In this study, the average age at diagnosis of cervical AIS was approximately 38 years, comparable to the reported average age of 35.2In the cervical ADC and mixed adenosquamous lesion (MASL) groups, the average age at diagnosis was approximately 46. The average age of tumor patients with high HPV prevalence, as reported in the scientific literature, is 44.8 years, significantly younger than the average age of patients with low HPV prevalence, with an average HPV prevalence of 49.8 years.5The average age at diagnosis of cervical AIS was lower than that of cervical ADC and MASL.6This finding supports thetheory that invasive adenocarcinomadevelopsas a precursor lesion, taking approximately 7 – 10 years to develop from in situ lesions, indicating an opportunity for screening and testing before progressing to invasive cancer. The success of Pap test cytology in reducing the incidence rate and mortality of cervical cancer ischiefly attributableto the early detection and treatment of SIL.
When HPV infection is detected, particularly HPV18 and HPV16, colposcopy should be performed, even if the cytological results are negative. In agreement with other studies, our data show that the pathogenicity of HPV18 is higher than that of HPV16.7,8 Pirog et al.9 found that HPV16 was the most common cause of infection, with a ratio of 1.6 between HPV16 and HPV18. In this study, recognized non-HPV-related cervical adenocarcinoma types have been excluded, and 17 cases (6.59%) did not have any detectable HPV infection. The specific reasons for this need further research. On the one hand, we consider that it may be due to the limited range of detected HPV types, or to limitations in technical sensitivity variability or degradation during sample storage. On the other hand, it may indicate that HPV has limited involvement in some cervical adenocarcinomas, and if the tumor lasts for a long time, HPVDNA may be lost during the tumor progression process. Epigenetic changes such as methylation, chromosomal abnormalities, and mutations in TP53 and other genes occur in cervical cancer, and there are differences between cervical squamous cell carcinoma and adenocarcinoma.10,11,12,13 There have also been studies indicating the complexity of the association between HPV and adenocarcinoma; with the development and progression of ADC, the driving force of HPV or HPV oncogenes is lost. This hypothesis is supported by the discovery of lower p16 [INK4a] expression. Positive expression in HPV- negative ordinary ADC indicates that there does not seem to be continuous E7 expression/pRB isolation/p16 inactivation.5,14,16
Our results also showed that the most common abnormal results in cervical screening were ASC-US and HSIL in the cytological examination. Nearly 1/3 of the cases were often initially diagnosed as NILM based on cytology, and only a few of them have true negative cytological interpretations. The main reason is that the histological lesions are deep, not shallow, and the cytology study is often unable to identify the lesion’s location.6,17 Most cytological diagnoses are false negatives due to various reasons, such as failure to locate the lesion site during cytological sampling, failure to achieve positive cells on the slides during the production process, and level of knowledge blind spots among cytologists. Cell pathologists should receive specialized training to enhance their ability to recognize various types of cells. For example, the difficulty in diagnosing AIS lies in the presence of subtle cytological features that are often overlooked or misunderstood as other cervical lesions, such as SIL, endometrial cells, tubal metaplasia, endometriosis, or reactive endometrial cells. 18The diagnosis of AGC has always been challenging for pathologists and lacks good inter-observer consistency. Thus, additional training of pathologists may represent an area of need that could improve the early diagnosis of cervical lesions.
Similar to previous reports, we also found that more than half of cervical glandular lesions are accompanied by squamous epithelial lesions, which are often the first to be detected.2,10 Therefore, cervical cytology screening is more effective for detecting changes in squamous intraepithelial lesions than in glandular epithelial diseases; an estimated 30-60% of glandular epithelial lesions are detected by chance during the follow-up of squamous cell abnormalities.18,19,20Overall, cytology has low sensitivity when screening for glandular diseases, and there is strong support for adding HPV testing to cytology to improve the screening performance.
When testing is positive for HPV18 and/or HPV16, there may be glandular disease present, regardless of the cytological results.5 The management guidelines for cervical cancer screening abnormalities based on the 2019 ASCCP are risk-based guidelines, and are not dependent on screening results. All initially HPV-positive individuals, regardless of the HPV subtype, are recommended to undergo cytological testing using the same standard.21 When a patient is diagnosed with AGC or AIS by cytology, regardless of the outcome of HPV testing, immediate colposcopy examination, cervical curettage (ECC), and endometrial curettage should be conducted for those over 35 years old. If AGC- FN is not proven through colposcopy, the HSIL/AIS should also be subjected to diagnostic cervical circumcision should be done forHSIL/AIS.
In summary, the advantages of cytological screening are its high specificity and the ability to detect HPV-negative cases; its disadvantages are its poor sensitivity, high requirements for cytological diagnostic physicians, intense subjectivity and significant results differences among pathologists. The advantages of HPV screening are its high sensitivity and its objective and direct results; the disadvantages are its poor specificity and inability to detect HPV-negative cases.The cytological examination is the inital basis for the initial diagnosis of glandular lesions; cytological examination should be combined with HPV detection to improve the sensitivity to detect glandular abnormalities. It is also necessary to strengthen standardized cytology training on cytology and to develop corresponding quality control standards.
In most cases, especially in mixed adenosquamous lesions, the final diagnosis of cervical adenomatous lesions relies on a combination of HP, Pap test, and/or biopsy/ECC testing. If necessary, LEEP/CKC biopsy may also be performed to thoroughly evaluate the glandular lesions thoroughly.18 In most cases with negative margins, if conservative treatment is required, it is relatively safe. However, 8.16% of patients still had residual glandular lesions after conservative treatment that were visible in total hysterectomy specimens. Notably, regardless of whether the margins were negative or positive cutting edge, our calculated residual rate of the lesion was 47.5% after LEEP/CKC surgery. This high residual rate highlights the difficulty of using conservative treatment for cervical glandular lesions.
In clinical practice, it can be argued that as long as the patient undergoes colposcopy, it is not important whether the tumor cells are considered squamous or glandular epithelial in origin. However, identifying and reporting atypical glandular cells can guide clinicians to pay special attention to the cervical canal and perform cervical curettage, which may lead to an early diagnosis.22
Castano et al. showed that screening is inefficient in preventingADC, but effective in detecting stage IA adenocarcinoma. In the absence of screening, adenocarcinoma is usually diagnosed in stage IB or worse. Therefore, stage IA adenocarcinoma is the most common diagnosis among women who undergo periodic screening. Among these women, there has been sufficient time since the last screening to develop stage IA cancer, but not enough time to develop to stage IB or higher.23 The impact of screening on adenosquamous carcinoma is similar to that of squamous carcinoma, although more stage IB or more severe adenosquamous carcinomas are detected. This finding suggests that squamous components must be stronger and/or appear earlier in the carcinogenic process to be detected through screening.
When screening for cervical cancer, it is necessary to ensure that the procedures being used provide clinical benefits, and efforts should be made to improve the detection rate, reduce the missed diagnosis rate, and reduce unnecessary bodily damage (such as excessive colposcopy and biopsy), as well as to reduce the excessive psychological burden and anxiety associated with screening, while also considering the cost of health resources.