Saturday, November 21, 2015

Journal Watch September - October 2015

Modern Pathology, Sept-Oct 2015

Intraductal tubulopapillary neoplasms of the bile ducts: clinicopathologic, immunohistochemical, and molecular analysis of 20 cases
Schlitter AM, Jang KT, Klöppel G, et al. Mod Pathol. 2015 Sep;28(9):1249-64.

Intraductal tubulopapillary neoplasm of the bile ducts is the biliary counterpart of pancreatic intraductal tubulopapillary neoplasm. In this report, 20 cases were studied focusing on the clinicopathologic features and molecular profiles. The tumors were predominantly intrahepatic (70%) with mean size of 6.9 cm. The neoplasms were immunoreactive for MUC1 (80%) and MUC6 (30%). 80% of the lesions were associated with invasive carcinoma. The overall survival was favorable: 1 year 100%, and 5 years 90%. Molecular studies showed low prevalence of alterations of common oncogenic signaling pathways in this tumor.

American Journal of Pathology, Sept-Oct 2015

Hepatic Progenitor Cells in Action: Liver Regeneration or Fibrosis?
Kaur S, Siddiqui H and Bhat MH. Am J Pathol. 2015 Sept;185:2342-2350.

This is a nice review of the current knowledge regarding hepatic progenitor cells and their role in both hepatic fibrosis and hepatic regeneration during liver injury.

Human Pathology, Sept-Oct 2015

Alternative lengthening of telomeres phenotype in malignant vascular tumors is highly associated with loss of ATRX expression and is frequently observed in hepatic angiosarcomas.
Liau JY, et al. Hum Pathol. 2015;46(9):1360-6.

Alternative lengthening of telomeres (ALT) can enable endless cancer cell replication. ALT has been associated with inactivation of α-thalassemia/mental retardation syndrome X-linked (ATRX) and death domain-associated (DAXX) protein. This study focused on ATRX/DAXX expression and ALT status in malignant vascular tumors. Loss of ATRX expression was observed in 21% (16/77) of the primary angiosarcomas and 9% (1/11) of epithelioid hemangioendotheliomas. DAXX expression was intact in all but 2 ATRX-deficient angiosarcomas. Telomere-specific FISH was ALT-positive in 28% (17/61) of the primary angiosarcomas and was highly associated with loss of ATRX expression, as 26/28 ALT-positive angiosarcomas were ATRX deficient. Primary liver angiosarcomas were ATRX deficient (8/13) and/or ALT positive (8/12), while none of the secondary angiosarcomas showed these findings. The only ATRX-deficient epithelioid hemangioendothelioma was positive for ALT. The study concludes that ALT and loss of ATRX expression are frequently observed in hepatic angiosarcomas.

Advance in Anatomic Pathology, Sept-Oct 2015

Update on the Liver Imaging Reporting and Data System: What the Pathologist Needs to Know
Tang A. et al . Advance in Anatomic Pathology. 2015, 22(5): 314-322.

Hepatocellular carcinoma (HCC) is frequently diagnosed noninvasively with imaging methods. In 2008, the American College of Radiology supported the development of the Liver Imaging Reporting and Data System (LI-RADS) for standardized terminology and reporting for the diagnosis of HCC. This article reviews the basic concepts of LI-RADS, emphasizing aspects that are most relevant to pathologists, including the categories, diagnostic algorithm, major features, and ancillary features for the diagnosis of HCC. Importantly, LI-RADS is designed to diagnose progressed HCC with high specificity and modest sensitivity, but not designed to detect early HCC and so have limited sensitivity for such lesions. Another relevant point to pathologists is that imaging detection of small (<1 cm) nodules is restricted. For these reasons LI-RADS require lesions to be 1 cm or greater for the noninvasive diagnosis of HCC.

American Journal of Clinical Pathology, Sept-Oct 2015

The Significance of Autoantibody Changes Over Time in Primary Biliary Cirrhosis
Tana MM et al. Am J Clin Pathol  2015;144:601-606

The significance of autoantibodies (AMA, ANA) in PBC disease stage and prognosis is unclear.  In this article, the authors tested serial serum samples from patients with PBC for autoantibodies, and correlated the levels of autoantibodies with clinical, laboratory, and histologic outcomes.  145 serum samples from 27 PBC patients were studied. The medium follow up time was 20 years. In the initial serum samples, the positivity for autoantibodies was:  AMA (93%), ANA (100%), SSA-52 (48%), sp100 (22%), gp210 (22%), centromere (19%), SS-A (15%), chromatin (4%), SS-B (4%), RNA polymerase III (0%), SLA (0%), Scl-70 (0%), respectively. Most antibody levels did not change significantly over time except for sp100 (a specific type of ANA). Furthermore, there was a significant inverse relationship between change in sp100 autoantibody level and fibrosis score on serial liver biopsy specimens. The data suggests that changing sp100 level despite treatment might indicate disease progression.

Histopathology, Sept-Oct 2015

Hypoxia after transarterial chemoembolization may trigger a progenitor cell phenotype in hepatocellular carcinoma.
Lai JP, Conley A, Knudsen BS, Guindi M. Histopathology. 2015 Oct;67(4):442-50.

