|Ahead of print publication
Spectrum of cervical epithelial abnormalities in immune surveillance patients and its association with CD4 count
Puneet Baveja1, Sharanjit Singh1, Arun Kumar Yadav2
1 Department of Pathology, Armed Forces Medical College, Pune, Maharashtra, India
2 Department of Community Medicine, Armed Forces Medical College, Pune, Maharashtra, India
|Date of Submission||28-Jan-2021|
|Date of Decision||11-Jun-2021|
|Date of Acceptance||11-Jun-2021|
Arun Kumar Yadav,
Department of Community Medicine, Armed Forces Medical College, Pune - 411 040, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: Cervical cancer is the fourth most common cancer worldwide. It is well-known that cervical carcinoma progresses from a preinvasive disease, which can be picked up easily by routine cervical smear examination. Studies have shown that dysplasia is five times more common in females with human immunodeficiency virus (HIV) than in healthy controls. This study aimed to find if any association existed between CD4 count, viral load, parity, hemoglobin level, age at first childbirth, duration of highly active antiretroviral therapy, and cervical epithelial abnormalities. Methods: The present study was a 4-year retrospective study conducted in the Department of Pathology at a tertiary care hospital of Western Maharashtra. The liquid-based Pap smear slides of HIV patients reported during the period were retrieved and reviewed. The data collected were tabulated and analyzed using the SPSS software. Statistical test was used to find an association between various clinicopathological variables and smear findings. Results: Pap smear abnormalities were found in 14% of the patients. The present study found a statistically significant association between Pap smear abnormalities and CD4 count, viral load, and the hemoglobin level of the patient. Conclusion: There is a high prevalence of Pap smear abnormalities in HIV-positive patients. CD4 count, hemoglobin level, and viral load can be used as surrogate markers for deciding the frequency of Pap smear in HIV patients.
Keywords: Cervical cancer, human immunodeficiency virus, immune surveillance, Pap smear
|How to cite this URL:|
Baveja P, Singh S, Yadav AK. Spectrum of cervical epithelial abnormalities in immune surveillance patients and its association with CD4 count. Med J DY Patil Vidyapeeth [Epub ahead of print] [cited 2022 Dec 6]. Available from: https://www.mjdrdypv.org/preprintarticle.asp?id=323678
| Introduction|| |
The human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) is a global health problem. Over 70 million people have been infected with HIV, 35 million have died, and 38 million people currently live with the disease. HIV infection and AIDS are different spectrum of the same disease. People with AIDS have an increased risk of developing various infections and malignancies. Among the malignancies, the common ones are Kaposi Sarcoma, Burkitt's lymphoma, cervical cancer, and primary central nervous system lymphoma. Other cancers that have increased incidence include Hodgkin's lymphoma, anal cancer, testicular cancer, and melanoma.
Cervical carcinomas are the fourth most common cancers in women and the seventh most common cancers worldwide. They are associated with considerable morbidity and mortality, particularly in developing countries. The incidence of cervical cancer in AIDS patients is higher because of increased association with human papillomavirus (HPV) infection, which is the single-most crucial etiological agent for cervical dysplasia. Pap smear More Details examination is a simple, cheap, safe diagnostic tool for the early detection of cervical cancer by detecting dysplastic squamous or glandular cells. However, with the advent of antiretroviral therapy (ART) and consequently improved survival, various studies have shown an increased risk of developing in situ cervical lesions and rapid progression to invasive tumors among HIV-infected women. In a multi-institutional study by Branca et al., various risk factors, clinical course, and follow-up of patients infected with HIV were studied. It was concluded that there is an increased risk of developing cervical cancer in these patients with abnormal cervical cytology and thus require earlier therapeutic intervention. Therefore, it is recommended to do cervical cytology at least twice a year following an initial diagnosis of HIV. However, if both are normal, then annual testing should follow.
Another critical factor is the CD4 count. The prevalence of HPV infection is more among HIV-positive females whose CD4 count is lower. The CD4 count is also found to be lower among the HIV infected having cervical cancer than HIV-infected without cervical cancer.
The data from India are lacking for cervical cytology in HIV. Hence, the present study was undertaken to detect precancerous and cancerous lesions and inflammatory lesions and highlight the importance of a detailed gynecological examination and cervical cytology in HIV-positive females registered and attending ART clinic at Tertiary care hospital in Western Maharashtra.
| Methods|| |
The study was conducted in the tertiary care hospital in Western Maharashtra. The tertiary care hospital has an ART center attached to it. The pap smear results of all the women registered at the HIV clinic at the tertiary care hospital were available. We did a retrospective record-based study of all the participants from April 2016 to April 2020.
