Risk Factors for Occult Invasive Cervical Cancer in Women with Abnormal Cervical Screening and Infeasible Diagnostic Conization

Cervical cancer is one of the most common cancers among females worldwide, and the second most frequent cancer among women in low-income and lower-middle-income countries. 1 , 2 Cervical cancer typically develops through precancerous lesions including high-grade squamous intraepithelial lesion (HSIL), also known as cervical intraepithelial neoplasia (CIN) grade 2 (CIN2), CIN3, and adenocarcinoma in situ (AIS). The primary cause of cervical cancer and its precursor is persistent infection of the lower genital tract with high-risk human papillomavirus (HrHPV). 3 , 4 In 2018, the World Health Organization (WHO) Director-General issued a global call for action towards the elimination of cervical cancer as a public health problem. Extensive international randomized control clinical trials have demonstrated that HPV vaccines are safe and highly effective against vaccine-type persistent infection and cervical precancerous lesions in women. 5 , 6 HPV vaccination has been promoted globally as primary prevention strategy for cervical cancer. Secondary prevention of cervical cancer is early detection and treatment of precancerous lesions. Cytology-based screening, including conventional cytology (Pap smear) and liquid-based cytology (LBC) has been a cornerstone of cervical cancer prevention for decades. 1 Compared to conventional Pap smear or LBC testing, HPV-based testing exhibits higher sensitivity and accuracy, lower variability, and better reproducibility. The American Cancer Society (ACS) recommends that individuals with a cervix initiate cervical cancer screening at the age of 25 and undergo primary HPV testing every 5 years until reaching the age of 65 (preferred); if primary HPV testing is not available, then individuals aged 25 to 65 years should be screened with cotesting (HPV testing in combination with cytology) every 5 years or cytology alone every 3 years (acceptable) (strong recommendation). 7 Cotesting or cytology testing alone are considered acceptable options for cervical cancer screening due to potential limitations in accessing primary HPV testing in certain settings. 4 Cervical cancer imposes a heavy disease burden on elderly females: half of all cervical cancer deaths in England occur in women aged 65 years and older, yet routine national cervical screening terminates at age 65 under the UK National Health Service (NHS) protocol. Most women over 65 have never undergone human papillomavirus (HPV) testing. 8 Women with consistent regular screening carry a 1/1200 lifetime risk of cervical cancer between ages 65 and 84, whereas under-screened counterparts face a far higher risk of 1/200. A single high-sensitivity HPV test could prevent over half of late-life cervical malignancies and related deaths. The age-related retraction of the transformation zone into the endocervical canal, which limits the sensitivity of both cytology and colposcopy in this population. The lower sensitivity of cytology in postmenopausal women due to epithelial atrophy and the paucity of diagnostic cells. 9 The role of HPV testing as a potentially more sensitive screening modality in elderly women. The cumulative effect of prior cervical procedures (eg conizations) on the feasibility of subsequent diagnostic procedures. Individuals with positive HPV and/or abnormal cytology results are referred to colposcopy and undergo colposcopy-guided biopsy and/or endocervical curettage (ECC). 10 Management options for CIN lesions include cryotherapy, thermal ablation, and loop electrosurgical excisions procedure (LEEP). Almost all cases of cervical cancer originate from the ecto- or endocervical mucosa in the transformation zone. 1 Cervical cancers arise from the precancerous lesions HSIL and AIS after a transforming infection with HrHPV. 11 , 12 In women who are elderly, postmenopausal, or who have undergone repeated cervical excisional procedure, the cervix may be completely flush with the vaginal vault, and the transformation zone may retract deep into the cervical canal. This makes it challenging to sample the transformation zone effectively during colposcopy. Diagnostic cervical conization becomes technically more difficult and often infeasible. 13 The American College of Obstetricians and Gynecologists has recommended hysterectomy as a treatment option for women with recurrent or persistent CIN 2/3, in cases where local excision is not feasible. 14 However, within this group, some individuals are diagnosed with invasive cervical cancer based on final histology of the hysterectomy specimens and therefore require further treatment. Notably, the 2023 National Comprehensive Cancer Network (NCCN) guidelines, conservative surgery (do not need extended surgery including parametrectomy and upper vaginectomy) is indicated for patients with FIGO stage IA2–IB1 cervical carcinoma who meet all of the following criteria: Cone biopsy, no LVSI, Negative cone margins, Squamous cell (any grade) or usual type adenocarcinoma (grade 1 or 2), or adenosquamous carcinoma, Tumor size ≤2 cm, Depth of invasion <10 mm on cone. If no conization, MRI must show <50% cervical stromal invasion, Negative imaging for metastatic disease (MRI recommended). 15 The objective of this study was to review the incidence of invasive cervical cancer after hysterectomy for abnormal cervical cytology and/or colposcopy-guided biopsy when cervical conization is not feasible. Meanwhile, we review the proportion of women who met the current conservative surgery criteria and can avoid extended surgery.

