Friday, September 27, 2019

HPHS Journal Watch: July/August 2019


Improvements in Histologic Features and Diagnosis Associated With Improvement in Fibrosis in Nonalcoholic Steatohepatitis: Results From the Nonalcoholic Steatohepatitis Clinical Research Network Treatment Trials.
Brunt EM, Kleiner DE, Wilson LA, et al. Hepatology. 2019 Aug;70(2):522-531.

This is a retrospective study focusing on outcomes from Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with NASH Trial (PIVENS) and Farnesoid X Receptor Ligand Obeticholic Acid in NASH Treatment Trial (FLINT) and analyzing baseline and final biopsies. This study sought associations between observed improvements in fibrosis with improvement in specific histologic features, nonalcoholic fatty liver disease activity score (NAS) ≥2, diagnostic category, and primary histologically based outcomes of two adult NASH treatment trials. In PIVENS 221/240 subjects had baseline and 96-week biopsies, and in FLINT 200/283 subjects had baseline and 72-week biopsies. Fibrosis improvement was seen in a greater total number of PIVENS (38%) treated subjects (pioglitazone 44%, vitamin E 41%) compared to FLINT total (29%) treated subjects and less likely in placebo subjects in both studies. Controlling for treatment group, fibrosis improvement was associated most strongly with resolution of NASH (PIVENS, odds ratio [OR], 3.9; 95% confidence interval [CI] 2.0-7.6; P < 0.001; FLINT, OR, 8.0; 95% CI 3.1-20.9; P < 0.001), and improved NAS by ≥2 (PIVENS, OR, 2.4; 95% CI 1.3-4.3; P = 0.003; FLINT, OR, 4.2; 95% CI 2.1-8.3; P < 0.001). Improved fibrosis was associated with improved steatosis, ballooning, Mallory-Denk bodies, and portal, but not lobular, inflammation. These findings support a strong link between histologic resolution of steatohepatitis with improvement in fibrosis in NASH.

Phenobarbital-Induced Liver Injury With Nodal Angiomatosis.
Cheng LT, Yeh MM, Lu CC. Hepatology. 2019 Jul;70(1):437-439.

This is a case report on an 18 year old presenting with fever, atypical lymphocytosis, and lymphadenopathy due to phenobarbital induced injury. The authors found approximately 90 and 41 cases of phenobarbital-induced liver injury reported in LiverTox and VigiBase, respectively. In their case, RUCAM scores for phenobarbital were 8 corresponding to “probable” status after excluding other etiologies. Histologic findings in the liver included interface hepatitis with inflammatory infiltrates in the portal area extending into the hepatic lobule. Foci of hepatocytic lytic necrosis, hepatocytic swelling, cholestasis, and acidophil bodies were observed. Although similar, autoimmune hepatitis was excluded based on clinical presentation and resolution of liver enzymes without steroids. Bone marrow revealed normal cellularity without abnormal blasts or malignant cells. Histological examination of the axillary lymph nodes showed a proliferation of small blood vessels in the sinus lined by hyperplastic endothelial cells, compatible with nodal angiomatosis. Bacillary angiomatosis and Kaposi sarcoma were reasonably excluded based on the absence of bacteria, neutrophils, Warthin-Starry staining, and malignant cells from nodal biopsy and negative serum tests.

American Journal of Surgical Pathology

Macrotrabecular Hepatocellular Carcinoma: An Aggressive Subtype of Hepatocellular Carcinoma.
Jeon Y, Benedict M, Taddei T, Jain D, Zhang X. Am J Surg Pathol. 2019 Jul;43(7):943-948.

The macrotrabecular (MT) subtype of hepatocellular carcinoma (MT-HCC) has recently been shown to have specific molecular alterations and a worse prognosis. Previous studies have defined MT-HCC as neoplasms with trabeculae >6 cells thick that comprise >50% of the tumor. The purpose of this study was to determine the significance of lesser proportions of a MT component. This retrospective study compared 41 HCCs with a MT component to 105 conventional HCCs (CV-HCC). HCCs with 10-29% MT component showed similar clinicopathologic features to CV-HCC. Meanwhile, HCCs with ³30% MT component more commonly showed the following characteristics compared to CV-HCC: tended to be larger; seen in non-cirrhotic livers; present in patients with chronic viral hepatitis B; contained anaplastic tumor cells; displayed microvascular invasion; had higher pathologic stage; were of higher histologic grade; associated with higher AFP levels. Patients that had HCCs with ³30% MT component had a decreased overall and recurrence-free survival. This study confirms prognostic findings from previous studies and the authors propose a lower cutoff for MT pattern requirement (³30% rather than >50% MT component) for diagnosis of MT-HCC.

Clinical Gastroenterology and Hepatology
Primary Gastrointestinal Stromal Tumor of the Liver
Hu HJ, Fu YY, Li FY. Clin Gastroenterol Hepatol. 2019 August;17(9):e106.

A 79-year-old woman presented with epigastric discomfort.  A mass was excised from the liver and additional studies including immunohistochemical stains (GIST1 and CD34) confirmed the presence of a gastrointestinal stromal tumor (GIST).  A primary from another site was not identified and the tumor was diagnosed as a primary hepatic GIST.

