HPHS Journal Watch: January/February 2021

American Journal of Surgical Pathology

Hepatoid Teratoma, Hepatoid Yolk Sac Tumor, and Hepatocellular Carcinoma: A Morphologic and Immunohistochemical Study of 30 Cases

Al-Obaidy KI, Williamson SR, Shelman N, et al. Am J Surg Pathol 2020; 45(1):127-36.

https://pubmed.ncbi.nlm.nih.gov/32991342/

This study identified histomorphologic and immunohistochemical features to distinguish hepatocellular carcinoma (HCC, n = 16) from metastatic hepatoid teratoma (HT, n = 2) and hepatoid yolk sac tumor (HYST, n = 12). To summarize, HT is distinguished from HYST by the presence of ductules and abortive portal tracts, lack of basement membrane deposits, consistent positivity for arginase and HepPar-1, and negativity for SALL4 and CDX2. HCC is distinguished from HYST by the absence of basement membrane deposits and negativity for SALL4, CK19, and CDX2.

American Journal of Clinical Pathology

SATB2 in Neoplasms of Lung, Pancreatobiliary, and Gastrointestinal Origins

De Michele S, Remotti H, Del Portillo A, et al.  Am J Clin Pathol January 2021;155:124-132

https://pubmed.ncbi.nlm.nih.gov/32914850/

While it is known that there is high sensitivity and specificity for expression of Special AT-rich binding protein 2 (SATB2) immunohistochemistry (IHC) in colorectal adenocarcinoma (CRC), there is limited and discordant data on its expression in specific subsets of pulmonary, gastric, small bowel, and pancreatobiliary adenocarcinomas (ADCAs). In this study, SATB2 IHC was performed on 335 neoplasms, including 40 lung ADCAs, 165 pancreatobiliary neoplasms (34 intraductal papillary mucinous neoplasms [IPMNs], 19 pancreatic  ADCAs, 112 cholangiocarcinomas [CCs]), and 35 gastric, 13 small bowel, 36 ampullary (AMP), and 46 CRC ADCAs.  The study found that SATB2 was positive in 3% of lung, 2% of CC, 17% of gastric, 38% of small bowel, and 6% of AMP ADCAs. All pancreatic ADCA/IPMNs were negative, and 87% CRCs were positive. SATB2 is not entirely specific for colorectal origin and can be expressed in a subset of gastrointestinal ADCAs. It is most useful in the differential of CRC vs lung and pancreatobiliary ADCAs.  Key Points highlighted in the article include: SATB2 was reported to have high sensitivity and specificity as a marker of colorectal adenocarcinoma although there is paucity of data on its expression in specific subgroups; similarly, to CDX2, SATB2 is also expressed in a subset of upper GI ADCAs but rarely expressed in pancreatobiliary ADCAs; SATB2 is more specific than CDX2 when used to rule in colorectal metastasis and rule out mucinous lung ADCAs and pancreatobiliary neoplasms.

Histopathology

Bile duct adenoma may be a precursor lesion of small duct type intrahepatic cholangiocarcinoma.

Sasaki M,  Sato Y, Nakanuma Y. 2021 Jan;78(2):310-320.

https://pubmed.ncbi.nlm.nih.gov/33405289/

Precursor lesions of small duct type intrahepatic cholangiocarcinoma (small duct iCCA) have not been clarified so far. The authors hypothesised that precursor lesions may be frequently distributed in the background liver of small duct iCCA. They histologically evaluated the presence of bile duct adenomas and von Meyenburg complexes as candidate precursor lesions in the background liver of small duct iCCA, with other primary liver carcinomas as control. Subjects included 28 patients with small duct iCCA, 29 with large duct iCCAs, 60 with combined hepatocellular-cholangiocarcinoma (Comb) and 40 with hepatocellular carcinoma (HCC). The prevalence of bile duct adenomas in the background liver was significantly higher in small duct iCCA (35.7%) compared to other primary liver carcinomas (Comb, 4.9%; 10%, HCC) (P < 0.01). The prevalence of bile duct adenomas was significantly associated with the presence of von Meyenburg complexes and ductal plate malformation-like patterns in small duct iCCAs and Combs. Von Meyenburg complexes were detected in 11 small duct iCCA (39.3%), five large duct iCCAs (17.2%), 10 Comb (16.4%) and 13 HCC (33.3%), respectively (P > 0.05). Small duct iCCAs showed altered expression of ARID1A (46.4%), p53 (39.3%), PBRM1 (14.3%), IMP3 (85.7%) and EZH2 (82.1%), whereas these markers were negative in bile duct adenomas. The authors conclude that bile duct adenomas may be precursor lesions of small duct iCCAs. Alteration of ARID1A, p53 or PBRM1 may be involved in the carcinogenesis of small duct iCCAs.

