The clinical impact of age-specific distribution combination patterns of cytology &amp; high-risk HPV status in the background of cervical intraepithelial neoplasia grade3 or greater

doi:10.21203/rs.3.rs-1623416/v1

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The clinical impact of age-specific distribution combination patterns of cytology & high-risk HPV status in the background of cervical intraepithelial neoplasia grade3 or greater

https://doi.org/10.21203/rs.3.rs-1623416/v1

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Purpose:

This is the first study to elucidate the significance of cytology & high-risk Human Papillomavirus (hrHPV) status in different age groups for detection of cervical intraepithelial neoplasia grade 3 (CIN3) and squamous cell carcinoma (SCC).

Methods:

There were 12 combinations based on cytology & hrHPV status (Cytology; ASC-US, LSIL, ASC-H and HSIL, hrHPV status; HPV16/18 positive (16/18+), hrHPV other than 16/18 positive (others+) and hrHPV negative (hrHPV-)). All patients were divided into 4 groups based on age (18-29, 30-39, 40-49, 50-).

1) For CIN3 and SCC (CIN3+) patients (n=84), the distribution of cytology & hrHPV was investigated in each age group.

2) For all patients (n=446), the frequencies of CIN3+ for each of 12 combinations were investigated in each age group.

Results:

1) In the 18-29 group, HSIL & 16/18+ accounted for as high as 54.5% of CIN3+. The proportion of HSIL & 16/18+ decreased markedly with increasing age, and there were no cases in the years 50- group. Instead, ASC-US & others+ gradually increased with age, up to 25%.

2) In the 18-29 group, all patients in the HSIL & 16/18+ group were diagnosed as CIN3+. On the contrary, no patients in hrHPV- & HSIL were diagnosed as CIN3+.Such a clear distinction was not observed in any other age group.

Conclusion:

For CIN3+, the distribution patterns of cytology & hrHPV status combination significantly varied among the different age groups. Accordingly, the clinical impact of the combination of cytology findings & hrHPV status can vary among age groups.

HPV Human Papillomavirus

Cytology

Cervical Intraepithelial Neoplasia

Grade III

Squamous Cell Carcinoma

Cervical Cancer

HPV Vaccine

Cervical cancer is a common gynecological cancer not only in Japan but also worldwide(1–3). Squamous cell carcinoma (SCC) accounts for approximately 80% of cervical cancers(4). SCC of the cervix usually develops via the occurrence of cervical intraepithelial neoplasia (CIN), and CIN grade3 (CIN3) is thought to be the precursor(5, 6). To date, screening for CIN3 or SCC (hereafter CIN3+) is widely performed by cytology tests (7). For many years, the cytology has been the first choice for screening, and recently, the presence of high-risk human papillomavirus (hrHPV) has also been assessed because CIN3 + cancer can develop due to hrHPV infection(8). HPV16 and HPV18 are two major carcinogenic subtypes of hrHPV(9). Besides, there are several high-risk subtypes, including 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68, which are associated with a high frequency of cervical cancer development(10). As a result, tests for hrHPV infection are also widely used as a screening method(10).

The presence of an hrHPV infection does not always indicate the presence of CIN or cervical cancer. Therefore, it is necessary to combine hrHPV status findings with those of cytology tests. In addition, patient age is not currently considered in screening today. In Japan, cervical cancer occurs most frequently in the age group of 40 to 50 years. After the age of 50 years, the frequency of cervical cancer declines to some extent with age but remains unchanged in those over 60 years of age. In other words, there are many patients with SCC even in older age. There have been several reports that refer to the different distribution patterns of hrHPV subtypes and cytology among age groups(11–14). If there is some difference in the distribution of hrHPV and/or cytology results among age groups, the meaning of the cytology results & hrHPV status combination should vary among age groups. However, there have been few reports that comprehensively observed the cytological background and the hrHPV status of CIN3 + patients and examined the screening among different age groups in detail.

