Grading of endocervical adenocarcinoma: a novel prognostic system based on tumor budding and cell cluster size

A novel 3-tiered grading system based on tumor budding activity and cell nest size has been validated to be highly prognostic in organ-wide squamous cell carcinomas. In this study, we applied a similar grading system with slight modification to assess the prognostic value in an institutional cohort of well annotated endocervical adenocarcinomas (EAC) consisting of 398 consecutive cases with surgical resection, no neoadjuvant chemotherapy, and higher than stage pT1a. Each case was reviewed by the International Endocervical Adenocarcinoma Criteria and Classification (IECC) and Silva pattern classification, and scored on tumor budding activity and cell cluster size to form the basis of a novel grading system. High budding activity, small tumor cell cluster size, and novel grade 3 were more frequently associated with a decreased overall survival time and tumor recurrence time (p < 0.001), and several other clinicopathologic factors including HPV-independent adenocarcinoma, lymphovascular invasion, lymph node metastasis, advanced FIGO stage, and Silva pattern C (p < 0.05). Moreover, the novel grading system was helpful in stratifying overall survival in HPV-associated adenocarcinoma (p = 0.036) and gastric-type adenocarcinoma (p = 0.033). On multivariate analysis, novel grade 3 was an adverse indicator for overall survival and tumor recurrence independently of age and FIGO stage (p < 0.05). By comparison, Silva pattern C was only associated with tumor relapse (p = 0.020) in HPV-associated adenocarcinomas whereas the conventional FIGO system was not associated with overall survival and tumor recurrence in EAC (p > 0.05). In conclusion, our study demonstrates that the grading system based on tumor budding activity and cell cluster size is robust in prognostic assessment that outperforms the conventional FIGO grading and Silva pattern classification in EAC. The novel grading system, if further validated, could be applicable in routine pathologic descriptions of EAC by providing useful information in clinical decision-making.