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Keywords:

  • cervical intraepithelial neoplasia 2 (CIN2);
  • progression;
  • cervical cancer;
  • human papillomavirus;
  • genotyping

Abstract

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

We examined incidence probabilities of cervical intraepithelial neoplasia 3 (CIN3) or more severe lesions (CIN3+) in 1,467 adult Japanese women with abnormal cytology in relation to seven common human papillomavirus (HPV) infections (16/18/31/33/35/52/58) between April 2000 and March 2008. Sixty-seven patients with multiple HPV infection were excluded from the risk factor analysis. Incidence of CIN3+ in 1,400 patients including 68 with ASCUS, 969 with low grade squamous intraepithelial lesion (LSIL), 132 with HSIL without histology-proven CIN2 (HSIL/CIN2(−)) and 231 with HSIL with histology-proven CIN2 (HSIL/CIN2(+)) was investigated. In both high grade squamous intraepithelial lesion (HSIL)/CIN2(−) and HSIL/CIN2(+), HPV16/18/33 was associated with a significantly earlier and higher incidence of CIN3+ than HPV31/35/52/58 (p = 0.049 and p = 0.0060, respectively). This association was also observed in LSIL (p = 0.0002). The 1-year cumulative incidence rate (CIR) of CIN3+ in HSIL/CIN2(−) and HSIL/CIN2(+) according to HPV genotypes (16/18/33 vs. 31/35/52/58) were 27.1% vs. 7.5% and 46.6% vs. 19.2%, respectively. In contrast, progression of HSIL/CIN2(+) to CIN3+ was infrequent when HPV DNA was undetected: 0% of 1-year CIR and 8.1% of 5-year CIR. All cervical cancer occurred in HSIL cases of seven high-risk HPVs (11/198) but not in cases of other HPV or undetectable/negative-HPV (0/165) (p = 0.0013). In conclusion, incidence of CIN3+ depends on HPV genotypes, severity of cytological abnormalities and histology of CIN2. HSIL/CIN2(+) associated with HPV16/18/33 may justify early therapeutic intervention, while HSIL/CIN2(−) harboring these HPV genotypes needs close observation to detect incidence of CIN3+. A therapeutic intervention is not indicated for CIN2 without HPV DNA.

