HPHS Journal Watch: January/February 2022

Archives of Pathology and Laboratory Medicine

HNF-1B is a More Sensitive and Specific Marker than C-Reactive Protein for Identifying Biliary Differentiation in Primary Hepatic Carcinomas.

Patil PA, Taddei T, Jain D, Zhang X. Arch Path Lab Med. 2022 Feb;146:220-226.


The authors of this study investigate the utility of HNF-1b immunohistochemistry in the differentiation between hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Seventy-four cases of intrahepatic cholangiocarcinoma showed expression of HNF-1b, and in 72 (97%) of those cases the expression was seen in >25% of tumor nuclei.  Conversely, out of sixty-five cases of HCC, weak HNF-1b staining was identified in only six (9%) tumors, and the expression was <25% of tumor nuclei. Overall, the authors conclude that HNF-1b is a good marker of biliary differentiation when considering HCC vs. intrahepatic cholangiocarcinoma.

American Journal of Clinical Pathology

The Histopathologic Features of Sickle Cell Hepatopathy: A Multi-Institutional Study

Saeed O, Panarelli N, Umrau K, et al. Am J Clin Pathol. 2022 Jan 6;157(1):73-81.


This multi-institutional study provides an important update on the histopathologic findings in the liver in patients with sickle cell disease (SCD). A total of 39 liver biopsies from 4 institutions were included. 33 patients (85%) had hemoglobin SS, 3 patients had hemoglobin SC, and 2 patients had sickle cell trait, with an average age of 27 years (range 3-64 years); 59% were female. At the time of liver biopsy, most patients had elevated enzymes and bilirubin (82.8% with elevated AST, 71.4% with elevated ALT, and 60% with elevated alkaline phosphatase; 77.1% with elevated total bilirubin, average 8.4 g/L) and 33.3% of patients with available data had hepatomegaly confirmed on imaging. 6 patients were positive for hepatitis C (n=4) and hepatitis B (n=2). The most common histopathologic features in sickle cell hepatopathy (SCH) were Kupffer cell erythrophagocytosis (76.9%), hemosiderosis (74.4%; severe in 38.5%), sinusoidal dilation (71.8%), and intrasinusoidal sickled red cells (69.3%). No confluent hepatocyte necrosis was identified in any case, but zone 3 hepatocyte atrophy and dropout were present in a minority of cases. Portal and/or lobular inflammation and bile duct injury were mild to none and present only in a minority of cases, such that significant inflammation and bile duct injury should prompt consideration for other etiologies. Bridging fibrosis or cirrhosis was present in 28.2% (none with HCV or HBV) and centrizonal sinusoidal fibrosis was common (69.2%).

Hepatocellular Carcinoma: Does the Background Liver With or Without Cirrhosis Matter?

Jain A, Mazer B, Deng Y, et al. Am J Clin Pathol. 2022 Feb 3;157(2):305-313.


This study compared the clinicopathologic features of hepatocellular carcinomas (HCCs) in non-cirrhotic versus cirrhotic livers. A total of 378 hepatocellular carcinoma (HCC) cases were included, of which 95 cases occurred in non-cirrhotic livers and 283 cases occurred in a cirrhotic background, confirmed histologically. Patients without cirrhosis were more likely to have hepatitis B (P <0.001) or no known liver disease (P <0.001) while hepatitis C was more common in patients with cirrhosis (P <0.001). HCCs occurring in non-cirrhotic livers were larger (P <0.001), more likely to have a macrotrabecular pattern (P <0.01), higher histologic grade (P <0.01), anaplastic tumor cells (P <0.001), higher rate of vascular invasion (P <0.01), and be of higher stage (P = 0.04). In addition, HCCs in non-cirrhotic livers were more likely to be of fibrolamellar (P = 0.02), macrotrabecular-massive (P = 0.03) or clear cell (P <0.01) subtypes. This study highlights important differences between HCCs occurring in non-cirrhotic and cirrhotic livers, but further studies will be needed to understand the pathogenesis and prognostic implications, as well as optimal treatment strategies.

Journal of Hepatology

Gene expression signature as a surrogate marker of microvascular invasion on routine hepatocellular carcinoma biopsies

Beaufrere A, Caruso S, Calderaro J, et al. J Hepatol. 2022 Feb;76(2):343-352.


This study used the NanoString technology on a set of 178 hepatocellular carcinoma (HCC) formalin-fixed paraffin-embedded (FFPE) samples to identify a 6-gene panel that may serve as a surrogate biomarker for microvascular invasion (MVI), a major risk factor for tumor recurrence and mortality in HCC. The 6-gene signature (downregulated – ROS1, UGT2B7, FAS, and ANGPTL7; upregulated – GMNN and MKI67) was identified from an initial panel of 200 genes selected for evaluation based on literature and RNA sequencing data from an independent set of HCC cases. This 6-gene signature was associated with MVI in the training set of FFPE surgical HCC samples (n=109), with 82% accuracy (82% sensitivity, 81% specificity). In the validation set (n=69), the 6-gene signature predicted MVI with 74% accuracy (73% sensitivity, 76% specificity). Even in small tumors (£3 cm), the 6-gene signature predicted MVI with an accuracy of 78% in biopsies. Furthermore, on multivariate analysis, the 6-gene signature was associated with overall survival in both the training and validation sets (hazard 2.29; 95% CI 1.03-5.07; p=0.041). Thus, the 6-gene signature may be a useful surrogate in predicting MVI in biopsy samples that may allow for better risk stratification and determination of optimal treatment.

