Staging and Management of Cervical Cancer at the Colposcopy Clinic of Bangabandhu Sheikh Sheikh Mujib Medical University (BSMMU), Bangladesh

Introduction

Cervical cancer (CC) is the fourth most common cancer in females around the world and the fourth leading cause of cancer death. It is estimated that 604,127 new cases occurred in 2020 that represent 7.7% of all female cancers worldwide. Total number of death due to CC was 341,831.1 Approximately 90% of deaths from CC occurred in low- and middle-income countries (LMICs). It is the second most common cancer among women in Bangladesh. CC constitutes approximately 12% of female cancer in this country.2 In developing countries, majority of the women with CC present with advanced disease, that often leads to high mortality and morbidity. The overall 5-year relative survival for early and localized cancers is 73.2% but can be as low as 7.4% for advanced stage disease.3 In Bangladesh, facilities for radiotherapy are available only in few government institutions and expensive in the private sector. Due to the late stage at diagnosis and inadequate management facilities, mortality rate from CC is still high in Bangladesh.

In LMICs risk factors like early marriage, early pregnancy, multiple sexual partners, sexually transmitted diseases, lack of screening program and low socioeconomic condition play important role for increased death related to CC. Human papilloma virus (HPV) infections especially oncogenic type HPV16 and HPV18 are regarded as the main cause of developing CC.4 CC can be prevented by primary prevention through vaccination and secondary prevention through screening. Screening can detect cervical precancer and cancer in early stage. Treatment of the precancer prevents conversion into malignancy and management of early CC reduces mortality and improve quality of life. Invasive CC initially spreads locally and then metastasizes to distant organs and cancer becomes an advanced disease with increase of stage. Staging at presentation is an important predictor for survival of women. It guides clinicians to plan the management. Staging is based on the results of physical examination, imaging scans, and biopsies. Clinical staging is mostly used for staging of CC as recommended by International Federation of Gynecology and Obstetrics (FIGO).5 Radical hysterectomy is a well-adopted surgical treatment that can be performed for stage I and IIA disease. Radiotherapy is applicable for women with CC of all stages and usually practiced for the management of advanced CC. Advanced imaging techniques like magnetic resonance imagings (MRIs), positron emission tomography scans, and computed tomography (CT) scans also help in staging. Imaging is used to diagnose the metastasis and micrometastasis in distal organ that helps in improving the quality of treatment and survival rate.6

In LMICs, CC screening program is poorly developed, and majority of the cases are diagnosed in advanced stage of the disease. Patients with advanced stage diseases have poor prognosis compared with patients who present at early stage disease.78 Therefore, diagnosis of early stage disease is crucial for good management plan for women with CC. With this vision, Government of Bangladesh (GOB) adopted a CC screening program since the year 2005. Visual inspection of cervix with acetic acid (VIA) method was considered as a method of screening due to its simplicity, low cost, potential for immediate linkage with investigations/treatment, and the possibility of rapid training to the service providers. VIA method is introduced within the existing government health infrastructure at district and subdistrict level.910111213141516 The GOB is trying to develop a nationwide population-based screening program through VIA for the women of 30 to 60 years of age with aim of performing the test every 5 years.16 Till now approximately 431 VIA centers have already been established at primary, secondary, and tertiary level healthcare facilities in 64 districts of Bangladesh.15 Screen-positive cases are being referred to the colposcopy clinics of tertiary care facilities (BSMMU/ MCHs), where evaluation and management are performed.121314 Fourteen government MCHs and BSMMU are functioning as referral centers through development of colposcopy clinics. During cervical screening, CC cases are incidentally diagnosed at different stages at VIA facilities and colposcopy centers. This retrospective cross-sectional study included women attending colposcopy clinic of BSMMU from January 2016 to June 2019. The main objective of this study was to find out the pattern of staging of CC at presentation and management offered to the women during the mentioned period. This study followed clinical staging mostly as FIGO staging 2014.5

Materials and Methods

This retrospective study was performed at the colposcopy clinic of BSMMU from January 2019 to June 2020. Patients were recruited from the colposcopy registry books at BSMMU where data are being preserved during their first and subsequent follow-up visits. CC cases diagnosed at the colposcopy clinic with known staging from January 2016 to June 2019 were recruited in this study. If there was obvious cervical growth, clinical staging was performed during the same visit, cervical biopsy was collected for histopathological examination, and women were referred to the Department of Gynaecological Oncology or Clinical Oncology at BSMMU. In addition to that, colposcopy diagnosed, and histopathology confirmed CC cases detected during the same duration were included in the study.

