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One hundred well-documented cases of uveal melanoma accessioned at the Armed Forces Institute of Pathology before 1970 were reviewed and reclassified to identify changes made in the Callender classification. We compared the new classification with the original classification to determine the effect of the changes on the prediction of outcome for the patient after enucleation. Staff pathologists had originally classified 52 of the 100 cases as spindle-cell type melanoma. Only 31 of the 100 cases were reclassified as spindle-cell types (two spindle-cell nevi and 29 spindle-cell melanomas). Tumors classified as mixed-cell type were further subdivided into groups based on the percentage and size of the epithelioid cells. Tumors formerly classified as spindle-cell type that contained small or rare epithelioid cells were reclassified as mixed-cell type. This improved the prediction of outcome for the patient. We found that nucleolar size and pleomorphism are important variables that should be considered in the classification of uveal melanomas., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Comparative genomic hybridization (CGH) was used to elucidate DNA sequence copy number imbalances in 100 archival formalin-fixed, paraffin-embedded (FFPE) uveal melanoma cases. Of these 100 cases, 51 were from patients who survived >or=9 years post diagnosis without evidence of metastasis; the remaining 49 patients died from metastatic disease. Viable probe was generated from 82 of the 100 cases, allowing correlation of CGH findings with survival for all but 18 cases. Copy number imbalances revealed by CGH were tested for univariate prognostic significance. The most powerful predictor of a poor prognosis was gain of 18q11.2, which was subsequently compared with other significant chromosomal regions, as well as histologic and clinical factors, in a multivariate analysis. There was also evidence of differential X chromosome involvement in the survival correlations between male and female cases, which may be of significance to prognosis. This large-scale CGH analysis of archival material is intended to direct further gene-specific study of malignancy in uveal melanoma.

Uveal melanoma is the most common intraocular tumor in adults and often results in unilateral blindness and/or death. Previous cytogenetic characterizations of this tumor consistently revealed chromosomal abnormalities involving chromosomes 3, 6, and 8; reports of other abnormalities vary in frequency. We defined cytogenetic abnormalities of this tumor using complementary in situ hybridization techniques on 10 uveal melanoma cell lines. Synthesis of comparative genomic hybridization (CGH) and spectral karyotyping (SKY) results revealed that chromosomal rearrangement is involved in DNA sequence copy number abnormalities throughout the genome, but monosomy 3 was not found. Monosomy 3 is thought to be a significant prognostic indicator, so its absence was investigated further. Fluorescence in situ hybridization (FISH) for chromosome 3 revealed approximately 1 centromere signal per cell, but probes for 3p and 3q revealed multiple telomere signals per cell, suggesting chromosomal rearrangement without whole-chromosome loss. Based on combined CGH, SKY, and FISH data, we propose that chromosome 3 is more frequently involved in chromosomal rearrangements than whole-chromosome loss in uveal melanoma. Future approaches should be designed to confirm and enhance the resolution of regions of imbalance in primary tumors. Once identified, conserved chromosomal alterations that contribute to uveal melanoma may reveal the underlying aspects of uveal melanoma onset, metastasis and resistance to current treatment modalities.

Uveal melanomas may arise in the iris, ciliary body or choroid. Choroidal melanomas are the most common and usually display a discoid, collar-button or mushroom-shaped growth pattern. Uveal melanomas are composed of spindle and epithelioid cells and are classified histopathologically as either spindle-cell-type or mixed-cell-type tumours. The most important factors predicting clinical behaviour and underlying biology are cell type, cytomorphometric features, largest tumour dimension, scleral invasion and mitotic figures. Other valuable prognostic factors are tumour-infiltrating lymphocytes and macrophages, and the presence of vascular loops.

Background: The expression of cyclooxygenase-2 (COX-2), an inducible prostaglandin (PG) synthase, has been investigated in various human malignant diseases, such as cutaneous melanoma. We investigated the expression of COX-2 in uveal melanoma and related the findings to prognostic factors., Methods: In 40 cases of uveal melanoma, immunostaining for COX-2 was done. COX-2 expression was related to histopathological prognostic markers, such as cell type, the presence of lymphocytic infiltration and vascular closed loops in the tumour, and cytomorphometry results., Results: COX-2 expression was found in 58% of the cases, and it correlated with markers of poor prognosis, such as epithelioid cell type and the presence of lymphocytic infiltration and vascular closed loops. The uveal melanomas expressing COX-2 had larger nuclei, as determined by cytomorphometry., Interpretation: Whereas epithelioid tumours carry a worse prognosis than spindle cell tumours, until now it has not been possible to give a strong indication of prognosis in mixed-cell tumours. This study showed that mixed-cell tumours, representing the majority of uveal melanomas, may be further subclassified according to COX-2 expression, which serves as a marker of poor prognosis. The role of COX-2 in uveal melanoma should be further elucidated, and the use of COX-2 inhibitors warrants investigation as adjuvant treatment for this life-threatening malignant disease.

