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From the1Ocular Oncology Service and 2Ophthalmic Pathology Laboratory, Department of Ophthalmology, Helsinki University Central Hospital, Helsinki, Finland.
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Abstract |
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METHODS. Charts, registry data, and histopathologic specimens of 289 consecutive patients with choroidal and ciliary body melanoma treated in the district of the Helsinki University Central Hospital, Finland, between 1962 and 1981 were audited. Definitions for coding the cause of death were adapted from the Collaborative Ocular Melanoma Study (COMS). Competing risks were taken into account by using cumulative incidence analysis and competing risks regression.
RESULTS. Of the 289 patients treated, 239 were deceased at the end of follow-up. The audited cause of death was uveal melanoma in 145 (61%) of them. The median follow-up of the 50 survivors was 28 years. The original histopathologic diagnosis of metastasis and second cancer was correct in 91% of all specimens, but immunohistochemical reassessment changed 10% of biopsy and 7% of autopsy diagnoses. Of 45 positive autopsies, 18% were performed without suspicion of melanoma. Uveal melanoma–related mortality was 31% (95% confidence interval [CI], 26–37) by 5 years, 45% (95% CI, 40–51) by 15 years, 49% (95% CI, 43–55) by 25 years, and 52% (95% CI, 45–58) by 35 years, according to cumulative incidence analysis. Of patients who died of uveal melanoma, 62%, 90%, 98%, and 100% did so within 5, 15, 25, and 35 years, respectively. Between 15 and 35 years, 20% to 33% of deaths were still due to uveal melanoma. By competing risks regression analysis, the hazard ratio was 1.08 (P = 0.0012) for each millimeter increase in tumor diameter, 2.27 (P = 0.0076) for extraocular growth, and 1.89 (P = 0.0011) for ciliary body involvement.
CONCLUSIONS. Metastatic uveal melanoma was the leading single cause of death throughout the study. Cumulative incidences provide a sound basis for patient counseling and design of trials.
Several case reports describe supposedly unusual malignant uveal melanomas that showed clinical metastasis more than 20 years after enucleation.7 8 9 10 These isolated reports cannot be used to quantitate the frequency of such a very late appearance of progressive metastasis. Few studies report survival data beyond 15 years, and the number of patients who remain under review at that time typically is low.11 12 13 14 15 16 17 In published Kaplan-Meier curves of melanoma-related mortality, latest deaths tend to occur between 10 and 18 years after diagnosis.11 18 19
The reasons for the scarcity of long-term survival data are that patients with uveal melanoma are mostly middle-aged or older, their life expectancy may be limited because of other illnesses, follow-up data of patients treated long ago are difficult to collect, the founding of national cancer registries is fairly recent, and patients may be difficult to trace long after treatment.
We determined the very long-term prognosis, defined as survival 15 years or more after treatment of a primary choroidal and ciliary body melanoma, in a consecutive series of patients from a defined region. Cause of death was audited by using cancer registry data and the patients’ charts and by immunohistochemical restaining of histopathologic specimens. We also tested statistically the sufficiency of follow-up to conclude whether cured patients were present in the data set. Cumulative incidence analysis and competing risks proportional hazards regression were used to estimate survival proportions most relevant for counseling of patients, most of whom are currently managed conservatively without access to histopathology.
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Patients and Methods |
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Eligibility Criteria and Study Design
Eligible for analysis in the study were patients who had choroidal and ciliary body melanoma managed a minimum of 20 years earlier. Iris melanomas were ineligible. This investigation was approved by the Institutional Review Board and adhered to the tenets of The Declaration of Helsinki.
Files of the Ophthalmic Pathology Laboratory, Department of Ophthalmology, Helsinki University Central Hospital, were searched from May 1962, when it was founded, to December 1981, to enroll all consecutive patients who underwent enucleation or exenteration. During this period, radical surgery was standard treatment for all but the smallest melanomas, which were observed for growth, and all eyes removed in the district were submitted to this laboratory. Two tumors diagnosed at autopsy and one rediagnosed as a nevus were excluded. Largest basal tumor diameter (LBD) and tumor height were measured from the sections or recorded from pathology reports.