Most of the women with CC had biopsy at the colposcopy clinic. Remaining had biopsy during examination under anesthesia (EUA) in the Department of Gynaecological Oncology at BSMMU. A good number of cases had EUA for confirmation of staging. In cases of advanced stage, disease staging was performed mostly by clinical examination at the colposcopy clinic. Women with early stage disease were referred to the Gynaecological Oncology and advance stage disease were referred to the clinical oncology outpatient department at BSMMU for further evaluation and management. The sociodemographic and reproductive health characteristics, examination findings, treatment received, and follow-up data of study women were collected from the colposcopy registry books at BSMMU. The data entry and analysis were performed using Statistical Package for the Social Sciences (SPSS) Version 17.0. The present research included data from January 2016 to June 2019 and therefore it considered clinical staging as previous FIGO staging (2014).5 Imaging techniques like intravenous urography, X-ray, CT scan, MRI, colposcopy, endocervical curettage, hysteroscopy, cystoscopy, and proctoscopy are also supportive in staging and these were incorporated in FIGO staging 2022.

Results

From January 2016 to June 2019, 575 (N) women with CC attended the colposcopy clinic of BSMMU. Among them, 52 patients were not included in the study due to unavailability of findings on staging and 523 patients of CC with known staging were recruited.

Among the 523 patients, 102 (19.50%) attended from Dhaka district, and 121 (30.80%) attended from other districts of Dhaka division with a distance from 20 to 70 km and rest of the study population attended from different far districts of Bangladesh (Table 1).

The mean age of the patients with CC was 48.59 (standard deviation [SD] ± 11.15) and the youngest patient was 26 years of age. Majority of the cases (333, 63.7%) presented between 31 and 50 years. Twenty-four women (4.6%) were younger than 30 years and 166 (31.7) were more than 50 years of age (Table 2). Majority of the patients (94.3%) were Muslim and rest 5.7% were Hindu. Mean age of first marriage was 15.18 ± 2.779 years and mean age of first delivery was 17.25 ± 2.913. Mean parity of the patients was 4.11 (SD ± 2.21).

Among the study population, 210 (40.2%) patients had staging done by EUA and staging of remaining patients was done by clinical examination and other investigations following FIGO staging. Table 3 shows the distribution of staging of CC patients according to age during diagnosis at BSMMU. Among 523 patients, about one-fifth (108; 20.7%) of patients presented with stage I and another one-fifth (123; 23.70%) presented with stage IIA disease. Almost half of the patients (240; 45.9%) were with stage IIB, 41 (7.8%) with stage III, and 11 (2.1%) patients were with stage IV disease. Among the patients with stage I disease, majority (82, 75.90%) of patients were in the 31 to 50 age group, 10 (9.30%) women were less than 30 years of age, and 16 (14.90) were more than 50 years of age. Similarly, among the patients with stage IIA, 81 (65.80) patients were in the age group 31 to 50, 7 (5.60) patients were less than 30 years of age, and 35 (28.40) patients were more than 50 years of age. Among the patients of stage IIB, 108 (45%) patients were in 41 to 50 years. In stage III and IV, maximum patients belonged to 51 to 60 years (29.30%, 45.50%, respectively). The peak age of presentation of CC was between 36 and 50 years of age and 55% of the cases presented during this time.

Among 523 women, 9 (1.40%) women had microinvasive squamous cell carcinoma, 427 (81.60%) had squamous cell carcinoma, and 33 (6.50%) had adenocarcinoma. Very small number of women had papillary adenocarcinoma, clear cell carcinoma, and small cell neuro endocrine carcinoma (Table 4).

Among the study population, 149 (28.50%) underwent radical hysterectomy with or without adjuvant therapy, 184 (35.14%) patients received radiotherapy with or without concurrent chemotherapy, and 152(29.10%) patients failed to avail treatment (Table 5).

