Frisch, Morten

Hjalgrim, Henrik

La Vecchia, Carlo

Levi, Fabio

Randimbison, Lalao

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Re: Nonmelanomatous SkinCancer Following Cervical,Vaginal, and VulvarNeoplasms: EtiologicAssociationLevi et al. (1) report elevated stan-dardized incidence ratios (SIRs) fornonmelanomatous skin cancer (NMSC)in women listed with cervical and vul-var/vaginal cancers in the Vaud cancerregistry, Vaud, Switzerland. This find-ing is interpreted as support for a role ofhuman papillomaviruses (HPVs) in theetiology of NMSC. We feel prompted tocomment on this interpretation and topresent additional observations that mayhelp clarify the topic.We identified all women reported tothe national cancer registry in Denmarkwith invasive cervical, vulvar/vaginal,and anal cancers during the period from1943 through 1990 and all women withcervical intraepithelial neoplasia (gradeIII) or carcinoma in situ during the pe-riod from 1958 through 1990. Womenwith colorectal, breast, and uterine cor-pus cancers (all HPV unassociated) dur-ing the period from 1943 through 1990were also identified. We followed allwomen for new cancers and calculatedSIRs and 95% confidence intervalsbased on the Poisson distribution as de-scribed previously (2).SIRs for cancer overall were signifi-cantly elevated in all anogenital cancercohorts (SIR 4 1.13–1.49), and SIRsfor NMSC were also consistently el-evated (SIR 4 1.20–1.81). Women withHPV-unassociated cancers also had el-evated SIRs for NMSC (SIR 4 1.14–1.35) (Table 1).The number of expected cancers, andthus the size of the SIR, depend on thecompleteness of cancer registration inthe population at large. Levi et al. (3)previously considered underregistrationof NMSCs to be substantial, but they didnot discuss this important point in theirrecent letter (1). What their SIR esti-mates tell is that women registered withcervical and vulvar/vaginal malignan-cies in Vaud, Switzerland, are statisti-cally more likely also to have a subse-quent registered NMSC than otherwomen in that population. We foundsimilar statistical associations forwomen with anogenital cancers in Den-mark but elevated SIRs for NMSC werenot a specific finding. Patients with ano-genital cancer had significantly in-creased SIRs for cancer in general, acontext hardly justifying speculationsabout the possible etiologic involvementof (anogenital types of) HPV in NMSCs.Moreover, patients with HPV-unassoci-ated cancers also had elevated SIRs forNMSC, which renders the proposed roleof HPV in NMSC even less appealing.Important common characteristics forall the women studied may be the closeclinical follow-up and an increased in-dividual alertness toward new symp-toms. Recalling the problem of under-registration, patients whose NMSCsactually end up in cancer registries maywell be those who, for a variety of rea-sons, have close contact to the healthcare system.The finding that patients with NMSCare not at any increased subsequent cer-vical cancer risk (4,5) was recently con-firmed by Levi et al. (6). This lack of anassociation further detracts from theidea that anogenital HPV types are in-volved in NMSCs. Inference of biologicsignificance from epidemiologic asso-ciations should not rest on statistical sig-nificance alone. Repeated, unsuccessfulattempts to explain a new association bypotential limitations in the data shouldprecede etiologic speculations. Suchconsiderations often favor alternative,Table 1. Observed and expected cases and standardized incidence ratios (SIRs) of subsequent cancers (overall) and nonmelanomatousskin cancers among women with anogenital cancers, colorectal cancer, breast cancer, and cancer of the uterine corpus in Denmark duringthe period from 1943 through 1990*Site of primary tumorNo. ofpatientsNo. ofperson-yearsAll cancers Nonmelanomatous skin cancersNo.observedNo.expectedSIR(95% CI†)No.observedNo.expectedSIR(95% CI†)HPV‡-associated