Modern pathology

Detection of DNA damage response in nonalcoholic fatty liver disease via p53-binding protein 1 nuclear expression.
Akazawa Y, Nakashima R, Matsuda K, et al. Modern Pathology. 2019 Jul;32(7):997-1007.

Nonalcoholic fatty liver disease is a major liver disease that leads to cirrhosis and/or hepatocellular carcinoma in a subset of patients.  The authors investigated nuclear 53BP1-positive foci formation as an indicator of DNA double-strand breaks in human nonalcoholic fatty liver disease tissues by immunofluorescence microscopy in 52 liver tissue samples, including 43 nonalcoholic fatty liver disease samples and 9 controls. They showed that the number of abnormal 53BP1-positive foci in hepatocytes (defined as three or more discrete nuclear foci and/or large foci greater than 1 μM) was significantly increased in nonalcoholic fatty liver disease compared to controls, both in nonalcoholic fatty liver and nonalcoholic steatohepatitis patients (p < 0.01). Analysis of 53BP1 expression might be a feasible technique to estimate genomic instability in nonalcoholic fatty liver disease.

Journal of Gastroenterology and Hepatology 

Screening for non‐alcoholic fatty liver disease in patients with type 2 diabetes mellitus using transient elastography.
Lai LL, Wan Yusoff WN, Vethakkan SR, et al. Gastroenterol Hepatol. 2019 Aug;34(8):1396-1403.

This paper studies the prevalence of NALFD and advanced fibrosis among T2DM patients. The study includes 557 patients (mean age 61.4 ± 10.8 years, male 40.6%). Of the 171 patients with liver stiffness measurement ≥ 8 kPa, 71 patients underwent liver biopsy. The majority had non-alcoholic steatohepatitis (83.1%) and ≥ F1 fibrosis (87.3%) while advanced fibrosis was seen in 36.6%. The prevalence of NAFLD and advanced fibrosis based on transient elastography was 72.4% and 21.0%, respectively. On multivariate analysis, independent factors associated with NAFLD were central obesity (OR 4.856, 95% confidence interval [CI] 2.749-8.577, P = 0.006), serum triglyceride (OR 1.585, 95% CI 1.056-2.381, P = 0.026), and alanine aminotransferase levels (OR 1.047, 95% CI 1.025-1.070, P < 0.001) while advanced fibrosis was associated with serum high-density lipoprotein cholesterol (OR 0.355, 95% CI 0.126-0.997, P = 0.049), alanine aminotransferase (OR 1.023, 95% CI 1.009-1.037, P = 0.001), γ-glutamyltransferase (OR 1.005, 95% CI 1.001-1.008, P = 0.017), and platelet levels (OR 0.995, 95% CI 0.992-0.999, P = 0.010). Seventy-one patients underwent liver biopsy.

Journal of Hepatology

Wilson’s disease: Fatal when overlooked, curable when diagnosed.
Ferenci P, Ott P. J Hepatol. 2019 Jul;71(1):222-224.

A snapshot summary of the highlights of Wilson’s disease (WD) could be found in the July issue. Briefly, WD is an autosomal recessive disorder caused by mutations in the ATP7B gene. Hepatic ATP7B protein regulates the whole body content of copper by mediating its excretion into bile or irreversible incorporation into ceruloplasmin. Liver histology is non-specific and may include the whole spectrum of liver pathology. Steatosis is a common finding in non-cirrhotic patients where it may resemble non-alcoholic steatohepatitis. Most often a range of tests including measurements related to copper metabolism (serum copper, ceruloplasmin, urinary copper excretion, hepatic copper content) and molecular genetic testing are needed to diagnose or exclude WD. Life-long treatment with copper-chelators (D-penicillamine triethylenetetramine, tetrathiomolybdate) or zinc is needed.

Glycolytic activation of peritumoral monocytes fosters immune privilege via the PFKFB3-PD-L1 axis in human hepatocellular carcinoma.
Chen DP, Ning WR, Jiang ZZ, et al. J. Hepatol. 2019. Aug;71(2), 333–343.

Programmed cell death 1 ligand 1 (PD-L1) expressed on antigen-presenting cells, rather than tumor cells, has been described to carry a key role in checkpoint blockade therapy.  Understanding of mechanisms that control the manifestation of PD-L1 on tumor-infiltrating monocytes/macrophages will usher development of new PD-L1 blockade schemes with high specificity and efficiency. The current study shows a novel mechanism by which metabolic switching links immune activation responses to immune tolerance in the tumor milieu, recognizing possible targets for upcoming immune-based anticancer therapies.

PD-L1 expression on antigen-presenting cells (APCs) is vital for T cell impairment, and PD-L1-expressing dendritic cells and macrophages may therapeutically predict the clinical efficacy of PD-L1/PD-1 blockade. The authors state that the current study provides proof that cellular glycolysis arbitrates the stimulation of monocytes by tumor microenvironmental signals, which lead to the induction of PD-L1 expression on these cells and consequent autologous CD8+ T cell suppression in peritumoral tissues of human HCC. Notably, a key glycolytic enzyme, PFKFB3, has been identified as an important mediator regulating PD-L1 expression on peritumoral monocytes by activation of the NF-jB signaling pathway.

American Journal of Clinical Pathology 

Albumin In Situ Hybridization Can Be Positive in Adenocarcinomas and Other Tumors From Diverse Sites.
Nasir A, Lehrke HD, Mounajjed T, et al. Am J Clin Pathol. 2019 Jul 5;152(2):190-199.

