Wednesday, July 26, 2017

HPHS JOURNAL WATCH: May-June 2017

Human Pathology

Shah SS, et al. Hum Pathol. 2017;64:13-18.

This study shows that 5.2% (9/172) resected HCCs were positive for CDX-2, while all 6 resected fibrolamellar carcinomas (FLCs) were negative. CDX2 expression was seen in 5/16 poorly differentiated, and 2.5% (4/156) in well and moderately differentiated HCC. These results show that CDX2 expression does not exclude a diagnosis of HCC.

Chen J, et al. Hum Pathol. 2017;64:118-127.

This study compares the characteristics of 23 cholangiolocellular carcinoma (referred to as combined hepatocellular-cholangiocarcinoma, cholangiolocellular subtype) and 79 conventional intrahepatic cholangiocarcinoma (ICC). Cholangiolocellular carcinoma showed less invasive growth, less involvement of liver capsule and absence of mucous production compared to ICC. Mutations of isocitrate dehydrogenase 1 (IDH1) or IDH2 were higher (35%) in cholangiolocellular carcinoma than in mass-forming ICC (4%) or non-mass forming ICC. The 5-year postresection survival was significantly better in cholangiolocellular carcinoma (52%) compared to mass forming ICC (40%) and non-mass forming ICC (0).

Histopathology

Goeppert B, Roessler S, Becker N, et al. Histopathology. 2017 Jun;70(7):1064-1071.

Expression patterns of deleted in malignant brain tumors 1 (DMBT1) was analyzed in 157 biliary tract cancer patients, including intrahepatic and extrahepatic cholangiocarcinoma, adenocarcinomas of the gallbladder, and BilIN 3. DMBT1 expression was high in BiLN3 compared to normal biliary epithelium and BTC (both p<0.0001). However, BTCs showed no significantly different expression levels compared to non-neoplastic biliary tissue (p=0.315). Absent DMBT1 expression in non-neoplastic biliary tissue in BTC patients was associated with poor survival. The authors conclude that DMBT1 expression is elevated in BilIN 3, but expression levels of DMBT1 in BTC declines to levels comparable to non-neoplastic biliary epithelium. Absent DMBT1 expression in non-neoplastic biliary tissues of BTC patients correlates with poor patient survival (p=0.027), and the aggregate findings suggest a tumor-suppressor role for DMBT1.

Liver Transplantation

Tan A, Florman SS, and Schiano TD. Liver Transpl. 2017 May;23(5):663-678.

This is a nice review article delineating several genetic disorders (including inherited cholestatic disorders, urea cycle disorders and hereditary hemochromatosis) which can potentially be transmitted following liver transplantation.

Haga H. Yan IK, Borrelli DA et al. Liver Transpl. 2017 Jun;23(6):791-803.
Hepatic ischemia/reperfusion injury (IRI) is associated with significant liver dysfunction and complications following liver surgery and transplantation. These authors studied the effects of systemically administered extracellular vesicles from mesenchymal stem cells (MSC-EV) in an experimental mouse model of hepatic IRI. Compared to controls, intravenous administration of MSC-EVs dramatically reduced the extent of tissue necrosis, decreased caspase-3-positive and apoptotic cells, reduced serum aminotransferase levels, and reduced RNA expression of several inflammatory cytokines such as IL6. MSC-EV increased cell viability and suppressed oxidative injury and nuclear factor kappa B activity in murine hepatocytes in vitro. The authors conclude that administration of extracellular vesicles from bone marrow derived MSCs may improve IRI by reducing hepatic injury through tempering the inflammatory response.

Journal of Hepatology

Moeini A, Sia D et al. J Hepatol. 2017; 952-961.

Molecular characterization of mixed HCC-CCA was studied including histologic features, whole genome expression profile, single-nucleotide polymorphism array and whole exome sequencing. In classic type, clonality analysis revealed HCC-like and iCC-like components were derived from same clone. Exome sequencing revealed an average of 63 non-synonymous mutations per tumor, among which TP53 was the most frequently mutated gene. Stem cell subclass tumors were characterized by SALL4 positivity, showed enrichment of progenitor like signatures (CK19, EpCAM), activation of MYC and IGF oncogenic pathways, and associate with poor prognosis. In contrast, cholangiolocellular carcinoma (CLC) showed NCAM positivity, chromosomal stability and enrichment of TGF-β and immune related signaling. The data suggest that CLC stands alone as an independent biliary-derived entity, not sharing any molecular traits of HCC.


Vesterhus M, Holm A, et al. J Hepatol. 2017; 1214-1222.

Biomarkers to predict prognosis of primary sclerosing cholangitis are lacking. Using a bead-based array targeting 63 proteins related to inflammation and fibrosis, the authors studied bile samples from 55 PSC patients and 20 controls, and identified 13 proteins that showed significant difference between PSC and control, and 18 proteins that showed significant difference between mild and advanced PSC. Further studies identified ICAM-1, MMP7, S100A4 and S100 A12 as the group of markers that collectively best distinguished PSC from controls, and Calprotectin alone as the protein best capturing the difference between mild and advanced PSC. In addition, serum analyses were performed in two independent cohorts. IL-8 was identified as the best predictor of transplant-free survival in PSC, and correlated with the ELF score and Mayo score.


