Antibodies against high‐risk human papillomavirus proteins as markers for invasive cervical cancer

Different human papillomavirus (HPV) genes are expressed during the various phases of the HPV life cycle and may elicit immune responses in the process towards malignancy. To evaluate their association with cervical cancer, antibodies against proteins from HPV16 (L1, E1, E2, E4, E6 and E7) and HPV18/31/33/35/45/52/58 (L1, E6 and E7) were measured in serum of 307 invasive cervical cancer cases and 327 controls from Algeria and India. Antibody response was evaluated using a glutathione S‐transferase‐based multiplex serology assay and HPV DNA detected from exfoliated cervical cells using a GP5+/6+‐mediated PCR assay. Among HPV16 DNA‐positive cases, seroprevalence of HPV16 antibodies ranged from 16% for HPV16 E1 to 50% for HPV16 E6 and all were significantly higher than controls. Seroprevalence of E6, E7 and L1 antibodies for HPV18 and for at least one of HPV31/33/35/45/52/58 were also higher in cases positive for DNA of the corresponding type (50% and 30% for E6 of HPV18 and HPV31/33/35/45/52/58 combined, respectively). E6 and E7 antibodies were rarely found in controls, but cross‐reactivity was evident among cancer cases positive for DNA of closely phylogenetically‐related HPV types. E6 or E7 antibodies against any of the eight HPV types were detected in 66.1% of all cervical cancer cases, as compared to 10.1% of controls. E6, and to a lesser extent E7, antibodies appear to be specific markers of HPV‐related malignancy. However, even among cases positive for the same type of HPV DNA, approximately one‐third of cervical cancer cases show no detectable immune response to either E6 or E7.     

Association between human papillomavirus infection and prostate cancer: A global systematic review and meta‐analysis

Although an increasing number of studies have been conducted to evaluate the association between human papillomavirus (HPV) infections and distribution of HPV types worldwide with the risk of prostate cancer (PC), the results remain inadequate. Hence, we investigated the association between HPV infection and PC risk using a meta‐analysis. Relevant studies from January 1990 to December 2016 were searched in PubMed, Web of sciences, and Scopus databases. Pooled odds ratio (OR) and their corresponding 95% confidence interval (CI) were calculated to find the association between the prevalence of HPV and prostate cancer risk. To do so, data from 24 studies with 5546 prostate cancer cases were pooled in order to evaluate the heterogeneity of chief parameters including study region, specimen type, HPV DNA source, detection technique, publication calendar period, and Gleason score. All statistical analyses were performed using STATA 11 and MedCalc 13. A significant positive association was found between HPV infection and PC risk (OR = 1.281; P = 0.026). The genotype 16 was more frequently found in patients with PC which significantly increased the cancer risk (OR = 1.60; P < 0.001). Age 65 and older could significantly escalate PC risk (OR = 3.564; P < 0.001). Our results clearly favor the potential pathogenetic link between HPV infection and increased risk of PC affirming that HPV infections could play a part in the risk of PC.     

Cutaneous alpha,beta and gamma human papillomaviruses in relation to squamous cell carcinoma of the skin: A population‐based study

Human papillomavirus (HPV) infection is common worldwide and, in immunodeficient populations, may contribute to the pathogenesis of keratinocyte cancers, particularly squamous cell carcinomas (SCC). However, their role in SCC in the general population is less clear. We conducted a comprehensive analysis to investigate the independent effects of seropositivity for cutaneous alpha, beta and gamma HPV types on risk of SCC, and a meta‐analysis of the available literature. In a population‐based case‐control study from New Hampshire, USA (n = 1,408), histologically confirmed SCC cases and controls were tested for L1 antibodies to alpha, beta and gamma cutaneous HPV types 2–5, 7–10, 15, 17, 20, 23, 24, 27b, 36, 38, 48–50, 57, 65, 75–77, 88, 92, 95, 96, 101, 103 and 107 using multiplex serology . An increasing risk of SCC with number of beta HPVs to which an individual tested positive was observed even among those seronegative for gamma types (p for trend = 0.016) with an odds ratio of 1.95 (95% confidence interval (CI) = 1.07–3.56) for four or more beta types positive. In a meta‐analysis of six case‐control studies, increased SCC risks in relation to beta HPV seropositivity were found across studies (meta odds ratio = 1.45, CI = 1.27–1.66). While the prevalence of gamma HPVs assayed was somewhat higher among SCC cases than controls, the association was only weakly evident among those seronegative for beta HPVs. Overall, the association between cutaneous HPVs and skin cancers appears to be specific to SCC and to genus beta HPVs in a general US population.     