Here we performed this study to elucidate the significance of cytology results and hrHPV status in different age groups. First, we examined the cytology results and hrHPV status of CIN3 + patients in detail in different age groups. Furthermore, we evaluated the frequency of CIN3 + for each combination of cytology results & hrHPV status and examined their significance as a screening for CIN3 + would differ by age. In addition, we also evaluated the clinical impact of the HPV vaccination. In Japan, a public HPV vaccine program for the 13–16 year old generation began in 2010. By 2013, the vaccination rate for those generation in Japan was approximately 70% (15, 16). However, due to repeated media reports of various symptoms after HPV vaccination, the government announced the suspension of active recommendation of the vaccine in April 2013, leading to a decline in vaccination rates to less than 1%. Therefore, the 1994–1999 births are called the ''vaccination generation'', while vaccination rates in earlier generations are 0% and those in later generations are also very low (17). In this study, the '' vaccination generation '' corresponds to the 18–24 age group.

Study design and patients

This was a cross-sectional study that aimed to investigate the relationship among cytology results, hrHPV status and clinicopathological findings. The patient examination flow chart is shown in Fig. S1. We first included patients who underwent cytology tests and were diagnosed with ASC-US, LSIL, ASC-H or HSIL in our department between April 2016 and January 2019. For ASC-US cytologies, a qualitative hrHPV test was performed. If the test was positive, hrHPV typing tests and colposcopy-directed biopsy were performed. For LSIL, ASC-H and HSIL results, we performed hrHPV typing tests and colposcopy-directed biopsy together. Biopsy results were divided into malignancy (SCC), CIN3, CIN2, CIN1 and no malignancy. CIN3 and SCC were then defined as CIN3+.

Collection of clinical data and cytology & hrHPV results

The cytology results, hrHPV status and histopathological diagnoses were extracted from the patients’ medical records. A patient’s age and history of pregnancy and childbirth at the time of the examination were confirmed from the patient’s medical record or by interviewing the patient. Cervical cytology was performed with a cervix brush (Rovers Medical Devices B.V., the Netherlands) using the conventional method of applying the cells directly onto a glass slide. The cytology results were analysed and classified according to the Bethesda system (18).

The qualitative hrHPV assessment for patients with an ASC-US cytology was performed with a Cobas HPV test (Roche Diagnostics K.K., Tokyo, Japan). This test uses a real-time PCR method to measure the presence or absence of 14 subtypes of HPV (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68). The hrHPV typing test was performed using the PCR-rSSO method (MEVGEN HPV kit, MBL, Nagoya, Japan). The test results specified “positive for HPV16/18” and "positive for an HPV subtype other than 16/18”.

The pathological diagnosis of the biopsy specimens was determined in consultation with a gynecological oncologist (K.Y.) and a pathologist specializing in gynecology.

Statistical analysis

For continuous variables, the Mann-Whitney U test or one-way ANOVA test was performed, and for categorical data, Fisher's exact test was used. When comparing three or more groups, we first tested whether there was a significant difference in the overall distributions. If so, Bonferroni's correction for multiple comparisons was applied when comparing two groups. A P < 0.05 was considered to indicate a significant difference. GraphPad PRISM ver. 9.0 was used as the statistical software.

Age background among different findings of cytology, hrHPV status and pathology

A total of 446 patients with the following cytology findings were included in this study: ASC-US: n=310: LSIL: n=44: ASC-H: n=38: and HSIL: n=54. hrHPV status was divided into three groups: no hrHPV infection (hrHPV-): n=263: infection with hrHPV subtypes other than 16/18 (others+): n=137: and HPV 16/18 infection (16/18+): n=46. The age and frequency of multiparity in each group are described in Table 1

We then examined the age distribution for each cytological abnormality status and hrHPV infection status. there were significant differences in the age distribution among the four cytology findings groups (Table1, Supplementary Fig. S2a). Details were described in supplementary information. There were also significant differences in the age distribution among the three hrHPV status groups p<0.0001, Fig. 1a). In detail, the age of 16/18+ group was significantly younger than that of the hrHPV- and others+ groups (median age, hrHPV-: 47.0: others +: 43.0: 16/18+: 37.0, hrHPV- vs. others+; p=0.0008, vs. 16/18+; p<0.0001, others+ vs. 16/18+; p=0.01, respectively, Table 1, Fig. 1a). There was no significant difference in the age distribution among the histopathological findings (Supplementary Table S1, Supplementary Fig. S2b).