Purpose: To summarize and compare the various histologic methodologies for using nucleoli to assess the malignant potential of uveal melanoma., Methods: This was an observational series of 100 samples of uveal melanoma in which histologic sections were studied. The cases were selected so that approximately half (n = 49) of the tumors were from patients who had died of metastatic malignant melanoma. The 51 remaining tumors were from patients who had survived at least 9 years without development of metastasis. Central sections from the uveal melanomas were stained using the colloidal silver nitrate stain for nucleolar organizing regions (AgNOR). These were compared with an adjacent hematoxylin and eosin (H&E)-stained section. A light microscope with a micrometer inset into the eyepiece (x10) was used at a final magnification of x1000 under oil immersion to measure the length of the nucleolus along the longest axis and the width perpendicular to that axis. From at least twenty cells selected from random fields throughout the tumor, the mean of the 10 longest and widest nucleoli (MLN) was calculated. Seven samples had to be discarded because the nucleoli were unmeasurable., Results: T-tests and Cox proportional hazard regression analysis indicated that the MLN of nucleolar length as measured on AgNOR-stained slides was as significant as cell type but was more significant than other histopathologic prognosticating variables measured and evaluated in this study. These prognosticators included tumor size, calculated as the largest tumor dimension; MLN width; and MLN length, as measured on H&E-stained sections., Conclusions: It has previously been demonstrated that AgNOR-stained nucleoli, unlike H&E-stained nucleoli, can be captured and measured by an automated image analyzer with prognostically significant results. This new method of simple oil-immersion measurements of the longest AgNOR-stained nucleoli length in microscopic sections of uveal melanoma provides an inexpensive and highly significant method for predicting outcome in patients with uveal melanoma. Because of the high contrast with the background, the silver-stained nucleoli clearly define the nucleolar boundaries, rendering them readily discernible and allowing greater ease and speed of measurement when compared with H&E-stained nucleoli. The method of random sampling that was used was comparable with linear sampling in predicting outcome. Highly necrotic tumors, however, had to be excluded from the study because of loss of nucleolar morphology.

Purpose: To report associations between prognosis, total tumor necrosis, scleritis, and episcleritis in choroidal and ciliary body melanomas., Methods: In this retrospective observational histopathologic study, 157 totally necrotic melanomas and 177 melanomas that were not totally necrotic of choroidal and ciliary body were retrieved from the Registry of Ophthalmic Pathology. The eyes were examined for the histologic evidence of inflammatory cells within the sclera and episcleral tissues. Contingency table, Kaplan-Meier, and Cox proportional hazard regression analyses were performed. In the survival analyses, only deaths with metastatic melanoma were considered as events in the statistical analysis., Results: Among the totally necrotic melanomas, 118 of 157 (75.1%) had both episcleritis and scleritis; two of 157 (1.3%) had scleritis only; 29 of 157 (18.5%) had episcleritis only; and eight of 157 (5.1%) had neither episcleritis nor scleritis. Among the non-necrotic melanomas, 23 of 177 (12.9%) had both episcleritis and scleritis; eight of 177 (4.5%) had scleritis only; 71 of 177 (40.1%) had episcleritis only; and 75 of 177 (42.3%) had neither episcleritis nor scleritis. Cox regression indicated that total necrosis and scleritis were prognostically significant (P <.05) when analyzed univariately but not significant when analyzed multivariately with tumor size., Conclusions: Scleritis and episcleritis were statistically significantly associated with total tumor necrosis. There was a higher incidence of episcleritis than scleritis in both the necrotic and non-necrotic tumor types. Associations with patient outcome were identified for necrosis and scleritis. However, these associations were statistically insignificant when the prognostic effect of tumor size was also considered in a multivariate model.