Schaberg KB, Kambham N, Sibley RK, et al. Am J Surg Pathol. 2017 Jun;41(6):810-819.

Adenovirus can lead to severe infection, including hepatitis, in immunocompromised patients.  The authors searched the archives from a single institution to compile the largest series to date (12 cases including biopsies as well as autopsies) of adenovirus hepatitis and review the histopathologic and clinical features.  All patients were immunocompromised and adenovirus hepatitis was fatal in all 4 adult patients and 5 of the 8 pediatric patients.  All patients presented with fever and had a hepatitic-dominant elevation in liver enzymes (mean AST 5879 U/L, mean ALT 1894 U/L, mean Alk Phos 453 U/L, mean total bilirubin 3.8 mg/dL).  Coagulative necrosis was seen in all cases, but the extent varied from focal to massive.  Necrosis was usually nonzonal, but half of cases showed an apparent accentuation of necrosis in periportal regions on biopsies.  Over half of cases were paucy inflammatory, but when inflammation was present, it tended to be focal, lymphohistiocytic and periportal.  All cases showed characteristic viral cytopathic effect (smudgy, glassy, predominantly basophilic intranuclear inclusions), most often in hepatocytes surrounding areas of necrosis.  Rarely, portal tract granulomas and viral inclusions were seen in biliary epithelium.  The minority of patients who survived their infection showed limited necrosis on initial biopsy and comparatively mild elevations in liver enzymes; these findings may be predictive of patients who are more likely to survive.  In conclusion, the authors remind us that adenovirus hepatitis is a serious and often fatal infection in immunocompromised hosts, more often seen in pediatric patients. 

Hepatology

Sun Y, Theise ND, You H, Jia J, et al. Hepatology 2017; 65(5): 1438-1450.

This study evaluated the utility of applying some of the histologic features of fibrosis regression, coined by Ian Wanless and colleagues as the hepatic repair complex (HRC). The authors examined 71 paired liver biopsies of chronic hepatitis B patients before and after entecavir-based therapy for 78 weeks. Fibrosis was categorized into one of three groups:

1.       Predominantly progressive: defined as more than 50% fibroseptal stroma showing wide/broad, loosely aggregated collagen fibers, often a mix of light and dark staining fibers on trichrome, which are moderately to markedly cellular containing, variably, inflammatory cells, macrophages, and ductular reactions.

2.       Predominantly regressive: defined as more than 50% fibroseptal stroma showing features of hepatic repair complex, namely thin, densely compacted stroma, largely darkly staining on trichrome, which are largely acellular.

3.       Indeterminate: defined as an uncertain mix/balance between progressive and regressive scarring.

Progressive, indeterminate, and regressive scarring was observed in 58%, 29%, and 13% of patients before treatment versus 11%, 11%, and 78% after treatment. Of the 55 patients who showed predominantly regressive changes on posttreatment liver biopsy, 53% has fibrosis improvement of at least one Ishak stage and 45% had improvement in terms of Laennec substage, collagen percentage area, and liver stiffness despite remaining in the same Ishak stage. The authors propose a “Beijing Classification” for liver biopsy assessment, which includes both the degree of fibrosis and the presence of progressive, indeterminate, or regressive features, in order to reflect the directionality of the fibrosis. In the same Hepatology issue, there is an editorial (pg. 1432-1434) on the study by Dr. David Kleiner.

Modern Pathology

Balitzer D, et al. Modern Pathology 2017; May (30): 773-783

Simplified criteria for diagnosis of autoimmune hepatitis are based on autoantibodies, serum immunoglobulin G, histologic features, and negative viral serology. A score of 6 points is necessary for the designation of probable autoimmune hepatitis and 7 points or more for definite autoimmune hepatitis. The presence of three histologic features (interface hepatitis, emperipolesis, and rosettes) is required for categorizing a case as typical (2 points). In the absence of all three features, a chronic hepatitis picture is considered compatible (1 point). This study used the modified histologic criteria (interface/lobular activity, number of plasma cells, and presence of biliary features) and compared the validity for the diagnosis of autoimmune hepatitis. Clinical data and liver biopsies were reviewed for 88 cases of autoimmune hepatitis, 20 primary biliary cholangitis, and 13 non-autoimmune acute hepatitis. Interface/lobular activity, number of plasma cells, copper/CK7 stains, and presence of biliary features were assessed. Using the modified histologic features, histologic score of 2 increased from 8 to 77%, and the total simplified score of >6 increased from 69 to 86%. There was no increase in total simplified score for primary biliary cholangitis or non-autoimmune acute hepatitis. Rosettes and emperipolesis are difficult to interpret, and lack sensitivity and sensitivity for autoimmune hepatitis diagnosis. The current histologic criteria used in the current simplified score lead to underscoring of autoimmune hepatitis cases. The modified histologic criteria increased the histologic score and led to a probable/definite diagnosis of autoimmune hepatitis in 17% of cases that would have otherwise been classified as non- autoimmune hepatitis by simplified score.