Follow-Up and Assessment of Cause of Death
A total of 240 patients had died by December 31, 2001. Complete data for all patients, except one whose identity could not be verified, were obtained from the Finnish Population and Cancer Registries and all hospitals and histopathology laboratories that had participated in management of uveal melanoma, its metastases, and other malignant tumors. Data for one patient who had emigrated was tracked manually. Records concerning terminal illness were obtained. Death certificates and histopathologic specimens were evaluated by consensus of two investigators to ascertain whether metastatic melanoma was present.
Definitions from the Collaborative Ocular Melanoma Study (COMS) were adapted.20 21 If a specimen represented melanoma metastasis by review or it could not be retrieved but the original report unquestionably mentioned moderate to heavy melanin or HMB-45 immunopositivity, the code was "dead with melanoma metastasis (confirmed metastasis)." If the report did not mention either characteristic or if only a fine-needle aspiration biopsy had been performed and clinical findings (e.g., hepatomegaly, elevated liver function tests, and abnormal liver imaging) were consistent with hepatic metastases, the code ended "suspected melanoma metastasis." If the death certificate specified melanoma, but clinical data were uninformative or the diagnosis was other than cancer when symptoms and clinical findings were consistent with hepatic metastases, it ended "possible melanoma metastasis."
If a specimen represented another malignancy by review, the code was "malignant tumor present, not metastatic melanoma (confirmed second cancer)." If there was evidence of a second primary cancer and the clinical course did not suggest hepatic metastasis, the coding ended "suspected second cancer," and if the death certificate specified other cancer but clinical data were uninformative it ended "possible second cancer."
The code was "no evidence of malignancy (confirmed nonneoplastic disease)" if the autopsy revealed no cancer. If the death certificate specified disease other than cancer, the patient was not registered in the cancer registry for a second cancer, the patient’s charts were consistent with the given diagnosis, and liver imagining and liver function test results or both were normal within 6 months before death, the code ended "suspected nonneoplastic disease." If neither test had been conducted within 6 months of death, the code ended "possible nonneoplastic disease." "Insufficient evidence to establish presence of malignancy" was used if original charts could not be retrieved.
Statistical Analysis
Analyses were performed on computer (Stata, ver. 7.0; Stata Software, College Station, TX, and R, ver. 1.4.0; available at http://www.r-project.org/ provided by The R Foundation for Statistical Computing, Vienna, Austria) software. All probabilities were two-sided, and P < 0.05 was considered significant.
Univariate analysis of survival was based on the cumulative incidence method, which appropriately handles failures from competing risks.22 This is mandatory when long-term survival is evaluated, because competing events increase with follow-up as patients become older. In the calculation of cumulative incidence, only patients alive at the study’s termination and those lost to follow-up were censored.22 We estimated mortality related to melanoma, second cancer, and nonneoplastic disease. Cumulative incidence between categories was compared with the Gray’s K-sample test.23 Age was divided in quartiles and LBD in three categories (<10, 10–15, and 
16 mm).
