Missed diagnosis of pelvic organ prolapse complicated with cervical cancer: a retrospective case series of five patients and review of literature.

Pelvic organ prolapse (POP) is a common condition in women, with estimates suggesting it occurs in 40% to 67% of parous women ( 1 - 3 ). While the occurrence of concurrent uterine prolapse with cervical cancer is not common ( 4 ). One of the common complications of POP, particularly procidentia, is the ulceration of the most dependent area of the prolapse, which is frequently the cervix ( 5 ). Chronic irritation from long-standing POP may lead to dysplasia and human papillomavirus (HPV)-independent carcinoma, representing only 5% of cervical cancers ( 6 ). However, the continuous injury of the cervical epithelium may contribute to the neoplastic process ( 7 ). Women with uterine prolapse are at an increased risk of chronic inflammation and direct mechanical irritation of the prolapsed areas, which may predispose them to a higher risk of cervical cancer development ( 4 , 8 ). The relationship between POP and non-HPV Papanicolaou (Pap) smear abnormalities is significant. A study found that the rate of non-HPV-associated abnormal Pap smears was higher in the POP group than in the non-POP group, and the rate of non-HPV Pap smear abnormality was significantly associated with increasing prolapse stage. This poses challenges for diagnosis and management ( 9 ). However, early detection and proper management of cervical cancer in patients with POP are crucial. A study by Wan et al. ( 10 ) highlighted the risk of missing a malignancy in surgical specimens following hysterectomy for uterine prolapse if routine pathological examination is not performed. The study found that 61.25% of cases had abnormal findings, including premalignant and malignant uterine conditions ( 11 ). However, one study showed that cervical cancer patients with complete uterine prolapse had more favorable survival outcomes with surgery-based treatment ( 12 ). Common complications include delayed treatment, invasive cancer progression, and complex surgical management. Early detection and tailored treatment strategies are crucial to improve patient outcomes ( 13 , 14 ). Additionally, cervical cancer complicating POP in elderly patients necessitates a multidisciplinary approach ( 15 ), the literature review examines the challenges in diagnosis due to overlapping symptoms. The literature review from 1989 to 2024 identified 22 case reports involving 26 patients (average age: 68.31 years), with the majority (83.36%) at advanced stages of prolapse (Stage III or IV). The predominant cancer types were cervical squamous cell carcinoma (SCC), representing 61.54% of cases, followed by vaginal SCC at 15.38%. Endometrial cancer was diagnosed in 11.54% of patients, with 7.69% of these cases being endometrioid carcinoma, and fallopian tube carcinoma accounted for 3.85% of the cases. On average, there was a 14.18 years delay from prolapse onset to cancer diagnosis. Treatments included hysterectomy, radiation, and chemotherapy. Among these cases, 42.30% had favorable outcomes, while 15.38% experienced adverse events, including two fatalities ( Table 1 ) ( 5 , 7 , 14 - 33 ). This underscores the importance of swift, precise diagnostics and a multidisciplinary approach, especially in older patients due to symptom overlap. POP, pelvic organ prolapse; NA, not applicable; FIGO, International Federation of Gynecology and Obstetrics. The retrospective analysis of five Chinese postmenopausal women further emphasizes diagnostic challenges, disease progression, and the significance of vigilant screening and tailored care to prevent missed diagnoses in POP patients, supporting a holistic management strategy. We present this article in accordance with the STROBE and AME Case Series reporting checklists (available at https://gpm.amegroups.com/article/view/10.21037/gpm-24-19/rc ).

Using a retrospective study design, we performed a case series study evaluating Chinese women with missed diagnosis of POP complicated with cervical cancer between June 2020 and June 2024. Data were obtained from electronic medical records, encompassing details such as age, obstetric history, body mass index (BMI), symptoms, medical history, laboratory findings, imaging studies, surgical procedures, operative details, complications, postoperative pathology reports, and postoperative diagnoses. Follow-up data were also collected after surgery to evaluate recurrence rates. The study was conducted in accordance with the Helsinki Declaration (as revised in 2013). Ethical approval was waived by the ethics committee as it was retrospective case series and no patient identifiable information was used. Written informed consent was obtained from the patients for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal. All the analyses were performed using SPSS 20.0 software (SPSS, Inc.; Chicago, IL, USA). Descriptive methods were employed to summarize the data. Continuous data were presented as medians and ranges to account for skewness, while categorical data were reported as percentages. No inferential statistics were used in the analysis due to the case series design.