Common polymorphisms in 5-lipoxygenase and 12-lipoxygenase genes and the risk of incident, sporadic colorectal adenoma

BACKGROUND: Lipoxygenases (LOX) are major enzymes that metabolize arachidonic acid to hydroxyl-eicosatetraenoic acids and leukotrienes, which have been implicated in inflammation and colorectal cancer risk. Polymorphisms in LOX genes may influence their function and/or expression and, thus, may modify the risk for colorectal adenoma. The authors investigated the associations of 3 polymorphisms (2 in 5-LOX, -1708 guanine-->adenine and 21 cytosine-->thymine; and 1 in 12-LOX, arginine 261 glutamine [Arg261Gln]) in LOX genes with the risk of colorectal adenoma and also explored possible interactions of these polymorphisms with several inflammation-pathway or arachidonic acid metabolism-pathway related factors with the risk of colorectal adenoma. METHODS: By using data from a community-based, case-control study of incident, sporadic colorectal adenoma that included 162 cases and 211 controls, the authors constructed multiple logistic regression models to estimate the odds ratios (OR) and 95% confidence intervals (95% CI) of colorectal adenoma after adjusting for potential confounders. RESULTS: Overall, there were no significant associations of the 2 5-LOX polymorphisms with the risk of colorectal adenoma. However, there was an inverse association between the Arg261Gln polymorphism in 12-LOX and colorectal adenoma (OR, 0.63; 95% CI, 0.40-1.00). A significant interaction also was observed between the 12-LOX polymorphism (Arg261Gln) and the use of nonsteroidal anti-inflammatory drugs (P(interaction) = .02). CONCLUSIONS: The current results suggested that polymorphisms of LOX genes may act independently or with other factors to affect the risk of colorectal adenoma. Further studies will be needed to confirm these findings. Cancer 2007 (c) 2007 American Cancer Society.     

Association of prostate stem cell antigen gene polymorphisms with the risk of stomach cancer in Japanese

A recent whole‐genome association study identified a strong association between polymorphisms in the prostate stem cell antigen (PSCA) gene and stomach cancer risk. In this case‐control study, we aimed to validate this association, and further to explore environmental factors possibly interacting with PSCA polymorphisms in 708 incident stomach cancer cases and 708 age–sex matched controls. The association between PSCA polymorphisms and Helicobacter pylori infection was also examined. We found that rs2294008 and rs2976392, which were strongly linked to each other (D′ = 1.00), were significantly associated with stomach cancer risk. Per allele odds ratio for rs2994008 was 1.40 (95% confidence interval: 1.19–1.65; p = 3.7 × 10^?5). We found significant interaction with a family history of stomach cancer in first‐degree relatives (p‐heterogeneity = 0.009). Similar to originally reported association, we found significant heterogeneity between diffuse and intestinal type (p‐heterogeneity = 0.007). No association was seen between PSCA polymorphisms and H. pylori infection. In conclusion, PSCA polymorphisms are associated with stomach cancer risk in Japanese. A possible interaction with family history warrants further evaluation. © 2009 UICC     

Association between polymorphisms in interleukin‐17A and interleukin‐17F genes and risks of gastric cancer