This study tested the expression of three markers in recurrent lesions of hepatocellular carcinoma (HCC) treated by TACE (Transcatheter Arterial Chemoembolization). The three markers are carbonic anhydrase IX (CAIX) [marker of hypoxia] as well as the cholangiocytic/progenitor markers cytokeratin (CK19) and epithelial cell adhesion molecule (EpCAM) [as markers of aggressive HCC biology]. The authors operated on the hypothesis that these markers were expressed in post-TACE hypoxic areas, and by implication contributed to a selection of aggressive clone that recurred. Out of 40 recurrent tumors, 19 expressed CAIX (versus 2/17 in untreated controls). They found that only recurrent tumors expressing CAIX co-expressed CK19 (6 of 19 tumors) and EpCAM (7/19), although EpCAM and CK19 were only co-expressed in 3 of 7 tumors that expressed EpCAM. This finding concluded that TACE paradoxically selected for aggressive tumor phenotype by causing hypoxia, which in turn “may trigger the expression of proteins that are normally associated with cholangiocytic/progenitor cell.

Journal of Gastroenterology and Hepatology, Sept-Oct 2015

Clinical outcomes of cryptogenic compared with non-cryptogenic cirrhosis: A retrospective cohort study
Mohammed OK. et al. Journal of Gastroenterology and Hepatology, 2015, 30(9):1423-8.

The consequences of cryptogenic versus non-cryptogenic cirrhosis were compared in a large, single academic center over 5-year duration. The study included 301 patients with cirrhosis (94 cryptogenic and 207 non-cryptogenic). Compared with non-cryptogenic cirrhosis, patients with cryptogenic cirrhosis were older (mean age 66.4 vs 60.7 years), had more females (43.6% vs 26.6%), had less disease severity (Child–Pugh C 8.5% vs 15.9%), and had a higher prevalence of the metabolic syndrome (83% vs 51.2%). Cryptogenic cirrhosis is associated with a longer duration of hospitalization compared with non-cryptogenic cirrhosis at an early stage of the disease. This difference is due to a greater burden of non-liver-related complications in the former. Kaplan–Meier survival analysis showed no significant differences in survival between both types of cirrhosis for all grades of severity.

Hepatology, Sept-Oct 2015

The Significance of Nonobstuctive Sinusoidal Dilation of the Liver: Impaired Portal Perfusion or Inflammatory Reaction Syndrome.
Marzano C, Cazals-Hatem D, Rautou PE et al. Hepatology. 2015 Sept;62:956-963.

This very nice review highlights conditions associated with nonobstructive sinusoidal dilation and discusses the pathogenic roles played by interleukin-6, Notch1 and VEGF.

Hepatic Lipid Droplet Biology: Getting to the Root of Fatty Liver.
Mashek DG, Khan SA, Sathyanarayan A et al. . Hepatology. 2015 Sept;62:964-967.

This review highlights recent advances in our knowledge of lipid droplet biology and associated liver disease.

The Severity of Steatosis Influences Liver Stiffness Measurement in Patients with Nonalcoholic Fatty Liver Disease.
Petta S, Maida M, Macaluso FS, et al. Hepatology. 2015 Oct;62:1101-1110.

In many chronic liver diseases (CLDs), the risk of liver-related and overall mortality, as well as therapeutic decision-making, is linked to the fibrosis stage.  Methods for noninvasive and rapidly performed point-of-care testing are being sought, especially for highly prevalent CLDs such as NAFLD. Vibration-controlled transient elastography (VCTE) by Fibroscan, which uses liver stiffness measurement (LSM) as a surrogate of liver fibrosis, has been validated in viral hepatitis. The authors of this paper assessed the impact of liver steatosis severity on LSM values and transient elastography accuracy in a 253 patient cohort of biopsy proven NAFLD. They report that among patients with low amounts of fibrosis (F0-F1 and F0-F2), median LSM values were significantly higher in subjects with severe steatosis (>66% on liver biopsy) and that about one-third of the subjects with BMI >30 kg/m2 had an unreliable LSM. They conclude that in patients with severe steatosis, LSM might overestimate liver fibrosis.

Salivary Microbiota Reflects Changes in Gut Microbiota in Cirrhosis with Hepatic Encephalopathy.
Bajaj JS, Betrapally NS, Hylemon PB et al. Hepatology 2015 Oct;62:1260-2171.

It has become well established that patients with cirrhosis have enteric dysbiosis and that an altered gut microbiome is associated with systemic inflammation and cirrhosis decompensation. The aim of this study was to evaluate the oral microbiome in cirrhosis and compare it with the stool microbiome. Ninety-day liver-related hospitalizations were also noted. The cohort consisted of 102 patients (43 with previous hepatic encephalopathy [HE]) and 32 age-matched controls. Thirty-eight patients were hospitalized within 90 days and these patients salivary dysbiosis was significantly worse and predicted this outcome independent of cirrhosis severity. Salivary inflammation was studied in an additional 86 age-matched subjects (43 controls and 43 patients with cirrhosis. Significantly higher inflammatory markers (interleukin-6 and interleukin-1β, secretory IgA and lower lysozyme and histatins 1 and 5 were found in the cirrhotic patients. The authors conclude that dysbiosis is present in both stool and saliva in cirrhosis patients and cirrhotic patients have impaired salivary defenses and worse inflammation. Salivary dysbiosis was greater in patients with cirrhosis who developed 90-day hospitalizations. These findings may reflect a global mucosal-immune interface dysfunction in cirrhosis.

