title: Metastatic ocular melanoma to the liver exhibits infiltrative and nodular growth patterns.
abstract: We examined liver specimens from 15 patients with uveal melanoma (UM) who had died of their disseminated disease. We found 2 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 <50-μm-diameter micrometastases in the sinusoidal spaces. These micrometastases appeared to expand, destroy adjacent hepatocytes, and form stage II 51- to 500-μm-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- to 500-μm-diameter nodules that surrounded the portal venule. These avascular nodules appeared to further expand to form stage III >500-μm-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 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 these changes include immune regulation within the sinusoidal space for the infiltrative pattern and changes in the VEGF/PEDF ratio for the nodular pattern.
authors.affiliation: Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA, USA 30322; Winship Cancer Institute, Emory University, Atlanta, GA, USA 30322. Electronic address: ophtheg@emory.edu.
authors.forename: Hans E
authors.initials: HE
authors.lastname: Grossniklaus
authors.affiliation: Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA, USA 30322.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta, GA, USA 30322.
authors.forename: Shuo
authors.initials: S
authors.lastname: You
authors.affiliation: Molecular and Clinical Cancer Medicine, Royal Liverpool and Broadgreen University Hospital NHS Trust, University of Liverpool, Liverpool, L69 3GA UK.
authors.forename: Conni
authors.initials: C
authors.lastname: McCarthy
authors.affiliation: Department of Pathology, Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark; Department of Ophthalmology, Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark.
authors.forename: Steffen
authors.initials: S
authors.lastname: Heegaard
authors.affiliation: Molecular and Clinical Cancer Medicine, Royal Liverpool and Broadgreen University Hospital NHS Trust, University of Liverpool, Liverpool, L69 3GA UK.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Coupland
mesh_terms: D000071916:AC133 Antigen / Q000032:analysis; D001344:Autopsy; D014408:Biomarkers, Tumor / Q000032:analysis; D017252:CD3 Complex / Q000032:analysis; D019002:CD56 Antigen / Q000032:analysis; D049109:Cell Proliferation; D003718:Denmark; D004739:England; D005136:Eye Proteins / Q000032:analysis; D005260:Female; D005455:Fluorescent Antibody Technique; D005845:Georgia; D006801:Humans; D008113:Liver Neoplasms / Q000737:chemistry / Q000276:immunology / Q000401:mortality / Q000556:secondary*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D008545:Melanoma / Q000737:chemistry / Q000276:immunology / Q000401:mortality / Q000556:secondary*; D008875:Middle Aged; D061206:Neoplasm Micrometastasis; D014411:Neoplastic Stem Cells / Q000737:chemistry / Q000473:pathology; D009414:Nerve Growth Factors / Q000032:analysis; D010641:Phenotype; D015843:Serpins / Q000032:analysis; D047368:Tumor Burden; D059016:Tumor Microenvironment; D014604:Uveal Neoplasms / Q000401:mortality / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis; D000098943:Uveal Melanoma; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D000071916:AC133 Antigen; D014408:Biomarkers, Tumor; D017252:CD3 Complex; D019002:CD56 Antigen; D005136:Eye Proteins; D020780:Matrix Metalloproteinase 9; D009414:Nerve Growth Factors; D015843:Serpins; D042461:Vascular Endothelial Growth Factor A; D000099174:Pigment Epithelium-Derived Factor; C522918:NCAM1 protein, human; C000606023:PROM1 protein, human; C467484:VEGFA protein, human; C579270:MMP9 protein, human
keywords: Growth patterns; Liver metastases; Micrometastases; NK cells; Ocular melanoma; PEDF