Cervical cancer is the third most commonly diagnosed cancer and the fourth most frequent cause of cancer death in women worldwide, with approximately 529,000 new cases and 275,100 deaths in 2008.1 Human papillomavirus (HPV) DNA is detected in most cervical cancers.2 More than 100 types of HPV have been identified, of which approximately 40 can infect the genital area including the cervix. Among them, 13–15 oncogenic types are thought to be responsible for most cases of cervical cancer.2–4 Cervical intraepithelial neoplasia (CIN) is a premalignant cervical disease caused by HPV infection. CIN contains a spectrum of lesions with different severity. Low-grade disease, CIN1, has minimal potential for progressing to cervical cancer. CIN2 and CIN3 are regarded as high-grade lesions. In the 2006 ASCCP guidelines for the management of women with CIN or adenocarcinoma in situ, treatment of CIN2/3 is recommended for adult women but not for adolescents.5 Because of the high risk of progression for both CIN2/3, and poor reproducibility of histological discrimination between the two CIN grades, CIN2/3 are managed in the same way. According to the guidelines, observation of CIN2/3 with sequential cytology and colposcopy is unacceptable, except in special circumstances such as in adolescent and young women, and treatment of CIN2/3 is not indicated during pregnancy. In adolescent and young women, either treatment or observation of CIN2 and CIN3 is acceptable, provided that the colposcopy result is satisfactory. When CIN2 is specified, observation is preferred. When CIN3 or adenocarcinoma in situ is specified, or the colposcopy result is unsatisfactory, treatment is recommended. In Japan, CIN2 lesions are usually followed up with repeated cytology and colposcopy in adult women as well as in adolescent and young women. This practice seems to be acceptable because around 40% of CIN2 regress spontaneously6 and conization is associated with adverse obstetrical outcomes.7 Regarding the natural history of CIN2, Ostör reported, on the basis of a literature review, that 20% of CIN2 progresses to CIN3 and 5% of CIN2 progresses to invasive cancer.8 As far as we could determine in our literature review, only a limited amount of data are available that report the HPV-related progression rate of CIN2 to CIN3 or more severe lesions (CIN3+). Meanwhile, Kataja et al. also reported that 20% of HPV-positive CIN2 progressed to CIN3 over a mean follow-up period of 45 months.9 Therefore, it is crucial to elucidate whether or not HPV genotyping is useful to screen patients with CIN2 for higher progression risk who would benefit from more intensive follow-up or therapeutic intervention. In Japan, this is of concern because the incidence of carcinoma in situ (CIS) and that of invasive cervical cancer are rapidly increasing among women aged ≤39 years.10 The oncogenic potential of HPV has been suggested to differ according to genotype.11 Persistent infection by oncogenic HPV, especially Type 16, has been shown to be associated with progression of a CIN lesion to a higher grade CIN.12 Of all oncogenic HPV types, Types 16 and 18 are the two most frequently detected HPVs in cervical cancer.13 The association between higher incidence of CIN3 in normal cytology or low-grade abnormal cytology (ASCUS/LSIL) with HPV 16 and 18 has been previously reported.14, 15 In contrast, Matsumoto et al. found that the incidence of CIN3 in mild abnormal cytology, and low-grade and moderate-grade CINs (LSIL/CIN1-2) for HPV16, −18, −31, −33, −35, −52 and −58 was significantly higher than other high- and low-risk types. However, they did not find a difference in CIN3 incidence probability among these seven oncogenic HPV genotypes.16 Consequently, in this study we aimed to clarify whether or not HPV genotyping is a useful tool to discriminate CIN2 patients who are at a higher risk for progression to CIN3+.

Material and Methods

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Study design

The study protocol was evaluated and approved by the institutional review board of Hokkaido University Hospital. Between April 2000 and March 2008, a total of 1,467 women with abnormal cytology (ASCUS, LSIL and HSIL) and no CIN3+ underwent HPV genotyping at the Cytology Center of Hokkaido Cancer Society. Among them, we found 67 cases with multiple HPV-type infection. The age distribution of the women was as follows: 59 women aged ≤29, 254 aged 30–39, 431 aged 40–49, 385 aged 50–59, 203 aged 60–69 and 68 aged ≥70. KK and HF provided histological diagnosis of biopsied specimens. The age of the women according to cytological abnormality was 50 years at median (range 22–78) for ASCUS, 49 (21–82) for LSIL and 46 (23–84) for HSIL. The follow-up period at median was 26 months and the range was 1–108 months.

Cervical cells were collected using a wooden extended-tip spatula, and cytology specimens were prepared using a conventional, non-liquid-based method. When the presence of CIN3+ was suspected, a biopsy was done under colposcopy. LSIL and HSIL without evidence of CIN3+ were followed up with repeated cytology at 3-month intervals and ASCUS at 6-month intervals. Each woman who needed to be followed up was informed by mail about the time of the next visit. If the woman did not appear for the next cytology, she was contacted by mail or by phone to encourage her to reschedule a visit to the Cytology Center. Histological evidence for the presence of CIN3+ was used as the endpoint of the study. Women who showed no abnormal cytological findings suggesting CIN in two consecutive visits exited the follow-up and returned for routine cytoscreening.