Gut, Sept-Oct 2015

Impact of common risk factors of fibrosis progression in chronic hepatitis C.
Rueger S, Bochud P-Y, Dufour J-F. et al.  Gut.  2015;64:1605-1615

The authors follow 1461 Swiss patients with chronic HCV hepatitis who had at least 1 biopsy and an estimated date of infection.  The factors that were associated with accelerated fibrosis (defined as ≥0.13 Metavir fibrosis units per year) were identified.  Older age at infection, male sex, genotype 3, and route of infection (intravenous drug use) were associated with accelerated progression.  Age at infection was the strongest contributor to accelerated fibrosis followed by route of infection.  This was confirmed in other cohorts and by a meta-analysis.  Diabetes, BMI, and HIV infection were not associated with accelerated fibrosis progression.  Three single nucleotide polymorphisms were also associated with fibrosis progression.  Although the important factors that favor fibrosis progression are not modifiable the knowledge of these factors may help prioritize treatment of HCV infection.

Gastroenterology, Sept-Oct 2015

Liver Stem Cells: Experimental Findings and Implications for Human Liver Disease.
Michalopoulos GK, Khan Z. Gastroenterology. 2015;149(4):876-82.

Nice review of histologic and experimental aspects of liver stem cells. The review emphasizes that the potential of hepatocytes to rescue cholangiocytes is widely accepted, while the possibility of cholangiocytes giving rise to liver progenitor cells and hepatocytes is not supported by experimental studies and remains controversial. Some studies in mice suggest that cholangiocyte to hepatocyte transdifferentiation can occur and depends on inhibition of hepatocyte proliferation The ability of hepatocytes and cholangiocytes to serve as potential stem cells for each other may help prevent more effectively than tissue-specific stem cells.

Genetic Landscape and Biomarkers of Hepatocellular Carcinoma.
Zucman-Rossi J, et al. Gastroenterology. 2015;149(5):1226-1239.

Comprehensive review on the genetics of hepatocellular carcinoma (HCC) including common abnormalities such as TERT promoter mutation (60%), TP53 and CTNNB1 mutations (25-30%), chromosomal aberrations [DNA amplifications in chromosome 6p21 (VEGFA) and 11q13 (FGF19/CNND1), homozygous deletions in chromosome 9 (CDKN2A)], and less frequently involved genes (AXIN1, ARID2, ARID1A, TSC1/TSC2, RPS6KA3, KEAP1, MLL2),. The potential for specific therapeutic approaches targeting the involved pathways is discussed. Based on genomic profiling data, 2 major molecular clusters (proliferation and nonproliferation) of HCC are described.

Clinical Gastroenterology and Hepatology, Sept-Oct 2015

Association Between Endogenous Sex Hormones and Liver Fat in a Multiethnic Study of Atherosclerosis
Lazo M et al. Clin Gastroenterol Hepatol. 2015;13(9):1686-1693
Metabolic abnormalities are considered the major cause for Nonalcoholic fatty liver disease (NAFLD). In previous studies with small sample size, the association between circulating sex hormones and metabolic abnormalities has been reported. The current study is however the first large cohort study to evaluate the association between circulating sex hormones (testosterone, estradiol, dehydroepiandrosterone, and sex hormone binding globulin (SHBG)) and fatty liver; included are 2835 postmenopausal women and 2899 men aged 45-84 years.. The data indicated that 1) higher levels of estradiol are associated with fatty liver in both men and women independent of demographic, anthropometric, and cardiometabolic risk factors. 2) Postmenopausal women with high level of bioavailable testosterone are at greater risk for fatty liver than women with low levels. 3) In men, higher levels of SHBG are associated with reduced risk for fatty liver.

Journal of Hepatology, September 2015

Hepatic cell proliferation plays a pivotal role in the prognosis of alcoholic hepatitis.
Lanthier N et al.  Journal of Hepatology 2015; 63: 609-621.

Alcoholic hepatitis (AH) is a distinct manifestation of alcoholic liver disease that is associated with significant morbidity and mortality. Many scoring systems have been developed to assess the disease severity of AH. However, there is no ideal prognostic scoring system for clinical use. In this study, Lanthier et al. investigated the association of liver progenitor cell (LPC), macrophage and gene expression patterns with prognosis of AH. Liver biopsies obtained from AH and abstinent alcoholic cirrhotic patients were studied by immunohistochemistry and microarray gene expression. The related cytokines in serum from AH and control patients were also measured. CD68+ macrophages, CK7+/ki-67- and CK7+/Ki67+ LPCs were increased in AH compared to abstinent cirrhosis. In the follow-up study, patients with significant expansion of liver macrophages and a high number of proliferating hepatocytes as well as proliferating LPCs showed a better outcome. In addition, when compared to controls, an obvious upregulation of genes involved in cell cycle, mitosis and proliferation pathways, as well as a high expression of SPINK1 was found in AH patients. The study suggested that increased proliferating hepatocytes and LPCs, high expression of certain genes, and macrophage expansion in biopsy samples might act as markers for favorable outcome. The data from the gene expression study provided important information to help identifying the potential targets for AH treatment.

