Elevated Body Mass Index as a Predictor of Cervical Cancer and Precancerous Lesions

Introduction

There is a new paradigm considering noncommunicable diseases as a major cause of ill health. Noncommunicable diseases lead to premature deaths in reproductive age, which are preventable and avoidable [1]. Data identified by the Basic Health Research Survey/Riskesdas in Indonesia, showed prevalence of obesity among adults doubled over the decade from 2007 to 2018, and that obesity has become a health burden. Obesity is a serious public health problem and is included in noncommunicable diseases. It is measured by the body mass index (BMI) and is linearly associated with increased morbidities in cervical cancer [2].

Cervical cancer is the fourth most frequently diagnosed cancer and the fourth leading cause of cancer death in women worldwide. In 2020, 604 000 new cases and 340 000 deaths worldwide were estimated [3,4]. Cervical cancer is the most commonly diagnosed cancer in 23 countries and is the leading cause of cancer death in 36 countries, with most found in sub-Saharan Africa, Melanesia, South America, and South-Eastern Asia [5,6]. The World Health Organization had been planning to cover 70% of women in the world to receive the screening by 2030. Unfortunately, the sustainable development goals to achieve universal health coverage is only 39% to 63% by 2030 [1]. In Global Cancer Statistics 2020, breast cancer cases reached 2 261 419 cases worldwide, with a cumulative risk in ages 0 to 74 years of 5.20% [6]. Of those with breast cancer, it is estimated that 8.2 in 100 000 would have cervical cancer, and the mortality rate is 2.2 per 100 000 for cervical cancer deaths. Cervical cancer is caused by human papillomavirus (HPV) infection. The HPV genotypes that are more likely to cause cervical cancer are subtypes 16 and 18, which are known as high-risk types. The other types are 31, 33, 35, 39, 51, 52, 56, 58, 59, 66, and 68. The high-risk subtypes will lead to cervical cancer if left untreated. In Indonesia, we have a national program called the National Cervical Cancer Elimination Plan for Indonesia 2023–2030. The goal of this program is to screen, identify, remove, or treat precancerous lesions that are more likely to progress to cancer. In 2020, Indonesia reached only 9.3% of the target screening coverage with the use of visual inspection of acetic acid testing. According to a study conducted at Dharmais National Cancer Hospital (DNCH), a national cancer center representing cancer data in Indonesia, it was estimated that there were approximately 396 914 new cancer cases and about 234 511 cancer-related deaths in the country. Based on DNCH data from 2021, there were 272 new cases of cervical cancer, accounting for 11.4% of all cases treated at DNCH that year. In comparison, Global Cancer Statistics 2020 reported 36 633 new cases of cervical cancer in Indonesia, representing 9.2% of all cancer cases nationally [7,8].

HPV is a sexually transmitted virus with around 200 identified viral subtypes, and each is differentiated by its genomic sequence. About 40 subtypes infect the mucosal epithelium and are classified into low-risk and high-risk, based on oncogenic potential. The International Agency for Research on Cancer classifies 12 high-risk HPV types as group 1 carcinogens: types 16,18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59. HPV 16 and 18 are most commonly associated with cervical cancer [9].

Most HPV infections clear within 2 years, but some persist. Obesity can decrease the body’s ability to clear an acquired infection. The increased risk of HPV acquisition and persistence can be explained by several pathways. The first is estrogen, adipokine, and cytokine production, which creates chronic inflammation. Second, immune suppression facilities the acquisition and persistence of HPV, without deterrence from the immune system. Third, angiogenesis that results from hypertension-induced hypoxia-inducible factor-1 has been proposed as a mechanism that increases the risk of HPV infection [3]. However, a study revealed no evidence of an association between obesity and incidence of persistent HPV infection, when differences in sexual behavior between women with obesity and women with normal weight were considered [10]. HPV infection persistence can cause high-grade cervical cancer that progress to cervical cancer.

The Cancer Incidence in Five Continents project was established in collaboration with the International Agency for Research on Cancer and the International Association of Cancer Registries, with obtained data of cervical cancer cases categorized by histological subtype, according to the third edition of the International Classification of Diseases for Oncology. As described in the Cancer Incidence in Five Continents project, those are squamous cell carcinoma, including 8050–8078, 8083–8084, and adenocarcinoma, including 8140–8141, 8190–8211, 8230–8231, 8260–8265, 8310, 8380, 8382–8384, 8440–8490, 8570–8574, and 8576 [11].

