Clinical and pathological prognostic factors in Merkel cell carcinoma.
Authors: Tovazzi Valeria , Lorini Luigi , Battocchio Simonetta , Zannoni Marina , Paolino Gaetano , Cingarlini Sara , Zamparini Manuel , Tomasoni Michele , Ravanelli Marco , Oberti Arianna , Grammatica Alberto , Buglione Michela , Magrini Stefano M. , Maroldi Roberto , Piazza Cesare , Facchetti Fabio , Scarpa Aldo , Berruti Alfredo , Bossi Paolo 
Published: June 2022

e21574

Background: From 25 to 50% of radically resected Merkel Cell Carcinomas (MCCs) develop local or distant recurrence with a 5 year Overall Survival (OS) of 35% and 13%, respectively. Due to the rarity of the disease, there are limited data about clinical/histological risk factors related to patients (pts) prognosis. Methods: We retrospectively evaluated a series of 57 MCCs pts treated with surgical curative intent at two Italian Centres from 2000 to 2020. For 43 of them, archival histological material was retrieved for further analysis. The following clinical and histological data were analyzed and related to time to relapse (TTR), OS and cancer specific survival (CSS): gender, age, Charlson Comorbidity Index value, immunodepression, surgical margins, re-excision and/or radiotherapy (RT) in case of positive margins, stage, perineural/lymphovascular infiltration, presence of inflammatory infiltrate (tumoral infiltrating lymphocyte (TILs) (> 1 positive cell per high-power field) and its composition CD3+, CD4+ T and CD8+ T cells), positivity for MCC-polyomavirus (MCCpV), Ki67 index and PDL1 expression CPS. Results: Pts were mainly female (52%), median age was 75 years (49-99), 70% were immunocompetent and 51% presented T1 stage. All pts received surgery as main treatment approach; in case of positive margins, pts received re-excision or RT, when feasible. During a median follow-up of 37 months (1- 188), 40% had a locoregional or distant recurrence. Median TTR of relapsed pts was 3 months (1-88); median OS and CSS in the whole population was 117 months (1-188) and not reached, respectively. At univariate analysis, only male gender was associated with a higher risk of relapse (HR 1.6; 1.07-2.55; p 0.02). Older age (HR 1.09; 1.04-1.14, p < 0.001), T stage ≥2 (HR 4.79, 1.99-11.53, p < 0.001) and positive margins after re-excision (HR 17.49, 1.09-279.74, p 0.043) were associated with shorter OS and negatively related to CSS. Re-excision and/or RT in cases of positive margins at diagnosis improved OS (HR 0.154, 95% CI 0.028-0.851, p = 0.032) and CSS (HR 0.15; 0.02-0.85, p 0.03). MCCpV positivity (HR 0.23, 0.08-0.62, p 0.004), TILs (HR 0.30, 0.11-0.80, p 0.017), a moderate or high content of CD3+ T cells (HR 0.33, 0.119-0.968, p 0.04), CD8+ T cells (HR 0.35, 0.12-0.99, p 0.04), and PDL1 CPS > 1 (HR 0.26, 0.08-0.82, p 0.02) resulted in longer OS. The impact of MCCpV positivity (HR 0.27; 0.08-0.88 p 0.03) and high TILs (HR 0.31, 0.09-0.99, p 0.04) was also confirmed for CSS. Conclusions: In primarily surgically treated MCCs, female gender, younger age, low T stage, positivity for MCCpV and tumoral immune cells infiltration were associated with better prognosis, as well as an aggressive management comprising re-excision and/or RT in case of positive margins.