The "histological replacement growth pattern" represents aggressive invasive behavior in liver metastasis from pancreatic cancer

Abstract

Background: In the case of liver metastasis (LM), tumors showing the replacement growth pattern (RGP), in which metastatic cells infiltrate and replace hepatocytes with minimal desmoplastic reaction and inflammatory cell infiltration, associate with a poor prognosis. The heterogeneity, frequency, and prognostic value of the RGP in LM from pancreatic cancer (PCa) are not well known.

Methods: In the circumference of treatment-naïve resected LMs from patients with PCa, the heterogeneity of the GP was assessed. Next, the clinicopathological features of LMs showing the RGP in needle biopsy specimens were investigated in patients with treatment-naïve advanced PCa.

Results: Thirteen of the 14 (93%) in all resected LMs and 7 of the 9 (78%) in RGP component GP in resected LMs showed homogeneous GP. A RGP was found in 50% of the needle biopsy specimens of LMs obtained from 107 patients. The median overall survival times in the RGP group and non-RGP group were 3.6 and 10.4 months. Multivariate analysis identified RGP as an independent poor prognostic factor. Median value of CD8 positive percentage in RGP was lower than that in non-RGP (0.75 vs 1.46, P = .04). Median overall survival times in low CD8 groups tend to be shorter than those in high CD8 group (8.2 vs 4.2 months).

Conclusion: Most LMs from PCa show a homogeneous GP. The RGP was observed in about a half of the LMs from PCa patients, and was identified as a poor prognostic factor.

Keywords: liver metastasis; pancreatic cancer; prognostic factor; replacement growth pattern; tumor microenvironment.

FIGURE 1

Study flow. A total of 293 PCa patients with pathologically proven liver metastasis prior to the start of anti‐cancer therapy were included in this study. The circumferential GPs were first investigated in 14 LMs resected by excisional biopsy. The data revealed that most LMs had an RGP component and that the majority showed a homogeneous GP. Factors associated with the presence of the RGP and survival analysis were performed using needle biopsy specimens of 107 LMs

FIGURE 2

Circumferential analysis using the 14 resected LMs. Thirteen of 14 LMs (93%) showed a homogeneous GP, including the RGP in 7 LMs (50%), desmoplastic GP in 2 LMs (14%), pushing‐type GP in 1 LM (7%), and an unclassified GP in 3 LMs (22%). Predominant‐RGP, desmoplastic GP, pushing‐type GP, and unclassified GP were observed in 8 (57%), 2 (14%), 1 (7%), and 3 (21%) LMs, respectively. Among the 9 LMs showing an RGP component, a predominant RGP was observed in 8 LMs (89%). The GP was regarded as homogeneous if the percentage of the circumference covered by the same GP was over 80%

FIGURE 3

Photomicrographs of a resected liver metastasis showing the replacement GP (hematoxylin and eosin stain). A, Loupe image of the resected liver specimen. Bar, 2500 μm. B, Resected liver specimen containing the tumor periphery. The whole region around the LM shows RGP (original magnification, 10×. Bar, 250 μm). C, RGP, in which the tumor cells replaced the hepatocytes without destroying the trabecular architecture of the liver, with no desmoplastic changes or inflammatory cell infiltration (original magnification, 40×. Bar, 100 μm). T, tumor; L, liver parenchyma

FIGURE 4

Photomicrographs of biopsied liver metastasis showing the RGP (hematoxylin and eosin staining, Gordon‐Sweet's reticulin staining, and immunostaining). RGP is represented in (A) and (B) with hematoxylin and eosin staining (original magnification, (A) 10×, (B) 40×. Bar, 100 μm), in (C) with Gordon‐Sweet's silver staining (original magnification, 40×. Bar, 100 μm), and in (D) with cytokeratin 7 staining (original magnification, 40×. Bar, 100 μm). The region in the black box in (A) is shown in (B). The RGP shows no desmoplastic stroma or inflammatory cells at the invasive front (black arrows). In (A) and (B), the tumor periphery is difficult to discern, but in (C) and (D), Gordon‐Sweet's silver staining was helpful for the detection of sinusoids and evaluation of preservation of the liver cell plate in the tumor. Cytokeratin 7 staining clearly revealed that the tumor cells and liver parenchyma were in close approximation, without compression of the liver cell plates. T, tumor; L, liver parenchyma

FIGURE 5

Overall survival (OS) curves of PCa patients with liver metastasis based on RGP analysis using needle biopsy specimens. CI, confidence interval; HR, hazard ratio