Variates of survival in metastatic uveal melanoma.

PURPOSE: The course and outcome of metastatic uveal melanoma are not well described. We evaluated the survival of our patients with metastatic uveal melanoma, described factors that correlated with survival, and evaluated the influence of screening tests on time of detection and survival. PATIENTS AND METHODS: All patients with metastatic uveal melanoma seen at Memorial Sloan-Kettering Cancer Center between 1994 and 2004 were identified from our database. We recorded date of initial diagnosis, date of metastatic disease, date of last follow-up, site of the first metastasis, how the first metastasis was discovered, treatment, and outcome of therapy. RESULTS: The estimated median survival of the 119 patients analyzed was 12.5 months; 22% of patients were alive at 4 years. Five variates correlated independently with prolonged survival: Lung/soft tissue as only site of first metastasis, treatment with surgery or intrahepatic therapy, female sex, age younger than 60, and a longer interval from initial diagnosis to metastatic disease. Discovering metastatic disease in asymptomatic patients did not correlate with overall survival; 89% of patients had a single organ as the site of first metastasis. Although liver was the most common site, 39.5% of patients had nonliver sites, most commonly lung, as the first site of metastasis. CONCLUSION: A substantial subset of patients with metastatic uveal melanoma survive more than 4 years with metastatic disease. Data on variates of survival and site of first metastasis may guide strategies for screening patients, although our data failed to show a survival advantage in discovering asymptomatic metastatic disease.     

Molecular pathways mediating liver metastasis in patients with uveal melanoma

Uveal melanoma arises from melanocytes located in the uveal tract of the eye and is the most common primary intraocular tumor in adults. Metastatic liver disease is the overwhelming cause of death in uveal melanoma patients, with almost 50% of patients developing liver metastases up to 15 years after diagnosis. Most of these patients do not present with any evidence of overt metastasis at the time of initial diagnosis although it is assumed that they have undetectable micrometastases. Currently, there are no therapeutic modalities to prevent or efficiently treat the metastatic disease in uveal melanoma patients. Recent discoveries have shed light on the molecular pathways that may contribute to the progression of liver metastasis. The aim of this review is to describe new insights into the genetic and molecular pathways that may play a role in the development of liver metastases in uveal melanoma patients.     

The insulin-like growth factor-I receptor inhibitor picropodophyllin causes tumor regression and attenuates mechanisms involved in invasion of uveal melanoma cells.

PURPOSE: Uveal melanoma has a high mortality rate due to a high incidence of metastasis (up to 50%), which preferentially occurs in the liver. Conventional chemotherapy, being the only therapeutic option today against metastatic uveal melanoma, has not proved to be effective. Therefore, new molecular targets important for malignant phenotype of uveal melanoma have to be found to design efficient pharmacologic agents. EXPERIMENTAL DESIGN: We previously reported data indicating that the insulin-like growth factor-1 receptor (IGF-IR) is a metastasis predictor as well as a therapeutic target for uveal melanoma. In the present study, we made use of the cyclolignan picropodophyllin (PPP), which is an inhibitor of the IGF-IR. RESULTS: We showed that PPP efficiently blocks growth and viability of uveal melanoma cells in cultures and causes tumor regression in xenografted mice. In addition, treatment with PPP inhibited several mechanisms involved in metastasis, including tumor cell adhesion to extracellular matrix proteins, activity and expression of matrix metalloproteinase 2, and cell migration as well as invasion through basement membranes and endothelial cell layers. Furthermore, PPP significantly delayed establishment of uveal melanoma tumors and drastically reduced the incidence of liver metastasis in mice. CONCLUSIONS: Our data suggest that IGF-IR is crucial for growth and survival as well as invasion and metastasis of uveal melanoma cells. Targeting this receptor may therefore comprise a strategy to treat ongoing disease (today incurable) as well as a strategy to prevent development of metastases in patients with primary disease.     