Chronic inflammation is the hallmark of the pathogenesis of Helicobacter pylori‐induced gastric cancer. Interleukin (IL)‐17A and IL‐17F are inflammatory cytokines expressed by a novel subset of CD4+ Th cells and play critical function in inflammation and probably in cancer. We conducted a case–control study including 1,010 gastric cancer patients and 800 healthy controls to assess the association between IL‐17A G197A and IL‐17F A7488G polymorphisms and risk of gastric cancer. Genotypes were determined by polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) and DNA sequencing. Logistic regression and Cox‐proportional hazards analyses were used to evaluate the associations between polymorphisms and gastric cancer susceptibility, clinicopathological features and survival. After adjusted for age and gender, IL‐17F 7488GA and GG genotypes were associated with an increased risk of gastric cancer compared with AA genotype [OR 1.51, 95% confidence interval (CI): 1.22–1.87 for GA; OR 1.61, 95% CI: 1.03–2.51 for GG]. Further stratification analyses indicated that the effect of IL‐17F 7488GA genotype was noteworthy in gastric cancer patients of noncardia, intestinal type, poorly and moderately differentiated, age older than 40, large tumor size and lymph node metastasis. IL‐17A 197AG genotype was associated with increased risk of poorly differentiated, TNM I/II, age of 40–65‐year subtypes of gastric cancer, but not with total gastric cancer risk (p = 0.098). No significant relationship was observed between polymorphisms and survival of gastric cancer patients. These findings suggest that polymorphism of IL‐17F 7488 involved in susceptibility to gastric cancer, which also influenced certain subtypes according to clinicopathological features, whereas IL‐17A 197 may be less relevant.     

Serum interleukin‐6 associated with hepatocellular carcinoma risk: A nested case–control study

Inflammatory markers have been associated with increased risk of several cancers, including colon, lung, breast and liver, but the evidence is inconsistent. We conducted a nested case–control study in the longitudinal cohort of atomic‐bomb survivors. The study included 224 hepatocellular carcinoma (HCC) cases and 644 controls individually matched to cases on gender, age, city and time and method of serum storage, and countermatched on radiation dose. We measured C‐reactive protein (CRP) and interleukin (IL)‐6 using stored sera obtained within 6 years before HCC diagnosis from 188 HCC cases and 605 controls with adequate volumes of donated blood. Analyses with adjustment for hepatitis virus infection, alcohol consumption, smoking habit, body mass index (BMI) and radiation dose showed that relative risk (RR) of HCC [95% confidence interval (CI)] in the highest tertile of CRP levels was 1.94 (0.72–5.51) compared to the lowest tertile (p = 0.20). RR of HCC (95% CI) in the highest tertile of IL‐6 levels was 5.12 (1.54–20.1) compared to the lowest tertile (p = 0.007). Among subjects with BMI > 25.0 kg/m², a stronger association was found between a 1‐standard deviation (SD) increase in log IL‐6 and HCC risk compared to subjects in the middle quintile of BMI (21.3–22.9 kg/m²), resulting in adjusted RR (95% CI) of 3.09 (1.78–5.81; p = 0.015). The results indicate that higher serum levels of IL‐6 are associated with increased HCC risk, independently of hepatitis virus infection, lifestyle‐related factors and radiation exposure. The association is especially pronounced among subjects with obesity.     

Night work and breast cancer: A population‐based case–control study in France (the CECILE study)

Night work involving disruption of circadian rhythm was suggested as a possible cause of breast cancer. We examined the role of night work in a large population‐based case‐control study carried out in France between 2005 and 2008. Lifetime occupational history including work schedules of each night work period was elicited in 1,232 cases of breast cancer and 1,317 population controls. Thirteen percent of the cases and 11% of the controls had ever worked on night shifts (OR = 1.27 [95% confidence interval = 0.99–1.64]). Odds ratios were 1.35 [1.01–1.80] in women who worked on overnight shifts, 1.40 [1.01–1.92] in women who had worked at night for 4.5 or more years, and 1.43 [1.01–2.03] in those who worked less than three nights per week on average. The odds ratio was 1.95 [1.13–3.35] in women employed in night work for >4 years before their first full‐term pregnancy, a period where mammary gland cells are incompletely differentiated and possibly more susceptible to circadian disruption effects. Our results support the hypothesis that night work plays a role in breast cancer, particularly in women who started working at night before first full‐term pregnancy.     

