Histological subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour classification

Caldéraro, Julien; Couchy, Gabrielle; Imbeaud, Sandrine; Amaddeo, Giuliana; Letouzé, Éric; Blanc, Jean‐Frédéric; Laurent, Césari; Hajji, Yacine; Azoulay, Daniel; Bioulac‐Sage, Paulette; Nault, Jean–Charles; Zucman‐Rossi, Jessica

doi:10.1016/j.jhep.2017.05.014

Cited by 533 publications

(676 citation statements)

References 38 publications

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“…Recently, HCCs with a macrotrabecular pattern were also reported to belong to the S2 signature subclass described by Hoshida and colleagues [18,34], and were correlated with the activation of the YAP oncogene and with the expression of the stemness markers K19 and EpCAM. Moreover, macrotrabecular-massive HCCs were found to belong to the G3 signature subclass described by Boyault et al [34], which is known to be an aggressive molecular subtype of HCC, and were correlated with poor survival, vascular invasion, TP53 mutation, and FGF19 amplification [19,34]. Therefore, IREs might represent distinct histopathologic and molecular characteristics of HCC via their association with the macrotrabecular pattern.…”

Section: Discussionmentioning

confidence: 95%

“…Hypoxia has been found to be involved in the maintenance of cancer stem cells, which are characterized by their ability to self-renew and propagate tumors, and play an important role in tumor maintenance and recurrence [32,33]. HCCs expressing stemness markers, such as K19 and EpCAM, are reportedly associated with poor prognosis and molecular signatures of aggressive biological behavior such as S2 (Hoshida et al [34]) and G1 (Boyault et al [35]) compared to HCCs that do not express these markers [18,19,[34][35][36][37][38]. Rhee et al [23] also recently reported a close association between the expression of the hypoxia marker CAIX and stemness markers including K19 and EpCAM in HCCs.…”

Section: Discussionmentioning

confidence: 99%

“…We additionally evaluated histopathologic characteristics and tumor microenvironmental factors on a representative whole-section slide, as follows: a macrotrabecular pattern was defined as cords of tumor cells thicker than 10 cells, as previously described [18]. The proportion of the tumor area showing a macrotrabecular pattern was recorded, and tumors with > 50% of their areas exhibiting macrotrabecular patterns were defined as macrotrabecular-massive type [19]. To assess the proportion of fibrous stroma of a tumor, the whole-section slide of each sample was stained with Sirius red and digitized with a high-resolution slide scanner (LS-4000ed; Nikon Corporation, Tokyo, Japan) [20].…”

Section: Histopathology and Immunohistochemistrymentioning

confidence: 99%

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Hepatocellular Carcinoma with Irregular Rim-Like Arterial Phase Hyperenhancement: More Aggressive Pathologic Features

Rhee

An²,

Kim

et al. 2018

Liver Cancer

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Background and Aims: The purpose of our study was to examine the histopathologic characteristics of hepatocellular carcinoma (HCC) with irregular rim-like arterial phase enhancement (IRE), which has been reported to be associated with more aggressive tumor behavior. Methods: We investigated 84 pathologically confirmed HCCs in 84 patients who underwent curative hepatic resection after gadoxetate-enhanced magnetic resonance imaging between January 2008 and February 2013. Two abdominal radiologists independently reviewed these images and classified HCCs into two categories: HCC showing IRE (IRE-HCC) and HCC showing hypoenhancement or diffuse arterial enhancement (non-IRE-HCC). Twenty-two HCCs were classified as IRE-HCCs, and 51 were classified as non-IRE-HCCs concordantly by both reviewers. The remaining 11 HCCs, on whose radiologic classifications the reviewers disagreed, were classified as HCCs with intermediate enhancement patterns. The HCC clinicopathologic characteristics and patient outcomes were then compared. Results: IRE-HCCs showed more frequent microvascular invasion (91 vs. 35%), lower microvascular density (246.5 vs. 426.5/mm²), higher proportions of sinusoid-like microvascular pattern (55 vs. 0%) and macrotrabecular pattern (45 vs. 0%), and larger areas of tumor necrosis (15 vs. 0%) and fibrous stroma (8.3 vs. 2.1%) than non-IRE-HCCs. IRE-HCCs also expressed higher levels of immunomarkers of hypoxia (carbonic anhydrase IX, 64 vs. 8%) and stemness (EpCAM, 50 vs. 20%). p values were < 0.001 for all comparisons except for EpCAM (p = 0.026). HCCs with intermediate enhancement patterns showed mixed/intermediate pathologic features from both IRE- and non-IRE-HCCs. IRE-HCC patients showed poorer 5-year disease-free survival after curative resection than non-IRE-HCC patients (p = 0.005). Conclusions: IRE-HCCs demonstrate aggressive histopathologic features, including more hypoxic and fibrotic tumor microenvironments and increased stemness, compared to non-IRE-HCCs. IRE might therefore serve as a noninvasive imaging biomarker for aggressive HCC.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Histopathology and Immunohistochemistrymentioning