In this retrospective case series study, five Chinese women with missed diagnosis of POP complicated with cervical cancer at our hospital were analyzed. The median age was 75 years (range, 71–86 years), and median BMI was 20.00 kg/m 2 (range, 14.67–28.70 kg/m 2 ). The POP duration varied from 1 to 50 years, with a median of 15 years. Comprehensive information on clinical symptoms, past history, gynecological examinations, laboratory biomarkers, imaging examination and various abnormalities are presented in Table 2 for all patients. Their POP-quantification and diagnosis are presented in Table 3 . BMI, body mass index; POP, pelvic organ prolapse; Pap, Papanicolaou; HPV, human papillomavirus; MRI, magnetic resonance imaging; CEA, carcinoembryonic antigen; AFP, alpha-fetoprotein; CA19-9, carbohydrate antigen 19-9; CA-125, carbohydrate antigen 125; LSIL, low-grade squamous intraepithelial lesion; HSIL, high-grade squamous intraepithelial lesion. Preoperatively, two patients had negative HPV tests and normal Pap smears, while the remaining three had positive HPV or concerning Pap smear results. No malignancy or atypical cells were found in cytology. A biopsy on Case 5 confirmed chronic cervicitis along with degeneration of the squamous epithelium and inflammatory infiltration within the cervical canal. Preoperatively, Case 1 underwent treatment for an ulcer and abscess with antibiotics and potassium permanganate baths for infection control and wound healing. Surgical procedures performed included vaginal hysterectomies, colpocleisis, perineorrhaphies, excision of a cervical neoplasm, dilation and curettage, laparoscopic bilateral salpingo-oophorectomy, laparoscopic lateral suspension. Case 1 had a minor bladder injury, and three patients underwent quick frozen pathology examinations. The operation times ranged from 47 to 120 minutes (median: 93 minutes), blood loss was 50 to 600 mL (median: 50 mL), and urinary catheters were removed after 3 to 15 days (median: 3 days). The postoperative hospital stay lasted 4 to 8 days (median: 4 days) ( Table 4 ). For Case 1, Figure 1 combines preoperative magnetic resonance imaging (MRI) scans of Stage IV prolapse with an ulcerated abscess, the postoperative specimen, and pathology results (SCC). Cases 2–5 each have a postoperative specimen and histopathology image ( Figures 2-5 ), demonstrating effective surgical treatment for cervical cancer. No adjuvant chemotherapy was needed in any case. In Case 1, a recommendation for post-operative adjuvant chemotherapy was made; however, the patient’s family declined due to her age and opted for regular follow-up in the outpatient clinic every 3 months instead. All patients were recommended to follow up in the outpatient clinic every 3 months, with a median postoperative follow-up of 11 months (range, 2–48 months). During this follow-up period, no recurrences were reported ( Table 4 ). CIN, cervical intraepithelial neoplasia; IHC, immunohistochemistry; CD10, cluster of differentiation 10; ALK, anaplastic lymphoma kinase; HPV, human papillomavirus; VaIN, vaginal intraepithelial neoplasia. Illustrates the perioperative and post-operative stages of a Case 1 involving Stage IV prolapse with complications. (A) Preoperative image showing Stage IV prolapse with local ulcer and abscess. (B) Imaging of MRI sagittal view, T2-weighted images showing complete POP formation of multiple abscesses in pelvic floor soft tissues. Key anatomical landmarks are identified: B, urinary bladder; P, pubic symphysis; Ur, urethra; Ut, uterus; I, inflammatory tissues; R, rectum. (C) Imaging of MRI coronal view, T2-weighted images showing complete POP formation of multiple abscesses in pelvic floor soft tissues. Anatomical structures include: B, urinary bladder; Ut, uterus; A, abscesses. (D) Postoperative sample of the prolapsed organ showing the formation of hard knots on the prolapsed organ. (E) Infiltration of squamous cell carcinoma in cervical H&E (magnification: ×20). (F) Well differentiated tumor H&E (magnification: ×200). (G,H) Tumor cell expressed squamous cell markers such as P63 IHC (magnification: ×100) and CK5/6 IHC (magnification: ×100) respectively. (I,J) Show negative expression of P16 IHC (magnification: ×100) (I) and low proliferation index of Ki67 IHC (magnification: ×100) (J). (K) Positive expression of P40 IHC (magnification: ×200) in the tumor cell. (L) Seven days post-operative image substantial recovery progress. MRI, magnetic resonance imaging; POP, pelvic organ prolapse; H&E, hematoxylin and eosin; IHC, immunohistochemistry. Case 2 post-operative pathology images