Recurrence and Mortality Risk of Merkel Cell Carcinoma by Cancer Stage and Time From Diagnosis.

IMPORTANCE: Merkel cell carcinoma (MCC) often behaves aggressively; however, disease-recurrence data are not captured in national databases, and it is unclear what proportion of patients with MCC experience a recurrence (estimates vary from 27%-77%). Stage-specific recurrence data that includes time from diagnosis would provide more precise prognostic information and contribute to risk-appropriate clinical surveillance. OBJECTIVE: To estimate risk of stage-specific MCC recurrence and mortality over time since diagnosis. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study included 618 patients with MCC who were prospectively enrolled in a Seattle-based data repository between 2003 and 2019. Of these patients, 223 experienced a recurrence of MCC. Data analysis was performed July 2019 to November 2021. MAIN OUTCOMES AND MEASURES: Stage-specific recurrence and survival, as well as cumulative incidence and Kaplan-Meier analyses. RESULTS: Among the 618 patients included in the analysis (median [range] age, 69 [11-98] years; 227 [37%] female), the 5-year recurrence rate for MCC was 40%. Risk of recurrence in the first year was high (11% for patients with pathologic stage I, 33% for pathologic stage IIA/IIB, 30% for pathologic stage IIIA, 45% for pathologic stage IIIB, and 58% for pathologic stage IV), with 95% of recurrences occurring within the first 3 years. Median follow-up among living patients was 4.3 years. Beyond stage, 4 factors were associated with increased recurrence risk in univariable analyses: immunosuppression (hazard ratio [HR], 2.4; 95% CI, 1.7-3.3; P < .001), male sex (HR, 1.9; 95% CI, 1.4-2.5; P < .001), known primary lesion among patients with clinically detectable nodal disease (HR, 2.3; 95% CI, 1.4-4.0; P = .001), and older age (HR, 1.1; 95% CI, 1.0-1.3; P = .06 for each 10-year increase). Among 187 deaths in the cohort, 121 (65%) were due to MCC. The MCC-specific survival rate was strongly stage dependent (95% at 5 years for patients with pathologic stage I vs 41% for pathologic stage IV). Among patients presenting with stage I to II MCC, a local recurrence (17 arising within/adjacent to the primary tumor scar) did not appreciably diminish survival compared with patients who had no recurrence (85% vs 88% MCC-specific survival at 5 years). CONCLUSIONS AND RELEVANCE: In this cohort study, the MCC recurrence rate (approximately 40%) was notably different than that reported for invasive melanoma (approximately 19%), squamous cell carcinoma (approximately 5%-9%), or basal cell carcinoma (approximately 1%-2%) following definitive therapy. Because more than 90% of MCC recurrences arise within 3 years, it is appropriate to adjust surveillance intensity accordingly. Stage- and time-specific recurrence data can assist in appropriately focusing surveillance resources on patients and time intervals in which recurrence risk is highest.

Postoperative, Single-Fraction Radiation Therapy in Merkel Cell Carcinoma of the Head and Neck.

PURPOSE: Conventionally fractionated, postoperative radiation therapy (cPORT; 50 Gy in 25 fractions) is considered for patients with Merkel cell carcinoma (MCC) to improve locoregional control. However, cPORT is associated with acute toxicity, especially in the head and neck (H&N) region, and requires daily treatments over several weeks. We previously reported high rates of durable local control with minimal toxicity using 8-Gy single-fraction radiation therapy (SFRT) in the metastatic setting. We report early results on a cohort of patients with localized H&N MCC who received postoperative SFRT if a cPORT regimen was not feasible. METHODS AND MATERIALS: Twelve patients with localized MCC of the H&N (clinical/pathologic stages I-II) and no prior radiation therapy to the region were identified from an institutional review board-approved prospective registry who underwent surgical resection followed by postoperative SFRT. Time to event was calculated starting from the date of resection before SFRT. The cumulative incidence of in-field locoregional recurrences and out-of-field recurrences was estimated with death as a competing risk. RESULTS: Twelve patients with H&N MCC were identified with clinical/pathologic stages I-II H&N MCC. Median age at diagnosis was 81 years (range, 58-96 years); 25% had immunosuppression. At a median follow-up of 19 months (range, 8-34), there were no in-field locoregional recurrences. A single out-of-field regional recurrence was observed, which was successfully salvaged. There were no MCC-specific deaths. No radiation-associated toxicities greater than grade 1 (Common Terminology Criteria for Adverse Events v5) were observed. CONCLUSIONS: Preliminary data suggest that SFRT could offer a potential alternative to cPORT to treat the primary site for localized H&N MCC, particularly in elderly or frail patients, with promising in-field local control and minimal toxicity. Further data with validation in larger cohorts are needed to confirm the sustained safety and efficacy of postoperative SFRT.