The authors evaluated 221 tumors for albumin mRNA. Albumin mRNA was detected in all hepatocellular carcinomas (HCCs) and 81% of intrahepatic cholangiocarcinomas. Carcinomas of lung (20%), gallbladder (39%), and breast (18%) origin showed expression. Yolk sac tumor (25%) and acinar cell carcinoma (29%) also showed expression. The authors discuss the potential diagnostic pitfalls of albumin ISH.


British Society of Gastroenterology and UK-PSC guidelines for the diagnosis and management of primary sclerosing cholangitis.
Chapman MH, Thorburn D, Hirschfield GM, et al. Gut. 2019 Aug;68(8):1356-1378.

When assessing the role of liver biopsy, the authors (quoting Am J Gastroenterol 2003;98:1155) are consistent with other recent guidelines (including, e.g., AASLD) that the newer imaging techniques have reduced the need for a liver biopsy. They suggest that there is a role when there is a clinical suspicion of IgG4-SC, PSC overlap/variant syndromes and for diagnosis of small duct PSC, and that biopsy may also help in otherwise unexplained cholestasis.

They provide a useful review of the range of pathological changes seen in PSC (Gut 1980; 21:870) but point out that onion skin fibrosis is rarely seen in a liver biopsy and that the biopsy usually only shows the generic features of chronic cholestasis. The way in which PSC can be staged histologically is also described (Hepatology 1981;1:632), although this is rarely done in practice. Overall, they recommend that liver biopsy is normally reserved for possible small duct PSC, assessment of suspected possible overlap variants, or instances where the diagnosis is unclear. They assess this as strong recommendation supported by moderate quality evidence.

Also included is a useful review of IgG4-related sclerosing cholangitis which emphasizes the role of biopsy and the diagnostic criteria. They point out that while FNA cytology is useful to exclude malignancy it cannot be relied upon to make the diagnosis of IgG4-RD. On the other hand, the safety and ease whereby biopsies of the major papilla can be taken makes this a useful site to obtain tissue from.

American Journal of Gastroenterology

Gastrointestinal Manifestations of Rheumatological Diseases.
Krӧner PT, Tolaymat OA, Bowman AW, et al. Am J of Gastroenterology. 2019 Sep;114(9):1441-54.

This is a useful review which, understandably, focuses on the gut involvement in these diseases, but hepato-biliary involvement is also covered.

Human Pathology

Evaluation of histologic changes in the livers of patients with early and late hepatic artery thrombosis.
Lee M, Agostini-Vulaj D, Gonzalez RS. Hum Pathol. 2019 Aug;90:8-13.

Hepatic artery thrombosis (HAT) following orthotopic liver transplant (OLT) is a common vascular postoperative complication that can occur early (<30 days since OLT) or late (>30 days since OLT). This study investigated the histopathologic features in biopsy and resection specimens of early and late HAT. 94 cases (25 biopsies and 69 explanted hepatectomies) from 69 patients were studied.  Common histologic findings in HAT included lobular necrosis, portal inflammation, ductular reaction, lobular cholestasis, and bile-tinged macrophages. Lobular necrosis was more common in early HAT and ductular reaction and bile in veins were more common in late HAT.  This study reports on the spectrum of findings and highlights potential diagnostic pitfalls.


Transferrin receptor 1 overexpression is associated with tumour de-differentiation and acts as a potential prognostic indicator of hepatocellular carcinoma.
Adachi M, Kai K, Yamaji K, Ide T, Noshiro, Kawaguchi, Aishima S. Histopathology. 2019 Jul;75(1):63-73.

The aim of this study is to clarify the role of iron regulatory protein in the progression of hepatocellular carcinoma (HCC) and patient outcome. The authors investigated the mRNA level of iron metabolism-related genes, including hepcidin, ferroportin 1 (FPN-1) and transferrin receptor (TFR)-1/2 in 210 cases of HCC. TFR-1/2 protein expression was then evaluated in surgical specimens from 210 cases using immunohistochemistry, and also compared the clinicopathological factors with TFR-1/2 expression. The mRNA expression levels of TFR-1 were significantly increased in HCC tissues compared with adjacent non-cancerous tissues (P = 0.0013), but there were no differences in other genes. High expression of TFR-1 in HCC was associated with the absence of alcohol abuse (P = 0.0467), liver cirrhosis (P < 0.0001), higher alpha-fetoprotein (AFP; P < 0.0001), smaller tumour size (P = 0.0022), poor histological differentiation (P < 0.0001) and morphological features (P < 0.0001). In contrast, high expression of TFR-2 in HCC was associated with lower AFP (P < 0.0001), well-differentiated histological grade (P < 0.0001) and morphological features (P = 0.0010). Multivariate analysis for both overall survival and recurrence-free survival indicated that high TFR-1 expression was a significant prognostic factor for poor outcome. The authors conclude that an inverse correlation of TFR-1 and TFR-2 expression in AFP and tumour differentiation. TFR-1 overexpression suggests a higher risk of recurrence and death in HCC patients following liver resection.