HPV genotyping

After written informed consent had been obtained, DNA was extracted from cells in the cytology specimens as previously described.17 We examined the seven types of oncogenic HPV (16, 18, 31, 33, 35, 52, 58) that are most frequently found in cervical cancer in Japan.18 HPV45 is quite rare in Japan, and, therefore, we did not perform genotyping for this HPV type. We used multiplex PCR with type-specific primers designed for the E6 and E7 regions19 for five of the seven types: Types 16, 18, 31, 52 and 58. Forward primer at E6 was as follows: Type 16, 5′-TGTATGTCTTGTTGCAGATCATCA-3′; Type 18, 5′-CCATTCGTGCTGCAACCG-3′; Type 31, 5′-GTATGGAACAACATTAGAAAAATTGAC-3′; Type 52, 5′-CTATTAGATGTATAATTTGTCAAACG-3′; and Type 58, 5′-ATGTAAAGTGTGCTTACGATTGC-3′. The combined use of these forward primers with the consensus reverse primer at E7 (E7CR3: 5′-TGAGCTGTCGCTTAATTGCTC-3′) enabled the identification of each HPV type from the size of the PCR amplicons after agarose gel electrophoresis. The PCR conditions were as follows: the mixture was denatured for 5 min at 95°C, then alternately cycled for denaturation at 95°C, annealing at 55°C and extension at 72°C for 30 sec periods over 35 cycles, followed by a final extension at 72°C for 7 min using a GeneAmp 9600 PCR System (Applied Biosystems, Foster City, CA).

We examined Types 33 and 35 by using the PCR-RFLP method. When type-specific PCR was negative, we performed PCR using two types of consensus primer sets designed for the E6 and E7 regions to amplify HPV DNA. The first primer set included pU1-M (forward: 5′-TGTCAAAAACCGTTGTGTCC-3′) and pU2-R (reverse: 5′-GAGCTGTCGCTTAATTGCTC-3′) reported by Fujinaga et al.19 The second primer set was E6CF4 (forward: 5′-ATTCTGTGTATGGAGAAACATTAGAA-3′) and E7CR3 (reverse: 5′-TGAGCTGTCGCTTAATTGCTC-3′) reported by Yamaguchi et al.17 We performed PCR first with pU-1M and pU-2R. The PCR conditions were as follows: denaturation for 30 sec at 94°C, annealing for 2 min at 55°C and extension for 30 sec at 72°C for 30 cycles followed by a final extension at 72°C for 7 min. We digested the amplicon with Ava I and Ava II. When the amplicon was cut by Ava I, the detected HPV was Type 35; when it was cut by Ava II, it was Type 33. When PCR using pU-1M and pU-2R gave negative results, we then performed PCR using E6CF4 and E7CR3 to confirm the negative results.

We classified the HPV status into three groups. We grouped the seven oncogenic HPV types (16, 18, 31, 33, 35, 52, 58) as prevalent-type (pt)-HPV. We designated any other high-risk HPV DNA for which we could not determine the genotype as un-genotyped (ug)-HPV. If we did not find any HPV DNA, we classified the case as having undetectable/negative-HPV (ud/n-HPV).

Statistical analysis

The Kaplan–Meier method was used to calculate the cumulative incidence rate (CIR) with pathological diagnosis of CIN3+ as the event. Women who were lost to follow-up and who exited the follow-up because of regression were censored at their last visit. The time to progression to or incidence of CIN3+ was compared between the categorized groups using the Mann–Whitney U-test. The difference between the cumulative incidence curves was compared using the log-rank test. Hazard risk for incidence of CIN3+ was evaluated using Cox regression analysis. Statistical significance was set at p < 0.05. All statistical analyses were carried out using the StatView J (version 5.0, SAS Institute Japan, Tokyo, Japan) software package.

Results

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Distribution of HPV genotypes

Regarding the 1,467 cases that included multiple HPV infection, HPV DNA, either pt-HPV or ug-HPV, was detected in 43.4% (637/1,467) of the cases. Multiple HPV DNA were detected in 67 cases (two types of HPV DNA in 65 cases and three types in two cases). The overall detection rates of HPV DNA in ASCUS, LSIL and HSIL were 32.4%, 33.6% and 70.9%, respectively. Regarding each HPV genotype, HPV16 was most frequently detected (11.7%), followed by HPV52 (10.0%), −58 (8.0%), −31 (4.4%), −18 (2.4%), −33 (0.9%) and −35 (0.5%). Each genotype in double and triple HPV infections was counted separately two or three times. ug-HPV was detected in 10.2% of the cases.

