Uveal Melanoma Metastasis Research Articles

Expression of osteopontin in different metastatic potential uveal melanoma and its significance

Background Osteopontin is highly expressed in many metastatic tumors,but its expression in uveal melanoma and the relationship of osteopontin with metastasis is still under investigation. Objective This study was to investigate the relationship between osteopontin expression and uveal melanoma metastatic potential.Methods Fifty samples of uveal melanoma were collected in Beijing Tongren Hospital.The expressions of osteopontin in the samples were detected using immunohistochemistry,and expressions of osteopontin mRNA in different metastatic potential uveal melanoma cell lines (MU M-2B,C918,OCM-1A) were analyzed using quantitative polymerase chain reaction (Q-PCR). Results Osteopontin was positively expressed in 10 samples of 13 patients with metastasis and 14 samples of 37 patients without metastasis,showing a significant difference between them (x2=5.888,P=0.000).There were 11 samples and 13 samples exhibiting the positive expression of osteopontin in 15 epithelial type and 35 non-epithelial type of uveal melanoma respectively with the significant difference (x2=5.510,P =0.000).The positive expressing numbers of osteopontin were 20 tumors of 30 affected tumors and 4 tumors of 20unaffected ciliary tumors with the significant difference (x2 =10.470,P =0.000 ).No significant differences in the expression of osteopontige were found between different gender,age,eyes,largest basal diameters and invasion of scleral canal( P =0.536,0.256,0.802,0.848,0.555 ).The relative expression value of osteopontin mRNA was in turn 1.00±0.04,0.91 ±0.03,0.08±0.01 in MUM-2B,C918,OCM-1A with the significant difference among three cell lines( F=33.135,P＜0.05).The osteopontige mRNA expression was significant enhanced in high metastatic potentialcell lines( MUM-2B,C918 ) compared with low metastatic potential cell lines( OCM-1 A) (P＜0.05 ),but no significant difference was seen between two high metastatic potential cell lines(MUM-2B,C918) (P=0.804). Conclusions Osteopontige expression is associated with the uveal melanoma cell line invasion and metastasis potential.These results imply that osteopontige expression maybe an indicator of uveal melanoma invasion and metastasis ability. Key words: Uveal melanoma; Osteopontin; Invasion and metastasis

Metastatic Uveal Melanoma

Uveal melanoma is the most common primary intraocular cancer in adults. Nearly half of primary uveal melanoma tumors metastasize, but there are currently no effective therapies for metastatic uveal melanoma. The recent discovery of mutations that underlie uveal melanoma metastasis, growth, and survival provide a key to the molecular understanding of this disease. Much work is now underway to leverage this knowledge to develop effective therapies. This review summarizes recently discovered molecular features of uveal melanoma and therapies being explored to capitalize on this knowledge.

Ocular Immune Privilege and Ocular Melanoma: Parallel Universes or Immunological Plagiarism?

Evidence of immune privilege in the eye was recorded almost 140 years ago, yet interest in immune privilege languished for almost a century. However, the past 35 years have witnessed a plethora of research and a rekindled interest in the mechanisms responsible for immune privilege in the anterior chamber of the eye. This research has demonstrated that multiple anatomical, structural, physiological, and immunoregulatory processes contribute to immune privilege and remind us of the enormous complexity of this phenomenon. It is widely accepted that immune privilege is an adaptation for reducing the risk of immune-mediated inflammation in organs such as the eye and brain whose tissues have a limited capacity to regenerate. Recent findings suggest that immune privilege also occurs in sites where stem cells reside and raise the possibility that immune privilege is also designed to prevent the unwitting elimination of stem cells by immune-mediated inflammation at these sites. Uveal melanoma arises within the eye and as such, benefits from ocular immune privilege. A significant body of research reveals an intriguing parallel between the mechanisms that contribute to immune privilege in the eye and those strategies used by uveal melanoma cells to evade immune elimination once they have disseminated from the eye and establish metastatic foci in the liver. Uveal melanoma metastases seem to have “plagiarized” the blueprints used for ocular immune privilege to create “ad hoc immune privileged sites” in the liver.