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
Eric Yee MD; University of Arkansas

Wednesday, August 28, 2019

President's Message July 2019

Dear Friends and Fellow Hepatophiles,

Hope everyone is enjoying the summer. The HPHS newsletter is back for a mid-year update. The results of the steatohepatitis survey have been compiled and posted on the website. The responses demonstrate the spectrum of terminology and concepts regarding fatty liver disease among our colleagues, and highlights the areas where additional studies and discussions can help to make the terminology and practice more homogeneous.

In the past few newsletters, I have introduced the Education, Membership, Newsletter and Executive committees. In recent years, the Website committee led by Dora Lam-Himlin and assisted by three committee members has played a crucial role in transforming the Society by maintaining the website, enabling online payment of dues and maintaining the Society’s presence in the Twitter world.

The HPHS Twitter account has expanded to more than 550 followers. I encourage you to follow the Society’s Twitter account and send any suggestions regarding the activities of the committee. The website is being redesigned and an improved version will be launched soon.  

I urge all members to actively participate in the Society’s endeavors by volunteering for a committee, contributing to case of the month, sharing ideas for member surveys and sending your feedback.

Sanjay Kakkar, MD
President, Hans Popper Society

Interesting Case July 2019

Case contributed by:
Regina Kwon, MD, MPH, and Kiyoko Oshima, MD, PhD
Johns Hopkins University School of Medicine

Clinical history
A 62-year-old man, recently diagnosed with cirrhosis due to alcohol use and previously unknown hepatitis C infection, was referred to our institution for transplant evaluation. CT imaging demonstrated a markedly nodular liver with scattered hypodense lesions up to 1 cm, considered likely to be cysts. A follow-up MRI identified a 2.2 cm nodule suggestive of either dysplasia or regeneration. Alpha-fetoprotein was 160 ng/mL. Three months later, the patient was admitted for acute kidney injury, hyponatremia, and hyperkalemia. His MELD-Na score was 34 and alpha-fetoprotein 47 ng/mL. His prognosis was considered poor. Soon thereafter, the patient underwent increased-risk deceased-donor liver transplant.

The explanted liver weighed 2,410 g and was diffusely nodular. Two regenerative nodules, measuring 0.6 cm and 2.3 cm, were identified.

Liver explant microscopic findings
The explant showed moderately differentiated hepatocellular carcinoma (HCC) involving more than 95% of the hepatic parenchyma, including the regenerative nodules identified during gross examination. A representative section was taken from each segment and all segments showed HCC.  The average tumor nodule size was 1 cm. Trabecular (nested) and pseudoglandular growth patterns were present. There was lymph-vascular space invasion, but large vessels were spared. The background liver showed cirrhosis, steatosis, chronic hepatitis, and mild iron overload (reticulin, iron, and Masson trichrome stains).

H&E stain: Trabecular architecture (x10) of the tumor. Inset x20

 H&E stain: Pseudoglandular architecture (x10) of the tumor. Inset x20.

H&E stain: Lymph-vascular space invasion (x10)

Cirrhotomimetic hepatocellular carcinoma (CM HCC).
 Other names used for this entity include diffuse HCC, infiltrative HCC, diffuse infiltrative HCC, and cirrhosis-like HCC.

Cirrhotomimetic hepatocellular carcinoma is relatively rare. Frequencies of up to 10% in autopsy specimens have been described, and one recent single-institution series reported an incidence of 13% over an eight-year period in patients with HCC. No specific risk factors for developing CM HCC have been identified beyond those known for developing HCC in general, although some studies suggest associations with younger age and hepatitis B infection.

The infiltrative pattern and lack of distinct borders of CM HCC make it difficult to detect by imaging. Moreover, since cirrhosis is nearly always present, the tumor is often indistinguishable from the heterogeneity of cirrhosis on imaging. The lack of consideration of this entity can have serious clinical consequences due not only to delays in growth treatment but also to the misallocation of donor livers.

Of all types of HCC, only the cirrhotomimetic type is defined by the gross findings. On examination, CM HCC is diffusely nodular, with nodules that cannot be readily differentiated from those of cirrhosis. Thin sections are necessary to rule out a conventional HCC that has a dominant nodule with satellite nodules, as this may be confused with CM HCC, particularly on imaging studies. Indeed, although CM HCC nodules may coalesce into a mass-like lesion, mimicking a dominant nodule, the two entities can be distinguished by the number of nodules: virtually all conventional dominant nodules have fewer than 10 satellite nodules, while in CM HCC, there are nearly always more than 30 satellites. Finally, because CM HCC may be geographically restricted within a broadly cirrhotic liver, it is important to identify and sample any nodules that differ in size or quality from the majority of nodules.

Microscopically, CM HCC consists of tumor nodules scattered throughout the hepatic parenchyma; when background cirrhosis is present, as is typically the case, the tumor is described as "interdigitating" among the cirrhotic nodules. However, this is an unreliable criterion, as conventional HCC may also show interdigitation. CM HCC is otherwise similar to traditional HCC and assumes one of the known patterns, such as solid, pseudoglandular, trabecular, and clear cell.

CM HCC is generally believed to have a poor prognosis, although this may not be true for all subtypes. For example, in a series of 26 CM HCCs, Clayton et al found that patients whose tumors had clear cell morphology and were “confined” (involving < 50% of the liver) experienced markedly better 5-year survival (67% vs. 13%) than those not meeting these criteria. In our case of an extensive CM HCC (involving > 50% of the liver) with pseudoglandular and trabecular morphologies, the patient experienced a recurrence in his transplanted liver within one year and bony metastases within 18 months.

