Blanc-Moya, R.

La Vecchia, C.

Levi, F.

Maspoli-Conconi, M.

Randimbison, L.

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Second neoplasms after cancersof unknown primaryEven in populations with optimal structures for cancerdiagnosis and certification, 3%–5% of neoplasms areclassified as cancer of unknown primary (CUP) [1]. In theVaud Cancer Registry, they account for 2%–3% of allneoplasms only [2].CUPs tend to have poor prognosis and hence shortsurvival, i.e. 1-year survival was 15% in the Vaud CancerRegistry [2]. Still, incidence of second primary cancers maybe increased after CUP. Thus, in the Swedish FamilyCancer Database, the standardized incidence ratio (SIR) ofsubsequent cancer following a CUP was 1.69, and severalcancers had increased SIR, including skin and infection-relatedcancer [1].We consider in the present report data on selectedcancers following CUP using the Vaud Cancer Registrydataset [2]. This includes incident cases of malignantneoplasms in the Canton [3], whose population according tothe 2000 Census was 616 000 inhabitants. Passive andactive follow-up is recorded, and each subsequent item ofinformation concerning an already registered case is used tocomplete the record of that patient. The present seriescomprises a total of 2163 first CUP diagnosed from 1974 to2007 and followed up to the end of 2007 for the occurrenceof a second primary cancer of any site and morphologicaltype [according to the standard International Classificationof Diseases for Oncology, 9th Edition (ICD-O-9), exceptbasal cell carcinoma of the skin], emigration or death, fora total of 1872.7 person-years. Calculation of expectednumbers was based on site-, sex-, age- and calendaryear-specific incidence rates, multiplied by thecorresponding number of person-years at risk. Thesignificance of the observed/expected ratios (SIRs) and thecorresponding 95% confidence intervals (CIs) were basedon the Poisson distribution.Overall, 43 second cancers were reported after CUP versus29.9 expected, corresponding to a SIR of 1.4 (95% CI1.0–1.9) (Table 1). Significant excess risks were observed forcancer of the oral cavity and pharynx (eight observed, SIR8.6, 95% CI 3.7–17.0). There were 8 squamous cellcarcinomas (SCCs) of the skin (SIR 2.1, 95% CI 0.9–4.2), 5cancers of the prostate (SIR 1.1, 95% CI 0.4–2.6) and 22other neoplasms (SIR 1.1, 95% CI 0.7–1.6).Thus, the present data confirm, and further quantify, theexistence of excess cancer risk following CUP. Part of suchexcess risk may be due to recurrences and diagnosis of primaryneoplasm, though the criteria for registration of second primaryneoplasms in the Vaud Cancer Registry were strict [4]. There isalso an increased medical surveillance after CUP diagnosis. Thismay account, partly or largely, for the slight apparent excess riskof prostate cancer restricted to the first year after CUP diagnosis(SIR 1.8, based on three cases) since prostate cancer is stronglyinfluenced by prostate-specific antigen and other diagnosticprocedures [5–7]. This cannot explain, however, the excess riskfor other neoplasm: the SIR for all sites was 1.2 (95% CI 0.6–2.0, based on 13 cases) during the first year after CUP, 1.3 (95%CI 0.6–2.2, 13 cases) from 1 to 4 years and 2.0 (95% CI 1.2–3.2,17 cases) ‡5 years after CUP diagnosis.The excess risk for oral, pharyngeal and skin SCC arehowever apparently greater than for other neoplasms. Sincesome of these neoplasms are related to infectious agents(human papillomavirus) [8–11], this supports the concept thatCUP-related (or treatment-induced) immunosuppression isa relevant underlying mechanism [12, 13] of the excess cancerrisk after CUP. No cervical cancer was observed after CUP. Thiscan be explained, however, by adequate surveillance for cervicalcancer in this population [14].F. Levi1,2*, R. Blanc-Moya1, M. Maspoli-Conconi2L. Randimbison1 & C. La Vecchia1,3,41Registre