Melanoma inhibitory activity: a novel serum marker for uveal melanoma

The aim of this study was to evaluate the tumour-associated antigen melanoma inhibitory activity (MIA) as a potential novel serological tumour marker in primary and metastatic uveal melanoma in both the laboratory and the clinical setting. In the laboratory setting, immunohistochemical staining with MIA antibody was performed in paraffin-embedded tissues from six amelanotic uveal melanomas and eight metastatic lesions of uveal melanomas. In the clinical setting, serum samples of 139 patients with uveal melanoma were examined; eight of these patients had overt metastatic disease. Sixty-one initially metastatic disease-free patients were followed over time (median follow-up 240 days, 95% confidence interval 60-883 days) and MIA levels were assessed repeatedly. A one-step enzyme-linked immunosorbent assay was used to quantify the MIA serum levels. In the laboratory setting, five of the six primary uveal melanomas and seven of the eight metastatic lesions stained immunohistologically positive for MIA. In the clinical setting, the 131 patients without overt metastatic disease demonstrated a median serum concentration of MIA of 6.6 ng/ml. In the eight patients with overt metastatic disease, the median serum concentration of MIA was 26.28 ng/ml. This difference was highly statistically significant (P < 0.001, analysis of variance). During follow-up, three initially metastatic disease-free patients developed overt metastatic disease, and the MIA level increased from a median of 6.6 ng/ml before to 29.2 ng/ml after clinical detection of metastatic disease. In the 58 other patients, the serum level remained stable during the entire follow-up period. In conclusion, MIA is expressed in primary and metastatic lesions of uveal melanomas, and a statistically significant elevation in MIA serum levels in patients who develop metastatic disease due to uveal melanoma indicates its promising role as a serum marker for monitoring uveal melanoma patients for metastasis.     

Uveal melanoma: natural history and treatment options for metastatic disease

In order to evaluate the natural history, prognostic parameters and treatment modalities for metastatic uveal melanoma, a review of the clinical data from the current literature was performed based on a Medline database search. Uveal melanoma represents approximately 5% of all melanomas. It is a distinct clinico-pathological entity, differing in many aspects from cutaneous melanoma. The clinical course is unpredictable and metastatic disease can develop very late after a long disease-free interval. Uveal melanoma metastasizes haematogenously, predominantly to the liver. The most Important prognostic parameters for primary uveal melanoma are tumour diameter, the patient's age and gender, histological features and tumour location. Systemic chemotherapy that is effective in cutaneous melanoma has failed to show activity in uveal melanoma. So far only the BOLD chemotherapy regimen (dacarbazine, lomustine, vincristine and bleomycin) combined with interferon-alpha has been shown to produce an objective tumour response in approximately 20% of previously untreated patients. For metastatic disease localized to the liver, intra-arterial application of fotemustine or carboplatin or chemoembolization with cisplatin have shown useful activity, resulting in a response in up to 40% of patients. Selected patients may benefit from palliative surgery. Immunotherapy with interleukin-2 or interferon-alpha has not shown consistent activity in metastatic uveal melanoma. In conclusion, patients with uveal melanoma metastatic to the liver should undergo one of the local treatment options. Carefully selected patients with extrahepatic disease or patients failing local treatment may benefit from systemic therapy using the BOLD regimen combined with interferon.     

Decreased endothelin receptor B expression in large primary uveal melanomas is associated with early clinical metastasis and short survival

The most devastating aspect of cancer is the metastasis of tumour cells to organs distant from the original tumour site. The major problem facing oncologists treating uveal melanoma, the most common cancer of the eye, is metastatic disease. To lower mortality, it is necessary to increase our understanding of the molecular genetic alterations involved in this process. Using suppression subtractive hybridisation, we have analysed differential gene expression between four primary tumours from patients who have developed clinical metastasis and four primary tumours from patients with no evidence of metastasis to date. We have identified endothelin receptor type B as differentially expressed between these tumours and confirmed this observation using comparative multiplex RT-PCR. In a further 33 tumours, reduced endothelin receptor type B expression correlated with death from metastatic disease. Reduced expression also correlated with other known prognostic indicators, including the presence of epithelioid cells, chromosome 3 allelic imbalance and chromosome 8q allelic imbalance. Endothelin receptor type B expression was also reduced in four out of four primary small cell lung carcinomas compared to normal bronchial epithelium. We also show that the observed down-regulation of endothelin receptor type B in uveal melanoma was not due to gene deletion. Our findings suggest a role for endothelin receptor type B in the metastasis of uveal melanoma and, potentially, in the metastasis of other neural crest tumours.     

