HPHS Journal Watch: November/December 2020


Poorly formed hepatic granulomas: a rare manifestation of acute T cell‐mediated rejection (TCMR).

Rais R, Chatterjee D, McHenry S, Byrnes K. Histopathology Nov;77(5):847-848.


Hepatic granulomas can result from various etiologies including infection, systemic diseases, drug/medications, and immune‐mediated injury. The authors describe a case of poorly formed hepatic granulomas in the early post‐transplant period that presented a diagnostic conundrum and potential diagnostic pitfall. A 65‐year‐old woman presented 3 months post‐liver transplant for epithelioid haemangioendothelioma with elevated aspartate aminotransferase (AST) of 144 units/l and alanine aminotransferase (ALT) of 170 units/l and normal alkaline phosphatase (77 units/l) and total bilirubin (1 mg/dl). The liver biopsy showed numerous portal, periportal and pericentral small non‐caseating poorly formed granulomas. The portal tracts were expanded by patchy lymphocytic inflammation with rare foci of endotheliitis and bile duct injury. These findings raised the histological suspicion for TCMR, despite the presence of granulomas. There were no features of antibody mediated rejection seen, including endothelial cell hypertrophy, portal edema or ductular reaction. Infectious workup was negative. Based on these findings, the patient was clinically diagnosed with TCMR, and induction corticosteroids were recycled. Her transaminases immediately decreased. She was discharged on a rapid steroid taper and transitioned to tacrolimus. Her ALT normalized by 3 weeks. This case highlights the importance of considering TCMR in the setting of granulomas, especially once infectious etiologies and drug/medication injury are adequately excluded, to reduce graft loss and decrease morbidity and mortality.

American Journal of Gastroenterology

Integrating Genomics Into Clinical Practice in Hepatocellular Carcinoma:  The Challenges Ahead

Pillai, A, Ahn J, Kulik L. Am J Gastroenterol Dec;115(12)1960-1969.


This article reviews the molecular changes underlying the development of liver cell cancer. Although it focuses on potential therapeutic options, it includes a very useful review about the pathways leading to the development of cancer in cirrhotic and non-cirrhotic livers. For example, based on the molecular profile, tumors can be divided into proliferative (of progenitor-like cell lineage) and non-proliferative (of hepatocyte-like lineage and associated with CTNNB1 mutations) with the former carrying a poorer outcome. The former are associated with HBV infection and the latter are associated with HCV and alcohol. The proliferative tumors are more likely to be poorly differentiated and show vascular invasion.

In Severe Alcoholic Hepatitis, Serum Keratin-18 Fragments Are Diagnostic, Prognostic, and Theragnostic Biomarkers

Atkinson SR, Grove JI, Liebig S, et al. Am J Gastroenterol Nov;115(11):1857-1868.


This paper demonstrated that in a large cohort of patients with severe AH, serum K18 strongly correlated with histological severity, independently associated with 90-day mortality, and predicted response to prednisolone therapy. They concluded that quantification of serum K18 levels could assist in clinical decision-making.

American Journal of Surgical Pathology

Mural Intracholecystic Neoplasms Arising in Adenomyomatous Nodules of the Gallbladder: An Analysis of 19 Examples of a Clinicopathologically Distinct Entity

Rowan DJ, Pehlivanoglu B, Memis B, et al. Am J Surg Pathol. 2020 Dec;44(12):1649-1657.


Although an association between adenomyomatous nodules (AMs) of the gallbladder and neoplastic change is controversial, this study supports that intracholecystic neoplasms (ICNs), including pyloric gland adenomas and intracholecystic papillary/tubular neoplasms, can rarely develop within AMs (estimated incidence of 0.1%). Notably, three identified cases of AM-ICN had a component of invasive carcinoma. The authors outline the clinical and pathologic features of AM-ICN and suggest that a detailed examination of AMs for potential neoplastic transformation may be warranted.

Journal of Gastroenterology and Hepatology

The November issue contains the abstracts presented at the Gastroenterological Society of Australia (GESA) Australian Gastroenterology Week (AGW) 2020 Virtual, 21–30 November 2020.

Clinical Gastroenterology and Hepatology

Contemporary Epidemiology of Chronic Liver Disease and Cirrhosis.

Moon AM, Singal AG, Tapper EB. Clin Gastroenterol Hepatol. 2020 Nov;18(12):2650-2666.


This paper may be a useful resource for hepatopathologists.  It provides updated data from the Centers for Disease Control and Global Burden of Disease Study on the morbidity and mortality of chronic liver disease.  It reports that chronic liver disease is increasing due to more people with metabolic syndrome, alcohol misuse and intravenous drug abuse.  The burden has increased 13% since 2000.

Hepatic Disorders With the Use of Remdesivir for Coronavirus 2019.