Prevalent and Diverse Intratumoral Oncoprotein-Specific CD8+ T Cells within Polyomavirus-Driven Merkel Cell Carcinomas.

Merkel cell carcinoma (MCC) is often caused by persistent expression of Merkel cell polyomavirus (MCPyV) T-antigen (T-Ag). These non-self proteins comprise about 400 amino acids (AA). Clinical responses to immune checkpoint inhibitors, seen in about half of patients, may relate to T-Ag-specific T cells. Strategies to increase CD8+ T-cell number, breadth, or function could augment checkpoint inhibition, but vaccines to augment immunity must avoid delivery of oncogenic T-antigen domains. We probed MCC tumor-infiltrating lymphocytes (TIL) with an artificial antigen-presenting cell (aAPC) system and confirmed T-Ag recognition with synthetic peptides, HLA-peptide tetramers, and dendritic cells (DC). TILs from 9 of 12 (75%) subjects contained CD8+ T cells recognizing 1-8 MCPyV epitopes per person. Analysis of 16 MCPyV CD8+ TIL epitopes and prior TIL data indicated that 97% of patients with MCPyV+ MCC had HLA alleles with the genetic potential that restrict CD8+ T-cell responses to MCPyV T-Ag. The LT AA 70-110 region was epitope rich, whereas the oncogenic domains of T-Ag were not commonly recognized. Specific recognition of T-Ag-expressing DCs was documented. Recovery of MCPyV oncoprotein-specific CD8+ TILs from most tumors indicated that antigen indifference was unlikely to be a major cause of checkpoint inhibition failure. The myriad of epitopes restricted by diverse HLA alleles indicates that vaccination can be a rational component of immunotherapy if tumor immune suppression can be overcome, and the oncogenic regions of T-Ag can be modified without impacting immunogenicity.

Patterns of distant metastases in 215 Merkel cell carcinoma patients: Implications for prognosis and surveillance.

Approximately one-third of Merkel cell carcinoma (MCC) patients eventually develop distant metastatic disease. Little is known about whether the location of the primary lesion is predictive of initial distant metastatic site, or if survival likelihood differs depending on the metastatic site. Such data could inform imaging/surveillance practices and improve prognostic accuracy. Multivariate and competing-risk analyses were performed on a cohort of 215 MCC patients with distant metastases, 31% of whom had two or more initial sites of distant metastasis. At time of initial distant metastasis in the 215 patients, metastatic sites (n = 305) included non-regional lymph nodes (present in 41% of patients), skin/body wall (25%), liver (23%), bone (21%), pancreas (8%), lung (7%), and brain (5%). Among the 194 patients who presented with MCC limited to local or regional sites (stage I-III) but who ultimately developed distant metastases, distant progression occurred in 49% by 1 year and in 80% by 2 years following initial diagnosis. Primary MCC locations differed in how likely they were to metastasize to specific organs/sites (P < .001). For example, liver metastases were far more likely from a head/neck primary (43% of 58 patients) versus a lower limb primary (5% of 39 patients; P < .0001). Skin-only distant metastasis was associated with lower MCC-specific mortality as compared to metastases in multiple organs/sites (HR 2.7; P = .003), in the liver (HR 2.1; P = .05), or in distant lymph nodes (HR 2.0; P = .045). These data reflect outcomes before PD1-pathway inhibitor availability, which may positively impact survival. In conclusion, primary MCC location is associated with a pattern of distant spread, which may assist in optimizing surveillance. Because it is linked to survival, the site of initial distant metastasis should be considered when assessing prognosis.