Learning points
1.      Cirrhotomimetic carcinoma is a rare aggressive subtype of hepatocellular carcinoma characterized by numerous small tumor nodules throughout the liver.
2.      This entity should not be confused with a dominant hepatocellular carcinoma with multiple satellite nodules. The gross examination is critical to accurate diagnosis.
3.      Imaging has poor sensitivity for detection of this entity.

The specimen was grossed by Dr. Lais Osmani.
Photography assistance by Norm Barker and George Lopez.

1.      Agni RM. Diagnostic histopathology of hepatocellular carcinoma: a case-based review . Semin Diagn Pathol. 2017;34(2):126-37.
2.      Clayton EF et al. Liver transplantation and cirrhotomimetic hepatocellular carcinoma: classification and outcomes. Liver Transpl. 2014;20(7):765-74.
3.      Kanematsu M, Semelka RC, Leonardou P, Mastropasqua M, Lee JK. Hepatocellular carcinoma of diffuse type: MR imaging findings and clinical manifestations. J Magn Reson Imaging. 2003;18(2):189-95.
4.      Torbenson MS. Hepatocellular carcinoma. In: Torbenson MS, Zhang L, Moreira RK, eds. Surgical Pathology of the Liver. 1st ed. Philadelphia, PA:Wolters-Kluwer; 2018. pp. 598-650.

Thursday, August 8, 2019

Steatohepatitis - member survey results

The results of the steatohepatitis survey are now available.  
Please CLICK HERE  to view.

Wednesday, July 31, 2019

HPHS Journal Watch: May/June 2019

Journal of Pathology

Genomic profiling of combined hepatocellular-cholangiocarcinoma reveals similar genetics to hepatocellular carcinoma.
Joseph NM, Tsokos CG, Umetsu SE, et al. J Pathol. 2019 Jun;248(2):164-178.

Combined hepatocellular-cholangiocarcinomas (CHC) have a prognosis similar to intrahepatic CC (ICC); staging and treatment generally follow ICC algorithms. The authors performed capture-based next-generation sequencing of 20 CHC and 10 ICC arising in cirrhosis. Intra-tumor heterogeneity was assessed by separately sequencing the HCC and CC components. CHC showed molecular profiles similar to HCC, even in the CC component. CHC harbored recurrent alterations in TERT (80%), TP53 (80%), cell cycle genes (40%; CCND1, CCNE1, CDKN2A), receptor tyrosine kinase/Ras/PI3-kinase pathway genes (55%; MET, ERBB2, KRAS, PTEN), chromatin regulators (20%; ARID1A, ARID2) and Wnt pathway genes (20%; CTNNB1, AXIN, APC). No CHC had alterations in IDH1, IDH2, FGFR2 or BAP1 (genes typically mutated in ICC). TERT promoter mutations were consistently identified in both HCC and CC components, supporting TERT alteration as an early event in CHC evolution. TP53 mutations were present in both components in slightly over half the TP53-altered cases. Amplifications of CCND1, MET, ERRB2 and Wnt pathway alterations, were often exclusive to one component, suggesting that these are late events in CHC evolution. ICC in cirrhosis revealed alterations similar to ICC in non-cirrhotic liver, including in IDH1 or IDH2 (30%), CDKN2A (40%), FGFR2 (20%), PBRM1 (20%), ARID1A (10%) and BAP1 (10%). The data demonstrated that CHC genetics are distinct from ICC (even in cirrhosis) and similar to HCC, which may have diagnostic and treatment implications.


Integrative Analysis Defines Distinct Prognostic Subgroups of Intrahepatic Cholangiocarcinoma.
Goeppert B, Toth R, Singer S, et al. Hepatology. 2019 May;69(5):2091-2106.

The authors performed an integrative analysis on 52 intrahepatic cholangiocarcinomas (iCCAs) using genetic and epigenetic data with a specific focus on DNA methylation components. Recurrent isocitrate dehydrogenase 1 (IDH1) and IDH2 (28%) gene mutations, recurrent arm-length copy number alterations (CNAs), and deletion of 3p21 or amplification of 12q15 were found. Integrative clustering of genetic and epigenetic data identified four iCCA subgroups with prognostic relevance further designated as IDH, high (H) (IDH and H showed frequent deletions in chromosome arms 3p and 6q), medium (M, intermediate genetic and epigenetic marks), and low (L, few methylation events and lack of CNAs) alteration groups. The prognosis of the H and M groups was significantly worse than that of the L group with decreased survival (L group 3-year survival rate was 91%, compared to 65%, 50%, and 36% for the IDH, H, and M groups). The authors concluded that using an integrative genomic and epigenomic analysis approach, four iCCA subgroups (IDH, H, M and L) with widespread genomic and epigenomic differences with prognostic significance were identified. The data presented also suggested differences in the cell-of-origin of the iCCA subtypes, bile duct–type iCCA resembled pancreatic adenocarcinoma, whereas cholangiolar-type iCCA showed similar patterns to a subgroup of hepatocellular carcinoma.

The Spectrum of Hepatic Involvement in Patients With Telomere Disease.
Kapuria D, Ben-Yakov G, Ortolano R, et al. Hepatology. 2019 Jun;69(6):2579-2585.