Human Pathology

Morphological heterogeneity in beta-catenin-mutated hepatocellular carcinomas: implications for tumor molecular classification

Torbenson M, McCabe CE, O’Brien DR, et al. Hum Pathol. 2022 Jan;119:15-27. https://pubmed.ncbi.nlm.nih.gov/34592239/

Beta-catenin (CTNNB1) mutations are common in hepatocellular carcinoma (HCC) and have known clinical implications; for example, mutated tumors are less likely to respond to immune checkpoint inhibitor therapies. This study of 338 The Cancer Genome Atlas cases evaluated the morphologic features associated with CTNNB1 mutations. The authors found that although CTNNB1-mutated HCCs are histologically heterogenous, there was an association between the “classic morphology” (defined as a well- to moderately-differentiated tumor with pseudoglands, thin trabecula and bile production) and men with CTNNB1 mutations. HCCs with the classic morphology were also less likely to have TP53 mutations. The study authors hypothesize that androgen production may play a role in this observation, but further studies are needed.


MicroRNA-15a/16-1 Prevents Hepatocellular Carcinoma by Disrupting the Communication Between Kupffer Cells and Regulatory T Cells.

Liu N, Chang CW, Steer CJ, Wang XW, Song G. 2022 Feb;162(2):575-589.


Although most HCC develop from chronic hepatitis, their tissue microenvironment is defined as immunosuppressive, and a variety of mechanisms have been proposed to explain this observation – for example, infiltration by regulatory T-cells (Tregs) and their effect on cytotoxic T cells (CTLs). Given that Kupffer cells account for approximately 15% of the total liver cell population, this mouse study investigates whether this population of cells might participate in tumor surveillance by releasing cytokines/chemokines that modulate migration and function of Tregs or CTLs, or both. The authors found that activation of AKT/Ras or c-Myc signaling promotes immunosuppression by driving C-C motif chemokine ligand 22 overproduction by Kupffer cells. However, microRNA-15a/16-1 recovers immune surveillance by disrupting the communication between Kupffer cells and regulatory T cells, which leads to the full prevention of hepatocellular carcinoma in AKT/Ras and c-Myc mice. MicroRNA-15a/16-1 therefore represents a potential immunotherapy against HCC.

American Journal of Gastroenterology

Endoscopic Ultrasound-Guided Liver Biopsy: Where Do We Stand?

Dawod E, Nieto J, Saab S. Am J Gastroenterol 2022 Feb;117:205–208.


The authors detail the expanding role of Endoscopic ultrasound-guided biopsy (EUS-LB) which has become a part of the armamentarium to investigate disorders of the liver. Its role has evolved from assessing focal liver lesions to investigating parenchymal liver disease. Regarding focal lesions, EUS-LB not only allows for tissue diagnosis of lesions found on radiographic imaging but can detect additional ones not otherwise seen. The increased sensitivity of EUS-LB allows for more accurate staging and determining treatment course for a variety of disorders. As compared to the percutaneous liver biopsy, EUS-LB minimizes the likelihood of sampling error. This method can take samples from both lobes of the liver and offer better safety than the conventional percutaneous and transjugular approaches.

Hepatology Communications

Covid-19 and Liver Injury: Role of Inflammatory Endotheliopathy, Platelet Dysfunction, and Thrombosis

McConnell MJ, Kondo R, Kawaguchi N, Iwakiri Y. Hepatol Commun. 2022 Feb;6(2):255-269.


The authors describe viral and inflammatory mechanisms of endothelial injury in general and more specifically in liver disease, particularly that mediated by SARS-CoV2.  The review article describes the inflammatory microenvironment during infection.  They suggest that vascular inflammation and thrombosis are possible mechanisms of Covid-related liver injury.

Correlation Between Clinical and Pathological Findings of Liver Injury in 27 Patients With Lethal COVID-19 Infections in Brazil

Santana MF, Guerra MT, Hundt MA, et al. Hepatol Commun. 2022 Feb;6(2):270-280.


The authors studied liver histopathology and correlated clinical data from 27 patients who died of COVID-19 in Brazil. They compared the hepatic histology in the cases and found that sinusoidal congestion and ischemic necrosis occurred in most cases, however, these appeared to be secondary to systemic causes and not intrahepatic thrombotic events.  They report that the hepatocellular injury that commonly occurs in patients with severe COVID-19 is not due to the vascular events that contribute to pulmonary or cardiac damage. However, the presence of inflammation and steatosis suggests that liver injury may result from a combination of inflammation, metabolic abnormalities, and perhaps direct viral injury.

Prepared by:
Lindsey Westbrook, MD (Editor); University of Colorado
Vishal Chandan, MBBS; University of California Irvine
Soo-Jin Cho, MD, PhD; University of California San Francisco
Ashim Das, MD; Post Graduate Institute of Medical Education and Research, India
Gillian Hale, MD, MPH; University of Utah
Mojgan Hosseini, MD; University of California San Diego
Meredith Pittman, MD; Maimonides Medical Center
Nafis Shafizadeh, MD; Southern California Permanente Medical Group
Heather Stevenson-Lerner, MD, PhD; University of Texas

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