Uveal Melanoma: A Study on Incidence of Additional Cancers in the Swedish Population

Louise Bergman,1 Bo Nilsson,2 Boel Ragnarsson-Olding,2 and Stefan Seregard1

PURPOSE. To investigate the occurrence of other primary malignancies before and after diagnosis of uveal melanoma in a Swedish population. METHODS. In the Swedish Cancer Registry 2995 patients with uveal melanoma were notied during the period 1960 to 1998. In the same registry, a search for additional malignancies among these patients was performed. A matched case control study with 2,916 patients and 14,577 population control subjects was set up for malignancies before diagnosis of uveal melanoma. Malignancies after diagnosis of uveal melanoma were evaluated in 2,995 patients through standardized incidence ratios (SIRs), based on the expected rates in the Swedish population. RESULTS. Before the diagnosis of uveal melanoma, the odds ratio (OR) for the risk of cancer was 1.25 (95% CI: 0.98 1.59). No signicantly increased risk was found for any specic malignancy. The OR for cutaneous melanoma was 1.74 (95% CI: 0.78 3.89). The risk of subsequent cancers was increased, SIR 1.13 (95% CI: 1.021.26). After reevaluation of archival specimens, the SIR of a cutaneous melanomas developing after a uveal melanoma was found to be 1.75 (95% CI: 0.873.12). CONCLUSIONS. An increased risk of second primary cancers was observed among Swedish patients with uveal melanoma. Metastases from uveal melanoma were found to be misclassied as cutaneous melanoma or as primary liver cancer. (Invest Ophthalmol Vis Sci. 2006;47:7277) DOI:10.1167/iovs.05-0884 he etiology and pathogenesis of uveal melanoma remains largely unknown. The role of ultraviolet (UV) radiation as a risk factor, or promoter for the development of uveal melanoma has been debated for decades, with both negative1 4 and supportive reports,59 as recently discussed in a review article by Singh et al.10 In contrast to the increasing incidence rates of UV-inducible cutaneous melanoma apparent in white populations during the past decades,1113 the incidence of uveal melanoma has not increased.14 16 The occurrence of additional primary tumors in patients with uveal melanoma or familiar clustering of cancers1720 may give indications of shared risk factors or a genetic predisposition, which could be further evaluated through case control studies and, in recent years, through genetic linkage studies. In this study, we examined the association between the occurrence of uveal melanoma and additional cancers, by using reports to the national Swedish Cancer Registry led during the period 1960 through 1998.

MATERIALS

AND

METHODS

The Swedish Cancer Registry, founded in 1958 is estimated to include more than 95% of the cancer cases in the population.21 Physicians and pathologists give compulsory independent reports of newly detected tumors to the registry, which ensures a high inclusion rate. The 10-digit national registration number identies each patient and avoids the risk of duplicate registration. For the whole period 1958 and onward, the site of tumor is available as the WHO ICD-7 code and the histopathology classication as the old histology code (WHO/HS/CANC/24.1). The registry does not accept death certicates only.22 Included in the Swedish Cancer Registry are invasive solid malignancies, lymphomas, leukemia, and hematologic disorders such as reticulosis, myelobrosis, and polycythemia vera. In situ malignant tumors of the breast, uterine cervix, gastrointestinal tract, skin, and prostate and some benign intracranial tumors are also included, but until recently (2003) basal cell carcinoma was not included. An investigation of the incidence of uveal melanoma in Sweden, based on reports to the Swedish Cancer Registry during the period January 1, 1960, to December 31, 1998, revealed 2997 cases in 2995 patients.14 In the patients with uveal melanoma, up to ve separate diagnoses of cancer were traced through the les in the Cancer Registry, along with the histology code and date of registration. Both the cancers occurring before the diagnosis of uveal melanoma and subsequent cancers were considered when investigating possible associations with uveal melanoma. The research protocol for the present study was approved by the Human Ethics Committee at the Karolinska Institute, in accordance with the statutes of the World Health Associations Declaration of Helsinki.

