In Australia, approximately 300 women are diagnosed as having invasive vulvar cancer each year, and 79 women died of the disease in 2009.1 Squamous carcinoma of the vulva, which comprises approximately 83% of these vulvar cancers,2 is known to be of mixed etiology. The keratinizing histopathologic type generally occurs in elderly women and is often associated with lichen sclerosus and/or differentiated vulvar intraepithelial neoplasia. The warty or basaloid type is generally seen in younger women. It has been associated with sexually transmitted human papillomavirus (HPV) infection and is often characterized by the presence of “usual type” vulvar intraepithelial neoplasia in association with the invasive component.3–5 Human papillomavirus DNA is found in approximately 40% of vulvar cancers overall.6,7 Human papillomavirus type 16 is associated with most of these, with the next most frequent HPV types being 18 and 33.5,6
Human papillomavirus is associated with a number of cancers, including cancers of the oropharynx and anus in both sexes, cancer of the penis in men, and cancers of the cervix, vagina, and vulva in women. A number of prior analyses in developed countries have documented increases in the overall rates and/or the HPV-attributable fraction of HPV-related cancers of the anogenital tract and oropharynx over the past 20 years. It has been proposed that both the overall increase in rates and the increase in the HPV-attributable fraction of these cancers are due to increasing exposure to HPV in younger cohorts.8,9 For example, a 2010 Australian analysis found that the incidence of cancers of the anus and oropharynx had increased significantly in both men and women over the 2 decades prior.10 Although no significant change in the overall age-standardized incidence of vulvar cancer was identified in this prior analysis, we hypothesized that if such a change occurred, it would be evident only in younger women. Therefore, the aim of the current study was to perform a more detailed analysis of trends in vulvar cancer in Australia in women of different age groups, to determine if there was evidence of an increasing incidence in younger cohorts born after 1950 (ie, <60 years in 2010), consistent with increased exposure to HPV over time. We also aimed to characterize any changes in mortality rates from vulvar cancer in women of different age groups.
MATERIALS AND METHODS
This analysis of vulvar cancer incidence was based on all histologically confirmed cases of invasive carcinoma of the vulva diagnosed in Australia between 1982 and 2009; data were obtained from the Australian Institute of Health and Welfare National Cancer Statistics database.1 The analysis for mortality included all verified vulvar cancer deaths for the period 1982 to 2011; mortality data were obtained on request from the Australian Institute of Health and Welfare National Mortality Database. Because of very small numbers of deaths from vulvar cancer in younger women (and thus concerns about small cell size and the implications for privacy), the mortality data were supplied as aggregate data over calendar years 1982 to 1986 and then in 5-year intervals up to 2007 to 2011, and in age strata from 0 to 54 years and then in 5-year age groups up to 85+ years.
Human Research Committee Ethics approval was not required for this study because we collated and analyzed publicly available aggregate data.
Age-standardized incidence and mortality rates were determined using the Australian 2001 Standard Population for standardization. We then calculated standardized rate ratios (SRRs) as the ratio of the average standardized rate at the end of the period relative to the average rate at the beginning of the period and 95% confidence intervals for the SRRs using Poisson approximation.11 Because of differences in data availability, we used 3-year averages from 2007 to 2009 and from 1982 to 1984 for incidence SRRs, and 5-year averages from 2007 to 2011 and from 1982 to 1986 for mortality SRRs, to yield measures of changes in rates from 1982 to 2009 for incidence and from 1982 to 2011 for mortality. For incidence, we also calculated the annual percent change (APC) using Joinpoint analysis, restricting analyses to a maximum of 1 Joinpoint over the period.12,13 We could not calculate APCs for mortality because data were supplied in 5-year aggregated blocks.
From 1982 to 2009, 5715 cases of invasive vulvar cancer were diagnosed in Australia. Figure 1A shows the incidence rates for vulvar cancer over time in Australia in specific decile age groups, and Figure 1B shows rates stratified by age groups <60 years and 60+ years. As shown in Tables 1 and 2, age-standardized incidence rates in women across all ages did not significantly change from 1982–1984 to 2007–2009 (from 2.1 to 2.5 per 100,000 women; SRR from the later to the earlier period, 1.13 [95% CI 1.00–1.27]), although there was a statistically significant increase noted in the average APC over the period (APC, 0.5%; P = 0.02). During the same period, there was a significant 84% increase in the incidence rates in women younger than 60 years (0.7–1.2 per 100,000 women; SRR, 1.84 [95% CI 1.49–2.26]; APC, 2.5%; P < 0.001) but no change in incidence for women 60+ years (9.4–9.0 per 100,000 women; SRR, 0.90 [95% CI, 0.79–1.04]; APC, −0.4%; P = 0.1). Results were broadly similar when we stratified by less than 70- and 70+-year age groups (data not shown).