Loss-of-function mutations in genes that encode for components of the telomere repair complex cause accelerated telomere shortening. Hepatic involvement has been recognized as a cause of morbidity. The authors reported the prevalence and characteristics of liver involvement in a cohort of patients evaluated serially at the National Institutes of Health. One hundred twenty-one patients with known or suspected telomere disease were screened; 40 patients with liver involvement were included with a median follow-up of 2.4 years. Forty patients (40%) with a median age of 42 years showed liver involvement. Liver enzyme profile revealed a cholestatic pattern; 8 (21%) had drug-related enzyme elevations. The most common imaging finding was increased hepatic echogenicity on ultrasound in 39% of patients, followed by hepatomegaly in 26%. Biopsies were available in 6 patients and demonstrated: nodular regenerative hyperplasia, steatohepatitis, hemosiderosis, cholestasis, and cirrhosis with hepatic steatosis. The authors concluded that hepatic involvement is common in patients with telomerase disease and can present in diverse ways, including elevated liver enzymes as well as histopathologic and imaging abnormalities.

American Journal of Surgical Pathology

Angiosarcoma of the Liver: Clinicopathologic Features and Morphologic Patterns.
Yasir S, Torbenson MS. Am J Surg Pathol. 2019 May;43(5):581-590.

Angiosarcoma rarely involves the liver and can be challenging to diagnose by clinical and radiologic means. Published morphologic descriptions on the histology of hepatic angiosarcomas are limited, so the authors evaluated 21 primary hepatic angiosarcomas to further characterize morphologic patterns. Four main growth patterns were identified and their relative frequencies are as follows: (1) 43% vasoformative mass forming, (2) 33% epithelioid/spindled mass forming, (3) 10% sinusoidal non-mass forming, and (4) 10% peliotic non-mass forming. This comprehensive analysis provides further knowledge on the spectrum of morphologic appearances of hepatic angiosarcoma. Such awareness can help pathologists recognize subtle clues on biopsies and also avoid mistaking epithelioid/spindled patterns as a poorly differentiated carcinoma or undifferentiated sarcoma.

90Y-TheraSpheres: The New Look of Yttrium-90.
Arnold CA, Pezhouh MK, Lam-Himlin D, Pittman ME, VandenBussche C, Voltaggio L. Am J Surg Pathol. 2019 May;43(5):688-694.

90Y-TheraSpheres (90Y-TS) and 90Y-SIRSpheres (90Y-SS) are two constructs used in delivery of selective internal radiation therapy/transarterial radioembolization (SIRT/TARE) for the treatment of unresectable liver tumors. This study is the first known published case series characterizing morphologic features of 90Y-TS. Histologically processed, nonradiated microspheres were compared to 90Y-TS from 15 hepatectomy specimens, showing 20-30 mm diameter colorless microspheres with identical features: occasional internal bulls’-eye structures with the condenser out and internal crosses under polarized light microscopy. It is important to be familiar with the appearance of 90Y-TS, as it is different from 90Y-SS and its colorless nature can make it easy to be mistaken for air bubble artifact. Recognition of 90Y-TS can help pathologists detect nearby malignancy or determine the cause of radiation-related injury.

Validation of a Congestive Hepatic Fibrosis Scoring System.
Bosch DE, Koro K, Richards E, Hoch BL, Jalikis F, Koch LK, Swanson PE, Truong CD, Liou I, Yu L, Bhattacharya R, Yeh MM. Am J Surg Pathol. 2019 Jun;43(6):766-772.

Liver biopsy is one approach for evaluating the extent of fibrosis in congestive hepatopathy (CH), which can impact a patient’s candidacy for heart transplant. This study was conducted on 38 liver biopsies from patients with clinically established heart failure and histologic features of CH  to provide more data on the use of a scoring system for staging fibrosis in CH (CHF score) that was originally proposed by the same principal investigator in 2014. Three rounds of scoring were conducting by seven GI/liver subspecialist pathologists; the same set of 38 liver biopsies was evaluated in each round. Glutamine synthetase immunohistochemistry (GS IHC) was also performed on 32 of the cases and provided in the third round to determine if loss of centrizonal staining in cases with higher fibrosis scores (as reported in previous studies) could also be confirmed. The investigators found that interobserver variability in CHF score was improved after a multiheaded microscope training session and provision of GS IHC along with Masson trichrome stains (weighted concordance coefficient S* = 0.66). Higher average CHF scores were associated with higher right atrial pressures, severity of right atrial dilation, presence of right ventricular dilation, elevated ALT, lower platelet counts, longer prothrombin times, and higher MELD scores. In summary, this study demonstrates the reproducibility of the CHF score and supports its clinical relevance by showing its association with known clinical and laboratory parameters of CH.

Clinical Gastroenterology and Hepatology

Unusual Liver Masses Found After Evaluation for Asymptomatic Alkaline Phosphatase Elevation
Berry S, Nissen N, Sundaram V. Clin Gastroenterol Hepatol. 2019 Jun;17(7):e71-e72.

The authors report a case of a 41-year-old woman with Gilbert’s syndrome who had increased alkaline phosphatase levels for 3 years ranging from 170 to 195 U/L, but was asymptomatic. She had previously taken oral contraceptives. Imaging showed hepatomegaly without fatty infiltration, two arterially enhancing lesions, and one with minimal enhancement.  There were numerous isointense hypoenhancing lesions in the right lobe, the largest measuring 6.3 cm. Biopsy showed dilated sinusoids, inflammation, and abnormal portal tracts consistent with inflammatory hepatic adenomatosis, defined as 10 or more hepatic adenomas.