HPV genotypes and CIN3+ incidence

To minimize a possible dilution effect when comparing risk factor profiles, we excluded the 67 cases with multiple HPV infection from the risk factor analyses. As a result, the analytical cohort included 1,400 women composed of 68 ASCUS cases, 969 LSIL cases and 363 HSIL cases (Fig. 1). The HSIL cases included 132 cases without histology proven CIN2 (HSIL/CIN2(−)) and 231 cases with histology-proven CIN2 (HSIL/CIN2(+)). The 5-year CIRs of CIN3+ in ASCUS, LSIL, HSIL/CIN2(−) and HSIL/CIN2(+) were 0%, 5.7%, 23.9% and 50.6%, respectively (Table 1). Table 2 shows the result of a Cox multivariate regression analysis of risk factors for incidence of CIN3+. Younger age (≤39 years), severe cytological abnormality (HSIL) and each high-risk HPV type were independent risk factors for the incidence of CIN3+. When we compared the HRs between the two groups of seven pt-HPVs that were divided sequentially in order of the HR magnitude obtained by the Cox multivariate regression analysis, we found that the difference was largest and most statistically significant between the subgroup containing HPV16/18/33 and the subgroup containing HPV31/35/52/58 (HR: 1.6, 95% CI: 1.1–2.2, p = 0.0066) (Fig. 2).

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Figure 1. Study design.

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Figure 2. Incidence risk of CIN3+ according to high-risk HPV types.

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Table 1. HPV status and incidence/progression rates to CIN3+ from LSIL, HSIL without histology-proven CIN2, and HSIL with histology-proven CIN2
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Table 2. Multivariate Cox regression model of risk factors for progression to CIN3+ among 1400 women with ASCUS/LSIL/HSIL
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Among 969 cases of LSIL, 23 developed CIN3+ and no cervical cancer was observed. The incidence ratio of CIN3 by HPV status was 17/89 (19.1%) in HPV16/18/33, and 5/118 (4.2%) in HPV31/35/52/58. There was only one CIN3 case among 762 ug-HPV or ud/n-HPV cases. CIN3 occurred in the HPV16/18/33 subgroup at a significantly higher CIR than in the HPV31/35/52/58 subgroup in LSIL cases (p = 0.0002) (Fig. 3).

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Figure 3. Cumulative incidence curves to CIN3+ in LSIL cases by HPV status. The seven prevalent HPV types were stratified into HPV16/18/33 and HPV31/35/52/58.