Prepared by:
Rish Pai, MD, PhD; Mayo Clinic Arizona
Sanjay Kakar, MD; University of California, San Francisco
Cindy Guy, MD; Duke University
Wenqing Cao, MD; New York University
Jingmei Lin, MD, PhD; Indiana University
Oyedele Adeyi, MD; University of Toronto
Charles Lassman, MD; University of California, Los Angeles

Journals Reviewed
American Journal of Surgical Pathology, Modern Pathology, Histopathology, Human Pathology, American Journal of Clinical Pathology, Journal of Pathology, Archives of Pathology and Laboratory Medicine, Advances in Anatomic Pathology, Hepatology, Journal of Hepatology, Liver Transplantation, Gastroenterology, Gut, Clinical Gastroenterology and Hepatology, Journal of Gastroenterology and Hepatology, American Journal of Gastroenterology, Nature

Tuesday, October 27, 2015

President's Message October 2015

Dear Friends and Colleagues,

I hope everyone has had a great start to this academic year. Our fall edition of newsletter is here for your reviewing pleasure. 

I would like to bring to your attention a new feature of our HPHS website, “Journal Watch” put together by diligent work of the members of the education committee. “Journal Watch” is a summary of the recent and seminal liver pathology related papers published in reputable journals. I will encourage all of you to refer to this new feature of our website. This is a great way for all of us to stay up to date with the literature. Please see the website for the latest edition.

Additionally, I would like to strongly encourage members to consider submitting your USCAP abstracts for our annual “Hans Popper Hepatopathology Society Trainee Award”. The award will be presented during our HPHS business meeting in Seattle in March 2016. 


Isabel Fiel, M.D.
President, Hans Popper Hepatopathology Society

Interesting Case October 2015

Clinical History:

An obese sixty year old gentleman with a history of GERD and hypertension presented to an emergency room with repeated bouts of sharp unremitting right upper quadrant pain over a one year period.  Imaging findings during clinical workup (see below) revealed changes concerning for gallbladder adenocarcinoma.  A biliary stent was placed, and the patient was referred to a tertiary center for further management.  Exploratory laparotomy demonstrated an indurated gallbladder which was densely adherent to the porta hepatis and the interface between segments 4B and 5.  A cholecystectomy and resection of the aforementioned liver segments was performed for presumed adenocarcinoma of the gallbladder.  


At initial evaluation: AST, 474; ALT, 358; alkaline phosphatase, 268; INR, 1.1


CT scan demonstrated heterogeneity of the fundus of the gallbladder and multiple benign hepatic cysts.  MRI and MRCP showed and thickened gallbladder wall with dilation and beading of the biliary tree but no evidence of common bile duct stones.  The clinical differential included malignancy, adenomyomatosis, inflammation, and infection.  

Cholecystectomy and Liver Segmentectomy Findings:

Sections of the gallbladder demonstrated a marked chronic inflammatory infiltrate with numerous germinal centers and plasma cells involving the lamina propria and muscularis mucosa, with focal involvement of the submucosa (Figures 1&2).   The submucosa was fibrotic.  Immunohistochemistry demonstrated polytypic plasma cells with clusters of up to 40 IgG4 positive plasma cells per 40x field (Figure 3). The superficial gallbladder wall demonstrated scattered IgG4 plasma cells and the deeper, more fibrotic portions of the gallbladder wall demonstrated prominent clusters of IgG4 positive plasma cells. The surface epithelium showed mild reactive changes but no dysplasia.  Sections of the liver segmentectomy showed normal architecture. Portal areas contained mild to moderate chronic inflammatory infiltrates.  A few portal areas demonstrated prominent clusters of lymphocytes.  Many portal areas did not contain a portal vein branch and in one septal portal area there was fibrous obliteration of the vein (Figure 4, white arrow).  The parenchyma demonstrated atrophy of zone 3 hepatocytes (blue arrow) compatible with portal vein compromise (Figure 5).

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5


Chronic cholecystitis consistent with IgG4 sclerosing disease with sclerosing portal venopathy.
No dysplasia or carcinoma.


Immunoglobulin G4 (IgG4)-related disease is a fibroinflammatory condition that is characterized by tumor-like swelling of involved organs, due to a dense lymphoplasmacytic infiltrate with numerous IgG4 positive plasma cells, a “storiform” pattern of fibrosis, eosinophilia, obliterative phlebitis, and in most cases elevated serum IgG4 concentrations above the upper limit of normal (>135 ng/dL) (N Engl J Med. 2012 Feb;366(6):539-51).  IgG4-related disease has been described in essentially every organ system, including the biliary tree.  It typically occurs in middle-aged men, especially in association with conditions such as type 1 (IgG4-related) autoimmune pancreatitis (AIP), IgG4-related tubulointerstitial nephritis, and retroperitoneal fibrosis.  However, the proportion of female patients  appear to be significantly higher than in men with respect to head and neck manifestations of the disease, such as IgG4-related sialadenitis and IgG4-related ophthalmic disease (Am J Surg Pathol. 2010;34(12):1812).  

IgG4-related sclerosing cholangitis is the second most common manifestation of the disease, second only to type 1 autoimmune pancreatitis (AIP).  The percentage of patients with AIP who have extrahepatic bile duct involvement is estimated to be between 71-100%, and rarely occurs in the absence of pancreatitis (Curr Opin Rheumatol. 2011;23(1):57).  It is imperative to distinguish IgG4-related cholangitis from primary sclerosing cholangitis since the former is typically responsive to steroid therapy (Gastroenterology. 2008 Mar;134(3):706-15).  Inflammatory bowel disease and cholangiocarcinoma, both of which are associated with primary sclerosing cholangitis, has not been reported in patients with IgG4-related sclerosing cholangitis (Curr Opin Gastroenterol. 2008;24(3):389).  The presence of clinical manifestations in extra-biliary organs, histomorphological findings such as IgG4 positive plasma cells, storiform interstitial fibrosis, and responsiveness to steroids, can all help differentiate  these two entities.  