High PTP4A3 phosphatase expression correlates with metastatic risk in uveal melanoma patients

A high percentage of uveal melanoma patients develop metastatic tumors predominantly in the liver. We studied the molecular profiles derived from gene expression microarrays and comparative genomic hybridization microarrays, to identify genes associated with metastasis in this aggressive cancer. We compared 28 uveal melanomas from patients who developed liver metastases within three years of enucleation with 35 tumors from patients without metastases or who developed metastases more than 3 years after enucleation. Protein tyrosine phosphatase type IV A member 3 (PTP4A3/PRL3), was identified as a strong predictor of metastasis occurrence. We demonstrated that the differential expression of this gene, which maps to 8q24.3, was not merely a consequence of 8q chromosome overrepresentation. PTP4A3 overexpression in uveal melanoma cell lines significantly increased cell migration and invasiveness in vivo, suggesting a direct role for this protein in metastasis. Our findings suggest that PTP4A3 or its cellular substrates could constitute attractive therapeutic targets to treat metastatic uveal melanomas.     

Targeted therapy for uveal melanoma

Uveal melanoma is the most common primary intra-ocular malignancy in adults. Overall mortality rate remains high because of the development of metastatic disease, which is highly resistant to systemic therapy. Improved understanding of the molecular pathogenesis of cancers has led to a new generation of therapeutic agents that interfere with a specific pathway critical in tumor development or progression. Although no specific genes have been linked to the pathogenesis of uveal melanoma, which differs from that of cutaneous melanoma, progress has been made in identifying potential targets involved in uveal melanoma apoptosis, proliferation, invasion, metastasis, and angiogenesis. This review focuses on the prospects for improving the systemic therapy of uveal melanoma using molecularly targeted agents that are currently in clinical use as well as agents being tested in clinical trials. Preclinical studies suggest potential benefit of inhibitors of Bcl-2, ubiquitin-proteasome, histone deactylase, mitogen-activated protein kinase and phosphatidylinositol-3-kinase-AKT pathways, and receptor tyrosine kinases. Modifiers of adhesion molecules, matrix metalloproteinase, and angiogenic factors also have demonstrated potential benefit. Clinical trials of some of these approaches have been initiated in patients with metastatic uveal melanoma as well as in the adjuvant setting after primary therapy.     

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.     

Combination hepatic arterial infusion therapy is effective for ocular melanoma metastasis to the liver

Regional treatments including chemotherapy have been applied to patients with malignant melanoma metastasis to the liver in clinical trials, but with limited efficacy. To improve efficacy, combination therapy may be beneficial. We had a case of multiple liver metastasis from right ocular malignant melanoma. The primary melanoma was surgically resected, and combination hepatic arterial infusion (HAI) therapy using dacarbazine, nimustine, vincristine (DAV), and cisplatin was applied to the metastatic focus. After HAI, marked regression of the liver metastatic focus was observed. Unfortunately, the patient passed away due to involvement of thrombotic thrombocytopenic purpura 9 months after the initial consultation, however, aggravation of the liver metastatic focus was not observed. Combination HAI therapy may have a potent therapeutic effect on malignant melanoma metastasis to the liver, and our regimen using DAV and CDDP may be beneficial to the improvement of prognosis without serious side effects.     

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.     

Protracted survival after resection of metastatic uveal melanoma

BACKGROUND: The objective of this study was to evaluate the usefulness of resection of metastatic uveal melanoma and to analyze the characteristics of patients who may benefit from surgical intervention. PATIENTS AND METHODS Twelve patients underwent surgical removal of metastasis between 1976 and 1998. Data regarding primary uveal melanoma, systemic metastasis, surgical procedures, and outcomes were reviewed retrospectively. RESULTS: There were seven patients with liver metastases, two with lung metastases, one with brain metastasis, and two patients with metastases in the liver and other organs. Median time to systemic metastasis was 8 years. Seven of 12 patients were asymptomatic when they were found to have metastasis. Ten patients underwent complete resection of metastasis. No significant surgical complications were experienced. Median recurrence free and overall survival periods after complete resection were 19 months (range, 6-78 months) and greater than 27 months (range, 11-86 months), respectively. Recurrence free and overall 5-year survival rates of those patients were 15.6% and 53.3%, respectively. Three of these patients had no further systemic recurrence. All patients whose time to systemic metastasis was within 5 years developed further systemic recurrence within 2 years after surgery. In contrast, in 8 patients whose time to systemic metastases was greater than 5 years, 4 patients either were recurrence free or developed second metastasis more than 4 years after surgery. CONCLUSIONS: Complete surgical removal of metastatic uveal melanoma provided unexpectedly long survival without significant morbidity for the selected patients. These results are encouraging and justify a trial in which patients eligible for resection are randomized between standard treatment and surgery.     

