HIV+ Status and Cervical Cancer: Cytological Aspects of Cervical Smear in Cameroon Setting ()
1. Introduction
Invasive cervical cancer is a pathology of viral aetiology, which generally takes more than 25 years to develop, from primary infection with an oncogenic papillomavirus of genital tropism to the different grades of histological pre-cancerous lesions, reflecting the persistence of infection to invasive cancer. For each grade of precancerous cervical lesion (CIN1, CIN2 or CIN3), there is a probability of regression to a normal epithelium, and a probability of persistence or progression to a more advanced stage [1]. Once mild dysplasia is identified, it usually takes between 10 and 20 years before invasive cervical cancer develops. 60% or more of mild dysplasia regress spontaneously and only 10% progress to moderate or severe dysplasia within 2 to 4 years.
In some cases, moderate or severe dysplasia may occur without going through the detectable stage of mild dysplasia.
Severe dysplasia is more likely to progress to invasive cancer, but less than 50% of cases progress to invasive cancer. This percentage is even lower among young women. In the early 1990s, it appeared that precancerous lesions and invasive cervical cancer were more common and more rapid in HIV infection [2]. It is estimated that the incidence of invasive cervical cancer is about 5 to 15 times higher in HIV− infected women than in the general population [3].
A prospective study conducted in 15 European countries between 1993 and 1999 among women aged 20 to 49 years shows that invasive cancer of the cervix is the AIDS classifying event in 2.5% of cases [4].
The incidence of cervical cancer remains high in women with HIV infection. In France, the incidence of cervical cancer increased from 33.7 per 100,000 woman-years (95% CI: 14.6 - 52.7) in 1996 to 21.5 per 100,000 women-years (95% CI: 6.6 - 36.5) in 2011 [5].
In the US, the standardized incidence rate of cervical cancer in HIV− infected women is 2.9 (95% CI 1.9 - 4.2), significantly higher compared to HIV− women.
However, the incidence is similar in HIV− infected women who are regularly screened for smear and treated for precancerous lesions and in HIV− women, which favors a positive impact of screening on the occurrence of cervical cancer [6].
In contrast, the effect of antiviral treatment on the incidence of this cancer remains controversial. Indeed, the stability of the cervical cancer rate in the US between 1992 and 2003 suggests a weak effect of anti-retroviral treatment, whereas, on the other hand, French data shows a risk of cancer twice as low in women under treatment for more than 6 months [6] [7].
The proportion of women infected with HIV is currently increasing and their survival is prolonged due to anti-retroviral drugs as well as efforts to prevent opportunistic infections by anti-infectious therapies [8]. However, we observe the emergence of cervical intraepithelial pathology that can lead to invasive carcinoma.
In Cameroon, a descriptive and retrospective study carried out between October 1992 and June 1995 in the city of Yaoundé among 65 HIV+ women and 50 HIV− women revealed 95% inflammatory smear, 1.5% low-grade squamous intraepithelial lesions in HIV+ women and 70% of inflammatory smears, 4% of low-grade squamous intraepithelial lesions in HIV− women with a difference not statistically significant [8].
However, HIV+ women appear to have pre-cancerous cervical lesions more frequently than HIV−, thus predisposing them to cervical cancer in the longer term [8]. The absence of a publication in Cameroon on the immune-histochemical contribution in the detection of precancerous lesions on cervical smears justifies the present study whose objective was to evaluate cervical smear abnormalities in HIV + women as well as their prevalence, as well as the prevalence of cervical HPV16 and HSV1 & 2 infection in both HIV+ women and HIV− women.
2. Methodology
Type of study: This was a cross-sectional analytical case-control study from July 2017 to December 2017 (6 months).
Patients and methods: This study included all women present in the day hospital and anatomo-pathology departments of Laquintinie Hospital during the study period and having agreed to participate following informed consent. Sampling was consecutive. Each participant’s clinical observation was done but variables of interest retained for this study were age, occupation, clinical variables (history of metrorrhagia and macroscopical aspect of the cervix), biological and cytological variables.
