Trends in age-standardized incidence rates of cancers of HPV-related cancer sites in Osaka, Japan: 1977–2019

Abstract

The trends in cancers of Human papillomavirus (HPV)-related cancer sites in Japan are insufficiently reported. We evaluated the long-term trends of them as a baseline before the effects of HPV vaccine introduction became apparent in Japan. This retrospective, population-based study used data from the Osaka Cancer Registry to analyze 39,349 cases between 1977 and 2019. For women, the ASIRs were particularly high for cervical cancer. For squamous cell carcinoma, the ASIR changed from a decrease (from high to low) to an increase (from low to high) around 2000, although the trend for females aged 40–59 has recently showed no significant change. The trend in ASIR for adenocarcinoma also shifted from an increase to no significant change in the 40–59 age group, but increased consistently in the ≤ 39 age group. Vaginal cancer exhibited no significant change, while cancers of the oropharynx, anus, and vulva have increased. For men, cancers of the oropharynx and anus consistently increased. Squamous cell carcinoma of the anus decreased from 1997 to 2004, but then increased thereafter. Similarly, penile cancer decreased from 1977 to 1995, but then increased. Future studies will observe how this trend changes as groups with high HPV vaccination rates reach cancer-susceptible ages.

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-026-50914-3.

Introduction

Cervical and oropharyngeal cancers are the two most common cancers caused by human papillomavirus (HPV) infection. Cervical cancer occurs in approximately 530,000 cases per year worldwide, whereas oropharyngeal cancer mainly affects men and occurs in approximately 30,000 cases per year worldwide¹. High-risk HPV types are the primary cause of cervical cancer and vaginal, vulvar, penile, and anal cancers^2,3. The prevalence of HPV types in different cancers depends partly on ethnicity, geographic location, tumor histology, and HPV detection methods. In 2020, The World Health Organization launched an ambitious strategy to eliminate HPV-caused cervical cancers worldwide by promoting universal HPV vaccination⁴.

Japanese public subsidy program for HPV vaccination began in fiscal year (FY) 2010 for women aged 13–16 years. The vaccination rate for women born between FY 1994 and FY 1999 reached somewhere between 55 and 80%⁵. In FY 2013, it was extended to include women aged 12–16 years. However, serious post-vaccination symptoms were repeated in the media soon after the program started. Two months later, the Ministry of Health, Labor and Welfare (MHLW) announced a ‘temporary suspension’ of its active recommendation for the HPV vaccine. The impact of media reports and the withdrawal of the recommendation led to a precipitous decline in HPV vaccination rates across Japan. Only 14% of those born in FY 2000 and only 1% of those born in FY 2001 were vaccinated in FY 2013^5,6.

It was not until 8 years later, in November of FY 2021, that the MHLW finally decided to end the suspension and restart proactive recommendation of the HPV vaccine. In an effort to compensate for the lost opportunities that created an 8-year cohort of mostly unvaccinated women, a ‘catch-up immunization program’ began in FY 2022, running until March 2025.

In this study, we aim to understand the trends of cancers of HPV-related cancer sites up to the era of HPV vaccine introduction and dissemination in Japan. This will enable estimation of the impact of the introduction and cessation of the HPV vaccine and to plan countermeasures.

Materials and methods

Study design

A trend analysis of cancers of HPV-related cancer sites was conducted using the Osaka Cancer Registry database, which contains information on the diagnosis and treatment of all cancers occurring in Osaka Prefecture, Japan. Cases registered from 1977 to 2019 with the following International Statistical Classification of Diseases and Related Health Problems (ICD)-10 codes were defined as cancers of HPV-related cancer sites: cervical cancer (C53), oropharyngeal cancer (C01, C02.4, C05.1-2, C09.0-1, C09.8-9, C10.0, C10.2-3, and C10.8-9), anal cancer (C21), vulvar cancer (C51), vaginal cancer (C52), and penile cancer (C60)⁷.

Setting

Upon application we received approval to use the Osaka Cancer Registry data in accordance with the Act on Promotion of Cancer Registry. We also obtained written permission from the Osaka Prefectural Government to use its data for research purposes. Osaka Prefecture has a population of approximately 8.8 million, accounting for approximately 7% of Japan’s total population.

