Detection ofin situand invasive endocervical adenocarcinoma on ThinPrep Pap Test: Morphologic analysis of false negative cases

Abstract

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.

Negative Pap tests in women with high‐grade cervical lesions on follow‐up biopsies: Contributing factors and role of human papillomavirus genotyping

“…This could significantly undermine the value of Pap test as the overinterpretation may jeopardize the specificity of cytology test for SIL. Nevertheless, the focused rescreening strategy for hrHPV‐positive NILM population could be significantly improved with reasonable modifications by requiring additional cytologic features that are commonly observed in misinterpreted cases, such as marked obscuring inflammation or hyperchromatic groups (HCG), as demonstrated in the current and previous studies …”

“…Taking the three high‐risk lesions on Pap tests (1 HSIL and 2 ASC‐H) together, the interpretation variances were apparently influenced by abundant inflammatory cells and obscuring cellular debris. Previous studies indicated additional contributing factors in false‐negative Pap tests, including low cellularity, presence of pale immature metaplastic cells, obscured nuclear features due to nuclear crowding and overlapping, and absence of koilocytes or abnormal hyperchromatic cells …”

Genetic variations in human papillomavirus and cervical cancer outcomes

“…HPV 18 frequently associates with glandular cancers (adeno in situ and adenocarcinoma) that are above the cervical transformation zone, high in the endocervical canal, and away from the mucosal surface, making sampling more difficult . This is highlighted by the increased adeno in situ detection when concurrent high grade squamous lesions are present in the cervix because they are identified during further work‐up of the squamous lesion …”

Diagnostic distribution and pitfalls of glandular abnormalities in cervical cytology: a 25-year single-center study

“…This indicates that identifying AIS in cytology is a rather challenging task. Previous studies have identified the pitfalls of the AIS cytologic diagnosis, also its suboptimal accuracy and low levels of interobserver agreement [30][31][32]. Some authors have also reported that many AIS lesions could be interpreted as AGC, AGC-FN, ADC, or squamous intraepithelial lesions in cervical cytology [32,33].…”