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.

Keywords: angiotropism; cutaneous melanoma; desmoplastic; extravascular migratory metastasis; histopathological growth patterns; liver; metastasis; pericytic mimicry; replacement; vascular co-option.

Figure 1

Replacement histopathological growth pattern (HGP). (A) Scanning magnification shows a fairly discrete metastasis (Met) with surrounding liver parenchyma (Liver). The box indicates the poorly defined metastasis–liver interface. (B) The interface (box) between the metastasis proper (most inferior portion of field) and surrounding liver parenchyma is poorly defined. Melanoma cells are dispersed throughout this interface and the surrounding hepatocytic plates as single cells, files of cells, and in small clusters beyond the main portion of the metastasis. These cells replace hepatocytes in the hepatic plates without altering their architecture or the architecture of the sinusoidal vasculature. Inset (upper left) illustrates the replacement HGP. The hepatic parenchyma (yellow) is infiltrated and replaced by melanoma cells (green). The melanoma cells are disposed along the abluminal surfaces of the sinusoidal vessels (red). (C) Melanoma cells (arrows) extending into the surrounding hepatic plates (Liver) some distance from the metastasis (Met) along the sinusoidal vessels. (D) Melan‐A immunostain with red chromogen highlights melanoma cells (arrows) extending into the surrounding liver parenchyma (Liver) along the external surfaces of sinusoidal vascular channels from the metastatic nodule (Met).

Figure 2

Desmoplastic histopathological growth pattern (HGP). (A) Scanning magnification depicts a metastasis (Met, inferior part of the field) with abrupt desmoplastic interface (arrowheads) separating the tumour from the surrounding liver parenchyma (box) (Liver, superior part of the field). The liver architecture is completely obliterated by the tumour mass. (B) An annulus of dense desmoplastic collagen (arrowheads) constitutes this interface between the metastasis (Met, inferior) and the liver parenchyma (Liver) observed in the superior half of this field. (C) High magnification of (B) showing the interface of the desmoplastic annulus (box, Desmoplasia) separating the liver parenchyma (Liver) completely from the metastasis (Met). Brackets indicate the peri‐tumoural zone containing lymphocytic infiltrates. This zone includes the outer part of the desmoplastic annulus and an adjoining rim of liver parenchyma (Liver). (D) Higher magnification of C. showing metastasis (Met)–liver interface with desmoplastic annulus (Desmoplasia). (E) Melan‐A immunostain (red chromogen) highlights melanoma cells (Met) separated from liver parenchyma by the band of desmoplasia.

Figure 3

Pushing histopathological growth pattern (HGP). (A) Scanning magnification shows a large discrete metastasis. The metastasis–liver interface is indicated by the box. (B) The metastatic nodule (Met, inferior half of field) compresses the overlying liver parenchyma (Liver, superior half of field) with horizontal disposition of hepatic plates. The metastasis–liver interface (arrowheads) is abrupt and characterised by the absence of desmoplasia and no infiltration of the overlying hepatic parenchyma. (C) Higher magnification of (B) melanoma cells (Met) do not invade the liver cell plates (Liver, superior) and desmoplasia is absent at the interface (arrowheads) between the metastasis and the liver parenchyma. Note the horizontal orientation of hepatocytes; this is not desmoplasia.

Figure 4

The effects of any replacement and 100% desmoplastic HGPs of CM liver metastases on overall survival analysed by the log‐rank test with Kaplan–Meier plots. Overall survival is from the time of diagnosis of liver metastases to death or to date of last follow‐up.

Figure 5

The effects of >50% replacement, >50% desmoplastic, and mixed HGPs of CM liver metastases on overall survival analysed by the log‐rank test with Kaplan–Meier plots. Overall survival is from the time of diagnosis of liver metastases to death or to date of last follow‐up.