Purpose: This study was performed to determine the prognostic significance of the presence of loops defined as periodic acid-Schiff-positive fibrovascular septa that completely surround lobules of tumor cells in cases of uveal melanoma., Methods: The presence of loops was evaluated using an ordinary light microscope and routinely stained periodic acid-Schiff and hematoxylin sections from 496 posterior uveal melanomas without knowledge of the follow-up data on the patient., Results: At 15 years, survival decreased from 67.5% to 33.8% when complete loops were present. Univariate Cox regression analysis indicated that the presence of loops was an indicator of poor outcome, and was better than age but not as good as the mean diameter of the largest nucleoli, cell type, or tumor size., Conclusions: The presence of loops, as evaluated in this study, was not as strong an indicator of poor outcome as were loops assessed in a previous study of 234 cases from another laboratory. The authors suspect this difference may be due to their only using routinely stained sections without a green filter, as was used in previously reported studies. The authors description of loops does not require any special equipment and gives sufficiently useful results to justify its inclusion by the pathologist in reports of such specimens. A description of vascular loops should be added to the use of the modified Callender cell type, tumor dimensions, mitotic count, extraocular extension, and lymphocytic infiltration in the final pathologic report.

Background: Automated image capture and analysis (AICA) has not previously been used to measure the size of nucleoli in uveal melanoma. In this study, the measurements were tested for a possible association with patient outcome., Methods: Sections from 63 uveal melanomas were stained using the silver stain for nucleolar organizing regions (AgNOR). AICA was used to measure the following five nucleolar features in ten microscopic fields of the tumor: area, circularity, maximum diameter, width, and length of the perimeter. For each tumor, the mean and standard deviation of each of the features were calculated based on all the nucleoli and on subsets of nucleoli with larger areas. For the five nucleolar features the mean of the largest value (MLV) in each of the ten fields was calculated. For comparison, a related visually measured nucleolar feature (MLN) was obtained from hematoxylin and eosin stained sections using a filar micrometer., Results: Thirty-four patients died with metastatic disease and 29 patients survived at least 5 years without metastasis. A greater proportion of nucleoli larger than 3 mm2 in greatest dimension were from patients who died of their disease. The means of the nucleolar features were less significant outcome discriminators than the standard deviations. Means and standard deviations based on subgroups of nucleoli larger than 3 or 3.5 mm2 in greatest dimension were better discriminators. The MLVs were as effective discriminators as the corresponding standard deviations of the larger nucleoli and were better discriminators than MLN., Conclusions: AICA of AgNOR stained sections of uveal melanoma provides an excellent method for predicting the outcome of patients with uveal melanoma.

Purpose: Primary orbital melanomas are rare tumors with a poorly defined biologic course. Most recorded experiences concern single case reports. The authors evaluated the applicability of several of the histopathologic prognostic indicators used for uveal melanomas to a series of primary orbital melanomas with known clinical follow-up., Methods: Twenty-one primary orbital melanomas, each with at least a 1-year follow-up after diagnosis, were evaluated for (1) modified Callender cell type, (2) mitotic count per 40 high-power fields, (3) lymphocyte count (less than versus greater than 100/20 high-power fields), (4) blue nevus component, and (5) largest tumor diameter., Results: All patients for whom race was recorded were white. The mean age at diagnosis was 42 years (range, 15-84 years). There was an associated blue nevus in 19 patients (90 percent), and in 10 patients (47.5 percent) there was some form of congenital melanosis. With a mean follow-up period of 4.5 years (range, 1-13 years), mortality from metastatic tumor occurred in 8 (38 percent) of 21 patients. Of these eight patients, there were liver metastases in seven (88 percent) and brain metastases in one (12 percent). Indicators of poor prognosis were tumors of mixed cell type with high mitotic count and greater patient age with underlying congenital melanosis., Conclusion: Most primary orbital melanomas occur in white patients and are associated with blue nevi. These tumors are similar to uveal melanomas with respect to prognostic indicators and pattern of metastasis.

Background: Posterior uveal melanomas with ciliary body involvement have greater mortality when compared with choroidal melanomas. This study was conducted to determine if this association is due to an independent effect or to correlations with other parameters., Methods: From the 4335 cases of uveal melanoma with follow-up data in the Registry of Ophthalmic Pathology, 664 were selected; therefore, approximately two thirds of the patients died of metastatic melanoma. Ciliary body involvement was determined by the location of the anterior tumor margin. Kaplan-Meier survival, Cox regression, and Gamel-Boag log-normal regression analyses were performed. Covariables included ciliary body involvement, largest tumor dimension, mean diameter of the largest ten nucleoli, and modified Callender classification., Results: Kaplan-Meier and univariate Cox analyses indicated a significant association between ciliary body involvement and tumor-related death but when included in a multivariate Cox model, ciliary body involvement was not statistically significant. Similarly, when ciliary body involvement was included in a multivariate Gamel-Boag model, ciliary body involvement was not statistically significant. Melanomas that involve the ciliary body were more likely to be larger (Student's t = 10.5; P = 10(-6)), contain larger nucleoli (Student's t = 2.43; P = 0.015), and be of mixed cell type (chi-square = 17.2; P = 3 x 10(-5))., Conclusions: Ciliary body involvement is associated with tumor-related mortality but this association is primarily due to ciliary body tumors being larger with more malignant cytology.