Primary Cancers before Uveal Melanoma

Previous cancers in any patient group is skewed in favor of malignancies with better prognosis compared to the cancers in the general population, which also contains individuals with lethal tumors, unable to develop ensuing cancers. Therefore, cancer cases notied before the diagnosis of uveal melanoma cannot be entered into an analysis based on expected rates from the general population. To evaluate the expected cancer incidence, we conducted a registry-based matched case control study. Controls were drawn from the Registry of the Total Population,23 based on the annual Swedish census. For each case, ve gender- and age (1 day)-matched control subjects were selected, who were alive on the day the index person received a diagnosis of uveal melanoma. The study participants were the patients with uveal melanoma (n 2,916, we could nd no matching control subjects for 79 patients) and 14,577 control subjects. Through this procedure, the case patients and control subjects experienced the same time at risk. The Swedish Cancer Registry was searched for malignancies registered during the period from January 1, 1958 (or date of birth if born later) until the date of diagnosis of uveal melanoma for each index case and its corresponding control. Cases registered as cancer in situ were excluded. Conditional logistic regression analysis was used to calculate odds ratios (OR), as an estimation of relative risks, with a 95% condence interval (CI).
Investigative Ophthalmology & Visual Science, January 2006, Vol. 47, No. 1 Copyright Association for Research in Vision and Ophthalmology

From the 1Department of Vitreoretinal Diseases, St. Eriks Eye Hospital, Stockholm, Sweden; and the 2Department of Oncology, Karolinska University Hospital, Stockholm, Sweden. Supported by grants from Crown Princess Margarethas Foundation for the Visually Impaired, Stockholm, Sweden; Synfra mjandets Research Fund, Stockholm, Sweden; and the St. Erik Foundation for Research in Ophthalmology, Stockholm, Sweden. Submitted for publication July 11, 2005; revised September 14, 2005; accepted November 28, 2005. Disclosure: L. Bergman, None; B. Nilsson, None; B. Ragnarsson-Olding, None; S. Seregard, None The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked advertisement in accordance with 18 U.S.C. 1734 solely to indicate this fact. Corresponding author: Louise Bergman, St. Eriks Eye Hospital, Polhemsgatan 50, SE 112 82 Stockholm, Sweden; louise.bergman@sankterik.se.

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Cancers Co-occurring with Uveal Melanoma

TABLE 1. Cancers Found Prior to Diagnosis of Uveal Melanoma ICD7 140 142 143144 145148 150 151 152 153 154 155 157 160 161 162163 170 171 172174 175 176 177 178 179 180 181 190 191 193 194 195 196 199 200 201 202 203 204207 208 209 Site Lip Salivary glands Mouth Pharynx Esophagus Stomach Small intest ne Colon Rectum and anus Primary liver, bile duct Pancreas Nose and sinuses Larynx Lung Breast Cervix Uterus Ovary Female genital organs Prostate Testis Male genital organs Kidney Other urinary organs Cutaneous melanoma Cutaneous (nonmelanoma) Nervous system Thyroid gland Other endocrine glands Bone Unspecied sites Non-Hodgkin lymphoma Hodgkin disease Reticulosis Myeloma Leukemias Polycythemia vera Myelobrosis Cases 4 2 1 2 2 12 5 1 2 25 8 7 1 3* 24 1 2 8 8 8 9 6 4 7 4 2 1 4 1

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Cancers Diagnosed after Uveal Melanoma

The subsequent primaries after uveal melanoma were investigated in 2995 patients. The time at risk was calculated from the date of diagnosis of uveal melanoma until death or emigration occurred otherwise until December 31, 1998. The expected number of malignancies, calculated as person-years at risk was estimated according to the incidence rates in the general Swedish population with respect to gender, age, and calendar period, using the software PYRS.24 The population was divided into four age groups (0 44, 4559, 60 74, and 75 years), four calendar periods (1960 1969, 1970 1979, 1980 1989, and 1990 1998), and by gender. The cases notied as in situ cancers were omitted in the analysis as the expected rates in the general population are based on invasive cancer. Cancer sites with ve or more expected cases (in total) were further analyzed with standardized incidence ratios (SIRs). The SIR was calculated by dividing the observed number of cancer cases by the number of expected cases. The 95% CIs were estimated, assuming a Poisson distribution of the observed cases. In the case of registered primary cutaneous melanoma a further investigation proved necessary, as the tumor in several instances was reported in close conjunction with the death of the patient, suggesting a possible confounding. Available histologic specimens were re-evaluated by an experienced pathologist (SS). When the archival specimen could not be traced (mostly in cases diagnosed early during the investigation period) or if the patient survived only 2 years or less after the diagnosis of the second melanoma, the possibility of a metastasis from the uveal melanoma could not be ruled out, especially if the underlying cause of death was recorded as melanoma. Therefore, cases classied as having a primary uveal melanoma followed by a primary cutaneous melanoma either had a conrmative archival cutaneous melanoma specimen or survived more than 2 years after the diagnosis of cutaneous melanoma, suggesting that uveal melanoma metastasis to the skin was unlikely. As the incidence of primary liver cancer was remarkably high, available archival specimens were re-evaluated to exclude any misclassied metastases to the liver. This included, when possible, staining using a panel of the melanocytic markers HMB-45, Melan-A, and S-100.