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Among 363 HSIL cases either with or without histology-proven CIN2, there were 140 CIN3 cases and 11 cases of cervical cancer, which included 10 microinvasive and one small (<2 cm) stage IB1 invasive cancer during the follow-up period. The incidence rate of CIN3+ in HSIL cases was higher in patients with pt-HPV and ug-HPV than in patients with ud/n-HPV (p < 0.0001). Management of CIN2 was our special concern and we wanted to clarify whether HPV genotype is related to progression of CIN2 to CIN3+ or not. Among 231 HSIL/CIN2(+) cases, 119 progressed to CIN3+, 92 regressed, 14 showed no change and 6 were lost to follow-up. The baseline age distribution of 119 patients with CIN2 who developed CIN3+ was 23–77 years (median: 44 years). The number of women aged 39 years or under was 77 out of 231 (33.3%) patients with CIN2. There were 35 incidences of CIN3+ and one incidence of invasive cancer among them. We also observed three incidences of CIN3 in 11 women aged 29 years or under. We compared the risk of progression to CIN3+ for HSIL/CIN2(+) cases between HPV16/18/33 and HPV31/35/52/58. CIN3+ occurred in the HPV16/18/33 subgroup significantly earlier and at a higher CIR than in the HPV31/35/52/58 subgroup with a p-value of 0.0060 (Fig. 4). The 1-year CIR from CIN2 to CIN3+ was as high as 46.6% for HPV16/18/33 compared with 19.2% for HPV31/35/52/58 and 0% for ug-HPV (Table 2). Median time for progression from CIN2 to CIN3+ in HPV16/18/33, HPV31/35/52/58 and ug-HPV was 12 months, 28.5 months and 48 months. The HPV16/18/33 subgroup developed CIN3+ significantly earlier than the HPV31/35/52/58 subgroup (p = 0.0040). Regression was observed in 39.8% of HSIL/CIN2(+) cases. The regression ratio by HPV status was 7/45 (15.6%) in HPV16/18/33 and 21/93 (22.6%) in HPV31/35/52/58. The regression ratio 61/69 (88.4%) in undetectable/negative-HPV cases was significantly higher than that in HPV16/18/33 and HPV31/35/52/58 (p < 0.0001).

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Figure 4. Cumulative progression curves to CIN3+ from HSIL with histology-proven CIN2 by HPV status. The seven prevalent HPV types were stratified into HPV16/18/33 and HPV31/35/52/58.

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Even in the absence of histological evidence for CIN2, we frequently observed incidence of CIN3+ in HSIL cases with HPV16/18/33, which showed increased 1- and 5-year CIRs at 27.1% and 47.0%, respectively. There was a significant relationship between incidence of CIN3+ and high-risk HPV subgroups in HSIL/CIN2(−) (p = 0.049).

Cervical cancer occurred only in HSIL cases. All cervical cancer occurred in cases of seven high-risk HPV types (11/198) but not in cases of other HPV types or undetectable/negative-HPV (0/165) (p = 0.0013). The HPV types associated with cervical cancer were HPV16 (4/50), HPV18 (3/13), HPV52 (2/58) and HPV58 (2/50). Notably, three cases of cervical cancer occurred in HSIL/CIN2(−) when HPV16/18 was positive (one with HPV16 and two with HPV18). HSIL with HPV16/18, even in the absence of histological diagnosis of CIN2, should be observed carefully. The ratio of cervical cancer incidence in cases of HPV16 and 18 (7/63 = 11.1%) was higher than in cases of the other five HPV genotypes (4/135 = 3.7%). There was a statistically significant difference between the two groups (p = 0.026).

Discussion

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

The distribution of oncogenic HPV genotypes in female population-based samples varies among different geographical regions, although HPV16 is the most common type in most continents.20 It is notable that HPV45 is quite rare in Japan. Onuki et al. reported no cases of Type 45 among 342 patients with normal cytology, 281 patients with CIN1, 291 with CIN2/3 or 131 with invasive cervical cancers.18 Similar findings were reported in Korea and China, where HPV33, −52 and −58 are more common.18, 21, 22 Therefore, we did not genotype for HPV45, and the present study is limited by a lack of data on HPV45. Another potential limitation of this study is that the study population did not include women with normal cytology.