Are liver function tests relevant for early detection of liver metastasis of uveal melanoma?

AbstractPurpose The liver is the main target for screening for uveal melanoma metastasis, which could be achieved by liver function tests (LFTs). The aim of our study is to analyze the relevance of LFTs for detection of metastatic disease in term of prognostic value and cost evaluationMethods Patients (n=88, who developed metastasis while undergoing semi‐annual follow‐up with LFTs including aspartate‐aminotransferase (AST), alanine‐aminotransferase (ALT), gammagutamylransferase (γGT), lactodeshydrogenase (LDH), and phosphatase alkaline (PA) were included. For assessing the level of LFTs for metastasis only the one preceding screening LFTs before the diagnostic by imaging was recorded. Consecutive patients (n=174) with uveal melanoma were chosen as control from patients who did not develop metastasisResults We were able to detect metastasis after LFTs abnormality in 40 (45%) patients. However, at the time of the one preceding screening LFTs before the metastasis diagnosis, 51(58%) patients had at least one abnormal LFT. The metastasis diagnosis was missed in 11 patients (13%). The overall sensitivity of LFTs ranged from 12.5 to 58.0% and the predictive positive value ranged from 9.4 to 38.6%. Interestingly we observed false positives in 20.3% with the variable “at least one abnormal LFT”. Using financial approach, we calculated the semi‐annual screening by LFTs.Conclusion Using the most important retrospective series analyzing semi‐annually all LFTs, we demonstrate that LFTs screening (AST, ALT, γGT, LDH and PA) is not relevant for detection of early metastasis even if the over cost induced by imaging requested for false positive is low

Surveillance Testing for Metastasis From Primary Uveal Melanoma and Effect on Patient Survival

To evaluate the quality of evidence about effectiveness of regular periodic surveillance testing for metastasis in patients with primary uveal melanoma (PUM) following treatment of the primary tumor in prolonging survival. Literature review and personal perspective of the authors. Identification and analysis of peer-reviewed articles on human PUM published between 1980 and 2009 that reported on "screening," "surveillance," or "systemic follow-up evaluation" for metastasis in patients with PUM following treatment of primary tumor. Of 4222 identified articles, only 31 were considered satisfactory for inclusion in this study. Satisfactory articles reported levels of specific biomarkers when metastasis was first confirmed (14), percentage of patients with abnormal results on surveillance testing (13), values of diagnostic markers (eg, sensitivity, specificity) associated with evaluated components of a surveillance regimen (7), survival time after first detection of metastasis from primary uveal melanoma (7), total survival time after initial diagnosis or initial treatment of primary uveal melanoma (3), percentage of patients whose metastatic tumors were detected by presymptomatic testing (5), surveillance regimens employed by different groups (1), and relationship with generally accepted clinical and histopathologic prognostic factors for primary uveal melanoma metastasis (1). However, none of these articles reported survival times of comparable subgroups of patients in which regular periodic surveillance for metastasis vs no surveillance was performed. Available evidence from the peer-reviewed literature does not provide any compelling evidence of survival benefit for any regimen or frequency of surveillance for metastasis relative to no such testing. In view of this, advisability of periodic surveillance for metastasis in routine clinical practice must be questioned.

Abstract 1415: The Notch ligand Jag 2 promotes growth and invasion in uveal melanoma cells

