Progression of Ocular Melanoma Metastasis to the Liver:  The 2012 Zimmerman Lecture

Figure 1. Stage 1 metastatic uveal melanoma. A, There are scattered stage 1 metastases arranged in clusters in the liver parenchyma (hematoxylin-eosin, original magnification ×25). B, An individual stage 1 metastasis (arrow) is present in a sinusoidal space (hematoxylin-eosin, original magnification ×100). C, Immunohistochemical staining for HMB45 (red reaction product) clearly highlights the stage 1 metastases (avidin-biotin complex with vector red chromagen, original magnification ×100). D, Immunohistochemical staining for Ki67, a proliferation marker, is positive (arrow) in less than 1% of nuclei in stage 1 metastases (avidin-biotin complex with diaminobenzedine chromagen, original magnification ×100).

Figure 2. Stage 2 metastatic uveal melanoma. A, A focal stage 2 uveal melanoma metastasis is present in the liver parenchyma (hematoxylin-eosin, original magnification ×25). B, Immunostaining for HMB45 is strongly positive in the melanoma cells (avidin-biotin complex with vector red chromagen, original magnification ×25). C, The sinusoidal spaces are lined with type 3 collagen highlighted with a reticulin stain in normal liver (original magnification ×25). D, There are pseudosinusoidal spaces in the stage 2 metastasis that are also lined with reticulin-positive type 3 collagen (original magnification ×25). E, Higher magnification demonstrates the pseudosinusoidal spaces (arrow) in the stage 2 metastases (hematoxylin-eosin, original magnification ×100). The hepatocytes have been destroyed. F, Immunohistochemical stains are positive for smooth muscle actin in activated stellate cells (myofibroblasts) lining the pseudosinusoidal spaces (avidin-biotin complex with diaminobenzedine chromagen, original magnification ×100).

Figure 3. Stage 3 metastatic uveal melanoma. A and B, The lobular growth patterns of metastases are shown (hematoxylin-eosin, original magnification ×10 [A]; Masson trichrome, original magnification ×10 [B]). The melanoma has expanded within the portal lobule and infiltrated the liver. Only small islands of hepatic parenchyma remain (between the arrowheads). The lobules are outlined by thick collagen bands that stain blue with a trichrome stain. C, The portal growth pattern of metastasis contains areas of necrosis (asterisk) and effaces or pushes aside the surrounding liver parenchyma (hematoxylin-eosin, original magnification ×10). The interface between a single large metastasis and a normal surrounding liver is demarcated with arrowheads. Higher magnification of a single stage 3 metastasis shows areas of necrosis and neovascularization (D [asterisk and arrow]; hematoxylin-eosin, original magnification ×100), mitotic figures (E [arrows]; hematoxylin-eosin, original magnification ×100), CD31-positive vascular channels (F [arrows]; avidin-biotin complex with diaminobenzedine chromagen, original magnification ×100), and Ki67-positive nuclei (G [arrows]; avidin-biotin complex with diaminobenzedine chromagen, original magnification ×100).

Figure 4. Numbers of stage 1 metastases, stage 2 metastases, and stage 3 metastases per section (ie, the metastasis count). There were significantly more stage 1 metastases than stage 2 metastases, and there were significantly more stage 2 metastases than stage 3 metastases, in all cases. Error bars represent 1 SEM.

Figure 5. Mean vascular density in stage 1, stage 2, and stage 3 metastases. There were no blood vessels identified in stage 1 metastases. The mean vascular density significantly increased from stage 2 to stage 3 metastases. Error bars represent 1 SEM.

Figure 6. Mitotic indexes of stage 1, stage 2, and stage 3 metastases. There were no mitotic figures in stage 1 metastases. There was a significant increase in the mitotic index in stage 2 and stage 3 metastases. Error bars represent 1 SEM.

Figure 7. Progression of ocular melanoma metastasis to the liver through stages 1, 2, and 3. A, In stage 1, up to 50 μm in diameter of avascular aggregates of melanoma (M) arise in sinusoidal spaces via the hepatic arteriole (A); blood flows in the sinusoidal space from the hepatic arteriole and portal venule (PV) toward the central vein (CV); bile flows in the opposite direction toward a bile ductule (BD). B, In stage 2, aggregates of melanoma coalesce to form 51 to 500 μm in diameter of metastases and co-opt the portal venule or infiltrate the hepatic lobule with loss of hepatocytes, proliferation of stellate cells, and the appearance of pseudosinusoidal spaces. C, In stage 3, metastases that measure greater than 500 μm in diameter may grow in a portal pattern in which they co-opt the portal venule (PV). D, Metastases may also infiltrate the hepatic lobule in the lobular pattern.