A retrospective chart review was performed for all women who underwent hysterectomy due to cervical neoplasia at the Obstetrics and Gynecology Hospital of Fudan University between January 2020 and July 2023. Subjects for the study were identified from the hospital’s electronic medical record archived database. Basic demographics and clinical details were recorded, including age, menopausal status, parity, number of previous local excision, latest LBC/HPV/biopsy/ECC results before hysterectomy, and the histologic findings at hysterectomy. The inclusion criteria were as follows: 1) patients with cytology results indicating HSIL, atypical squamous cells-cannot exclude HSIL (ASC-H), or cancer; or 2) patients with colposcopy biopsy/ECC histopathology indicating HSIL or AIS regardless of the cytology or colposcopy impression; or 3) patients who tested positive for high-risk HPV and had cytology results indicating atypical squamous cells-undetermined significance (ASC-US), atypical glandular cells (AGC), or low grade squamous intraepithelial lesion (LSIL); or 4) patients with a colposcopy impression indicating HSIL; and 5) cervical conization were considered not possible based on colposcopy evaluation. The exclusion criteria were as follows: 1) local excision was considered technically feasible, but the hysterectomy was done for other indications; 2) previous local excision for cervical neoplasia within the past 2 years, regardless of margin status; 3) previous local excision for cervical neoplasia with positive margin. A flowchart of the study selection process is shown in Figure 1 . Figure 1 Flowchart of the study. Fudan Univ. hysterectomy flowchart: cervical neoplasia exclusions & pathology outcomes. The study at OBGY Hospital of Fudan University (Jan 2020 - Jul 2023) involved 6794 hysterectomy cases for cervical neoplasia. Exclusions were preoperative conization diagnosis (6075 cases), recent local excision (81 cases), excision with positive margin (47 cases) and other indications (141 cases). Included were 450 cases where hysterectomy was necessary due to conization infeasibility. These were categorized by pathology: HSIL or AIS biopsy (421 cases), HSIL cytology with less severe biopsy (16 cases) and less severe cytology and biopsy but HSIL colposcopy impression (13 cases). Final pathology showed 375 cases (83.3%) as less than or equal to HSIL: negative (64), LSIL (22), HSIL/CIS (282), AIS (7). Invasive cancer was in 75 cases (16.7%), with frozen section detecting 28 (38.4%) and missing 45 (61.6%), with detailed stages for each group. Flowchart of the study. The t -test was used to assess differences in continuous variables that were normally distributed between the groups. To quantify the correlation between categorical variables, Pearson χ2 test or Fisher exact test was used. A logistic regression model was used to analyze the relationship between the variables and risk of invasive cervical cancer. All statistical tests were two-sided. The results were considered statistically significant at p<0.05. This study was approved by the institutional review board of the Obstetrics and Gynecology Hospital of Fudan University. Patient data confidentiality was strictly maintained throughout the study. All patient records and clinical information were de-identified prior to data extraction and analysis. Personal identifiers, including names, medical record numbers, and contact information, were removed. Access to patient data was restricted to authorized research personnel only, and all electronic data were stored on secure, password-protected institutional servers with encrypted backup. No individually identifiable patient information appears in this manuscript. All procedures were performed in accordance with the principles of the Declaration of Helsinki and relevant local regulatory requirements.

