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Background and Objective: Immune checkpoint inhibitor (ICI)-based therapy has achieved impressive success in various cancer types. Several ICIs have been unprecedentedly approved as the treatment regimens for advanced hepatocellular carcinoma (HCC) in recent decade. Meanwhile, numerous clinical trials are being performed to exploit more ICIs into initially unresectable HCC and postoperative HCC to expectantly induce adequate tumor downstaging for further resection or implement adjuvant treatment for relapse-free survival, respectively. In this review, we aim to summarize some pragmatic histomorphologic, immunohistochemical, and molecular pathologic parameters which promisingly indicate the response of neoadjuvant/conversion ICI-related therapy and predict the efficacy of adjuvant/therapeutic ICI-related therapy for HCC. Methods: We searched PubMed using the terms hepatocellular carcinoma, immunotherapy, immune checkpoint inhibitor, immune checkpoint blockade, conversion therapy, neoadjuvant therapy, adjuvant therapy, biomarker, pathologic evaluation, pathologic assessment till February 2023. Key Content and Findings: Although there is no consensus regarding the pathologic evaluation of relevant HCC specimens, it is encouraging that a few of studies have concentrated on this field, and moreover, the methods and parameters noted on other cancer types are also worthy of reference. For the pathologic assessment of HCC specimens underwent immunotherapy, a suitable sampling scheme, identifying immunotherapy-related pathologic response, and quantification of pathologic response rate should be emphasized. For the patients of HCC who are scheduled to receive immunotherapy, tumor-infiltrating lymphocyte, intratumoral tertiary lymphoid structure, programmed cell death ligand 1, Wnt/ß-catenin, microsatellite instability and mismatch repair, tumor mutational burden and tumor neoantigen, as well as some other signaling pathways are the potential predictive biomarkers of treatment response of ICI. Conclusions: The management of HCC in the era of immunotherapy arises a brand-new pathological challenge that is to provide an immunotherapy-related diagnostic report. Albeit many related researches are preclinical or insufficient, they may tremendously alter the immunotherapy strategy of HCC in future.
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Background: Microvascular invasion (MVI) is closely correlated with poor clinical outcomes in patients with hepatocellular carcinoma (HCC). A grading system of MVI is needed to assist in the management of HCC patient. Methods: Multicenter data of HCC patients who underwent liver resection with curative intent was analyzed. This grading system was established by detected number and distance from tumor boundary of MVI. Survival outcomes were compared among patients in each group. This system was verified by time-receiver operating characteristic curve, time-area under the curve, calibration curve, and decision curve analyses. Cox regression analysis was performed to study the associated factors of prognosis. Logistic analysis was used to study the predictive factors of MVI. Results: All patients were classified into 4 groups: M0: no MVI; M1: 1~5 proximal MVIs (≤1 cm from tumor boundary); M2a: >5 proximal MVIs (≤1 cm from tumor boundary); M2b: ≥1 distal MVIs (>1 cm from tumor boundary). The recurrence-free survival (RFS), overall survival (OS), and early RFS rates among all the individual groups were significantly different. Based on the number of proximal MVI (0~5 vs >5), patients in the M2b group were further divided into two subgroups which also showed different prognosis. Multiple methods showed this grading system to be significantly better than the MVI two-tiered system in prognostic evaluation. Four multivariate models for RFS, OS, early RFS, late RFS, and a predictive model of MVI were then established and were shown to satisfactorily evaluate prognosis and have a great discriminatory power, respectively. Conclusion: This MVI grading system could precisely evaluate prognosis of HCC patients after liver resection with curative intent and it could be employed in routine pathological reports. The severity of MVI from both adjacent and distant from tumor boundary should be stated. A hypothesis about two occurrence modes of distal MVI was proposed.
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Background: The lack of effective biomarkers for the treatment of postoperative recurrence in hepatocellular carcinoma (HCC) persists despite lenvatinib therapy. This study aims to identify beta-actin (ACTB) as a predictive biomarker for lenvatinib that can facilitate individualized treatment for HCC. Methods: This retrospective study included a subset of patients with HCC who underwent partial hepatectomy, with some receiving postoperative lenvatinib treatment and others not receiving lenvatinib treatment. A propensity score matching (PSM) analysis of patients who underwent treatment with or without lenvatinib following HCC partial hepatectomy was performed. Immunohistochemistry was employed to determine the levels of ACTB expression in HCC samples obtained from matched patients (n=225) enrolled in this study. The X-Tile was employed to determine the optimal cut-off point of ACTB levels for predicting time to recurrence (TTR). To assess the correlation between ACTB levels and lenvatinib efficacy, a subgroup analysis of TTR was conducted. A Cox regression model with an interaction term was utilized to assess the predictive significance of the model. Subsequently, a nomogram was developed and its discriminative ability and predictive accuracy were assessed using the concordance index (C-index) and calibration curve. For the investigation of the ACTB expression, HCC and para-tumoral normal tissues were employed. The patient-derived xenograft (PDX) model was utilized to validate the correlation between ACTB levels and lenvatinib responsiveness. Results: After PSM, a total of 76 patients who underwent postoperative lenvatinib treatment were included in the analysis, with a median TTR of 24.35 months. Early-stage HCC patients with lower levels of ACTB exhibited a more favorable response to lenvatinib therapy compared to those with higher levels. The reduced expression of ACTB was indicative of the benefits of lenvatinib, as opposed to higher levels {hazard ratio (HR) =0.243 [95% confidence interval (CI): 0.096-0.619], P<0.001, P value for interaction =0.014}. In approximately 81.8% of cases involving HCC patients, there was an observed increase in the expression of ACTB. Multivariate analysis of the lenvatinib cohort revealed Child-Pugh [HR =5.416 (95% CI: 1.390-21.104), P=0.015], Barcelona Clinic Liver Cancer (BCLC) stage [HR =2.508 (95% CI: 1.116-5.639), P=0.026], and ACTB [HR =5.879 (95% CI: 2.424-14.259), P<0.001] score as independent factors for TTR, and all were included in the nomogram. The survival probability based on the calibration curve showed that the prediction of the nomogram was in good agreement with the actual observation. The C-index of the nomogram for predicting survival was 0.76 (95% CI: 0.71-0.84). Moreover, the PDXs derived from tumors exhibiting low levels of ACTB expression demonstrated a heightened sensitivity to lenvatinib treatment. Conclusions: In patients with tumors treated with lenvatinib, low ACTB expression can predict a lower risk of recurrence. The validation of this potential biomarker in independent cohorts is necessary prior to its implementation for precision treatment stratification in patients undergoing partial hepatectomy for early-stage HCC.
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Intrahepatic cholangiocarcinoma (iCCA) can originate from the large bile duct group (segment bile ducts and area bile ducts), small bile duct group (septal bile ducts and interlobular bile ducts), and terminal bile duct group (bile ductules and canals of Hering) of the intrahepatic biliary tree, which can be histopathological corresponding to large duct type iCCA, small duct type iCCA and iCCA with ductal plate malformation pattern, and cholangiolocarcinoma, respectively. The challenge in pathological diagnosis of above subtypes of iCCA falls in the distinction of cellular morphologies, tissue structures, growth patterns, invasive behaviors, immunophenotypes, molecular mutations, and surgical prognoses. For these reasons, this expert consensus provides nine recommendations as a reference for standardizing and refining the diagnosis of pathological subtypes of iCCA, mainly based on the 5th edition of the World Health Organization Classification of Tumours of the Digestive System.