Staging of ciliary body and choroidal melanomas based on anatomic extent.

PURPOSE: To refine the anatomic classification and staging of ciliary body and choroidal melanomas in the TNM classification. PATIENTS AND METHODS: Tumor largest basal diameter and thickness of 7,369 patients were analyzed based on registry data from five ocular oncology centers. T categories were derived empirically by dividing data into blocks representing 3- × 3-mm fractions. Blocks with similar survival were grouped together so that no T category comprised a large majority of tumors, and each was uniform in survival, using randomly drawn 60% building and 40% validation data sets. Presence of ciliary body involvement (CBI) and extraocular extension (EXE) was analyzed among 5,403 patients to define T subcategories. Stages were generated by iteratively combining subcategories with similar survival. RESULTS: Of the 7,369 tumors analyzed, 24% were classified as T1, 33% as T2, 31% as T3, and 12% as T4. Ten-year Kaplan-Meier survival estimates for the T categories were 89%, 77%, 58%, and 39%, respectively (P < .001). Survival of patients in four subcategories based on presence or absence of CBI and EXE differed significantly within each T category (P = .018 for T1; P < .001 for T2 to T4). EXE exceeding 5 mm in largest diameter carried a worse prognosis than smaller extensions (P < .001) and was assigned a separate subcategory. Ten-year Kaplan-Meier survival estimates for stages I, IIA to IIB, and IIIA to IIIC were 88%, 80%, 67%, 45%, 27%, 10%, respectively (P < .001). CONCLUSION: This evidence-based anatomic classification provides a basis for staging ciliary body and choroidal melanomas in the seventh edition of the Cancer Staging Manual of the American Joint Committee on Cancer.

Mortality after uveal and conjunctival melanoma: which tumour is more deadly?

PURPOSE: We aimed to model and compare mortality rates for uveal melanoma (UM) and conjunctival melanoma (CM) by adjusting for differences in tumour size and local recurrence. METHODS: Population-based mortality data for 240 and 85 patients with primary UM and CM and 91 and 23 patients with disseminated UM and CM, respectively, were compared with cumulative incidence analysis. Cox proportional hazards multivariate regression with time-dependent variables was used to adjust for differences in tumour diameter, thickness and recurrence rates. RESULTS: The 10-year cumulative incidences of metastatic death from UM and CM were 39% (95% confidence interval [CI] 33-45) and 32% (95% CI 21-44), respectively. After adjusting for tumour size, risk of death from CM was higher than from UM (hazard ratio [HR] 1.9; p = 0.039). Additional adjustment for more frequent local recurrence of CM diminished the difference (HR 1.5; p = 0.25). Survival periods after systemic metastasis of UM and CM were comparable (median 8 months). CONCLUSIONS: Clinical observations show longer survival after primary CM than after primary UM. This reflects the smaller average size of CM. However, a primary CM of a given size is more deadly than a UM of equivalent size because primary CM tends to recur after treatment and, possibly, because additional lymphatic dissemination occurs with CM.

Tumor, node, metastasis classification of malignant ciliary body and choroidal melanoma evaluation of the 6th edition and future directions.

PURPOSE: The tumor, node, metastasis classification of malignant uveal melanoma has been revised. We evaluated how the 6th edition (TNM6) improves on the previous one (TNM5). DESIGN: Population-based, retrospective, cross-sectional study. PARTICIPANTS: Two hundred eighty-nine consecutive patients who had a ciliary body and choroidal melanoma treated in the district of the Helsinki University Central Hospital, Finland, between 1962 and 1981. METHODS: Tumor dimensions, ciliary body involvement, and extraocular extension were evaluated from histopathologic sections and pathology reports. Tumors were assigned into categories and stages according to TNM6, TNM5, and 2 previously proposed size classifications. MAIN OUTCOME MEASURES: Proportion of tumors classified in each category and melanoma-specific survival by category and stage. RESULTS: Of the 289 melanomas, 5% were classified as pT1, 63% as pT2, 22% as pT3, and 7% as pT4 according to TNM6. The corresponding percentages based on TNM5 were 8%, 17%, 63%, and 10%. Of pT2 tumors in TNM6, 4% came from pT1, 65% from pT3, and 4% from pT4 category of TNM5. Of 28 melanomas with extraocular growth, 29% were classified as pT2 in TNM6 rather than pT4 in TNM5. The 10-year survival estimate was 2 percentage points lower for pT1, 7 percentage points higher for pT2, 17 percentage points lower for pT3, and 13 percentage points lower for pT4 by TNM6 compared with TNM5; TNM6 (P<0.0001) and the modified alternative size classifications (P = 0.0022 and P = 0.0026) divided tumors according to prognosis better than TNM5. The 10-year survival for stage I, II, and III tumors was 2 percentage points lower, 7 points higher, and 23 points lower by TNM6, which was not better than TNM5 in separating patients according to prognosis (P = 0.47). The alternative size classifications provided more equal categories and fitted the data set better than TNM5 regarding prognosis. CONCLUSIONS: TNM6 is an improvement over TNM5 in some, but not all, respects. Areas for development include taking into account ciliary body involvement and extraocular extension in more detail and combining into each stage tumor categories with similar rather than different prognosis. An evidence-based, multicenter approach would be beneficial.

