Risk factors of cervical cancer (CC) development are well investigated, however, those influencing the risk of a potential false negative cytology preceding diagnosis of an invasive CC are not. We have aimed to explore these factors according to the data from Organised Cervical Cancer Screening Programme (OCCSP) in Poland. A total of 2.36 million of Pap tests sampled in 2010–2012 within OCCSP were merged with the Polish National Cancer Registry to identify CC cases after abnormal cytology and after normal cytology within 3 years of screening. Of 1460 invasive CCs, 1025 were preceded by abnormal and 399 by normal cytology result. Multivariate logistic analysis indicated that the presence of microorganisms in the Pap (OR = 2.18, 95% CI 1.65–2.87), evaluation by smaller (below 9000 slides processed per year) laboratories (OR = 1.60, 95% CI 1.22–2.09) and non‐squamous histology of cancer increased the odds for a potential false negative result (OR = 3.39, 95% CI 2.37–4.85 for adenocarcinoma, OR = 1.99, 95% CI 1.11–3.55 for other types of carcinoma), whereas cervical ectropion, other macroscopic changes on the cervix and smoking decrease the odds for a potential false negative Pap test result preceding CC (OR = 0.61, 95% CI 0.45–0.82, OR = 0.41, 95% CI 0.25–0.67, OR = 0.60, 95% CI 0.46–0.78, respectively). Proper triage of women with microscopic signs of microorganisms in the Pap smear should be reconsidered and cytology should be assessed in laboratories processing over 9000 slides annually to decrease the odds for negative Pap test result in 2 years before CC diagnosis. Information on macroscopic changes on the cervix provided to cytomorphologist may reduce the risk of a potential false negative cytology result.

We have aimed to study reasons for reporting false-negative cytology results preceding diagnosis of interval cervical cancers (CC) in Poland. Data on all Pap smears collected in the organised screening in 2010-2015 were retrieved from the electronic database and linked with Polish National Cancer Registry (PNCR) data. False-negative results were defined as those sampled and assessed normal up to 3.5 years before diagnosis of invasive CC. False-negative slides were then seeded among twice as many randomly selected slides from the same lab and reviewed independently by three expert cytomorphologists. New diagnosis was established when experts agreed on a result. Of 48 selected false-negative slides, 1 case was diagnosed as a low-grade abnormality, 22 cases as a high-grade abnormalities, 3 cases as unsatisfactory for evaluation and 5 as no intraepithelial lesion of malignancy (NILM) by all three experts. There was no agreement in 17 cases. Percentages of agreement between experts was 64.6. Interobserver agreement rate was moderate with Fleiss' κ values. Our pilot study indicates evaluation errors as the main reason of false-negative cytology preceding interval CC in the organized screening programme in Poland. True lack of abnormal cells on the slide is the next reason.

False negative (FN) results in cervical cancer (CC) screening pose serious risks to women. We present a comprehensive literature review on the risks and reasons of obtaining the FN results of primary CC screening tests and triage methods and discuss their clinical and public health impact and implications. Misinterpretation or true lack of abnormalities on a slide are the reasons of FN results in cytology and p16/Ki-67 dual-staining. For high-risk human papillomavirus (HPV) molecular tests, those include: truly non-HPV-associated tumors, lesions driven by low-risk HPV types, and clearance of HPV genetic material before sampling. Imprecise disease threshold definition lead to FN results in visual inspection with acetic acid. Lesions with a discrete colposcopic appearance are a source of FN in colposcopic procedures. For FAM19A4 and hsa-miR124-2 genes methylation, those may originate from borderline methylation levels. Histological misinterpretation, sampling, and laboratory errors also play a role in all types of CC screening, as well as reproducibility issue, especially in methods based on human-eye evaluation. Primary HPV-based screening combined with high quality-assured immunocytochemical and molecular triage methods seem to be an optimal approach. Colposcopy with histological evaluation remains the gold standard for diagnosis but requires quality protocols and assurance measures.

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