Vaudois des Tumeurs and Unite´ d’Epide´miologie du Cancer,Institut Universitaire de Me´decine Sociale et Pre´ventive (IUMSP), CentreHospitalier Universitaire Vaudois et Faculte´ de Biologie et Me´decine,Lausanne, 2Registre Neuchaˆtelois des Tumeurs, Neuchaˆtel, Switzerland,3Department of Epidemiology, Istituto di Ricerche Farmacologiche MarioNegri, Milan, 4Department of Occupational Medicine, Universita` degliStudi di Milano, Milan, Italy(*E-mail: fabio.levi@inst.hospvd.ch, fabio.levi@chuv.ch)fundingThe work of CLV is supported by the Associazione Italiana perla Ricerca sul Cancro (No. 10068).disclosureThe authors declare no conflict of interest.Table 1. Observed (O) and expected (E) number of second primarycancers following 2163 first cancers of unknown primary site (Vaud,Switzerland, 1974–2007)Site of second primary O E SIR 95% CIOral cavity and pharynx 8 0.93 8.61 3.71–16.97Skin, squamous cellcarcinoma8 3.73 2.14 0.92–4.22Prostate 5 4.51 1.11 0.36–2.59Other sitesa 22 20.74 1.06 0.67–1.61All sites 43 29.91 1.44 1.04–1.94aInclude: one cancer of esophagus, liver, biliary tract, lung, skin melanoma,male breast, endometrium, testis, bladder, thyroid and lymphoma; twocancers of kidney; three cancers of stomach, colorectum, female breast.SIR, standardized incidence ratio; CI, confidence interval.1464 | letters to the editor Volume 22 |No. 6 | June 2011letters to the editor Annals of Oncologyreferences1. Shu X, Liu H, Ji J et al. Subsequent cancers in patients diagnosed with cancerof unknown primary (CUP): etiological insights? Ann Oncol 2011; in press.doi:10.1093/annonc/mdr059.2. Levi F, Te VC, Erler G et al. Epidemiology of unknown primary tumours. Eur JCancer 2002; 38: 1810–1812.3. Levi F, Te VC, Randimbison L, Choffat R. Cancer incidence in Vaud, Switzerland,1998-2002. In Curado MP, Edwards B, Shin HR et al. (eds), Cancer Incidence inFive Continents. Vol. 9. Lyon, France: IARC 2007; IARC Scientific PublicationsNo. 160: 377.4. Levi F, Boffetta P, La Vecchia C. High constant incidence rates of second primaryneoplasms. Eur J Cancer Prev 2008; 17: 385–388.5. Levi F, La Vecchia C, Boyle P. The rise and fall of prostate cancer. Eur J CancerPrev 2000; 9: 381–385.6. Levi F, La Vecchia C, Randimbison L et al. Incidence, mortality and survival fromprostate cancer in Vaud and Neuchatel, Switzerland, 1974-1994. Ann Oncol1998; 9: 31–35.7. Collin S M, Martin RM, Metcalfe C et al. Prostate-cancer mortality in theUSA and UK in 1975-2004: an ecological study. Lancet Oncol 2008; 9:445–452.8. Iannacone MR, Michael KM, Giuliano AR et al. Risk factors for cutaneous humanpapillomavirus seroreactivity among patients undergoing skin cancer screeningin Florida. J Infect Dis 2010; 201: 760–769.9. Syrjanen S. The role of human papillomavirus infection in head and neckcancers. Ann Oncol 2010; 21 (Suppl 7): vii243–vii245.10. Levi F, Randimbison L, La Vecchia C. Nonmelanomatous skin cancer followingcervical, vaginal, and vulvar neoplasms: etiologic association. J Natl Cancer Inst1998; 90: 1570–1571.11. Levi F, Te VC, Randimbison L, La Vecchia C. Second primary cancers after in situand invasive cervical cancer. Epidemiology 2001; 12: 281–282.12. Kinlen L. Immunosuppressive therapy and acquired immunological disorders.Cancer Res 1992; 52 (Suppl 19): 5474s–5476s.13. Hemminki K, Jiang Y, Steineck G. Skin cancer and non-Hodgkin’s lymphoma assecond malignancies. Markers of impaired immune function? Eur J Cancer2003; 39: 223–229.14. Levi F, La Vecchia C, Randimbison L, Te VC. Incidence, mortality and survivalfrom invasive cervical cancer in Vaud, Switzerland, 1974-1991. Ann Oncol1994; 5: 747–752.doi:10.1093/annonc/mdr267Published online 6 May 2011Volume 22 |No. 6 | June 2011 letters to the editor | 1465Annals of Oncology letters to the editor

Second neoplasms after cancers of unknown primary

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