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.

Keywords: angiotropism; desmoplastic; histopathological growth patterns; liver; metastasis; replacement; uveal melanoma; vascular co-option.

Figure 1

Histopathological growth patterns. (A) Replacement histopathological growth pattern: melanoma cells (blue) invade the liver cell plates, replace the hepatocytes (red), and co‐opt the sinusoidal blood vessels (purple endothelial cells). There is no angiogenesis. VL, vascular lumen of sinusoidal vessels. (B) Desmoplastic histopathological growth pattern: melanoma cells (blue) are separated from the liver (red hepatocytes) by a rim of desmoplastic tissue (yellow) which contains newly formed blood vessels (angiogenesis, orange endothelial cells). Melanoma cells do not invade the liver cell plates. (C) Pushing histopathological growth pattern: melanoma cells (blue) push away the liver cell plates (red hepatocytes) and do not invade the liver cell plates. New blood vessels (angiogenesis, orange endothelial cells) are formed in the metastasis.

Figure 2

Replacement histopathological growth pattern. (A) Scanning magnification shows a discrete metastasis abutting the liver capsule. Lv, surrounding uninvolved liver parenchyma. (B) The interface (broad zone extending from upper right quadrant to lower left quadrant) between the metastasis (upper left quadrant) and surrounding liver parenchyma (Lv) (lower right quadrant) is poorly defined. Melanoma cells (detected by the presence of cytoplasmic melanin and cytological atypia) are dispersed throughout this peripheral interface as single cells (arrowheads) and small clusters beyond the main portion of the metastasis. These cells replace hepatocytes in the hepatic plates without altering their architecture. (C) Melanoma cells (arrow) extending into the surrounding hepatic plates some distance from the metastasis along the sinusoidal vessels. Red asterix indicates vascular lumen. Black arrow identifies melanoma cells. (D) HMB45 immunostain with red chromogen highlights melanoma cells extending into the surrounding liver parenchyma. Inset; Melanoma cells expressing HMB45 are disposed along the abluminal endothelial surface of a sinusoidal vessel in the hepatic parenchyma. The endothelial cell lining is highlighted by CD31 (DAB brown chromogen).

Figure 3

Desmoplastic histopathological growth pattern. (A) Small round metastasis (M) with abrupt desmoplastic interface (arrowheads) separates the tumour from the surrounding liver parenchyma. The liver architecture is completely obliterated by the tumour mass. Lv, surrounding uninvolved liver parenchyma. (B) An annulus of dense desmoplastic collagen constitutes this interface (arrowheads). Liver parenchyma (Lv) is observed in the upper half of this field and the metastasis (M) in the lowermost portion of the field. (C) High magnification of B. Note the rim of peri‐tumoural lymphocytes (Ly), which are at the interface of the desmoplastic annulus (D) and the surrounding liver parenchyma.

Figure 4

Electron microscopy of replacement HGP. This field shows the lumen of a sinusoidal vascular channel (upper third of field) which contains an erythrocyte and exhibits an attenuated endothelial cell lining. A melanoma cell (in the lower two‐thirds of the field) is identified by cytoplasmic melanosomes (dense bodies). The melanoma cell is disposed along the abluminal surface of the sinusoidal vessel.

Figure 5

(I) The effects of replacement and desmoplastic HGPs of UM liver metastases on overall survival analysed by the Log Rank test with Kaplan–Meier plots. (A) Overall survival from the time of diagnosis of liver metastases to death or to date of last follow‐up. (B) Overall survival from the time of diagnosis of the primary UM to death or to date of last follow‐up. (C) Disease‐free survival from the time of diagnosis of the primary UM to death or to the development of liver metastases. (II) The effects of prognostic factors on survival analysed by the Log Rank test with Kaplan–Meier plots. (A) Overall survival from the time of diagnosis of the primary UM to death or to date of last follow‐up: the effects of Cassoux high‐risk status (M3/8g). (B) Overall survival from the time of diagnosis of the primary UM to death or to date of last follow‐up: the effects of tumour diameter (LTD). (C) Disease‐free survival from the time of diagnosis of the primary UM to death or to the development of liver metastases: the effects of Cassoux high‐risk status.