Clinicopathological correlation of invasive squamous cell carcinoma of uterine cervix: A cross-sectional study

Use your smartphone to scan this QR code and download this article ABSTRACT Objective: Cervical cancer is a common cancer in females. Clinicopathological features vary and are heterogeneous in different studies. This study was taken up to know the clinicopathological correlation in squamous cell carcinoma (SCC) of the cervix in our population. Methods: This is a cross-section study. Histologically confirmed cases of squamous cell carcinoma of the cervix are considered. Clinical history, socio-demographic details, clinical findings including stage and histological grade of the disease are noted and statistically analyzed. Result: The age range of cases was 30-80 years, with a mean of 54.2±12.0. The age range at marriage was 12-23 years, with a mean of 15.7±2.1. Parity ranged from 1 to 11, with a mean of 3.6±1.6. The p-value between bleeding pervagina and other symptoms versus no bleeding per-vagina and other symptoms, stage of disease between pre & peri-menopausal, and post-menopausal cases were 0.011 and 0.020, respectively. Growth followed by bleeding was common clinical findings. The p-value between the stage of the disease and age, histological grade and parity, histological grade and clinical features was 0.032, 0.001, and 0.031 respectively. Conclusion: Younger age group cases and pre & peri-menopausal women present the disease at an early stage. Older age women present at an advanced stage. Higher parity had a higher risk of cervical cancer of well differentiated SCC. Bleeding per-vagina was a more common clinical presentation in post-menopausal women. Clinical features of bleeding per vagina with other symptoms were more common in well differentiated SCC.


INTRODUCTION
Cervical cancer is a major health problem and is leading cancer in women, especially in developing regions of the world, resulting in mortality and morbidity in their prime reproductive age. The age standardized rates estimated are 30 per 100,000 women. However, the incidence and mortality are decreased by 75 to 80% by a well programmed screening procedure in developed countries. Pap test for screening cervical cancer has tremendously decreased the incidence of cervical cancer. However, in developing countries, despite the existence of a screening procedure, the women present at the late stage of the disease with high mortality [1][2][3][4] .
The risk factors are early marriage, early age of first sexual intercourse, early age of first pregnancy, multiple pregnancies, increased parity, use of oral contraceptive pills, multiple sexual partners, low socioeconomic status with nutritional/vitamin deficiencies, poor genital hygiene especially penile hygiene of a male partner, rural women, African-American race, tobacco smoking, sexually transmitted disease, Human Papilloma virus infection, Herpes Simplex virus infection, co-infection with HIV, immune compromised status especially in renal transplanted cases and genetic susceptibility [2][3][4][5][6][7] . In addition, lack of awareness of screening programmes, geographical inaccessibility, lack of an oncologist, negligence of initial symptoms along with financial constraints is responsible for a late presentation and diagnosis [7][8][9] . Clinicopathological studies are done and published in English literature. Clinicopathological features vary and are heterogeneous in different studies. Hence we have taken up this study to know the clinicopathological correlation in squamous cell carcinoma (SCC) of the cervix in our population.

MATERIAL AND METHODS
This is a cross sectional study done from October 2017 to September 2018. Ethical clearance for the study was obtained from the Institutional Ethical Committee. Clinically diagnosed and histopathologically confirmed 75 new cases of invasive SCC of the cervix were considered for the study. The exclusion criteria were Post-chemotherapy cases, post-radiotherapy cases, recurrence of the disease, cervical intraepithelial squamous neoplasia, glandular neoplasia, ade-nocarcinoma of the cervix, metastatic deposits (secondary deposits) in the cervix. Following informed consent from the patients, the socio-demographic profile including clinical presentation and physical examination findings as: age, hospital number, biopsy number, presenting complaints, menstrual history, personal history, past history, family history, perabdominal examination findings, per-speculum examination findings, per-vaginal examination findings and per-rectal examination findings were noted in a semi-structured proforma. The clinical stage and histological grade of the disease were also noted. The staging was done as per the FIGO staging system 10 .
Histologically the cases were classified as keratinizing and non-keratinizing types 11 . Keratinizing squamous cell carcinomas were further classified as well differentiated (WDSCC), moderately differentiated (MDSCC), and poorly differentiated (PDSCC). The non-keratinizing squamous cell carcinomas were further classified as small cell type (NKSCSCC) and large cell type (NKLCSCC). The data were entered in Microsoft Excel sheet. The data was analyzed using SPSS version 22. The categorical data were recorded as frequency and proportions. Continuous data was entered as mean, standard deviation, and confidence intervals. Significance of difference between the groups was estimated using standard 't' test and chi-square test, p-value <0.05 was considered as statistically significant.