Montastruc F, Thuriot S, Durrieu G. Clin Gastroenterol Hepatol. 2020 Nov;18(12):2835-2836.


This paper does not specifically mention any histopathologic features in the liver in response to remdesivir.  However, hepatopathologists should be aware of this possible association with liver injury since this agent is being used more frequently in clinical practice.

Ectopic Thyroid Gland Tissue in the Liver.

Chen M, Hu J, Cai X. Clin Gastroenterol Hepatol. 2020 Dec;18(13):e157.


This interesting case includes some nice histology images.

Advances in Anatomic Pathology

Histopathologic and Autopsy Findings in Patients Diagnosed With Coronavirus Disease 2019 (COVID-19): What We Know So Far Based on Correlation With Clinical, Morphologic and Pathobiological Aspects.

Al Nemer A. Adv Anat Pathol. 2020 Nov;27(6):363-370.


This article describes common laboratory and histopathologic features in autopsy cases of COVID.  Focal to moderate microvesicular steatosis and mild lobular and portal activity were reported in some cases. Others reported sinusoidal dilatation and mild lobular lymphocytic infiltration.  RT-PCR assay for SARS-CoV-2 was performed in some cases and was not always positive.  More studies are needed.

Hepatology Communications

Exploratory Study of Autoantibody Profiling in Drug-Induced Liver Injury with an Autoimmune Phenotype.

Lammert C, Zhu C, Lian Y, et al. Hepatol Commun. 2020 Sep 1;4(11):1651-1663.


Differentiating primary autoimmune hepatitis (AIH) from drug-induced hepatitis (i.e., DILI) can be a challenge.  This group did antibody profiling and determined that differences in IgG and IgM may be able to assist.  It appears that primary AIH had increased IgG and IgM, while DILI had mainly increased IgM.  Further studies are needed.

Journal of Hepatology

COVID-19 and the liver

Jothimani D, Radhika V, Abedin MF,  et al. J of Hepatology 2020 73(5):1231–1240.


In the current pandemic, hepatic involvement has been seen in 14–53% of patients with COVID-19, particularly in those with severe disease. Cases of acute liver injury have been documented and are linked with higher mortality. Hepatic manifestations in COVID-19 could be linked to direct viral cytopathic effect, marked immune reaction, sepsis or drug-induced liver injury. The proposed mechanism of viral entry is by way of the host angiotensin-converting enzyme 2 (ACE2) receptors that are amply found in type 2 alveolar cells, which are also expressed in the GI tract, vascular endothelium, and cholangiocytes. Currently a gap in data on the impact of COVID-19 on chronic liver disease exists and this field of study will benefit with further research.

American Journal of Clinical Pathology

Molecular and Immunohistochemical Analysis of Mucinous Cystic Neoplasm of the Liver

Van Treeck BJ, Lotfalla M, Czeczok TW, et al. Am J Clin Path 154(6): 837–847.


The histopathological hallmark of mucinous cystic neoplasm of the liver is neoplastic mucinous and/or biliary epithelium bordered by ovarian-type stroma. The ovarian-type stroma has been shown to express estrogen receptor by immunohistochemistry, signifying possible hormonal sensitivity. The molecular biology of mucinous cystic neoplasm of the liver is still largely unexplored. In this study, transcriptome sequencing and immunohistochemistry were performed on a series of mucinous cystic neoplasms. These tumors showed significantly increased RNA expression of ovarian stromal markers WT1, PR, and ER2 and sex cord stromal markers SF-1, inhibin-α, and calretinin in comparison to nonneoplastic liver tissue. Pathway analysis also identified upregulation of the hedgehog and Wnt pathways and downregulation of T-helper 1 and T-helper 2 pathways.  In summary, mucinous cystic neoplasm of the liver mimics ovarian tissue at the morphologic, DNA, RNA, and protein levels. These data support the concept that this tumor arises from ectopic primitive gonadal tissue and/or stromal cells with capacity to transdifferentiate to ovarian cortical cells.

Journal of Pathology

Multiregional whole-genome sequencing of hepatocellular carcinoma with nodule-in-nodule appearance reveals stepwise cancer evolution

Takeda H, Takai A, Kumagai K, et al.  J Pathol. 2020 Dec;252(4):398-410.