anogenital cancersCervix, preinvasive§ 30 294 374 640 2212 1801.9 1.23 (1.18–1.28) 263 190.0 1.38 (1.22–1.56)Cervix, invasive 32 307 360 290 3399 3020.0 1.13 (1.09–1.16) 362 295.8 1.22 (1.10–1.36)Vulva/vagina 3840 23 956 360 297.0 1.21 (1.09–1.34) 60 33.2 1.81 (1.38–2.33)Anus 684 3724 65 43.6 1.49 (1.15–1.90) 6 5.0 1.20 (0.44–2.61)HPV‡-unassociated cancersColon/rectum 54 635 197 300 2800 2665.5 1.05 (1.01–1.09) 371 308.0 1.20 (1.08–1.33)Breast 85 243 589 484 6122 6384.2 0.96 (0.94–0.98) 929 688.8 1.35 (1.26–1.44)Uterine corpus 19 254 178 442 2172 2147.9 1.01 (0.97–1.05) 267 234.4 1.14 (1.01–1.28)*Inclusion period restricted to the period from 1958 through 1990 for women with preinvasive cervical cancer.†CI 4 confidence interval.‡HPV 4 human papillomavirus.§Women diagnosed with cervical carcinoma in situ or cervical intraepithelial neoplasia (grade III) are included.Journal of the National Cancer Institute, Vol. 91, No. 6, March 17, 1999 CORRESPONDENCE 565usually less spectacular, explanations ofnew findings. Other HPV types may beinvolved, but current epidemiologic andmolecular biologic evidence still doesnot suggest the involvement of anogeni-tal HPV types in most NMSCs (7).MORTEN FRISCHHENRIK HJALGRIMREFERENCES(1) Levi F, Randimbison L, La Vecchia C. Non-melanomatous skin cancer following cervical,vaginal, and vulvar neoplasms: etiologic asso-ciation [letter]. J Natl Cancer Inst 1998;90:1570–1.(2) Frisch M, Melbye M. Risk of lung cancer inpre- and post-menopausal women with ano-genital malignancies. Int J Cancer 1995;62:508–11.(3) Levi F, La Vecchia C, Te VC, Mezzanotte G.Descriptive epidemiology of skin cancer in theSwiss Canton of Vaud. Int J Cancer 1988;42:811–6.(4) Frisch M, Melbye M. New primary cancersafter squamous cell skin cancer. Am J Epide-miol 1995;141:916–22.(5) Frisch M, Hjalgrim H, Olsen JH, Melbye M.Risk for subsequent cancer after diagnosis ofbasal-cell carcinoma. A population-based, epi-demiologic study. Ann Intern Med 1996;125:815–21.(6) Levi F, La Vecchia C, Te VC, Randimbison L,Erler G. Incidence of invasive cancers follow-ing basal cell skin cancer. Am J Epidemiol1998;147:722–6.(7) de Villiers EM. Human papillomavirus infec-tions in skin cancers. Biomed Pharmacother1998;52:26–33.NOTESAffiliation of authors: Department of Epidemi-ology Research, Danish Epidemiology Science Cen-ter, Statens Serum Institut, Copenhagen, Denmark.Correspondence to present address: MortenFrisch, M.D., Ph.D., Viral Epidemiology Branch,Division of Cancer Epidemiology and Genetics,National Cancer Institute, National Institutes ofHealth, Executive Plaza South, Rm. 8015, Rock-ville, MD 20852 (e-mail: Frischm@mail.nih.gov).Supported by The Direktor E. Danielsen ogHustrus Foundation, The Foundation for the Ad-vancement of Medical Science, and The DanishCancer Society (grant 96-100-17).RESPONSEFrisch and Hjalgrim suggest that in-creased diagnosis of nonmelanomatousskin cancer may, partly or totally, ex-plain the excess incidence observed af-ter diagnosis of cervical, vaginal, or vul-var neoplasms in the Vaud cancerregistry dataset (1).Such a differential diagnostic atten-tion is a function of the completeness ofregistration of nonmelanomatous skincancer. This completeness is uniquelyhigh in the Vaud population, which haslong been particularly well surveyedwith reference to skin neoplasms. In thisarea, in fact, surgically resected cutane-ous lesions have traditionally been ex-amined pathologically, and incidencedata of nonmelanomatous skin cancersfrom this registry have been used as ref-erence estimates over the last two de-cades (2–4). Thus, registered incidenceof nonmelanomatous skin cancers dur-ing the period from 1988 through 1992was appreciably higher in Vaud (100cancers per 100 000 males and 76 can-cers per 100 000 females; world stan-dard) than in Denmark (53 cancers per100 000 males and 43 cancers per 100 