Microcirculation and tumor-infiltrating macrophages in choroidal and ciliary body melanoma and corresponding metastases.

PURPOSE: To investigate the relationship between progression to hepatic metastasis and tumor-infiltrating macrophages and microcirculation attributes in uveal melanoma, a cancer that almost invariably disseminates hematogenously to the liver. METHODS: A cross-sectional histopathologic analysis of 48 hepatic metastases and corresponding primary choroidal and ciliary body melanomas was conducted, by using statistical tests appropriate for paired data. Main outcome measures were the number and type of CD68-immunopositive, tumor-infiltrating macrophages, extravascular matrix loops and networks identified with periodic acid-Schiff stain, and microvascular density (MVD) counted as the number of discrete structures labeled by monoclonal antibody QBEND/10 to the CD34 epitope. RESULTS: Hepatic metastases had a significantly lower grade of pigmentation (P < 0.0001), more frequent epithelioid cells (P = 0.0027), more intermediate and dendritic types of CD68-immunopositive macrophages than round ones (P = 0.0031), and a higher MVD (median difference, 15 counts more/0.313 mm2, P = 0.0003) than the primary uveal melanomas that spawned the metastases. The frequency of tumors with extravascular loops and networks did not increase on metastasizing. The survival of the patient after diagnosis of disseminated disease tended to be shorter if hepatic metastases had a high MVD (P = 0.098), adjusting for the size of the specimen. CONCLUSIONS: Of the markers studied, the presence of epithelioid cells and MVD most closely parallel progression of uveal melanoma from primary tumor to metastasis. These two tumor characteristics may be interrelated, and high MVD may help to predict survival after detection of hepatic metastases. The results also suggest that the grade of pigmentation and morphologic type of tumor-infiltrating macrophages are interrelated.

Macrophages and microcirculation in regressed and partially regressed irradiated choroidal and ciliary body melanomas.

PURPOSE: To investigate how tumour-infiltrating macrophages and microcirculation attributes of uveal melanomas regressed after brachytherapy and whether primarily enucleated melanomas differ. METHODS: A case-control analysis of 34 matched pairs of irradiated and nonirradiated choroidal and ciliary body melanomas with main outcome variables being area of necrosis, extravascular matrix loops and networks, tumour-infiltrating macrophages in nonnecrotic areas identified with mAb PG-M1 to the CD68 epitope, and microvascular density (MVD) determined by mAb QBEND/10 to the CD34 epitope. RESULTS: Comparison of primarily enucleated eyes to eyes with irradiated, secondarily enucleated melanomas revealed significantly more necrosis (median difference, +9%, P = 0.0012) and lower MVD (median difference, -10 counts/0.313 mm(2), P = 0.011) in the latter. In eyes managed with brachytherapy, loops and networks tended to be less frequent (P = 0.077). Number and type of macrophages were similarly distributed, being moderate to high in about 95% (P = 0.67) of the matched pairs, and intermediate to dendritic in 79% (P = 0.90). In the irradiated eyes, presence of epithelioid cells and the number and type of macrophages showed no association with microcirculation attributes, whereas in the primarily enucleated tumours, high number of macrophages was associated with high MVD (P < 0.001). CONCLUSIONS: This study suggests that regression after brachytherapy reduces MVD. The difference cannot be attributed to different numbers of tumour-infiltrating macrophages and different cell type in nonnecrotic areas of the tumour.

Very long-term prognosis of patients with malignant uveal melanoma.

PURPOSE: To investigate the very long-term prognosis of patients with uveal melanoma and the clinical characteristics influencing it. 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.