Multiorgan Involvement of Dormant Uveal Melanoma Micrometastases in Postmortem Tissue From Patients Without Coexisting Macrometastases

Abstract

Objectives: Almost half of all patients diagnosed with uveal melanoma will die of metastatic disease. This has been attributed to early seeding of micrometastases. We investigate the presence, density, organ involvement, and characteristics of micrometastases of uveal melanoma in tissue obtained at autopsy of patients with and without coexisting macrometastases.

Methods: Patients diagnosed with primary uveal melanoma at a national referral center between 1960 and 2020 (n = 4,282) were cross-referenced with autopsy registers at nearby hospitals. Eleven patients were included. Formalin-fixed, paraffin-embedded tissue samples obtained during autopsy were examined with routine histology, immunohistochemistry, and immunomagnetic separation.

Results: Micrometastases were detected in 5 of 5 patients with and in 5 of 6 patients without coexisting macrometastases. Micrometastases were identified in several sites, including lungs, kidneys, myocardium, and bone marrow. Their highest density per mm2 of tissue was seen in the liver. Of 11 examined patients, 2 had at least 1 BAP-1-positive metastasis. All micrometastases had immune cell infiltrates and no or very low proliferative activity.

Conclusions: We demonstrate multiorgan involvement of apparently dormant micrometastases in patients with uveal melanoma. This suggests that micrometastases are present in nearly all patients diagnosed with primary uveal melanoma, regardless of coexisting macrometastases.

Keywords: Autopsy; Dormancy; Immunomagnetic separation; Macrometastases; Metastasis; Micrometastases; Ophthalmology; Pathology; Postmortem; Uveal melanoma.

FIGURE 1

Micrometastases in the liver, lungs, and myocardium. A, Patient 1. Infiltration of hepatic sinusoids in an infiltrative/replacement growth pattern (H&E, ×20). B, Patient 1. Infiltration of hepatic sinusoids in a nodular fashion, resembling the desmoplastic and pushing growth patterns (H&E, ×20). Tumor cells in the lung of patient 3 with perivascular growth and growth in the interalveolar septa (asterisks), melanocyte marker MelA/MART1 (red chromogen; C, ×10; D, ×40). E, Patient 3. Tumor cells in the myocardium growing around cardiomyocytes (H&E, ×20). F, Patient 3. The same area of the myocardium stained with melanocyte marker SOX10. Scattered mitoses are present (arrows, ×20).

FIGURE 1

Micrometastases in the liver, lungs, and myocardium. A, Patient 1. Infiltration of hepatic sinusoids in an infiltrative/replacement growth pattern (H&E, ×20). B, Patient 1. Infiltration of hepatic sinusoids in a nodular fashion, resembling the desmoplastic and pushing growth patterns (H&E, ×20). Tumor cells in the lung of patient 3 with perivascular growth and growth in the interalveolar septa (asterisks), melanocyte marker MelA/MART1 (red chromogen; C, ×10; D, ×40). E, Patient 3. Tumor cells in the myocardium growing around cardiomyocytes (H&E, ×20). F, Patient 3. The same area of the myocardium stained with melanocyte marker SOX10. Scattered mitoses are present (arrows, ×20).

FIGURE 2

Examples of micrometastases of uveal melanoma, with framed area shown in paired image. A, B, Liver, patient 1. Micrometastases predominantly displayed an infiltrative or replacement growth pattern (H&E). C, D, Liver, patient 1. Nodular growth (previously described as desmoplastic and pushing growth pattern) was less common (H&E). E, F, Myocardium, patient 3. Sheets of infiltrative tumor cells (H&E). G, H, Myocardium, patient 3. The same area stained with melanocyte marker MelA/MART1. I, J, Liver, patient 3. All but 2 micrometastases were BAP-1 negative (inset, positive internal control). (A, C, E, G, I, ×5; B, D, F, H, J, ×40.)

FIGURE 2

Examples of micrometastases of uveal melanoma, with framed area shown in paired image. A, B, Liver, patient 1. Micrometastases predominantly displayed an infiltrative or replacement growth pattern (H&E). C, D, Liver, patient 1. Nodular growth (previously described as desmoplastic and pushing growth pattern) was less common (H&E). E, F, Myocardium, patient 3. Sheets of infiltrative tumor cells (H&E). G, H, Myocardium, patient 3. The same area stained with melanocyte marker MelA/MART1. I, J, Liver, patient 3. All but 2 micrometastases were BAP-1 negative (inset, positive internal control). (A, C, E, G, I, ×5; B, D, F, H, J, ×40.)

FIGURE 3

Boxplots, micrometastases (MIC) per square millimeter of examined tissue. A, B, The density of micrometastases was greater in the liver than in other organs (Mann-Whitney U, P = .002). C, Patients with concurrent macrometastases (MAC) had a higher density of micrometastases than patients without concurrent macrometastases (P = .002). D–F, There were no significant differences in the density of micrometastases in hearts (myocardium, P = .17), livers (P = .98), or lungs (P = .99) from patients with vs without concurrent macrometastases. Note that y-axis scale varies. BM, bone marrow; NS, nonsignificant. *P < .01. **P < .05.