RESULTS
The age distribution of the cases is shown in Table 1. The age range was 30-80 years of age, with a mean age of 54.2±12.0. Maximum cases were seen in the age group of 40-49 and 60-69 years (25.3%)   followed by 50-59 years (24%). 74.7% of cases were postmenopausal, and 25.3% of cases were pre and peri-menopausal groups. Table 2 shows the age at menopause among the cases where the majority of females had attained menopause between 45-49 years (33.3%) of age group followed by 40-44 years (21.3%). The age range was 40-57 years, with a mean of 46.3±3.9 years. Table 3 shows age at marriage among the cases where maximum cases were at 15 years (26.6%) followed by 14 years (16%) of age. The age range was 12-23 years, with a mean of 15.7±2.1 years of age. Table 4 shows the parity in cases where maximum cases had parity of ≥5 (28%) followed by 4 (26.6%). Parity ranged from a 1-11with a mean of 3.6±1.6. Table 5 shows the varied clinical presentation in cases among pre & peri-menopausal and post-menopausal women. The P-value between bleeding per-vagina and other symptoms versus no bleeding per-vagina and other symptoms between pre & peri-menopausal and post-menopausal cases was 0.011. In pre & perimenopausal, women bleeding per-vagina and white discharge per vagina were approximately equally seen. Table 6 shows per-speculum findings of cases, among pre & peri-menopausal and post-menopausal women. Growth followed by bleeding is the common findings in both pre & peri-menopausal and post-menopausal women. The P-value for per-speculum findings between pre & peri-menopausal and post-menopausal cases was 0.760. Table 7 shows per-vaginal findings of cases, among pre & peri-menopausal and post-menopausal women. The P-value of per-vaginal findings between pre & peri-menopausal and postmenopausal cases was 0.347. Table 8 shows the stages of the disease in cases in both pre & peri-menopausal and post-menopausal women. Maximum cases were seen in stage III (40%). However, maximum cases in pre & perimenopausal women were seen in stage II (36.8%), and in post-menopausal women, it was seen in stage IV (48.2%). The P-value of the stage of disease between pre & peri-menopausal and post-menopausal cases was 0.020. Table 9 shows the histological grade of the disease in cases in both pre & peri-menopausal and post-menopausal women. Keratinizing SCC was maximum, constituted 90.6% of cases, and nonkeratinizing 9.2%. Among keratinizing SCC, maximum cases were WDSCC (56%) followed by MDSCC (21.3%). The P-value of grade of disease between pre & peri-menopausal and post-menopausal cases was 0.46. There was a statistically significant association between the stage of the disease and the age of the cases with a p-value of 0.032. However, there was no statistically significant association between the stage of the disease with age at marriage (p=0.259), parity (p=0.752), clinical features (p=0.334) and perspeculum examination findings (p=0.295).
There was a statistically significant association between the histological grade of the disease with parity of the cases (p<0.001) and clinical features of the disease (p=0.031). However, there was no statistically significant association between histological grade and age of cases (p=0.132), age at marriage (p=0.578), and per-speculum examination findings (p=0.629).