Hospitals and authorized clinics provided information on all cancer cases occurring in Osaka Prefecture to the Cancer Registry Office at the Osaka International Cancer Center, which registered this information. Specifically, we applied to use the following data: sex, age at diagnosis, and ICD-O-3 code 3rd Edition (International Classification of Diseases for Oncology), ICD-10 code, date of diagnosis, occasion of cancer detection, staging classification, treatment method, life and death classification, and survival date.

The histological type of cancer was determined using the morphology code of the ICD-O3M. Cases registered as 8052, 8070, -73, 8075, 8076 and 8082-84 were classified as squamous cell carcinoma (SCC). Cases registered as 8140, 8144, 8147, 8200, 8210, 8211, 8215, 8255, 8260, 8261, 8263, 8266, 8380, 8384, 8430, 8440, 8470 and 8480-82 were classified as adenocarcinoma. Histological classification was harmonized according to the ICD-O-3 codes provided by the Osaka Cancer Registry, which retrospectively standardized earlier cases. Data quality over time was assessed using the proportions of microscopically verified cases (MV%) and death certificate only cases (DCO%) (Supplementary Table).

Statistical analysis

The ASIR was calculated per 100,000 population. We calculated the ASIRs by cancer type, age group, and histological type. The Japanese model population of 1985 was used as the standard population. We used the Joinpoint 4.8.0.1 package by which the number and location of the ASIR inflection points (Joinpoints) were determined⁸, and the annual percent change (APC) between Joinpoints was calculated. The minimum and maximum numbers of Joinpoints was set at zero and three, respectively, referencing a similar past study⁹, and we used Stata MP 17 software. The Y-axis scale varies depending on the disease.

In the analysis by age, the patients were classified into three groups: ≤ 39 years old, middle-aged between 40 and 59, and ≥ 60 years, or into two groups: ≤ 59 years old and ≥ 60 years old. The two-group categorization was specifically for vulvar cancer cases. For vulvar cancer, most cases in the older age group of women are composed of lichen sclerosis, which is not caused by HPV. We therefore categorized the cases of vulvar cancer into two groups: those occurring in the younger/middle-aged group, most of which were HPV-positive, and those in the older group, most of which were not HPV-negative.

Results

Basic characteristics of study population: number of incidences of the cancers of HPV-related cancer sites in women and men

The characteristics of the subjects analyzed are shown in Table 1. Over 43 years, there were 39,349 cases of cancers of HPV-related cancer sites in Osaka Prefecture. There were 32,995 cases among women, and just 6353 cases in men, so there were approximately five times more cases among women than in men. Among women, cervical cancer was significantly more frequently observed, accounting for 28,784 cases, which was 87.2% of all cancers of HPV-related cancer sites in women overall. Among men, oropharyngeal cancer was the most common, with 4486 cases, which was 70.6% of all cancers of HPV-related cancer sites in men overall.

Table 1.

Basic characteristics of the study targets: the case number of the cancers of HPV-related cancer sites in women and men.

