Molecular and histological correlations in liver cancer Calderaro, Julien; Ziol, Marianne; Paradis, Valérie ...
Journal of hepatology,
September 2019, 2019-09-00, 20190901, 2019-09, Letnik:
71, Številka:
3
Journal Article
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Hepatocellular carcinoma (HCC) is a highly heterogeneous cancer, both at the molecular and histological level. High-throughput sequencing and gene expression profiling have identified distinct ...transcriptomic subclasses and numerous recurrent genetic alterations; several HCC subtypes characterised by histological features have also been identified. HCC phenotype appears to be closely related to particular gene mutations, tumour subgroups and/or oncogenic pathways. Non-proliferative tumours display a well-differentiated phenotype. Among this molecular subgroup, CTNNB1-mutated HCCs constitute a homogeneous subtype, exhibiting cholestasis and microtrabecular and pseudoglandular architectural patterns. Another non-proliferative subtype has a gene expression pattern similar to that of mature hepatocytes (G4) and displays a steatohepatitic phenotype. In contrast, proliferative HCCs are most often poorly differentiated, and notably include tumours with progenitor features. A novel morphological variant of proliferative HCC – designated “macrotrabecular-massive” – was recently shown to be associated with angiogenesis activation and poor prognosis. Altogether, these findings may help to translate our knowledge of HCC biology into clinical practice, resulting in improved precision medicine for patients with this highly aggressive malignancy. This manuscript reviews the most recent data in this exciting field, discussing future directions and challenges.
Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a tumour that exhibits both hepatocytic and biliary differentiation. Classical risk factors for hepatocellular carcinoma (HCC) seem to also ...predispose patients to the development of cHCC-CCA. The pathological definition of cHCC-CCA has significantly evolved over time. The last 2019 WHO classification highlighted that the diagnosis of cHCC-CCA should be primarily based on morphology using routine stainings, with additional immunostaining used to refine the identification of subtypes. Among them, “intermediate cell carcinoma” is recognised as a specific subtype, while “cholangiolocellular carcinoma” is now considered a subtype of iCCA. Increasing molecular evidence supports the clonal nature of cHCC-CCA and parallels its biphenotypic histological appearance, with genetic alterations that are classically observed in HCC and/or iCCA. That said, the morphological diagnosis of cHCC-CCA is still challenging for radiologists and pathologists, especially on biopsy specimens. Identification of cHCC-CCA’s cell of origin remains an area of active research. Its prognosis is generally worse than that of HCC, and similar to that of iCCA. Resection with lymph node dissection is unfortunately the only curative option for patients with cHCC-CCA. Thus, there remains an urgent need to develop specific therapeutic strategies for this unique clinical entity.
Molecular analysis of primary liver malignancies has provided a refinement of the pathological diagnosis of this entity and the identification of an increasing number of tumor subtypes of ...hepatocellular proliferation, either malignant (hepatocellular carcinomas) or benign (hepatocellular adenomas). Besides the diagnosis, a combined pathomolecular approach can also provide further insights into patient prognosis, and help select patients who can benefit from targeted therapies. Hepatocellular carcinomas define a heterogeneous group of malignant hepatocellular proliferation at various levels: macroscopic, histological and molecular. While most carcinomas occur in patients with chronic liver diseases and advanced fibrosis in the background liver, some arise from the malignant transformation of a pre‐existing hepatocellular adenoma. TERT promoter mutations are the most frequent genomic alterations observed in the process of malignancy, and they occur early in the process of liver carcinogenesis. Overall, a more active biopsy strategy should be considered a key step in the management of patients with HCC.
Hepatocellular adenoma (HCA) is a rare benign liver neoplasm which predominantly occurs in women in the reproductive age group taking oral contraception. Since 2002, the terminology HCA has defined ...an heterogeneous group of neoplastic benign hepatocellular proliferations composed of different subtypes. The genotype-phenotype classification led to the description of 5 well-recognized subtypes based on morphological and immunophenotypical features, that are currently used in practice: HNF1A inactivated HCA, inflammatory HCA, β-catenin mutated HCA, sonic hedgehog HCA, and unclassified HCA. The main complications observed in HCAs are bleeding and malignant transformation. Risk of malignant transformation into hepatocellular carcinoma (HCC), more frequent in men, is also dependent to tumor size and HCA subtype, reaching 40% in β-catenin mutated HCA. The distinction of HCA from well-differentiated HCC remains difficult in some cases, leading to the diagnosis of so-called “atypical/borderline HCA”. The management of HCA is now based on multidisciplinary approach including clinicians, radiologists, and pathologists integrating gender, tumor size, and HCA subtyping.
•Hepatocellular adenoma is a rare benign liver neoplasm which predominatly occurs in women.•The genotype-phenotype classification led to the description of 5 well-recognized subtypes.•The main complications observed in hepatocellular adenomas are bleeding and malignant transformation.•Risk of malignant transformation into hepatocellular carcinoma is dependent to gender, tumor size and subtype.
Hepatocellular adenomas (HCA) are rare benign liver tumors occurring in young women taking contraception. They are associated with rare complications such as bleeding or malignant transformation into ...hepatocellular carcinoma. A molecular classification has divided HCA in several subgroups linked with risk factors, clinical behaviour, histological features and imaging: HNF1A inactivated HCA, Inflammatory HCA, CTNNB1 mutated HCA in exon 3, CTNNB1 mutated in exon 7 and 8 HCA, sonic hedgehog HCA and unclassified HCA. CTNNB1 mutated HCA in exon 3 and sonic hedgehog HCA have been linked with a high risk of malignant transformation and bleeding respectively. Herein, we review how molecular classification has modified our understanding of the pathophysiology and risk factors of HCA development, analysing its impact on clinical care in the field of diagnosis and therapeutic stratification.