Control Subject 6 6 6 3 2 19 6 59 28 4 5 9 25 123 24 25 24 4 80 2 1 15 37 23 28 22 7 20 2 1 22 4 1 5 5 5

RESULTS
Primary Cancers before Uveal Melanoma
Before the diagnosis of uveal melanoma, 154 patients had a registered cancer and, in total, 161 malignancies were found. In the control group, 631 patients experienced 661 cancers (Table 1). This provided a tendency of an overall elevated risk of previous cancers in patients with uveal melanoma with an OR of 1.25 (95% CI: 0.98 1.59), compared with the population controls (Table 2). No statistically signicant increased risk was found in any specic group of cancer. Patients registered with cutaneous melanoma had an OR of 1.74 (95% CI: 0.78 3.89). Because 8 cutaneous melanomas were found among the cases and 23 in the control group, applying a post hoc analysis revealed that, to detect this difference (with a power of 80% and a two-sided of 0.05), a sample size of 15,462 patients and 77,308 control subjects would be needed. The proportion of morphologically classied uveal melanomas (through local resection, primary or secondary enucleation) was 90.2% (n 2704) in the Swedish uveal melanoma cohort, and a previous investigation of a random sample of these specimens (n 916) revealed a misclassication rate of 0.33%,14 which indicates that there was a small likelihood that a choroidal metastasis had been misclassied as a uveal melanoma.

n 2,916 patients with uveal melanoma and in 14,577 age- and sex-matched control subjects from the general Swedish population * Including a malignant melanoma of the vulva.

Cancers Diagnosed after Uveal Melanoma

During the period 1960 through 1998, the patients with uveal melanoma in the Swedish Cancer Registry accumulated 24,847

person-years of observation. Of the 2995 patients with uveal melanoma, 334 (11%) had one or more additional registrations of a primary cancer after the diagnosis of uveal melanoma. The in situ cases were not included in the analysis, as the expected rates are based on invasive cancers. Two additional registrations of a second cancer were found in 38 patients, and 1 patient had three cancers apart from the primary uveal melanoma. If multiple cancer registrations from the same site were found in a patient, only the rst registration was put into analysis. The cancer sites were collapsed into the major ICD-7 groups. The observed cases as they appeared in the Swedish Cancer Registry and the expected number of malignant tumors are presented in Table 3. After re-evaluation of archival specimens and adjustment for the probably misdiagnosed cases of cutaneous melanoma and primary liver cancer, the SIRs were calculated (Table 4). An elevated overall risk was found for patients with uveal melanoma experiencing development of a second primary cancer, with an SIR of 1.13 (95% CI; 1.021.26). The evaluation of available archival specimens (n 19) from the 29 patients registered with cutaneous melanoma after diagnosis of uveal melanoma revealed 9 with primary cutaneous melanoma. Ten of the specimens (registered as cutaneous melanoma) disclosed a melanoma metastasis to the skin, liver, or muscle tissue. Also, 18 patients died within 2 years after the

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TABLE 2. OR with 95% CI for Previous Cancers in Various Organ Systems ICD-7 140209 140150 153154 170 171176 177 180181 190 191 194195 200209 Site of Previous Cancer All sites Lip-esophagus Colon-anus Breast Female genital organs Prostate Urinary system Cutaneous melanoma Cutaneous (nonmelanoma) Endocrine glands Lymphoma/leukemia Cases 161 7 17 25 19 24 16 8 9 11 12 Control Subjects 661 23 87 123 77 80 52 23 28 27 42 OR 1.25 1.52 0.97 1.02 1.24 1.52 1.32 1.74 1.62 1.88 1.46

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95% CI 0.981.59 0.653.54 0.571.63 0.661.58 0.752.05 0.962.43 0.662.64 0.783.89 0.763.35 0.507.07 0.693.08

P 0.07 0.33 0.89 0.94 0.41 0.08 0.44 0.18 0.23 0.35 0.32

n 2,916 patients with uveal melanoma; 14,577 age- and sex-matched control subjects.

