HPHS Journal Watch:  Sept/Oct 2023

Advances in Anatomic Pathology 

Pathologic Diagnosis of Well-differentiated Hepatocellular Lesions: A Practical Approach to Diagnosis With Particular Focus in Core Needle Biopsies and Utilization of Ancillary Techniques

Chopra S, Dhall D. Adv Anat Pathol. 2023 Sep; 30(5):307-319. 


This review article discusses the diagnosis of well-differentiated hepatocellular lesions including focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) including the utility of immunohistochemistry and molecular ancillary testing on core-needle biopsy and a discussion of the differential diagnosis of each entity. The article also discusses the use of the diagnostic term “atypical hepatocellular neoplasm or hepatic neoplasm of uncertain malignant potential (HUMP)” on core-needle biopsies.

The Spectrum of Digestive Tract Histopathologic Findings in the Setting of Severe Acute Respiratory Syndrome Coronavirus-2 Infection: What Pathologists Need to Know

Al-Zaidi RS. 2023 Sep;30(5):342–51. 


This review article discusses the histologic alterations of the liver and digestive system in patients infected with severe acute respiratory syndrome coronavirus-2, including an in-depth discussion of how ACE2 expression in hepatic sinusoidal and portal endothelial cells results in vascular changes such as phlebosclerosis reminiscent of veno-occlusive disease and variable degrees of portal vein and capillary endotheliitis. Histologic features of pathologic features of “post-COVID-19 cholangiopathy” are also discussed.

American Journal of Gastroenterology

Quality of Tissue Samples Obtained by Endoscopic Ultrasound-Guided Liver Biopsy: A Randomized, Controlled Clinical Trial

Lariño-Noia J, Fernández-Castroagudín J, de la Iglesia-García D, et al. Am J Gastroenterol. 2023 Oct 1;118(10):1821-1828. 


In the last decade, endoscopic ultrasound-guided liver biopsy (EUS-LB) has emerged as an interesting alternative to standard methods. Some retrospective and prospective single-arm studies have shown that EUS-LB is an accurate and safe procedure with some advantages over other approaches. Adequacy of liver tissue sample has been defined by the American Association for the Study of Liver Diseases (AASLD) and the Royal College of Pathologists as a specimen of at least 20 mm in length, which includes at least 11 complete portal tracts (CPT), and ideally obtained with a 16-gauge needle. This study aimed to compare the quality of the samples obtained by EUS-LB following an optimized procedure and sample processing protocol vs percutaneous LB with a 16-gauge Tru-Cut needle for the evaluation of parenchymal liver diseases through a single-center, randomized, controlled clinical trial. The percentage of adequate tissue samples was 32.6% and 70.4% for percutaneous LB and EUS-LB, respectively (P < 0.001). Total specimen length was longer after EUS-LB (23.5 vs 17.5 mm, P=0.01), whereas the number of CPT was similar in both groups. Sample fragmentation occurred more often after EUS-LB (P < 0.001). No differences in adverse events were found. Satisfaction reported with both procedures was high. In conclusion, compared with percutaneous LB, EUS-LB provides a higher rate of adequate liver tissue samples for the histologic diagnosis of parenchymal liver diseases.

American Journal of Surgical Pathology

Clinicopathologic Features of Severe Acute Hepatitis Associated with Adenovirus Infection in Children

Liang J, Kelly DR, Pai A, et al. Am J Surg Pathol. 2023 Sep 1;47(9):977-989. 


This retrospective study describes the histologic features identified in liver core biopsy specimens from eleven children hospitalized with adenovirus infection. These children were found to have active hepatitis with portal, interface, and lobular activity including plasma cells and neutrophils. Although IHC for adenovirus was negative in all patients, the virus was detected by PCR in 10/11 of the liver samples. When compared to liver biopsies from patients without adenovirus, the degree of inflammation and biliary injury was greater in the adenovirus cohort. 

Hepatic Angiosarcomas with Sinusoidal Growth Patterns

Soon GST, Chen ZE, Wu TT, et al. Am J Surg Pathol. 2023 Sep 1;47(9):1045-1051. 