During the study period, a total of 450 women who had undergone hysterectomy due to abnormal cervical cytology and/or colposcopy biopsy, in which cervical conization was considered technically infeasible, were identified. The age of these women at the time of hysterectomy ranged from 34 to 86 years with an average of 61.9 (standard deviation [SD] 7.9) years. Out of these, 412 women (412/450, 91.6%) were postmenopausal with an average menopausal duration of 13.5 (SD 7.0) years. Additionally, 214 women (214/450, 47.6%) were multiparous. Among the participants, 72 (72/450, 16.0%) women had previously undergone local excision of the cervix; of these women, 61 had undergone one excision, 8 had undergone two excisions, and 3 had undergone three excisions. The average age of women who had previously cervical local excision was 54.4 (SD 8.1) years, while the average age was 63.4 (SD 7.0) years for patients without cervical local excision history (p <0.001). Furthermore, 17 women had received previous cervical and/or vaginal laser ablation treatment due to cervical and/or vaginal LSIL. Of the total 450 women, 9 (2.0%) had upper vaginal contracture, which led to incomplete cervical exposure. Among these, one woman had previously undergone vaginal laser ablation treatment, and one woman had undergone both cervical local excision and vaginal laser ablation treatment. In the remaining 441 women, local excision was considered infeasible because of complete flushing of the cervix with the vaginal vault caused by menopausal atrophy and/or previous conization. In all 450 women, the average length of the cervix indicated by ultrasound was 22.5 (SD 4.5) cm. The average length of the cervix in women who had or had not previously undergone cervical local excision was 22.4 (SD 5.4) cm and 22.6 (SD 4.4) cm, respectively (p=0.75). Representative colposcopy images are shown in Figure 2 . Figure 2 Representative colposcopy images of visual inspection after 3% acetic acid solution ( A and C ) and Lugol’s solution application ( B and D ). The cervix images are from a woman with a final histology of HSIL ( A and B ), and a woman with a final histology of stage IB2 squamous cell cancer ( C and D ). Both women’s cervix was completely flush with the vaginal vault. Colposcopy images of the cervix after acetic acid (A,C) and Lugol superscript subscript’s solution (B,D), showing HSIL and stage IB2 cancer. Representative colposcopy images of visual inspection after 3% acetic acid solution ( A and C ) and Lugol’s solution application ( B and D ). The cervix images are from a woman with a final histology of HSIL ( A and B ), and a woman with a final histology of stage IB2 squamous cell cancer ( C and D ). Both women’s cervix was completely flush with the vaginal vault. Table 1 shows the clinical characteristics of the women enrolled, the type of cytology abnormality, the type of colposcopy biopsy/ECC abnormality, and preoperative tumor mark and imaging examination. Cytology abnormalities were categorized as negative, low grade (ASC-US, LSIL); high grade (ASC-H, HSIL), AGC, and cancer. Of these 450 women enrolled, 75 (75/450, 16.67%) were diagnosed with invasive cervical cancer based on final histology of the hysterectomy specimens. No difference was noted in age, personal and family history, parity, previous treatment, and degree of colposcopy biopsy abnormality between women diagnosed with invasive cervical cancer and those with ≤HSIL in final histology. There were significant differences in serum SCCA level, degree of cytologic abnormality, HPV type, degree of ECC abnormality, and preoperative imaging examination between the two groups of women in univariate analysis. Ultrasound revealed cervical masses and/or abnormal echoes in 27 individuals, of which 13 (13/27, 48.1%) were confirmed as invasive cervical cancer after surgery. Among 69 women who underwent pelvic magnetic resonance imaging (MRI), 27 women revealed cervical masses and/or abnormal signals, of whom 13 women were confirmed as invasive cervical cancer after surgery. A multivariate logistic regression analysis indicated that cytology of high grade/ cancer (OR 2.33, 95% CI 1.48–4.58, p = 0.01), HPV16/18 infection (OR 4.62, 95% CI 2.42–7.94, p < 0.001), HSIL of ECC (OR 2.45 95% CI 1.40–4.68, p = 0.02), and cervical masses and/or abnormal echoes revealed by