showing. (A) Gross image of the uterus (0.8 cm polypoid new organism of the cervix). (B) Squamous cell carcinoma invaded in the cervical stroma (H&E, magnification: ×40). (C) The tumor cell nests were irregular and poorly differentiated (H&E, magnification: ×100). (D) Positive expression of P63 IHC (magnification: ×200), in the tumor cell. (E) Positive expression of CK5/6 IHC (magnification: ×200) in the tumor cell. (F) Diffuse positive expression of P16 IHC, (magnification: ×200) in the tumor cell. (G) The proliferation index of Ki67 IHC (magnification: ×200) was about 60%. (H) Positive expression of P40 IHC (magnification: ×200) in the tumor cells. H&E, hematoxylin and eosin; IHC, immunohistochemistry. Case 3 post-operative pathology images showing. (A) Gross image of the uterus (slightly hypertrophic and eroded cervix with a 0.5 cm × 0.5 cm cervical polyp). (B) Gross image of the vulva. (C) Gross image of the adnexa (inflammation of the fallopian tubes with mesosalpinx endometriosis). (D) Normal cervical squamous epithelium and multiple leiomyomas with degeneration and calcification (H&E, magnification: ×40). (E) Chronic inflammation of the cervix and cervical endometrium with erosion, suggestive of chronic cervicitis (H&E, magnification: ×40). (F) Physiological atrophy of the endometrium (H&E, magnification: ×40). H&E, hematoxylin and eosin. Case 4 post-operative pathology images showing. (A) Gross image of the uterus (appears atrophied with a thin, smooth endometrium). (B) CIN III lesions and the micro-invasive squamous cell carcinoma (H&E, magnification: ×100). CIN, cervical intraepithelial neoplasia; H&E, hematoxylin and eosin. Case 5 post-operative pathology images showing. (A) Gross image of the uterus (showed cervical atrophy, uterine atrophy, a smooth endometrium, and an intact cervical canal). (B) The micro-invasive squamous cell carcinoma in cervical stroma (H&E, magnification: ×40). (C) The high-power field of the micro-invasive squamous cell carcinoma (H&E, magnification: ×100). (D) CIN III lesions and the micro-invasive squamous cell carcinoma (H&E, magnification: ×200). H&E, hematoxylin and eosin; CIN, cervical intraepithelial neoplasia.

This study highlights the missed diagnosis of POP complicated by cervical cancer, a challenging condition often overlooked. By examining clinical presentations, diagnostic challenges, and treatment outcomes, it rises awareness and emphasize the need for improved diagnostic strategies, particularly in elderly patients with overlapping symptoms. It underscores the importance of vigilant assessment to prevent misdiagnosis and ensure timely management for optimal patient care. In literature, there is limited evidence on the prevalence of missed diagnosis of POP complicated with cervical cancer. The risk of unanticipated uterine cancer and cervical cancer in women undergoing hysterectomy for uterovaginal prolapse were 0.53% for uterine cancer and 0.09% for cervical cancer according to American College of Surgeons National Surgical Quality Improvement Program database from the 2015–2018 ( 34 ). Mahnert et al. ( 35 ) used statewide data in Michigan and found an incidence of 0.3% for cervical cancer in a cohort of 670 patients undergoing hysterectomy for prolapse. In an underscreened population, another database from the 2007–2019 showed the rates of cervical dysplasia or cancer were 0.41% (3/729) for patients undergoing hysterectomy for POP ( 36 ). In the context of cervical cancer, missed diagnosis can lead to delayed treatment, which can result in disease progression and poorer prognosis. POP patients with cervical cancer had a mean age of 74 years at diagnosis, and 20% of cases being Stage III cervical cancer and all cases having Stage III–IV uterovaginal prolapse ( 13 ). Delayed diagnosis and advanced stage at diagnosis can limit treatment options and decrease the likelihood of successful treatment outcomes. Furthermore, missed diagnosis of cervical cancer in the context of POP can also impact the choice of treatment. Surgical intervention is often required for both the tumor and the prolapse, and missed diagnosis may result in the need for secondary surgeries, which can affect the patient’s quality of life ( 31 ). Additionally, missed diagnosis can lead to inadequate preoperative evaluation and planning, potentially affecting the surgical approach and outcomes ( 21 ). Based on the general understanding of missed diagnosis in cervical cancer and the challenges associated with managing POP and cervical cancer concurrently, it is reasonable to assume that missed diagnosis can have negative