Introduction to the Liver Imaging Reporting and Data System for Hepatocellular Carcinoma
Tang A, Singal AG, Mitchell DG, Hecht EM, Fowler KJ, Kulik L, Parikh ND, Kono Y, Sirlin CB. Clin Gastroenterol Hepatol. 2019 Jun;17(7):1228-1238.

This paper highlights the different imaging modalities used to diagnose hepatocellular carcinoma, including the Liver Imaging Reporting and Data System (LI-RADS) criteria.

A Multicenter Study Into Causes of Severe Acute Liver Injury
Breu AC, Patwardhan VR, Nayor J, Ringwala JN, Devore ZG, Ganatra RB, Hathorn KE, Horton L, Iriana S, Tapper EB. Clin Gastroenterol Hepatol. 2019 May;17(6):1201-1203.

The differential diagnosis of an increase in alanine aminotransferase (ALT) level and/or aspartate aminotransferase (AST) level of ≥1000 IU/L often is stated to include 3 main etiologies: ischemic hepatitis, acute viral hepatitis (typically hepatitis A and hepatitis B), and drug-induced (more specifically, acetaminophen/paracetamol) liver injury (DILI). This study was conducted to confirm these causes were correct.  They determined that these three etiologies accounted for approximately 51.8% of acute liver injury.  Pancreaticobiliary complications were also common.  Their main conclusion was that the differential for acute liver injury should be expanded beyond ischemic, viral, and drug (Tylenol)-related causes.

Journal of Gastroenterology and Hepatology

Association between HLA‐DQA1/DRB1 polymorphism and development of hepatocellular carcinoma during entecavir treatment
Kozuka R, Enomoto M, Sato-Matsubara M, et al. J Gastroenterol Hepatol. 2019 May;34(5):937-946.

This paper examines the association between single-nucleotide polymorphisms (SNPs) and development of hepatocellular carcinoma (HCC) during entecavir (ETV) treatment in nucleos(t)ide analog-naïve patients with chronic hepatitis B virus infection. They conclude that patients with AA genotype in the HLA-DQA1/DRB1 gene or cirrhosis should be carefully followed up as a population potentially at higher risk of HCC during ETV treatment.

Clinical and pathological features of combined hepatocellular–cholangiocarcinoma compared with other liver cancers
Wakizaka K, Yokoo H, Kamiyama T, et al. J Gastroenterol Hepatol. 2019 Jun;34(6):1074-1080.

Combined hepatocellular-cholangiocarcinoma (CHC) is a primary liver cancer containing both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) elements. This paper tries to clarify the clinicopathological features. The clinical features of CHC, including sex, hepatitis B virus infection, and α-fetoprotein were similar to HCC, while its prognosis and pathological features, including vascular invasion and lymph node metastasis, were similar to ICC. Carcinoembryonic antigen levels and tumor size were independent prognostic factors in patients with CHC.

Journal of Hepatology

EASL Clinical Practice Guidelines: Drug-induced liver injury
European Association for the Study of the Liver. Journal of Hepatology 2019 Jun; 70(6): 1222–1261.

Visit the June edition of JOH for the latest clinical practice guidelines by the European Association for the Study of Liver for drug-induced liver injury (DILI) focusing on idiosyncratic DILI.  Some highlights include lists of drugs associated with intrinsic versus idiosyncratic DILI, known herbal and dietary supplements involved in hepatotoxicity, drugs associated with hepatic adverse reactions, assessments for exclusion of underlying diseases in DILI diagnosis, management of immune-mediated liver injury induced by immune checkpoint inhibitors, and histological features indicative of poor prognosis.  Since liver biopsy is not required for diagnosis if the suspected drug is a known hepatotoxic compound, liver biopsy is recommended to provide information supporting the diagnosis of DILI or an alternative, to rule out autoimmune hepatitis, when resolution fails following drug withdrawal, and to provide prognostic information.  Click on the link above for the latest on DILI. 

Human Pathology

Identification of key challenges in liver pathology: data from a multicenter study of extramural consults
Torbenson MS, Arnold CA, Graham RP, et al. Hum Pathol. 2019 May; 87: 75-82.

Extramural consultation for challenging pathology cases is an important part of patient care. This study identified challenges in liver pathology by analyzing data from 541 cases.  Cases were submitted for questions on medical (61%) and tumor pathology (39%). This analysis of consult patterns identifies challenging areas in medical and tumor liver pathology, which benefit from consult services and can be focused on by continuing medical educational activities.


Accuracy of FibroScan Controlled Attenuation Parameter and Liver Stiffness Measurement in Assessing Steatosis and Fibrosis in Patients With Nonalcoholic Fatty Liver Disease
Eddowes PJ, Sasso M, Allison M, et al. Gastroenterology. 2019 May; 156(6): 1717-1730.