Liver Transplantation

Sequential Protocol Biopsies Post-Liver Transplant From Donors With Moderate Macrosteatosis: What Happens to the Fat?

Croome K, Livingston D, Croome S, et al. 2021 Feb;27(2):248-256.

https://pubmed.ncbi.nlm.nih.gov/32779325/

The number of steatotic deceased donor livers encountered has continued to rise as a result of the obesity epidemic. Little is known about the histological characteristics of moderately macrosteatotic livers over time in the recipient following liver transplantation (LT). The authors evaluated all recipients undergoing LT at Mayo Clinic Florida with donor livers with moderate macrosteatosis (30%-60%) from 2000-2017 (n = 96). Routine protocol liver biopsies were performed 1-week and 6-months following LT. Of the 96 moderate macrosteatosis LTs, 70 recipients had post-LT protocol liver biopsies available and comprised the study cohort. Median donor allograft macrosteatosis at the time of transplant was 33% (IQR, 30%-40%) compared with 0% (IQR, 0%-2%) at 1-week (P < 0.001) and 0% (IQR, 0%-0%) at 6-months (P < 0.001) following LT. Biopsies at 1-week post-LT displayed pericentral necrosis in 57.1% of recipients and lipopeliosis in 34.3% of recipients. In the 6-month post-LT biopsies, cholestasis was seen in 3 (4.3%) of the recipients, whereas grade 2 fibrosis was seen in 6 recipients (8.6%). Graft survival at 5 years in the present cohort was 74.0%. Moderate macrosteatosis (30%-60%) in the donor allograft demonstrates complete reversal on liver biopsies performed as early as 7 days following LT and remains absent at 6-months following LT. Both pericentral necrosis and lipopeliosis are common features on day 7 biopsies. Despite these encouraging findings, the perioperative risks of using these livers (postreperfusion cardiac arrest and primary nonfunction) should not be understated. Long-term graft survival is acceptable in patients who are able to overcome the immediate perioperative risk of using moderately steatotic donor livers.

Hepatology

Genetics of Hepatocellular Carcinoma: Approaches to Explore Molecular Diversity.

Caruso S, O’Brien DR, Cleary SP, et al. Hepatology. 2021 Jan;73 Suppl 1:14-26.

https://pubmed.ncbi.nlm.nih.gov/32463918

This is a review article on molecular alterations of hepatocellular carcinoma.

Molecular Targets in Cholangiocarcinoma.

O’Rourke CJ, Munoz-Garrido P, et al. Hepatology. 2021 Jan;73 Suppl 1:62-74.

https://pubmed.ncbi.nlm.nih.gov/32304327

The study reviews therapeutic potential of different classes of molecular targets at various stages of development in CCA, targeting epithelia (oncogenic, developmental, metabolic, epigenomic) and tumor microenvironment (angiogenesis, checkpoint regulation).

Biopsy Pathology and Immunohistochemistry of a Case of Immune-Mediated Drug-Induced Liver Injury With Atabecestat.

De Jonghe S, Weinstock D, Aligo J, et al. Hepatology. 2021 Jan;73(1):452-455.

https://pubmed.ncbi.nlm.nih.gov/32488886

The case report describes a 74 year old female on this medication used in the treatment of Alzheimer’s disease. The histologic features described included centrilobular necroinflammatory changes, associated CD8 predominant lymphocytes, macrophages with lipofuscin and rare eosinophils. Interface activity was not seen.

Human Pathology

Interobserver agreement in pathologic evaluation of bile duct biopsies

Liu YJ, Rogers J, Liu YZ et al. 2021 Jan;107:29-38.

https://pubmed.ncbi.nlm.nih.gov/33129823/

Intraductal biopsy is commonly used for evaluation of the etiology of biliary strictures and interpretation is frequently challenging. The diagnosis often suffers from interobserver disagreement. This is the first study evaluating interobserver agreement with assessing five diagnostic categories: negative for dysplasia (NED), indefinite for dysplasia (IND), low-grade dysplasia (LGD), high-grade dysplasia (HGD), and carcinoma (CA). Eighty-five biopsies were evaluated by eight pathologists.  Agreement was fair in the first/initial round of evaluation. After a consensus/training session, agreement improved to an overall moderate. However, interobserver reproducibility was high for carcinoma, but only fair to moderate for all other categories. Read more to better understand the nuances of this study.