Abstract Uveal melanoma is the most common primary intraocular cancer in the adults, and up to 50% of patients die from hematogenous visceral metastases which are extremely resistant to chemotherapy. Using oligonucleotide expression array analysis of mRNA from primary uveal melanomas, we found that the Jag 2 ligand was 1.9 fold more expressed in tumors which metastasized than those which did not. Other Notch pathway members were also significantly induced in the metastatic cohort. We then used quantitative RT PCR to analyze mRNA extracted from a second cohort of 30 snap-frozen primary tumors, and confirmed that elevated Jag 2 mRNA levels were significantly associated (p = 0.048) with the metastatic Class 2 signature as compared to non-metastatic Class 1 uveal melanoma. To directly examine the importance of Jag 2 in driving cellular growth and invasion, we introduced the ligand into a uveal melanoma cell line, Mel 290, which has low baseline levels of Notch activity as measured by expression of the pathway targets Hes1, Hey1 and Hey2. The Jag 2-GFP-MSCV-infected cells showed a 2.5 to 6 fold induction of Notch targets Hey 1 and Hes1, indicating that pathway activity had been induced. While overall growth of the Jag 2-GFP-MSCV infected cultures as measured by MTT increased only slightly, overexpression of Jag 2 induced an approximately 3 fold increase in clonogenic growth in soft agar. Finally, we assayed the migratory properties of the cells using a wound-healing (“scratch”) assay, as well as their ability to invade Matrigel. Jag 2 expressing cells showed increased motility in both of these tests, with a significant (p = 0.0003) approximately 2 fold induction of transwell invasion capacity. Our data suggest that expression of the Notch ligand Jag 2 may play an important role in uveal melanoma growth and metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1415. doi:10.1158/1538-7445.AM2011-1415

The left ventricle as the first site of uveal melanoma metastasis 13 years after treatment of the primary tumor

Treatment of patients with metastatic uveal melanoma is very challenging because the tumor commonly spreads to the liver, surgical resection of metastases is rarely possible, and there is no standard effective systemic therapy. We report the case of a 38-year-old man, who presented with metastatic involvement of the left ventricle as the first site of uveal melanoma recurrence 13 years after treatment of his primary tumor. The metastatic tumor was considered unresectable. We describe the patient's medical management over the next 3 years, the course of his disease, and the results of our review of the literature.

Radioembolization as Salvage Therapy for Hepatic Metastasis of Uveal Melanoma: A Single-Institution Experience

The purpose of this study was to assess the safety and efficacy of radioembolization in the management of hepatic metastasis of uveal melanoma after failure of immunoembolization or chemoembolization. From January 2007 through April 2009, 32 patients underwent radioembolization therapy for hepatic metastasis of uveal melanoma. Pretreatment tumor burdens were divided into three categories: less than 25% (n = 25), 25-50% (n = 5), and greater than 50% (n = 2). Toxicity, extrahepatic disease, and hepatic tumor response were assessed 1 month and then every 3 months after treatment. Best radiographic response of hepatic metastasis was determined with the Response Evaluation Criteria in Solid Tumors criteria. Overall survival and progression-free survival of hepatic metastasis were estimated by Kaplan-Meier analysis. Differences in survival between subgroups were evaluated by log-rank test in univariate analysis. The clinical follow-up period ranged from 1.0 to 29.0 months (median, 10.0 months). The median overall survival was 10.0 months, and the progression-free survival of hepatic metastasis, 4.7 months. Twenty-two patients died 1.0-29.0 months (median, 5.8 months) after treatment owing to progression of liver disease (n = 13), extrahepatic disease (n = 4), or both (n = 5). Patients who had a pretreatment tumor burden less than 25% had longer median overall survival (10.5 vs 3.9 months, p = 0.0003) and progression-free survival (6.4 vs 3.0 months, p = 0.03) than patients who had a pretreatment tumor burden of 25% or greater. Patients who had a complete response (n = 1), partial response (n = 1), or stable disease (n = 18) had longer median overall survival (14.7 vs 4.9 months, p = 0.0006) and progression-free survival of hepatic metastasis (7.9 vs 3.1 months, p < 0.0001) than patients with tumor progression (n = 12). Self-limiting grade 1-2 systemic toxicity included tiredness (n = 9), indigestion (n = 2), and abdominal discomfort (n = 5). Grade 3-4 hepatic toxicity was attributed to tumor progression. Radioembolization is safe and effective salvage therapy for limited metastasis of uveal melanoma.