The biology and management of uveal melanoma

Uveal melanoma is the most common primary intraocular malignancy in adults. Overall mortality rate remains high because of the frequent development of metastatic disease, especially hepatic metastasis. While traditional systemic chemotherapies provide only marginal benefit to patients, local treatments for hepatic metastases, such as immunoembolization, have improved patient prognoses. Progress has also been made in identifying potential targets in the pathways involved in apoptosis, proliferation, invasion, metastasis, and angiogenesis of uveal melanoma. Among these pathways, the c-Kit, c-Met, and IGF-1R signal pathways and the PTEN-related P13K-Akt pathway are the most important targets. Clinical trials using blockades of these pathways in conjunction with strategies to facilitate apoptosis is a direction for future clinical trials. Application of these approaches in the adjuvant setting after primary therapy for high-risk uveal melanoma patients is also a future consideration to improve the clinical outcome of this disease.     

Whole-body F-18-fluoro-2-deoxyglucose positron emission tomography/computed tomography imaging in the follow-up of metastatic uveal melanoma

Metastasis has been reported in the follow-up of up to 50% of uveal melanoma patients. Established oncological diagnostic modalities in tumor follow-up so far have limited sensitivity and specificity. The diagnostic value of combined positron emission tomography (PET)/computed tomography (CT) scans in the follow-up of patients with metastatic uveal melanoma was assessed. Eleven patients with successfully treated and one patient with suspected uveal melanoma underwent combined PET/CT scan. The indication for PET/CT scan was heterogenous and ranged from suspected metastatic choroidal melanoma in conventional imaging (n=3) to exclusion of further organ involvement before local therapy of liver metastases (n=5) and restaging after local or systemic therapy of metastases (n=4). PET/CT scan showed vital metastases from uveal melanoma in all patients (n=12). Ten patients showed vital hepatic metastases (83%), five osseous (42%), four lymphatic (33%), two pulmonary (17%), one adrenal (8%) and one had muscular metastases (8%). Six patients showed multiple organ involvement (50%). In addition, PET/CT scan correctly identified a primary intraocular tumor and ruled out pulmonary metastatic involvement with suspicious intrapulmonary findings in a CT scan and chest X-ray in two patients. It could also confirm an equivocal intrahepatic finding in an MRI scan as a vital metastasis. PET/CT scan is a very sensitive and specific tool for the detection and localization of metastatic disease in patients with uveal melanoma, assessing both anatomical morphology and cell metabolism in one single examination. With novel therapeutic approaches in evolution, PET/CT scanning can be of great importance for therapy planning and monitoring.     

Characterization of the typical multidrug resistance profile in human uveal melanoma cell lines and in mouse liver metastasis derivatives

Uveal melanoma is the most common intraocular malignancy. To study its biology, stable cell lines provide a useful tool, but these are very difficult to obtain. A stable and rapidly growing human choroidal melanoma cell line composed of pure epithelioid cells was established and maintained for at least 4 years. In vivo transplantation into BALB/cByJ nude mice induced vascularized tumours at the injection sites. Interestingly, two of three cases produced a liver metastasis. Other uveal melanoma cell lines displaying different morphological aspects were also obtained. To avoid the bias due to uncertain immunologically based staining approaches, several methods were juxtaposed to establish the multidrug resistance (MDR) profile. All the uveal melanomas studied expressed significant levels of the MDR-related MDR1, MRP1 (MDR-related protein 1) and LRP/MVP (lung resistance protein/major vault protein) messenger RNAs (mRNAs), produced their corresponding proteins and were able to functionally extrude daunomycin. When compared with the established MEWO skin melanoma cell line, our data showed that both primary and metastatic uveal melanomas intrinsically expressed the typical MDR phenotype, which precludes the use of any anticancer drugs known to be substrates of MDR-related proteins to treat the disease. Moreover, it appears that the metastasizing process does not change the status of the MDR phenotype.     

A new allogeneic model for metastatic melanoma

Metastatic melanoma cells, clonally derived from an affected lymph node of an ultraviolet-irradiated laboratory opossum, were allografted subcutaneously into suckling young, juveniles and adults to determine their tumorigenicity and metastatic potential. All injected 1- and 3-week-old suckling young survived well beyond weaning at 8 weeks. One died 12 weeks after injection from the effects of rampant metastatic involvement, while the rest were killed 13 to 26 weeks after injection. At necropsy, most animals showed extensive primary tumour growth, many showed metastasis to nodes and/or lungs, and in some there was dissemination to distant sites including liver and spleen. Animals injected as juveniles or adults rejected the allografts. Injection of allogeneic malignant melanoma cells during early postnatal development facilitates successful, long-term allografting and metastasis without concomitant immunosuppressive agents. Developmental lack of self-recognition (immunological immaturity) or induced tolerance may be responsible. This unique model system will be useful for further metastasis studies and may be valuable for investigations of novel antineoplastic therapies.     

