assess the processes (e.g. stakeholder engagement and adaptive management) of planned, ongoing or completed NbS projects for a wide variety of environmental contexts and societal challenges. This will help persuade policy makers to consider NbS as one of the solutions in flood management issues, next to or in combination with e.g. engineering solutions or changing land use. We also identified that, while the IUCN Standard is straightforward to use and incorporates stakeholder input, the environmental context specificity as well as guidance depth on resources for assessment can be improved.
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AIM: Avelumab has been approved worldwide for treatment of metastatic Merkel cell carcinoma (mMCC), a rare and aggressive skin cancer. This study evaluated outcomes in patients with mMCC in France who received avelumab as second-line or later (2L+) treatment in routine clinical practice. METHODS: This retrospective, noninterventional study evaluated all patients diagnosed with mMCC using two databases: CARADERM (French national database of rare dermatological cancers) and SNDS (national healthcare database), identified via probabilistic linkage. Eligible patients initiated avelumab as 2L+ treatment between August 2016 and December 2019 and were followed for 24 months. The primary endpoint was overall survival (OS) at 24 months. RESULTS: Overall, 180 patients who received 2L+ avelumab were identified (112 from CARADERM, 68 after SNDS linkage). Median age at diagnosis was 74.0 years and 177 (98.3 %) had received chemotherapy alone as first-line treatment. Median follow-up was 13.1 months. Median OS from start of avelumab was 14.6 months (95 % CI, 9.9-21.3) in the overall population, 15.9 months (95 % CI, 8.6-28.3) in CARADERM patients, and 13.3 months (95 % CI, 6.7-19.1) in non-CARADERM patients. OS rates at 12 and 24 months were 53.8 % (95 % CI, 46.2 %-60.8 %) and 40.5 % (95 % CI, 33.2 %-47.6 %), respectively. In evaluable patients (CARADERM database), median progression-free survival was 3.6 months (95 % CI, 2.7-7.5) and the objective response rate was 55.3 % (95 % CI, 45.3-65.4), including complete response in 31.9 %. CONCLUSIONS: Real-world outcomes with 2L+ avelumab treatment for mMCC are consistent with clinical trial findings, supporting the recommendation of avelumab as a standard of care.
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Merkel cell carcinoma (MCC) is an aggressive skin cancer for which Merkel cell polyomavirus integration and expression of viral oncogenes small T and Large T have been identified as major oncogenic determinants. Recently, a component of the PRC2 complex, the histone methyltransferase enhancer of zeste homolog 2 (EZH2) that induces H3K27 trimethylation as a repressive mark has been proposed as a potential therapeutic target in MCC. Because divergent results have been reported for the levels of EZH2 and trimethylation of lysine 27 on histone 3, we analyzed these factors in a large MCC cohort to identify the molecular determinants of EZH2 activity in MCC and to establish MCC cell lines' sensitivity to EZH2 inhibitors. Immunohistochemical expression of EZH2 was observed in 92% of MCC tumors (156 of 170), with higher expression levels in virus-positive than virus-negative tumors (P = 0.026). For the latter, we showed overexpression of EZHIP, a negative regulator of the PRC2 complex. In vitro, ectopic expression of the large T antigen in fibroblasts led to the induction of EZH2 expression, whereas the knockdown of T antigens in MCC cell lines resulted in decreased EZH2 expression. EZH2 inhibition led to selective cytotoxicity on virus-positive MCC cell lines. This study highlights the distinct mechanisms of EZH2 induction between virus-negative and -positive MCC.
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Carcinoma de Células de Merkel , Poliomavirus de Células de Merkel , Neoplasias Cutáneas , Humanos , Carcinoma de Células de Merkel/patología , Histonas/metabolismo , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Neoplasias Cutáneas/patología , Poliomavirus de Células de Merkel/genética , Antígenos Virales de Tumores/genética , Antígenos Virales de Tumores/metabolismoRESUMEN
To assess the role of radiotherapy in anti-PD-1-treated melanoma patients, we studied retrospectively a cohort of 206 consecutive anti-PD-1 monotherapy-treated advanced melanoma patients (59% M1c/d, 50% ≥ 3 metastasis sites, 33% ECOG PS ≥ 1, 33% > 1st line, 32% elevated serum LDH) having widely (49%) received concurrent radiotherapy, with RECIST 1.1 evaluation of radiated and non-radiated lesions. Overall (OS) and progression-free (PFS) survivals were calculated using Kaplan−Meier. Radiotherapy was performed early (39 patients) or after 3 months (61 patients with confirmed anti-PD-1 failure). The first radiotherapy was hypofractionated extracranial radiotherapy to 1−2 targets (26 Gy-4 weekly sessions, 68 patients), intracranial radiosurgery (25 patients), or palliative. Globally, 67 (32.5% [95% CI: 26.1−38.9]) patients achieved complete response (CR), with 25 CR patients having been radiated. In patients failing anti-PD-1, PFS and OS from anti-PD-1 initiation were 16.8 [13.4−26.6] and 37.0 months [24.6−NA], respectively, in radiated patients, and 2.2 [1.5−2.6] and 4.3 months [2.6−7.1], respectively, in non-radiated patients (p < 0.001). Abscopal response was observed in 31.5% of evaluable patients who radiated late. No factors associated with response in radiated patients were found. No unusual adverse event was seen. High-dose radiotherapy may enhance CR rate above the 6−25% reported in anti-PD-1 monotherapy or ipilimumab + nivolumab combo studies in melanoma patients.