Order of HPV/Chlamydia infections and cervical high‐grade precancer risk: A case‐cohort study

Interactions of carcinogenic human papillomaviruses (most notably HPV types 16/18/31/33/45), and HPV6 or Chlamydia trachomatis are not well understood. We have used seroconversions to study effects the order of these infections has on the risk of high‐grade cervical precancer. In a cohort of 94,349 Finnish women with paired sera from consecutive pregnancies within an average of 2.4 years, 490 were diagnosed with cervical CIN3/AIS. Serum antibodies to HPV6/16/18/31/33/45 and C. trachomatis were measured in paired sera of the cases and a subcohort of 2,796 women with a minimum of two pregnancies. HPV16‐adjusted rate ratios (RR) and confidence intervals were estimated by stratified Cox model. Compared to dual seropositivity already at the first serum sampling, RRs related to HPV6 seropositivity before and after HPV31 seroconversion were 0.4 (95% CI 0.0, 4.4) and 10 (95% CI 1.8, 57). Furthermore, RR related to seroconversions of both HPV18/45 and C.trachomatis between the consecutive pregnancies was 28 (95% CI 4.3, 190). Virtually concomitant HPV18/45 and C.trachomatis infections are associated with very high CIN3 risk.     

The influence of type‐specific human papillomavirus infections on the detection of cervical precancer and cancer: A population‐based study of opportunistic cervical screening in the United States

There are limited data on the prospective risks of detecting cervical precancer and cancer in United States (US) populations specifically where the delivery of opportunistic cervical screening takes place outside managed care and in the absence of organized national programs. Such data will inform the management of women with positive screening results before and after widespread human papillomavirus (HPV) vaccination and establishes a baseline preceding recent changes in US cervical cancer screening guidelines. Using data reported to the statewide passive surveillance systems of the New Mexico HPV Pap Registry, we measured the 3‐year HPV type‐specific cumulative incidence of cervical intraepithelial neoplasia grade 2 or more severe (CIN2+) and grade 3 or more severe (CIN3+) detected during real‐world health care delivery across a diversity of organizations, payers, clinical settings, providers and patients. A stratified sample of 47,541 cervical cytology specimens from a screening population of 379,000 women underwent HPV genotyping. Three‐year risks for different combinations of cytologic interpretation and HPV risk group ranged from <1% (for several combinations) to approximately 70% for CIN2+ and 55% for CIN3+ in women with high‐grade (HSIL) cytology and HPV16 infection. A substantial proportion of CIN2+ (35.7%) and CIN3+ (30.9%) were diagnosed following negative cytology, of which 62.3 and 78.2%, respectively, were high‐risk HPV positive. HPV16 had the greatest 3‐year risks (10.9% for CIN2+,8.0% for CIN3+) followed by HPV33, HPV31, and HPV18. Positive results for high‐risk HPV, especially HPV16, the severity of cytologic interpretation, and age contribute independently to the risks of CIN2+ and CIN3+.     