diagnosis of the second melanoma, of which 7 had biopsyvalidated liver metastases. With a high degree of certainty, 11 patients were considered to have primary uveal melanoma followed by primary cutaneous melanoma, with 9 patients with histopathology conrming primary cutaneous melanoma and 2 patients surviving 8 and 10 years, respectively, after diagnosis of cutaneous melanoma (because most patients with
TABLE 3. Registrations of Subsequent Primary Malignancies ICD7 Site All sites Lip Tongue Salivary glands Mouth Pharynx Esophagus Stomach Small intestine Colon Rectum and anus Primary liver, bile duct Pancreas Nose and sinuses Larynx Lung Breast Cervix Uterus Ovary Female genital organs Prostate Testis Male genital organs Kidney Other urinary organs Cutaneous melanoma Cutaneous (nonmelanoma) Nervous system Thyroid gland Other endocrine glands Bone Unspecied sites Non-Hodgkin lymphoma Hodgkin disease Myeloma Leukemias Polycythemia vera Myelobrosis Total Expected 306.1 1.7 0.4 0.2 0.7 0.1 2.8 16.6 1.3 25.5 14.5 9.3 10.3 0.1 1.3 23.1 30.4 2.5 7.1 6.3 1.1 49 0 0.1 9.7 16 6.3 14.7 6.7 1.4 3.7 0 10.3 7.9 0.6 4.4 6.1 0.8 0.2 Total Observed 374 2 0 1 0 4 2 14 2 30 16 19 14 2 1 19 28 4 10 6 2 54 0 1 10 19 29 10 10 3 6 1 19 14 0 9 8 2 3

140 141 142 143144 145148 150 151 152 153 154 155 157 160 161 162163 170 171 172174 175 176 177 178 179 180 181 190 191 193 194 195 196 199 200 201 203 204207 208 209

overt, disseminated uveal melanoma would have died after 2 years). When only conrmed cases were included, the risk of cutaneous melanoma developing after primary uveal melanoma was not found to be signicantly elevated, (SIR 1.75; 95% CI: 0.873.12). Applying a post hoc analysis of the SIRs of primary cutaneous melanoma after uveal melanoma, our study of 2995 patients had a 53% power (two-sided of 0.05) to detect the difference. To reach a power of 80% with a signicance level of 0.05 would require 14 cases of primary cutaneous melanoma. A reduced risk of development of invasive nonmelanoma skin cancer was observed (SIR 0.68). In total, 10 cases were observed (14.7 expected), but an additional 14 in situ skin cancers were registered. Of 19 cases of registered primary liver cancer, 10 specimens were available for reassessment. Six specimens had parafn blocks allowing for new sections to be stained with immunohistochemistry; 4 of these were found to be metastatic melanomas and 2 were conrmed to be primary hepatic cancers. An additional four specimens were not preserved in parafn blocks. Reassessment on morphologic grounds conrmed two cases of bile duct cancer, but two cases featured undifferentiated cancer, in which metastatic melanoma could not be ruled out. When these percentages were extrapolated to the whole group of patients with registered primary liver cancers, 40% (n 8) of the patients had a conrmed hepatic or bile duct cancer, 40% had metastatic melanoma, and 20% (n 4) had undifferentiated cancers nonpermissive to classication. This suggests a corrected SIR of 0.86 (95% CI: 0.371.69) of primary liver cancer among the patients with uveal melanoma. A reduced risk of a primary lung cancer, with an SIR of 0.82 (95% CI: 0.50 1.28) was also observed. Both in the case of breast and ovarian cancers, the number of observed cases was below the expected numbers.

DISCUSSION
The use of nationwide, population-based registries when investigating possible associations between cancers is advantageous in reducing the biases of diagnosis and selection and provides better statistical power when a rare cancer, such as uveal melanoma, is studied. Previous studies using population-based databases, such as the Connecticut Tumor Registry, have pointed out increased risks (relative risk [RR] 1.31) for development of a second primary cancer in patients who have cancer, where environmental exposures such as smoking and diet, treatment with chemotherapy or radiation, and a genetic predisposition for cancer may interact.25 In the same registry, eye cancer was associated with both an increased risk of a second cancer and cutaneous melanomas, but the results are

n 2,995 patients with uveal melanoma patients as notied in the Swedish Cancer Registry during the period 1960 1998.

