SummaryWe examined liver specimens from 15 patients with uveal melanoma (UM) who had succumbed to their disseminated disease. We found two distinct growth patterns of UM metastasis: infiltrative (n=12) and nodular (n=3). In the infiltrative pattern, individual UM cells with a CD133+ cancer stem cell-like phenotype were present and formed aggregates of Stage I <50µm diameter micrometastases in the sinusoidal spaces. These micrometastases appeared to expand, destroy adjacent hepatocytes and form Stage II 51-500µm diameter and then Stage III >500µm diameter metastases, which were encapsulated by collagenized fibrous septae. In the nodular growth pattern, CD133+ melanoma cells aggregated adjacent to portal venules, and subsequently appeared to grow and efface the adjacent hepatocytes to form Stage II 51-500µm diameter nodules that surrounded the portal venule. These avascular nodules appeared to further expand to form Stage III >500µm diameter nodules that exhibited vascularization with minimal fibrosis. The tumor stem cell-like phenotype seen in individual UM cells was lost as the tumors progressed. There were CD56+ natural killer (NK) cells in sinusoidal spaces and CD3+ lymphocytes in periportal areas. The nodular growth pattern showed UM cells expressing MMP9 and VEGF. UM cells in both above-described growth patterns exhibited variable BAP1 expression. We propose that changes in the liver microenvironment are related to metastatic UM growth. We hypothesize that immune regulation within the sinusoidal space for the infiltrative pattern and changes in the VEGF:PEDF ratio for the nodular pattern.Correspondence to: Hans E. Grossniklaus MD, L.F. Montgomery Ophthalmic Pathology Laboratory, BT428 Emory Eye Center, 1365 Clifton Road, Atlanta, GA 30322 ophtheg@emory.edu. HHS Public Access IntroductionUveal melanoma (UM) is the most common primary intraocular malignancy in adults with an annual incidence of 6-7 cases/1,000,000 in the Caucasian population. 1 Approximately 40% of UM metastasize to the liver within 10 years of diagnosis of the primary intraocular tumor 2 , and when UM metastasizes, the liver is typically the initial site of metastasis in 95% of cases. 3 The life expectancy of patients with metastatic UM is only 4 to 6 months 1 , and at present there are no highly effective treatments for these metastases. 4 The Zimmerman hypothesis, which was formulated in the late 1970s, proposed that enucleation of the eye for UM potentiated hematogenous spread of the tumor and a 2-year post-enucleated risk of death. 5 This theory was subsequently disproven, particularly when investigators calculated primary and metastastic UM doubling times. Their extrapolation demonstrated that small, clinically undetectable UM micrometastases were present in the liver, even at the time of diagnosis of the primary intraocular tumor in patients who ultimately succumbed from hepatic metastasis. 6 Our laboratory corroborated those results when we found small hepatic UM micrometastases in liver specimens obtained post-mortem from patients wh...
The liver is the organ usually affected by metastatic uveal melanoma (MUM). Current treatments are almost always ineffective and mortality remains high. In this study, copy number variations (CNVs) were identified in 12 metastatic and five matched primary UMs (PUMs). Our data revealed a wide spectrum of genetic alterations in MUM. Most common were amplifications of chromosome (chr.) 8q; alterations on chr. 3 included monosomy, isodisomy, and large regions of homozygosity (ROH). Genomic profiles of PUM-MUM pairs varied in their degree of similarity and complexity. However, within the pairs, 135 genes were consistently altered. Protein expression of C-MYC and BAP1 was examined by immunohistochemistry (IHC); a positive association between IHC and CNVs was seen for C-MYC. This comprehensive catalogue of CNVs associated with MUM should facilitate the identification of key alterations that drive tumor growth. This would have the potential to select urgently needed novel, targeted, therapeutic regimens.
EATCL is a clinicopathological entity with a grim prognosis and with tumour cells representing a unique neoplastic equivalent of CTLs arrested in varying stages of activation.
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