From 1982 to 2011, 1586 deaths from invasive vulvar cancer occurred in Australian women. Figure 2A shows the mortality rates for vulvar cancer over time in Australia for women younger than 60 years and for each decile age group in older women, and Figure 2B shows the rates stratified by ages <60 years and 60+ years. As shown in Tables 1 and 2, age-standardized mortality in women across all ages significantly decreased by 22% from 1982–1986 to 2007–2011 (from 0.7 to 0.5 per 100,000 women; SRR, 0.78 [95% CI 0.66–0.93]). However, this was driven by declines in older women—rates in women 60+ years decreased by 24% (SRR, 0.76 [95% CI 0.63–0.91]), whereas rates in women younger than 60 years were stable (SRR, 1.05 [95% CI 0.62–1.79]).
We identified distinctive and differing trends in incidence and mortality rates for invasive vulvar cancer in women of different age groups in Australia. In women younger than 60 years, we found an 84% increase in the incidence of invasive vulvar cancer for 3 decades, whereas in older women, no change in incidence rates was observed. By contrast, mortality rates have remained stable in younger women and decreased by 24% in older women. The major strengths of our analysis are the use of national population-based data and the relatively long reporting period (covering 27 years). The detailed analysis by age group, for both incidence and mortality, is, to our knowledge, the first such comprehensive study of trends in vulvar cancer in Australia. A limitation of this study is that detailed information on histologic type, stage, treatment, and hospital is not routinely available in cancer registries in Australia. Because this study examined national trends using cancer registry data, we were unable to analyse according to these factors at a national, population-based level.
Our results for trends in incidence are broadly comparable to the few available long-term analyses of population-based trends in other countries. Our findings of a 2.5% average increase per year in Australian women younger than 60 years and stable incidence in older women over the last 3 decades are comparable, for example, to those from a review of vulvar squamous cell carcinoma registrations from the Danish Cancer Registry. For the period 1978 to 2007, they found an average 1.6% (95% CI, 0.5%–2.7%) annual increase in incidence in women younger than 60 years, but stable incidence in women 60+ years.14 A Dutch study of trends in squamous vulvar cancer over the period 1989 to 2010 also identified a comparable average annual increase in incidence in women younger than 60 years of 3.5% (95% CI, 2.0–4.9)15; this study also identified increasing incidence in women 60+ years, but only from 2004 onward. A recent study in England reported an increase in the incidence of invasive vulvar cancer in women aged up to 70 years since 1990; in this study, a decrease in incidence for women 80 years or older was identified over the same period.16
Analysis of in situ and invasive vulvar carcinomas from the US Surveillance Epidemiology and End Results database, which considered cases diagnosed over the period 1973 to 2004, also identified an increase in vulvar cancer incidence.17 An annual increase in invasive vulvar cancer of 1.0% (95% CI, 0.6%–1.4%) across all age groups was identified (as was an increase in in situ cancers of 3.5% [95% CI, 2.9%–4.1%]); the authors concluded that the effects were seen across all ages, although detailed analysis for specific age groups was not presented. A more recent analysis of population-based data from the United States and Canada showed an increased incidence of invasive squamous cell vulvar cancer over the period 1973 to 2010 in the United States and 1992 to 2008 in Canada.18
Although not population based, a number of single institutional reviews have also identified an increasing presentation of younger women with vulvar cancer.19,20 For example, a retrospective chart review of patients with vulvar cancer presenting to a university hospital in Germany from 1980 to 1989 compared with 1998 to 2007 found that the number of women treated for vulvar squamous cell carcinoma had nearly doubled, and the percentage of women aged 50 years or younger had increased 4-fold (11.3% vs 41.2%).19
Our findings of an increased vulvar cancer incidence in younger women are consistent with data from other developed countries but diverge somewhat from international trends in elderly women (>70 years). If cohort effects and HPV exposure underlie the observed findings, some of the differences in the findings for elderly women are likely to, at least partly, reflect differences in population behavior in the past and the timing of the analysis in relation to cohort age and HPV exposure. More recent analyses are more likely to identify changes in rates in older women because these will reflect birth cohorts more likely to have been exposed to HPV infection. In addition, there may be geographic differences in the HPV-attributable fraction in vulvar cancers.
