Replacement and desmoplastic histopathological growth patterns: A pilot study of prediction of outcome in patients with uveal melanoma liver metastases

Abstract

Up to 50% of uveal melanomas (UM) metastasise to the liver within 10 years of diagnosis, and these almost always prove rapidly fatal. As histopathological growth patterns (HGPs) of liver metastases of the replacement and desmoplastic type, particularly from colon and breast carcinoma, may import valuable biological and prognostic information, we have studied HGP in a series of 41 UM liver metastases originating from 41 patients from the period 2006–2017. Twenty patients underwent enucleation while 21 had radiation therapy. Analysis of UM by array comparative genomic hybridisation revealed: 25 (64%) patients with high risk (monosomy3/8q gain); 13 (33%) intermediate risk (M3/8normal or disomy3/8q gain); and 1 low risk (disomy3/8normal). The principal HGP was replacement in 30 (73%) cases and desmoplastic in 11 (27%) cases. Cases with replacement demonstrated striking vascular co‐option/angiotropism. With the development of liver metastasis, only the replacement pattern, largest primary tumour diameter, and R2 (incomplete resection) status predicted diminished overall survival (OS; p < 0.041, p < 0.017, p < 0.047, respectively). On multivariate analysis, only HGP (hazard ratio; HR = 6.51, p = 0.008) and resection status remained significant. The genomic high‐risk variable had no prognostic value at this stage of liver metastasis. Chi‐square test showed no association of HGP with monosomy 3 or 8q gain. Eighteen of 41 (44%) patients are alive with disease and 23 (56%) patients died with follow‐up ranging from 12 to 318 months (mean: 70 months, median: 47 months). In conclusion, we report for the first time the frequency of the replacement and desmoplastic HGPs in liver UM metastases resected from living patients, and their potential important prognostic value for UM patients, as in other solid cancers. These results may potentially be utilised to develop radiological correlates and therapeutic targets for following and treating patients with UM metastases.

Transcriptome Profiling Reveals New Insights into the Immune Microenvironment and Upregulation of Novel Biomarkers in Metastatic Uveal Melanoma

“…Any tumour infiltrating lymphocytes (TILs) present in mUM were CD8+ T-cells with low expression of cytotoxic markers, such as Granzyme B, and they were typically “excluded” from the tumour core [ 25 ]. These results, which were supported by others and suggest CD8+ T-cell exhaustion [ 27 , 28 ], were corroborated by our earlier study using NanoString analyses of six hepatic mUM by Figueiredo et al 2020 [ 26 ]. We showed that within mUM, conventional immune checkpoint regulators (CTLA-4, PD1 and PD-L1) were low and that immune suppressive genes (e.g., HLA-DRA , CD38 , CD74 , LGALS3 ) were increased [ 26 ].…”

“…As previously described [ 25 , 27 , 28 , 43 ], the predominant lymphocyte population present within most mUM were exhausted CD8+ TILs (82.5%) showing either an “altered excluded” or “altered immunosuppressed” pattern, corresponding to a low or intermediate immunoscore, respectively. Interestingly, those mUM with a “high” TIL immunoscore had upregulation of the CD25/ILR2A , corresponding to regulatory T-cells (Tregs), and thereby creating a TME characterized by immunosuppression directed against tumour antigen-specific effector T cells, B cells, and plasma cells, ultimately leading to immune exhaustion and/or anergy [ 44 , 45 , 46 , 47 ].…”

Association between the histopathological growth patterns of liver metastases and survival after hepatic surgery in breast cancer patients

“…This indicates that the presence of the distinct HGPs may depend on the type of primary tumor. Comparable to what has been described for colorectal cancer [7][8][9] and uveal melanoma 12 , we confirm the association between R-HGP and poor outcome after resection of LM. In contrast, D-HGP may thus identify breast cancer patients who can be offered (repeated) hepatic surgery to prolong survival.…”

Synergic Interactions Between Hepatic Stellate Cells and Uveal Melanoma in Metastatic Growth

“…Importantly, we also observed that the xenografts had defining characteristics of desmoplastic or replacement HGPs [27]. Barnhill and collaborators previously determined that the replacement pattern was correlated to shorter overall survival of UM patients [30].…”