IgG4-related sclerosing cholangitis in the absence of AIP is rare, and as in the current case, can mimic extrahepatic cholangiocarcinoma.  It is seen primarily in middle to older age men.  A recent study compared material from patients with IgG4-related sclerosing cholangitis without AIP, to those with IgG4-related sclerosing cholangitis and AIP, and to those with extrahepatic cholangiocarcinoma, primary sclerosing cholangitis, and secondary sclerosing cholangitis.  The histomorphologic features that helped distinguish IgG4-related sclerosing cholangitis from these other entities include a marked degree of bile duct injury, higher percentage of lymphoid follicle formation, a higher percentage of perineuritis, as well as a more diffuse and dense lymphoplasmacytic infiltrate.  The authors also found that the presence of more than 50 IgG4-positive plasma cells per high power field in a biopsy specimen was sufficient to exclude cholangiocarcinoma. Therefore biopsy specimens with fewer than 50 IgG4  positive plasma cells  did not adequately exclude the presence of unsampled cholangiocarcinoma (Scand. J. Gastroenterol. 2015 Apr;50(4):447-453) 

Case Contributed by:
Ramir Arcega, MD and Charles Lassman, MD, Ph.D.
UCLA David Geffen School of Medicine 

Friday, September 18, 2015

Journal Watch July-August 2015

American Journal of Gastroenterology, July-August 2015

Long-Term Prognostic Significance of Persisting Histological Activity Despite Biochemical Remission in Autoimmune Hepatitis.
Harpreet K et al.  Am J Gastro 2015;2110:993-9

The clinical significance of persistent histologic activity despite biochemical remission in patients with autoimmune hepatitis is unknown.  The authors studied 120 patients with autoimmune hepatitis who received immunosuppression and underwent liver biopsy at least 6 months after sustained biochemical remission (normal ALT and serum globulins).  Despite having biochemical remission, 55/120 (46%) had persistent histologic activity (defined as HAI ≥4).  No differences were seen in patients who achieved histologic remission compared to those who did not with regard to pretreatment clinical, laboratory, or histologic parameters.  No differences in treatment and time to biochemical remission was observed between these two groups.  However, serum ALT and AST were lower in those who achieved histologic remission.  The presence of HAI ≥4 on follow-up biopsy was associated with decreased fibrosis regression (60% versus 32%, p=0.004).  Finally, patients who did not achieve histologic remission had reduced transplant-free and overall survival.

American Journal of Surgical Pathology, July-August 2015

One Hundred Thirteen Consecutive Transgastric Liver Biopsies for Hepatic Parenchymal Diseases: A Single-institution Study.
Nakanishi, Y et al.  Am J Surg Pathol 2015;39:968-76

In this study, the authors present their results from 113 transgastric liver biopsies performed at a single institution (using QuickCore needle, ProCore needle, and Flex needle).  The transgastric biopsies were compared to 100 percutaneous and 100 transjugular biopsies.  The main reason for obtaining transgastric liver biopsies was assessment of fatty liver disease (43%) followed by elevated LFTs (25%).  In contrast percutaneous liver biopsies were performed mainly for grading and staging chronic hepatitis (45%).  The main indication for transjugular liver biopsy was to evaluate for cirrhosis.  In contrast to transjugular and percutaneous biopsies, transgastric biopsies were often quite fragmented and contained >10 tissue fragments with a median fragment length of 4 mm.  Most transgastric biopsies yielded less complete portal tracts; although biopsies obtained from the Flex needle performed as well as transjugular and percutaneous biopsies. Using the QuickCore neede a median of 2 complete portal tracts was obtained whereas 9 and 12 portal tracts were obtained using the ProCore and Flex needle respectively.  Transgastric biopsies were less likely to be adequate for staging and diagnosis as only 42%, 75% and 85% of the QuickCore, ProCore and Flex needle biopsies, respectively were deemed.  All transgastric biopsies contained gastric mucosa.

Ipilimumab-associated Hepatitis: Clinicopathologic Characterization in a Series of 11 Cases.
Johncilla, M et al.  Am J Surg Pathol 2015;39:1075-84

Ipilimumab is a monoclonal antibody directed against CTLA4 on T-cells and is most often used to treat metastatic melanoma.  Ipilimumab has been associated with a wide variety of immune-mediated side effects including colitis, enteritis, pancreatitis, nephritis and generalized lymphadenopathy.  The authors study 11 cases of ipilimumab associated hepatitis.  No patient had preexisting liver disease and 10 patients had normal LFTs before ipilimumab treatment.  Two patterns of hepatitis were observed, panlobular hepatitis and zone 3 hepatitis.  Three patients with panlobular hepatitis also had zone 3 necrosis and central vein endotheliitis was commonly seen. The inflammatory cell infiltrate consisted mostly of lymphocytes and histiocytic aggregates whereas plasma cells were usually rare, although in 3 patients they were more prominent.  In one patient steatohepatitis was identified and another showed cholangitis.  Discontinuation of ipilimumab resulted in improvement of LFTs in all patients.  All patients were also treated with steroids.