DISCUSSION
Globally 13% of all deaths are due to cancer. Cervical cancer constitutes 5 th deadliest cancer worldwide, causing 5% of cancer death in females. It was leading cancer in women 50 years back and has decreased because of screening programmes which detect precancerous lesions and malignancy in the early stage 8 14 . In the present study, the age range was 30-80 years of age, with a mean age of 54.2±12.0. There was a statistically significant association between age and stage of the disease (p=0.032), indicating younger age group cases presented with early stage and older age group presented with a late stage of the disease. There was statistical significant association between the stage of disease versus pre & peri-menopausal and post-menopausal cases (p=0.020) indicating that pre & peri-menopausal women present the disease in a relatively early stage compared to post-menopausal who present in late stage of the disease probably because of atrophied cervix and relatively less volume    of healthy cervical tissue resulting in fast spread of the disease. Hence younger patients and patients in the pre & peri-menopausal age group presented at an early stage in the present study. There was no statistical association between age and histological grade of the disease in the present study. The age distribution in various studies compared to the present study is shown in Table 10, where maximum cases are seen between 40-59 years of age in all studies. Early marriage is a risk factor as frank cases with late stage of the disease is noted when the age of marriage was between 15-19 years followed by 20-24 years 8 .Age at the marriage of fewer than 20 years was 49.25% of cases in a study by Afroj et al. 9 83% and 17% of cases had first coitus at less than or equal to 20 years and more than 20 years, respectively, in a study by Jain et al. 7 . Amaro-Filho SM et al., in their study, states that the advanced stage was also associated with the age of marriage at less than 17 years but not statistically significant (p=0.752) 14 . Cervical carcinoma behaves as a sexually transmitted disease 8 . There was no statistical association between age at marriage in cases with stage and histological grade of the disease in the present study. The age range for marriage was 12-23 years, with mean 15.7±2.1 years of age. Maximum cases were between 15-18 years (69.3%), followed by 12-14 years (25.3%). Among cases between 15-18 years, 59.6% of cases were in the advanced stage. Frank cervical cancer with the late stage was seen maximum with parity of ≥4 followed by 3 in a study by Patil N et al. 5 . Among cases, 3.8% were nulliparous, and 96.2% were multiparous in a study by Jyothi V et al 6 . Amaro-Filho SM et al., in their study, states that advanced stage (stage III & IV) shows a significant statistical association (p<0.005) with more than four pregnancies 14 . In the present study, parity ranged from 1 to 11, with a mean of 3.6±1.6. There was no statistically significant association between parity and stage of the disease in the present study. However, 55% of para 4 cases and 66.6% of para ≥5 were in an advanced stage (stage III & IV). There was a statistically significant correlation between parity and histological grade of the disease (p=0.001) which indicates that higher parity had a higher risk of cervical cancer of WDSCC followed the MDSCC histological type. The parity in various studies compared with the present study is shown in  9 . In the present study, there was a significant association between bleeding per-vagina and other symptoms versus no bleeding per-vagina and other symptoms between pre & peri-menopausal and postmenopausal cases (p=0.011) which indicates that bleeding per-vagina was a more common clinical presentation in post-menopausal women than in pre & peri-menopausal which can be due to atrophic cervix and age-related changes of blood vessels. There was also a statistical association between clinical presentation and histological grade of the disease (p=0.031) suggesting that the clinical features of bleeding per vagina with other symptoms were more common in WDSCC, followed by MDSCC than in cases without bleeding per vagina. In the present study, there was no statistical association between clinical presentation and stage of the disease. The clinical presentation in cases in various studies compared with the present study is shown in Table 12, where bleeding per-vagina is the most frequent presentation in the present study and study by Gaikwad et al 12 . WDPV was the most frequent presentation in a study by Patil et al., Gundrajakuppam et al.,and Jain et al. 5,7,8 . Postcoital bleeding was the most frequent presentation in the study by Afroj et al. 9 .
The per-speculum findings in cases in various studies compared with the present study are shown in Table 13. The most frequent finding is growth, as reported by Gundrajakuppam et al. (81.5%) and also in the present study (65.3%) 8 . In a study by Jain et al. the most frequent finding was ulcer (72%) 7 .
The commonest per-vaginal examination findings reported is frank growth, which bleeds on touch 8 . Cervical growth was noted in 9.2% of cases in a study by Gaikwad SL et al. 12 . In the present study, growth which bleeds on touch was the commonest presentation. There was no statistical association between perspeculum findings with stage and histological grade of the disease.  13 . In the present study, the keratinizing and non-keratinizing types constituted 90.8% and 9.2%, respectively. There is no significant difference in the prognosis between histological types of tumors within any stage. However, large-cell cancers have a better prognosis than keratinizing cancers, and small-cell cancers have the worst prognosis. The stage of the disease has a definite impact on prognosis 13 . In the present study, the cases were not followed up for prognosis. The limitation of the present study is that the cases were not followed up for prognosis. However a few objective conclusions were drawn by this study which can be generalized by doing a similar study in a larger population as; younger age group cases and pre & peri-menopausal women present the disease at an early stage compared to post-menopausal women, older age presents with advanced stage, maximum cases were seen between 15-18 years of age of marriage, higher parity had a higher risk of cervical cancer of WDSCC and advanced stage, bleeding per-vagina was a more common clinical presentation in post-menopausal women than in pre & perimenopausal, a growth which bleeds on touch was the common clinical examination findings in both pre & peri-menopausal and post-menopausal, clinical features of bleeding per vagina with other symptoms were more common in WDSCC than cases without bleeding per vagina and other symptoms.

CONCLUSION
Cases with younger age present with early stages of cancer. Cervical cancer screening should be done in older age women more frequently, especially when the clinical feature is bleeding per vagina as they present with advanced stage. Young age at marriage and high parity are high risk factors for cervical cancer. WD-SCC is associated with high parity and bleeding per vagina.