Purpose: To investigate using immunohistochemistry the unusual finding that tumor infiltrating lymphocytes (TIL) in uveal melanomas are associated with a higher mortality rate., Methods: We performed immunohistochemistry for B and T lymphocytes on 80 uveal malignant melanomas, which previously had been reported to contain more than 100 TIL per 20 high-powered fields. In a second study of 90 patients, we counted the number of immunohistochemically stained T lymphocytes per 20 high-powered fields in uveal melanomas from 30 patients who survived at least 15 years after enucleation, from 30 patients who died with metastasis within 2 years, and from 30 patients who died with metastasis more than 10 years after enucleation., Results: T cells predominated in 73.8% of the 80 patients, and B cells were more prevalent in 13.8%. T cells were usually scattered, and B cells were usually in clumps. Post-enucleation 18-yr mortality from metastasis was 73% for patients with either T- or B-cell predominance of their TIL. The mortality rate was 32% for patients with few TIL. The patients who survived at least 15 yrs after enucleation had fewer T lymphocytes infiltrating their uveal melanomas than the two groups of patients who died with metastasis., Conclusions: The pattern of the TIL was different for T and B cells in uveal melanomas. T-lymphocytic infiltration is associated with death due to metastasis.

Background: For certain types of cancer, resection alone rarely achieves a cure, but patients nevertheless tend to have a prolonged survival before they die of the tumor. For other types of cancer, the opposite scenario prevails, suggesting that those biologic mechanisms that allow a curative resection are not identical to those that determine survival time among uncured patients., Methods: The multivariate log-normal model can be used to detect the association of cured fraction and median survival time of patients with specific prognostic covariates. This model was applied to survival data from 2892 patients with intraocular melanoma who were treated by enucleation., Results: This analysis showed that large tumor size and pleomorphic nucleoli within the tumor were associated independently with a low probability of cure and short median survival time. Advanced patient age and mixed cell type, however, were highly associated with only a short median survival time., Conclusions: For patients with intraocular melanoma treated only by enucleation, the median survival time is not modulated by the same biologic factors that determine the likelihood of a curative resection.

Using data on 4726 cases of uveal melanoma collected by the Registry, of Ophthalmic Pathology at the Armed Forces Institute of Pathology, my co-workers and I have been studying the biology of haematogenous metastasis. We have developed methods for evaluating separately the relationships between prognostic factors and cure-rate and median survival time for uncured patients. We have discovered that size of the tumour and size of the largest nucleoli in the cells of the uveal melanomas related equally to cure-rate and median survival time. The presence of Callender's epitheloid-type cells in the tumour and increased patient age had little effect on cure-rate but dramatically reduced the median survival time.

For 740 selected cases of uveal melanoma from the Armed Forces Institute of Pathology, the following features were determined: the age and sex of the patient, Callender cell type (CT), and largest tumor dimension (LTD). In addition, special morphometric devices were used to measure the standard deviation of nucleolar area (SDNA) and the mean of the largest nucleoli (MLN) from a single routine hematoxylin and eosin-stained section of each tumor. Univariate analysis using the Cox proportional-hazards model revealed that LTD, CT, SDNA, and MLN correlated equally with death from metastatic melanoma (P greater than 10(-6). Age correlated less highly (P less than 0.002), and sex had no relationship to mortality. Multivariate analysis revealed that adding LTD as a prognostic covariate to either CT, SDNA, or MLN yielded a substantial increase in prognostic value. Because MLN can be measured more easily than SDNA and is more reproducible than CT, it can be a useful cytologic index of the malignant potential of uveal melanomas.

The authors reviewed the clinical and histopathologic features of 32 patients with cutaneous malignant melanoma of the eyelid. The lower eyelid was more frequently the site of origin than the upper eyelid (21 patients, 66% of cases). A clinical diagnosis of melanoma was made in only 2 of 13 patients (15%) for whom the clinical diagnosis was listed. Clinical findings of pigmentation, ulceration/hemorrhage, or growth were documented in 25 (78%) patients. The histopathologic classification of the melanomas included nodular (19 patients, 59%), superficial spreading (7 patients, 22%), and lentigo maligna (6 patients, 19%). Associated histopathologic findings included solar elastosis (13 patients, 41%), nevus (12 patients, 38%), and basal cell carcinoma (4 patients, 13%). One of eighteen patients with follow-up data available died of metastatic melanoma.