We then examined the influence of the HPV vaccine in detail. Because the HPV vaccination was performed mainly for young generation, we categorized the whole population by age, and calculated the percentages of the 16/18+ and others+ frequencies for each age group. The results are shown in Fig. 1b and c. As for 16/18+ frequency, which were more common in younger age groups, they were particularly high in the 25-39 age group, while clearly lower in the 18-24 age group (18-24: 8.3%, 25-29: 16.7%, 30-34: 23.9%, 35-39: 21.2%, Fig. 1b). On the other hand, others+ frequency was much higher in the 18-24 age group at 66.7%, while there was no clear difference among other age groups (Fig. 1c).

Comparison of hrHPV status in CIN3+ patients in different age groups

Next, we focused on CIN3+ (CIN3: n=76 and SCC: n=8) cases. We first examined hrHPV status and found significant differences in the age distribution among the three groups (p=0.0024, Fig. 2a). In detail, the age distribution of 16/18+ group was significantly younger than that of the others+ and hrHPV- groups (median age: 16/18+: 36.5 vs. others+: 43.0, p=0.035, vs. hrHPV-: 45.0, p=0.0029, respectively, Table 2, Fig. 2a).

We then evaluated the influence of the HPV vaccine. As before, we categorized the CIN3+ population by age and calculated the percentages of the 16/18+ and others+ for each age group. The results are shown in Fig. 2b and c. As for 16/18+ cases, 16/18+ frequency was especially high in the 25-39 age group, while it was apparently lower in the 18-24 age group at 0% (18-24: 0.0%, 25-29: 60.0%, 30-34: 50.0%, 35-39: 66.7%, Fig. 2b). On the other hand, there was completely different trend in the 18-24 age group, with the others+ frequency at 100%, compared to the 25-29, 30-34, and 35-39 age groups (25-29: 40.0%, 30-34: 35.7%, 35-39: 33.3%, Fig. 2c). In addition, others+ frequency tended to be higher in older age groups (40-44: 47.4%, 45-49: 53.8%, 50-54: 66.7%, 55-59: 100.0%, 60-: 55.6%, Fig. 2c).

Comparison of cytology in CIN3+ patients in different age groups

We also examined differences in background cytology findings and age distribution and found significant differences in the age distribution among the cytology findings (p=0.043, Fig. 3a). Next, we compared the distribution of cytology findings among the 84 CIN3+ patients by dividing the overall group into 4 groups (18-29: n=11, 30-39: n=26, 40-49: n=32 and 50-: n=15) based on age (Fig. 3b). In the 18-29 age group, the proportion of HSIL was prominently high at 81.8%, and much low in the 50- age group (0-39: 34.6%, 40-49: 43.8%, 50-: 26.7%, Fig. 3b). On the other hand, the proportion of ASC-US increased with age (18-29: 9.1%, 30-39: 23.1%, 40-49: 31.3%, 50-: 33.3%, Fig. 3b).

Comparison of cytology & hrHPV combinations in CIN3+ patients in different age groups

Since both the background cytology and hrHPV findings in CIN3+ differed significantly among years, we examined the correlation between cytology and hrHPV findings in each age group. There were 12 groups based on cytology & hrHPV combinations, and all patients with the 11 combinations (except for ASC-US & hrHPV-) were given a biopsy.　And we calculated the percentage of CIN3+ patients in each age group (Fig. 3c-f).

In the 18-29 age group, all cases of CIN3+ with 16/18+ were cytology HSIL (16/18+ & HSIL: 54.5%; 6 out of 11 patients, & ASC-H: 0.0%, & LSIL: 0.0%, & ASC-US: 0.0%, Fig. 3c), and more than half of others+ cases were also cytology HSIL(others+ & HSIL: 27.2%; 3 out of 11 patients, & ASC-H: 0.0%, & LSIL: 9.1%; 1 out of 11 patients, & ASC-US: 9.1%; 1 out of 11 patients, Fig. 3c). There was no hrHPV- case. This clear contrast was not seen in other age groups. Even in 16/18+ cases, cytology HSIL was found in less than half of the CIN3+ in the over 30 age group, and no cases in the over 50 age group. As for the case of others +, the number of cases with ASC-US cytology was higher than that with HSIL in the over 30 age group. Especially in the over 40 age group, ASC-US & others+ was the most common group in CIN3+ background (40-49: 25.0%; 8 out of 32 patients, 50-: 26.7%; 4 out of 15 patients, respectively, Fig. 3e, 3f). As for the hrHPV- cases, the cytology showed at least ASC-H.