Table 5 shows different treatment modalities according to the stages of the disease. Among 108 stage I patients, 37 (34.26%) patients underwent radical hysterectomy and adjuvant therapy was not advised due to early disease. Nine of these 37 cases were microinvasive squamous cell carcinoma and were suspected by VIA, evaluated by colposcopy and diagnosis was confirmed by histological examination. Another 37(34.26%) patients with stage I disease underwent radical hysterectomy followed by adjuvant therapy.

Among 123 patients with stage IIA disease, 73 (59.30%) patients underwent radical hysterectomy followed by adjuvant therapy, another 8 (6.6%) patients received radiotherapy or concurrent chemoradiation. Among 240 patients with stage IIB disease, 18 (7.50%) patients received radiotherapy and 133(55.40%) patients received concurrent chemoradiation. Furthermore, among 52 patients with stage III and IV disease, 6 received radiotherapy and 16 received concurrent chemoradiation. Altogether, among 523 study population, 152 (29.1%) did not attend BSMMU further and could not be followed up further.

Discussions

The mean age of the study population with CC was 48.59 (SD ± 11.15) and median age was 48.00 years. Studies in India revealed that the median age of patients at presentation was 54 and 54.7 years17 Detection of CC at comparatively lower age in the present study may be a reflection of earlier detection of CC patients in an unscreened population during a screening program.

In this study, 333 (63.7%) patients presented between 31 and 50 years of age. However, the peak age of presentation was from 36 to 50 years of age and 55% of the cases presented during this time. This indicates that women of 30 to 50 years should get the highest priority in the screening program in Bangladesh. There are resource limitations to execute CC screening program and particular attention to this group of women will pick up more precancer and early cancer. However, the findings of this study indicated that about one-third of the CC developed among women who were more than 50 years of age, and these women never had an opportunity to avail screening in their life time. Studies in India and Egypt also revealed increasing age of menopause as a significant risk factor for CC.1819 The World Health Organization (WHO) recommended upper limit of screening of women as 49 years of age,2021 and limiting screening at 49 years of age will fail to detect almost one third of the CC cases in Bangladesh and more in India. GOB adopted 60 years of age as the upper limit for CC screening.16 Inclusion of higher age group in the CC screening program may be a reflection of stakeholder's view for covering the women with higher age of this unscreened population.

Mean age of marriage and first delivery of the study population were 15.18 ± 2.779 and 17.25 ± 2.913, respectively. More than 80% of them were married before 18 years of age and had their first delivery before 20 years. A case–control study in Egypt reported young age at marriage (<18 years) as a significant risk factor for CC.19 Though the legal age of marriage for women in Bangladesh is 18 years, a large proportion of marriages still take place before the women reach this age. Awareness on benefit of delaying marriage needs to be created for reducing risk of CC. In this study, mean parity of the patients was 4.11 (SD ± 2.21) and 490 (93.60%) patients were multipara and 204 (39%) were grandmultipara. A pooled analysis of 10 case–control studies by the International Agency for Research on Cancer (IARC) involving eight developing countries of Africa, South America, Asia, and Europe found that parity increased the risk of both invasive and in situ carcinoma of the cervix.22 All this information indicate that parity is consistently associated with CC risk and declining parity should have a positive impact in reducing CC in developing countries. The GOB is proactive to provide high-quality family planning services for limiting childbirth. However, more efforts need to be given on this aspect as high parity is still common in this country.

About two-fifth (231, 44.2%) of this study population presented in early stage of the disease (stage I and IIA). The clinical stage of CC and the tumor size at the time of diagnosis are significant prognostic factors for CC. Therefore, eventual outcome of these early diagnosed cases in this study is likely to be promising with considerable decline of the mortality and further research is necessary with these early diagnosed cases. Almost similar proportion of early presentation of the disease was observed (Table 6) in studies at BSMMU (44.20%) and Dhaka Medical College Hospital (37.31%).2324 These findings reflected that a good proportion of patients presented with early stage disease at tertiary care centers with referral facilities for CC screen-positive women. A comparatively smaller proportion of women (24.37%) presented with early stage disease (stage I and IIA) to Delta Medical College and Hospital of Bangladesh, a cancer treatment center without referral facilities for screen-positive women.25 This reflects that even a cancer care center without screen-positive management facility receives early stage disease because of having a national screening program at different level of healthcare system of the country. All these studies revealed that tertiary care centers of Bangladesh receive considerable number of early CC and a good number of them were in operable condition. Successful expansion of the screening program and improving population coverage is, therefore, one of the effective ways for reducing death from CC.

