Received Date: 31/01/2018; Accepted Date: 26/03/2018; Published Date: 01/04/2018
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Introduction: To determine the number of occasional CIN2 and CIN3 in patients with high risk HPV(HRHPV) positive and relationship between HR HPV positive and normal cytology. Study was conducted to evaluate the pathologic findings in women with high risk HPV positive in Mashhad city. Material and methods: This descriptive cross-sectional study was performed on 325 women from 18-65 years old, who refer for cervical cancer screening from June 2015 to 2016 in an academic hospital of Medical Sciences of Mashhad. Both thin prep cytology and HPV testing by Cobas 4800 test was done for everyone. Then high risk HPV positive cases underwent colposcopy and cervical biopsy. Data were analysed by SPSS software (version18), Statistical tests Chi-square and t-test were used and P<0.05 was considered significant. Results: From total 325 women in 100 normal pap smear samples, HR HPV was positive in 20 cases (20%). In 47 patients with positive HR HPV, colposcopy and biopsy detect: normal pathology in 5 patients (11%), low grade squamous intraepithelial lesion (LSIL) in 39 patients (83%), and high grade squamous intraepithelial lesion (HSIL) in 3 of patients 6%. The most HR-HPV in 39 of patients with LSIL cases was other HPV 28 patients (72%). In 4 cases of HSIL 2 patients had positive HPV16 (50%) and one patient had positive HPV16 and HPV18 (25%), one patient with CIN3 had negative HRHPV. Based on use of HPV tests and colposcopy we could detect despite in HRHPV negative patients (325 samples) 3 cases of CIN2+ and one patient with had CIN3. Conclusion: The most common HPV type in Mashhad, Iran is other’s HR HPV but the most sever cellular dysplasia is seen in patients with positive HPV 16, 18. Vaccination with bivalent or Quadra valent is effective in prevention of cervical cancer.
Prevalence, High risk HPV, Low grade squamous intraepithelial lesion, Highgrade squamous intraepithelial lesion
Cancer of the cervix is the 2nd most common female cancer in the women aged 15 to 44 years in World [1,2]. It ranks as the 12th most frequent cancer among women in Iran and the 9th most frequent cancer among women between 15 and 44 years of age in Iran [3,4]. Fact Sheet 2014 reported that in Iran with a population of 29.48 million women ages 15 years and older, every year 947 women are diagnosed with cervical cancer and 370 died from the disease. HPV cervical infection led to cervical morphological lesions ranging from normal to different stages of precancerous lesions (CIN-1, CIN-2, CIN-3/CIS) and invasive cervical cancer. Evaluation of HPV infection is by means of HPV DNA detection in cervical cells (fresh tissue, paraffin embedded or exfoliated cells). The prevalence of HPV increases with severity of the lesion . Schiffman et al. in study of HPV DNA testing in cervical cancer screening, recommend that HPV test for screening in high-risk (HSIL) women in province of Costa Rica . Worldwide, HPV-16 and 18, the two vaccine-preventable types infection, contribute to over 70% of all cervical cancer cases, between 41%-67% of highgrade cervical lesions and 16-32% of low-grade cervical lesions. After these HPV, the six most common HPV (HR HPV) types are in all world regions, namely 31, 33, 35, 45, 52 and 58; these account for an additional 20% of cervical cancers worldwide . The Cobas HPV Test provides both pooled high-risk HPV DNA results (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68) in addition to detect of HPV16 and HPV 18 . Although HPV16, 18, 31, 52 and 58 are cited among the top 10 most common HPV genotypes worldwide, there is significant variation in the prevalence of HRHPV genotypes between countries . ASCCP ACOG recommends HPV tests for Screening of cervical cancer . In the 2014 FDA (Federal Drug Administration) confirmed the use of HR HPV tests as the first step in the cervical cancer screening , and in 2015, Experts Association confirmed the Primary Screening with HPV test . In 2016 SSCCP recommend HR HPV and cytology testing as a screening for cervical cancer in women over the age of 25 years . in the study of Anderson LA et al. HPV DNA test was detected in 262/545 (48.1%) of CINI samples, 280/425 (65.9%) of CIN II lesions, 633/779 (81.3%) of CIN III specimens, 59/64 (92.2%) of SCCs and 9/14 (64.3%) of AC samples . The aim of this study is cervical pathologic findings in women with high risk HPV positive in Mashhad (North-East of Iran).
The aim of this study is pathologic findings in women with high risk HPV positive in Mashhad and prevalence CIN2+ in patients with High Risk HPV positive and relationship between HR HPV positive and cytology.
Total 325 women with 18-45 years old from June 2015 to 2016, who refer to gynecologic university clinic for screening of cervical cancer, written consent was received from all patients. Liquid base cytological samples were taken; also HR HPV by cobas 4800 test for all was performed. Based on patient's age, cytology, HPV status, and clinical complaint, colposcopy was performed by experience genecology-oncologist. Finally Statistical tests Chi-square and t-test were used and P<0.05 was considered.