The authors of this study report on thirteen cases of hepatic angiosarcoma with a sinusoidal growth pattern, a rare subtype of a rare tumor. Of note, four patients required multiple biopsies prior to diagnosis. The notable histologic features for this malignancy included sinusoidal dilation, congestion, increased sinusoidal lining cellularity, and most importantly the cytologic atypia of the lining endothelial cells. Helpful immunostains included ERG, for diffuse staining of malignant cells; Ki-67, for increased proliferative rate; and p53 and c-MYC, which are mutually exclusive mutations in angiosarcoma.  


Incidence and Risk Factors for Hepatocellular Carcinoma in Cirrhosis: The Multicenter Hepatocellular Carcinoma Early Detection Strategy (HEDS) Study

Reddy KR, McLerran D, Marsh T, et al. Gastroenterology. 2023 Oct;165(4):1053-1063.e6.


The multicenter Hepatocellular Carcinoma Early Detection Strategy study of the National Institutes of Health performed this largest prospective study of a U.S. cohort of patients with cirrhosis to evaluate HCC incidence and associated risk factors. The study prospectively enrolled 1723 patients with cirrhosis who were undergoing standard surveillance for HCC. The incidence of HCC was found to be 2.4% per 100 person-years. The majority were men (53.2%), obese or severely obese (median body mass index, 30.2 kg/m2), and white (86.3%); 42.0% had a history of hepatitis C virus infection, 20.7% had alcoholic liver disease, and 24.9% had nonalcoholic fatty liver disease.


Targeting PPAR-gamma counteracts tumour adaptation to immune-checkpoint blockade in hepatocellular carcinoma

Xiong Z, Chan SL, Zhou J, et al. Gut. 2023 Sep;72(9):1758-1773. 


Despite breakthroughs in immune-checkpoint blockade (ICB) therapies for advanced hepatocellular carcinoma (HCC), most patients still succumb to the primary or acquired resistance. The authors aimed to investigate the mechanisms underlying tumor adaptation to immune-checkpoint targeting. Tumor cell-intrinsic peroxisome proliferator-activated receptor-gamma (PPARγ) upregulation orchestrates a myeloid-derived suppressor cell (MDSC)-enriched and T cell-dysfunctional tumor microenvironment (TME) through vascular endothelial growth factor-A (VEGF-A) trans-activation. Genetic or pharmacological inhibition of PPARγ augments antitumor immunity and overcomes ICB resistance in multiple immune-cold HCC models. PPARγ upregulation correlates with poor response in cancer patients undergoing ICB monotherapies. The authors established two mouse models of adaptive ICB resistance that recapitulate the immune landscape of human ‘cold’ HCC and enable identification of actionable targets to improve ICB response. This study provides mechanistic insights into how targeting an upstream driver of VEGF augments antitumor immunity and ICB efficacy. These findings may be of great value to accelerate the clinical development of PPARγ inhibitors for combined immunotherapy in HCC and other PPARγ-expressing malignancies.

SARS-CoV-2 and the liver: clinical and immunological features in chronic liver disease

Luxenburger H, Thimme R. Gut. 2023 Sep;72(9):1783-1794. 


The authors reviewed the clinical and immunological features of SARS-CoV-2 infection in individuals with chronic liver disease (CLD). Compared with healthy individuals, the SARS-CoV-2-specific adaptive immune responses are impaired in patients with CLD after both, natural infection and vaccination but improve at least partially after booster vaccination. This is highly relevant for the daily clinical routine since liver injury in SARS-CoV-2 might aggravate the clinical course of infection. This is also true for liver transplant recipients, patients with CLD, and those with cirrhosis, in whom SARS-CoV-2 infection can be more severe compared with the general population. Thus, patients with CLD in particular benefit from a prophylactic vaccination. The authors also discussed the development of autoimmune-like hepatitis (ALH), which is a rare side effect of COVID-19 vaccination, and it should be included in the differential diagnosis of elevated liver enzymes.