Archives of Pathology and Laboratory Medicine, July-August 2015

Comparison of 5 Immunohistochemical Markers of Hepatocellular Differentiation for the Diagnosis of Hepatocellular Carcinoma.
Nguyen, T et al Arch Pathol Lab Med.  2014;139:1028-34

The authors compare the efficacy of 5 hepatocellular markers (arginase-1, hep par1, glypican-3, polyclonal CEA, and bile salt export pump transporter) in the diagnosis of hepatocellular carcinoma.  The authors included well differentiated, moderately differentiated and poorly differentiated hepatocellular carcinoma.  Of the 79 HCC cases, only 1 case failed to stain with arginase-1 (a poorly differentiated HCC).  Importantly, hep-par1 failed to stain 14/39 poorly differentiated HCC.  Polyclonal CEA and BSEP also performed poorly in high-grade tumors.  Gylpican 3 staining increased with increasing tumor grade.  Arginase 1 and glypican 3 immunohistochemistry may be most useful in the diagnosis of poorly differentiated hepatocellular carcinoma.

Clinical Gastroenterology and Hepatology, July-August 2015

Identification and Characterization of Cefazolin-induced Liver Injury.
Alqahtani SA et al. Clin Gastroenterol Hepatol. 2015;13(7):1328-1336

Cefazolin is a commonly used first generation Cephalosporins, for which drug induced liver injury (DILI) is generally considered rare. A recent ongoing prospective study from the United States, Drug Induced Liver Injury Network (DILIN), identified 19 out of 1212 (2%) patients with DILI attributed to Cefazolin, making Cefazolin the sixth most common single agent in the data set.  Cefazolin induced liver injury has a latency period of about 20 days (1-3 weeks), and shows a self-limited moderate to severe clinical course characterized by a cholestatic biochemical and histologic pattern. The study also identified 14 more patients with DILI attributed to other Cephalosporins, a few of them were associated with severe injury and death. For the first time, the authors describe the clinical presentations, laboratory tests and histopathology of cephazolin induced DILI, and identify Cephalosporins as a relative common cause of antibiotic-associated liver injury.

Gut, July-August 2015

A genomic and clinical prognostic index for hepatitis C-related early-stage cirrhosis that predicts clinical deterioration.
King Y et al.  Gut 2015;64:1296-1302

Cirrhosis due to HCV is increasing.  While eradication of the virus decreases the risk of disease progression, it does not eliminate the risk.  In a prior study, the authors developed a 186-gene expression panel that can risk stratify patients with HCV.  In this study the authors implemented the 186-gene signature using an FDA-approved clinical diagnostic assay platform.  The authors of this study developed a prognostic gene expression signature in an attempt to risk stratify HCV patients with cirrhosis.  Using RNA isolated from FFPE samples, the authors validate this gene signature using a training cohort.  A 145 patient validation cohort was appropriately risk stratified using this gene panel as the high-risk group experienced more frequent hepatic decompensation (HR=7.36), overall death (HR=3.57), and liver-related death (HR=6.49).  Importantly, the prognostic association remained statistically significant in Child-Turcotte-Pugh class A patients (n = 121) indicating that it will be useful in patients with “early cirrhosis”.

Gastroenterology, July-August 2015

Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease.
Angulo P, et al. Gastroenterology. 2015;149(2):389-397.

Editorial: The Hierarchical Model of NAFLD: Prognostic Significance of Histologic Features in NASH.
Loomba R, et al. Gastroenterology. 2015;149(2):278-81.

This study examines prognostic significance of histologic features in 619 NAFLD cases. Older age, diabetes, current smoking and presence of fibrosis (as well as stage of fibrosis) were associated with death or liver transplantation. Ballooning and portal inflammation were significant associations, but not in multivariate analysis. Stage 3 and stage 4 fibrosis were the only features associated with liver-related events (defined as variceal bleeding, HCC, liver-related death, liver transplant). Steatosis grade, lobular inflammation and NAFLD score were not associated with overall mortality or liver-related events.

Hepatology, May 2015

Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up.
Ekstedt M, et al. Hepatology. 2015;61(5):1547-54.

The outcome in 229 biopsy-proven NAFLD with mean available follow-up of 26.4 years was compared to a reference population. NAFLD patients had higher risk of cardiovascular disease, hepatocellular carcinoma, infections and cirrhosis. NAFLD patients with stage 3 and stage 4 fibrosis had increased mortality, but not those with no fibrosis or lower stage of fibrosis.

Journal of Gastroenterology and Hepatology, July-August 2015

Usefulness of endoscopic ultrasound-guided sampling using core biopsy needle as a percutaneous biopsy rescue for diagnosis of solid liver mass: Combined histological-cytological analysis.
Lee YN. Et al. J Gastroenterology and Hepatology. July, 2015; 30(7):1161-1166.

In this study, the diagnostic accuracy of EUS-guided fine needle biopsy (EUS-FNB) was studied. Twenty-one patients underwent EUS-FNB after the failure of a percutaneous biopsy for liver solid mass. The median number of needle passes was 2.0 (range, 1-5). On-site cytology and cytology with Papanicolaou stain showed malignancy in 16 (76.2%) and 17 patients (81.0%), respectively. In histology with H&E stain, 19 patients (90.5%) were diagnosed malignancy and optimal to IHC stain. The overall diagnostic accuracy for malignancy and specific tumor type were 90.5% and 85.7%, respectively. No complications were seen. In summary, EUS-FNB with core biopsy needle may be helpful in the management of patients who are unable to diagnose using percutaneous liver biopsy.