consequences for patient outcomes. Early and accurate diagnosis is crucial for timely and appropriate treatment, which can improve prognosis and overall patient outcomes. Due to preoperative missed diagnosis of cervical cancer in patients with POP, the choice of surgical method may be affected, and a second surgery may be required, which may even affect postoperative treatment and efficacy. Four out of five patients (4/5) in this study were all misdiagnosed with cervical cancer before surgery, and two out of five patients (2/5) were diagnosed with cervical cancer after intraoperative freezing. It is important for all patients to receive postoperative supplementary treatment and regular follow-up, it should be taken seriously by clinical doctors. The common reasons for missed diagnosis of POP complicated with cervical cancer include inadequate evaluation of abnormal Pap smears or cervical biopsies, failure to perform indicated procedures such as conization or biopsy, misinterpretation of pathology results, lack of preoperative screening tests, and failure to biopsy a gross cervical lesion. These factors contribute to missed opportunities for more timely diagnosis and highlight the importance of adhering to established guidelines for cervical cancer detection ( 37 , 38 ). Older age has been identified as a risk factor for delayed diagnosis of uterine cervical lesions ( 39 ). A Pap smear during the pre-invasive detectable phase was significantly negatively associated with the development of invasive cervical cancer in women over 65 years old ( 40 ). Advanced age was associated with a reduced likelihood of adequate screening for cervical cancer ( 41 ). Menhaji et al. ( 9 ) found that the rate of non-HPV-associated abnormal Pap smears was higher in the POP group than in the non-POP group. It suggests that regular screening and evaluation are crucial, especially for elderly POP patients over 70 years old. Wang et al. ( 42 ) also supports the importance of regular screening in older age groups. But elderly women, especially those over 75 years old, are less likely to have had Pap testing ( 43 ). It is important for healthcare practitioners to consider age-related factors and ensure appropriate screening and evaluation for older women. This highlights the importance of patient education and awareness about cervical cancer screening. This underscores the importance of healthcare providers making efforts to improve attendance rates of Pap smear screening in elderly women. Abnormal vaginal bleeding is a significant risk factor for delayed diagnosis of cervical cancer ( 39 ). Several studies identified post-menopausal bleeding as a high-risk symptom for cervical cancer, which could be mistaken for benign symptoms in patients with POP. Therefore, it is crucial to consider these atypical symptoms and conduct thorough evaluations in patients with POP to avoid missed diagnoses of cervical cancer ( 44 , 45 ). We should be vigilant for elderly woman with POP who developed new-onset vaginal bleeding ( 15 ). Chronic inflammation caused by POP and friction may contribute to missed diagnosis of cervical cancer. One study found that poor cervical cytology before colposcopy, unsatisfactory colposcopy, and positive high-risk HPV (HR-HPV) detection were risk factors for missed cervical intraepithelial neoplasia (CIN) 2+ in low-grade squamous intraepithelial lesion (LSIL) pathologically diagnosed by colposcopy-assisted biopsy ( 46 ). Incomplete evaluation of cervical dysplasia or microinvasion on biopsy and false-negative cervical cytology were identified as risk factors for improper simple hysterectomy in cervical cancer patients ( 47 , 48 ). Additionally, a retrospective review found that missed opportunities for screening and early diagnosis of cervical cancer were associated with lack of prior visits recorded, absence of prior cytology, and failure to adhere to screening guidelines ( 49 ). Another reason for missed diagnosis is the delay in seeking medical care. Reis et al. ( 50 ) identified obstacles to seeking medical care as a theme in their qualitative study on the experiences of women with advanced cervical cancer. A study found that women with POP lack awareness about cervical cancer and screening services, leading to delayed care-seeking behavior. This finding suggest that healthcare providers should sensitize women with POP to seek timely screening and treatment services for cervical cancer ( 51 ). Furthermore, the complexity of managing patients with both POP and cervical cancer can contribute to missed diagnosis. Also, a common reason for missed diagnosis