Association of variants in the interleukin‐27 and interleukin‐12 gene with nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is multifactorial, and the genetic background may be a crucial etiologic factor. Interleukin‐12 (IL‐12) is a multifunctional cytokine that induces interferon (IFN)‐gamma secretion and plays an important role in antitumor immunity. Interleukin‐27 (IL‐27) is a novel IL‐12 family member, the present studies demonstrate that IL‐27 mediates potent antitumor activity. Variations in the DNA sequence in the IL‐12 and IL‐27 gene may lead to altered cytokines production and/or activity, and so this can modulate an individual's susceptibility to NPC. To test this hypothesis, we investigated the relationship of IL‐12 and IL‐27 gene polymorphisms and NPC in a Chinese population. We analyzed single nucleotide polymorphisms (SNPs) of IL‐12 gene 16974 A/C and IL‐27 gene ?964 A/G, 2905 T/G, 4730 T/C in 302 patients with NPC and 310 age‐ and sex‐matched controls, using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) and DNA sequencing methods. There were significant differences in the genotype and allele distribution of 16974 A/C polymorphism of the IL‐12 gene among cases and controls. The 16974 CC and AC genotypes were associated with a significantly increased risk of NPC as compared with the 16974 AA genotypes (OR = 2.225, 95% CI 1.395–3.549, P = 0.001 and OR = 1.834, 95% CI 1.239–2.716, P = 0.002, respectively). The 16974 C allele was associated with a significantly increased risk of NPC as compared with the 16974 A allele (OR = 1.334, 95% CI 1.065–1.670, P = 0.012). However, genotype and allele frequencies of the IL‐27 gene ?964 A/G, 2905 T/G, 4730 T/C polymorphisms in NPC patients were not significantly different than that in healthy controls (P > 0.05). Our data suggest that IL‐12 gene may play a role in the development of NPC. © 2009 Wiley‐Liss, Inc.     

Prevalence of high‐risk human papillomavirus and cervical intraepithelial neoplasias in a previously unscreened population—A pooled analysis from three studies

Population prevalence of human papillomavirus (HPV) and cervical intraepithelial neoplasias (CIN) is an important indicator to judge the disease burden in the community, to monitor the performance of cervical cancer screening program and to assess the impact of HPV vaccination program. India being a country without any cervical cancer screening program has no published data on the population prevalence of CIN and only a few large community‐based studies to report the high‐risk HPV prevalence. The objective of our study was to study HPV and CIN prevalence in a previously unscreened population. We pooled together the results of three research studies originally designed to assess the performance of visual inspection after acetic acid application and Hybrid Capture 2 (HC 2). Nearly 60% of the screened women had colposcopy irrespective of their screening test results. The diagnosis and grading of cervical neoplasias were based on histology. The age standardized prevalence of HPV by HC 2 test was 6.0%. Age‐adjusted prevalence of CIN1 and CIN2 was 2.3% and 0.5%, respectively. The age‐adjusted prevalence of CIN3 was 0.4% and that of invasive cancer was 0.2%. The prevalence of high‐risk HPV was relatively low in the population we studied, which is reflected in the low prevalence of high‐grade CIN. The prevalence of CIN3 remained constant across age groups due to absence of screening.     

Laryngeal cancer risk associated with smoking and alcohol consumption is modified by genetic polymorphisms in ERCC5, ERCC6 and RAD23B but not by polymorphisms in five other nucleotide excision repair genes

Laryngeal cancer is known to be associated with smoking and high alcohol consumption. Nucleotide excision repair (NER) plays a key role in repairing DNA damage induced by these exposures and might affect laryngeal cancer susceptibility. In a population‐based case‐control study including 248 cases and 647 controls, the association of laryngeal cancer with 14 single nucleotide polymorphisms (SNPs) in 8 NER genes (XPC, XPA, ERCC1, ERCC2, ERCC4, ERCC5, ERCC6 and RAD23B) was analyzed with respect to smoking and alcohol exposure. For genotyping, sequence specific hybridization probes were used. Data were evaluated by conditional logistic regression analysis, stratified for age and gender, and adjusted for smoking, alcohol consumption and education. Pro‐carriers of ERCC6 Arg1230Pro showed a decreased risk for laryngeal cancer (OR = 0.53, 95% CI 0.34–0.85), strongest in heavy smokers and high alcohol consumers. ERCC5 Asp1104His was associated with risk in heavy smokers (OR = 1.70, 95% CI 1.1–2.5). Val‐carriers of RAD23B Ala249Val had an increased cancer risk in heavy smokers (OR = 1.6, 95% CI 1.1–2.5) and high alcohol consumers (OR = 2.0, 95% CI 1.1–3.4). The combined effect of smoking and alcohol intake affected risk, at high exposure level, for ERCC6 1230Pro carriers (OR = 0.47, 95% CI 0.22–0.98) and RAD23B 249Val carriers (OR = 2.6, 95% CI 1.3–4.9). When tested for gene–gene interaction, presence of 3 risk alleles in the XPC‐RAD23B complex increased the risk 2.1‐fold. SNPs in the other genes did not show a significant association with laryngeal cancer risk. We conclude that common genetic variations in NER genes can significantly modify laryngeal cancer risk. © 2009 UICC     

