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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 4  |  Page : 780-784

Distribution of human papillomavirus genotypes and its relationship to clinicopathology in invasive cervical carcinoma in Zhejiang Province, China


1 Department of Gynecologic Oncology, Zhejiang Cancer Hospital, Hangzhou, China
2 Department of Gynecologic Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, China
3 Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, China

Date of Web Publication27-Jun-2018

Correspondence Address:
Jianqing Zhu
Department of Gynecologic Oncology, Zhejiang Cancer Hospital, Banshan Bridge, Guangji Road #38, Hangzhou 310022
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.231428

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 > Abstract 


Aims: This study aims to investigate the prevalence of human papillomavirus (HPV) genotypes and analyze the relationship of HPV infectious status to clinicopathologic characteristics of invasive cervical carcinoma (ICC) in Zhejiang Province.
Materials and Methods: All consecutive patients diagnosed with the International Federation of Gynecology and Obstetrics stage IA to IV ICC, treated at our institutions between January 2007 and December 2008 were enrolled. The associations between the clinicopathologic parameters and the HPV status were assessed by the Pearson Chi-square test.
Results: Out of 1169 patients, 1072 (91.70%) patients had detectable HPV, the HPV-positive rate seemed to be higher as the severity of pathology increased and preferred to squamous cell carcinoma (SCC). HPV-16/-58/-18/-52 was the most prevalent types found in Zhejiang Province. HPV-16 was preferred to SCC (P = 0.049), while HPV-58 seemed to be more likely in non-SCC (P = 1.18E-6), deep stromal invasion (DSI)-positive (P = 0.001), lymphovascular space invasion (LVSI)-positive (P = 4.84E-6), and lymph node metastasis (LNM)-positive (P = 7.98E-4). HPV-52 was more common in surgery patients who were beyond 35 years old (P = 0.02), as well as in DSI-positive (P = 0.014) patients. However, there were no significant differences regarding HPV-58 to any clinicopathologic parameters.
Conclusions: HPV-16/-18/-58/-52 was the most commonly identified types in Zhejiang Province, which contributed for vaccine development. Furthermore, HPV-16 was preferred to SCC, while HPV-58 seemed to be more likely in non-SCC, DSI-positive, LVSI-positive, and LNM-positive patients, and HPV-52 was more common in surgery patients who were beyond 35 years old, as well as in DSI-positive patients.

Keywords: Cervical carcinoma, genotype, human papillomavirus, vaccine


How to cite this article:
Chen Z, Zhou J, Chen Y, Zhu J. Distribution of human papillomavirus genotypes and its relationship to clinicopathology in invasive cervical carcinoma in Zhejiang Province, China. J Can Res Ther 2018;14:780-4

How to cite this URL:
Chen Z, Zhou J, Chen Y, Zhu J. Distribution of human papillomavirus genotypes and its relationship to clinicopathology in invasive cervical carcinoma in Zhejiang Province, China. J Can Res Ther [serial online] 2018 [cited 2019 Nov 12];14:780-4. Available from: http://www.cancerjournal.net/text.asp?2018/14/4/780/231428




 > Introduction Top


Despite widespread well-organized screening and early therapeutic schedule have been carried out, cervical cancer remains the third most common female malignant disease and is still one of the leading causes of cancer-related deaths in developing countries.[1] Approximately, one-third new cases occur in China and present rising, younger trend.[2]

Human papillomavirus (HPV) comprises a diverse group of small, nonenveloped, double-stranded DNA viruses. More than 200 genotypes of HPV have been identified, of those, a subset of HPVs, such as type-16, -18, -31, -33, and others have been designated as high-risk HPVs (hr-HPV).[3],[4] It is well known that persistent infection of hr-HPV is a necessary causal event in cervical carcinogenesis, and result in at least 99.7% of cervical cancers.[4],[5] Moreover, the prevalence of the HPV genotypes varies by geographic areas, for example, HPV-16 and -18 are by far the most prevalent and oncogenic HPV types worldwide, HPV-45 and -33 are more prevalent in Africa, HPV-33 and -31 in Europe, HPV-31, -33, and -45 in northern and southern America, while HPV-58 and -52 in Asia.[6] Therefore, the knowledge of the regional HPV genotype is crucial to the prevention and treatment of invasive cervical carcinoma (ICC), which highlights the need for timely study in this region.

Although cervical carcinoma can be treated by radical surgery with or without chemotherapy and/or radiotherapy, some patients with high-risk factors have an unfavorable prognosis.[7] Clinicopathologic characteristics for cervical carcinoma include International Federation of Gynecology and Obstetrics (FIGO) stage, lymph node metastasis (LNM), parametrial or vaginal invasion, cell differentiation, lymphovascular space invasion (LVSI), and deep stromal invasion (DSI).[8],[9],[10],[11] However, the relationship of HPV genotypes to the prognosis of ICC remains controversial.