For comparison, the Kaplan-Meier estimate24 of melanoma-related mortality was calculated. In the calculation of the Kaplan-Meier estimate, patients who die of unrelated causes are also censored. Deaths that occur after the first competing risk event contribute more to the estimate than is appropriate, and the melanoma-related mortality is overestimated.22 The magnitude of the discrepancy depends on the timing and number of competing risk events. Survival curves were plotted to show mortality rather than survival to ease comparison with cumulative incidence.24
Evidence for the presence of cured ("immune") patients in the data was tested according to Maller and Zhou.25 26 The null hypothesis was that there are no cured patients. Reverse censoring suggested that censoring distribution was uniform, and the corresponding statistical Table A.2 was used.25 If the null hypothesis is rejected, cured patients either are present or follow-up is insufficient to be decisive.25 The sufficiency of follow-up was tested by the qn test of Maller and Zhou,25 26 which is based on the distance between the largest censored and uncensored failure time. Both tests are nonparametric and make no assumption of the type and shape of the survival distribution.25 27
Multivariate analysis of melanoma-related survival was based on competing risks proportional hazards regression.28 Because cumulative incidence analysis suggested that mortality would not differ within the two lowest and two highest age quartiles, age at diagnosis was dichotomized according to its median. Tumor dimensions were modeled as continuous variables. Models were compared with each other by using the deviance test.29
For comparison, the hazard rate (HR) was calculated by using the more commonly applied Cox proportional hazards regression,30 in which melanoma-related deaths after the first competing risk event contribute more to the statistics than is appropriate.
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Results |
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TopAbstractPatients and MethodsResultsDiscussionReferences |
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Biopsy and Autopsy Histopathology
A surgical or core needle biopsy to diagnose metastases or second primary cancer was performed in 77 (27%) patients. The original report identified 54 (70%) as melanoma metastases, 22 (29%) as second cancer, and 1 (1%) as nonneoplastic. Autopsy was performed in 70 (29%) of the 239 deceased patients. According to the autopsy report, 25 (36%) died without malignancy. Metastatic melanoma was recorded in 42 (60%) and second cancer in 3 (4%) autopsies.
Reassessment of 60 biopsy specimens showed the diagnosis to be incorrect in 6 (10%; 95% CI, 8–29). Five were amelanotic, epithelioid cell melanoma metastases to the liver and not hepatocellular and metastatic colonic carcinoma, and one was an anaplastic glioma. The diagnosis in 3 (7%; 95% CI, 1–18) of 45 autopsies in which a malignancy was found was incorrect. One presumed cholangiocarcinoma was in fact metastatic uveal melanoma and two presumed melanoma metastases were misdiagnosed metastatic mucocellular and anaplastic carcinoma of unknown origin.
Of 40 autopsies in which metastatic uveal melanoma was confirmed, 7 (18%; 95% CI, 7–33) were performed without suspicion of melanoma metastasis (e.g., because of presumed cerebrovascular accident, renal failure after hip surgery, and second cancer). This represented 10% (95% CI, 4–20) of all autopsies and 5% (95% CI, 2–10) of all deaths due to uveal melanoma.
Audited Cause of Death
The cause of death on the death certificate was melanoma in 132 patients (55%), second cancer in 27 (11%), and nonneoplastic disease in 79 (33%; Table 1 ). The audited cause of death was uveal melanoma in 145 patients (61%), second cancer in 17 (7%), and no evidence of malignancy in 75 (31%). Of the original diagnoses of metastatic melanoma and second cancer, 98% and 52%, respectively, were correct (Table 1) .
The audited cause of death was considered confirmed in 128 (54%) patients, suspected in 28 (12%), and possible in 63 (23%; Table 1 ). Of melanoma metastases and second cancers, 63% and 65%, respectively, were confirmed.
All-Cause Mortality
For all-cause mortality, Kaplan-Meier (Fig. 2A) and cumulative incidence estimates are identical.22 The all-cause mortality by 15, 25, and 35 years was 65%, 79%, and 88%, respectively, Table 2 shows the corresponding survival estimates.
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Competing Causes of Death
The cumulative incidence of dying of a second cancer or nonneoplastic disease by 25 years was 6% (95% CI, 3–8) and 24% (95% CI, 19–29), respectively (Fig. 3A , Table 2 gives the corresponding survival estimates). The Kaplan-Meier method exaggerated mortality by 6 and 21 percentage points, respectively (Table 2) .