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TABLE 4. SIR with 95% CI for Subsequent Cancers ICD7 Site All sites* Stomach Colon Rectum and anus Primary liver, bile duct* Pancreas Lung Breast Uterus Ovary Prostate Kidney Other urinary organs Cutaneous melanoma* Cutaneous (nonmelanoma) Nervous system Thyroidendocrine glands Unspecied sites Non-Hodgkin lymphoma Leukemias Total Expected 306.1 16.6 25.5 14.5 9.3 10.3 23.1 30.4 7.1 6.3 49 9.7 16 6.3 14.7 6.7 5.1 10.3 7.9 6.1

Cancers Co-occurring with Uveal Melanoma

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Total Observed 346 14 30 16 8 14 19 28 10 6 54 10 19 11 10 10 9 19 14 8

SIR 1.13 0.84 1.18 1.10 0.86 1.36 0.82 0.92 1.41 0.95 1.10 1.03 1.19 1.75 0.68 1.49 1.76 1.84 1.77 1.31

95% CI 1.021.26 0.461.42 0.791.68 0.631.79 0.371.69 0.742.28 0.501.28 0.611.33 0.682.59 0.352.07 0.831.44 0.491.90 0.571.62 0.873.12 0.331.25 0.722.74 0.813.35 1.112.88 0.972.97 0.572.58

151 153 154 155 157 162163 170 172174 175 177 180 181 190 191 193 194195 199 200 204207

n 2995 Swedish patients with uveal melanoma. * Adjusted after re-evaluation of archival specimens.

not readily transferable to the subset of patients with uveal melanoma, as retinoblastoma and other eye malignancies were included in the analysis.26 In Finland, Teppo et al.27 found an increased risk for a second malignancy in patients who had the rst cancer diagnosed before the age of 50, but not in the general population of persons with cancer. A study based on the Danish Cancer Registry28 found an elevated risk of second cancers in male patients with uveal melanoma, but not in females and no signicantly raised risks for either cutaneous melanoma or nonmelanoma skin cancers. Case control studies conducted in patients with uveal melanoma have produced inconsistent results. Turner et al.29 found an increased prevalence of non basal-cell carcinomas and gynecological cancers, whereas Lischko et al.30 and Holly et al.31 found nonsignicant increased rates of both skin- and non-skin cancers in patients with uveal melanoma, compared with those in control subjects. Concurrent second cancers in patients with uveal melanoma have been reported to occur in 8% to 13%.30 33 Our ndings, with data from a nationwide, populationbased survey of patients with uveal melanoma over a 39-year period and with minimal loss to follow-up (due to emigration in nine cases), indicate that uveal melanoma is associated with a raised risk of a second primary cancer. According to the risk ratios, 13% more cancer cases occurred among Swedish patients with uveal melanoma compared with the expected rates in the general population. The risk of actual development of two primary cancers is most variable, depending on factors such as applied treatment, curability, and age at diagnosis of the rst cancer. The median age at diagnosis of uveal melanoma in our survey was 64 years for both men and women, and most of the patients underwent primary enucleation (86.4%). Brachytherapy (ruthenium episcleral plaque) was applied in 12.9% of the cases and 0.7% received therapy with charged particles (protons). The use of chemotherapy in patients with uveal melanoma has been restricted to palliation, and because of the short life expectancy of patients with metastases the risk of inducing another cancer is probably negligible. In the setting of uveal melanoma, it is therefore unlikely that the management would inict an elevated risk of second primary cancer.

Our initial ndings of a substantially raised risk of primary liver cancer are concordant with the results (SIR 5.10) Swerdlow et al.28 reported from the Danish Cancer Registry. Although, after reevaluation of the archival specimens the SIR was adjusted to 0.86 (95% CI: 0.371.69) as primary liver cancer was only conrmed in 4 of 10 specimens whereas 4 of 10 specimens were melanoma metastases. An association between breast cancer and uveal melanoma has been suggested, the proposed linkage through BRCA2 gene mutations.34,35 In patients with uveal melanoma, the prevalence of BRCA2 mutations are rare, probably not more than 2% to 3%.36,37 In the Swedish patients with uveal melanoma, we found a relative risk of female breast cancer of 0.92 (95% CI: 0.611.33). As expected, the identication of patients possibly carrying a rare mutation would be diluted in a population-based investigation. Although both cutaneous and uveal melanocytes are derived from the neural crest, the malignant melanomas arising in the skin and uvea display discrepancies, both in their clinical behavior and on a genetic and molecular level.38 43 Solar light is established as one causative factor in cutaneous melanoma44 but the role of UV light as a risk factor for uveal melanoma is questionable.10 An association has been proposed between the two entities through the dysplastic nevus syndrome (DNS), also called familial atypical mole-and-melanoma (FAM-M) syndrome, an autosomal dominant condition predisposing the carrier to cutaneous melanoma. The denition of DNS has varied in the literature and consequently the prevalence, which makes it difcult to compare the investigations in which dysplastic nevi and cutaneous melanoma were reported to occur more often in patients with uveal melanoma and their close relatives than by chance alone.45 49 In a previous case control study, we did not detect a higher frequency of uveal nevi in patients with DNS.50 Case reports of coexistent primary uveal and cutaneous melanoma have been scarce,48,51,52 but a recent population-based investigation by Shors et al.53 using the SEER database pointed out a 4.6-fold increased risk of development of cutaneous melanoma in the presence of an initial uveal melanoma, ndings that were supported by information from the Swedish Family-Cancer database, with a sig-