The authors compared the immunohistochemical reactivity of 13 uveal nevi and 20 uveal melanomas for HMB-45, S-100 protein, and neuron-specific enolase (NSE) in formalin-fixed, paraffin-embedded sections. All 33 of the lesions were positive for HMB-45. The false-negative rates for S-100 protein and NSE were 21% and 18%, respectively. If only strongly positive reactions were considered, more than 50% of the tumors would be interpreted as negative for S-100 protein and NSE. Nevi stained with less intensity than melanomas using all three antibodies. The expression of HMB-45 appeared to be greater in active nevi than in inactive nevi. There was a weak association between S-100 protein reactivity and the ability of the uveal melanomas to metastasize (P = 0.1); however, the standard deviation of nucleolar area was a much better predictor (P = 0.02). These results indicate that pathologists will find HMB-45 to be a useful tool in differentiating uveal melanoma from nonmelanocytic tumors.

A randomized controlled clinical trial of methanol-extracted residue of bacille Calmette-Guerin adjuvant treatment of posterior uveal melanoma was undertaken. Of 113 patients, 34 patients received adjuvant immunotherapy and 79 patients received no treatment. No difference in survival was observed between the adjuvant-treated group and the control group of patients. This study found that the size of the tumor was a highly significant risk factor for death caused by metastasis of uveal melanomas. The standard deviation of the nucleolar area of the neoplastic cells was a significant risk factor, even though patients with tumors composed of Callender's spindle-type cells were not included in the study.

Two features of eyes enucleated for posterior uveal melanoma that may serve as indicators for traumatic enucleation and relate to dissemination of tumor cells at the time of enucleation are myelin artifact of the optic nerve head and acute hemorrhage within the tumor. Myelin artifact occurs when crushed optic nerve tissue is squeezed into the eye at the time of enucleation. Intralesional hemorrhage may occur during surgery and may be correlated with fluctuations in intraocular pressure. We reviewed 519 cases of posterior uveal melanoma treated by enucleation between 1950 and 1970. Without knowledge of the follow-up data, we examined histologic sections for myelin artifact, intralesional hemorrhage, subretinal hemorrhage, Callender cell type, size of tumor, necrosis, and scleral or orbital invasion. Neither myelin artifact nor intralesional hemorrhage were independent prognostic risk factors. These findings do not support or refute the hypothesis that excessive trauma during enucleation results in a worse prognosis.

Forty-six eyes with uveal melanoma were scanned with a computerized diagnostic ultrasound system before enucleation, and light microscope sections were obtained. Tumors were characterized by ultrasonically measured dimensions and power spectrum analysis, which provided information not available in conventional A- or B-scan ultrasonography. Histopathologic features, including cell clustering pattern, cell type, pigmentation, vascularity, and necrosis, were quantified. Statistically significant correlations were found between parameters derived from the power spectrum and histologic characteristics. Patients were followed up for up to ten years with 14 deaths occurring because of metastases. Using a Cox relative risk model with histopathologic data, a risk model comprising pigmentation and cell type (P less than .0001) was obtained. Using ultrasonic characteristics, a model comprising tumor volume and scatterer concentration (P = .0062) was obtained. The results suggest that ultrasonic tissue characterization and three-dimensional biometry may provide improved in vivo prognostic indicators for uveal melanoma.

We obtained maximum likelihood estimates (MLEs) of the proportion cured pi c and mean log survival time mu t for a sample of 4355 patients with intraocular melanoma whose survival times subsequent to treatment were assumed to follow a log-normal distribution. Following stratification by tumour size, MLEs of pi c and mu t derived for each stratum correlate inversely with tumour size. We then expressed pi c and mu t as continuous functions of tumour size and calculated MLEs for the parameters of these functions from the entire sample. This investigation documents for ocular melanoma a significant relationship of tumour size to both cured fraction and mean log survival time.

