Urothelial carcinoma with sarcomatoid variant: A preliminary study of clinical and pathological features.
Authors: Sirgiovanni Grazia , Francesconi Simona , Guida Annalisa , Caserta Claudia , Mosillo Claudia , Calandrella Maria Letizia , Macrini Serena , Cortesi Enrico , Ascani Stefano , Bracarda Sergio 
Published: February 2022

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Background: Muscle-invasive urothelial carcinoma (UC) with sarcomatoid variant (SV) (SV-UC) occurs in 0.1-0.3% of UC cases, and has been related with worse prognosis. Due to rarity of SV-UC, there are still limited evidences about the predictive role of sarcomatoid differentiation and no agents has been tested for SV-UC. We aim to investigate clinical and pathology features of SV-UC in a high grade UC (HG-UC) patients (pts) cohort. Methods: A retrospective analysis was performed on pts with HG-UC referring to our center between December 2012 and June 2021. Pts were reviewed for availability of histological tumor samples to evaluate the presence of SV. The expression of PD-L1 was evaluated in SV-UC sample by immunohistochemistry (IHC) using Ventana (SP263) assay. An IHC expression > 5% was considered positive. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method and compared with the log-rank test. The Chi-Square test, t-test or Wilcoxon-Mann-Whitney test were used to assess difference between the groups as appropriate. Results: A cohort of 73 HG-UC pts were analyzed and a total of 6 SV-UC has been identified (8.2%). Two cases (2.7%) presented both SV and rhabdoid features. The median age at diagnosis was 69 years (54-81). SV-UC occurs equally in male and female (50%) vs 9% of affected female in HG-UC group (p = 0.02). Of four patients experiencing a metastatic disease (67%), two were metastatic at diagnosis (33%). One patient had an upper tract UC (17%), while remaining samples originated from bladder. Of note, in 4/6 of pts (67%) a squamous histology was reported (vs 10.5% in HG-UC group; p = 0.1). SV was found in > 30% of tissue sample in 4/6 cases, 15% in one case, undefined in the remaining one. The PD-L1 expression in SV-UC tissues was > 50% in 5/6 of cases (83%), negative in the remaining one ( < 5%). All pts in SV-UC group had advanced stage of desease: 4/6 had pT3 stage (67%), 2/6 had pT4 stage (33%) and 4/6 had positive loco-regional lymph nodes. All SV-UC pts had local recurrence. Four pts with metastatic desease were treated with chemotherapy, and 3 received also immunotherapy. The majority of treated pts (2/3) achieved progression as best first line response (22% in HG-UC). With a median follow up of 33 months (range 2-110), median PFS was 1.3 and 6.3 months (HR 0.51, 95%CI 0.11-2.17, P = 0.36) and median OS was 8.9 vs 20.3 months in SV-UC and HG-UC group, respectively (HR 0.51, 95%CI 0.11-2.17, P = 0.36). Conclusions: This analysis explored incidence and clinico-pathologic features of SV in pts with HG-UC, identifying an often underestimated subpopulation. Compared to HG-UC, SV-UC appears to be associated with lower M:F ratio, squamous histology, advanced disease and higher PD-L1 expression. Our initial results confirmed an association with shorter PFS and OS. The major limitation of our series is the small number of cases, a larger study is already planned.