Hepatology Communications

Incidence and risk factors of graft-versus-host disease after liver transplantation: A national study 2010-2020

Huang Y, Wang Y, Chase RC, Yang L. Hepatol Commun. 2023 Sep 27;7(10):e0271. 


This retrospective cohort study used the National Readmission Database to calculate the incidence of graft-versus-host disease (GVHD) after liver transplantation and found an incidence rate of 1.0% in the United States with a mean time of 79.4 days after liver transplantation to GVHD development. The mortality rate associated with GVHD hospitalization was high, with over 40% of patients dying and an additional 20% receiving palliative care consults within 1 calendar year. The authors found that alcohol-associated liver disease was associated with a lower risk of GVHD whereas a secondary diagnosis of COVID-19 on index admission was associated with an elevated risk of GVHD.


Artificial intelligence-based reticulin proportionate area – a novel histological outcome predictor in hepatocellular carcinoma

Patil A, Salvatori R, Smith L, et al. Histopathology. 2023 Oct; 83 (4): 512-525.


The author developed and validated a supervised artificial intelligence (AI) model to specifically recognize and quantify the reticulin framework in normal livers and HCCs using routine reticulin staining. Histological reticulin proportionate area (RPA) was defined as reticulin area/total viable tumor area.  A cohort of 101 consecutive HCC resections were included (median age = 68 years, 64 males, median follow-up time = 49.9 months). AI model RPA reduction of > 50% (compared to normal liver tissue) was predictive of metastasis [hazard ratio (HR) = 3.76, P = 0.004], disease-free survival (DFS) [HR = 2.48, P < 0.001] and overall survival (OS)[HR = 2.80, P = 0.001]. In a Cox regression model, which included clinical and pathological variables, RPA decrease was an independent predictor of DFS and OS and the only independent predictor of metastasis. Similar results were found in the moderately differentiated HCC subgroup (WHO grade 2), in which reticulin quantitative analysis was an independent predictor of metastasis, DFS, and OS.

Pathological overview of steatohepatitic hepatocellular carcinoma in a surgical series

Trapani L, Beaufrère A, Hobeika C, et al. Histopathology. 2023 Oct;83(4):526-537.


This single-center retrospective study included 297 surgically resected HCCs. Pathological features including steatohepatitic (SH) criteria (steatosis, ballooning, Mallory-Denk bodies, fibrosis, and inflammation) were assessed. SH-HCC was defined by the presence of at least four of the five SH criteria and the SH component represented >50% of the tumor area. According to this definition, 39 (13%) HCC cases corresponded to SH-HCC and 30 cases (10%) corresponded to HCC with an SH component (<50%). SH criteria in SH-HCC and non-SH-HCC were distributed as follows: ballooning (100% versus 11%), fibrosis (100% versus 81%), inflammation (100% versus 67%), steatosis (92% versus 8%), and Mallory-Denk bodies (74% versus 3%). Inflammation markers (c-reactive protein [CRP] and serum amyloid A [SAA]) were significantly more expressed in SH-HCC compared to non-SH-HCC (82% versus 14%, P = <0.001). Five-year recurrence-free survival (RFS) and 5-year overall survival (OS) were similar for SH-HCC and non-SH-HCC (P = 0.413 and P = 0.866, respectively). The percentage of SH component does not impact OS and RFS. The study confirmed the relatively high prevalence (13%) of SH-HCC. Ballooning is the most specific criterion for this subtype. The percentage of the SH component does not impact prognosis.

Use of orcein as an adjunct stain in the evaluation of advanced liver fibrosis

Nguyen ED, Ding CC, Umetsu SE, et al. Histopathology. 2023 Oct;83(4):538-545.