Biopsies of hepatocellular carcinoma with no reticulin loss: an important diagnostic pitfall

Yasir S, Chen ZE, Said S, et al. 2021 Jan;107:20-28.

https://pubmed.ncbi.nlm.nih.gov/33039370/

Distinguishing well differentiated hepatocellular carcinoma (HCC) from benign hepatocellular lesions can be challenging based on morphology alone because some well differentiated HCCs have no or minimal cytological and architectural atypia. Rarely, however, HCCs show normal or near normal patterns of reticulin, with insufficient changes to reliably make a diagnosis based on reticulin abnormalities. The authors studied 11 HCC with no reticulin loss and compared them to a control group of macroregenerative nodules and dysplastic nodules. Additional stains incorporated into the study included Ki-67, glypican 3, and/or AFP. Read more to learn how approach these challenging cases.

Hepatocellular neoplasms arising in genetic metabolic disorders: steatosis is common in both the tumor and background liver

Cheng L, Jain D, Kakar S, et al. 2021 Feb;108:93-99.

https://pubmed.ncbi.nlm.nih.gov/33245984/

Hepatocellular neoplasms can develop in multiple genetic metabolic disorders. The authors conducted a retrospective review of nine patients with rare genetic metabolic disorders who developed hepatocellular neoplasms. Steatosis is a common finding in both the tumor (6/9 cases, 67%) and background liver parenchyma (8/9 cases, 89%). These findings raise consideration of steatosis playing a possible role in tumorigenesis in these genetic metabolic disorders. Pathologists should consider an underlying genetic metabolic disorder when young patients with hepatocellular neoplasm show steatosis in both the tumor and background liver.

Gastroenterology

Chronic Liver Diseases and the Microbiome-Translating Our Knowledge of Gut Microbiota to Management of Chronic Liver Disease

Acharya C, Bajaj JS. 2021 Jan;160(2):556-572.

https://pubmed.ncbi.nlm.nih.gov/33253686/

Chronic liver disease is reaching epidemic proportions with the increasing prevalence of obesity, nonalcoholic liver disease, and alcohol overuse worldwide. Most patients are not candidates for liver transplantation even if they have end-stage liver disease. There is growing evidence of a gut microbial basis for many liver diseases, therefore, better diagnostic, prognostic, and therapeutic approaches based on knowledge of gut microbiota are needed. This article reviews the questions that need to be answered to successfully translate our knowledge of the intestinal microbiome and the changes associated with liver disease into practice.

Modern Pathology

Prediction of early recurrence of hepatocellular carcinoma after resection using digital pathology images assessed by machine learning

Saito A, Toyoda H, Kobayashi M, et al. 2021 Feb;34417–425.

https://pubmed.ncbi.nlm.nih.gov/32948835/

The pathological characteristics of the early recurrence of HCC have not yet been elucidated. The authors attempted to predict the early recurrence of HCC after resection based on digital pathologic images of hematoxylin and eosin-stained specimens and machine learning applying a support vector machine (SVM). The 158 HCC patients meeting the Milan criteria who underwent surgical resection were included in this study. The patients were categorized into three groups: Group I, patients with HCC recurrence within 1 year after resection (16 for training and 23 for test); Group II, patients with HCC recurrence between 1 and 2 years after resection (22 and 28); and Group III, patients with no HCC recurrence within 4 years after resection (31 and 38). The SVM-based prediction method separated the three groups with 89.9% (80/89) accuracy.

Liver biopsy findings in patients on immune checkpoint inhibitors

Cohen JV, Dougan M, Zubiri L, et al. 2021 Feb;34:426–437.

https://pubmed.ncbi.nlm.nih.gov/32884128/

28 liver biopsies had a predominantly hepatitic pattern of inflammation, including 11 biopsies with granulomas and 10 with endothelialitis. Eight biopsies had a mixed hepatocytic and cholangitic pattern of injury, including 6 with granulomas and 4 with endothelialitis. Sixteen patients had a predominantly cholangitic pattern, with portal-based inflammation. Three patients had a pattern resembling fatty liver, and five had mild nonspecific changes. The three most common histologic patterns correlated with the pattern of LFT abnormalities. The majority of patients with a cholangitic pattern had competing causes for elevated LFTs, including disease progression or concomitant chemotherapy. The pattern of inflammation did not predict the need for steroids, the length of time that steroids were required, or the need for secondary immunosuppression.

