Invasive stratified mucin-producing carcinoma (ISMC) of the cervix: a clinicopathological and molecular analysis of 59 cases with special emphasis on histogenesis and potential therapeutic targets

Aims: This study aimed to better characterize the clinical and molecular features in invasive stratified mucin-producing carcinoma (ISMC), an uncommon aggressive subtype of endocervical adenocarcinoma (EAC). Methods and Results: We recruited 59 ISMC for clinicopathological analysis, immunohistochemistry (n = 56), and targeted next-generation sequencing (n = 17). Our cases contained 29 pure and 30 mixed-type ISMC. Five patients developed local recurrence at 6-32 months (median: 13 months), and died of disease at 16-55 months (median: 16 months). Pure and mixed-type ISMC showed no significant difference in overall survival and tumour relapse (P > 0.05) except larger tumour size in the pure-type (P = 0.009). Compared to the usualtype EAC (n = 217), ISMsC were more frequently associated with large tumour size (P = 0.003), advanced FIGO stage (P = 0.017), lymph node metastasis (P = 0.022), Silva pattern C (P < 0.001), and poor overall survival and short tumour recurrence. SOX2 expression was observed in 82.1% (46/56) ISMC, substantially higher than p63 expression (P < 0.001), while positive SOX17 was present in 3.6% (2/56) cases. PD-L1 was positive in 41/56 ISMC (73.21%) (combined positive score: range: 1-92, median: 22). Three ISMC patients (17.65%) had PIK3CA mutations, while one each (5.88%) patient harboured an ERBB2, TP53, STK11, and PTEN mutation, respectively. Conclusion: We conclude that ISMC is clinically more aggressive than the usual-type EAC. ISMC may originate from cervical reserve cells with bidirectional differentiation. PD-L1 overexpression and the molecular profiles raise the possibility that a subset of ISMC patients may benefit from anti-PD-L1 immunotherapy and other targeted therapy, such as mTOR inhibitor and T-DM1.