This study assessed the potential utility of Orcein (OR) and Trichrome (TC) staining patterns to evaluate the quality of fibrosis in various settings of advanced fibrosis. Sixty-five liver resection/explant specimens with advanced fibrosis caused by different elements were reviewed. Twenty-two cases were scored as progressive (P), 16 as indeterminate (I), and 27 as regressive (R) using TC stain based on the Beijing criteria. The OR stains confirmed 18 of 22 P cases. The remaining P cases showed either stable fibrosis or mixed P and R. Of the 27 R cases, 26 were supported by OR stain, with many showing thin perforated septa typically seen in adequately treated viral hepatitis cases. The 16 I cases showed a variety of OR staining patterns, which allowed for further subclassification than using TC stain alone. Viral hepatitis cases were enriched for regressive features (17 of 27).

Analysis of various ATP-binding cassette transporters revealed quantification of ABCB4 as a potential diagnostic tool in primary sclerosing cholangitis (PSC)

ThoeniC, PercianiCT, NakibD, et al. Histopathology. 2023 Oct;83(4):559-568. 


ATP-binding cassette transporters are important proteins in regulating bile constituent transport between hepatocytes and the bile canalicular system. It has been previously reported that two particular ATP-binding cassette transporters, ABCB4 and ABCB11, have altered expression in patients with primary sclerosing cholangitis (PSC). This study included liver samples from 201 patients, including 43 patients with PSC and 51 patients with primary biliary cholangitis (PBC). The expression of ATP-binding cassette transporters, including ABCB1, ABCB4, ABCB11, ABCG5/8, and FXR1, was analyzed using nanoString nCounter and immunohistochemistry for validation of differently expressed transporters seen in PSC liver samples in comparison to non-PSC liver specimens. Strikingly, ABCB4 was the only ATP-binding cassette transporter showing increased gene and protein expression (increased expression at the bile canalicular membrane) in hepatocytes of PSC livers when compared to non-PSC liver specimens. Furthermore, ABCB4 protein expression also correlates with disease stage in PSC.

TSC2 inactivation, low mutation burden and high macrophage infiltration characterize hepatic angiomyolipomas

Giannikou K, Klonowska K, Tsuji J, et al. Histopathology. 2023 Oct;83(4):569-581. 


TSC1 or TSC2 inactivating mutations that lead to mTORC1 hyperactivation have been reported in hepatic angiomyolipomas (hAML).  The aim of this study was to identify other somatic events at the genomic level and changes in tumor microenvironment (TME) that contribute to tumorigenesis in hAML. The authors performed exome sequencing in nine sporadic hAML tumors and deep-coverage targeted sequencing for TSC2 in three additional hAML. Immunohistochemistry and multiplex immunofluorescence were carried out for 15 proteins to characterize the tumor microenvironment and assess immune cell infiltration. Inactivating somatic variants in TSC2 were identified in 10 of 12 (83%) cases, with a median allele frequency of 13.6%. Five to 18 somatic variants (median number: nine, median allele frequency 21%) not in TSC1 or TSC2 were also identified, mostly of uncertain clinical significance. Copy number changes were rare, but detection was impaired by low tumor purity. Immunohistochemistry demonstrated numerous CD68+ macrophages of distinct appearance from Küpffer cells. Multiplex immunofluorescence revealed low numbers of exhausted PD-1+/PD-L1+, FOXP3+, and CD8+ T cells.

Journal of Hepatology

Morphologic and molecular analysis of liver injury after SARS-CoV-2 vaccination reveals distinct characteristics

Uzun S, Zinner CP, Beenen AC, et al. J Hepatol. 2023 Sep;79(3):666-676.


In this study, the authors compare and contrast SARS-CoV-2 vaccine-induced liver injury (VILI; 6 patients) with autoimmune hepatitis (AIH; 9 patients). While rare, it has been previously published that SARS-CoV-2 vaccination can result in liver injury that resembles AIH clinically, biochemically, morphologically, and serologically. In the patients studied, VILI and AIH showed similar histomorphologic findings, although more pronounced centrizonal necrosis was seen in VILI. Using gene expression profiling, immune repertoire sequencing, and multiplex immunofluorescence (IF), the authors show that VILI showed greater involvement of mitochondrial metabolism and oxidative stress-related pathways and less involvement of interferon response pathways; VILI showed dominance of CD8+ effector T-cells and CD79a+ B- and plasma cells whereas AIH showed a dominance of CD4+ effector T-cells. The authors conclude that VILI is related but distinct from AIH and may be more closely related to drug-induced autoimmune-like hepatitis.

