Low Nuclear Grade and Absence of Necrotic Tumor Debris from Cervical Biopsy Predict a Negligible Risk for Nodal Metastasis and Tumor Recurrence in Usual Type Cervical Adenocarcinomas: A Multi-Institutional Study

Background:  The metastatic or recurrent potential of clinically localized HPV-associated endocervical adenocarcinoma (HPVA EAC) is difficult to predict. There is a need to develop a practical method that can accurately distinguish apparently localized tumors with a high probability of nodal metastasis (NM) or tumor recurrence (TR) at the initial biopsy phase, where findings can be incorporated into management decisions.  Methods: This retrospective study included 794 specimens from 397 patients with primary HPVA EAC treated at 19 institutions.  For each patient, data from a paired cervical biopsy (prior to surgery, n=397) and resection specimen, including lymphadenectomy (n=397) were reviewed.   A variety of tumoral pathologic/histologic features were examined in each paired-specimen, including tumor nuclear grade (TNG) and necrotic tumor debris (NTD).  TNG was assigned on a three-tiered scale of increasing abnormalities (TNG1, TNG2, and TNG3).  Any relationships with standard clinicopathologic variables and patient outcomes including NM and TR were evaluated.  Findings: Biopsy tumors with low-risk histologic features (TNG1 and NTD-negative) showed markedly better outcomes, with a 0% rate of lymph node metastases or lymphovascular invasion (LVI) and a 1.4% (a single case) rate of tumor recurrence. In contrast, biopsies with TNG 2/3 and/or NTD-positive, showed significantly worse outcomes, with a rate of 19.1% NM, a rate of 12.9% TR, and a rate of 9.6% LVI.  The findings remained statistically significant on multivariate analyses.    Interpretation: The findings may be of potential clinical utility in the risk stratification of patients with HPVA EACs, and may allow patients with a minimal risk of nodal metastases and tumor recurrence to be identified at the biopsy phase, thereby facilitating more personalized, possibly fertility sparing management options.   Funding:  Mark and Jane Gibson Endowment fund and department start-up fund, UTSW Medical Center; Natural Science Grant of China and Cervical Cancer Research Award, Zhengzhou, China. Declaration of Interest: None to declare. Ethical Approval: The institutional review board at every participating institution approved this study.