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

Ly, Long V.; Odish, Omar F. F.; Wolff-Rouendaal, D. De; Missotten, Guy S.; Luyten, Gregorius P M; Jager, Martine J.

doi:10.1167/iovs.09-3824

Cited by 24 publications

(16 citation statements)

References 39 publications

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“…24 Although currently not assumed to be of prognostic relevance, the type of driving oncogene involved may have a significant supplemental effect on longterm survival and outcome. Mutations in GNAQ and GNA11 have been shown to be mutually exclusive, 16 with tumors harboring only a single mutation in either gene.…”

Section: Discussionmentioning

confidence: 99%

Genetic and clinico-pathologic analysis of metastatic uveal melanoma

et al. 2014

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Uveal melanoma is the most common malignant tumor of the adult eye. Fifty percent of tumors will eventually metastasize, and there are no effective treatments for them. Recent studies of uveal melanoma have identified activating mutations in GNAQ and GNA11, loss-of-function mutations in the tumor suppressor gene BAP1, and recurrent mutations in codon 625 of SF3B1. Previous studies have reported the existence of a higher frequency of GNA11 than GNAQ mutations, frequent BAP1 loss, and rare SF3B1 mutations in metastatic uveal melanoma. We analyzed a cohort of 30 uveal melanoma metastases for the occurrence of GNAQ, GNA11, and SF3B1 mutations, as well as BAP1 loss, and correlated these parameters with clinical and histopathologic features. Most (92%) tumors were composed of cells with an epithelioid or mixed (o100% spindle cells) morphology. Tumor samples composed exclusively of spindle cells were rare (n ¼ 2, 8%). Most tumors showed a moderate to marked degree of nuclear pleomorphism (n ¼ 24, 96%), and contained hyperchromatic, vesicular nuclei with variably conspicuous nucleoli. GNA11 mutations were considerably more frequent than GNAQ mutations (GNA11, GNAQ, and wild-type in 18 (60%), 6 (20%), and 6 (20%) cases, respectively). SF3B1 mutation was found in 1 of 26 tumors (4%), whereas loss of BAP1 expression was present in 13 of 16 tumors (81%). Patients with GNA11-mutant tumors had poorer disease-specific survival (60.0 vs 121.4 months, P ¼ 0.03) and overall survival (50.6 vs 121.4 months, P ¼ 0.03) than those with tumors lacking GNA11 mutations. The survival data, combined with the predominance of GNA11 mutations in metastases, raises the possibility that GNA11-mutant tumors may be associated with a higher risk of metastasis and poorer prognosis than GNAQ-mutant tumors. Further studies of uveal melanoma are required to investigate the functional and prognostic relevance of oncogenic mutations in GNA11 and GNAQ.

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Section: Discussionmentioning

confidence: 99%

Genetic and clinico-pathologic analysis of metastatic uveal melanoma

et al. 2014

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“…A strong association has been observed between tumor cell ingrowth into blood vessels and extraocular extension, which is known to indicate a poor survival probability [24,25]. To form a metastatic tumor, the circulating malignant cells must exit the circulation and enter an organ, which in case of uveal melanoma is usually the liver [26,27].…”

Section: Vasculature and Metastatic Diseasementioning

confidence: 99%

Anti-Angiogenic Therapy in Uveal Melanoma

Filali¹,

Velden²,

Luyten³

et al. 2011

Current Concepts in Uveal Melanoma

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For several decades, targeting of tumor-related vessels has been regarded as a potential anticancer therapy. Such anti-angiogenic therapy is based on the assumption that a tumor cannot grow beyond the limits of diffusion (about 1-2 mm) of oxygen and nutrients from capillaries, unless angiogenesis takes place. Vascular endothelial growth factor (VEGF) plays a key role in angiogenesis, regulating vasopermeability as well as the proliferation and migration of endothelial cells. In several types of cancer (colon carcinoma, soft tissue sarcomas and gastric cancer), serum VEGF levels are a marker for disease stage and an indicator of metastasis. VEGF levels are significantly elevated in uveal melanoma patients with metastatic disease compared to patients without metastases. Anti-angiogenic therapy, such as bevacizumab, is currently used for the treatment of metastases of several malignancies. Anti-angiogenic therapy has not yet been tested for the treatment of primary uveal melanoma or related metastatic disease. Clinicians, however, have a broad experience with anti-angiogenic agents in patients with uveal melanoma by treating the complications of radiation therapy. We will discuss tumor angiogenic processes and related molecular pathways in uveal melanoma. The role of VEGF and the potential use of current commercially and experimentally available anti-angiogenic drugs for the treatment of primary uveal melanoma and/or metastatic disease will be explained below.

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“…As can be seen in Figure 1, the absence of any cells with monosomy 3 was significantly associated with a favorable prognosis and the low cutoff level of 5% for detecting monosomy 3 described in our previous report showed a significant high hazard ratio (15.5). However, because 6 patients who had at least 30% of monosomy 3 were still alive after 5 years, we have to take into account that metastases can occur many years after enucleation, 25 and we will, therefore, have to evaluate these data again at 10 years' follow-up.…”

Section: Commentmentioning

confidence: 99%

Effect of Heterogeneous Distribution of Monosomy 3 on Prognosis in Uveal Melanoma

Bronkhorst

Maat²,

Jordanova³

et al. 2011

Archives of Pathology &Amp; Laboratory Medicine

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in situ hybridization (FISH) analyses on tumor sections and on isolated nuclei showed that even low numbers of cells with monosomy of chromosome 3 adversely affected survival.Objective.-To determine what percentage of uveal melanoma cells with monosomy of chromosome 3 influences patient mortality.Design.-To determine the presence of monosomy 3, karyotyping and FISH on cultured cells and FISH on isolated nuclei were performed on 50 primary uveal melanomas. Clinical and pathologic prognostic factors were assessed and compared with 5-year survival data. Analyses were performed using Cox proportional hazards test, log-rank analysis, sensitivity, specificity, and positive and negative likelihood ratios.Results.-Combined karyotyping and FISH on cultured cells showed monosomy 3 in 19 of 50 cases (38%), whereas determination of the monosomy 3 status by FISH on isolated nuclei with a threshold of 5% assigned 31 of 50 cases (62%) to the monosomy-3 category. When monosomy 3 on isolated nuclei with a cutoff value of 5% was used, a significant difference in 5-year survival was present (hazard ratio, 15.5; P = .007), indicating that monosomy 3 in greater than 5% of tumor cells is related to death due to metastases.Conclusion.-In uveal melanoma, the presence of greater than 5% of cells with monosomy 3, as determined by FISH on isolated nuclei, is associated with the development of metastases within 5 years after enucleation.

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

Abstract: 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.

Cited by 24 publications

References 39 publications

Genetic and clinico-pathologic analysis of metastatic uveal melanoma

Genetic and clinico-pathologic analysis of metastatic uveal melanoma

Anti-Angiogenic Therapy in Uveal Melanoma

Effect of Heterogeneous Distribution of Monosomy 3 on Prognosis in Uveal Melanoma

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