A Comparative Transcriptomic Analysis of Uveal Melanoma and Normal Uveal Melanocyte

BackgroundUveal melanoma is the most common primary intraocular tumor in adults in western countries. It is associated with very severe visual morbidity and may lead to distant metastases even after successful treatment of the primary tumor. In order to gain better insight into molecular mechanisms related to tumorigenesis and metastasis of uveal melanoma, we used next-generation sequencing technology (SOLiD, Life Technologies) to acquire global transcriptome alteration between posterior uveal melanoma cells and normal uveal melanocyte.ResultsFrom mRNAs of the cultured uveal melanoma cells and normal uveal melanocytes, we annotated more than 3.7×107 and 2.7×107 sequencing tags based on human Ensembl databases, respectively. For detailed analysis, we chose 5155 well-annotated genes mainly involved in the MAPK signaling pathway, cell cycle, cell adhesion junction, apoptosis, and P53 signaling pathways as well as melanogenesis. In an effort to confirm the authenticity of our sequencing results, we validated twenty-one identically differentially expressed genes by using quantitative real time PCR from cultured cell lines of other posterior uveal melanoma cells and normal uveal melanocytes.ConclusionWe have identified a large number of potentially interesting genes for biological investigation of uveal melanoma. The expression profiling also provides useful resources for other functional genomic and transcriptome studies. These 21 potential genes could discriminate between uveal melanoma cells and normal uveal melanocyte, which may be indicative of tumorigenesis process. Our results further suggest that high-throughput sequencing technology provides a powerful tool to study mechanisms of tumogenesis in the molecular level.

Circulating Tumor Cells in Uveal Melanoma

Despite advances in the diagnosis and local tumor control, the overall mortality rate for uveal melanoma remains high because of the development of metastatic disease. The clinical and histopathological systems currently being used to classify patients are not sufficiently accurate to predict metastasis. Tumor genotyping has demonstrated significant promise but obtaining tumor tissue can be problematic. Furthermore, assessment of tumor tissue does not indicate whether tumor cells have actually been shed and cannot indicate whether treatment is reducing metastasis. The detection of circulating tumor cells in blood has been shown to be a prognostic biomarker that can be used to monitor the effectiveness of therapy in patients with metastatic carcinoma. Uveal melanoma disseminates hematogenously, and the detection of circulating melanoma cells may potentially be useful for diagnosis, risk stratification, and the monitoring of disease progression and treatment efficacy. PCR-based and immunomagnetic cell isolation techniques, derived from studies in patients with cutaneous melanoma, have been tested. For various biological and technical reasons, they have not demonstrated the accuracy and reproducibility required for an effective prognostic assay in patients with uveal melanoma. Assessments have been confounded by false positives and negatives and thus, correlations between circulating melanoma cells and survival have not yet been established. Circulating melanoma cell detection is a valuable tool for investigating metastasis in uveal melanoma and also has the potential to become a standard part of uveal melanoma management. However, more research on the biology of uveal melanoma as well as improvements upon the current technologies are needed.

Prediction of metastasis of primary uveal melanoma by the insulin‐like growth factor‐1 receptor

Abstract Purpose To study whether immunoreactivity for the insulin‐like growth factor‐1 receptor (IGF‐IRα) independently predicts metastasis of primary uveal melanoma in a consecutive Finnish data set. Methods Population‐based, retrospective cohort study of 167 choroidal and ciliary body melanomas enucleated from 1972 to 1981 with long‐term survival data. Immunostaining was done by using the avidin‐biotinylated peroxidase complex method, rabbit polyclonal antibodies (N‐20 diluted 1:500) to IGF‐IR and heat pretreatment. Survival was assessed by Cox multivariate regression analysis. Results The tumour area could be reliably measured from 128 (77%) of the 167 consecutive slides which had a choroidal or ciliary body melanoma. The remaining 39 specimens were technically not satisfactory. No significant associations were observed between IGF‐1R immunopositivity and tumor location (P=0.38), largest basal diameter (LBD) (P=0.62), cell type (P=0.84), tumor pigmentation (P=0.59), presence of tumor‐infiltrating macrophages (P=0.33), mean of the ten largest nucleoli (MLN) (P=0.37), presence of extravascular matrix patterns (P=0.67), and microvascular density (MVD) (P=0.39). Adding IGF‐1R did not improve a multivariate model predicting risk of metastasis from primary ciliary body and choroidal melanoma. Conclusion The results suggest that immunoreactivity for IGF‐IRα may not independently predict metastasis of primary uveal melanoma. Because old formalin‐fixed, paraffin‐embedded material was studied, partial loss of antigenicity can not be ruled out as a contributing factor.