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MCC (Merkel cell carcinoma) is an aggressive neuroendocrine cutaneous neoplasm. Integration of the Merkel cell polyomavirus (MCPyV) is observed in about 80% of the cases, while the remaining 20% are related to UV exposure. Both MCPyV-positive and -negative MCCs-albeit by different mechanisms-are associated with RB1 inactivation leading to overexpression of SOX2, a major contributor to MCC biology. Moreover, although controversial, loss of RB1 expression seems to be restricted to MCPyV-negative cases.The aim of the present study was to assess the performances of RB1 loss and SOX2 expression detected by immunohistochemistry to determine MCPyV status and to diagnose MCC, respectively.Overall, 196 MCC tumors, 233 non-neuroendocrine skin neoplasms and 70 extra-cutaneous neuroendocrine carcinomas (NEC) were included. SOX2 and RB1 expressions were assessed by immunohistochemistry in a tissue micro-array. Diagnostic performances were determined using the likelihood ratio (LHR).RB1 expression loss was evidenced in 27% of the MCC cases, 12% of non-neuroendocrine skin tumors and 63% of extra-cutaneous NEC. Importantly, among MCC cases, RB1 loss was detected in all MCPyV(-) MCCs, while MCPyV( +) cases were consistently RB1-positive (p < 0.001). SOX2 diffuse expression was observed in 92% of the MCC cases and almost never observed in non-neuroendocrine skin epithelial neoplasms (2%, p < 0.0001, LHR + = 59). Furthermore, SOX2 diffuse staining was more frequently observed in MCCs than in extra-cutaneous NECs (30%, p < 0.001, LHR + = 3.1).These results confirm RB1 as a robust predictor of MCC viral status and further suggest SOX2 to be a relevant diagnostic marker of MCC.
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Carcinoma de Células de Merkel , Poliomavirus de Células de Merkel , Infecciones por Polyomavirus , Neoplasias Cutáneas , Infecciones Tumorales por Virus , Carcinoma de Células de Merkel/diagnóstico , Carcinoma de Células de Merkel/patología , Humanos , Poliomavirus de Células de Merkel/metabolismo , Infecciones por Polyomavirus/complicaciones , Infecciones por Polyomavirus/metabolismo , Proteínas de Unión a Retinoblastoma , Factores de Transcripción SOXB1/metabolismo , Neoplasias Cutáneas/patología , Infecciones Tumorales por Virus/complicaciones , Ubiquitina-Proteína LigasasRESUMEN
Although virus-negative Merkel cell carcinoma (MCC) is characterized by a high frequency of UV-induced mutations, the expression of two viral oncoproteins is regarded as a key mechanism driving Merkel cell polyomavirusâpositive MCC. The cells in which these molecular events initiate MCC oncogenesis have yet not been identified for both MCC subsets. A considerable proportion of virus-negative MCC is found in association with squamous cell carcinoma (SCC), suggesting (i) coincidental collision, (ii) one providing a niche for the other, or (iii) one evolving from the other. Whole-exome sequencing of four combined tumors consisting of SCC in situ and Merkel cell polyomavirusânegative MCC showed many mutations shared between SCC and MCC in all cases, indicating a common ancestry and thereby a keratinocytic origin of these MCCs. Moreover, analyses of the combined cases as well as of pure SCC and MCC suggest that RB1 inactivation in SCC facilitates MCC development and that epigenetic changes may contribute to the SCC/MCC transition.
Asunto(s)
Carcinoma in Situ , Carcinoma de Células de Merkel , Carcinoma de Células Escamosas , Poliomavirus de Células de Merkel , Neoplasias Cutáneas , Carcinoma de Células de Merkel/genética , Carcinoma de Células de Merkel/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Humanos , Poliomavirus de Células de Merkel/genética , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patologíaRESUMEN
Merkel cell carcinoma (MCC) is a rare skin cancer, accounting for less than 1% of all cutaneous malignancies. It is found predominantly in white populations and risk factors include advanced age, ultraviolet exposure, male sex, immunosuppression, such as AIDS/HIV infection, haematological malignancies or solid organ transplantation, and Merkel cell polyomavirus infection. MCC is an aggressive tumour with 26% of cases presenting lymph node involvement at diagnosis and 8% with distant metastases. Five-year overall survival rates range between 48% and 63%. Two subsets of MCC have been characterised with distinct molecular pathogenetic pathways: ultraviolet-induced MCC versus virus-positive MCC, which carries a better prognosis. In both subtypes, there are alterations in the retinoblastoma protein and p53 gene structure and function. MCC typically manifests as a red nodule or plaque with fast growth, most commonly on sun exposed areas. Histopathology (small-cell neuroendocrine appearance) and immunohistochemistry (CK20 positivity and TTF-1 negativity) confirm the diagnosis. The current staging systems are the American Joint Committee on Cancer/Union for international Cancer control 8th edition. Baseline whole body imaging is encouraged to rule out regional and distant metastasis. For localised MCC, first-line treatment is surgical excision with postoperative margin assessment followed by adjuvant radiation therapy (RT). Sentinel lymph node biopsy is recommended in all patients with MCC without clinically detectable lymph nodes or distant metastasis. Adjuvant RT alone, eventually combined with complete lymph nodes dissection is proposed in case of micrometastatic nodal involvement. In case of macroscopic nodal involvement, the standard of care is complete lymph nodes dissection potentially followed by post-operative RT. Immunotherapy with anti-PD-(L)1 antibodies should be offered as first-line systemic treatment in advanced MCC. Chemotherapy can be used when patients fail to respond or are intolerant for anti-PD-(L)1 immunotherapy or clinical trials.