The investigators conducted multiregional whole-genome sequencing on HCCs with a nodule-in-nodule appearance, consisting of inner hypervascular HCC (dedifferentiated) surrounded by hypovascular HCC (well-moderately differentiated) arising from a common origin. According to the genetic landscape of the inner and outer regions, together with the pathological and radiological findings, they examined the stepwise evolution of cancer cells from slow-growing HCC to rapid-growing HCC. The series included 5 cases (3 hepatitis C positive, 1 Hepatitis B sAg positive, 1 alcohol) with histologic evidence of chronic hepatitis and some with cirrhosis. They demonstrated that most tumor cells comprosing hypovascular well-differentiated HCCs harbored thousands of point mutations and even several structural variations, including chromosomal translocations and chromothripsis, as the trunk events. Telomerase reverse transcriptase (TERT)-associated aberrations, including promoter mutations, chromosomal translocation, and hepatitis B virus DNA integration, as well as abnormal methylation status, were commonly detected as the trunk aberrations, while various liver cancer-related genes, which differed in each case, had additionally accumulated in the inner dedifferentiated nodules. The authors concluded that genomic alterations associated with the TERT gene could be the key driver events to form the hypovascular HCC, and additional case-specific driver mutations accumulate during the progression phase, forming intra- and inter-tumoral heterogeneity, confirming the importance of genetic testing before targeting therapy.


Roles of Trained Immunity in the Pathogenesis of Cholangiopathies: A Therapeutic Target

Yan C, Koda S, Wu J, et al. Hepatology. 2020 Nov;72(5):1838-1850.


This is an interesting review article that discusses the role of immunity in the pathogenesis of cholangiopathies and epigenetic alterations leading to cholangiocarcinoma.

Human Pathology

Hepatocellular carcinomas can be Special AT-rich sequence-binding protein 2 positive: an important diagnostic pitfall

Lee W, Li X, Chandan VS.  Hum Pathol. 2020 Nov;105:47-52


Special AT-rich sequence-binding protein 2 (SATB2) is a sensitive and specific marker for tumors originating within the colon and appendix. In this study, the authors evaluated SATB2 expression in 46 HCCs. Nineteen (41%) of 46 HCCs were positive for SATB2. SATB2 expression in HCCs was more commonly seen in poorly differentiated tumors (11 of 13 cases, 85%) than well and moderately differentiated tumors (8 of 33 cases, 24%). Awareness of this phenomenon is important as SATB2 expression in a liver tumor does not completely exclude a diagnosis of HCC.

Details of human epidermal growth factor receptor 2 status in 454 cases of biliary tract cancer

Hiraoka N, Nitta H, Ohba A, et al. Hum Pathol. 2020 Nov;105:9-19.


The aim of this study was to investigate the clinicopathological characteristics and HER2 status of patients with biliary tract cancers (BTCs). HER2 protein expression by IHC, HER2 gene amplification by FISH, and both HER2 protein and gene levels simultaneously by gene-protein assay were examined from 454 patients who underwent surgical resection for BTCs (110 intrahepatic cholangiocarcinomas [ICC], 67 perihilar extrahepatic cholangiocarcinomas [ECC-Bp], 119 distal extrahepatic cholangiocarcinomas [ECC-Bd], 80 gallbladder carcinomas [GBC], and 79 ampullary carcinomas [AVC]). HER2 status was assessed according to the guidelines for HER2 testing in gastroesophageal adenocarcinoma. HER2-positive status was detected in 14.5% of BTCs. Read on to get a better understanding of the caveats.

Progression of Fatty Liver Disease in Children Receiving Standard of Care Lifestyle Advice

Xanthakos SA, Lavine JE, Yates KP, et al. Gastroenterology. 2020 Nov;159(5):1731-1751.


Little is known about clinical and histological outcomes of children with fatty liver disease. A study of 139 children who received only standard of care lifestyle advice and placebo in 2 double-blind, randomized clinical trials found that over 2 years features of fatty liver decreased in approximately half of the children, but histologic features of disease severity increased in approximately one-third and 5% developed type 2 diabetes. Complete resolution of NAFLD was rare. Although standard of care lifestyle advice can reduce features of fatty liver disease in some children, a significant subset develop worsening disease, particularly with decreasing glycemic control and weight gain. More effective interventions are needed for children who fail to respond to standard lifestyle advice.

Outcomes of Pregnant Women With Cirrhosis and Their Infants in a Population-Based Study

Flemming JA, Mullin M, Lu J, et al. Gastroenterology. 2020 Nov;159(5):1752-1762.


Pregnancy in women with cirrhosis is increasing and associated with adverse outcomes for mothers and their newborns. However, liver-related events, need for transplant, and maternal mortality by 1 year post-partum are rare.

Prepared by:
Nafis Shafizadeh MD (Editor); Southern California Permanente Medical Group
Daniela Allende MD; Cleveland Clinic
Vishal Chandan MBBS; University of California Irvine
Robert Goldin MD; Imperial College, London
Bella Goyal MD; California Pacific Pathology Medical Group
Grace Guzman MD; University of Illinois
Mojgan Hosseini MD; University of California San Diego
Heather Stevenson-Lerner MD PhD; University of Texas
Lindsey Westbrook MD; University of Colorado

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