Aagenaes syndrome/lymphedema cholestasis syndrome 1 is caused by a founder variant in the 5’-untranslated region of UNC45A

Almaas R, Atneosen-Asegg M, Ytre-Arne ME, et al. J Hepatol. 2023 Oct;79(4):945-954.


In this study, the authors identify the genetic alteration responsible for Aaegenaes syndrome/lymphedema cholestasis syndrome 1, an autosomal recessive condition characterized by neonatal cholestasis, lymphedema, and giant cell hepatitis. Using whole-exome sequencing, whole-genome sequencing, and/or Sanger sequencing, the authors identified a c.-98G>T variant in the 5’-untranslated region of UNC45A in all tested patients. 19 patients were homozygous for this variant and seven were compound heterozygous for this variant combined with various other assumed loss-of-function variants either within the coding regions or in the exon/intron boundary. Liver biopsies from these patients (8 patients, performed within 4 months of age) demonstrated cholestasis, paucity of bile ducts, and giant cell hepatitis; biopsies from after the neonatal period (2 patients) showed portal-based and sinusoidal fibrosis, one patient with paucity of bile ducts, and mild cholestasis; giant cells were infrequent or absent. Immunohistochemistry showed variable mislocalization of BSEP and MRP2.

Liver Transplantation

Fluorescence confocal microscopy on liver specimens for full digitization of transplant pathology

Kinzler MN, Schulze F, Reitz A, et al. Liver Transpl. 2023 Sep 1;29(9):940-951.


Fluorescence confocal microscopy (FCM) is a rapidly evolving tool that provides real-time virtual HE images of native tissue. Data about the potential of FCM as an alternative to frozen sections for the evaluation of donor liver specimens are lacking so far. This prospective study evaluated the value of FCM in liver specimens. Conventional histology and FCM scans of 50 liver specimens (60% liver biopsies, 26% surgical specimens, and 14% donor samples) were evaluated according to the German Society for Organ Procurement. A comparison of FCM scans and conventional frozen sections revealed almost perfect levels of agreement for cholangitis (κ = 0.877), fibrosis (κ = 0.843), and malignancy (κ = 0.815). Substantial levels of agreement could be obtained for macrovesicular steatosis (κ = 0.775), inflammation (κ = 0.763), necrosis (κ = 0.643), and steatohepatitis (κ = 0.643). Levels of agreement were moderate for microvesicular steatosis (κ = 0.563). The strength of agreement between frozen sections and FCM was superior to the comparison of conventional HE and FCM imaging.

Modern Pathology

Borderline Hepatocellular Adenomas: A Practical Diagnostic Approach Based on Pathologic and Molecular Features

Poté N, Caruso S, Caderaro J et al. Mod Pathol. 2023 Sep;36(9):100211.


The goal of this study is to better define the morphologic and molecular characteristics of borderline hepatocellular adenomas. To that end, the authors analyzed 106 liver tumors, comprised of a mixture of borderline adenomas, typical adenomas, adenomas with malignant transformation, and hepatocellular carcinomas. While the category of borderline adenoma demonstrates numerous histologic and molecular changes, molecular evaluation of paired HCA and HCC tissue in transformed adenomas suggests an important role for TERT promotor mutation during malignant transformation. The authors ultimately suggest that borderline adenomas should be resected if there is evidence of (1) beta-catenin activation and/or (2) TERT promotor mutation or other high-risk molecular alterations.

Prepared by:
Lindsey Westbrook, MD (Editor); University of Colorado 
Dana Balitzer, MD; University of California San Francisco

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

Joseph Misdraji, MD; Yale School of Medicine

Meredith Pittman, MD; Maimonides Medical Center

Daniel Roberts, MD; Cleveland Clinic

Xuefeng Zhang, MD; Cleveland Clinic

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