Inhibitory isoforms of VEGF in uveal melanoma

Abstract Purpose Uveal melanoma (UM) affects around 600 new patients in the UK each year with half of these being treated at the Liverpool Ocular Oncology Centre. UM is an unusual tumour in that gross chromosomal abnormalities are strongly associated with metastatic spread, especially monosomy 3 &amp; chromosome 8q gain. Mechanisms that underlie this remain unclear. Methods Angiogenesis is a requirement for tumour survival &amp; metastasis. Vascular Endothelial Growth Factor (VEGF) is known to be the most potent stimulator of angiogenesis and increased expression of VEGF‐A is linked to enhanced metastatic potential in UM. Treatment with bevacizumab (anti‐VEGF therapy) suppresses hepatic micrometastasis of ocular melanoma cells in animal models. However, VEGF‐A data in UM are variable, with some studies demonstrating no correlation between VEGF‐A expression and metastasis or survival. Results VEGF‐A was accepted as a single pro‐angiogenic family of protein isoforms generated from alternatively spliced mRNA (VEGF189, VEGF165 etc). However, recently a family of sister isoforms named VEGFxxxb, where xxx is the amino acid number and b a different six C‐terminus amino acids (VEGF189b, VEGF165b) has been discovered. The VEGFxxxb variants are exactly the same size as pro‐angiogenic VEGFxxx, yet are antiangiogenic. VEGF165b is down‐regulated in primary cutaneous melanoma that later metastasises, and over‐expression of VEGFxxxb isoforms confers a protective anti‐tumour effect. Conclusion Immunohistochemical expression of pro‐ and anti‐angiogenic VEGF‐A in 19 UM was assessed using pan‐VEGF‐A and VEGF165b specific antibodies. A statistically significant reduction in expression of VEGF165b was observed in monosomy 3 UM (non‐parametric ANOVA; p&lt;0.05). This suggests that VEGF165b expression may be a useful predictor of UM metastasis.

Association between Gene Expression Profile, Proliferation and Metastasis in Uveal Melanoma

Purpose: Uveal melanomas cluster into two molecular groups based on their gene expression profile. Tumors with the class 1 signature rarely metastasize, whereas those with the class 2 signature have a very high rate of metastasis. However, the biological basis for this metastatic propensity of class 2 tumors remains unclear. Towards such an explanation, this study was conducted to determine whether class 2 tumors have a higher proliferative rate than class 1 tumors.Materials and Methods: The study included 28 primary uveal melanomas with extensive clinical, pathologic, and genetic annotation, including age, gender, ciliary body involvement, tumor basal diameter, thickness, cell type, gene expression profile, status of chromosomes 3 and 8p, aneuploidy, and clinical outcome. Immunopositivity for Ki-67 was determined by counting all positive nuclei in representative whole tumor sections.Results: Ki-67 positivity was significantly associated with class 2 gene expression profile, loss of chromosome 3 and increased aneuploidy (P = 0.04, P = 0.004, and P = 0.03, respectively). Ki-67 positivity showed a borderline significant association with epithelioid cell type (P = 0.07). Receiver operating characteristic (ROC) analysis of Ki-67 positivity, using the class 2 signature as an endpoint, identified a Ki-67 score of approximately 20 cells per high power field as the optimal cut-off point between low and high risk for metastasis (log rank test, P = 0.01).Conclusions: On average, class 2 uveal melanomas have a higher proliferative rate than class 1 tumors. Further work is needed to determine whether loss of chromosome 3, increased aneuploidy, or other factors may be responsible for the increased proliferation.