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13. Thorn M, Bergstrom R, Adami HO, Ringborg U. Trends in the incidence of malignant melanoma in Sweden, by anatomic site, 1960 1984. Am J Epidemiol. 1990;132:1066 1077. 14. Bergman L, Seregard S, Nilsson B, Ringborg U, Lundell G, Ragnarsson-Olding B. Incidence of uveal melanoma in Sweden from 1960 to 1998. Invest Ophthalmol Vis Sci. 2002;43:2579 2583. 15. Singh AD, Topham A. Incidence of uveal melanoma in the United States: 19731997. Ophthalmology. 2003;110:956 961. 16. Vajdic CM, Kricker A, Giblin M, et al. Incidence of ocular melanoma in Australia from 1990 to 1998. Int J Cancer. 2003;105:117 122. 17. Fearon ER. Human cancer syndromes: clues to the origin and nature of cancer. Science. 1997;278:10431050. 18. Goldgar DE, Easton DF, Cannon-Albright LA, Skolnick MH. Systematic population-based assessment of cancer risk in rst-degree relatives of cancer probands. J Natl Cancer Inst. 1994;86:1600 1608. 19. Hemminki K, Vaittinen P. Familial cancers in a nationwide family cancer database: age distribution and prevalence. Eur J Cancer. 1999;35:1109 1117. 20. Houlston RS, Damato BE. Genetic predisposition to ocular melanoma. Eye. 1999;13:43 46. 21. Mattsson B, Wallgren A. Completeness of the Swedish Cancer Register: non-notied cancer cases recorded on death certicates in 1978. Acta Radiol Oncol. 1984;23:305313. 22. The Swedish Cancer Registry. In: The National Board of Health and Welfare/The Centre for Epidemiologist/The Swedish Cancer Registry. Available at http://www.sos.se/epc/english/cancereng. htm. Accessed on September 30, 2002. 23. Ofcial Statistics of Sweden. Stockholm: The National Swedish Central Bureau of Statistics Annual Publications; 1960 1998. 24. Coleman M, Douglas A, Hermon C, Peto J. Cohort study analysis with a FORTRAN computer program. Int J Epidemiol. 1986;15: 134 137. 25. Boice JD Jr, Curtis RE, Kleinerman RA, Flannery JT, Fraumeni JF Jr. Multiple primary cancers in Connecticut, 1935 82. Yale J Biol Med. 1986;59:533545. 26. Tucker MA, Boice JD Jr, Hoffman DA. Second cancer following cutaneous melanoma and cancers of the brain, thyroid, connective tissue, bone, and eye in Connecticut, 1935 82. Natl Cancer Inst Monogr. 1985;68:161189. 27. Teppo L, Pukkala E, Saxen E. Multiple cancer: an epidemiologic exercise in Finland. J Natl Cancer Inst. 1985;75:207217. 28. Swerdlow AJ, Storm HH, Sasieni PD. Risks of second primary malignancy in patients with cutaneous and ocular melanoma in Denmark, 19431989. Int J Cancer. 1995;773779. 29. Turner BJ, Siatkowski RM, Augsburger JJ, Shields JA, Lustbader E, Mastrangelo MJ. Other cancers in patients with uveal melanoma and their families. Am J Ophthalmol. 1989;107:601 608. 30. Lischko AM, Seddon JM, Gragoudas ES, Egan KM, Glynn RJ. Evaluation of prior primary malignancy as a determinant of uveal melanoma: a case-control study. Ophthalmology. 1989;96:1716 1721. 31. Holly EA, Aston DA, Ahn DK, Kristiansen JJ, Char DH. No excess prior cancer in patients with uveal melanoma. Ophthalmology. 1991;98:608 611. 32. Kindy-Degnan N, Char D, Kroll S. Coincident systemic malignant disease in patients with uveal melanoma. Can J Ophthalmol. 1989;24:204 206. 33. Collaborative Ocular Melanoma Study Group. Second primary cancers after enrollment in the COMS trials for treatment of choroidal melanoma: COMS Report No. 25. Arch Ophthalmol. 2005;123: 601 604. 34. Easton DF, Steele L, Fields P, et al. Cancer risks in two large breast cancer families linked to BRCA2 on chromosome 13q12-13. Am J Hum Genet. 1997;61:120 128. 35. Sinilnikova OM, Egan KM, Quinn JL, et al. Germline brca2 sequence variants in patients with ocular melanoma. Int J Cancer. 1999;82:325328. 36. Hearle N, Damato BE, Humphreys J, et al. Contribution of germline mutations in BRCA2, P16(INK4A), P14(ARF) and P15 to uveal melanoma. Invest Ophthalmol Vis Sci. 2003;44:458 462.