CYP1A1, GSTM1 and GSTT1 genetic polymorphisms and gastric cancer risk among Japanese: A nested case–control study within a large‐scale population‐based prospective study

Cytochrome P450 (CYP) 1A1 and glutathione S‐transferases (GST) M1 and T1 are major enzymes in the carcinogen metabolizing pathway. We examined the association between single nucleotide polymorphisms (SNPs) of CYP1A1 (rs4646421, rs4646422 and rs1048943), GSTM1 and GSTT1 and gastric cancer risk in Japan. This is a nested case–control study (457 cases and 457 matched controls) of our population‐based cohort involving 36,745 subjects who answered a baseline questionnaire and supplied blood samples. The odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were calculated using conditional logistic regression models. We found that CYP1A1 (rs4646422) variant allele was associated with a statistically significant increased risk of gastric cancer compared with the homozygous wild‐type genotype (OR = 1.65; 95% CI = 1.17–2.32). GSTM1 null, GSTT1 null and GSTM1/T1 both or either null genotypes were associated with increased risk, but not statistically significantly. Combination of the CYP1A1 (rs4646422) variant allele and GSTM1/T1 both or either null genotypes was associated with a statistically significant increased risk compared with the combination of the CYP1A1 homozygous wild‐type genotype and the GSTM1/T1 both active genotypes. In addition, compared with CYP1A1 (rs4646422) homozygous wild‐type genotypes in those who were never‐smokers, CYP1A1 variant alleles in those who smoked ≥30 pack‐years were associated with an increased risk; neither gene–gene nor gene–environment interactions were significant. The CYP1A1 (rs4646422) polymorphism might be involved in gastric carcinogenesis among the Japanese population.     

Risk of skin cancer and other malignancies in kidney,liver, heart and lung transplant recipients 1970 to 2008—A Swedish population‐based study

Organ transplant recipients are at increased risk of a wide range of malignancies, especially cutaneous squamous cell carcinomas (SCC). Few previous population‐based studies have quantified and compared cancer risks according to graft type and with long‐term follow‐up. Using nationwide Swedish registers, we identified 10,476 recipients transplanted from 1970 to 2008 and followed them for cancer occurrence. Relative risks of cancer in comparison with the general population were expressed as standardized incidence ratios (SIR) and within the transplanted cohort as incidence rate ratios (IRR). During a total follow‐up of 93,432 person‐years, patients were diagnosed with 1,175 cancers excluding SCC, and with 2,231 SCC, SIR_{cancer excl SCC} 2.4 (95% CI, 2.2–2.5); SIR_SCC 121 (95% CI, 116–127). Cancer risks were most increased among heart and/or lung recipients SIR_{cancer excl SCC} 3.3 (95% CI, 2.8–4.0); SIR_SCC 198 (95% CI, 174–224), followed by kidney SIR_{cancer excl SCC} 2.3 (95% CI, 2.1–2.4); SIR_SCC 121 (95% CI, 116–127) and liver recipients SIR_{cancer excl SCC} 2.3 (95% CI, 1.9–2.8); SIR_SCC 32 (95% CI, 24–42). During follow‐up, risk of cancer excluding SCC remained stable while risk of SCC tripled over 20 years irrespective of graft type, partly due to a subgroup of patients developing new SCCs at a rapidly increasing rate. In summary, post‐transplant cancer risk varied by transplanted organ and by cancer site, with the bulk of the excess risk driven by an exceptionally high and accelerating risk of SCC. These findings underscore the importance of regular skin screening in organ transplant recipients.     

