La Vecchia, Carlo

Levi, Fabio

Randimbison, Lalao

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CORRESPONDENCENonmelanomatous SkinCancer Following Cervical,Vaginal, and VulvarNeoplasms: EtiologicAssociationHuman papillomavirus infection isthe major cause of cancers of the cervix,vagina, and vulva (1). Nonmelanoma-tous skin cancers have been associatedwith human papillomavirus infectionin patients with epidermodysplasia ver-ruciformis and in patients who are im-munosuppressed or nonimmunosup-pressed, although the data are scant(1,2).We used the cancer registry of theSwiss Canton of Vaud (with a popula-tion of approximately 600 000 in 1990)for the period from 1974 through 1994to obtain additional quantitative infor-mation on this topic, which has patho-genic and public health implications.Data were collected for women who hadin situ or invasive neoplasms of the cer-vix, vagina, or vulva and for womenwho had nonmelanomatous skin cancer.These data were then used to calculatethe incidence of nonmelanomatous skincancer in women who had been regis-tered with an in situ or invasive neo-plasm of the cervix, vagina, or vulva (3).The registry is tumor based, and mul-tiple primary tumors in the same personare entered separately. The basic infor-mation available consists of sociodemo-graphic characteristics of the patient, theprimary site of the tumor, the histologictype of the tumor according to the stan-dard International Classification of Dis-eases (ICD) for Oncology (4), and thetime of diagnostic confirmation. Passiveand active follow-ups are recorded, andeach subsequent item of informationconcerning a registered cancer is used tocomplete the record of that patient.Since 1974, a registration schemethat applies the standardized rules usedfor incident cancers has been used forcarcinoma in situ and severe dysplasia(CIN III, cervical intraepithelial neopla-sia III) of the uterine cervix (ICD code:180.0–180.9), vagina (ICD: 184.0), andvulva (ICD: 184.1–184.3) (4).In the present study, when all syn-chronous neoplasms were excluded,there were 2339 histologically con-firmed cases of carcinoma in situ of thecervix uteri, nine cases of carcinoma insitu of the vagina, and 85 cases of car-cinoma in situ of the vulva. The studyalso included 789 cases of invasive neo-plasms of the cervix, 69 cases of inva-sive neoplasms of the vagina, and 153cases of invasive neoplasms of thevulva. These cases were followed to theend of 1996 for the occurrence of can-cer, migration, or death.We calculated the expected numbersof individuals with nonmelanomatousskin cancer based on site-, age-, and cal-endar-period-specific incidence rates,multiplied by the observed number ofperson-years at risk. The statistical sig-nificance of the observed/expected ra-tios (standardized incidence ratio [SIR])and the corresponding 95% confidenceinterval (CI) were based on the Poissondistribution.Table 1 gives the observed and ex-pected numbers of nonmelanomatousskin neoplasms after diagnosis of insitu or invasive neoplasms of the cer-vix, vagina, and vulva. A statisticallysignificant excess of skin cancer wasregistered after cervical neoplasms(44 observed and 24 expected; SIR 41.8; 95% CI 4 1.3–2.5) and vulvarneoplasms (13 observed and four ex-pected; SIR 4 3.2; 95% CI 4 1.7–5.5).Likewise, three nonmelanomatousskin cancers were observed aftervaginal neoplasms versus one expected(SIR 4 2.9; 95% CI 4 0.6–8.6). Over-all, 60 skin cancers were observed ver-sus 29 expected (SIR 4 2.1; 95% CI 41.6–2.7).An excess of nonmelanomatous skincancer after diagnosis of carcinomain situ of the cervix has been reported(5,6). The present data extend thisobservation to other neoplasms ofthe lower female genital tract and, there-fore, provide epidemiologic support tothe suggestion of a possible role of humanpapillomavirus infection in the etiology ofnonmelanomatous skin cancer (7).FABIO LEVILALAO RANDIMBISONCARLO LA VECCHIAREFERENCES(1) International Agency for Research on Cancer(IARC). Monographs on the evaluation of car-cinogenic risks to humans No. 64, human pap-illomaviruses. Lyon: IARC; 1995.