A screening perspective; different clinical impacts of cytology & hrHPV combinations for each age group

Next, we investigated the viewpoints of screening. We examined how much the cytology findings or hrHPV status reflected the presence of CIN3+. Therefore, we compared the frequency of CIN3+ by cytology findings and hrHPV infection status in 232 patients who underwent histological examination. As expected, the frequency of CIN3+ was significantly different depending on the cytology findings and hrHPV status (p<0.0001, Supplementary Fig. S3a, S3b). In addition, CIN3+ was more precisely reflected by using a combination of cytology findings & hrHPV status (Supplementary Fig S3c). Details were described in supplementary information.

We however found that the cytology findings and hrHPV status in CIN3+ differed significantly among age groups. Therefore, we examined how much the cytology findings or hrHPV status reflected the presence of CIN3+ for each age group. We investigated the frequency of CIN3+ for the each of 12 groups that combined cytology findings and hrHPV infection status in each age group (Fig. 4).

In the 18-29 age group, the frequency of CIN3+ was clearly higher in HSIL & 16/18+ and HSIL & others+ than in other combinations (HSIL & 16/18+: 100%; 6 out of 6 patients, HSIL & others+: 42.9%; 3 out of 7 patients, Fig. 4a). On the other hand, CIN3+ was not detected in any of the cytology findings with hrHPV-. This clear contrast was characteristic of this age group.

In the 30-39 age group, a relatively high frequency of CIN3+ was found in 16/18+ cases regardless of cytology findings (16/18+ & HSIL: 80.0%; 4 out of 5 patients, & ASC-H: 83.3%; 5 out of 6 patients, & LSIL: 100%; 4 out of 4 patients, & ASC-US: 28.6%; 2 out of 7 patients, Fig. 4b). Also, the frequency of CIN3+ was relatively high in the case of cytology HSIL regardless of hrHPV status (HSIL & 16/18+: 80.0%; 4 out of 5 patients, & others+: 42.9%; 3 out of 7 patients, & hrHPV-; 66.7%; 2 out of 3 patients, Fig. 4b). On the other hand, CIN3+ was detected to some extent in others+ & ASC-US and & LSIL (19.0%; 4 out of 21 patients, 40.0%; 2 out of 5 patients, respectively, Fig. 4b).

This tendency was similar in the 40-49 age group, with a relatively high frequency of CIN3+ in cases of 16/18+ regardless of cytology findings (16/18+ & HSIL: 100%; 4 out of 4 patients, & ASC-H: 100%; 3 out of 3 patients, & LSIL: 0%; 0 out of 1 patients, & ASC-US: 50.0%; 2 out of 4 patients, Fig. 4c). The frequency of CIN3+ was also relatively high in the case of cytology HSIL regardless of hrHPV status (HSIL & 16/18+: 100.0%; 4 out of 4 patients, & others+: 83.3%; 5 out of 6 patients, & hrHPV-: 83.3%; 5 out of 6 patients, Fig. 4c). On the other hand, CIN3+ was detected to some extent in others+ & ASC-US, & LSIL (26.7%; 8 out of 30 patients, 22.2%; 2 out of 9 patients, respectively, Fig. 4c).

In the 50- age group, CIN3+ was detected to some extent in all combinations except for hrHPV- & LSIL (0%; 0 out of 3 patients, Fig. 4d). Unlike other age groups, there was no strong bias of CIN3+ frequency in cytology HSIL or 16/18+ cases.

In this study, we comprehensively analyzed the pathological status of cervical lesions for each combination of cytology & hrHPV status from the viewpoint of different age groups. To the best of our knowledge, this is the first report to examine the background cytology & hrHPV findings of CIN3 + in detail in different age groups.

First, we found that the background hrHPV types differed significantly among the age groups in not only whole population but also in the CIN3 + population. Specifically, younger patients had a greater involvement of HPV16/18 types, while older patients had more cases of hrHPV negativity.

Since we cannot ignore the influence of HPV vaccination for hrHPV infection status, we also evaluated it in this study. In Japan, large-scale vaccination started in 2010, mainly for 12–16 years old women. Those generation corresponds to 18–24 years old group in this study, and the 16/18 + frequency in this group is clearly lower than that in 25–39 age group in both the overall and CIN3 + population. Especially among CIN3+, there was no 16/18 + cases in 18–24 age group. Since we cannot check the vaccination history of each patient, we cannot prove a direct influence of HPV vaccine in each patient. It is estimated in epidemiological studies that about 70% of this generation has been vaccinated (15, 16). We can at least assume that the large-scale vaccination should have not a little influence on the apparent change in the 16/18 + frequency in 18–24 years group.

