Clinical Outcomes of HPV-associated and Unassociated Endocervical Adenocarcinomas Categorized by the International Endocervical Adenocarcinoma Criteria and Classification (IECC)

The International Endocervical Adenocarcinoma Criteria and Classification (IECC) categorizes endocervical adenocarcinomas (ECAs) on the basis of morphologic features linked to etiology (ie, human papilloma virus [HPV] infection), resulting in separation of ECAs into HPV-associated (HPVA) and unassociated or non-HPVA (NHPVA) types. NHPVAs are reported to be large and present at high stage in older individuals. Our aim was to examine the clinical outcomes in these tumor types. Full slide sets of 205 ECAs were collected from 7 institutions worldwide and classified on the basis of IECC criteria and the presence or absence of HPV. Clinical and morphologic parameters were correlated with follow-up data. Statistical analysis of overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS) were conducted using the Kaplan-Meier survival analysis and compared using the log-rank test for univariate analysis. Multivariate survival analysis was conducted, and the survival endpoints considered were OS, DFS, and PFS. Statistically significant survival differences (OS, DFS, and PFS) were found when comparing the following categories: HPVA>NHPVA (ie, survival was superior in the setting of HPVAs), including patients treated with surgery followed by adjuvant therapy; usual-type HPVA>mucinous HPVA; FIGO grade 3 HPVA>NHPVA; HPVA>NHPVA, both with lymphovascular invasion; and HPVA>NHPVA in patients with pelvic recurrences. Although there were trends favoring HPVA outcomes over those of NHPVA, these differences were not statistically significant in the following categories: mucinous HPVA versus NHPVA; HPVA versus NHPVA, both with lymph node metastases at presentation; and HPVA versus NHPVA in patients with distant metastasis. Survival for both HPVA and NHPVA was similar when surgery without adjuvant therapy was used. FIGO grading did not have prognostic significance in HPVAs. Multivariable analysis of HPVAs indicated nearly significant statistical associations between stage and both OS and DFS (P=0.07 and 0.06, respectively), and between Silva invasion pattern and OS (P=0.09). Multivariate analysis of NHPVAs indicated a statistically significant association between OS and age (P=0.03), stage (P=0.02) and tumor size (P=0.002), and between DFS and stage (P=0.004) and tumor size (P=0.004). Multivariate analysis of HPVAs and NHPVAs together revealed nearly significant associations between OS and HPV status and stage (both [P=0.06]). For DFS, stage was a significant variable (P=0.04), whereas HPV status and tumor size were nearly significant (P=0.06 and 0.07, respectively). Clinical outcome studies support the idea that the IECC classification not only separates ECAs on the basis of HPV status (usually assessed on H&E slides), but also has important clinical relevance.