Journal of Gastroenterology and Hepatology

Clinical profile of non‐alcoholic fatty liver disease in nonobese patients

Lum JHM, Cheah MCC, Leow WQ, et al. 2021 Jan;36(1):257-261.

https://pubmed.ncbi.nlm.nih.gov/32557741/

Non‐alcoholic fatty liver disease (NAFLD) is associated with metabolic syndrome. Worryingly, it has been increasingly reported among nonobese patients. This study aims to analyse patient characteristics of biopsy‐proven NAFLD in an Asian cohort and explore differences stratified by body mass index (BMI). Of all the patients with NAFLD, 21.7% (57/263) were nonobese. Relative to the obese subjects, the nonobese subjects had a higher mean age (54.0 ± 12.9 vs 49.5 ± 12.5 years, P = 0.017). Otherwise, there was no difference in terms of gender distribution. With regards to laboratory data, there was a higher bilirubin level (25.6 ± 50.8 μmol/L vs 15.6 ± 15.9 μmol/L, P = 0.020), lower albumin level (38.6 ± 7.29 g/L versus 40.5 ± 4.76 g/L, P = 0.018), lower platelet count (213 ± 81.9 vs 257 ± 82.0, P < 0.001), and a higher prothrombin time (11.0 ± 3.08 s vs 10.5 ± 0.83 s, P = 0.025) among the nonobese patients. There was a lower incidence of diabetes among the nonobese group.

Gut

Neutrophils interact with cholangiocytes to cause cholestatic changes in alcoholic hepatitis

Takeuchi M, Vidigal PT, Guerra MT, et al. 2021 Feb;70:342-356.

https://pubmed.ncbi.nlm.nih.gov/33214166/

Recent scoring systems for alcoholic hepatitis (e.g. Gastroenterology 2014;146:1231–1239)  have identified cholestasis as an important prognostic factor. This very interesting paper examined whether bile ducts participate in the pathogenesis of this process. The work described included tissue culture, animal models, and detailed histological studies.  In the last of these, neutrophils in contact with bile ducts were quantified in liver biopsies from patients with alcoholic hepatitis and controls, and this was correlated with clinical and other pathological findings. Type 3 inositol 1,4,5-trisphosphate receptor (ITPR3), an apical intracellular calcium channel necessary for cholangiocyte secretion, was used to reflect cholestatic changes.  RNA-seq analysis implicated integrin β1 (ITGB1) in neutrophil-cholangiocyte interactions and interference with ITGB1 on cholangiocytes blocked the ability of neutrophils to reduce cholangiocyte ITPR3 expression.

The authors concluded that neutrophils bind to ITGB1 on cholangiocytes to contribute to cholestasis in alcoholic hepatitis. This previously unrecognised role for both portal neutrophils and cholangiocytes opens up new approaches for understanding the pathogenesis of the changes seen in alcoholic hepatitis.

Hepatocellular carcinoma tumour volume doubling time: a systematic review and meta-analysis

Nathani P, Gopal P, Rich N, et al. 2021 Feb;70:401-407.

https://pubmed.ncbi.nlm.nih.gov/32398224/

This paper, which was based on a systemic literature review, addressed tumour volume doubling time in liver cell cancer and found that it was approximately 4-5 months. The most consistent correlates of rapid growth were underlying HBV, smaller tumour size, alpha fetoprotein doubling time, and poor tumour differentiation.

Clinical Gastroenterology and Hepatology

Women Have a Lower Risk of Nonalcoholic Fatty Liver Disease but a Higher Risk of Progression vs Men: A Systematic Review and Meta-analysis.

Balakrishnan M, Patel P, Dunn-Valadez S, et al. Clin Gastroenterol Hepatol. 2021 Jan;19(1):61-71.

https://pubmed.ncbi.nlm.nih.gov/32360810/

This study conducted a metanalysis and showed that women are at a lower risk of acquiring NAFLD; however, once they get it, they are at a higher risk of having fibrosis progression.

Serum Levels of α-Fetoprotein Increased More Than 10 Years Before Detection of Hepatocellular Carcinoma.

Hughes DM, Berhane S, de Groot CAE,  et al. Clin Gastroenterol Hepatol. 2021 Jan;19(1):162-170.

https://pubmed.ncbi.nlm.nih.gov/32389887/

This study showed that changes in AFP over time could help with the diagnosis of HCC. They describe their algorithm/model as one that might be able to be used to assign patients to high-risk vs low-risk groups.  It will assist in determining the patients that need more frequent HCC surveillance.

IgG:IgM Ratios of Liver Plasma Cells Reveal Similar Phenotypes of Primary Biliary Cholangitis With and Without Features of Autoimmune Hepatitis.

Lee BT, Wang Y, Yang A, et al. Clin Gastroenterol Hepatol. 2021 Feb;19(2):397-399.

https://pubmed.ncbi.nlm.nih.gov/31751773/

This study showed that even though AIH tends to show more IgG+ plasma cells by biopsy and PBC tends to show more IgM+ plasma cells by biopsy, PBC patients with superimposed AIH have phenotypes that are similar to PBC, rather than AIH.

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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