Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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


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.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. Aughton K, Kalirai H, Coupland SE. MicroRNAs and uveal melanoma: understanding the diverse role of these small molecular regulators. Int J Mol Sci 21:5648 (2020)

  2. Bustamante P, Piquet L, Landreville S, Burnier JV. Uveal melanoma pathobiology: Metastasis to the liver. Semin Cancer Biol 71:65–85 (2021)

  3. Rowcroft A, Loveday BPT, Thomson BNJ, Banting S, Knowles B. Systematic review of liver directed therapy for uveal melanoma hepatic metastases. HPB (Oxford) 22:497–505 (2020)

  4. Barnhill R, Vermeulen P, Daelemans S, van Dam PJ, Roman-Roman S, Servois et al. Replacement and desmoplastic histopathological growth patterns: A pilot study of prediction of outcome in patients with uveal melanoma liver metastases. J Pathol Clin Res 4:227–240 (2018)

  5. Latacz E, Höppener D, Bohlok A, Leduc S, Tabariès S, Fernandez Moro C, et al. Histopathological growth patterns of liver metastasis: updated consensus guidelines for pattern scoring, perspectives, and recent mechanistic insights. Br J Cancer In Press, (2022).

  6. Latacz E, Caspani E, Barnhill R, Lugassy C, Verhoef C, Grünhagen D et al. Pathological features of vessel co-option versus sprouting angiogenesis. Angiogenesis 23:43–54 (2020)

  7. Lugassy C, Kleinman HK, Vermeulen PB, Barnhill RL. Angiotropism, pericytic mimicry and extravascular migratory metastasis: an embryogenesis-derived program of tumor spread. Angiogenesis 23:27–41 (2020)

  8. Barnhill R, van Dam PJ, Vermeulen P, Champenois G, Nicolas A, Rawson RV et al. Replacement and desmoplastic histopathological growth patterns in cutaneous melanoma liver metastases: frequency, characteristics, and robust prognostic value. J Pathol Clin Res 6:195–206 (2020)

  9. Drew J, Machesky LM. The liver metastatic niche: modelling the extracellular matrix in metastasis. Dis Model Mech 14:dmm048801 (2021)

  10. Lugassy C, Scolyer R, Long G, Menzies A, Mischel P, Barnhill RL. PDGFBR expression in anti-BRAF resistant melanoma: are angiotropic melanoma cells a source of BRAF resistance and disease progression? J Cutan Pathol 41: 159–160 (2014)

  11. Maten MV, Reijnen C, Pijnenborg JMA, Zegers MM. L1 cell adhesion molecule in cancer, a systematic review on domain-specific functions. Int J Mol Sci 20:4180 (2019)

  12. Hall H, Carbonetto S, Schachner M. L1/HNK-1 carbohydrate- and beta 1 integrin-dependent neural cell adhesion to laminin-1. J Neurochem 68:544–553 (1997)

  13. SenGupta, S., Parent, C.A. & Bear, J.E. The principles of directed cell migration. Nat Rev Mol Cell Biol 22:529–547 (2021)

  14. Abe K, Katsuno H, Toriyama M, Baba K, Mori T, Hakoshima T, Kanemura Y, Watanabe R, Inagaki N. Grip and slip of L1-CAM on adhesive substrates direct growth cone haptotaxis. Proc Natl Acad Sci USA 115:2764–2769 (2018)

  15. Er EE, Valiente M, Ganesh K, Zou Y, Agrawal S, Hu J et al. Pericyte-like spreading by disseminated cancer cells activates YAP and MRTF for metastatic colonization. Nat Cell Biol 20:966–978 (2018)

  16. Ganesh K, Basnet H, Kaygusuz Y, Laughney AM, He L, Sharma R et al. L1CAM defines the regenerative origin of metastasis-initiating cells in colorectal cancer. Nat Cancer 1:28–45 (2020)

  17. Sekiguchi R, Yamada KM. Basement membranes in development and disease. Curr Top Dev Biol 130:143–191(2018)

  18. Giannelli G, Falk-Marzillier J, Schiraldi O, Stetler-Stevenson WG, Quaranta V. Induction of cell migration by matrix metalloprotease-2 cleavage of laminin-5. Science 277:225–228 (1997)

  19. Qin Y, Rodin S, Simonson OE, Hollande F. Laminins and cancer stem cells: Partners in crime? Semin Cancer Biol 45:3–12 (2017)

  20. Bressan C, Saghatelyan A. Intrinsic mechanisms regulating neuronal migration in the postnatal brain. Front Cell Neurosci 14:620379 (2021)

  21. Matarredona ER, Pastor AM. Neural stem cells of the subventricular zone as the origin of human glioblastoma stem cells. Therapeutic implications. Front Oncol 9:779 (2019)

  22. Sun T, Patil R, Galstyan A, Klymyshyn D, Ding H, Chesnokova A et al. Blockade of a laminin-411-notch axis with CRISPR/Cas9 or a nanobioconjugate inhibits glioblastoma growth through tumor-microenvironment cross-talk. Cancer Res 79:1239–1251 (2019).