The authors evaluated the long-term results of iridocyclectomy to remove a lesion of the iris or ciliary body in 52 patients. The mean follow-up time was 8.5 years. The excised lesions were benign in 53% of the cases, spindle cell-type melanomas in 19% of the cases, mixed cell- or epithelioid cell-type melanomas in 25%, and an adenocarcinoma of ciliary epithelium in 2%. Visual outcome was generally good, with 43% of the patients achieving visual acuity of 6/7.5 or better and 57% achieving 6/15 or better. In 29% of the patients, enucleation was finally required, and in 10% of the patients there was metastasis of the melanoma. In 11 of the 15 patients who had a subsequent enucleation, the tumor was a melanoma of mixed cell or epithelioid cell type, and in 12 of these 15 patients the surgical margin was involved by the tumor in the iridocyclectomy specimen. All five patients with metastatic disease had melanomas of mixed cell or epithelioid cell type with involvement of the surgical margin in the iridocyclectomy specimen.

A study relating the intralesional infiltration of lymphocytes and plasma cells to patient survival was performed on cases of uveal malignant melanoma accessed at the Armed Forces Institute of Pathology, Washington, DC (AFIP) between 1954 and 1971. The authors examined 1193 cases using light microscopy. Of the 1078 cases with technically acceptable histologic sections, 134 tumors contained 100 or more lymphocytes per 20 high-power (X400) microscopic fields (20 HPF). The prevalence was 12.4%. This was designated the "high lymphocytic" group. An equivalent number of cases with fewer lymphocytes comprised the "low lymphocytic" group. The survival rate at 15 years was 36.7% for patients in the high lymphocytic group and 69.6% for patients in the low lymphocytic group. Using the Cox model, the authors found that an increased number of lymphocytes per 20 HPF was significantly associated with decreased survival (chi-square = 21.2, P = less than 0.0001). A significant association was observed even when we controlled for other risk factors (chi-square = 6.98, P = 0.008).

A clinicopathologic study of 41 cases of primary acquired melanosis has provided information concerning the rate of progression to melanoma and has provided histologic parameters useful in predicting which lesions are likely to progress to malignant melanoma. A clinicopathologic study of 131 conjunctival melanomas has provided information concerning the clinical and histologic parameters associated with a fatal outcome. Highlights of these two studies are presented together with implications for diagnosis and therapy.

In a retrospective study of choroidal and ciliary body malignant melanomas in black patients, we found that the death rates due to metastatic melanoma after enucleation were equivalent for 39 blacks and 3,339 whites. When compared with a control group of whites, it was found that blacks were more likely to have secondary glaucoma and inflammation prior to enucleation. Of the histopathologic features analyzed, the presence of necrosis or mixed or epithelioid type cells within the tumor was associated with increased mortality in blacks. The histopathologic features of malignant melanomas in blacks and whites were similar, except that tumor necrosis and heavy pigmentation were found more frequently in tumors of blacks.

Uveal melanomas are slow growing tumors that may infiltrate out of the eye, mainly following ciliary vessels or nerves, or invade blood vessels, but only rarely do they produce metastatic disease before discovery and treatment. There are, however, large gaps in our knowledge of the frequency and rate of growth of small tumors to those of moderate or large size. We have estimated the mortality from untreated uveal melanomas to be 1% per year or less. Almost all information concerning prognostic factors has been gained from studies based on cases treated by enucleation. The same information is not necessarily applicable to untreated tumors. A study of deaths from metastatic uveal melanomas reveals a striking relationship to enucleation, regardless of whether one deals with cases in which the eye had been symptomatic for a long or short time. Following a low preoperative mortality of 1% or less, the annual mortality rises to about 4% during the first year and then peaks at 8 to 12% during the second year, tapering off during the next three to five years to return to a remarkably constant level of 1 to 2% thereafter. We postulated that this relationship of peak mortality to enucleation is attributable mainly to an often overwhelming dissemination of tumor cells taking place during surgery or to a lowering of the host's immunologic defense mechanisms as a consequence of the operation, or both. We urge the pooling of all available information gained from clinical studies made on untreated tumors and recommend prospective studies of a variety of other methods of treating uveal melanomas in addition to the standard enucleation.

We have observed that the fatality rate of patients with posterior uveal melanomas rapidly increased from a very low rate prior to enucleation to a maximum of 8% per year during the second year after enucleation. These data suggest to us that events related to enucleation have a deleterious effect on survival, and we have postulated that these events are either the iatrogenic dissemination of tumor cells or an adverse effect on the immune-defense system, or both. Others have proposed that the relationship between enucleation and increased mortality is only happenstance. They would attribute the onset of symptoms to the rapid growth of the malignant tumor and thus claim that this brings the patient to enucleation soon after the tumor becomes malignant. We have studied 2105 cases on file in the REgistry of Ophthalmic Pathology and have found that enucleation was not always performed shortly after the onset of visual disturbance. In one third of the cases, enucleation was delayed until onset oment was not obtained until the tumor measured larger than 15 mm in diameter. Using Zelen's method to infer the natural history of uveal melanoma, we found that the mean time it took for a small tumor (less than 10 mm in diameter) to become a large tumor (greater than 15 mm) was approximately 7 years. The average age of patients treated for medium-sized tumors was 5 years less than that of patients treated for larger tumors. This is interpreted as evidence of an average delay of 5 years in the treatment of large melanomas. If this delay is taken into consideration, then the patients treated with medium-sized tumors had a worse survival during the first 7 years than did patients whose treatment was delayed until the tumor became large. After the seventh year, however, the survival was better. These findings support our hypothesis that the postoperative increase in mortality during the first several years, particularly among patients with tumors of medium size, was related to enucleation.