	1977–1982		1983–1988		1989–1994		1995–2000		2001–2006		2007–2012		2013–2018		2019		Total
	n	%	n	%	n	%	n	%	n	%	n	%	n	%	n	%	n	%
HPV-related cancer (all)
< 39	695	13.7	609	12.0	463	9.1	476	9.4	726	14.4	911	18.0	1,047	20.7	138	2.7	5,065	100.0
40–59	2,731	18.1	2,375	15.8	1,724	11.4	1,524	10.1	1,671	11.1	2,095	13.9	2,513	16.6	445	3.0	15,078	100.0
60 <	2,080	10.9	2,214	11.5	1,905	9.9	2,015	10.5	2,357	12.3	3,392	17.7	4,421	23.0	805	4.2	19,189	100.0
Unknown	0	0	0	0	0	0	1	5.9	1	5.9	8	47.0	6	35.3	1	5.9	17	100.0
Total	5,506	14.0	5,198	13.2	4,092	10.4	4,016	10.2	4,755	12.1	6,406	16.3	7,987	20.3	1,389	3.5	39,349	100.0
HPV-related cancer (male)
< 39	15	17.1	16	18.2	4	4.6	7	7.9	16	18.2	17	19.3	12	13.6	1	1.1	88	100.0
40–59	85	5.3	140	8.7	189	11.7	236	14.6	278	17.2	275	17.0	347	21.5	64	4.0	1,614	100.0
60 <	150	3.2	248	5.3	271	5.8	445	9.6	642	13.8	1,068	23.0	1,528	32.9	296	6.4	4,648	100.0
Unknown	0	0	0	0	0	0	0	0	0	0	2	66.7	1	33.3	0	0	3	100.0
Total	250	4.0	404	6.4	464	7.3	688	10.8	936	14.7	1,362	21.4	1,888	29.7	361	5.7	6,353	100.0
HPV-related cancer (female)
< 39	680	13.7	593	11.9	459	9.2	469	9.4	710	14.3	894	18.0	1,035	20.8	137	2.7	4,977	100.0
40–59	2,646	19.6	2,235	16.6	1,535	11.4	1,288	9.6	1,393	10.4	1,820	13.5	2,166	16.1	381	2.8	13,464	100.0
60 <	1,930	13.3	1,966	13.5	1,634	11.2	1,570	10.8	1,715	11.8	2,324	16/0	2,892	19.9	509	3.5	14,540	100.0
Unknown	0	0	0	0	0	0	1	7.1	1	7.1	6	43.0	5	35.7	1	7.1	14	100.0
Total	5,256	15.9	4,794	14.5	3,628	11.0	3,328	10.1	3,819	11.6	5,044	15.3	6,098	18.5	1,028	3.1	32,995	100.0
Oropharynx (all)
< 39	7	8.1	12	13.7	5	5.8	12	13.8	19	21.8	14	16.1	18	20.7	0	0	87	100.0
40–59	62	4.0	106	6.9	161	10.4	197	12.7	264	17.0	304	19.6	385	24.9	70	4.5	1,549	100.0
60 <	88	2.2	156	4.0	218	5.6	350	8.9	507	12.9	957	24.4	1,364	34.7	288	7.3	3,928	100.0
Unknown	0	0	0	0	0	0	0	0	0	0	1	100.0	0	0	0	0	1	100.0
Total	157	2.8	274	4.9	384	6.9	559	10.1	790	14.2	1,276	22.9	1,767	31.8	358	6.4	5,565	100.0
Oropharynx (male)
< 39	5	10.4	9	18.8	2	4.2	6	12.5	8	16.7	10	20.8	8	16.6	0	0	48	100.0
40–59	45	3.7	90	7.5	133	11.0	171	14.1	205	17.0	227	18.8	282	23.3	55	4.6	1,208	100.0
60 <	71	2.2	126	3.9	183	5.7	307	9.5	417	12.9	789	24.4	1,107	34.3	229	7.1	3,229	100.0
Unknown	0	0	0	0	0	0	0	0	0	0	1	100.0	0	0	0	0	1	100.0
Total	121	2.7	225	5.0	318	7.1	484	10.8	630	14.0	1,027	22.9	1,397	31.2	284	6.3	4,486	100.0
Oropharynx (female)
< 39	2	5.1	3	7.7	3	7.7	6	15.4	11	28.2	4	10.3	10	25.6	0	0	39	100.0
40–59	17	5.0	16	4.7	28	8.2	26	7.6	59	17.3	77	22.6	103	30.2	15	4.4	341	100.0
60 <	17	2.4	30	4.3	35	5.0	43	6.2	90	12.9	168	24.1	256	36.7	59	8.4	698	100.0
Total	36	3.3	49	4.6	66	6.1	75	7.0	160	14.8	249	23.1	369	34.2	74	6.9	1,078	100.0