ultrasound (OR 10.70, 95% CI 4.29–27.72, P < 0.001) were the predictive factors for invasive cervical cancer in women with abnormal cervical cytology and/or colposcopy biopsy when cervical conization is not possible. Table 1 Characteristics of Women Who Underwent Hysterectomy Due to an Abnormal Cervical Cytology and/or Colposcopy Biopsy When Cervical Conization Was Considered Technically Infeasible ≤HSIL (n=375) Invasive Cervical Cancer (n=75) p Age (years) 62.1±7.6 (34–79) 61.3±9.4 (35–86) 0.479 a Hypertension  Yes 109 (29.1%) 22 (29.3%) 0.963 b  No 266 (70.9%) 53 (70.7%) Diabetes  Yes 34 (9.1%) 6 (8.0%) 0.767 b  No 341 (90.9%) 69 (92.0%) Autoimmune disorders  Yes 13 (3.5%) 2 (2.7%) 1.000 c  No 362 (96.5%) 73 (97.3%) Psychiatric disorders  Yes 10 (2.7%) 1 (1.3%) 0.700 c  No 365 (97.3) 74 (98.7%) Personal history of malignant tumor  Yes 27 (7.2%) 3 (4%) 0.310 b  No 348 (92.8%) 72 (96%) Family history of malignant tumor  Yes 35 (9.3%) 12 (16%) 0.085 b  No 340 (90.7%) 63 (84%) Parity  0 2 (0.5%) 0 (0) 0.523 c  1 199 (53.1%) 35 (46.7%)  ≥2 174 (46.4%) 40 (53.3%) Mode of delivery  Vaginal delivery 331 (88.3%) 66 (88%) 0.891 c  Cesarean delivery 42 (11.2%) 9 (12%)  Nullipara 2 (0.5%) 0 (0) Previous cervical and/or vaginal laser treatment  Yes 15 (4%) 2 (2.7%) 0.750 c  No 360 (96%) 73 (97.3%) Previous cervical local excision  Yes 58 (15.5%) 14 (18.7%) 0.605 b  No 317 (84.5%) 61 (81.3%) Serum SCCA level  < threshold 230 (61.3%) 41 (54.7%) <0.001 b  ≥threshold 17 (4.5%) 13 (17.3%)  Unknown 128 (34.2%) 21 (28%) Cytology  Negative 79 (21.1%) 11 (14.7%) 0.013 c  Low grade 116 (30.9%) 12 (16%)  High grade 140 (37.4%) 43 (57.3%)  AGC 2 (0.5%) 0 (0)  Cancer 2 (0.5%) 1 (1.3%)  Unknown 36 (9.6%) 8 (10.7%) HPV  Negative 8 (2.1%) 2 (2.7%) <0.001 c  16/18 included 138 (36.8%) 54 (72%)  Other HrHPV 219 (58.4%) 17 (22.6%)  Unknown 10 (2.7%) 2 (2.7%) Biopsy  Negative 59 (15.8%) 5 (6.7%) 0.061 c  LSIL 38 (10.1%) 6 (8%)  HSIL 260 (69.3%) 57 (76%)  AIS 4 (1.1%) 0 (0)  Unknown 14 (3.7%) 7 (9.3%) ECC  Negative 101 (27%) 3 (4%) <0.001 c  LSIL 18 (4.8%) 1 (1.3%)  HSIL 192 (51.2%) 54 (72%)  AIS 5 (1.3%) 1 (1.3%)  Unknown 59 (15.7%) 16 (21.4%) Cervical mass and/or abnormal echo detected by ultrasound  Yes 10 (2.7%) 17 (22.7%) <0.001 c  No 365 (97.3%) 58 (77.3%) Cervical mass and/or abnormal signal detected by MRI  Yes 14 (3.7%) 13 (17.3%) <0.001 b  No 33 (8.8%) 9 (12%)  Unknown 328 (87.5%) 53 (70.7%) Frozen section  Negative 196 (52.2%) 9 (12%) <0.001 c  LSIL 11 (2.9%) 0 (0)  HSIL/CIS 148 (39.5%) 34 (45.3%)  AIS 4 (1.1%) 2 (2.7%)  Squamous cell carcinoma 0 (0) 27 (36%)  Adenocarcinoma 0 (0) 1 (1.3%)  Unknown 16 (4.3%) 2 (2.7%) Notes : a t test, b Pearson χ2 test, c Fisher exact test. Characteristics of Women Who Underwent Hysterectomy Due to an Abnormal Cervical Cytology and/or Colposcopy Biopsy When Cervical Conization Was Considered Technically Infeasible Notes : a t test, b Pearson χ2 test, c Fisher exact test. Table 2 shows the intraoperative frozen sections report, the final histology from the hysterectomy specimens, and adjuvant treatment. Out of 432 women undergoing intraoperative frozen sections examination, 73 women were finally diagnosed with invasive cervical cancer, of whom 28 (28/73, 38.4%) women were detected from frozen sections. Among these 28 women who were detected to have invasive cervical cancer by intraoperative frozen sections, 21 women underwent complete parametrectomy/ upper vaginectomy + pelvic lymphadenectomy during surgery and avoided the need for reoperation. The final tumor stages of these 28 women were as follows: IA1 (5/28, 17.86%), IA2 (1/28, 3.57%), IB1 (7/28, 25.0%), IB2 (6/28, 21.43%), IB3 (1/28, 3.57%), IIA1 (2/28, 2/28%), IIA2 (1/28, 3.57%), IIB (2/28, 7.14%), IIIC1 (2/28, 7.14%), and IIIC2 (1/28, 3.57%). Among the 73 patients with invasive cervical cancer on final hysterectomy pathology, invasive lesions were missed on intraoperative frozen section in 45 cases (45/73, 61.6%). The majority (80%) of these missed cases presented with stage IA1 disease (stromal invasion ≤3 mm) or small IA2 lesions (stromal invasion ≤5 mm). Eight patients had stage IB1 carcinoma with a median stromal invasion depth of 8 mm (range, 6–15 mm). One patient had stage IIA1 disease with only 1 mm stromal invasion but vaginal involvement. One patient was diagnosed with stage IIIC2 disease: enlarged pelvic