nicant SIR of 5.04 for development of cutaneous melanoma 1 to 10 years after an uveal melanoma.54 The reverse, an increased risk of uveal melanoma after a primary cutaneous melanoma was not found in either study. In our investigation, to minimize the risk of including uveal melanoma metastases, we omitted the registered cases of cutaneous melanoma (18 patients) diagnosed only at autopsy or within 2 years of the patients death, which still leaves an SIR of 1.75. If we had calculated the standardized incidence ratios directly from the notications in the Cancer Registry, and disregarded the possibility of a miscoded metastatic uveal melanoma, the SIR would be 4.60 (95% CI: 3.08 6.61). This nding could indicate that previously published SIRs in patients with uveal melanoma may have included cases in which metastatic uveal melanoma was miscoded as primary cutaneous melanoma. Although misclassications of metastatic uveal melanomas in cancer registries probably have inated incidence ratios, coexistence of uveal and cutaneous melanoma appears to be more common than previously believed. Using stringent criteria, we could not conrm that patients with uveal melanoma are at a statistically signicant increased risk of development of subsequent cutaneous melanoma. However, lesions reported as subsequent primary cutaneous melanoma but unavailable for histopathological conrmation (and therefore withdrawn from analysis in our study) may have included true cases of primary cutaneous melanoma. Our ndings could provide some support for dermatological examination after diagnosis of uveal melanoma.

References
1. Mooy CM, Van der Helm MJ, Van der Kwast TH, De Jong PT, Ruiter DJ, Zwarthoff EC. No N-ras mutations in human uveal melanoma: the role of ultraviolet light revisited. Br J Cancer. 1991;64:411 413. 2. Dolin PJ, Johnson GJ. Solar ultraviolet radiation and ocular disease: a review of the epidemiological and experimental evidence. Ophthalmic Epidemiol. 1994;1:155164. 3. English DR, Armstrong BK, Kricker A, Fleming C. Sunlight and cancer. Cancer Causes Control. 1997;8:271283. 4. Scotto J, Fraumeni JF Jr, Lee JA. Melanomas of the eye and other noncutaneous sites: epidemiologic aspects. J Natl Cancer Inst. 1976;56:489 491. 5. Seddon JM, Gragoudas ES, Glynn RJ, Egan KM, Albert DM, Blitzer PH. Host factors, UV radiation, and risk of uveal melanoma: a case-control study. Arch Ophthalmol. 1990;108:1274 1280. 6. Vajdic CM, Kricker A, Giblin M, et al. Sun exposure predicts risk of ocular melanoma in Australia. Int J Cancer. 2002;101:175182. 7. Tucker MA, Shields JA, Hartge P, Augsburger J, Hoover RN, Fraumeni JF Jr. Sunlight exposure as risk factor for intraocular malignant melanoma. N Engl J Med. 1985;313:789 792. 8. Li W, Judge H, Gragoudas ES, Seddon JM, Egan KM. Patterns of tumor initiation in choroidal melanoma. Cancer Res. 2000;60: 37573760. 9. Holly EA, Aston DA, Char DH, Kristiansen JJ, Ahn DK. Uveal melanoma in relation to ultraviolet light exposure and host factors. Cancer Res. 1990;50:57735777. 10. Singh AD, Rennie IG, Seregard S, Giblin M, McKenzie J. Sunlight exposure and pathogenesis of uveal melanoma. Surv Ophthalmol. 2004;49:419 428. 11. Chang AE, Karnell LH, Menck HR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer. 1998;83:1664 1678. 12. Mansson-Brahme E, Johansson H, Larsson O, Rutqvist LE, Ringborg U. Trends in incidence of cutaneous malignant melanoma in a Swedish population 1976 1994. Acta Oncol. 2002;41:138 146.

