Microvascular loops and networks in uveal melanoma.

Microvascular patterns--three-dimensional architectural arrangements of microvessels and extravascular matrix in uveal melanoma--were discovered when investigators were looking for histopathological features of sufficient size to be imaged clinically. Evidence that these patterns may be formed by tumour cells and that they may be able to conduct plasma and blood as well as discovery of similar elements in other cancers make them of general importance. Of nine different patterns described, closed microvascular loops and networks have been studied most extensively. When cell type, microvascular density and nucleolar size are controlled for, these two patterns independently predict time to metastasis. In addition to visualization in tumour specimens stained with periodic acid-Schiff reagent, they can often be visualized clinically on confocal indocyanine green angiography. The presence of networks is clinically associated with probability of growth of small uveal melanocytic tumours and with the rate of regression of uveal melanoma after brachytherapy. Networks are also associated with development of exudative retinal detachment from uveal melanoma. Histopathological studies show that loops and networks are less common in tumours enucleated after irradiation and that they are frequently repeated in metastases of uveal melanoma. Avenues for immediate future research include detailed elucidation of the histogenesis of microvascular patterns and determination of these patterns in metastatic melanoma to identify new histopathological characteristics for prognostication when clinical metastases have developed.

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.

Nucleolar diameter and microvascular factors as independent predictors of mortality from malignant melanoma of the choroid and ciliary body.

PURPOSE: To determine whether nucleolar diameter and microvascular factors are independent predictors of mortality in malignant uveal melanoma of the choroid and ciliary body. METHOD: A population-based retrospective cohort study was conducted of melanoma-specific and all-cause mortality in 167 consecutive patients who had an eye enucleated because of choroidal and ciliary body melanoma from 1972 through 1981. The largest nucleoli were measured from digital photographs of silver-stained tumors along a central 5-mm-wide linear field parallel to the base of the tumor. The mean of the 10 largest nucleoli (MLN) was calculated. Microvascular loops and networks and microvascular density (MVD) were assessed. Kaplan-Meier and Cox regression analyses were performed. Associations between MLN and other variables were determined. RESULTS: The MLN could be determined in 126 (75%) melanomas. It ranged from 2.60 to 6.18 microm (median, 4.05). The association of large MLN with the presence of epithelioid cells (P = 0.017) and high MVD (P = 0.0053) was statistically significant. MLN was not significantly associated with tumor diameter and microvascular loops and networks. The 10-year melanoma-specific survival decreased with MLN (0.74, 0.60, and 0.42, arranged in tertiles; P = 0.0060), presence of loops and networks (P = 0.0001), and increasing MVD (P = 0.0001). By Cox regression, MLN was an independent predictor of survival, when adjusting in turn for presence of epithelioid cells, loops and networks, and MVD. In multivariate models with MVD, the independent prognostic information carried by MLN decreased, but the model as a whole was a better predictor of survival. The magnitude of this effect depended on whether MLN was modeled as a continuous or categorical variable. CONCLUSIONS: In this population-based data set, MLN and microvascular loops and networks were unrelated, independent predictors of survival. MLN and MVD were found to be partially interrelated. Multivariate models that included MVD in addition to MLN fitted better with observed melanoma-specific survival than models that excluded MVD.