An Accurate, Clinically Feasible Multi-Gene Expression Assay for Predicting Metastasis in Uveal Melanoma

Uveal (ocular) melanoma is an aggressive cancer that often forms undetectable micrometastases before diagnosis of the primary tumor. These micrometastases later multiply to generate metastatic tumors that are resistant to therapy and are uniformly fatal. We have previously identified a gene expression profile derived from the primary tumor that is extremely accurate for identifying patients at high risk of metastatic disease. Development of a practical clinically feasible platform for analyzing this expression profile would benefit high-risk patients through intensified metastatic surveillance, earlier intervention for metastasis, and stratification for entry into clinical trials of adjuvant therapy. Here, we migrate the expression profile from a hybridization-based microarray platform to a robust, clinically practical, PCR-based 15-gene assay comprising 12 discriminating genes and three endogenous control genes. We analyze the technical performance of the assay in a prospective study of 609 tumor samples, including 421 samples sent from distant locations. We show that the assay can be performed accurately on fine needle aspirate biopsy samples, even when the quantity of RNA is below detectable limits. Preliminary outcome data from the prospective study affirm the prognostic accuracy of the assay. This prognostic assay provides an important addition to the armamentarium for managing patients with uveal melanoma, and it provides a proof of principle for the development of similar assays for other cancers.

Whole-Genome Microarray Detects Deletions and Loss of Heterozygosity of Chromosome 3 Occurring Exclusively in Metastasizing Uveal Melanoma

To detect deletions and loss of heterozygosity of chromosome 3 in a rare subset of fatal, disomy 3 uveal melanoma (UM), undetectable by fluorescence in situ hybridization (FISH). Multiplex ligation-dependent probe amplification (MLPA) with the P027 UM assay was performed on formalin-fixed, paraffin-embedded (FFPE) whole tumor sections from 19 disomy 3 metastasizing UMs. Whole-genome microarray analyses using a single-nucleotide polymorphism microarray (aSNP) were performed on frozen tissue samples from four fatal disomy 3 metastasizing UMs and three disomy 3 tumors with >5 years' metastasis-free survival. Two metastasizing UMs that had been classified as disomy 3 by FISH analysis of a small tumor sample were found on MLPA analysis to show monosomy 3. No ubiquitous gene deletions of chromosome 3 were seen in the remaining 17 metastasizing disomy 3 UMs by MLPA. aSNP analysis revealed 95 deleted genes and 16 genes with loss of heterozygosity (LOH) on chromosome 3 in the disomy 3 metastasizing UMs that were not deleted or showing LOH in the nonmetastatic tumors. MLPA can detect monosomy 3 cell populations in FFPE whole tumor sections previously missed by FISH performed on small tumor samples. Consistent deletion and LOH of genes on chromosome 3 occur in metastasizing disomy 3 UM and are detectable by aSNP analysis. Ninety-five genes were found to be deleted, and 16 genes showed LOH exclusively in disomy 3 metastasizing UM, suggesting a potential role for these genes in UM metastasis.

CXCR4-CXCL12 and VEGF correlate to uveal melanoma progression

Despite improvements in early diagnosis of uveal melanoma, prognosis is still poor due to metastases development. Neoangiogenesis and migration are requisites to metastasis promotion. Cross-talking between CXCR4-CXCL12 axis and the VEGF pathway was shown to favours tumour progression. CXCR4-CXCL12-VEGF expression was evaluated by immunohistochemistry in 53 selected cases of primary uveal melanoma and in liver melanoma metastases. CXCR4 protein was detected in 41.4 per cent cases, CXCL12 in 43.4 per cent cases and VEGF expression in 39.6 per cent cases. A significant correlation was found between CXCR4 and VEGF expression (p=0.011), CXCL12 and both tumour dimension and (p=0.006) and epithelioid-mixed cytotype (p=0.012). The two cases of uveal melanoma liver metastases in our series showed CXCR4 expression, weak immunoreactivity for CXCL12 and absent VEGF immunostaining. These data indicate that CXCR4-CXCL12 axis and its cross-talking with VEGF plays a role in uveal melanoma metastases and may be new prognostic markers in UMM. Moreover, these results suggest that targeted inhibition of CXCR4 could be introduced to control metastasis development in UMM.