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37. Scott RJ, Vajdic CM, Armstrong BK, et al. BRCA2 mutations in a population-based series of patients with ocular melanoma. Int J Cancer. 2002;102:188 191. 38. Iwamoto S, Burrows RC, Kalina RE, et al. Immunophenotypic differences between uveal and cutaneous melanomas. Arch Ophthalmol. 2002;120:466 470. 39. Singh AD, Wang MX, Donoso LA, Shields CL, De Potter P, Shields JA. Genetic aspects of uveal melanoma: a brief review. Semin Oncol. 1996;23:768 772. 40. Sour N, Bressac-de Paillerets B, Desjardins L, et al. Individuals with presumably hereditary uveal melanoma do not harbour germline mutations in the coding regions of either the P16INK4A, P14ARF or cdk4 genes. Br J Cancer. 2000;82:818 822. 41. Wang X, Egan KM, Gragoudas ES, Kelsey KT. Constitutional alterations in p16 in patients with uveal melanoma. Melanoma Res. 1996;6:405 410. 42. Edmunds SC, Kelsell DP, Hungerford JL, Cree IA. Mutational analysis of selected genes in the TGFbeta, Wnt, pRb, and p53 pathways in primary uveal melanoma. Invest Ophthalmol Vis Sci. 2002;43: 28452851. 43. Cree IA. Cell cycle and melanoma: two different tumours from the same cell type. J Pathol. 2000;191:112114. 44. Elwood JM, Jopson J. Melanoma and sun exposure: an overview of published studies. Int J Cancer. 1997;73:198 203. 45. Singh AD, Shields CL, Shields JA, Eagle RC, De Potter P. Uveal melanoma and familial atypical mole and melanoma (FAM-M) syndrome. Ophthalmic Genet. 1995;16:53 61.

Cancers Co-occurring with Uveal Melanoma

77

46. van Hees CL, Jager MJ, Bleeker JC, Kemme H, Bergman W. Occurrence of cutaneous and uveal melanoma in patients with uveal melanoma and their rst degree relatives. Melanoma Res. 1998; 8:175180. 47. Hammer H, Toth-Molnar E, Olah J, Dobozy A. Cutaneous dysplastic naevi: risk factor for uveal melanoma. Lancet. 1995;346:255256. 48. Bataille V, Pinney E, Hungerford JL, Cuzick J, Bishop DT, Newton JA. Five cases of coexistent primary ocular and cutaneous melanoma. Arch Dermatol. 1993;129:198 201. 49. Hurst EA, Harbour JW, Cornelius LA. Ocular melanoma: a review and the relationship to cutaneous melanoma. Arch Dermatol. 2003;139:10671073. 50. Seregard S, af Trampe E, Mansson-Brahme E, Kock E, Bergenmar M, Ringborg U. Prevalence of primary acquired melanosis and nevi of the conjunctiva and uvea in the dysplastic nevus syndrome: a case-control study. Ophthalmology. 1995;102:1524 1529. 51. Scull JJ, Alcocer CE, Deschenes J, Burnier MN Jr. Primary choroidal melanoma in a patient with previous cutaneous melanoma. Arch Ophthalmol. 1997;115:796 798. 52. Gilbert CM, el Baba F, Schachat AP, Grossniklaus H, Green WR. Nonsimultaneous primary choroidal and cutaneous melanomas: report of a case. Ophthalmology. 1987;94:1169 1172. 53. Shors AR, Iwamoto S, Doody DR, Weiss NS. Relationship of uveal and cutaneous malignant melanoma in persons with multiple primary tumors. Int J Cancer. 2002;102:266 268. 54. Hemminki K, Zhang H, Czene K. Association of rst ocular melanoma with subsequent cutaneous melanoma: results from the Swedish Family-Cancer Database. Int J Cancer. 2003;104:257258.