On the other hand, in the over 40 age group, the number of 16/18 + cases were low and others + cases accounted for more than half. hrHPV- cases were also found in the over 40 age group. Onuki et al. reported that the prevalence of HPV16/18 in CIN2-3 or SCC was highest in the 20–29 age group (SCC: 90% and CIN2-3: 53.9%), and SCC decreased with age to 56.3% and CIN2-3 decreased to 25.0% in the 60 + age group (19). Giannella et al. also reported that cases of CIN3 with hrHPV types other than HPV16/18 increased with age, with a significant difference when the age range was 30 and 45 years old (< 30: 23.6%, 30–44: 32.1%, > 45: 38.0%, p = 0.0004) (20). Our results are also consistent with those of previous reports. This suggests that vaccination which mainly covers HPV16/18 may not prevent the development of all cervical cancer throughout life. For this reason, it may be necessary to consider boost vaccination of the currently approved 9-valent vaccine.

Intriguingly, we also found that the cytology findings also differed significantly among the age groups as well as hrHPV status even in the CIN3 + population. It is possible that the difference in hrHPV associated with CIN3 + may have led to the differences in cytology findings. However, even with the same hrHPV background such as 16/18+, all cases of CIN3 + with 16/18 + were cytology HSIL in under 29 years old group, whereas no cases of CIN3 + with 16/18 + were cytology HSIL in over 50 years old group. We speculate that the difference of the time required for carcinogenesis can be the reason of the different of cytology findings among CIN3 + cases.

CIN3 + cases in under 29 years old group, who are mainly caused by persistent HPV16/18 infection, may require a relatively short time for their carcinogenesis, resulting in uniform characteristics (HSIL-dominant). On the other hand, in older CIN3 + cases, it is thought that the time required for carcinogenesis differs largely among cases. Therefore, the carcinogenesis background of CIN3 + is not as uniform as in younger patients, which may be reflected in the heterogeneous combination pattern of cytology findings & hrHPV status in elder age groups. There are several reports that refer to the correlation between age and prognosis in cervical cancer (21–24), which may indicate the difference in features of cervical cancer between in older patients and younger patients. Our findings of more heterogeneous cytological status in older CIN3 + patients may reflect its unique characteristics, which require a longer time from HPV infection to carcinogenesis.

From the perspective of screening for CIN3+, we first confirmed that cytology with HSIL or the presence of HPV16/18 is very important for suspecting the presence of CIN3+. In addition, we revealed the concrete frequency of CIN3 + for each cytology finding & hrHPV status combination. Our results should be clinically useful if physicians feel there is some discrepancy between cytology findings or hrHPV status and the histopathological findings. Taking our precise CIN3 + frequencies among each combination into account, they can consider whether further investigations should be planned.

Our study additionally suggests that age-specific perspectives are important for the screening of CIN3+. First, the significance of hrHPV status is relatively more important in younger patients. There was a very high frequency of CIN3 + in 16/18 + cases, and conversely, the frequency of CIN3 + was very low in hrHPV- cases. When we consider the indication of conization for young patients, their cytology findings and hrHPV status can be taken into account because conization is significantly related to a high incidence of preterm birth (25, 26). On the other hand, the distinction is not as clear in older patients as it is in patients under 29 years old. Nonetheless, in the 30–39 and 40–49 age groups, CIN3 + is detected in a relatively high frequency in 16/18 + cases regardless of cytology findings, and in cytology HSIL regardless of hrHPV status. However, this distinction gets unclear in over 50 years old group. In this age group, CIN3 + can be detected to some extent in all hrHPV & cytology combinations except for LSIL & hrHPV-. We should assume the presence of CIN3 + if there is some abnormality in the cytology or hrHPV findings in elderly patients. If there is any clinical suspicion, diagnostic conization can be considered more aggressively in elderly patients.

Since our study was a retrospective study in a single center, there are some limitations, including the number of cases and patients’ backgrounds. There are also reports that colposcopy-directed biopsies do not extract all CIN lesions (27, 28), so pathological assessment can be insufficient. However, since this was a single-center study, we believe that there is a consistency regarding the diagnostic criteria. In Japan, where the HPV vaccine has not progressed at all due to social factors and the population is aging rapidly, the early detection of cervical cancer is still extremely important. Based on our results, we can propose different screening protocols based on age, which can detect CIN3 + more efficiently.