For most applications of the Cox Model, a simple exponential relationship is assumed between covariates of this model and relative force of mortality (lambda). A method has been developed to examine this relationship in detail for data sets that contain a sufficient number of deaths. This method was applied to 3680 cases of intraocular melanoma with 1178 deaths over 20 years of follow-up, using largest tumor dimension (LTD) as a predictor of tumor-related death. Results indicated that the transform lambda = exp[beta log LTD] provides a closer approximation to observed mortality for this data set than the more traditional lambda = exp [beta LTD]. Additional applications to mathematically generated data sets revealed a close correspondence between lambda estimated by this method and the lambda programmed into each data set.

Five-year survival data were available in 78 cases originally classified as uveal melanomas in patients less than 20 years old. Forty-two were malignant melanomas arising from the choroid and/or ciliary body; 13 patients from this group died of metastatic disease. Factors that significantly correlated with fatality were a red, painful eye, extraocular extension at enucleation, basal tumor diameter greater than 10 mm, increased mitotic activity, and tumor necrosis. There were 36 iridic tumors; nine were reclassified as nevi. Of the 27 patients with iridic melanomas, only four died of metastases. The predominant factors relating to fatal outcome were glaucoma, extension of tumor into the ciliary body, diffuse growth, deep angle invasion, scleral invasion by tumor cells, and increased mitotic activity. Except for their relative rarity, uveal melanomas in children and adolescents did not differ significantly from their counter-parts in adults.

Of 650 eyes with posterior uveal melanomas that were accessioned at the Armed Forces Institute of Pathology from 1975 to 1983, 28 were aphakic and eight were pseudophakic. In ten of these 36 cases, the cataract had been unilateral. Only two patients had been examined with preoperative A-scan ultrasonography to obtain the axial length of the eye. None of the patients had been examined for possible intraocular tumors by either A- or B-scan ultrasonography. We believe that in many of these cases the tumor was large enough to have been detected at the time of cataract surgery. Thus, if the lens is too opaque for the fundus to be viewed, B-scan ultrasonography should be used before cataract extraction.

A reappraisal of survival data on patients with uveal melanomas has led us to these impressions: (a) that the mortality rate before enucleation is low, estimated at 1% per year; (b) that the mortality rate rises abruptly following enucleation, reaching a peak of about 8% during the second year after enucleation; and (c) that approximately two-thirds of the fatalities could be attributed to the dissemination of tumour emboli at the time of enucleation. From these impressions we believe the following conclusions are warranted: (a) enucleation as it has been performed in the past may have for many patients an adverse rather than a beneficial effect with respect to the development of metastatic disease from malignant melanoma of the choroid and ciliary body. (b) A long-term follow-up study of untreated patients with melanomas of the choroid and ciliary body is indicated. (c) New techniques for enucleation designed to prevent the dissemination of tumour cells must be developed and tested to enable the ophthalmic surgeon to remove safely the tumour-containing eye that has developed such complications as uncontrollable glaucoma, panophthalmitis, or proptosis from extraocular extension.

Uveal melanoma is the most common primary intraocular neoplasm in adults. Those histopathologic features that distinguish uveal nevi from small melanomas, and those that distinguish highly malignant from less malignant lesions, have been the subject of controversy over the past decades. This controversy arises primarily from the subjective methods by which such histopathologic distinctions are made, and the resulting ambiguities may have misguided the clinician in his management of certain uveal lesions. With methods made possible by modern technology, pathologists can now assess the malignant potential of uveal melanomas by objective measurement of cytologic structures within the tumor.