The authors estimated the accuracy of FibroScan vibration-controlled transient elastography controlled attenuation parameter (CAP) and liver stiffness measurement (LSMs) in assessing steatosis and fibrosis in patients with suspected nonalcoholic liver disease (NAFLD). Data from 450 consecutive adults who underwent liver biopsy analysis for suspected NAFLD at 7 centers in the United Kingdom from March 2014 through January 2017 were collected.  Biopsies were scored by 2 blinded expert pathologists according to nonalcoholic steatohepatitis clinical research network criteria. Diagnostic accuracy was estimated using the area under the receiver operating characteristic curves (AUROCs) for the categories of steatosis and fibrosis. In a prospective analysis of patients with NAFLD, we found CAP and LSM by FibroScan to assess liver steatosis and fibrosis, respectively, with AUROC values ranging from 0.70 to 0.89. 


Impact of tumour budding grade in 310 patients who underwent surgical resection for extrahepatic cholangiocarcinoma.
Ogino M, Nakanishi Y, Mitsuhashi T, Hatanaka Y, Amano T, Marukawa K, Nitta T, Ueno T, Ono M, Kuwabara S, Yamada T, Hirano S. Histopathology. 2019 May;74(6):861-872.

This study evaluated the prognostic impact of tumour budding grade and its association with clinicopathological and epithelial–mesenchymal transition (EMT)‐related features in perihilar cholangiocarcinoma (PHCC) or distal cholangiocarcinoma (DCC). It included 195 PHCC and 115 DCC patients (n=310). In both PHCC and DCC patients, high tumour budding grade was associated with poor histological differentiation, higher pT factor, presence of lymphatic, venous, perineural invasion and regional lymph node metastasis. In PHCC patients, residual invasive tumour in the resected margin was also associated with high tumour budding grade. For both PHCC and DCC patients, high tumour budding grade was an independent adverse prognostic factor in multivariate analysis (P < 0001 and P = 0.046, respectively). Immunohistochemical examination revealed that the number of tumour buds increased in patients with tumors showing a mesenchymal profile (negative for E‐cadherin and positive for vimentin). The authors concluded that higher tumour budding grade is associated with invasive clinicopathological features, adverse postoperative prognosis and EMT status in extrahepatic cholangiocarcinoma.

Molecular profiling of the biphasic components of hepatic carcinosarcoma by the use of targeted next-generation sequencing.
Zhang X, Bai Q, Xu Y, Wang W, Chen L, Han J, Zhu H, Zhang Z, Hou Y, Zhou J, Zhou Y, Ji Y. Histopathology. 2019 May;74(6):944-958.

This study evaluated the clinicopathological and immunohistochemical (IHC) and molecular features of hepatic carcinosarcoma (HCS). This study included 13 cases of HCS. Molecular alterations were analyzed in separately microdissected carcinomatous and sarcomatous components in 8 cases by using targeted next‐generation sequencing with a panel of 329 cancer‐related genes. The most common gene alterations found in both components were TP53 (75%, 6/8) and NF1/2 (38%, 3/8) mutations and VEGFA amplification (25%, 2/8), which may be strongly associated with HCS tumorigenesis. Amplifications involving MET (38%, n = 3/8) and PDGFRA (25%, n = 2/8) were present only in the sarcomatous components, whereas mutation affecting ERBB4 (25%, n = 2/8) and amplifications of CCND1 and FGF3/4/19 (38%, n = 3/8) were present only in the carcinomatous components, indicating their involvement in the clonal evolution of HCS. The authors conclude that HCS could have been of monoclonal origin, and that the diverse clonal evolution might be driven by special molecular alterations in each tumour component. This study also identified multiple therapeutic targets in HCS, which may be valuable for the personalized treatment of HCS.


Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis
Strnad P, Buch S, Hamesch K, et al. Gut. 2019 Jun; 68(6): 1099-1107.

It is well established that homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis; the significance of heterozygous carriage is less clear. In this study the impact of the two most relevant AAT variants (‘Pi*Z’ and ‘Pi*S’) on subjects with non-alcoholic fatty liver disease (NAFLD) or alcoholic liver disease (ALD) were studied. These variants are present in up to 10% of Caucasians. The Pi*Z variant presented in 14% of patients with cirrhotic NAFLD and 6% of cirrhotic ALD but only in 2% of their corresponding groups without liver fibrosis.  In contrast, the Pi*S variant was not associated with NAFLD-related cirrhosis and only borderline with ALD cirrhosis. The authors conclude that the Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers and should be considered in genetic counselling of affected individuals. Histopathologists have a significant role in identifying these cases. 

American Journal of Gastroenterology

Spectrum of Liver Disease in Hepatitis B Virus (HBV) Patients Co-infected with Human Immunodeficiency Virus (HIV): Results of the HBV-HIV Cohort Study.

Sterling RK, Wahed AS, King WC, et al. Am J Gastroenterol. 2019 May; 114(5): 746-757.

The histologic spectrum of liver disease in HBV/HIV coinfection is poorly defined. In this prospective study, liver biopsies in 114 patients coinfected with HBV and HIV were assessed by a central pathology committee chaired by Dr. David Kleiner. Liver biopsies showed significant periportal, lobular, and portal inflammation in 14%, 31%, and 22% respectively. 37% of biopsies had significant fibrosis (Ishak stage ≥2); 24% had advanced fibrosis (Ishak stage ≥3). Higher ALT and lower platelet count, but not HBV DNA, were independently associated with advanced fibrosis.

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
Eric Yee MD; University of Arkansas