Sarcomatoid hepatocellular carcinoma: From clinical features to cancer genome

Abstract

Background: Sarcomatoid hepatocellular carcinoma (HCC) is a rare and highly lethal histological subtype of HCC, with completely unknown genetic etiology and therapeutic targets.

Methods: We included 16 patients with sarcomatoid HCC receiving radical resection among 6731 cases of pathological confirmed HCC in year 2008 to 2018 in our hospital. We compared the clinical features, prognosis and cancer genome between 15 sarcomatoid HCC and propensity score-matched 75 non-sarcomatoid HCC patients. The other concurrent case was analyzed using phylogenetic tree to assess the tumor heterogeneity and evolution.

Results: Sarcomatoid HCC group showed larger tumor size, more advanced differentiation grade, lower tumor free survival (p = 0.038) and overall survival (p = 0.001), and sarcomatoid type was an independent risk factor for patient death. Integrating sarcomatoid subtype into AJCC staging could increase the diagnostic curve in predicting patient survival. The cancer genome spectrum showed sarcomatoid HCC group had significant higher mutation rates in CDKN2A, EPHA5, FANCM and MAP3K1. Mutations in CDKN2A significantly reduced tumor-free and overall survival in sarcomatoid HCC patients. Moreover, 46.6% sarcomatoid HCC patients had druggable mutations in cell cycle pathway genes, which were targeted by Abemaciclib, et al. We also found sarcomatoid and non-sarcomatoid lesions might originate from a common progenitor but progress differently.

Conclusion: Our cancer genome analysis showed a specific genomic profile of sarcomatoid HCC, which were characterized by a high mutation rate in cell cycle genes particularly CDKN2A. The results indicate CDK4/6 inhibitors including abemaciclib, ribociclib and palbociclib as potential therapeutic targets and may help for therapeutic decision making.

Keywords: genome; sarcomatoid hepatocellular carcinoma; survival; therapy.

FIGURE 1

The comparison of survival curves between patients with sarcomatoid HCC and non‐sarcomatoid HCC. (A) tumor‐free survival curves; (B) patient overall survival curves

FIGURE 2

The histopathological presentation of sarcomatoid HCC (case 1–6)

FIGURE 3

The molecular diversity between sarcomatoid HCC and non‐sarcomatoid HCC. (A) The comparison of immunohistochemistry markers; (B) The overview of clinically relevant genomic alterations in two groups; (C) The differential genomic alterations between the two groups; (D) The comparison of druggable mutations

FIGURE 4

The phylogenetic analysis in a patient with concurrent sarcomatoid HCC and non‐sarcomatoid HCC. (A) The computer tomography scan of sarcomatoid HCC (segment VII, blue circle) and non‐sarcomatoid HCC (segment IV, red circle); (B) The hematoxylin and eosin (HE)‐staining; (C) The overview of somatic variants in the two lesions; (D) The phylogenetic tree