In each case, data regarding clinical history, gynecological examination findings, relevant laboratory data including Pap smear results and CD4 cell counts, viral load at the time of performing of PAP smear were retrieved from the case files of the patients. The PAP smear test, CD4 count, and viral load sent in the same sitting were considered. Each Pap smear was preserved as liquid-based cytology.
All HIV-positive females of age between 18 years and 69 years who had been or were sexually active and were registered at HIV clinic at tertiary care hospital in Western Maharashtra were included in the study. Unmarried women below the age of 18 years, pregnant patients, postnatal patients, patients with a history of hysterectomy, and apparent cervical cancer were excluded from the study.
A data collection form to extract the data from the records was designed, standardized, and pretested. Liquid-based cytology slides were reviewed, and reporting was done according to the Bethesda system of reporting of cervical cytology. Patients were categorized as negative for Intraepithelial lesion or malignancy (NILM), atypical squamous cells of undetermined significance (ASC-US), atypical squamous cells - cannot exclude high grade intraepithelial lesion (ASC-H), low grade squamous intraepithelial lesion (LSIL), High Grade squamous intraepithelial lesion (HSIL), and Squamous cell carcinoma (SCC). Glandular abnormalities were also reported if found histopathological correlation was reviewed wherever applicable/available.
Institutional ethical clearance (IEC) was obtained before starting the study vide their letter no. IEC/2020. Data were collated in MS Excel. The results were recorded in percentages and tables. Contingencies tables were made. The Fisher's exact test was used to find any association between CD4 counts, viral load, hemoglobin levels, and Pap smear findings. P < 0.05 was considered statistically significant. Data were analyzed using the SPSS software version 20 IBM Corp. (2017). IBM SPSS Statistics for Windows. Armonk, NY, USA: IBM Corp.
| Results|| |
Pap smear results were available for 157 cases that meet all the inclusion criteria and none of the exclusion criteria during the study period. The mean age group was 40.1 years (standard deviation [SD] = 14 years). The mean age at first pregnancy was 19.3 years (SD = 3 years). Eleven patients (7%) had a history of first childbirth before the age of 16 years. Out of 101 patients (64.33%) with age at first pregnancy less than mean age, 84 patients (83.2%) had normal smears and 17 patients (16.8%) had squamous epithelial abnormalities. No glandular abnormalities were found. Fifty-six (35.67%) patients had age at first pregnancy > the mean age of group, out of which 51 patients (91.1%) had normal smears and five patients (8.9%) had epithelial abnormalities; however, association between age at first pregnancy and Pap smear finding was not statistically significant.
In total, 22 patients (14%) had abnormal smears. The most common epithelial abnormality was LSIL (36.36%) followed by ASC-US (27.27%), HSIL (22.72%), atypical squamous cell, cannot exclude HSIL (ASC-H) (9.09%), SCC (4.54%). Out of the rest 135 cases that were NILM, 23 cases (17.03%) were inflammatory, followed by 8 cases (5.92%) with bacterial vaginosis, 3 cases (2.22%) with evidence of candidiasis infection, and 7 cases (5.18%) with atrophic smears.
Distriution of patients with sociodemographic factors is given in [Table 1]. Mean parity was 2.36. 4 patients did not have any child out of which 2 were taking treatment for infertility, 24 patients (15.3%) had single child, 61 patients (38.9%) had 2 children, 53 patients (33.8%) had 3 children, 14 patients (8.9%) had 4 children, and 1 patient (0.6%) had 5 children. Twenty-three patients (14.7%) had a history of whitish discharge P/V, 2 patients (1.3%) had a history of herpes genitalis, 7 patients (4.4%) presented with itching and pain P/V and were found to have genital ulcer. Mean duration of highly active ART (HAART) 6.54 years (10 months–15 years). Eighty-one patients had duration of HAART less than mean value and 76 patients had duration of HAART more than the mean value. The mean hemoglobin level was 10.18 g% (range 5.3–14.3 g%). Mean hemoglobin levels in patients with normal smears were 10.41 g% compared to 8.86 g% in patients with abnormal smears (P < 0.05).