The detection rate of high-risk HPV determined by PCR reported in the literature is 17.9%23 and 53%24 for ASCUS, 33.3%,25 55.5%24 and 72.4%26 for LSIL, and 57.1%,25 81.7%26 and 87.5%24 for HSIL. The detection rate in this study, 33.6% for LSIL and 70.9% for HSIL, seems to be relatively low. The detection rate of high-risk HPV can vary because of differences in the PCR method used27 and the definition of high-risk HPV. For instance, regarding LSIL cases, a meta-analysis in Japan showed a detection rate of high-risk HPV as high as 72.4%.26 However, the definition of high-risk HPV in that meta-analysis included 18 HPV types (16/18/26/31/33/35/39/45/51/52/53/56/58/59/66/68/73/82). If the definition is limited to seven prevalent types (16/18/31/33/35/52/58), the detection rate decreases to 43.2%, which is not largely different from the rate in this study. We focused on the seven prevalent types of high-risk HPV in Japan.18 Our results demonstrated that the presence of a subgroup of prevalent HPV types (16/18/33) indicates a higher risk of incidence/progression to high-grade CIN and cervical cancer than other HPV types (31/35/52/58), which is contrary to a recently published paper from Japan.16 Matsumoto et al. reported that these seven oncogenic HPV types have a higher risk for the incidence of CIN3+ in LSIL/CIN1-2 lesions compared with other oncogenic HPV types in Japan.16 They observed that the occurrence risk of CIN3 in LSIL cases for HPV16 and 18 was not different from that of other oncogenic HPV types (31, 33, 35, 52, 58). On the contrary, Khan et al. reported that HPV16 and −18 in negative, equivocal and mildly abnormal cytology were associated with a higher risk for incidence of CIN3+.14 The results of the present study suggested that there are differences in risk of earlier incidence of CIN3+ among the high-risk oncogenic HPV types, which indicates that some grouping of oncogenic HPV types might be useful for more effective CIN2 management. We found that HPV16/18/33 were associated with higher risk of CIN3+. However, the actual number of women with HPV18 or −33 infection was only 35 (2.4% of 1,467 cases) and 13 (0.9%), respectively. A low detection rate of these two types of HPV has been previously reported in Japanese women. The reported HPV18 detection rate was 0%,28 4.0%16 and 4.8%29 in low-grade CIN/LSIL and 2.2%,29 2.8%28 and 4.7%16 in high-grade CIN/HSIL. The HPV33 detection rate was 1.2%,28 1.4%29 and 1.9%16 in low-grade CIN/LSIL and 0.7%,29 4.1%16 and 5.6%28 in high-grade CIN/HSIL. Therefore, our HPV type-specific detection rates correspond with those of previous studies. Because the number of positive cases for each high-risk HPV type was relatively small, the 95% confidence intervals of the CIN3+ incidence HRs were rather wide and comparisons of the HRs between each HPV type hardly found statistical significance. For this reason, we conducted a comparison by categorizing the HPV types into two groups. By doing so, the 95% CIs for the two groups became narrower and we could find a statistically significant difference in the HRs between the groups, as shown in Figure 2. The similar method was used in a recent study.16

The role of multiple HPV infection in the progression of CIN and cervical carcinogenesis has been a matter of concern. However, because the effect of multiple HPV infection has not been fully elucidated, we excluded women with multiple HPV type infection from the analyses to avoid a possible dilution effect in the risk factor analysis. Some investigators found a positive relationship between multiple HPV type infection and progression of CIN.30 However, other investigators could not find a relationship between multiple HPV type infection and CIN or cervical cancer.16, 31 In the current study, multiple high-risk HPV type infection was not related to progression to CIN3+ (data are not shown).