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The Kaplan-Meier method grossly exaggerated mortality of the highest age quartile (2, 6, 5, and 17 percentage points per quartile, Fig. 2E ). The cumulative incidence estimate was comparable for the two lowest (42% vs. 40% at 20 years) and highest age quartiles (56% vs. 56%), suggesting change around the median age (57 years; P = 0.050; Fig. 2F ). In all quartiles in which patients survived beyond 25 years, melanoma deaths still occurred. Death of nonneoplastic disease became increasingly common with age (5%, 18%, 24%, and 38%, respectively; P < 0.0001; Fig. 2G ).
By tumor location, the Kaplan-Meier method exaggerated mortality by 6 and 7 percentage points, respectively (Fig. 3A) . Melanoma-related deaths were more frequent (71% vs. 43% at 25 years, P < 0.0001; Fig. 3B ) and noncancer deaths less frequent (P = 0.0067) when the tumor involved the ciliary body than when it was limited to the choroid. After 20 years, melanoma-related deaths occurred only among patients with choroidal melanoma. With extraocular extension, Kaplan-Meier estimates were 7 and 13 percentage points higher than cumulative incidences, respectively (Fig. 3C) . Melanoma-related deaths were more frequent if extraocular extension was present (72% vs. 46%; P < 0.0001, Fig. 3D ).
The Kaplan-Meier method exaggerated mortality by tumor size by 1, 9, and 8 percentage points, respectively (Fig. 3E) . The cumulative incidence estimates increased with increasing LBD (18%, 52%, 59% for small, medium-sized, and large tumors at 25 years, respectively, Fig. 3F ; P = 0.00022). Noncancer mortality was not associated with tumor size (P = 0.80, Fig. 3G ).
Cured patients were likely to be present in all subgroups by tumor location, extrascleral growth, and tumor size (Table 3) . There was sufficient follow-up to be confident of their presence among those who had extrascleral extension (P > 0.95) and nearly enough among those in whom the tumor involved the ciliary body (Table 3) . Follow-up was insufficient (P = 0.10) in patients with small and large melanomas for us to be confident of the presence of cured patients.
Multivariate Analysis
By multivariate competing risks and Cox regression, tumor height lost significance in models that included LBD. Gender, ciliary body involvement, extraocular growth, and LBD were significantly associated with risk of melanoma-related death (Table 5) . In contrast to Cox regression, age at diagnosis (HR 1.01) lost significance and was omitted from the final competing risk model, which included LBD (HR 1.08 for each 1-mm increase; P = 0.0012), extraocular growth (HR 2.27; P = 0.0011), and ciliary body involvement (HR 1.89; P = 0.0076) as independent predictors of melanoma-related death. Gender (HR 1.36 for females, P = 0.095) was not excluded as an independent predictor of melanoma-related mortality (Table 5) .
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Discussion |
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TopAbstractPatients and MethodsResultsDiscussionReferences |
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Of 1205 deaths caused by uveal melanoma in the Registry of Ophthalmic Pathology, Armed Forces Institute of Pathology, Washington, D.C., only 59 (4.9%) occurred after 15 years,16 and the corresponding numbers were 8 (4.1%) of 197 deaths in the Moorfields Eye Hospital, London,32 and 3 (4.5%) of 67 deaths registered at the University of Iowa, Iowa.13 All these figures are roughly half of our estimates (9.6%), suggesting that late melanoma-related deaths have been underestimated in previous series that were based on nonaudited registry data.6 13 17 32
A histopathologic audit showed that from 7% to 10% of original cancer diagnoses that had not been based on immunohistochemistry were incorrect. Most often, amelanotic melanoma metastasis had been confused with second cancer. Biopsy and autopsy were almost equally likely to result in misdiagnosis, but biopsy was more likely than autopsy to underestimate metastatic melanoma. These results extend our previous observations33 and cast doubt on the appropriateness of using nonaudited registry data in prognostic studies.