Anus (all)
< 39	8	18.2	7	15.9	3	6.8	5	11.4	6	13.6	9	20.5	6	13.6	0	0	44	100.0
40–59	33	7.8	35	8.2	55	13.0	64	15.1	76	17.9	61	14.3	89	20.9	12	2.8	425	100.0
60 <	70	4.4	117	7.3	115	7.1	183	11.4	277	17.2	323	20.0	452	28.1	73	4.5	1,610	100.0
Unknown	0	0	0	0	0	0	0	0	0	0	1	50.0	1	50.0	0	0	2	100.0
Total	111	5.3	159	7.6	173	8.3	252	12.1	359	17.3	394	19.0	548	26.3	85	4.1	2,081	100.0
Anus (male)
< 39	5	21.7	4	17.4	0	0	1	4.4	4	17.4	6	26.1	3	13.0	0	0	23	100.0
40–59	16	6.6	17	7.1	33	13.8	40	16.7	54	22.5	31	12.9	43	17.9	6	2.5	240	100.0
60 <	26	3.4	56	7.2	49	6.3	84	10.8	140	18.0	145	18.6	238	30.6	40	5.1	778	100.0
Total	47	4.5	77	7.4	82	7.9	125	12.0	198	19.0	182	17.5	284	27.3	46	4.4	1,041	100.0
Anus (female)
< 39	3	14.3	3	14.3	3	14.3	4	19.0	2	9.5	3	14.3	3	14.3	0	0	21	100.0
40–59	17	9.2	18	9.7	22	11.9	24	13.0	22	11.9	30	16.2	46	24.9	6	3.2	185	100.0
60 <	44	5.3	61	7.3	66	7.9	99	11.9	137	16.5	178	21.4	214	25.7	33	4.0	832	100.0
Unknown	0	0	0	0	0	0	0	0	0	0	1	50.0	1	50.0	0	0	2	100.0
Total	64	6.2	82	7.9	91	8.7	127	12.2	161	15.4	212	20.4	264	25.4	39	3.8	1,040	100.0
Penis
< 39	5	29.4	3	17.6	2	11.8	0	0	4	23.5	1	5.9	1	5.9	1	5.9	17	100.0
40–59	24	14.5	33	19.9	23	13.8	25	15.1	19	11.5	17	10.2	22	13.2	3	1.8	166	100.0
60 <	53	8.3	66	10.3	39	6.1	54	8.4	85	13.3	134	20.9	183	28.5	27	4.2	641	100.0
Unknown	0	0	0	0	0	0	0	0	0	0	1	50.0	1	50.0	0	0	2	100.0
Total	82	9.9	102	12.4	64	7.7	79	9.5	108	13.1	153	18.5	207	25.1	31	3.8	826	100.0
Cervix
< 39	672	13.8	582	12.0	448	9.2	448	9.2	689	14.2	879	18.1	1,009	20.7	134	2.8	4,861	100.0
40–59	2,570	20.4	2,153	17.1	1,444	11.5	1,190	9.5	1,266	10.1	1,660	13.2	1,946	15.5	347	2.7	12,576	100.0
60 <	1,747	15.4	1,741	15.4	1,384	12.2	1,249	11.0	1,248	11.0	1,633	14.4	1,992	17.5	348	3.1	11,342	100.0
Unknown	0	0	0	0	0	0	0	0	1	20.0	2	40.0	2	40.0	0	0	5	100.0
Total	4,989	17.3	4,476	15.6	3,276	11.4	2,887	10.0	3,204	11.1	4,174	14.5	4,949	17.2	829	2.9	28,784	100.0
Vulva
< 39	1	4.0	1	4.0	4	16.0	4	16.0	4	16.0	4	16.0	6	24.0	1	4.0	25	100.0
40–59	19	9.9	23	12.0	16	8.3	22	11.5	26	13.5	30	15.6	45	23.5	11	5.7	192	100.0
60 <	90	7.6	87	7.4	88	7.5	109	9.3	171	14.5	248	21.0	332	28.2	54	4.5	1,179	100.0
Unknown	0	0	0	0	0	0	0	0	0	0	1	25.0	2	50.0	1	25.0	4	100.0
Total	110	7.9	111	7.9	108	7.7	135	9.6	201	14.4	283	20.2	385	27.5	67	4.8	1,400	100.0
Vagina
< 39	2	6.5	4	12.9	1	3.1	7	22.6	4	12.9	4	12.9	7	22.6	2	6.5	31	100.0
40–59	23	13.5	25	14.7	25	14.7	26	15.3	20	11.8	23	13.5	26	15.3	2	1.2	170	100.0
60 <	32	13.5	47	9.6	61	12.5	70	14.3	69	14.1	97	19.8	98	20.1	15	3.1	489	100.0
Unknown	0	0	0	0	0	0	1	33.3	0	0	2	66.7	0	0	0	0	3	100.0
Total	57	8.2	76	11.0	87	12.6	104	15.0	93	13.4	126	18.2	131	18.9	19	2.7	693	100.0