lymph nodes detected intraoperatively were positive for metastasis on biopsy, while cervical frozen section only showed HSIL. If preoperative pelvic MRI had been performed, interdisciplinary collaboration could guide targeted sampling for cervical intraoperative frozen section, potentially improving detection of cervical lesions. Table 3 shows the characteristics of women with invasive cervical cancer detected or undetected by frozen sections. The final tumor stage of invasive cervical cancer of 2 women who did not undergo frozen sections examination was IA1 and IA2, respectively. In 53 women who only underwent hysterectomy, 31 women with stage IA1 disease and no lymphatic vascular space invasion (LVSI) underwent observation without adjuvant treatment. Three women with stage IA2 disease and no LVSI underwent observation without adjuvant treatment. Nine women underwent reoperation for complete parametrectomy/ upper vaginectomy+ pelvic lymphadenectomy. Four women underwent reoperation for pelvic lymphadenectomy. Six women received adjuvant external beam radiation with concurrent weekly platinum-containing chemotherapy. Table 2 Details Corresponding to Final Pathology (n=450) Characteristics n ≤HSIL (n=375, 83.3%)  Negative 64 (17.1%)  LSIL 22 (5.8%)  HSIL/CIS 282 (75.2%)  AIS 7 (1.9%) Pathological type of Invasive cancer (n=75, 16.7%)  Squamous cell carcinoma 65 (86.7%)  Adenocarcinoma 2 (2.7%)  Adenosquamous carcinoma 4 (5.3%)  Adenoid basal carcinoma 3 (4%)  Adenoid cystic carcinoma 1 (1.3%) AJCC 9 th Tumor stage of invasive cancer (n=75)  1a1 32 (42.7%)  1a2 13 (17.3%)  1b1 14 (18.8%)  1b2 7 (9.3%)  1b3 1 (1.3%)  2a1 4 (5.3%)  2a2 1 (1.3%)  2b 3 (4%) Invasive cancers underwent reoperation (n=75)  Yes 13 (17.3%)  No 62 (82.7%) Abbreviation : AJCC, the American Joint Committee on Cancer. Table 3 Characteristics of Women with Invasive Cervical Cancer Detected or Undetected by Frozen Sections Detected by Frozen Sections (n=28) Undetected by Frozen Sections (n=45) p Serum SCCA level  < threshold 14 (50%) 26 (57.8%) 0.013 b  ≥threshold 9 (32.1%) 3 (6.7%)  Unknown 5 (17.9%) 16 (35.5%) Cytology  Negative 5 (17.9%) 6 (13.3%) 0.305 b  Low grade 4 (14.3%) 8 (17.8%)  High grade 13 (46.3%) 28 (62.2%)  Cancer 1 (3.6%) 0 (0)  Unknown 5 (17.9%) 3 (6.7%) HPV type  Negative 0 (0) 2 (4.4%) 0.857 b  16/18 included 21 (75%) 32 (71.2%)  Other HrHPV 6 (21.4%) 10 (22.2%)  Unknown 1 (3.6%) 1 (2.2%) Biopsy  Negative 5 (17.9%) 0 (0) 0.018 b  LSIL 1 (3.6%) 5 (11.1%)  HSIL 19 (67.8%) 36 (80%)  Unknown 3 (10.7%) 4 (8.9%) ECC  Negative 1 (3.6%) 2 (4.4%) 0.800 b  LSIL 1 (3.6%) 0 (0)  HSIL 19 33 (73.4%)  AIS 0 (0) 1 (2.2%)  Unknown 7 (25%) 9 (20%) Cervical mass and/or abnormal echo detected by ultrasound  Yes 11 (39.3%) 6 (13.3%) 0.021 a  No 17 (60.7%) 39 (86.7%) Cervical mass and/or abnormal signal detected by MRI  Yes 9 (32.1%) 4 (8.9%) 0.018 b  No 1 (3.6%) 8 (17.8%)  Unknown 18 (64.3%) 33 (73.4%) Frozen sections report  Negative 0 (0) 9 (20%) <0.001 b  HSIL/CIS 0 (0) 35 (77.8%)  AIS 0 (0) 1 (2.2%)  Squamous cell carcinoma 27 (96.4%) 0 (0)  Adenocarcinoma 1 (3.6%) 0 (0) Histology  Squamous cell carcinoma 24 (85.7%) 39 (86.7%) 0.109 b  Adenocarcinoma 0 (0) 2 (4.4%)  Adenosquamous carcinoma 3 (10.7%) 1 (2.2%)  Adenoid basal carcinoma 0 (0) 3 (6.7%)  Adenoid cystic carcinoma 1 (3.6%) 0 (0) AJCC 9 th Tumor stage  1a1 5 (17.9%) 26 (57.8%) <0.001 b  1a2 1 (3.6%) 10 (22.2%)  1b1 7 (25%) 8 (17.8%)  1b2 7 (25%) 0 (0)  1b3 1 (3.6%) 0 (0)  2a1 3 (10.7%) 1 (2.2%)  2a2 1 (3.6%) 0 (0)  2b 3 (10.7%) 0 (0) Whether meet the conservative surgery criteria  Yes 5 (17.9%) 36 (80%) <0.001 a  No 23 (82.1%) 9 (20%) Notes : a Pearson χ2 test, b Fisher exact test. Details Corresponding to Final Pathology (n=450) Abbreviation : AJCC, the American Joint Committee on Cancer. Characteristics of Women with Invasive Cervical Cancer Detected or Undetected by Frozen Sections Notes : a Pearson χ2 test, b Fisher exact test. Among the 22 women who underwent complete parametrectomy/ upper vaginectomy + pelvic lymphadenectomy during surgery, none met the criteria for conservative surgery. Among the 9 women who underwent reoperation for complete parametrectomy/ upper vaginectomy + pelvic lymphadenectomy, 3 met the criteria for conservative surgery. Among the 4 women who underwent reoperation for pelvic lymphadenectomy, 3 met the criteria for