A metastasis modifier locus on human chromosome 8p in uveal melanoma identified by integrative genomic analysis.

PURPOSE: To identify genes that modify metastatic risk in uveal melanoma, a type of cancer that is valuable for studying metastasis because of its remarkably consistent metastatic pattern and well-characterized gene expression signature associated with metastasis. EXPERIMENTAL DESIGN: We analyzed 53 primary uveal melanomas by gene expression profiling, array-based comparative genomic hybridization, array-based global DNA methylation profiling, and single nucleotide polymorphism-based detection of loss of heterozygosity to identify modifiers of metastatic risk. A candidate gene, leucine zipper tumor suppressor-1 (LZTS1), was examined for its effect on proliferation, migration, and motility in cultured uveal melanoma cells. RESULTS: In metastasizing primary uveal melanomas, deletion of chromosome 8p12-22 and DNA hypermethylation of the corresponding region of the retained hemizygous 8p allele were associated with more rapid metastasis. Among the 11 genes located within the deleted region, LZTS1 was most strongly linked to rapid metastasis. LZTS1 was silenced in rapidly metastasizing and metastatic uveal melanomas but not in slowly metastasizing and nonmetastasizing uveal melanomas. Forced expression of LZTS1 in metastasizing uveal melanoma cells inhibited their motility and invasion, whereas depletion of LZTS1 increased their motility. CONCLUSIONS: We have described a metastatic modifier locus on chromosome 8p and identified LZTS1 as a potential metastasis suppressor within this region. This study shows the utility of integrative genomic methods for identifying modifiers of metastatic risk in human cancers and may suggest new therapeutic targets in metastasizing tumor cells.     

Metastatic uveal melanoma: biology and emerging treatments

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.     

Bilateral breast masses as initial presentation of widely metastatic melanoma

BACKGROUND AND OBJECTIVES: Malignant melanoma is the most rapidly increasing cancer in the world. Metastatic disease occurs in 20% of patients. Metastatic cancer to the breast is rare, but primary breast cancer is one of the leading causes of death in women. In the present study, a large personal series of breast biopsies is reviewed, and 2 cases of metastatic malignant melanoma to both breasts are reported. METHODS: A personal series of 1,200 breast biopsies from 1975 to 1998 were reviewed. In this series, 2 cases of metastatic melanoma to both breasts were identified. RESULTS: Two female patients, ages 31 and 34 years, were evaluated for bilateral breast masses. Both were treated with simple excision of the breast tumor. Postoperatively, both patients were found to have widespread metastatic disease to the brain, lung, and liver. Despite aggressive treatment with chemotherapy and radiation, the patients died at 6 and 22 months, respectively, after the initial presentation. CONCLUSION: Bilateral breast metastasis from malignant melanoma is rare. Care must be taken to make a correct diagnosis of metastatic melanoma rather than of primary breast cancer. An incorrect diagnosis of anaplastic carcinoma can lead to major surgical procedures that are of no value. The long-term prognosis of patients with bilateral breast metastasis from malignant melanoma is poor.     

Uveal melanoma

Uveal melanoma, which arises from melanocytes residing in the stroma, is the most common primary intraocular tumor in adults. Up to 50% of patients with primary uveal melanoma will ultimately develop distant metastasis, the liver being involved in up to 90% of individuals and the median survival reported to be 4-5 months. The current treatment of metastatic uveal melanoma is limited by the lack of effective systemic therapy. The intrinsic resistance of uveal melanoma to conventional systemic chemotherapy has led researchers to evaluate new approaches. Molecular biology and a better knowledge of cancer cells allowed the development of target therapies: these refer to drugs designed to interact with a specific molecular pathway known to have a critical role in tumor growth or progression. Several drugs, such as bevacizumab, imatinib and MEK-inhibitors, are currently under investigation as single agents or in combination with chemotherapeutic drugs for the treatment of metastatic uveal melanoma. Finally, ipilimumab, which targets the immune compartment, was reported to increase overall survival in cutaneous melanoma patients, with preliminary evidence of similar activity in ocular melanoma.