Tsai JH, et al. Modern Pathology 2017; June (30): 834-842
Non-alcoholic steatohepatitis is a slowly progressive disease, although patients may rarely present in acute liver failure. This study characterizes clinicopathologic features of 6 patients who had aggressive non-alcoholic steatohepatitis following rapid weight loss (4) or malnutrition (2) and developed severe hepatic dysfunction. Four patients either died or received an urgent liver transplant. Pathologic findings were characterized by advanced alcoholic steatohepatitis-like features, including severe centrizonal pericellular fibrosis, central scar with perivenular sclerosis/veno-occlusion with superimposed hepatocellular dropout, prominent hepatocyte ballooning, and numerous Mallory–Denk bodies, although any of them had a history of excess alcohol consumption. The mechanism of liver injury in aggressive steatohepatitis is unclear, but rapid fat mobilization may be a potential cause of oxidative stress in the liver injury.

Gastroenterology and Hepatology

Bonacini M, Shetler K, Yu I, Osorio RC, Osorio RW. Clin Gastroenterol Hepatol. 2017; May;15(5):776-779.
This brief report of acute liver failure due to toxic mushroom exposure aimed to evaluate mortality due to mushroom poisoning and factors associated with survival without liver transplantation. Twenty-seven patients presented within 24 hours after ingesting toxic mushrooms. Amanita phalloides was the cause in 41% and Amanita ocreata was the cause in 11%. All patients had elevated liver transaminases, with a median alanine aminotransferase of 2185 IU/L. Of these patients, 3 died, 1 received liver transplant, and the remaining survived without transplant. Overall, the probability of poor outcome (transplant or death) due to Amanita hepatotoxicity was 17% in those who have a peak total bilirubin >2 mg/dL (signifying hepatocellular jaundice). Patients who have bilirubin >2 mg/dL or AST >4000 IU/L at presentation or follow up need to be evaluated for transplant.

Tanaka A, Tazuma S, Okazaki K, Nakazawa T, Inui K, Chiba T, Takikawa H. Clin Gastroenterol Hepatol. 2017; Jun;15(6):920-926.

IgG-4 related sclerosing cholangitis is clinically distinct from primary sclerosing cholangitis and found often in association with autoimmune pancreatitis. This article showcases the largest case series of IgG-4 related sclerosing cholangitis (527 patients) and describes the clinical features in detail. The majority of patients were male (83%) and the median age at presentation was 66 years. The presenting symptoms included jaundice (35%), pruritus (13%), abdominal pain (11%), and cholangitis (10%). Eighty-four percent had elevated IgG4 levels. Even though 28% were asymptomatic (28%), 95% of these patients had evidence of other IgG4-related organ involvement. Sixty-three patients had pathologic samples, but the findings were not described in this paper. Diagnoses were based on Japanese criteria. There was an excellent response to prednisolone in 90% of patients. Death from hepatobiliary disease was rare in a 5–10 year period, none of the patients required liver transplant was not required in any of the patients, and cholangiocarcinoma was seen in less than 1%. Based upon this large data set, it appears that IgG-4 related sclerosing cholangitis is a generally benign condition with excellent response to treatment with corticosteroids, and overall good prognosis over a 10-year period. It is noted, however, that there is the possibility that IgG4-sclerosing cholangitis might be able to progress to cryptogenic cirrhosis, in which any diagnostic evidence such as elevated IgG-4 levels or typical radiographic findings are no longer present.

Mukewar S, Sharma A, Lackore KA, Enders FT, Torbenson MS, Kamath PS, Roberts
LR, Kudva YC. Clin Gastroenterol Hepatol. 2017; Jun;15(6):927-933.

This is the largest study of glycogenic hepatopathy in diabetes type 1 patients. It is also a case control study comparing type 1 diabetic patients with and without glycogenic hepatopathy. The purpose was to determine whether type 1 diabetics with glycogenic hepatopathy have more frequent diabetic ketoacidosis (DKA) episodes and evidence of poor glycemic control. The study shows that over half of the patients with glycogenic hepatopathy more frequently had recurrent DKA and elevated HbA 1c levels compared with type 1 diabetics with normal liver enzymes.  Glycogenic hepatopathy did not lead to adverse long-term outcomes and the liver enzymes eventually normalized in most patients on follow-up.


Prepared by:
Daniela Allende, MD (Editor), Cleveland Clinic
Wenqing Cao, MD; New York University
Cynthia Guy, MD; Duke University
Sanjay Kakar, MD; University of California, San Francisco
Jingmei Lin, MD, PhD; Indiana University
Rish Pai, MD, PhD; Mayo Clinic Arizona
Nafis Shafizadeh, MD; Southern California Permanente Medical Group
Eric Yee, MD; University of Oklahoma
Maria Westerhoff, MD; University of Washington

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