Risk of high‐grade precancerous lesions and invasive cancers in high‐risk HPV‐positive women with normal cervix or CIN 1 at baseline—A population‐based cohort study

Infection with high‐risk human papillomavirus (HR‐HPV) is transient and clears on its own in majority of the women. Only a few women who have persistent infection may finally develop cervical intraepithelial neoplasia (CIN) or cervical cancer in later years. The risk of progression in the HR‐HPV‐positive women with normal cervix or low‐grade lesion on colposcopy and histopathology at baseline is less studied. We performed a longitudinal study on 650 HR‐HPV‐positive women with colposcopy and/or histopathology‐proved normal or CIN1 diagnosis at baseline to assess the cumulative risk of development of high‐grade CIN. After a mean follow‐up of 2.1 person years of observation (PYO) (range 0.1–5.1), the cumulative incidence of CIN2+ (6.4%; 3.0/100 PYO) was significantly higher in women who had persistent HR‐HPV infection compared to those who cleared the infection (adjusted HR 6.28; 95% CI 2.87–13.73). The risk of viral persistence in women aged 50–60 years was two times higher compared to women aged 40–49 years and three times higher compared to women aged 30–39 years. The probability of having persistent infection increased progressively with higher viral load at baseline (adjusted HR 3.29, 95% CI 2.21–4.90 for RLU ≥100; adjusted HR 2.69, 95% CI 1.71–4.22 for RLU 10–100). Women with increasing viral load at follow‐up had four times higher risk of developing CIN2 or worse lesions as compared to those with decreasing load (20.9% vs 4.8%; p < 0.001). In the context of developing countries where cytology or genotyping triaging is not feasible, colposcopy referral of HR‐HPV‐positive women with advancing age, viral persistence, and increasing viral load may be considered.     

Incidence and outcome of acquisition of human papillomavirus infection in women with normal cytology—A population‐based cohort study from Taiwan

Little is known about acquisition of human papillomavirus (HPV) and its outcome among older women with negative HPV testing and normal cytology. A longitudinal 3‐yr follow‐up of nested‐cohort subjects (n = 8825) from a population‐based cervical cancer screening study whose Pap and HPV tests were negative at baseline were conducted. Every active HPV‐negative (n = 413) participant had 12‐mo follow‐ups of Pap smear and HPV testing. Colposcopy was performed if either HPV‐positive or cytology was abnormal. The cytology and histology information of the remaining subjects (passive HPV‐negative, n = 8412) was obtained from national registry database. Median age of participants was 45 yr (range, 30–73 yr). The incidence of new acquisition was 4.2/100 woman‐years. The 3‐yr cumulative total HPV acquisition rate was 11.1% (95% confidence interval [CI]: 8.1–14.1). Increased number of sexual partners (≥2 vs. 1) of the participant was associated with risk of acquisition (odds ratio [OR]: 5.0, 95% CI: 2.0–12.6) by multivariate analysis. Three cases of ≥ cervical intraepithelial neoplasia (CIN) 2 were identified in 3‐yr follow‐up in active HPV‐negative subjects. HPV genotypes in the dysplastic tissue were actually present at baseline samples after reanalysis. From the passive HPV‐negative group, only 1 case progressed to CIN2 probably after HPV acquisition. Negative Pap and HPV tests assured a very low risk of developing ≥ CIN2 within 3 yr despite incident HPV infection.