Our very long-term Kaplan-Meier estimates were similar to those reported in a unique 10-year nationwide cohort of 292 Danish patients treated from 1943 to 195234 and subsequently observed for 25 to 35 years.35 36 This study found survival proportions at 20 and 25 years to be 42% and 40%, respectively, compared with 45% and 44% in our study. The similarity of the results of our regional series based on a much later 20-year cohort with 20 to 40 years of follow-up suggests that the figures are robust. They are consistent with the opinion that the prognosis of uveal melanoma has not appreciably improved over time,37 despite the fact that the number of patients with extraocular growth has decreased from 17% in the Danish study34 and 10% in ours.
The Kaplan-Meier estimates reflect the theoretical situation that melanoma would be the only possible cause of death.22 38 Cumulative incidence estimates, which take competing risks into account,38 are more accurate when the actual risk of dying has to be cited in patient counseling and as an aid in calculating accrual for prospective studies. Kaplan-Meier estimates are too pessimistic for the former and too optimistic for the latter purpose. Our study provides estimates that apply in the long term and to melanomas of all sizes. During the first decade, the difference between the estimates was minor, but eventually Kaplan-Meier analysis exaggerated melanoma-related mortality by 25% (10% units). Actual melanoma-related mortality reached 50% by 30 years rather than by 15 years, as estimated by the Kaplan-Meier method.19 33
The earlier and the more frequent the competing risk events are, the larger is the difference between the two estimates.22 This was evident especially when analyzing the effect of age at diagnosis. In the highest age quartile, competing risks were very frequent and the Kaplan-Meier analysis grossly overestimated mortality. According to competing risks regression, age was not an independent predictor of melanoma-related death, in striking contrast to our Cox proportional hazards regression, suggesting confounding from competing risks in previous Cox regression analyses that identified age as an independent prognostic factor.13 38 39 Gender was of borderline significance. It may be that, for example, earlier and more frequent cardiovascular deaths in men in part prevented an equal number of melanoma deaths from occurring compared with females.
Although we did not observe melanoma deaths more than 34 years after diagnosis, metastasis after 40 years has been reported.7 8 Care must be taken when ascribing very late deaths to the original primary cancer, because of the possibility of a second primary melanoma developing in the other eye, skin, and mucous membranes.8 Statistical tests recently developed for assessing the presence of cured patients among long-term survivors26 27 failed to provide conclusive evidence of their presence in our series, notwithstanding the 20- to 40-year follow-up, supporting the concept that very late metastases indeed are part of the spectrum of disseminated uveal melanoma. This field of survival statistics is in its infancy, and the tests available are relatively crude and conservative.25 It is still unlikely that a follow-up for patients with uveal melanoma will ever be available that is sufficiently long to allow the conclusion that all remaining survivors are cured.
Our study confirms that uveal melanoma typically can lead to death caused by delayed metastasis several decades after the primary tumor was definitively treated. Where the metastatic cells reside, in apparent dormancy, and the events leading to delayed progressive clinical metastasis are important to identify. Evidence for the presence of cured patients was found in subgroups that had a short rather than long median survival. One independent epidemiologic study has provided evidence that mechanisms governing cure of uveal melanoma are not identical with those that determine survival time among uncured patients.6 These observations support the idea that the ability of uveal melanoma cells to escape from the eye is not strictly linked with their ability to grow progressively.
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Footnotes |
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Submitted for publication May 28, 2003; revised July 8, 2003; accepted July 30, 2003.
Disclosure: E. Kujala, None; T. Mäkitie, None; T. Kivelä, 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: Emma Kujala, Department of Ophthalmology, Helsinki University Central Hospital, Haartmaninkatu 4 C, PL 220, FIN-00029 HUS, Helsinki, Finland; emma.kujala{at}hus.fi.
Abbreviations: SE, standard error; HR, hazard ratio; CI, confidence interval; LBD, largest basal diameter.
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