Journal of Hepatology, July-August 2015

Targeting cyclin dependent kinase 5 in hepatocellular carcinoma – A novel therapeutic approach.
Ehrlich SM et al.  Journal of Hepatology 2015; 63: 102-13.

Recently, dysregulation of cyclin dependent kinase 5 (Cdk5) has been linked to malignancy, including cancers of the prostate, pancreas, thyroid, lung, cervix, myeloma, and breast. In the study, the role of Cdk5 in HCC progression was investigated. Increased expression of Cdk5 and its activator P35 were seen in HCC compared to normal liver tissues. Overexpression of Cdk5 promoted HCC cell growth in vitro. Genetic (siRNA and shRNA) or pharmacologic (roscovitine) inhibition of Cdk5 expression reduced HCC cell proliferation and tumor growth in a xenograft mouse model. Furthermore, HCC cell line and xenografts were treated with CDK5 inhibition plus DNA-damage-inducing chemotherapeutics to examine the effect on cancer cell proliferation and tumor growth. Data showed that down regulation of Cdk5 expression enhanced the sensitivity of various DNA damaging agents in HCC. The study suggested that CDK5 might be a novel treatment target, and combination of CDK5 inhibition and DNA-damaging agent could serve as an effective therapeutic approach for HCC.

Breast tumor kinase/protein tyrosine kinase 6 (Brk/PTK6) activity in normal and neoplastic biliary epithelia.
Mizuguchi Y et al. Journal of Hepatology 2015; 63:399-407

In this article, using immunohistochemistry, the authors found BRK protein was expressed at low level in normal intrahepatic bile ducts. The expression of BRK was significantly higher in CC cell lines and a majority of CC compared to normal tissues. High expression of BRK in CC was associated with extrahepatic location and well differentiation. Studies in vitro revealed BRK co-localized with EGFR and ErbB2/neu, and promoted tumor growth. Knock down BRK by siRNA significantly reduced tumor cell proliferation. The data indicated the important role of BRK in HCC progression, suggesting that BRK might serve as a target for HCC treatment.

Modern Pathology, July-August 2015

The liver in heart failure: a biopsy and explant series of the histopathologic and laboratory findings with a particular focus on pre-cardiac transplant evaluation.
Louie CY., et al. Modern Pathology July 31st, 2015 (28):932-943

Liver biopsies are commonly obtained as part of the work up before heart transplantation in patients with longstanding right heart failure, particularly if ascites, abnormal liver function tests or abnormal abdominal imaging are noted as part of the pre-transplant evaluation. In these cases, the liver biopsy findings may be used to further risk stratify patients for isolated heart or combined heart and liver transplantation. Thus, it is important to be able to correlate the histologic changes with post-transplant outcomes.  In this report, the pathologic and clinical findings in liver explants from six patients who underwent combined heart-liver transplantation and preoperative liver biopsies from 21 patients who underwent heart transplantation without simultaneous liver transplantation were studied. The changes related to chronic passive congestion were staged as follows: stage 0-no fibrosis; stage I-pericellular fibrosis; stage II-bridging fibrosis; and stage III-regenerative nodules. Thirteen biopsies showed bridging fibrosis in 13 and 6 had regenerative nodules. Fifteen patients were alive at 1 year post transplant. Only three patients had a postoperative course that was characterized by signs and symptoms of chronic liver disease. Pre-transplant liver biopsies from these 3 patients all showed at least stage II fibrosis. These 3 patients survived for 3, 6, and 10 months after cardiac transplant. It appears that the presence of bridging fibrosis was not significantly associated with postoperative survival (P=0.336) or postoperative liver failure (P=0.257). In conclusion, patients with bridging fibrosis may still be considered viable candidates for isolated heart transplantation.

Infiltrative (sinusoidal) and hepatitic patterns of injury in acute cellular rejection in liver
allograft with clinical implications
Siddiqui A. et al. Modern Pathology July 31st, 2015 (28) 1275–1281

Two patterns of acute cellular rejection (ACR), sinusoidal infiltrative and hepatitic, were described in this study. Twenty-eight cases of ACR with rejection activity index 5 or above were included. Among them, 15 (54%) had typical, 6 (21%) hepatitic and 7 (25%) sinusoidal infiltrative ACR. Sinusoidal infiltrative ACR occurred later (124 versus 50 days; P=0.032) and had a higher rise in baseline AST compared with the conventional one (289 vs 109 U/l; P=0.046). Only one out of seven patients with sinusoidal infiltrative ACR (14% versus 40% in typical ACR) failed Solu-Medrol boluses and required thymoglobulin. Patients with hepatitic ACR had similar AST (P=0.12) but higher bilirubinemia than typical one (160 vs 35 mol/l; P=0.039) and required thymoglobulin in four out of six (67% vs 40%) instances. Patients with sinusoidal infiltrative ACR had higher AST than the typical one but better Solu-Medrol response compared with both the typical and hepatic ACR.

Nature July-August 2015

Self-renewing diploid Axin2+ cells fuel homeostatic renewal of the liver.
Wang B, et al. Nature 2015 Aug 13;524(7564):180-185.