  23. McLean IW, Burnier MN, Zimmerman LE et al. Atlas of tumor pathology. Tumors of the eye and ocular adnexa. America Registry of Pathology, Armed Forces Institute of Pathology, Washington, DC, 1994.

  24. Barnhill RL, Ye M, Batistella A, Stern MH, Roman-Roman S, Dendale R, Lantz O et al. The biological and prognostic significance of angiotropism in uveal melanoma. Lab Invest. 97:746–759 (2017)

  25. Ramtohul T, Ait Rais K, Gardrat S, Barnhill R, Román-Román S, Cassoux N et al. Prognostic implications of MRI melanin quantification and cytogenetic abnormalities in liver metastases of uveal melanoma. Cancers (Basel) 13:2728 (2021)

  26. Viros A, Fridlyand J, Bauer J, Lasithiotakis K, Garbe C, Pinkel D et al. Improving melanoma classification by integrating genetic and morphologic features. PLoS Med. 5:e120 (2018)

  27. Cassoux N, Rodrigues MJ, Plancher C, Asselain B, Levy-Gabriel C, Lumbroso-Le Rouic L et al. Genome-wide profiling is a clinically relevant and affordable prognostic test in posterior uveal melanoma. Br J Ophthalmol 98:769–774 (2014)

  28. Massagué J, Ganesh K. Metastasis-initiating cells and ecosystems. Cancer Discov 11:971–994 (2021)

  29. Lugassy C, Eyden BP, Christensen L, Escande JP. Angio-tumoral complex in human malignant melanoma characterised by free laminin: ultrastructural and immunohistochemical observations. J Submicrosc Cytol Pathol 29:19–28 (1997)

  30. Lugassy C, Dickersin GR, Christensen L, Karaoli T, LeCharpentier M, Escande JP et al. Ultrastructural and immunohistochemical studies of the periendothelial matrix in human melanoma: evidence for an amorphous matrix containing laminin. J Cutan Pathol 26:78–83 (1999)

  31. Govaere O, Wouters J, Petz M, Vandewynckel YP, Van den Eynde K, Van den Broeck Aet al. Laminin-332 sustains chemoresistance and quiescence as part of the human hepatic cancer stem cell niche. J Hepatol 64:60917 (2016)

  32. Govaere O, Petz M, Wouters J, Vandewynckel YP, Scott EJ, Topal B et al. The PDGFRα-laminin B1-keratin 19 cascade drives tumor progression at the invasive front of human hepatocellular carcinoma. Oncogene 36:6605–6616 (2017)

  33. Rousselle P, Scoazec JY. Laminin 332 in cancer: When the extracellular matrix turns signals from cell anchorage to cell movement. Semin Cancer Biol 62:149–165 (2020)

  34. Qin Y, Shembrey C, Smith J, Paquet-Fifield S, Behrenbruch C, Beyit LM et al. Laminin 521 enhances self-renewal via STAT3 activation and promotes tumor progression in colorectal cancer. Cancer Lett 476:161–169 (2020)

  35. Lugassy C, Vermeulen PB, Ribatti D, Pezzella F, Barnhill RL. Vessel co-option and angiotropic extravascular migratory metastasis: a continuum of tumour growth and spread? Br J Cancer. 126:973–980 (2022)

  36. Virchow RLK (1978) Cellular pathology, special ed., 204–207. London: John Churchill (1859)

  37. Cofre J, Abdelhay E. Cancer is to embryology as mutation is to genetics: hypothesis of the cancer as embryological phenomenon. ScientificWorldJournal 2017:3578090 (2017)

  38. Aiello NM, Stanger BZ. Echoes of the embryo: using the developmental biology toolkit to study cancer. Dis Model Mech 9:105–114 (2016)

  39. Pitsidianaki I, Morgan J, Adams J, Campbell K. Mesenchymal-to-epithelial transitions require tissue-specific interactions with distinct laminins. J Cell Biol 220:e202010154 (2021)