Contralateral eyelid metastasis of uveal melanoma with further systemic dissemination

The usual way of dissemination of an uveal malignant melanoma comprises hematogenous metastases to various organs, liver in the first place. Uncommon development of the disease is always possible, while unusual ways of dissemination and secondary deposits in the unexpected sites have been observed. We presented an unusual case of a patient with uveal melanoma metastatic to the contralateral eyelid with very fast further dissemination in the manner typical for primary malignancies. This observational case report included a 70-year-old male, enucleated for uveal melanoma in his left eye, appeared again 2.5 years later with a fast growing contralateral eyelid metastasis, followed by submandibular lymph node involvement on the same side and further systemic dissemination. The first revealed solitary contralateral eyelid metastasis of uveal melanoma is extremely rare, such as an uncommon secondary deposit with a strange way of further dissemination.

Intravascular Presence of Tumor Cells as Prognostic Parameter in Uveal Melanoma: A 35-Year Survey

Invasion of tumor cells into blood vessels is essential for metastasis of uveal melanoma. The occurrence of ingrowth of tumor cells in blood vessels in uveal melanoma was analyzed, and this parameter was compared with the survival of the patients. Between 1972 and 2007, 643 eyes primarily enucleated for uveal melanoma were evaluated histopathologically. Survival data were obtained from charts and from the Integral Cancer Center patient registry. No vascular ingrowth of tumor cells occurred in 59% of the eyes, whereas 18% had tumor cell ingrowth in vessels inside the tumor, 10% in vessels outside the tumor, and 8% in vessels inside as well as outside the tumor. The presence of any intravascular ingrowth of tumor cells correlated significantly with the diameter (P < 0.01) and prominence of the tumor (P < 0.01), as well as with non-spindle-cell type (P = 0.03) and intrascleral ingrowth (P < 0.01), and was associated with a worse survival. When extravascular matrix patterns were not included in the multivariate analysis, intravascular ingrowth came out as an independent prognostic factor, but this was not the case when extravascular matrix patterns were included in the multivariate model. Intravascular ingrowth of tumor cells in uveal melanoma occurs frequently in combination with well-known histopathologic factors such as large tumor size, epithelioid cell type, and intrascleral ingrowth.

Metastasis of Uveal Melanoma Millimeter-by-Millimeter in 8033 Consecutive Eyes

To determine the rate of metastasis of uveal melanoma on the basis of tumor thickness in millimeters. Retrospective medical record review. The mean (median) patient age was 58 (59) years. A total of 8033 eyes were examined. Of the 285 eyes with iris melanoma, the mean tumor thickness was 2.7 mm and metastasis occurred in 0.5%, 4%, and 7% at 3, 5, and 10 years, respectively. Of the 492 eyes with ciliary body melanoma, the mean tumor thickness was 6.6 mm and metastasis occurred in 12%, 19%, and 33% at 3, 5, and 10 years, respectively. Of the 7256 eyes with choroidal melanoma, the mean tumor thickness was 5.5 mm and metastasis occurred in 8%, 15%, and 25% at 3, 5, and 10 years, respectively. For all uveal melanoma, metastasis at 5, 10, and 20 years was 6%, 12%, and 20% for small melanoma (0-3.0 mm thickness), 14%, 26%, and 37% for medium melanoma (3.1-8.0 mm), and 35%, 49%, and 67% for large melanoma (>8.0 mm). More specifically, metastasis per millimeter increment at 10 years was 6% (0-1.0 mm thickness), 12% (1.1-2.0 mm), 12% (2.1-3.0 mm), 16% (3.1-4.0 mm), 27% (4.1-5.0 mm), 28% (5.1-6.0 mm), 29% (6.1-7.0 mm), 41% (7.1-8.0 mm), 50% (8.1-9.0 mm), 44% (9.1-10.0 mm), and 51% (>10.0 mm). Clinical factors predictive of metastasis by multivariate analysis included increasing patient age, ciliary body location, increasing tumor diameter, increasing tumor thickness, having a brown tumor, and the presence of subretinal fluid, intraocular hemorrhage, or extraocular extension. Increasing millimeter thickness of uveal melanoma is associated with increasing risk for metastasis.

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

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. 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. 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). 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.