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L1CAM and laminin vascular network: Association with the high-risk replacement histopathologic growth pattern in uveal melanoma liver metastases

Abstract

The replacement histopathologic growth pattern (rHGP) in melanoma liver metastases connotes an aggressive phenotype (vascular co-option; angiotropic extravascular migratory spread) and adverse prognosis. Herein, replacement and desmoplastic HGP (dHGP) were studied in uveal melanoma liver metastases (MUM). In particular, L1CAM and a “laminin vascular network” were detected at the advancing front of 14/20 cases (p = 0.014) and 16/20 cases (p = 6.4e–05) rHGPs, respectively, but both were absent in the dHGP (8/8 cases) (p = 0.014, and p = 6.3e–05, respectively). L1CAM highlighted progressive extension of angiotropic melanoma cells along sinusoidal vessels in a pericytic location (pericytic mimicry) into the hepatic parenchyma. An inverse relationship between L1CAM expression and melanin index (p = 0.012) suggested differentiation toward an amelanotic embryonic migratory phenotype in rHGP. Laminin labeled the basement membrane zone interposed between sinusoidal vascular channels and angiotropic melanoma cells at the advancing front. Other new findings: any percentage of rHGP and pure rHGP had a significant adverse effect on metastasis-specific overall survival (p = 0.038; p = 0.0064), as well as predominant rHGP (p = 0.0058). Pure rHGP also was associated with diminished metastasis-free survival relative to dHGP (p = 0.040), possibly having important implications for mechanisms of tumor spread. In conclusion, we report for the first time that L1CAM and a laminin vascular network are directly involved in this high-risk replacement phenotype. Further, this study provides more detailed information about the adverse prognostic effect of the rHGP in MUM.

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Fig. 1: Replacement and desmoplastic histopathological growth patterns in uveal melanoma liver metastases.
Fig. 2: L1CAM and laminin expression in uveal melanoma liver metastases.
Fig. 3: Metastasis-free survival with reference to chromosome 3 status and histopathological growth patterns in uveal melanoma liver metastases.
Fig. 4: Metastasis-specific survival and overall survival associated with histopathological growth patterns in uveal melanoma liver metastases.

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by Uveal Melanoma (UM) Cure 2020 project under the European Union’s Horizon 2020 research and innovation program (grant agreement No 667787)”. Period 2015–2021. RAS is supported by an Australian National Health and Medical Research Council Practitioner Fellowship (APP1141295). Support from Deborah McMurtrie and John McMurtrie AM and The Cameron Family is gratefully acknowledged. The authors also acknowledge support from colleagues at their respective institutions.

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RB and CL wrote the manuscript, RB, CL, PV developed the methodology, RB, CL, PV collected and analyzed data. SVL performed statistical analyses and analyzed data. GC and AN performed immunohistochemistry, scanned glass slides, and managed glass microslides. PM and SPN collected data. All the authors reviewed and approved the manuscript.

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Correspondence to Raymond Barnhill.

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This study was approved by the institutional ethics committees of Curie Institute in Paris France; the Melanoma Institute of Australia; and The University of Texas MD Anderson Cancer Center. Written informed consent for the use of tissue specimens and data for research was signed by each patient.

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Barnhill, R., van Laere, S., Vermeulen, P. et al. L1CAM and laminin vascular network: Association with the high-risk replacement histopathologic growth pattern in uveal melanoma liver metastases. Lab Invest (2022). https://doi.org/10.1038/s41374-022-00803-w

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