Detection of in situ and invasive endocervical adenocarcinoma on ThinPrep Pap Test: Morphologic analysis of false negative cases

BACKGROUND: The goal of this study was to calculate the sensitivity and false negative (FN) rate of ThinPrep Pap Test (TPPT) and carefully analyze missed cases for educational purposes. MATERIALS AND METHODS: Patients with histologically proven adenocarcinoma in-situ (AIS) or invasive endocervical adenocarcinoma (EAC) over a 17-year-period (1998-2015) were identified. The TPPT immediately preceding the histological diagnosis of AIS/ECA was designated as index Pap (IP). Paps up to 122 months before histologic diagnosis of AIS/ECA were considered for this study. All available negative and unsatisfactory TPPT were re-reviewed. RESULTS: There were 78 patients with histologically-proven AIS (56) or ECA (22) with 184 TPPTs, and 95 of these TPPTs were abnormal. Of the abnormal cases, 55.7% TPPTs were diagnosed as endocervical cell abnormality (atypical endocervical cells/AIS/ECA). Notably, 44.2% of abnormal TPPTs were diagnosed as squamous cell abnormality (atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion/high grade squamous intraepithelial lesion). Including the diagnoses of squamous cell abnormality, the sensitivity of index TPPT for histologically-confirmed AIS/ECA was 88%. Eighty-eight of 184 TPPT, including 10 IP, were negative = 87, or unsatisfactory = 1. Forty-two of these slides were available for re-review. Upon review, 21 TPPT (50%) were confirmed negative and 21 TPPT (50%) were reclassified as abnormal = 20, or unsatisfactory = 1. Of the FN cases, the main difficulty in correct diagnosis was the presence of few diagnostic cell clusters which had less feathering, and consisted of smaller, rounder cells in small and tighter clusters, with nuclear overlap. In particular, nuclear overlap in three-dimensional groups precluded the accurate diagnosis. Rare FN cases showed squamous cell abnormality on re-review, and rare cases showed obscuring blood or inflammation. CONCLUSION: A significant proportion of AIS/EAC is discovered after Pap showing squamous cell abnormality. FN cases were most commonly related to nuclear overlap in tight three-dimensional clusters.