Excluded were all those who expressed the refusal as well as those who were under anti-retroviral treatment.
The cervical smears were performed in the anotomo-pathology department of the Laquintinie hospital after spreading on seven different slides, two of which were fixed with the hairspray for Papanicolaou staining, three fixed with the acetone-methanol mixture of equal volume for the HPV search and two fixed on simple methanol for HSV research. The search for HSV type 1 & 2 excretion was done using the indirect immunofluorescence technique using DAKO’s “Rabbit Anti-Herpes simplex virus type 1 and type 2”.
The search for excretion of the human papilloma virus was by the indirect immuno-peroxidase technique using the antibodies directed against the papilloma virus protein P16ink4a.
The slides used for viral research were stored for 10 minutes in the refrigerator at 4˚C and then dried in the open air and wrapped in aluminum foil, then transported to the virology laboratory of the Faculty of Medicine and Biomedical Sciences of Yaoundé where viral research was done.
HIV serologies were performed at the day hospital of the Laquintinie hospital using Enzygnost HIV Integral (enzyme immunoassay) test, simultaneously testing for HIV antigens and anti-HIV antibodies.
Both groups of women were compared with the chi square test with a significance level of P < 0.05.
3. Results
Our study population consisted of 108 women including 34 HIV+ women (31.50%) matched to 74 HIV− women (68.50%); a ratio of 1 HIV+ woman to 2.17 HIV− women.
The natural history of cervical cancer takes shape with the precocity of unprotected sex in an environment of social precariousness exposing to a multi sexual partnership and therefore to sexually transmitted infections including HPV.
These variables commonly associated with HPV infection have not been studied in our series; however, the age and occupation variables were invariably distributed in both groups.
The mean age was 40.07 with extremes of 21 and 71 years and a standard deviation of 9.99 with a peak in the 31 - 40 age group in both groups [Table 1]; housewives were in majority [Table 2].
Socio-Demographic Characteristics
The metrorrhagia variable was more frequent in HIV− women (29.73%) than in HIV+ women (20.59%), with a statistically insignificant difference (P = 0.8336) [Table 3].
Macroscopic cervical lesions included eight (8) variables including abnormal staining, ulceration, budding, contact hemorrhage, condyloma, cervical blocking mass, necrosis, loss of substance.
The data analysis revealed that abnormal cervical coloration, contact hemorrhage, and condyloma were the most common lesions in HIV+ women with a statistically significant difference compared to the control group (HIV−); concerning the coloration of the cervix (33.82% against 42.68% P = 0.006549) the contact hemorrhage (33.82% against 24.39% P = 0.00666) and the condylomas (8.82% against 2.44% P = 0.00588) [Table 4].
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Table 1. Population distribution by age range.
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Table 2. Population distribution by occupation.
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Table 3. Population distribution according to history of metrorrhagia.
Macroscopic Lesions of the Cervix
The study of microscopic cervical lesions involved four (4) variables, including inflammation of the cervix, hemorrhage, reshuffling lesions and dysplasia of the cervix.
It showed a high prevalence of metaplastic reshuffling lesions and cervical dysplasia in the HIV + population of 26.47% versus 6.76% (P = 0.00461) and 35.29% versus 8.10% (P = 0.0004301) [Table 5 and Table 6].
Microscopic Lesions of the Cervix
Research of Viral Markers by Immuno-Histochimics
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Table 4. Summary of macroscopic lesions of the cervix.
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Table 5. Frequency of reshuffling metaplastic lesions of the cervix according to HIV status.
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Table 6. Frequency of dysplastic lesions of the cervix according to HIV status.
In our series of 108 women, we found many more HPV markers in HIV+ women than in HIV− women; 21 out of 34 HIV+ (61.76%) versus 23 out of 74 HIV− (31.08%) (P = 0.0025775) [Table 7].