In this series of 3,432 cases of malignant melanoma of the choroid and ciliary body, mortality from metastasis 15 years after enucleation was 46 per cent. This mortality was at least ten times greater than has been observed with tumors of the iris, probably owing to the greater size and more malignant cytology of choroidal and ciliary body tumors. In 56 per cent of the 3,432 cases, the melanomas were composed of a mixture of spindle and epithelioid cells. The 15-year mortality of patients with melanomas of mixed cell type was three times that of patients with tumors of pure spindle cell type. In 30 per cent of the cases in this series, the melanomas of the choroid and ciliary body were larger than 15 mm in diameter. Size was highly correlated with mortality. The distribution of deaths following enucleation in the 3,432 cases was a log-normal function of time from enucleation. This indicated that metastasis occurred in these fatal cases close to the time of enucleation. The authors were also able to infer that many years were usually required for these uveal melanomas to grow from small (7 to 10 mm in diameter) to large (greater than 15 mm in diameter). These observations are consistent with the hypothesis that dissemination of tumor cells at the time of enucleation has been a major cause of metastasis with small and medium-sized uveal melanomas.

Current follow-up information was obtained for 91 of 100 patients with tumors of the uveal tract for whom transscleral 32P tests had been performed and the eye had been enucleated because of malignant melanoma. The 32P uptake test was found to correlate better with outcome than either mitotic activity or invasion of the sclera. However, the correlation was not as good as that observed for tumor size and cell type. While most of the prognostic information in the 32P uptake value could be determined from the size of the tumor, none of the 13 tumors with 32P uptake less than 100% developed metastatic melanoma. The amount of necrosis within the tumor correlated with a bad prognosis and lower 32P uptake. There were three cases of spindle-cell nevi, all with positive 32P uptake values and none with metastasis.

The radioactive phosphorus uptake of 30 samples fron nine uveal melanomas was determined by liquid scintillation counting. These in vitro measurements correlated positively with clinical (in vivo) 32P values and with the number of mitotic figures and percentage of epithelioid cells (PEC) within the specimens. Three possible explanations were found for the failure of previous workers to demonstrate a correlation between cell type and clinical 32P. (1) Cell type, using Callender's classification, provides only a crude estimate of the PEC within a tumor; in particular, tumors of mixed cell type can vary widely in epithelioid cell content. (2) The rate of 32P absorption is not su-ficiently sensitive to distinguish spindle cell tumors from mixed cell tumors with a low PEC. (3) Clinical 32P measurements may be affected by extraneous factors that cause large deviations from the expected values.

One hundred well-documented cases of uveal melanoma accessioned at the Armed Forces Institute of Pathology before 1970 were reviewed and reclassified to identify changes made in the Callender classification. We compared the new classification with the original classification to determine the effect of the changes on the prediction of outcome for the patient after enucleation. Staff pathologists had originally classified 52 of the 100 cases as spindle-cell type melanoma. Only 31 of the 100 cases were reclassified as spindle-cell types (two spindle-cell nevi and 29 spindle-cell melanomas). Tumors classified as mixed-cell type were further subdivided into groups based on the percentage and size of the epithelioid cells. Tumors formerly classified as spindle-cell type that contained small or rare epithelioid cells were reclassified as mixed-cell type. This improved the prediction of outcome for the patient. We found that nucleolar size and pleomorphism are important variables that should be considered in the classification of uveal melanomas.

The nucleolar area of uveal melanomas, measured from standard hematoxylin-and-eosin-stained microslides , has been shown in previous work to correlate well with survival following enucleation of the tumor-bearing eye. Despite this correlation, the accuracy of the original system for measuring nucleolar area was affected by several sources of error: (1) the algorithm by which area was computed underestimated true area, (2) geometric and optical factors caused overestimation of nucleolar area unless measured in the center of the microscopic field of view and (3) the area of small nucleoli, as the result of several possible mechanisms, contains less useful information than the area of large nucleoli. This paper presents methods introduced to reduce error from these sources and demonstrates that the predictive value of nucleolar measurements is relatively insensitive to high levels of random variation.

Forty uveal melanomas were examined, half of which had proved fatal. Twenty cells were selected from each tumor, and six cytologic features were measured on each of these cells. It was found that the cells selected from fatal tumors had longer nuclei, more nucleoli, and greater nuclear pleomorphism than those selected from nonfatal tumors. Also, cells from melanomas classified as mixed cell type by the Callender classification had wider nuclei and longer nucleoli than those from tumors classified as spindle B cell type. Since the former cell type is associated with a worse prognosis, these features would probably assist in assigning prognosis to a large group of randomly selected malanomas. Thus, five nuclear characteristics (long nuclei, wide nuclei, long nucleoli, multiple nucleoli, and nuclear pleomorphism) should prove useful for predicting death from the dissemination of uveal melanoma.