conservative surgery. Among the 6 women who received concurrent chemoradiotherapy, 4 met the criteria for conservative surgery. The diagnostic performance of transvaginal ultrasound (TVUS), pelvic magnetic resonance imaging (MRI), combined TVUS-MRI, and intraoperative frozen section for identifying invasive cervical cancer was calculated using permanent paraffin histopathology as the reference standard ( Table 4 ). Transvaginal ultrasound (all patients): sensitivity 22.7%, specificity 97.3%, PPV 63.0%, NPV 86.3% for detecting invasive cervical cancer. Pelvic MRI (69 patients): sensitivity 59.1%, specificity 70.2%, PPV 48.1%, NPV 78.6% for detecting invasive cervical cancer. Routine preoperative pelvic MRI may enhance diagnostic sensitivity and PPV in high-risk patients, which needs to be confirmed in prospective research. Combined TVUS plus pelvic MRI: sensitivity 78.1%, specificity 57.1%, PPV 51.0%, NPV 82.1% for detecting invasive cervical cancer. Intraoperative frozen section (432 patients): sensitivity 38.4% (28/73), specificity 100%, PPV 100%, NPV 88.7% for detecting invasive cervical cancer. Table 4 The Diagnostic Performance of Sensitivity, Specificity, Positive Predictive Value (PPV), Negative Predictive Value (NPV) of Transvaginal Ultrasound (TVUS), MRI, TVUS/MRI and Frozen Section Were Calculated Based on the Final Paraffin Histopathology as the Reference Standard Final Pathology Invasive Cancer Final Pathology No Cancer Sensitivity Specificity PPV NPV TVUS 22.67% 97.33% 62.96% 86.29 Positive 17 10 Negative 58 365 MRI 59.09 70.21% 48.15% 78.57% Positive 13 14 Negative 9 33 TVUS/MRI 78.13% 57.14% 51.02% 82.05% Positive 25 24 Negative 7 32 Frozen Section 82.05% 100% 100% 82.05% Positive 28 0 Negative 45 359 The Diagnostic Performance of Sensitivity, Specificity, Positive Predictive Value (PPV), Negative Predictive Value (NPV) of Transvaginal Ultrasound (TVUS), MRI, TVUS/MRI and Frozen Section Were Calculated Based on the Final Paraffin Histopathology as the Reference Standard

According to the American Society of Colposcopy and Cervical Pathology (ASCCP) guideline, cervical cancer screening should begin at age 25 and continue until age 65. However, approximately 20% of cervical cancers occur in women 65 years and older. 7 , 16 , 17 It has been observed that elderly women beyond the screening age are more commonly diagnosed with advanced-stage disease. 18 Recent studies have reported higher mortality rates in elderly women compared to younger women. 19 Cervical conization, either cold-knife or LEEP procedures, has been widely used for treating biopsy-proven HSIL lesions, with ideal therapeutic effects. 20 This cervical local excision plays a crucial role in identifying microinvasive cervical cancer and contributes to reducing the incidence of cervical cancer. 21 , 22 However, in women with cervical abnormality when cervical conization is not feasible, cervical cancer may be neglected. Cheung et al reported a 3.6% incidence of invasive cervical cancer in women who underwent hysterectomy due to abnormal cervical smear results when local excision was considered technically infeasible. 13 In our study, the incidence (16.67%) of occult invasive cervical cancer in this population was higher than that reported by Cheung et al It may be attributed to the women enrolled in our study had at least a high grade abnormal cervical cytology or high grade colposcopy results, which result in an increase in the incidence of invasive cervical cancer. The independent predictive value of high-grade cytology/cancer (OR 2.33) and HPV16/18 infection (OR 4.62), high-grade squamous intraepithelial lesion (HSIL) of endocervical curettage (OR 2.45) and cervical masses and/or abnormal echoes detected by ultrasound (OR 10.70). This study addresses a clinically important yet underrepresented scenario: the management of women with abnormal cervical cancer screening results in whom diagnostic conization is technically infeasible. While major guidelines (ASCCP, ESGO) provide management algorithms for screen-positive women, these algorithms uniformly assume that diagnostic conization is technically feasible. Our study provides evidence to support clinical decision-making in scenarios where these algorithms cannot be applied, a situation increasingly prevalent among aging populations worldwide. The role of preoperative