of POP complicated with cervical cancer is the similarity of symptoms between the two conditions. Both conditions can present with symptoms such as abnormal vaginal bleeding, pelvic pain, and a sensation of a bulge or protrusion in the vagina. These overlapping symptoms can lead to misdiagnosis or delayed diagnosis of cervical cancer in the presence of POP. It is important for healthcare providers to maintain a high index of suspicion and consider further evaluation, such as imaging or biopsy, to rule out cervical cancer in patients with POP ( 52 ). Adhering to established diagnostic protocols and guidelines is essential to prevent missed diagnoses. It is important for healthcare providers to be aware of these risk factors and ensure comprehensive evaluation and appropriate screening for patients with POP to avoid missed diagnoses of cervical cancer. Early detection and timely intervention are crucial for improving outcomes in these cases. Dawkins et al. ( 15 ) highlighted the importance of a multidisciplinary approach involving urogynecologists, gynecologic oncologists, and radiation oncologists in managing cervical cancer complicating POP. Ota et al. ( 32 ) proposed a combined surgery for cervical cancer and POP. Therefore, a multidisciplinary approach is necessary for proper management. Studies have explored various treatment approaches for cervical cancer in patients with POP. A multidisciplinary approach, including chemoradiotherapy followed by radical hysterectomy, has shown success in treating these conditions ( 7 ). Surgery-based treatment may also have a positive effect on survival outcomes in cervical cancer patients with complete uterine prolapse ( 1 ). Our cases, consistent with Yang et al. ( 53 ), emphasize the need for rigorous cervical cancer screening, especially in those undergoing gynecological diagnostic procedures. The case presented by Zhu et al. ( 54 ) underscores the crucial role of employing innovative therapies, such as brachytherapy, when confronting intricate clinical scenarios. Despite this, a standardized optimal management protocol remains elusive. Our cases, along with others in the literature, demonstrate that late-stage diagnoses often necessitate more aggressive therapies and can lead to less favorable outcomes ( 7 , 13 ). The patient education and counseling strategies outlined by Nemirovsky et al. ( 55 ) are vital, as they ensure patients have a comprehensive understanding of their condition and potential complications. Additional research and studies are needed to yield more precise information on prognosis outcomes specifically in this patient population. The American Urogynecologic Society Prolapse Consensus Conference highlighted the importance of assembling interdisciplinary teams to address the complex scientific dimensions of POP ( 56 ). Dällenbach et al. ( 57 ) highlights the need for a blend of scholarly understanding and surgical dexterity in treating anterior POP, illustrating the challenges of detecting coexisting conditions. Both studies underscore the value of embracing a holistic perspective that recognizes the interconnection between gynecological and urological factors. Such collaborative endeavors can shed light on the optimal handling of POP and its associated complications, including cervical cancer ( 56 ).

In conclusion, the missed diagnosis of cervical cancer in patients with POP is a significant concern. Regular screening and evaluation should be conducted in these patients to ensure early detection and appropriate management, especially for elderly POP patients over 70 years old. Preoperative screening methods may have limitations in detecting cervical abnormalities in POP patients. Attention should be paid to POP patients with new cervical organisms, cervical erosion, and concurrent local cervical infections, and timely cervical biopsy should be performed. It is important for healthcare providers to be aware of the possibility of cervical cancer in patients with POP. Accurate diagnosis, appropriate screening, and tailored treatment strategies are crucial in managing cervical cancer in the presence of POP. A multidisciplinary approach involving urogynecologists, gynecologic oncologists, and radiation oncologists may be necessary for optimal treatment outcomes. Further research could focus on improving diagnostic strategies and screening methods for cervical cancer in women with POP. Additionally, studies could explore the effectiveness of different treatment approaches and management strategies for women with both conditions.

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