000females) (5). This should have substan-tially reduced any potential ascertainmentbias in our Swiss population.This line of reasoning is supportedalso by the appreciably stronger excessrisk in our dataset (overall standardizedincidence ratio [SIR] after cervical,vaginal, and vulvar cancers 4 2.1; 95%confidence interval 4 1.6–2.7) com-pared with an SIR of 1.3 (685 observedversus 519 expected cases) in the Dan-ish dataset. This excess risk of morethan twofold can hardly be explainedonly by surveillance or ascertainmentbias. Further support for this viewcomes from Table 1, which gives ex-pected and observed numbers of all neo-plasms and of nonmelanomatous skinneoplasms during the period from 1974through 1994 [thus updating a previousreport (6)] after colorectal, breast, andendometrial cancers, i.e., the three neo-plasms unlikely to be related to humanpapillomavirus infection selected byFrisch and Hjalgrim. The SIRs for noneof these neoplasms were above unity ormaterially different between nonmela-nomatous skin neoplasms and other can-cers. Thus, in the Vaud population, in-cidence of nonmelanomatous skincancer is elevated after human papillo-mavirus-related neoplasms but not afterother selected cancers. Likewise, in theSwedish record-linkage cohort study(7), the incidence of cervical, vulvar,and vaginal cancers was significantly el-evated in patients with squamous cellcarcinoma of the skin.FABIO LEVILALAO RANDIMBISONCARLO LA VECCHIAREFERENCES(1) Levi F, Randimbison L, La Vecchia C. Non-melanomatous skin cancer following cervical,vaginal, and vulvar neoplasms: etiologic asso-ciation [letter]. J Natl Cancer Inst 1998;90:1570–1.(2) Lee JA. Melanoma and exposure to sunlight.Epidemiol Rev 1982;4:110–36.(3) Levi F, La Vecchia C, Te VC, Mezzanotte G.Descriptive epidemiology of skin cancer in theSwiss Canton of Vaud. Int J Cancer 1988:42:811–6.(4) Levi F, Franceschi S, Te VC, Randimbison L,La Vecchia C. Trends of skin cancer in theCanton of Vaud, 1976–92. Br J Cancer 1995;72:1047–53.(5) Levi F, Lucchini F, Boyle P, Negri E, La Vec-chia C. Cancer incidence and mortality in Eu-rope. J Epidemiol Biostat 1998;3:295–373.(6) Levi F, Randimbison L, Te VC, Rolland-Portal I, Franceschi S, La Vecchia C. Multipleprimary cancers in the Vaud Cancer Registry,Switzerland, 1974–89. Br J Cancer 1993;67:391–5.(7) Wassberg C, Thorn M, Yuen J, Ringborg U,Hakulinen T. Second primary cancers in pa-tients with squamous cell carcinoma of theskin: a population-based study in Sweden. IntJ Cancer 1999;80:511–5.NOTESAffiliations of authors: F. Levi, L. Randimbi-son, Registre Vaudois des Tumeurs, Institut Uni-versitaire de Me´decine Sociale et Pre´ventive, Lau-sanne, Switzerland; C. La Vecchia, Istituto diRicerche Farmacologiche “Mario Negri,” and Is-tituto di Statistica Medica e Biometria, Universita`degli Studi di Milano, Milan, Italy.Correspondence to: Fabio Levi, M.D., RegistreVaudois des Tumeurs, CHUV-Falaises 1, CH-1011 Lausanne, Switzerland (e-mail: fabio.levi@inst.hospvd.ch).Table 1. Observed and expected cases of cancer and standardized incidence ratios (SIRs), withcorresponding 95% confidence intervals (CIs), of subsequent cancers (overall) and nonmelanomatousskin cancers among women with colorectal cancer, breast cancer, and cancer of the uterine corpus inVaud, Switzerland, during the period from 1974 through 1994Site ofprimary tumorAll cancers Nonmelanomatous skin cancersNo.observedNo.expectedSIR(95% CI)No.observedNo.expectedSIR(95% CI)Colorectum 142 155.5 0.9 (0.8–1.1) 32 41.4 0.8 (0.5–1.1)Breast 479 405.7 1.2 (1.1–1.3) 122 104.7 1.2 (1.0–1.4)Uterine corpus 94 110.6 0.9 (0.7–1.0) 26 28.5 0.9 (0.6–1.3)566 CORRESPONDENCE Journal of the National Cancer Institute, Vol. 91, No. 6, March 17, 1999

Re: Nonmelanomatous Skin Cancer Following Cervical, Vaginal, and Vulvar Neoplasms:Etiologic Association [CORRESPONDENCE]

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