Replacement and desmoplastic histopathological growth patterns in cutaneous melanoma liver metastases: frequency, characteristics, and robust prognostic value

Abstract

Among visceral metastatic sites, cutaneous melanoma (CM) metastasises initially to the liver in ~14–20% of cases. Liver metastases in CM patients are associated with both poor prognosis and poor response to immunotherapy. Histopathological growth patterns (HGPs) of liver metastases of the replacement and desmoplastic type, particularly from colorectal cancer and uveal melanoma (UM), may impart valuable biological and prognostic information. Here, we have studied HGP in 43 CM liver metastases resected from 42 CM patients along with other prognostic factors from three institutions. The HGPs (replacement, desmoplastic, pushing) were scored at the metastasis–liver interface with two algorithms: (1) 100% desmoplastic growth pattern (dHGP) and any (≥1%) replacement pattern (any‐rHGP) and (2) >50% dHGP, >50% rHGP or mixed (<50% dHGP and/or rHGP, pushing HGP). For 1 patient with 2 metastases, an average was taken to obtain 1 final HGP yielding 42 observations from 42 patients. 22 cases (52%) had 100% dHGP whereas 20 (48%) had any replacement. Cases with rHGP demonstrated vascular co‐option/angiotropism. With the development of liver metastasis, only rHGP (both algorithms), male gender and positive resection margins predicted diminished overall survival ( p = 0.00099 and p = 0.0015; p = 0.034 and p = 0.024 respectively). On multivariate analysis, only HGP remained significant. 7 of 42 (17%) patients were alive with disease and 21 (50%) died with follow‐up after liver metastases ranging from 1.8 to 42.2 months (mean: 20.4 months, median: 19.0 months). 14 (33%) patients with previously‐treated metastatic disease had no evidence of disease at last follow up. In conclusion, we report for the first time replacement and desmoplastic HGPs in CM liver metastases and their prognostic value, as in UM and other solid cancers. Of particular importance, any rHGP significantly predicted diminished overall survival while 100% dHGP correlated with increased survival. These results contribute to a better understanding of the biology of CM liver metastases and potentially may be utilised in managing patients with these metastases.

Different Forms of Tumor Vascularization and Their Clinical Implications Focusing on Vessel Co-option in Colorectal Cancer Liver Metastases

“…Hereby, a predominantly desmoplastic HGP was also associated with a significantly improved OS compared to predominantly replacement HGP or mixed HGP (Barnhill et al, 2020). Moreover, this favorable prognostic effect of the desmoplastic HGP was even stronger when pure desmoplastic HGP were compared to any amount of replacement HGP (Barnhill et al, 2020), which is similar to the previously described results that Galjart et al (2019) reported in a cohort of patients with CRCLM.…”

“…Hereby, a predominantly desmoplastic HGP was also associated with a significantly improved OS compared to predominantly replacement HGP or mixed HGP (Barnhill et al, 2020). Moreover, this favorable prognostic effect of the desmoplastic HGP was even stronger when pure desmoplastic HGP were compared to any amount of replacement HGP (Barnhill et al, 2020), which is similar to the previously described results that Galjart et al (2019) reported in a cohort of patients with CRCLM. In another analysis focused on HGP in LM derived from breast cancer, LM displaying any amount of desmoplastic HGP were associated with significantly improved progression free survival and OS when compared to LM with a pure replacement HGP (Bohlok et al, 2020).…”

Clinico‐metabolic characterization improves the prognostic value of histological growth patterns in patients undergoing surgery for colorectal liver metastases

“…[12][13][14][15][16][17][18][19] The histopathological growth pattern (HGP) of liver metastases has now repeatedly been demonstrated as a reproducible, independent, and strong prognostic factor in patients who underwent resection of CRLM. [20][21][22] Two main HGPs have been described in CRLM: (1) Desmoplastic HGP (DHGP), characterized by a fibrous or connective tissue rim surrounding the metastasis and separating tumor from liver cells, with numerous immune cells at the tumor-liver interface (TLI) and angiogenesis and, (2) Replacement HGP (RHGP), characterized by cancer cells growing into the liver parenchyma resulting in direct contact between cancer cells and liver cells, minimal to absent immune cell infiltrate at the TLI and tumor vascularization relying on the use of pre-existing hepatic vessels, that is, vessel cooption. 23,24 A third, but uncommon HGP pattern has been observed, defined as the pushing HGP (PHGP), in which the metastasis pushes away the liver tissue, without desmoplastic rim and without invasion of cancer in the liver cell plates.…”

Morphological Characteristics and Clinical Significance of Different Types of Tumor Vessels in Patients with Stages I-IIA of Squamous Cervical Cancer

“…We previously suggested that the formation of tumor vessels can occur not only due to sprouting angiogenesis, vessel co-option, vasculogenic mimicry, intussusceptive angiogenesis, or vasculogenesis [26,34,61,62], but also due to the formation of "cavitary" structures in the tumor stroma, being then lined by the endothelium and merged into the blood vessels of the organ [31,32]. We hypothesized that there are two main mechanisms for the formation of such structures.…”

“…Despite the fact that the heterogeneity of tumor vessels has been confirmed by numerous studies, to date, there has been no classification of tumor vessels that takes account of both the features of their morphology and its relationship with the clinical and morphological characteristics of the pathological process and with long-term results of treatment. A number of existing classifications are based on the origin and degree of vessel maturity, as well as their relationship with the type of histopathological tumor growth patterns [ 26 , 33 , 34 ].…”