imaging in the detection of occult cervical cancer in elderly women warrants particular attention. We herein report a case of polypoid cervical endometriosis. Preoperative magnetic resonance imaging was suggestive of cervical carcinoma. Histological evaluation of the colposcopic directed biopsy and diagnostic LEEP specimen demonstrated chronic cervicitis, whereas biopsy of the endocervical polyp initially indicated complex endometrial hyperplasia. Definitive histopathologic examination following total hysterectomy verified the diagnosis of polypoid cervical endometriosis, without morphologic evidence of invasive carcinoma. Zheng et al previously described a comparable case in which preoperative MRI raised suspicion of cervical malignancy, with the final diagnosis of polypoid endometriosis established on paraffin pathology. 23 The atypical glandular architecture and papillary growth pattern of the lesion render it susceptible to misdiagnosis as cervical carcinoma. 24 So, radical hysterectomy could not be performed directly for the MRI suspected tumor, accurate differentiation including frozen section intraoperatively is essential to avoid overtreatment. Direct radical hysterectomy carries a high risk of overtreatment under such circumstances. Therefore, we adopted a staged strategy: initial total hysterectomy, followed by supplementary parametrectomy if intraoperative frozen section confirmed invasive carcinoma. It is important to recognize that intraoperative frozen section examination has inherent limitations in the detection of microinvasive disease, particularly for lesions with a depth of invasion less than 3 mm. In the present study, 61.6% of invasive cancers were not identified by frozen section, and the majority of these cases were stage IA1 and IA2 tumors. However, after comprehensive preoperative evaluation, most patients with such small lesions meet the criteria for conservative surgery, and the omission of radical parametrectomy and lymphadenectomy in these cases is unlikely to compromise oncological outcomes. This observation further highlights the critical importance of thorough preoperative imaging assessment to identify patients with more advanced disease who would benefit from intraoperative frozen section pathology and radical surgery. Persistent HrHPV infection is a known risk factor for cervical cancer. However, due to health consciousness and economic factors, many women, especially elderly women, do not undergo regular cervical cancer screening. Consequently, it becomes challenging to assess the duration of HPV infection in women within this study. The WHO categorizes HPV into carcinogenic HPV subtypes (Group 1); probably carcinogenic HPV subtypes (Group 2A); possibly carcinogenic HPV subtypes (Group 2B); low-risk HPV subtypes (Group 3) and those not classified with respect to carcinogenic potential. HPV 16, HPV 18 and HPV 45 are the most common ones in Group 1 HPV involved in cervical squamous and glandular carcinogenesis. 12 Our results are consistent with the WHO report. In our study, we found that HPV16/18 infection was the predictive factor for invasive cervical cancer in women with abnormal cervical cytology and/or colposcopy biopsy when cervical conization was considered technically infeasible. This suggests that more proactive management be needed for this group of women. Bogani G et al had also assessed 77 patients who developed HPV-related lower genital tract dysplasia after hysterectomy for HSIL and early-stage cervical cancer. They found that HPV vaccination had potentially protective effect against lower genital tract dysplasia. 25 We will continue to test HPV in the follow-up of these women in order to diagnose lower genital tract dysplasia in time. In postmenopausal women, the transformation zone is often retracted into the cervical canal as a result of age-dependent changes. This, combined with epithelial atrophy, poses challenges in collecting biopsies/ECC for potential precancerous or cancerous lesions. Several guidelines recommend performing the large loop excision of the transformation zone (LLETZ) in women referred with abnormal cytology and an incomplete visualized transformation zone during colposcopy, in order to ensure accurate diagnosis. 