Trend in ASIR of cancers of HPV-related cancer sites by cancer site in women and men

The results of Joinpoint analysis on ASIRs for each cancer of HPV-related cancer sites in women and men from 1977 to 2019 are shown in Fig. 1. For women, the ASIR was particularly high for cervical cancer. However, since 2015, cervical cancer has exhibited no significant change after a period of increase. Vaginal cancer demonstrated no significant change between 1977 and 2019, while cancers of the oropharynx, anus, and vulva increased between 1996 and 2019, between 1977 and 2019, and between 1997 and 2019, respectively, with no cancer sites showing a decreasing trend. Among men, we observed an increase in cancers of the oropharynx, anus, and penis between 1977 and 2019, between 1977 and 2019, and between 1995 and 2019, respectively.

Fig. 1.

Age-standardized incidence rate (ASIR) of cancers of HPV-related cancer sites by cancer type in women and men.

The results for all 39,349 cancers of HPV-related cancer sites cancers diagnosed between 1977 and 2019 were similar to those for the 32,995 female cases from between 1977 and 2016 (Supplementary Fig. 1). In women, the trend remained unchanged from 2016 to 2019, but in men, there was a consistent and significant increase. The increase from 2001 to 2019 was more pronounced than the increase from 1997 to 2001 (APC = 4.2, 95% CI  + 3.5 to + 5.0 vs. 1.7, 95% CI + 0.9 to + 2.5, respectively).

The ASIR of oropharyngeal cancer was increasing in Japanese men consistently throughout the 43 year period, but only began to increase in women in 1996 (Supplementary Fig. 2). However, the ASIR for men was overwhelmingly higher than for women. Significant difference was not observed between men and women in the other cancers.

Trend in ASIR of cervical cancer by age group and histological type

The results of Joinpoint analysis on ASIRs by age group for cervical cancers divided into SCC and adenocarcinomas from 1977 to 2019 are shown in Fig. 2. For SCC, the ASIR shifted from decline to increase in 1998 for the under 39 and the middle-aged groups, and in 2002 for the older group. In adenocarcinoma, as in SCC, only the trend in the middle-aged group has leveled off since 2007. Adenocarcinoma is consistently increasing in patients under 39 years of age, while the ASIR significantly increased only between 1997 and 2007 for those aged 40 to 59, and only after 1993 for those aged ≥ 60.

Fig. 2.

ASIR of cervical cancer by age group and histological type.

Trend in ASIR of anal cancer by histological types for both sexes

The results of Joinpoint analysis on ASIRs by histological types for anal cancers from between 1977 and 2019 are shown in Fig. 3. Most HPV-positive anal cancers are SCC, so anal cancer was classified as SCC or ‘other histological types’. The trend of SCC in anal cancer decreased between 1997 and 2004 (APC = − 1.4, 95% CI − 3.4 to + 0.7) but then increased between 2004 and 2019 (APC = 0.9, 95% CI + 0.2 to + 1.6).

Fig. 3.

ASIR of anal cancer by histological types for both sexes.

Trend in ASIR of vulvar cancer by age group

The results of Joinpoint analysis on ASIRs by age group for vulvar cancers from 1978 to 2019 are shown in Fig. 4. Excluding the year 1977, when there were zero cases of vulvar cancer reported, the trend exhibited no significant change at low level from 1978 to 1995 in the younger group (≤ 59 years old) (APC =  − 3.8, 95% CI − 8.2 to + 0.8). Then, from 1995 to 2019, there was a significant increase (APC = 5.8, 95% CI + 3.7 to + 7.9).

Fig. 4.

ASIR of vulvar cancer by age group.

Discussion

We analyzed the trends of cancers of HPV-related cancer sites that were reported within Osaka Prefecture, Japan, from between 1977 and 2019. Regional cancer registries in Japan have been compiled for many years at the regional level, with prefectures and some cities as the implementing entities. Hospitals and authorized clinics had provided information on all cancer cases occurring in Osaka Prefecture to the Cancer Registry Office at the Osaka International Cancer Center, which registered that information and also collected death information from local governments (municipalities). Annual accuracy assessments of the Osaka Cancer Registry ensure compliance with international standards. The percentage of registrations by death certificate information only (DCO) among all the patients, which is a qualitative accuracy measure, is required internationally to be less than 10%. A high DCO percentage means that there is a leakage of registration from medical institutions, suggesting that the number of incidents may be estimated to be smaller than it is. A lower DCO percentage in the number of incidents suggests a higher reliability of the cancer diagnoses. The DCO percentage for all cancers (excluding epithelial cancers) in the Osaka Cancer Registry in 2019 was only 1.9%. Among new cancer registries, those whose cancer diagnosis was confirmed by contacting a medical institution in a retrospective survey are considered death certification initiated (DCI), which is an indicator of quantitative accuracy (completeness index). The DCI rate for all cancers (excluding epithelial cancer) in the Osaka Cancer Registry in 2019 was only 2.6%.