confidence: 99%

See 1 more Smart Citation

Hepatocellular Carcinoma with Irregular Rim-Like Arterial Phase Hyperenhancement: More Aggressive Pathologic Features

Rhee

An²,

Kim

et al. 2018

Liver Cancer

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“…Actually, studies have shown that the tumor‐intrinsic activation of specific signaling pathways can affect immune‐cell infiltration. In HCC, mutations of CTNNB1 (associated with Hoshida's S3 and Boyault's G5/6 subclasses) and TP53 (associated with Hoshida's S1/2 and Boyault's G1 to G3 subclasses) are major mutations, and recent comprehensive molecular analysis revealed associations between CTNNB1 mutation, and lower lymphocytic infiltration as confirmed in the current study. Mechanistically, in melanoma, CTNNB1 mutation decreases the recruitment of proinflammatory DCs and T cells through decreased chemokine CCL4 expression .…”

Section: Discussionmentioning

confidence: 99%

Landscape of immune microenvironment in hepatocellular carcinoma and its additional impact on histological and molecular classification

Kurebayashi¹,

Ojima²,

Tsujikawa³

et al. 2018

Hepatology

336

346

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“…3,7 To our knowledge, there have been few reports to date regarding sarcomatoid HCC, with the largest study reporting only 40 cases from Taiwan. 3,5 The current study was important because we specifically examined treatment options and outcomes among >100 patients with sarcomatoid HCC using a nationwide database. 3,5 The current study was important because we specifically examined treatment options and outcomes among >100 patients with sarcomatoid HCC using a nationwide database.…”

Section: Discussionmentioning

confidence: 99%

Management and outcomes among patients with sarcomatoid hepatocellular carcinoma: A population‐based analysis

Tsilimigras

Farooq

et al. 2019

Cancer

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Background Few data are available regarding the management and outcomes among patients with sarcomatoid hepatocellular carcinoma (HCC) due to its rarity. Methods Patients diagnosed with sarcomatoid HCC from 2004 through 2015 were identified in the National Cancer Data Base. Overall survival (OS) was calculated among patients with sarcomatoid versus conventional HCC using a 1:3 propensity score matching based on sex, age, and American Joint Committee on Cancer (AJCC) stage of disease. Results The final analytic cohort included 104 patients with sarcomatoid HCC and 312 patients with conventional HCC. Patients with sarcomatoid HCC more often had a larger median tumor size (8.5 cm vs 5.4 cm; P < .001) and poorly or undifferentiated tumors (52.9% vs 13.8%; P < .001) compared with patients who had conventional HCC. 5‐year OS was worse among patients with sarcomatoid versus conventional HCC (5.7% vs 30.1%; P < .001). Subgroup analysis demonstrated worse 5‐year OS among patients with sarcomatoid versus conventional HCC among patients treated with either curative‐intent or palliative therapies. Stage‐specific subgroup analysis indicated a worse OS among patients with AJCC stage I, stage II, or stage III sarcomatoid HCC. On multivariable analysis, uninsured status, advanced AJCC stage (stage III/stage IV), and histological sarcomatoid subtype were independently associated with worse outcomes (all P < .05). Conclusions Sarcomatoid HCC is a very rare variant of HCC, which was associated with larger tumor size and worse tumor grade on presentation. On propensity score matched analyses that controlled for known confounding factors, patients with sarcomatoid HCC had a worse stage‐for‐stage long‐term survival compared with patients who had conventional HCC.

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Histological subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour classification

Cited by 533 publications

References 38 publications

Hepatocellular Carcinoma with Irregular Rim-Like Arterial Phase Hyperenhancement: More Aggressive Pathologic Features

Hepatocellular Carcinoma with Irregular Rim-Like Arterial Phase Hyperenhancement: More Aggressive Pathologic Features

Landscape of immune microenvironment in hepatocellular carcinoma and its additional impact on histological and molecular classification

Management and outcomes among patients with sarcomatoid hepatocellular carcinoma: A population‐based analysis

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