Abstract Cholangiocarcinoma (CCA) is an aggressive tumor with a poor prognosis due to its late clinical presentation and the lack of effective non-surgical therapies. Unfortunately, most of the ...patients are not eligible for curative surgery owing to the presence of metastases at the time of diagnosis. Therefore, it is important to understand the steps leading to cell dissemination in patients with CCA. To metastasize from the primary site, cancer cells must acquire migratory and invasive properties by a cell plasticity-promoting phenomenon known as epithelial-mesenchymal transition (EMT). EMT is a reversible dynamic process by which epithelial cells gradually adopt structural and functional characteristics of mesenchymal cells, and has lately become a center of attention in the field of metastatic dissemination. In the present review, we aim to provide an extensive overview of the current clinical data and the prognostic value of different EMT markers that have been analyzed in CCA. We summarize all the regulatory networks implicated in EMT from the membrane receptors to the main EMT-inducing transcription factors (SNAIL, TWIST and ZEB). Furthermore, since a tumor is a complex structure not exclusively formed by tumor cells, we also address the prominent role of the main cell types of the desmoplastic stroma that characterizes CCA in the regulation of EMT. Finally, we discuss the therapeutic considerations and difficulties faced to develop an effective anti-EMT treatment due to the redundancies and bypasses among the pathways regulating EMT.
Liver resection (LR) for hepatocellular carcinoma (HCC) as the first‐line treatment in transplantable patients followed by “salvage transplantation” (ST) in case of recurrence is an attractive ...concept. The aim was to identify patients who gain benefit from this approach in an intention‐to‐treat study. From 1998 to 2008, among 329 potential candidates for liver transplantation (LT) with HCC within the Milan criteria (MC), 138 with good liver function were resected (LR group) from a perspective of ST in case of recurrence, and 191 were listed for LT first (LT group). The two groups were compared on an intention‐to‐treat basis with special reference to management of recurrences and transplantability after LR. Univariate and multivariate analyses were performed to identify resected patients who developed recurrence beyond MC. Five‐year overall and disease‐free survival was similar in both groups: LT versus LR group, 60% versus 77% and 56% versus 40%, respectively. Among the 138 patients in the LR group, 20 underwent LT before recurrence, 39 (28%) had ST, and 51 (37%) with recurrence were not transplanted including 21 within MC who were excluded for advanced age, acquired comorbidities, or refusal and 30 (22%) with recurrence beyond MC. Predictive factors for nontransplantability due to recurrence beyond MC included microscopic vascular invasion (hazard ratio HR 2.38 range, 1.10‐7.29), satellite nodules (HR 2.46 range, 1.01‐6.68), tumor size > 3 cm (HR 1.34 range, 1.03‐3.12), poorly differentiated tumor (HR 3.18 range, 1.31‐7.70), and liver cirrhosis (HR 1.90 range, 1.04‐3.12). Conclusion: The high risk of failure of ST after initial LR for HCC within MC suggests the use of tissue analysis as a selection criterion. The salvage LT strategy should be restricted to patients with favorable oncological factors. (HEPATOLOGY 2012;;55:132–140)
Aims
Immunotherapies represent a new alternative therapeutic approach for hepatocellular carcinomas (HCCs), and have shown promising results when used in combination therapy. The aim of this study ...was to evaluate the potential of transarterial chemoembolisation (TACE) to modulate programmed death‐1 (PD‐1) and programmed death‐ligand 1 (PD‐L1) expression profiles in a cohort of surgically treated HCCs.
Methods and results
A total of 82 surgically treated HCCs from patients who had undergone (n = 32) or not undergone (n = 50) preoperative TACE were included in the study. Immunohistochemical expression of PD‐1 and of PD‐L1 were analysed and compared according to TACE treatment. Pretreatment biopsies, which were available for 30 cases (20 with TACE and 10 without), were similarly analysed. Follow‐up data were retrieved from patients' charts. PD‐1 expression (≥1%) in intratumoral inflammatory cells (ICs) was observed in 46% of HCCs, and PD‐L1 expression (≥1%) in ICs and PD‐L1 expression in tumour cells (TCs) were observed in 46% and 16% of HCCs, respectively. A low level of PD‐1 expression (<1%) was associated with strong and diffuse glutamine synthetase overexpression (8% versus 27%, P = 0.024). HCCs from patients with TACE pretreatment showed significantly higher PD‐L1 expression in TCs than those from patients without TACE pretreatment (2% versus 0.4%, P = 0.027). PD‐1 expression in ICs and PD‐L1 expression in both ICs and TCs were higher in TACE‐resected tumours than in corresponding pre‐TACE biopsies (respectively: 1.8% versus 8.1%, P = 0.034; 0.8% versus 7.1%, P = 0.032; and 0% versus 2.4%, P = 0.043).
Conclusion
Our results, showing increases in PD‐1 expression and PD‐L1 expression in HCCs following TACE, support the use of TACE in combination with immunotherapy in selected cases to optimise tumour response.
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