Diagnostic value of cytology in detecting human papillomavirus-independent cervical malignancies: a nation-wide study in Korea

Abstract

Background: Human papillomavirus (HPV) independent cervical malignancies (HPV-IDCMs) have recently been classified by the World Health Organization (WHO) 5th edition. These malignancies have historically received limited attention due to their rarity and the potential for evasion of HPV-based screening.

Methods: We retrospectively reviewed 5,854 biopsy-confirmed cervical malignancies from 22 institutions over 3 years (July 2020-June 2023). Histologic classification followed the WHO guidelines. HPV independence was confirmed by dual negativity for p16 and HPV; discordant cases (p16-positive/HPV-negative) underwent additional HPV testing using paraffin-embedded tissue. Cytological results were matched sequentially to histological confirmation.

Results: The prevalence of HPV-IDCM was 4.4% (257/5,854) overall and was 3.6% (208/5,805 cases) among primary cervical malignancy. Patient age of HPV-IDCM was 29 to 89 years (median, 57.79). Its histologic subtypes included primary adenocarcinoma (n = 116), endometrial adenocarcinoma (n = 35), squamous cell carcinoma (n = 72), metastatic carcinoma (n = 14), carcinoma, not otherwise specified (n = 10), neuroendocrine carcinoma (n = 3), and others (n = 7). Among 155 cytology-histological matched cases, the overall and primary Pap test detection rates were 85.2% (132/155) and 83.2% (104/125), respectively. The interval between cytology and histologic confirmation extended up to 38 months.

Conclusions: HPV-IDCMs comprised 3.6% of primary cervical malignancies with a high detection rate via cytology (83.2%). These findings affirm the value of cytological screening, particularly in patients with limited screening history or at risk for HPV-independent lesions, and may guide future screening protocols.

Keywords: Cytology; Human papillomavirus viruses; Papanicolaou test; Prevalence; Uterine cervical neoplasms.

Fig. 1.

Flow chart of study inclusion. Hr, high risk; HPV, human papillomavirus.

Fig. 2.

A representative case of human papillomavirus–independent squamous cell carcinoma with cytohistologic and p16 immunohistochemical findings. (A) The cytological findings showed many atypical squamous cells with high nuclear to cytoplasmic ratio, hyperchromatic nuclei, irregular nuclear contour, prominent 2–3 nucleoli, and dense hyperkeratotic cytoplasms (Pap test). (B) p16 immunocytochemical staining failed to demonstrate nuclear-cytoplasmic expression. (C) The scanning view of punch biopsied tissue revealed infiltrating nests with thick keratin pearl (inset). (D) Some irregular atypical squamous nests invaded to stroma (red arrows). (E) p16 immunohistochemistry failed to demonstrate a block positivity.

Fig. 3.

A chronological sequence of delayed (11 months) diagnosis in a 71-year-old woman with human papillomavirus (HPV) independent cervical malignancies. (A) Three-dimensional cluster of atypical hyperchromatic nuclei are seen, suggestive of atypical glandular cells, undetermined significance favor neoplastic (AGUS-N) (2022-07-18). (B) No definite abnormality is identified in punch biopsied tissue (2022-08-01). (C) No glandular/squamous epithelial dysplasia was identified in loop electrosurgical excision procedure conization (2022-08-11). (D) A cluster of atypical epithelial cells with abundant dense cytoplasm are seen, atypical squamous cells cannot excluded high-grade intraepithelial lesion (ASC-H) (2022-09-26). (E) Overlapping clusters of atypical epithelial cells with hyperchromatic nuclei and dense cytoplasm were seen, ASC-H (2023-01-30). (F, G) The hysterectomy specimen showed a deeply invading atypical glands through the full thickness of the uterine cervical wall. The tumor is composed of gastric type–glands (2023-06-13).