The aim of the present study was to investigate the prevalence of main HPV genotypes and analyze the relationship of HPV infectious statuses to clinicopathologic characteristics in ICC in Zhejiang Province.


 > Materials and Methods Top


Patients and tissue specimens

All consecutive patients diagnosed with the FIGO stage IA to IV ICC, treated at the Zhejiang Cancer Hospital, Zhejiang Province, China between January 2007 and December 2008 were eligible for this study. Cervical exfoliated cell samples were available for HPV DNA chip analysis before therapy. The Local Institutional Ethics Committee approved the study and informed consents were obtained from the patients.

DNA extraction and polymerase chain reaction amplification

All the cervical exfoliated cell samples were obtained by cytobrush and collected in Surepath™ solution (TriPath Imaging ® Inc). Then, centrifuged 2 ml of the samples at 13.000 rpm for 15 min removed supernatant and resuspended the pellet in 200 ml PBS buffer. DNA extracts were prepared with the QIAamp DNA Blood Mini kit3 (QIAGEN) following the Blood and Body Fluid Spin protocol.

HPV genotyping by HybriMax used an HPV GenoArray Test Kit (HybriBio Ltd., Chaozhou, China) according to the manufacturer's instructions.[12] A negative control and a positive control (HPV DNA from SiHa) were used to avoid false-positive reactions.

Human papillomavirus genotyping

HPV genotyping was performed following a HPV GenoArray test kit (Hybribio Limited, Hong Kong), which could identify 21 HPV genotypes, including 15 high-risk groups (HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -53, -56, -58, -59, -66, and -68), 6 low-risk groups (HPV-6, -11, -42, -43, -44, and -81).

The following clinical and histological parameters were evaluated in relation to HPV status: age at surgery, FIGO stage, histological types, differentiation, DSI, LVSI, and LNM.

Statistical analysis

Statistical analyses were performed with SPSS 16.0 software package (IBM, Armonk, NY). P < 0.05 was considered statistically significant. Summary statistics are presented as frequencies and percentages. The Pearson Chi-square test was used to assess the association between the clinicopathologic parameters and the HPV status.


 > Results Top


Patient characteristics

A total of 1169 patients, included 413 patients (35.3%) with Stage I, 526 patients (45.0%) with Stage II, 224 patients (19.2%) with Stage III, and 6 patients (0.5%) with Stage IV, were identified. Of those, 1092 patients were diagnosed as squamous cell carcinoma (SCC), 41 as adenocarcinoma (ADC), 25 as adenosquamous carcinoma (ASC), 9 as clear cell carcinoma, and 2 as small cell carcinoma. Totally, 617 patients received surgery (2 of them received cervical conization surgery); others were treated by radiotherapy and/or chemotherapy. The median age of the patients with ICC was 48.2 years (range: 22–86 years).

Human papillomavirus-positive rate and infection status

1072 (91.70%) of the 1169 cervical samples from patients had detectable HPV: the hr-HPV-positive rate was 91.53%, while the low-risk HPV-positive rate was 4.88%. As shown in [Table 1], among the ICC, included SCC, ADC, ASC, and other carcinomas, the HPV-positive rate was higher with SCC than ASC (P = 0.03), but no difference was observed between SCC and ADC (P = 0.127). The HPV-positive rate seemed to be higher as the severity of pathology increased. The proportions of single-or multiple-type (co-, tri-, tetra-infection, or more) infection were 77.16% (902), 12.23% (143), 1.28% (15), and 1.03% (12), respectively. The mean age of the positively detected women was 47 years (range 16–86 years). It seems that neither pathology nor FIGO stage showed any relationship to HPV infection status.
Table 1: Prevalence of human papillomavirus genotypes in 1169 cases of invasive cervical carcinoma

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Human papillomavirus epidemiological distribution

HPV-16 was the major HPV genotype in ICC (62.1% of all genotypes), then with the subsequent types followed by HPV-18 (10.95%), -58 (10.52%), -52 (7.96%), -33 (3.93%), -31 (3.93%), -68 (1.88%), -53 (1.88%), -45 (1.20%), -81 (1.2%), -66 (0.77%), -59 (0.68%), -6 (0.60%), -39 (0.43%), -11 (0.43%), -56 (0.26%), -42 (0.26%), -43 (0.17%), -44 (0.17%), and HPV-35 and -51 were not detected. As shown in [Figure 1], HPV-16, -58, -18, and -52 were the most prevalent types found in Zhejiang Province.
Figure 1: Distribution of human papillomavirus genotypes in hospital-based female population in Zhejiang Province. Human papillomavirus-16 dominates the pathogenesis of invasive cervical cancer, followed by human papillomavirus-58, -18, -52, and other types