Differential Outcomes Among Immunosuppressed Patients With Merkel Cell Carcinoma: Impact of Immunosuppression Type on Cancer-specific and Overall Survival.

OBJECTIVES: Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine skin cancer with higher incidence among whites, elderly, and immunosuppressed patients. Although immunosuppressed MCC patients are at higher risk of recurrence and MCC-related death, it is unknown whether immunosuppression type is associated with differential outcomes. MATERIALS AND METHODS: We retrospectively evaluated 89 nonmetastatic MCC patients with a diagnosis of chronic immunosuppression. Immunosuppression was categorized as chronic lymphocytic leukemia (31% of cohort), other hematologic malignancies (18%), solid organ transplant (21%), autoimmune disease (21%), and human immunodeficiency virus acquired deficiency syndrome (8%). Progression-free survival (PFS) and MCC-specific survival (MSS) were estimated with the cumulative incidence function. Overall survival (OS) was estimated by the Kaplan-Meier method. RESULTS: With a median follow-up of 52 months, 53 deaths occurred (42 from MCC, 7 unknown, and 4 non-MCC). Two-year PFS, MSS, and OS were 30%, 55%, and 52%, respectively. Human immunodeficiency virus/acquired deficiency syndrome and solid organ transplant patients were diagnosed with MCC at a younger age (median 55 and 59 y, respectively) and with more advanced stage disease compared with other immunosuppressed subgroups. PFS did not significantly differ among the 5 immunosuppression subgroups (P=0.30), but significant differences were observed in MSS and OS (both P=0.01). Controlling for potential confounders for OS, including age and stage, immunosuppression type was still significantly associated with risk of death (P=0.01). CONCLUSIONS: Among immunosuppressed MCC patients, recurrent MCC is the major cause of mortality. The risk of death from MCC differs among immunosuppression types, suggesting important biological differences in host-tumor immune interactions.

Effect of Patient Immune Status on the Efficacy of Radiation Therapy and Recurrence-Free Survival Among 805 Patients With Merkel Cell Carcinoma.

PURPOSE: Patients with Merkel cell carcinoma (MCC) with chronic immunosuppression (IS) have worse outcomes, but the mechanisms are not well understood. We hypothesized that these differences may be mediated in part by differential response to treatment, and we evaluated whether radiation therapy (RT) efficacy is altered among IS compared with immune-competent (IC) patients with MCC. METHODS AND MATERIALS: Among 805 patients with MCC, recurrence-free survival (RFS) and patterns of first recurrence were compared between 89 IS and 716 IC patients with stage I to III MCC treated with curative intent. We used a Fine and Gray's competing risk multivariable analysis to estimate associations with RFS. RESULTS: IS and IC patients with MCC had similar demographic and disease characteristics. Most (77% IC, 86% IS) were irradiated (median, 50.4 Gy IC, 50.3 Gy IS), although more IS patients were irradiated to the primary site (97% vs 81%). With a median follow-up of 54.4 months, IS patients had inferior RFS (2-year: 30% vs 57%; P < .0001) and higher rates of local recurrence as the first site of relapse (25% vs 12%; P = .0002). The association between RT and RFS differed by immune status (interaction P = .01). Although RT was associated with significantly improved RFS among IC patients (hazard ratio 0.56, 95% confidence interval 0.44-0.72), no difference in RFS was observed with RT among IS patients (hazard ratio 1.49, 95% confidence interval 0.70-3.17). CONCLUSIONS: Radiation therapy efficacy at current standard RT doses for MCC is impaired among immunosuppressed patients with MCC. Although a strong link between durability of RT response and immune function does not appear to be evident in most cancers, our results may reflect an especially dynamic interaction between immune status and RT efficacy in MCC.