The rate of High Risk HPV-positive was 79 patients (24%). We had 100 normal pap tests; the prevalence of HR. HPV in this group was 20% (20 patients from 100 people). The most common HPV typing were others HR HPV type 13 (13%) in addition HPV 16 in 3(3%) and HPV 18, 16 and others (all HR- HPV types) in 2(2%) patient was detected (Tables 1 and 2). In 79 patients with HRHPV we have 47 pap test with this results: 17 case negative, 15 case ASCUS, and 15 patients with LSIL (Table 3). In 47 patients with HR-HPV colposcopy was performed and we found: 5 normal pathology (11%), 39 LSIL (83%) which is the most pathologic finding and 3 HSIL (6%) (Table 4). The result of pathology and colposcopy evaluation confirmed that 4 cases with CN2,3. Test pap smear could show only 2 cases of CIN 2,3 (50%) also HPV testing detected only three of the patients (75%) and all of two method missed one patient with CIN3. In these four patients with CIN2-3, the result of pap test was in one patient ASCUS, in one patient LSIL and in two patient normal.
Table 1. The prevalence of positive HRHPV in women with normal pap smear.
|Normal pap smear||HRHPV positive||HRHPV negative|
Table 2. The HPV type distribution in women with normal pap smear.
|Others HPV only||HPV16 only||HPV18 only||others HPV+ 16||Others HpV+18||HPV16+18||othersHPV +16+18||total|
Table 3. The relation between patients with HRHPV positive and pap smear (cytology).
Table 4. The results of pathologic finding in patients with HRHPV positive.
|CIN2-3||CIN1||Normal pathology||HRHPV positive|
In 37 samples with LSIL the most common HPV typing was others HPV (22%). In 4 samples with CIN2-3 (HSIL), HPV16 was (50%) and HPV 18 was (25%) and others HPV (0%), this means that although others HPV is the most common HR-HPV in all population but the HPV 16 and then 18 are responsible for 100% of patients with HSIL. In one patient with negative HR-HPV and normal pap smear, because of cervical abnormality colposcopy and biopsy was performed and we could detected CIS in this patient (Tables 5 and 6).
Table 5. The relation between CIN1 and HPV type distribution.
|Others+16||HPV18||HPV16||Others HPV||Total CIN1|
Table 6. The relation between HRHPV and CIN2-CIN3 (HSIL).
|HRHP Vnegative||HPV16+18||Others HPV||HPV18||HPV16||CIN2-CIN3|
The most common HPV type in Mashhad was others HR HPV, but the most sever cellular dysplasia is seen in patients with positive HPV 16, 18. A systematic review of the literature was conducted regarding the worldwide HPV-prevalence and type distribution by WHO in 2017, according to this meta-analysis, the prevalence of HPV in women with normal cytology is 7.2% in world and 7.4% in Iran [5-7]. In current study, in 100 sample of normal pap smear, the prevalence of high risk HPV was 20%. The most common type was only Others HPV (13%), then only HPV 16 in 3 (3%) this is more than what is recorded by WHO. In a research that was performed in Iran by Shafaghi during 2010-2012, in 216 patients with high risk HPV positive, the prevalence of different cytology was 55% normal, 21.8% ASCUS, 17.6% LSIL and 5.5% HSIL . In our study in 47 patients with positive HR-HPV, cytological findings were 36% normal, 32% ASCUS 32% LSIL and 0% HSIL. Pathologic findings in 47 patients with HR-HPV positive in our study were 11% normal, 83% LSIL and 6% HSIL. The prevalence of HPV 16 and18 according to WHO, in 38191 LSIL samples were 25.8% in the world and 24% in Western Asia . In our study in 39 CIN1, the Others HPV prevalence were 72% and HPV16 and 18 is 30% that is similar to this report. In the WHO 2017 data in 50202 HSIL cases, HPV 16, 18 in the world 51.9% and in Western Asia 52.3%.In our study, 4 patients with CIN2 -3 the most common type was HPV16 (50%) and then type 18 (25%)and HPV 16,18 is 75%. This means that although Others HRHPV is the most common type in the general population and in individuals with LSIL, but in patients with CIN2-3 HPV16 and 18 is the most common type. In one patient (25%), HPV test and cytology was negative but because of cervical abnormality we perform colposcopy and biopsy and in situ carcinoma was detected. In article of Remmink et al. all patients that progress to CIN had continuous HPV-positive, after 36 month of follow -up, if HPV was negative or if there was low risk HPV, progression to CIN  was not observed.
We must note that we can treat HPV related disease with anti HPV drugs especially DNA targeted antiviral. Bashkin et al. has with usage HTI-1968 as a potent and selective, inhibiting the growth of these high-risk HPV types. Nanotechnology has been attracted in cancer therapy, Wakaskar RR et al. has made a wide research in this way .
Based on the high prevalence of HR HPV in our area in recent years, we recommend education about preventing the spread of infectious diseases and also avoiding high-risk and sexually-insensitive behaviors. Also we can treat HPV related disease and prevent of progress of the disease. Our study limitation is a small sample, so we will sample more in the future.
Regarding the high prevalence of HR HPV in Mashhad, which is an example of the whole of Iran, HPV tests is a necessary and supplementary test with pap-smear for detection of HSIL and we emphasis on careful physical examination and perform direct colposcopy and biopsy in patients with abnormal appearance of cervix. Also we urge the authorities to pay attention to this problem and the need for vaccination in girls aged 11-16 years.
As the COBAS test is approved by the FDA (Food and Drug Administration) and has high sensitivity and specificity therefore, the probability of sampling is incorrect so we emphasize that correct sampling is very important for correct results.
Authors have no conflict of interest.