Precancerous cervical lesions (PCL) of the cervix refer to the changes to the cervical cells in a transformation zone. A precancerous cell is the precursor cell that will become a cancer cell. The PCL in the cervix can be removed using a procedure called large loop excision of the transformation zone (LLETZ). To expedite the process in women with less severe abnormalities, or in cases of persistent HPV infections, clinicians opt for surgical excision of the cervical tissue, such as LLETZ, as women find LLETZ acceptable because the follow-up period after the LLETZ procedure is short [12].

Based on the World Health Organization, this condition can exist in 3 stages: (1) cervical intraepithelial neoplasia stage 1 (CIN1), or mild dysplasia; (2) cervical intraepithelial neoplasia stage 2 (CIN2), or moderate dysplasia; and (3) cervical intraepithelial neoplasia stage 3 (CIN3), or severe dysplasia/carcinoma in situ. If left untreated, CIN2 or CIN3, referred as cervical intraepithelial neoplasia stage 2 plus (CIN2+), can progress to cervical cancer [9,13].

A meta-analysis showed a significant relationship between a high BMI and the high risk of developing female reproductive tumors [14]. Another study showed most PCL are modifiable, which is related to socio-demographic characteristics, sexual behaviors, and BMI [15]. There are few fatty acid metabolism mechanisms from synthesis until transcription that over-express and/or dysregulate and inhibit proteins and enzymes during the process [16]. A pilot study showed the prevalence of dyslipidemia from high total cholesterol and low high-density lipoprotein as PCL, but also high triglycerides and low-density lipoprotein as invasive lesions [17]. Also, visceral obesity which is calculated with by the visceral fat to subcutaneous fat ratio showed that patients without visceral obesity had better prognosis than those with visceral obesity [18].

A large study showed metabolic reprogramming has as a role in tumor survival from host immunity, acidification, hypoxia, and proliferation of a good tumor microenvironment [19]. The progressivity of cancer cell proliferation requires huge energy and macromolecules, and expedites the synthesis of lipids. Fatty acids, as the biggest energy producers, have a variety of oncogenic processes. Additionally, exogenous fatty acids play a dominant role, and tumor cells have the capability to synthesize fatty acids de novo. Also, dietary fat and abnormal gut microbiota induce lipid accumulation. Unsaturated fatty acids subject tumor cells to oxidative stress and bind membrane phospholipids, which are more sensitive to ferroptosis, a programmed cell death that depends on iron, especially the imbalance of lipid peroxide accumulation and inactivity of antioxidants [20,21]. These previous studies have found some effect of fat accumulation as a proinflammatory agent in obesity and its association with PCL or cervical cancer. However, a better understanding of the role of BMI in HPV infection progression to PCL remains unclear in recent studies, and BMI remains an underrated risk factor related to PCL or cervical cancer. Based on these phenomenon, in this study, we aimed to evaluate the effect of BMI and the risk of cervical cancer/PCL screened using LLETZ results available in a population with limited access to routine screening, in Prof. Dr. Margono Soekarjo General Hospital Purwokerto, Indonesia.

Material and Methods

ETHICS COMMITTEE APPROVAL:

The research was approved by the Ethics Committee of Prof. Dr. Margono Soekarjo General Hospital Purwokerto, Indonesia, on February 1, 2025, with approval number 420/01783.

DECLARATION OF PATIENT CONSENT:

The authors explained to the patients that the use of the clinical findings obtained from the study would be reported in a scientific journal for the advancement of medical knowledge and that patient identification and data would be confidential. All patients gave their informed consent.

STUDY DESIGN AND SETTINGS:

This was an observational, case-control study conducted from August 2022 to February 2024 (3 years) at Prof. Dr. Margono Soekarjo Provincial General Hospital in Central Java, Indonesia.

We did not perform matching between the groups; however, we assessed the baseline demographic characteristics of both groups. The analysis showed no statistically significant differences between the groups in terms of these baseline characteristics. This suggested that potential confounding variables related to demographic factors did not influence the occurrence of PCL. In addition to the baseline analysis, we applied exclusion criteria as part of our study design to further eliminate potential confounding factors. BMI was the only variable of interest that we aimed to further explore for its possible association with the development of PCL.

STUDY POPULATION:

A total of 68 patients were included in this study after being referred from primary health care physicians for having positive visual inspection with acetic acid (VIA) test results. These patients were referred to the Regional General Hospital Margono Soekarjo for the LLETZ procedure. The inclusion criteria for this study were all referred patients with a positive VIA test result who consented to undergo LLETZ and had complete data. The exclusion criteria were patients who refused to undergo LLETZ or had incomplete secondary data. There was 1 patient with a positive VIA test who refused to do LLETZ, and 4 patients had a positive VIA test but had incomplete data.