A study in Karnataka, India (stage I—7.36%, stage IIA—9.21%) and North East India (stage I—4.10%) revealed relatively smaller proportion of CC cases with early disease and this was related to lack of awareness and absence of efficient screening program in the mentioned parts of India during the mentioned period.82627 On the other hand, comparatively higher proportion of patients presented with stage I disease in rural Kerala (12.80%) and Trivandrum (11.10%), where state is running national CC screening program.2829 These studies stressed on the importance of formulating public health policies with improving awareness and implementation of CC screening programs. Nepal developed screening services in limited areas. Study in Nepal showed closer proportion of patients presented with stage I and IIA disease (22.10%).30 The finding is again probably related to strength of existing screening program in the mentioned areas. All these studies indicated that screening program helps in early detection and the program expansion and gradual improvement of population coverage are very important to prevent advanced stage disease.

In this study, approximately 55.80% of the CC presented with advanced disease (stage IIB, III, and IV). Even with the presence of existing developing national screening program throughout the country, this high number of patients with advanced disease is probably a reflection of the poor health-seeking behavior of women and absence of organized screening program with low screening coverage of the country. However, the proportion of advanced disease was quite lower than Karnataka (82.90%),26 Nepal (80.90%),30 where large number of women presented with advanced disease.

A timely intervention through rapid scale up of the program toward different levels of healthcare should help in improvement of the screening coverage. This study revealed that BSMMU received considerable number of early CC in operable condition through the screening program including nine microinvasive CC without obvious growth. Even adjuvant therapy was not necessary after Wertheim's hysterectomy among 37 (34.26%) of 108 stage I cases due to localized disease. It indicates that screening program helps in early detection and the program execution is very important to reduce the necessity of radiotherapy that is particularly important in countries like Bangladesh with very much inadequate radiotherapy facilities.

Altogether, among 523 study population,152 (29.1%) women could not be contacted and followed up. Though many of them were operable, 29 (26.90%) patients with stage I and 38 (30.90) with stage IIa disease did not attend further and could not be contacted further over telephone. One of the important constrain of receiving treatment at the moment is inadequate treatment facilities and infrastructure problem. Patients may have to wait for several weeks for operation due to inadequate bed arrangement. Research in Dhaka Medical College focused on challenges of CC treatment in Bangladesh including inadequate treatment facilities in women's cancer ward. There was lots of barriers in establishment of women cancer ward in Dhaka Medical College.31 In this study, approximately 80% patients attended from other districts than Dhaka and 50% from distant districts. About 70% of the patients who leaves in other districts than Dhaka could not be contacted further. With increasing diagnosis of CC, adequate facilities for navigation of patients to diagnostic workup and appropriate treatment based on stage of the disease should be ensured. Gynecologic oncological operation and radiotherapy facilities should be made available at all tertiary care centers. Altogether, government should take necessary steps to improve the services.

In this study, approximately 292(55.80%) of the CC presented with advanced disease and among them 173 (59.24%) patients received radiotherapy with or without chemotherapy and 85 (29.10%) could not be followed up and their treatment modalities are not known. As BSMMU was not well equipped for radiotherapy, majority of the advanced disease were referred to other facilities for radiotherapy. However, in all the radiotherapy facilities, there is a long waiting list for treatment. Moreover, the overall facilities for radiotherapy are very much inadequate in Bangladesh and many equipment at tertiary centers are nonfunctional. Due to the late stage at diagnosis and inadequate management facilities, mortality rate from CC is high in Bangladesh. There is a big disparity regarding radiotherapy facility between developed and developing countries. In developed countries, there are at least one radiotherapy unit for every 250,000 people. A survey conducted among 20 LMICs in 2015 found that one radiotherapy unit was for every 5 million people and sometimes one unit for every 20 million people.32 In these LMICs with a huge burden of advanced stage CC, the only option is treating with radiotherapy. There are 30 countries worldwide that do not have any radiation machine, of them, 15 countries were from Africa and Asia.33 Loss of contact and treatment failure are well-known drawbacks. There may be other social constrains like ignorance, transport problems, lack of strong navigation system, and social support system for diagnosed patients.