(2) Shamanin V, zur Hausen H, Lavergne D,Proby CM, Leigh IM, Neumann C. Humanpapillomavirus infections in nonmelanomaskin cancers from renal transplant recipientsand nonimmunosuppressed patients. J NatlCancer Inst 1996;88:802–11.(3) Levi F, Te VC, Randimbison L, La Vecchia C.Statistics from the Registry of the Canton ofVaud, Switzerland, 1988–1992. In: ParkinDM, Whelan S, Ferlay J, Raymond L, YoungJ, editors. Cancer incidence in five continents,vol VII. Lyon: IARC Sci Publ No. 143; 1997.p. 674–7.(4) World Health Organization. International Clas-sification of Diseases for Oncology (ICD-O).Geneva: World Health Organization; 1976.(5) Bjorge T, Hennig EM, Skare GB, Soreide O,Thorensen SO. Second primary cancers inpatients with carcinoma in situ of theuterine cervix. The Norwegian experience1970–1992. Int J Cancer 1995;62:29–33.(6) Levi F, Randimbison L, Vecchia CL, Fran-ceschi S. Incidence of invasive cancers follow-ing carcinoma in situ of the cervix. Br J Can-cer 1996;74:1321–3.Table 1. Observed and expected cases, in Vaud, Switzerland, from 1974 through 1994, andstandardized incidence ratios (SIRs) of subsequent nonmelanomatous skin cancer after an initialdiagnosis of in situ or invasive neoplasms of the cervix, vagina, and vulva, as well as thecorresponding 95% confidence intervals (CIs)Site of in situ orinvasive primary tumorNo. of nonmelanomatous skin cancersSIR (95% CI)Observed ExpectedCervix (n 4 3128) 44 24 1.8(1.3–2.5)Vagina (n 4 78) 3 1 2.9(0.6–8.6)Vulva (n 4 238) 13 4 3.2(1.7–5.5)Total (n 4 3444) 60 29 2.1(1.6–2.7)1570 CORRESPONDENCE Journal of the National Cancer Institute, Vol. 90, No. 20, October 21, 1998(7) Burk RD, Kadish AS. Treasure hunt for humanpapillomaviruses in nonmelanomatous skin can-cers. J Natl Cancer Inst 1996;88:781–2.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, Italy.Correspondence to: Fabio Levi, Registre Vau-dois des Tumeurs, CHUV-Falaises 1, CH-1011Lausanne, Switzerland (e-mail: fabio.levi@inst.hospvd.ch).We gratefully acknowledge the contribution ofthe Vaud Cancer Registry’s staff and the collabo-ration of the pathological laboratories operating inthe Canton of Vaud.Re: Distinguishing SecondPrimary Tumors From LungMetastases in Patients WithHead and Neck SquamousCell CarcinomaThe recent paper by Leong et al. (1)highlights progress regarding a long-standing oncology dilemma in distin-guishing a solitary metastatic depositfrom a new cancer in patients withknown prior cancer. The specific clini-cal scenario is familiar to those who fre-quent head and neck tumor boards—specifically, the patient with knownhead and neck cancer (squamous cellcarcinoma) who simultaneously or sub-sequently manifests a solitary pulmo-nary nodule, which is similarly con-firmed as squamous cell carcinoma.Many head and neck oncologistshave turned wistfully toward their tumorboard pathologist with the simple ques-tion, ‘‘Is this a metastasis or a new pri-mary tumor?’’ The promise of this pub-lished work by Leong et al. (1) is that weare moving closer to providing the cli-nician with molecular diagnostic tools toanswer the question more precisely.Judicious application of moleculartechniques to complement clinical judg-ment in the ‘‘metastasis versus primarytumor’’ scenario will clearly prove ben-eficial in selected circumstances. Never-theless, maximizing clinical thinking be-fore soliciting molecular ‘‘truth telling’’will be important. In their abstract,Leong et al. state ‘‘. . . a solitary SCC[squamous cell carcinoma] in the lungmore likely represents a metastasis thanan independent lung cancer.’’ However,this is largely dependent on the patientcohort selected. The study group in thepaper by Leong et al. is dominated bypatients with advanced, lymph node-positive, and/or recurrent head and neckcancers. Of the 16 patients studied, 13presented with stage IV tumors and 15were lymph node positive at presenta-tion. These represent compelling prog-nostic features for locoregional diseaserecurrence and eventual distant metasta-ses. Thus, it is not surprising that 12 of16 lung tumors appeared to representmetastases in this group of patients withhighly advanced-stage disease for whomclinical judgment would largely dictatethe same. This is by no means meant todetract from the importance of this work.Rather, it is suggested that such molecularanalysis may prove far more important inpatients with earlier stage disease forwhom the clinical likelihood of distantmetastasis is deemed far lower.Approximately one quarter to onethird of the patients with head and neckcancer present with stage I or stage IIdisease (lymph node negative); in thesepatients, lung metastases would be dis-tinctly unusual. For these patients, thecost of mistakenly assuming a meta-static process could be tragic, and thevalue of confirming a molecular distinc-tion may be critical to optimizingtherapy recommendations.Leong et al. state in the ‘‘Discus-sion’’ section, ‘‘Most solitary lung nod-ules in patients with HNSCC [head andneck squamous cell carcinoma] may ac-tually reflect advanced tumor spread.’’These authors would not wish to inad-vertently mislead the general oncologistinto thinking that this is true for all pa-tients with head and neck cancer. Thisconclusion is strongly influenced by theclinical staging of the original tumors. Amolecular examination of 16 patientswith early stage head and neck tumorswho manifest solitary pulmonary nod-ules might well lead others to draw theopposite conclusion. Nevertheless, theseadvances in tumor fingerprinting willsurely provide tangible benefits to se-lected cancer patients in whom the judi-cious application of molecular data willcomplement and clarify clinical judgment.PAUL M. HARARIREFERENCE(1) Leong PP, Rezai B, Koch WM, Reed A, EiseleD, Lee DJ, et. al. Distinguishing second pri-mary tumors from lung metastases in patientswith head and neck squamous cell carcinoma.J Natl Cancer Inst 1998;90:972–7.NOTECorrespondence to: Paul M. Harari, M.D., De-partment of Human Oncology, 600 Highland Ave.K4/B100, Madison, WI 53792-0600.RESPONSEWe welcome Dr. Harari’s refreshingembrace of a novel strategy for the reso-lution of a long-standing oncologicimpasse. Comparative microsatelliteanalysis is a highly effective tool in dis-tinguishing second lung tumors fromlung metastasis. No doubt, similar ge-netic strategies addressing equally rel-evant clinical issues will play an in-creasing role in the integrated multidisci-plinary approach to patients with head andneck squamous cell carcinoma (HNSCC)and cancers at other sites.As always, caution and discretionmust be exercised when generalizingstudy results to the individual patient.Our study reflects the experience of alarge tertiary care center where patientsare often referred for management of ad-vanced HNSCC. As Dr. Harari pointsout, the incidence of solitary lung me-tastases will probably be lower in pa-tient populations over represented bylow-stage HNSCCs. For the individualpatient with HNSCC, however, micro-satellite analysis remains a valid andvaluable tool for discerning the nature ofa solitary lung tumor. The use of suchmolecular approaches is not intended toreplace sound clinical judgment but tofacilitate it.WILLIAM H. WESTRAWAYNE M. KOCHDAVID SIDRANSKYJIN JENNOTESAffiliations of authors: W. H. Westra (Depart-ment of Otolaryngology–Head and Neck Surgeryand Pathology), W. M. Koch, D. Sidransky, J. Jen(Department of Otolaryngology–Head and NeckSurgery), The Johns Hopkins Medical Institutions,Baltimore, MD.Correspondence to: William H. Westra, M.D.,The Johns Hopkins Medical Institutions, Depart-ment of Pathology, 600 N. Wolfe St., Baltimore,MD 21287-6417.Journal of the National Cancer Institute, Vol. 90, No. 20, October 21, 1998 CORRESPONDENCE 1571

Nonmelanomatous Skin Cancer Following Cervical, Vaginal, and Vulvar Neoplasms: Etiologic Association

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