  40. Itoh K, Fushiki S. The role of L1cam in murine corticogenesis, and the pathogenesis of hydrocephalus. Pathol Int 65:58–66 (2015)

  41. Rodrigues M, Mobuchon L, Houy A, Alsafadi S, Baulande S, Mariani O et al. Evolutionary routes in metastatic uveal melanomas depend on MBD4 alterations. Clin Cancer Res. 25:5513–5524 (2019)

  42. Lugassy C, Péault B, Wadehra M, Kleinman HK, Barnhill RL. Could pericytic mimicry represent another type of melanoma cell plasticity with embryonic properties? Pigment Cell Melanoma Res. 26:746–754 (2013)

  43. Bald T, Quast T, Landsberg J, Rogava M, Glodde N, Lopez-Ramos D, Kohlmeyer J, Riesenberg S, van den Boorn-Konijnenberg D, Hömig-Hölzel C, Reuten R, Schadow B, Weighardt H, Wenzel D, Helfrich I, Schadendorf D, Bloch W, Bianchi ME, Lugassy C, Barnhill RL, Koch M, Fleischmann BK, Förster I, Kastenmüller W, Kolanus W, Hölzel M, Gaffal E, Tüting T. Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. Nature. 507:109–13 (2014)

  44. Orchard GE, Calonje E. The effect of melanin bleaching on immunohistochemical staining in heavily pigmented melanocytic neoplasms. Am J Dermatopathol 20:357–361 (1998)

  45. Hoek KS, Eichhoff OM, Schlegel NC, Döbbeling U, Kobert N, Schaerer L, Hemmi S, Dummer R. In vivo switching of human melanoma cells between proliferative and invasive states. Cancer Res 68:650–656 (2008)

  46. Mariani P, Piperno-Neumann S, Servois V, Berry MG, Dorval T, Plancher C, Couturier J, Levy-Gabriel C, Lumbroso-Le Rouic L, Desjardins L, Salmon RJ. Surgical management of liver metastases from uveal melanoma: 16 years’ experience at the Institut Curie. Eur J Surg Oncol. 2009 35:1192–1197 (2009)

  47. Frenkel S, Nir I, Hendler K, Lotem M, Eid A, Jurim O, Pe’er J. Long-term survival of uveal melanoma patients after surgery for liver metastases. Br J Ophthalmol. 93:1042–1046. (2009)

  48. Rodrigues M, Mobuchon L, Houy A, Fiévet A, Gardrat S, Barnhill RL, Popova T, Servois V, Rampanou A, Mouton A, Dayot S, Raynal V, Galut M, Putterman M, Tick S, Cassoux N, Roman-Roman S, Bidard FC, Lantz O, Mariani P, Piperno-Neumann S, Stern MH. Outlier response to anti-PD1 in uveal melanoma reveals germline MBD4 mutations in hypermutated tumors. Nat Commun. 9:1866 (2018)

  49. Starmans MPA, Buisman FE, Renckens M, Willemssen FEJA, van der Voort SR, Groot Koerkamp B, Grünhagen DJ, Niessen WJ, Vermeulen PB, Verhoef C, Visser JJ, Klein S. Distinguishing pure histopathological growth patterns of colorectal liver metastases on CT using deep learning and radiomics: a pilot study. Clin Exp Metastasis 38:483–494 (2021)

  50. Cheng J, Wei J, Tong T, Sheng W, Zhang Y, Han Y, Gu D, Hong N, Ye Y, Tian J, Wang Y. Prediction of histopathologic growth patterns of colorectal liver metastases with a noninvasive imaging method. Ann Surg Oncol. 26:4587–4598 (2019)

  51. Han Y, Chai F, Wei J, Yue Y, Cheng J, Gu D, Zhang Y, Tong T, Sheng W, Hong N, Ye Y, Wang Y, Tian J. Identification of predominant histopathological growth patterns of colorectal liver metastasis by multi-habitat and multi-sequence based radiomics analysis. Front Oncol. 10:1363 (2020)

  52. Wei S, Han Y, Zeng H, Ye S, Cheng J, Chai F, Wei J, Zhang J, Hong N, Bao Y, Zhou J, Ye Y, Meng X, Zhou Y, Deng Y, Qiu M, Tian J, Wang Y. Radiomics diagnosed histopathological growth pattern in prediction of response and 1-year progression free survival for colorectal liver metastases patients treated with bevacizumab containing chemotherapy. Eur J Radiol. 142:109863 (2021)

Download references


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.

Author information

Authors and Affiliations



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.

Corresponding author

Correspondence to Raymond Barnhill.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

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.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI:


Quick links