Based on the large and long-term population-based cancer registry data, we observed that the ASIR of cervical cancer initially decreased, then increased, and subsequently showed no significant change in the 40–59 age group. However, it is important to note that adenocarcinoma, which is less commonly detected by screening and which responds less well to treatment than SCC, has consistently increased among those ≤ 39 years of age. In oropharyngeal cancer, the trend of consistent increase in men and recent increasing trend among women may be a concerning indicator of future increase in cases. SCC of anal cancer and vulvar cancer in those < 59 years of age has also shifted from no significant change to increase and should be noted. No significant changes have been observed in vaginal cancer.

Changes in trends of cancers of HPV-related cancer sites might be attributed to differing smoking rates and changes in sexual activity. The significant decrease in cervical cancer incidence in all age groups since 1977 might be attributed to improved environmental sanitation and the introduction of cervical cancer screenings. In our hypothesis, widespread condom use may partly explain the decline in cervical cancer trends. However, factors contributing to the significant increase in cervical cancer trends among women in their 30 s, 40 s, and 50 s since around 2000 may include increased sexual activity and higher smoking rates which are the risk factors of cervical cancer^10–12. Adolescent sexual activity increased from the 1970s to around 2000, and smoking rates doubled slowly from the 1960s to around 2000¹³. From the 1960s to around 2000, smoking rates in people in their 20 s and 30 s slowly doubled¹⁴.

It was only in the middle-aged group (40–59 years) that we observed trend shift from increase to no significant change of the ASIR by age group after 2012. We compared the calculated trends of cervical SCC in the period following the introduction of the national HPV vaccination program (Supplementary Fig. 3a). The year 2012 is only three years after the government first approved the HPV vaccine for private use, and self-funded HPV vaccination rate was shown to be low¹⁵. Meanwhile, the development of cervical cancer usually takes more than 10 years from the time of infection due to the long-term process of cervical intraepithelial neoplasia development¹⁶. A study based in the United States reported the observation that HPV vaccination contributed to a significant reduction in cervical SCC in young women aged 20–24 within the relatively short six years of the FDA approval of the HPV vaccine¹⁷. However, the changes in ASIR we found in the middle-aged group of Japanese women in our analysis, which shifted from increase to no significant change, are thought to be unlikely to due to the effect of the HPV vaccine because it was not approved until 2009. We examined trends in cervical adenocarcinoma in relation to the time period following the introduction of the national HPV vaccination program (Supplementary Fig. 3b). After 2007, trend shifted from increase to no significant change in the ASIR was observed in the middle-aged group (40–59 years old). However, the trend changed before governmental approval, so we do not consider this to be a reduction effect due to HPV vaccination.

This trend shift of cervical cancer rates among women in their 40 s and 50 s in recent years may be due to the gradual decline in smoking rates among women in their 20 s and 30 s since around 2000. Recently, sexual activity is also thought to have declined, which is expected to influence future cervical cancer trends. It will take several more years before the reduction in ASIR of cervical cancer achieved by the HPV vaccine is confirmed in Japan.

Differences in trends among cancer types may be due to the proportion of HPV contribution to each cancer and the distribution of HPV types. HPV causes 7–8% of all human malignancies and is associated with 96% of cervical cancers, 93% of anal cancers, 64% of vaginal cancers, 51% of vulvar cancers, 36% of penile cancers, and 63% of oropharyngeal cancers^18–20. Two of the 12 highest-risk HPV types, type 16 and type 18, account for 70% of cervical cancers worldwide and about 60% in Japan²¹. Type 16 is detected in 70–90% of oropharyngeal cancers²². As sexual activity, smoking rates, and HPV distribution vary from country to country, it is possible that the trend for each cancer may also differ in part from country to country. The different ages at which each cancer is most prevalent may lead to different trends in the incidence of each cancer. For instance, cervical cancer peaks in the 40 s, but anal cancer peaks in the 60 s, suggesting that the trend change of cervical cancer may occur earlier than that for anal cancer.