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The relationship of human papillomavirus status to clinicopathologic parameters

The associations of HPV genotypes with seven clinicopathologic parameters were shown in [Table 2]. The Pearson Chi-square test identified that HPV infection were more common in patients with SCC compared to other types (P = 0.02), but no associations were found in age at surgery (P = 0.05), FIGO stage (P = 0.51), differentiation (P = 0.49), DSI (P = 0.97), LVSI (P = 0.39), and LNM (P = 0.92). Furthermore, the four most prevalent types, HPV-16, -58, -18, and -52, were also analyzed with clinicopathological subgroups. HPV-16 was preferred to SCC (P = 0.049), while HPV-58 seemed to be more likely in non-SCC (P = 1.18E-6), DSI-positive (P = 0.001), LVSI-positive (P = 4.84E-6), and LNM-positive (P = 7.98E-4). Moreover, HPV-52 was more common in surgery patients who were beyond 35 years old (P = 0.02), as well as in DSI-positive (P = 0.014) patients. However, there were no significant differences regarding HPV-58 to any clinicopathologic parameters.
Table 2: The relationship of human papillomavirus status to clinicopathologic parameters

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 > Discussion Top


ICC is still a leading cause of cancer-related death in women worldwide, with an estimated 528.000 new cases and 266.000 deaths in 2012.[13] So far, ICC continues to be a global concern, especially in developing areas, which account for 83% of all cases.[14]

Fortunately, HPV is firmly established as the principal causative agent for cervical carcinoma, which provides clear direction for anti-ICC therapy.[5] Therefore, the knowledge of the regional HPV genotype is crucial to establish a framework for therapeutic strategies. With a good accordance to (Hybrid Capture II) HC-II and (in situ hybridization) ISH for HPV detection and more suitable for clinical use, HybriMax was selected. Previous studies showed that the distribution of HPV possessed geographic variations, and the geographic variations in HPV distribution were proven to be relevant to the distribution of cancer biology.[6] In this study, the HPV-positive rate was 91.7% of women with ICC, slightly lower than previous data of 99.7%.[4] HPV-16 is consistently the most prevalent type, and HPV-16, -58, -18, and -52 were the most prevalent types found in Zhejiang Province. The relatively high prevalence of HPV-52 and HPV-58 to ICC was consistent with our former study.[15] Of note, additional information we provided was that HPV-16 was preferred to SCC, while HPV-58 seemed to be more likely in non-SCC, DSI-positive, LVSI-positive, and LNM-positive patients. Moreover, HPV-52 was more common in surgery patients who were beyond 35 years old, as well as in DSI-positive patients, but no significant differences regarding HPV-58 to any clinicopathologic parameters.

Until now, neither the role played by each HPV type found in multiple-type infections in a lesion (in a random fashion or a competitive or cooperative relationship exists), nor the type-specific contribution of HPV to cervical intraepithelial neoplasia (CIN) and ICC progression is clear. Jaisamrarn suggested a paradoxical result that coinfection could increase the risk of progression to a CIN but also increase the chance of clearance.[16] Pista found a significant association between multiple infections and disease severity.[17] Balbi concluded multiple HPVs infection is a significant risk factor for high-grade CIN.[18] In addition, Trottier showed that multiple HPV infection may synergistically boost carcinogenesis.[19] However, Cuschieri showed that multiple hr-HPV infection did not have a higher risk than a single hr-HPV infection.[20] In this study, the proportions of single- or multiple-type infection were 77.16% and 14.54%, respectively. But neither pathology nor FIGO stage showed any relationship to HPV infection status.

HPV infection has been identified as an important initial event in the oncogenesis of ICC; however, the prognostic role of HPV genotype in ICC still remains controversial. Some found HPV-18 was associated with a poorer prognosis compared with HPV-16 positive tumors, while others did not find a prognostic value of HPV genotype.[21] Moreover, a few studies found that HPV-negative tumors were more aggressive. Our data were not shown.

There are several limitations of the data in this report. Since we do not know how many women had cancer from our region but never had a diagnosis, and this could introduce as selection bias. Another source of potential bias is false-negative laboratory reporting.


 > Conclusions Top


This study adds to the growing literature on the distribution of HPV genotypes in ICC. HPV-16/-18/-58/-52 was the most commonly identified types in our population, which contributed for vaccine development. Furthermore, HPV-16 was preferred to SCC, while HPV-58 seemed to be more likely in non-SCC, DSI-positive, LVSI-positive, and LNM-positive patients, and HPV-52 was more common in surgery patients who were beyond 35 years old, as well as in DSI-positive patients.

Financial support and sponsorship

This study was supported by The Zhejiang Province Nature Foundation (No. LQ16H160016) and the Zhejiang Province Health Department Foundation (No. 2015KYA037).

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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