19 However, in clinical practice, due to severe atrophy of the cervix and vagina, LEEP and LLETZ cannot be implemented, which is exactly the situation of the women in our study. In our study, we found that the presence of cervical masses and/or abnormal echoes detected by preoperative ultrasound was a predictive factor of invasive cancer. Although only a small portion of women underwent pelvic MRI, women with pelvic MRI findings indicating cervical abnormalities were more likely to have invasive cervical cancer detected after surgery. Therefore, we recommend a thorough preoperative pelvic imaging evaluation for women who cannot undergo conization, even if no invasive cancer was indicated. Frozen sections can assist in detection of cervical cancer during surgery and help in determining the optimal surgical plan. In our study, although not all cases of invasive cervical cancers were identified by frozen sections, they still proved to be effective. It is important to note that most of the invasive cervical cancers undetected by frozen sections were at stage IA1 without LVSI, which did not require reoperation or additional adjuvant treatment. Therefore, we recommend performing intraoperative frozen section examination if conditions permit. As for women with incidentally found invasive cervical cancer after hysterectomy but meeting the criteria for conservative surgery, pelvic lymphadenectomy is still required. Therefore, patients should still be fully informed of the possibility of reoperation. However, this study has several limitations. The prevalence of invasive disease in our group of women may have been underestimated because some women may have opted for expectant management. The retrospective nature of this study may influence the results and limit its application. The strengths of our study are the large size of the study population and the comprehensive investigation of preoperative variables. We selected all available cases based on fully colposcopy evaluation by specialist in cervical disease to reduce the selection bias caused by preoperative misdiagnosis. Also, the feasibility of cervical conization was jointly evaluated and decided by specialist in cervical disease and gynecological oncology. In addition, we have analyzed the application value of intraoperative frozen section pathology in diagnosing cervical invasive cancer, determining the appropriate surgical extent and avoiding second surgery. Moreover, by analyzing the risk factor of invasive cancer verified by final pathology, we have proposed a suitable population for intraoperative frozen section as an adjunctive diagnostic method which optimize the utilization of pathological resources. Our study has certain limitations. First, our study was conducted in a single center. Secondly, the study covers a relatively longer time span. With the advancement of diagnostic and treatment techniques, there was inevitably selection bias in the early cases. An important limitation of the present study is that the selection of patients for pelvic MRI was not governed by a standardized protocol but relied on the clinical judgment of attending physicians, which may lead to selection bias. Accordingly, the diagnostic performance of MRI observed in this study should be interpreted with caution. We are currently in the process of developing a prospective study to validate and further examine our findings.

In elderly women with abnormal cancer screening and technically infeasible cervical conization, the incidence of occult invasive cervical cancer is considerable. In patients with abnormal screening results and infeasible conization, when characterized by cytology of high grade/ cancer, HPV16/18 infection, HSIL of endocervical curettage, and cervical masses and/or abnormal echoes detected by ultrasound, caution should be raised for invasive cancer and more comprehensive imaging evaluation should be conducted. Intraoperative frozen-section pathology is recommended for patients with high-risk profiles to identify subtle early lesions undetectable by gross visual inspection and a small subset of locally advanced occult cervical carcinoma to guide appropriate surgical strategies (eg lymph node biopsy, radical parametrectomy and lymphadenectomy). The subsequent diagnostic and treatment plan should be determined according to the postoperative pathological findings, and additional surgery or other adjuvant therapy may be required.