In Japan, the HPV vaccine is not yet available for men as part of a routine and subsidized immunization program. Consequently, few men have received the vaccine, creating a potential reservoir for HPV infections. Although the incidence rates of cancers of HPV-related cancer sites are lower among men than women, there has been a remarkable increase in the cancers of HPV-related cancer sites among men in Japan. For women, the HPV vaccination-related governmental recommendations have been resumed and catch-up vaccination has begun, but the efficacy of the HPV vaccine has not yet been confirmed. In order to obtain compelling evidence, with real world data, the effectiveness of the HPV vaccine in preventing cervical cancer in Japan, future trends must be closely monitored.

This strength of this study lies in its analysis of a large, quality-assured, population-based, long-term cancer registry database. However, even with such large-scale data, subgroup analyses based on factors such as age or histological type result in smaller sample sizes, so statistically robust results may not have been obtained, particularly for rare cancers. Furthermore, as this is a long-term analysis spanning 43 years from 1977 to 2019, there may be potential biases, such as changes in trends in screening rates of cervical cancer and in accuracy of diagnosis, and improvement of registration of cancer cases during that period. Moreover, based on a previous similar study⁹, we set the minimum joinpoints to 0 and the maximum to 3, though it is unclear whether this is optimal. In addition, there are still several limitations. The Osaka Prefecture Cancer Registry has high coverage, but not all cancer cases are necessarily registered. Despite the use of MV% and DCO% as indicators of data quality, residual misclassification and temporal changes in registration practices cannot be excluded. Japan’s universal health insurance system likely results in an extremely high treatment rate, yet there may still be cervical cancer patients who did not seek treatment. Moreover, the cancers of HPV-related cancer sites were analyzed in the present study, and the analyzed data did not include information on HPV infection status. Nevertheless, by examining changes in trends by cancer type, age, and histological type, we were able to reasonably estimate the long-term trends of each HPV-related cancer site. This study observed only the trends in ASIR across Osaka Prefecture. Since it did not include individual-level data on HPV infection, sexual activity, or smoking status, the ASIRs of cancers caused by confirmed HPV infection remain unknown, and the impact of sexual activity and smoking as factors influencing changes in incidence rates is also uncertain. There also may be a possibility that trend change in ASIR is attributed to the cohort effect based on birth year.

In conclusion, the trend of cancers of HPV-related cancer sites among men and women in Osaka Prefecture increased. In the future, it will be important to observe how this trend changes as groups with high HPV vaccination rates reach cancer-susceptible ages and as the HPV vaccine becomes more widespread in Japan. Most importantly, it is hoped that the HPV vaccine will become widespread in Japan.

Abbreviations

ASIR

Age-standardized incidence rate

APC

Annual percent change

CI

Confidence interval

HPV

Human papillomavirus

FY

Fiscal year

Author contributions

Asami Yagi: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Validation, Visualization and Writing—original draft. Sayaka Ikeda: Methodology and Writing—review & editing. Atsuko Sakakibara: Methodology and Writing—review & editing. Yuri Ito: Conceptualization, Methodology and Writing—review & editing. Tomio Nakayama: Conceptualization and Supervision. Yumi Ota: Methodology and Writing—review & editing. Eiji Kobayashi: Conceptualization & Supervision. Kayo Nakata: Data acquisition, Writing—review & editing. Toshitaka Morishima: Data acquisition, Writing—review & editing. Isao Miyashiro: Data acquisition, Writing—review, editing & Supervision. Yutaka Ueda: Conceptualization, Funding acquisition, Investigation, Methodology, Project administration, Resources, Visualization and Writing—review & editing, Supervision. All authors have discussed the results and have contributed to and agreed with the final manuscript.

Funding

A Health and Labour Sciences Research Grant (23EA1002) from the MHLW and AMED Grant (Number 24ck0106XXXh000X) supported this research.

Data availability

The data that support the findings of this study are available from Osaka Prefectural Government but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of Osaka Prefectural Government. Data can be obtained by submitting an application for use at the following link: https://oici.jp/ocr/data/datause_guide.html.

Declarations

Competing interests

AY and YU have each previously received a lecture fee from Merck Sharp & Dohme (MSD). The remaining authors do not have any competing interests to declare.

Ethical approval

This study was conducted according to the principles of the Declaration of Helsinki, and was approved by the Ethics Committee of the Osaka University Hospital.