Our study on a large group of patients with vulvar SCCs (201 cases), with regard to cervical (pre)malignancies, showed that 9% of all patients with available cytology of the cervix had a smear suggestive for a HSIL. Divided between the two pathways, 35% of the patients with uVIN-related vulvar SCCs had a smear suggestive for a HSIL, compared with only 2% of patients whose vulvar SCC was dVIN related (P
<0.001). For uVIN-related SCCs, this is a more than 10-fold incidence compared with the overall incidence of a HSIL in The Netherlands (Vereniging Integrale Kankercentra, 2009). In 19% (n
=7) of the total 37 patients with a uVIN-related vulvar SCC, a histologically proven cervical HSIL or SCC was found during a follow up of 20 years. Moreover, all of these uVIN-related vulvar SCCs and cervical lesions in the same patient showed the identical hrHPV type. These identical hrHPV types were seen in vulvar SCCs and cervical lesions even after an interval of more than 10 years. This may be one long-standing infection or a new infection with the exact same type of virus. Particularly as less common types were found as well, a long-standing infection is most likely. Furthermore, if a patient's immune system is not able to clear a hrHPV infection, that patient is thought to be more prone to develop multicentric (pre)malignancies. In most cases, the cervical lesion preceded the vulvar SCC, although vulvar SCCs preceding cervical lesions were seen as well. The difficulty is whether the date of diagnosis accurately reflects the origin of the lesions. It may well be possible that these lesions had initially been asymptomatic and present for a longer period before diagnosis. Our data suggest that the identical long-standing hrHPV infection is causing these multicentric (pre)malignancies. This emphasises the concept that a patient with a hrHPV-related ano-genital (pre)malignancy is at a higher risk to develop another hrHPV-related (pre)malignancy. We previously reported that 41% of uVIN patients had a past, simultaneous or future HPV-induced cervical, vaginal or anal lesion (van de Nieuwenhof et al, 2009a
). Unfortunately, in this cohort of vulvar SCC patients, we were not able to retrieve data about other multicentric sites of the lower female ano-genital tract prone to hrHPV infection. This higher risk to develop other hrHPV-related (pre)malignancies obliges us to differentiate between dVIN and uVIN lesions followed by a precise examination of the entire lower female ano-genital tract in case of a vulvar carcinoma, especially in case of a tumour from the uVIN-related pathway.
In general, several studies showed that patients with uVIN-related vulvar SCC are younger than dVIN/LS-related vulvar SCC patients (Hording et al, 1994
; Hampl et al, 2006
; Hoevenaars et al, 2008
; van de Nieuwenhof et al, 2009a
). In our study, we confirm this observation with a significant difference in age distribution between the two different groups, 72 years for the hrHPV-unrelated and 54 years for the hrHPV-related groups (P
<0.001). If we compare the median age for cervical SCC, which is caused by hrHPV in nearly 100% of the cases, with the median age for uVIN/hrHPV-related vulvar SCC, we find a comparable age, 51 years and 54 years, respectively (Hacker, 2000
). This may suggest that a hrHPV infection brings about an earlier age of onset of uVIN-related vulvar carcinogenesis compared with the dVIN-related vulvar carcinogenesis. In this study, cervical (pre)malignancies with compatible hrHPV types were diagnosed as well before, simultaneous as after a uVIN-related vulvar SCC.
We found a hrHPV prevalence of 23.4% for vulvar SCC in general. The percentage of hrHPV DNA-positive vulvar SCC (23.4%) is slightly higher than the percentage of tumours with adjacent uVIN (18.4%). These findings confirm that not all hrHPV infections finally lead to vulvar SCC. As hrHPV often resolves spontaneously, most likely these five percent additional infections were transient infections, yet to be cleared.
Of the 201 patients, in 56 cases (28%) no cervical smear information was available: this may be because of the limitation in coverage of the PALGA database (national coverage from 1991 onwards) or because of the fact that these women never had a cervical smear taken. Worth mentioning is that 87% of these women exceeded the age limit to be invited for the national screening program for cervical cancer. Still, at diagnosis, in 105 of the 201 (52%) cases no cervical smear was taken around the diagnosis of the vulvar SCC. Approximately one-fifth of the vulvar SCCs is uVIN related, and simultaneous cervical and vulvar infections have previously been described (Adamek et al, 2003
; Lara-Torre and Perlman, 2004
; Feng and Kiviat, 2005
; Goffin et al, 2006
). Therefore, a cervical smear should always be taken during the diagnostic process of patients with a uVIN-related vulvar SCC. During the studied period (1988–2007), the role of hrHPV became more evident. In this study, for all patients diagnosed after 2002, a cervical smear was taken. This suggests that the cervical smear is now more embedded in the diagnostic routine of vulvar SCC. Our results show that it is important not to overlook or underestimate the possibility of a multicentric HPV infection, causing both cervical and vulvar (pre)malignancies. Although there is no evidence, probably because of the low number of patients that developed a HSIL lesion after vulvar SCC, we would suggest: all vulvar SCC patients have a cervical smear during the diagnostic process of their vulvar SCC; for uVIN-associated vulvar SCC patients a 2-yearly cervical smear should be performed during follow up.
In conclusion, patients with a uVIN-related vulvar SCC have an increased incidence of cervical (pre)malignancies with identical hrHPV types in both cervical and vulvar (pre)malignancies. This points to the multicentric development of (pre)malignancies and emphasises the necessity to differentiate between dVIN- and uVIN-related vulvar tumours. The examination of the entire lower female ano-genital tract in case of a hrHPV-related vulvar lesion should therefore be obligatory.