Atypical Endocervical Cells in Pap Smears: Diagnostic Challenges and the Role of HPV Primary Screening

Cervical cancer is the fourth most common malignancy among women worldwide and the third most common cause of cancer mortality. Cervical cancer comprises two distinct histological types: squamous cell carcinoma (SCC) and endocervical adenocarcinoma (EAC), of which SCC is the most common. In recent decades, both the relative and absolute incidences of EAC have increased, particularly in high- income countries.

Most existing cervical cancer research is based on SCC and its precursor lesions. In this thesis, we focused on the diagnostics of EAC and its precursor lesion, adenocarcinoma in situ (AIS). We investigated the cytomorphological features associated with EAC and AIS, along with the features obscuring their diagnoses and the features leading to their false-positive diagnoses. Additionally, we evaluated the diagnostic reproducibility in cytology, as well as the performance of HPV primary screening in detecting EAC and AIS.

We found that most histological lesions behind cytological endocervical cell atypia are purely squamous. A combination of cytomorphological features, including palisading cell borders, nuclear pleomorphism and the lack of single atypical cells in conventional Pap smears, predict histological EAC and AIS. The reproducibility of the more severe cytopathological diagnoses is of a moderate level and better than that of the milder cytological changes and glandular and squamous features. In EAC and AIS Pap smears, marked nuclear enlargement and nuclear pleomorphism are the most common features in Pap smears, with good consensus of the neoplastic nature and of the endocervical cell origin of the lesion. In turn, degenerative changes and a lack of nuclear enlargement are the most frequent features encountered in samples with low consensus.

Squamous metaplasia, significant mixed inflammation, tubal metaplasia and microglandular hyperplasia are the most common benign causes of the misdiagnosis of endocervical cell atypia in cytology. Lack of nuclear crowding and lack of degenerative changes are the best cytomorphological features in separating benign endocervical cell atypias from those harbouring malignancy.

In our study, no neoplastic lesions were found among hrHPV-negative patients presenting with endocervical cell atypia in cytology. One hrHPV-negative gastric-type EAC was missed by the HPV primary screening during the investigated 4-year screening period.