CIN2 diagnosis has poor reproducibility. As such, we need to have a prudent treatment plan for this diagnosis. In Japan, we usually employ expectant management for CIN2 using cytology, colposcopy and biopsy. On the other hand, some other countries often manage CIN2 and CIN3 similarly. Following the ASCCP 2006 consensus guidelines,5 the American College of Obstetricians and Gynecologists (ACOG) addressed recommendations for the management of CIN, in which non-pregnant women 21 years and older with CIN2 or CIN3 can be treated by either excision or ablation.32 It was also recommended that for adolescents and pregnant women with CIN2 or CIN3, either observation with colposcopy, or treatment with excision/ablation is acceptable. In treating women of reproductive age with conization, we need to recognize that there exist post-surgical cervical stenosis33 and obstetrical risks7 after this intervention. We would be able to construct an individualized algorithm for CIN2 management if the risk of progression to CIN3+ from CIN2 could be predicted by HPV genotyping. The present study has shown that the risk of early progression from CIN2 to CIN3+ is related to HPV genotype. The 1-year cumulative progression rate of CIN2 with HPV16/18/33 was as high as 46.6%, which is remarkable compared with HPV31/35/52/58 and ug-HPV at the rates of 19.2% and 0%, respectively. Because of the high risk of progression to CIN3+ in HPV16/18/33-positive CIN2, this lesion may require earlier surgical intervention than other CIN2. Two additional points are to be noted: (1) any high-risk HPV-positive CIN2 is associated with a significant ultimate risk of CIN3+ at longer observation intervals irrespective of the HPV genotype found; (2) HSIL with HPV16/18/33 is associated with a significant incidence risk of CIN3+ even if a colposcopy-guided biopsy did not reveal histological evidence of CIN2, in which the 1-year CIR of CIN3+ was as high as 27.1%. The former observation seems to correspond to a previous report that the risk of cervical cancer for any given high-risk HPV type is not different from others. Munoz et al. showed that the type-specific odds ratio for cervical cancer seemed different among various high-risk HPV types, but the difference was not statistically significant because of the wide 95% confidence intervals. Because cervical cancer is the ultimate form of progression of cervical epithelial neoplasia, our observation does not contradict their findings, but we would like to emphasize the possibility that there may be type-specific differences in progression speed from mild intraepithelial lesions to higher grade intraepithelial lesions and cervical cancer.

Regarding invasive cervical cancer, the HSIL cases with HPV16/18 developed lesions more frequently compared with the other HPV genotypes in this study. This observation corresponds to the notion proposed by Franceschi and Clifford, which was based on the HPV type-specific prevalence reported in their three systematic reviews.34 They showed that only HPV16 and −18 are more frequently found in invasive cervical squamous cell carcinoma (SCC) compared with HSIL and LSIL, and HPV33 and −45 are found at approximately equal frequencies in SCC and LSIL. It is likely that the oncogenic HPVs possess similar potency to make cellular changes to HSIL from LSIL, but HPV16 and −18 have a more potent oncogenic property to convert CIN to invasive cancer compared with other oncogenic HPVs. Therefore, although the current study showed that HPV16/18/33 had a higher risk for CIN3+ occurrence, the presence of HPV16 and −18 would be the most serious risk factor for CIN2 progression to invasive cancer.

The proportion of young women included in this study was rather small. Women aged 39 years or under accounted for 22.4% of the cohort. In 1982, the Japanese Government enacted the Health and Medical Service Law for the Aged, which then recommended annual screening for women aged 30 years and over. In 2004, the law was revised, and biannual screening for women aged 20 years and over was initiated. The screening rate for cervical cancer in Japan as of 2010 is reported to be only 24.3%, which is very low compared with other developed countries.35 Furthermore, only a few young women participate in cervical cancer screening programs: 10.2% of women aged 20–24 years, and 24.2% of those aged 25–29 years,36 which may explain the increase in incidence and mortality among young women.10 These situations explain the small proportion (22.4%) of young women aged 39 years or under in this study cohort. Although it is difficult to draw definitive conclusions owing to the small number of young patients in our study, therapeutic intervention may be justified for young women with CIN2 who are positive for HPV16/18/33 because we observed 35 incidences (46.8%) of CIN3 and one cervical cancer in 77 women aged 39 years and under with this condition.

In conclusion, the pace and the cumulative rate of incidence of CIN3+ in women with cytological abnormalities and CIN2 depend on HPV genotype. HPV genotyping is a useful predictor of the risk of CIN3+ incidence in women with abnormal cervical cytology and CIN.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

The supporting organization played no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. Authors (M.H., H.F., S.H., T.S., Y.S., M.A., M.K., M.K., H.W., K.K., N.S.) declare that they have no conflict of interest relevant to this article.

References

  1. Top of page
  2. Abstract
  3. Material and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References