Clinicopathological indices to predict hepatocellular carcinoma molecular classification

Abstract

Background & Aims Hepatocellular carcinoma (HCC) is the second most lethal cancer due to lack of effective therapies. Although promising, HCC molecular classification, which enriches potential responders to specific therapies, has not yet been assessed in clinical trials of anti-HCC drugs. We aimed to overcome these challenges by developing clinicopathological surrogate indices of HCC molecular classification. Methods HCC classification defined in our previous transcriptome meta-analysis (S1, S2, and S3 subclasses) was implemented in an FDA-approved diagnostic platform (Elements assay, NanoString). Ninety-six HCC tumors (training set) were assayed to develop molecular subclass-predictive indices based on clinicopathological features, which were independently validated in 99 HCC tumors (validation set). Molecular deregulations associated with the histopathological features were determined by pathway analysis. Sample sizes for HCC clinical trials enriched with specific molecular subclasses were determined. Results HCC subclass-predictive indices were: steatohepatitic (SH)-HCC variant and immune cell infiltrate for S1 subclass, macrotrabecular/compact pattern, lack of pseudoglandular pattern, and high serum alpha-fetoprotein (>400 ng/mL) for S2 subclass, and microtrabecular pattern, lack of SH-HCC and clear cell variants, and lower histological grade for S3 subclass. Macrotrabecular/compact pattern, a predictor of S2 subclass, was associated with activation of therapeutically targetable oncogene YAP and stemness markers EPCAM/KRT19. BMP4 was associated with pseudoglandular pattern. Subclass-predictive indices-based patient enrichment reduced clinical trial sample sizes from 121, 184, and 53 to 30, 43, and 22 for S1, S2, and S3 subclass-targeting therapies, respectively. Conclusions HCC molecular subclasses can be enriched by clinicopathological indices tightly associated with deregulation of therapeutically targetable molecular pathways.

Immunohistochemistry panel segregates molecular types of hepatocellular carcinoma in Brazilian autopsy cases

“…In conclusion, in the present autopsy cohort we found relevant associations between immunohistochemical markers with morphological features of tumors, especially that of histological grading of HCC [35] . The expression of K19, p53, ERK1, ERK2, vimentin and nuclear beta-catenin showed an association with pathological markers of higher-grade tumors, as opposed to cases expressing/over-expressing EGFR, MET and caspase 3.…”

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

“…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].…”

“…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.…”

“…In cases of multiple tumors, all histopathologic analyses were performed on the largest lesion of each patient; this was the same lesion in which arterial enhancement pattern classification was performed. 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].…”

Molecular classification of hepatocellular carcinoma: potential therapeutic implications

“…For example, TERT activation is most frequently and commonly seen across etiologies despite the wide variety of molecular alterations leading to the pathway activation such as HBV integration, genomic DNA amplification or promoter mutation [61]. Interestingly, the S2 subclass (common theme #2) is relatively more frequent in HBV-related HCC – also less associated with cirrhosis – suggesting that HBV genomic integration leads to enrichment of this molecular subclass and supporting the presence of etiology-specific bias in the affected pathways [57,62–66]. …”