SAMPLE SIZE ESTIMATION:

We tested all the patients with positive VIA test results who consented to undergo the LLETZ procedure. We included 63 patients who had positive VIA test results and underwent the LLETZ procedure, following the symptoms of PCL, based on the International Federation of Gynecology and Obstetrics (FIGO) or with positive VIA test results. We used the LLETZ procedure in line with FIGO guidelines.

The study population was divided into patients with positive CIN (41 patients) upon VIA results and histopathological confirmation and those with negative CIN (22 patients). The analysis of PCL characteristics showed associations, which are visualized in Figure 1.

STATISTICAL METHODS:

Odds ratios and chi-square tests were used to determine the correlation between BMI and cervical cancer. Statistical analysis was performed using IBM SPSS Statistics version 29.0.1.0 (IBM Corp, Armonk, NY, USA).

DATA COLLECTION:

Samples were collected from interviews and registered data of patients who came to the gynecology and oncology polyclinics at the Prof. Dr. Margono Soekarjo Provincial General Hospital. The data were collected based on the FIGO guidelines, as follows. (1) Leucorrhea was defined as a white or clear, non-offensive discharge that varies with the menstrual cycle. (2) Vaginal bleeding was defined as any bleeding from vagina that was not part of a menstrual period. (3) Menstrual cycle was classified into 4 categories: frequency, duration, regularity, and bleeding volume. Frequency was classified as absent or amenorrhea, short (<24 days), normal (24–48 days), and prolonged (>38 days). Duration was classified into short (<4 days), normal (4–8 days), and prolonged (>8 days). Regularity was classified as regular (<7 days) and irregular (>7 days). (5) BMI was classified as normal BMI (18.5–24.9 kg/m²) and abnormal BMI (≥25 kg/m²). The physician measured the weight and height of patients in the polyclinic.

PCL and cervical cancer diagnoses were classified into (1) positive PCL/cervical cancer and (2) negative PCL/cervical cancer, upon histopathological confirmation results.

We minimized the patients’ recall bias by retrospectively re-checking the medical records in the hospital regarding the patients’ previous health visits.

Results

Table 1 shows the patient characteristics by the cervical cancer/PCL-positive group and cervical cancer/PCL-negative group. The collected characteristics were age, educational background, parity, BMI, history of vaginal bleeding and leucorrhea, history of hormonal contraception, sexual partners, menstrual cycle, menstrual frequency, and menstrual interval. There were no significant differences between groups in age, parity, history of vaginal bleeding and leucorrhea, history of hormonal contraception, sexual partners, menstrual cycle, menstrual frequency, and menstrual interval. There were significant differences between the groups in educational background (P=0.006) and BMI status ≥25 kg/m2 (P=0.040).

Table 2 shows the data analysis comparing the BMI of patients in the cervical cancer/PCL-positive group with that of patients in the cervical cancer/PCL-negative group. Out of 63 patients, 26 (41.3%) with abnormal BMI were confirmed to have cervical cancer or PCL. Our findings demonstrated that BMI was statistically significantly related to the occurrence of cervical cancer and PCL [OR 3.033; 95% CI 1.034–8.899; P=0.04]. This means those who had an abnormal BMI were at a 3.033-fold higher risk of having cervical cancer or PCL than those who had a normal BMI.

Table 3 shows the data analysis using multivariate logistic regression, conducted to assess the association between independent variables (body mass index, parity, history of hormonal contraception, sexual partner history, and age of first sexual intercourse) and the likelihood of having cervical cancer. Among the models tested, the second model demonstrated the best model fit with the lowest Akaike information criterion value, 35.710, and Nagelkerke R2 of 1.077, thus indicating modest explanatory power. Although none of the predictors reached conventional statistical significance (P<0.05), BMI approached significance (P=0.057) and was associated with an odds ratio of 3.022 (95% CI: 0.966–9.450), suggesting a potentially meaningful relationship with the dependent variables.

Discussion

RESEARCH LIMITATIONS:

The study was conducted at Margono Soekardjo General Hospital Purwokerto in Indonesia, where routine HPV screening, the criterion standard for cervical cancer risk detection, was not feasible. The study was limited by a small sample size and low resource setting. These limitations may have led to underdiagnosis or misclassification of cases, potentially influencing the strength and accuracy of the associations found. Future research with a larger sample size and access to molecular testing is necessary to confirm and expand on these findings.

Conclusions

Obesity is an underrecognized risk factor for the development of cervical cancer and PCL in women. A higher-than-normal BMI increases the probability of developing cervical cancer and PCL, and a higher BMI worsens the progressivity of the disease and the overall health burden.