Recent analyses have identified changing trends in other HPV-related cancers. For example, in the United States, the incidence of oral squamous cell carcinoma has increased over time,8 and the HPV-attributable fraction in cancers of the oropharynx has increased from 16% in 1984 to 1989 to 72% from 2000 to 2004.9 Rates of oropharyngeal cancers have also increased in Australia over the period 1982 to 2005,10 with a corresponding increase in the HPV-attributable fraction in these cancers in both sexes.21 Rates of anal cancers in both males and females have also increased in the United Kingdom between 1960 and 200422 and in Australia from 1982 to 2005.10
Our results for vulvar cancer incidence are consistent with, but build upon, a previous analysis of trends in vulvar cancer incidence in Australia, which identified no change in rates of vulvar cancer incidence overall.10 When we used the SRR as a measure of the change in incidence, we also identified no significant change when trends were considered across women of all ages. When the APC was used as a measure and given that we had access to an additional four years of data compared with the previous study, we did identify a significant trend in the APC. Our findings extend those from the earlier Australian study by identifying distinct trends by age group and by also identifying trends in mortality rates.
It is not possible to predict the future trends in incidence rates of vulvar cancer because these depend on a range of underlying factors including past and future exposure to risk factors and the uptake of the HPV vaccine by the community. However, assuming rates stay at those identified in the current study (ie, at around the rates observed in 2009–2011), population growth and aging are expected to drive increases in the overall case numbers for vulvar cancer. Using projections for population aging from the Australian Bureau of Statistics, if current rates are maintained, the burden of disease is expected to grow by 42% to 413 cases in 2030, and the number of deaths is expected to grow by 39% to 97 deaths in 2030. Over the longer term, HPV vaccination is expected to somewhat counteract this effect.
Our findings for trends in vulvar cancer mortality are broadly consistent with other studies internationally. We observed a significant decrease in mortality for women 60+ years, which drove an overall observed decrease in mortality across all ages. A population-based study in England also reported a significant decrease in mortality for women aged 60+ years between 1990–1994 and 2006–2010.16 Consistent with this, recent analyses of vulvar cancer data from the United States (for the period 1973–2010) and Canada (1992–2008) have demonstrated an increase in 2- and 5-year relative survival ratios for all age groups, and particularly for women 80 years and older.18 However, other population-based studies from the Netherlands have reported stable mortality rates for vulvar cancer.15,23
Over the past 30 years, surgery for vulvar cancer has become less radical, with more emphasis on vulvar conservation for the primary lesion and unilateral groin dissection for unilateral malignancies.24–26 An institutional review of 175 American patients treated between 1990 and 2005 found survival among the lower-risk group was preserved, despite the less radical surgery, and the 5-year survival rates for patients with advanced vulvar cancer improved. The authors concluded that younger women presenting with less advanced disease and the widespread introduction of adjuvant (chemo)radiation were likely to have been critical in reducing recurrence rates and improving overall survival from vulvar cancer.24
The decreasing mortality rates that we observed in older women may also reflect earlier diagnosis. Although past generations of women have been reluctant to present with vulvar problems, better access to health information on the Internet and changing social mores have meant that most women present with relatively small lesions that are amenable to surgical resection. In addition, the treatment for women in specialized gynecologic oncology centres, as is advocated by Australian national guidelines, has likely contributed to the improvements in mortality.23 The stable mortality rates that we observed in women younger than 60 years may reflect the fact that younger women are more likely to present with early-stage disease, which has a more favorable prognosis, and most recurrences are localized to the vulva and have a high cure rate, usually with further excision.25
In conclusion, we found that the incidence of vulvar cancer has substantially increased in Australian women younger than 60 years. Although an ecologic analysis of the type presented here cannot demonstrate causality, this increase is consistent with findings from other developed countries and also with the likely timing of increasing levels of population exposure to HPV due to changing sexual mores in women born from the 1950s onward. Because most HPV-related vulvar cancers are caused by HPV types 16 and 18, which are included in first-generation HPV vaccines, the introduction of HPV vaccination in Australia in 2007 is expected to provide current generations of young women with a level of protection against developing vulvar cancer as they age. We have also demonstrated that the mortality rate for older women has significantly decreased over the same period, despite a more conservative approach to management. This is presumably related to earlier stage at diagnosis and possibly better centralization of care.
We thank the Australian Institute of Health and Welfare National Cancer Statistics Database for providing data for this study. K.C. receives salary support from the National Health and Medical Research Council Australia and from Cancer Institute NSW. We thank Megan Smith for repeating and checking the statistical calculations presented here.
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