In this study, we did not have a positive result for the search for Herpes Simplex Virus type 1 and 2 excretions by indirect immunofluorescence.
4. Discussion
The aim of this study was to contribute to research and documentation on cervical cancer in Cameroonian women infected with HIV.
The results obtained were discussed based on clinical, cytological and immunohistochemical variables.
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Table 7. Research of HPV in both groups.
Epidemiology
Thirty-four (34) out of 108 subjects in our sample were HIV positive; a prevalence of 31.50%.
This prevalence is high compared to data from the literature; this is because some recruited patients were known HIV+ from the onset.
Clinical, cytological and immunohistochemical data
Regarding the appearance of the cervix, 33.82% of HIV+ subjects had an abnormal cervical coloration compared to 42.68% in HIV− subjects with a statistically significant difference (P = 0.006549). The same observation is reported by other authors including MBAKOP [8].
Contact hemorrhage was found in 33.82% of HIV+ subjects against 24.39% in HIV− subjects; the HIV+ status in this light had an influence on the occurrence of contact hemorrhages at the cervix (P = 0.00666); this observation agrees with that of other authors [9] [10] [11].
Regarding growths, 14.72% of HIV+ women had a budding cervix against 21.95% among HIV− with however a non-significant statistical difference; which suggests that other determinants apart from HIV infection would participate in the budding of the cervix.
However, 8.82% of HIV+ subjects had flat condyloma versus 2.44% in the matched group with a statistically significant difference (P = 0.00588); this high prevalence attests to the correlation between flat condyloma and HIV+ status [10] [11].
The HIV+ status did not have a significant influence on the occurrence of cervical ulcerations (7.35% in HIV+ versus 6.10% in HIV−, P = 0.1856).
The mass obstructing the cervix, the necrosis and the loss of substances found in this study do not seem to us to be related to the serological status.
Metaplastic shuffling as well as dysplasia were strongly correlated here to HIV+ status; this finding agrees with the data of the literature [10] [11].
The same is true for HPV infection, where 61.76% of HPV 16 positive serology is found in HIV+ women (21 cases) compared to 31.08% in HIV− (23 cases) women, with a difference statistically significant (P = 0.0025775) [9] [10] [11].
On the other hand, the excretion of HSV 1 & 2 is not found in this study and does not seem to correlate with the HIV serological profile.
But our study reveals a strong correlation between papilloma and the occurrence of cervical dysplasia as reported by other authors [9] [10] [11] [12] [13].
The limits of our study
This study, however, has limitations because of the choice of the site (Laquintinie hospital), whose users mainly come from poor social strata and the payment nature of the basic analyzes like the cervical smear which limited the sample (108). All of which does not allow absolute conclusions. The same is true for the technique used for viral excretion (immunofluorescence).
5. Conclusions
The results of our study confirm the data of the literature making HIV+ status the determining factor in the emergence of cervical dysplasia.
As such we suggest the following:
- To include systematic screening for cervical lesions in all HIV+ women regardless of age;
- To systematically search for HPV excretion in all HIV+ women with cellular dysplasia;
- To intensify educational activities on HIV/AIDS and cervical cancer in Cameroon;
- To systematically put HIV+ women with cellular dysplasia under anti-retroviral therapy even if the CD4 count is normal and the viral load undetectable.
Acknowledgements
All authors thank the administration of the hospital laquintinie and the staff of the departments of gynecology and anatomo-pathological for all the facilities granted to them during this study.
Data from the Literature
HIV infection is a determining factor in the emergence of viral HPV-induced cervical dysplasia
The Contribution of Our Study to Research
Our study confirms data from the literature and suggests screening strategies for dysplasias in HIV+ women.
Contribution of the Authors
ESSOME collected the data, designed the manuscript and wrote the article. ENGBANG, MVE KOH, NANA, BOTEN and TOCKI read and corrected the article, FEWOU supervised the writing, corrected the article and validated the final version