Conclusion

This study shows the majority of carcinoma cervix patients who attended BSMMU colposcopy clinic was outside of Dhaka city. The majority of them was married and experienced motherhood below 18 years of age. The predominant phase of cervical carcinoma observed at the colposcopy clinic at BSMMU, a secondary screening facility designed for the detection of early and preinvasive stages of cervical cancer, was found to be in an advanced stage. The majority of carcinoma cervix was squamous cell carcinoma type than adenocarcinoma. About one-third of patients attending the colposcopy clinic did not receive treatment and this situation is disappointing. The study also shows the numbers of carcinoma cervix is decreasing over the years. The whole scenario represents the health system of the country and its efficacy. Further study should be performed to address this gap and the government should emphasize the issues.

One of the main limitations of the study is that the reported stage distribution of CC is based on data from only one colposcopy center, which raises concerns about the generalizability of the findings to the entire country. Staging of the cancer was primarily determined through clinical methods, as advanced imaging modalities were not available due to financial constraints and lack of facilities. This limitation could have affected the accuracy of the cancer staging. Another limitation is that approximately 10% of the CC patients included in the study did not have their stage ascertained. Additionally, one-third of the patients were lost to follow-up, and their treatment status remained unknown. These factors could have had an impact on the main outcome measures and introduced bias into the results. Lastly, the study lacks information on the recurrence status of CC among the patients after treatment and this limits the understanding of the long-term outcomes and effectiveness of the treatments provided.

Recommendation

Women aged 30 to 50 years should get the highest priority in the screening program in Bangladesh. The GOB should provide more efforts to implement marriage law and provide high-quality family planning services for limiting childbirth. Screening program helps in early detection of CC and the program expansion and gradual improvement in population coverage are very important to prevent advanced-stage disease. One of the important constraints of receiving treatment is infrastructure problems and inadequate treatment facilities at the GOB level and high treatment costs at the private level. Appropriate evaluation and treatment services for CC should be established in all tertiary care centers and a navigation system for the patients immediately after diagnosis should be arranged. The capacity of health systems should be improved to ensure the treatment of cancer patients on time. In addition to this, measures to vaccinate adolescent girls can be performed. Moreover, woman's education and empowerment are important sociodemographic factors and need special attention to improve awareness and health-seeking behavior.

Bangladesh currently lacks a population-based cancer registry (PBCR), which is considered the gold standard for obtaining accurate information about cancer incidence in a specific population. PBCRs monitor all cancer cases within a defined area, providing a comprehensive and clearer understanding of cancer occurrences. Additionally, they play a crucial role in ensuring high-quality cancer care audits and identifying areas where healthcare can be improved. At present, Bangladesh relies on hospital-based cancer registries, but these may not fully represent the entire spectrum of cancer cases in the population. Such registries are likely to miss numerous cancer cases as they primarily capture data from patients who seek treatment within the hospital system. Individuals who do not have access to hospital care or choose to receive treatment outside hospitals will not be accounted for in these registries. To address this issue and enhance public health data systems at the national level, it is essential for the GOB and international agencies to take proactive measures. This includes improvements in civil registration and vital statistics systems, allowing for better monitoring of diseases and health outcomes. It is also crucial to maximize the use of available data to inform public health policymakers and decision-makers effectively. One significant step would be the establishment and strengthening of national cancer registries in Bangladesh. These PBCRs would provide comprehensive and reliable data on cancer incidence, enabling better planning and resource allocation for cancer care and treatment. By incorporating data from all segments of the population, including those without hospital access, a more accurate and representative picture of cancer occurrences can be achieved. Overall, by taking necessary actions to improve the public health data system, especially in terms of cancer registries, Bangladesh can enhance its ability to address cancer-related challenges and make informed decisions to improve public health outcomes.