In the current study, we first revealed the concrete frequency of CIN3 + for every combination of cytology & hrHPV status. In addition, the distribution of cytology & hrHPV status varied widely among different age groups. Furthermore, the meaning of each cytology & hrHPV status combination regarding CIN3 + can vary among age group. We believe that the results of this study are important for understanding the characteristics of elder cervical cancer patients.

Conflict of interest statement

All authors declare that they have no conflict of interest.

Author contributions All authors read and approved the final manuscript.

Sakai M: Project development, Data Collection, Data analysis, Interpretation of data, Manuscript writing/editing

Yamanoi K: Project development, Data analysis, Interpretation of data, Manuscript writing/editing

Matsumura N: Project development, Data analysis, Interpretation of data,

Sumitomo M: Project administration

Acknowledgements We would like to thank the patients who participated in this study and all the staff at the Department of Obstetrics and Gynecology, Toyooka Public Hospital for their cooperation

Funding No funding.

Author information

Affiliations

Department of Obstetrics and Gynecology, Toyooka Public Hospital, Hyogo, Japan

Mie Sakai, Tsutomu Ohara, Haruka Suzuki, Tatsuki Kadomoto, Yoshihide Inayama, Shimpei Shitanaka, Masahiro Sumitomo, Noriomi Matsumura & Koji Yamanoi

Department of Obstetrics and Gynecology, Shiga General Hospital, Shiga, Japan

Mie Sakai

Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan

Tsutomu Ohara, Haruka Suzuki, Yoshihide Inayama, Shimpei Shitanaka & Koji Yamanoi

Department of Gynecology and Obstetrics, Takamatsu Red Cross Hospital, Kagawa, Japan

Tatsuki Kadomoto

Department of Gynecology and Obstetrics, Kindai University Graduate School of Medicine, Osaka, Japan

Noriomi Matsumura

Corresponding author

Correspondence to Koji Yamanoi

Ethics approval and consent for participate In the present study, patients were not required to give informed consent for the study because we used anonymous clinical data that were obtained after each patient agreed to treatment by written consent. The design of this study was approved by the Ethics Committee of the hospital (Number: 226).

Consent to publish Not applicable.

Code availability Not applicable.

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Table1 Clinical background of patients; Age and proportion of multiparous in each cytology and hrHPV status

	number	Median age	(25%tile to 75%tile)	multiparous
Total	446	44	(36.0 to 53.0)	82.10%
Cytology
ASC-US	310	46	(39.0 to 56.0)	84.20%
LSIL	44	35.5	(30.0 to 46.5)	72.70%
ASC-H	38	46	(38.0 to 58.3)	76.30%
HSIL	54	39	(29.0 to 45.0)	81.50%
hrHPV^e status
Negative	263	47	(40.0 to 57.5)	84.80%
others+	137	43	(35.0 to 50.0)	78.10%
16/18+	46	37	(32.75 to 43.0)	80.40%

ASC-US: atypical squamous cells of undetermined significance;

LSIL: low grade squamous intraepithelial lesion;

ASC-H: atypical squamous cells cannot exclude HSIL;

HSIL: high grade squamous intraepithelial lesion;

hrHPV: high-risk human papillomavirus;

negative: no hrHPV infection;

others+: infection with hrHPV subtypes other than 16/18;

16/18+: HPV 16/18 infection

Table 2 Age background in each cytology and hrHPV status for CIN3+ patients

	number	Median age	(25%tile to 75%tile)
CIN3+ total	84	41	(33.0 to 47.0)
Cytology
ASC-US	22	42	(37.0 to 49.0)
LSIL	10	34.5	(33.25 to 45.0)
ASC-H	16	44	(36.25 to 57.75)
HSIL	36	40	(31.25 to 44.25)
hrHPV status
negative	12	45	(41.75 to 52.25)
others+	40	43	(36.0 to 49.5)
16/18+	32	36.5	(31.25 to 42.5)

CIN3+: CIN3 and SCC.

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The clinical impact of age-specific distribution combination patterns of cytology & high-risk HPV status in the background of cervical intraepithelial neoplasia grade3 or greater

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