The associations of various clinicopathological factors and pap smear are shown in [Table 2]. The mean CD4 count was 584 per cu.mm. (range 38–1616 per cubic mm). Seven patients (4.45%) had CD4 count <200 per cu.mm. Sixty-five patients had CD4 count <500/cu.mm., of which 44 patients (67.7%) had normal smears and 21 patients (32.3%) had abnormal smears. Ninety-two patients had CD4 count >500/cu.mm. of which 91 patients (98.9%) had normal smears and only 1 patient (1.1%) had abnormal smear (P < 0.05). Minimum viral load was target not detected and maximum viral load was 50,270 copies/ml. One hundred and twenty-two patients (77.7%) had viral load < 20 copies/ml, of which 118 patients (96.7%) had normal smears and 4 patients (3.3%) had abnormal smears. Thirty-five patients had viral load more than 20 copies/ml, of which 17 patients (48.6%) had normal smears and 18 patients (51.42%) had abnormal smears (P < 0.05). Mean viral load in patients with normal smear was 443.64 copies/ml as compared to 4822.73 copies/ml in patients with abnormal smears.
|Table 2: Association of various clinicopathological factors with Pap smear findings|
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| Discussion|| |
The incidence of HIV is increasing with time, and it is now a global pandemic. Globally, cervical cancers comprise around 15% of all cancers compared to South-east Asia where cervical carcinoma includes 20%–30% of all cancers. India alone accounts for one quarter of cervical cancer burden of the world.
HIV-positive women have a higher rate of persistence of HPV infections and thus have a higher risk of developing cervical abnormalities and later on progression to invasive carcinoma. In a study, it was found that HIV positive females have 2–5 times higher cervical epithelial abnormalities and then invasive carcinoma as compared to HIV-negative females population.
The prevalence of cervical smear abnormalities in our study was 14%. This is comparable to a study done by Gupta et al. and Madan et al., and was low as compared to a study by Kusumam et al. 42% and Seethalakshmi et al. 58.8%., Our study revealed that 86% of patients had normal smears which is comparable with a study by Ampan et al. 84.6%, Lebenson et al. 79.6%, and BM Jha et al. 87.89%. The majority of cervical smear abnormalities were in the age group between 32 and 46 years of age which was similar to a study by Gupta et al. which had most patients with abnormal smears in the age group of 34–49 years, Madan et al. in which most patients fell in the age group of 31–40 years and Kusuman et al. which found most of abnormal smears in the age group of 36–50 years.
Among the epithelial cell abnormalities in HIV-positive patients, LSIL contributed most common abnormality (36.36%) which was in contrast to other studies by Gupta et al. which had HSIL as the most common abnormality. Similar to the present study, another study by Paramsothy et al. found LSIL in high proportion of HIV patients (43%). The majority of smears in the present study were NILM which was similar to other studies, [Table 3]. In the present study, 8 cases of bacterial vaginosis (5.92%) and 3 cases (2.22%) were reported as consistent with candidal species which was similar to a study by Gupta et al. (3.03% and 2.27%). Atrophic smear was noted in seven cases (5.18%) which is similar to the study by Jha in which 5.89% patients had atrophic smear.
|Table 3: Comparison of squamous epithelial cell abnormalities on pap smear in the present study with other similar studies|
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CD4 count <200/cumm was found in seven patients (4.45%) which is similar to the study by Gupta et al. (6.25%). A higher incidence of epithelial abnormalities was seen in patients with CD4 count < 500/cu.mm. and was found to be statistically significant. Similar to CD4 count, viral load and hemoglobin levels were found to be statistically significant and were found to have an association with epithelial abnormalities. The importance of these findings in the screening of epithelial abnormalities may further be explored.
High risk (HR) HPV genotypes such as HPV 16, 18, 31, 33 have been implicated in the pathogenesis of SCC of Cervix. Studies have documented high proportion of HIV-infected women carrying varieties of HR genotypes. HR – HPV types express oncogenic proteins that inactivate tumor-suppressor genes, activate cyclins, inhibit apoptosis, and combat cellular senescence leading to malignant transformation of infected cells. HPV infection of the cervix is transmitted venereally. It may remain dormant for long periods, get cleared by intact immunological mechanisms or become productive in those having immunosuppression. Women with low CD4 count (<100/cumm) have significantly higher risk of persistent HPV infection due to immunesuppression, thereby increasing the risk of cervical cancer.
Being a retrospective study, the main limitation of our study is that it is a retrospective study. Some key statistics that we intended to study were not available in the past records and hence could not be studied.
We had used liquid-based cytology technique for reporting on cervical smears which minimized unsatisfactory smears, and slides had less obscuring material in form of blood, mucus, inflammatory cells which enabled us to study epithelial abnormalities much better in comparison to conventional Pap smears.
| Conclusion|| |
Routine Pap smear examination is advised in female patients with HIV. In our study, Pap smear abnormalities showed an association with CD4 count, viral load, hemoglobin level; however, there was no association with age, parity, age at first pregnancy, and time since initiation of HAART.
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Conflicts of interest
There are no conflicts of interest.
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