This report revolutionizes how we think about liver regeneration and hepatocytes renewal and shifts emphasis away from the Canals of Hering to the perivenular zone. The authors, using the wnt-responsive Axin2 gene lineage-traced renewal of hepatocytes by diploid, Axin2-expressing, cells in the perivenular zone of mice liver. This study demonstrate the presence of diploid Axin2 cells ONLY around hepatic veins, and that these cells differ from hepatocytes which are almost always non-diploid (having 4N-32N polyploidy). The authors surmised that being polyploid was a disadvantage to hepatocytes’ ability to self-renew. The lineage tracing in this study showed ability of these diploid Axin2 cells to replace all hepatocytes all the way to periportal hepatocytes over one year. They also demonstrate that like glutamine synthetase, Axin2 also responds to wnt signaling in an autocrine manner; that wnt signal originated from the hepatic vein endothelial cells, and that hepatocytes renewed by these Axin2 cells lost Axin2 expression as they migrated away from the hepatic vein vicinity towards hepatocytes, in the manner that they lost glutamine synthetase. The renewed hepatocytes take up carbamoyl-phosphate synthase 1, which replace GS and Axin2. Lastly the authors proved that Axin2 truly self-renewed and not preplaced by new Axin2 cells by using other cell labelling methods; i.e. “..while Axin2+ cells can give rise to all the hepatocytes along the lobule, they are not replaced by unlabeled Axin2− cells”. Other findings include Tbx3 gene dependence of Axin2 cells renewability. This study clearly revolutionizes traditional thinking about liver regeneration.

Prepared by:
Rish Pai, MD, PhD; Mayo Clinic Arizona
Sanjay Kakar, MD; University of California, San Francisco
Cindy Guy, MD; Duke University
Wenqing Cao, MD; University of Rochester
Jingmei Lin, MD, PhD; Indiana University
Oyedele Adeyi, MD; University of Toronto
Charles Lassman, MD; University of California, Los Angeles

Journals Reviewed
American Journal of Surgical Pathology, Modern Pathology, Histopathology, Human Pathology, American Journal of Clinical Pathology, Journal of Pathology, Archives of Pathology and Laboratory Medicine, Advances in Anatomic Pathology, Hepatology, Journal of Hepatology, Liver Transplantation, Gastroenterology, Gut, Clinical Gastroenterology and Hepatology, Journal of Gastroenterology and Hepatology, American Journal of Gastroenterology, Nature

Tuesday, July 21, 2015

Journal Watch May-June 2015

American Journal of Surgical Pathology, June 2015

Hyaline Droplets in Kupffer Cells: A Novel Diagnostic Clue for Autoimmune Hepatitis.  
Tucker SM, et al.  Am J Surg Pathol. 2015 Jun;39(6):772-8.

The authors of this study compare autoimmune hepatitis liver biopsies from 30 children to those with hepatitis B and hepatitis C in order to identify any characteristic histologic features of pediatric autoimmune hepatitis.  In half of the pediatric autoimmune hepatitis cases, hyaline droplets were identified in Kupffer cells.  Hyaline droplets were associated with markedly elevated serum IgG levels, and immunohistochemical analysis demonstrated that the globules were positive for IgG, occasionally for IgA, and rarely for IgD.  None of the biopsies from pediatric patients with hepatitis C contained hyaline droplets.  Only one patient with hepatitis B contained hyaline droplets.  The hyaline droplets were readily identified on a PAS/D stain.  The well circumscribed globular and waxy appearance of the hyaline droplets separates it from other material often seen within Kupffer cells.  The authors suggest that hyaline droplets within Kupffer cells can be helpful in the diagnosis of autoimmune hepatitis.  

Am J Pathology, June 2015

Profiles of Cancer Stem Cells Subpopulations in Cholangiocarcinomas. 
Cardinale V et al. Am J Pathol 2015 Jun;185(6):1724-1739

Cancer stem cells (CSCs) from human cholangiocarcinoma (CCA) subtypes (mucin-secreting intrahepatic and perihilar versus a peripheral mixed subtype) where characterized for immunohistochemical markers and tumorogenic potential (subcutaneous injection versus injection into normal and cirrhotic murine livers). The authors found that human CCAs were rich in CSCs and that CSC subpopulations generate different types of cancers depending on the microenvironment.

Histopathology, Apr-Aug 2015

Loss of CD155 expression predicts poor prognosis in hepatocellular carcinoma.
Qu, P, et al.  Histopathology. 2015 Apr;66(5):706-14.

Abnormal nuclear expression of Pygopus-2 in human primary hepatocellular carcinoma correlates with a poor prognosis.

Zhang, S, et al.  Histopathology. 2015 Aug;67(2):176-84.

Low expression of B-cell associated 31 protein in human primary hepatocellular carcinoma correlates with a poor prognosis

Tan, N., et al.  Histopathology. 2015 May 15.

Three papers published recently in Histopathology found three separate markers that correlated with various adverse outcome indices of hepatocellular carcinoma. These are loss of CD155, an immune modulator (Histopathology. 2015 Apr;66(5):706-14); abnormal nuclear expression of Pygopus-2, a co-activator of the Wnt/b-catenin transcriptional and an enhancer of b-catenin function (Histopathology. 2015 Aug;67(2):176-84.); and low expression of BAP31, a B-cell receptor associated protein which when depleted with EpCAM, decreased cyclins D1 and E expression causing suppression PI3K/Akt signaling (Histopathology. 2015 May 15. Epub ahead of print]). The three studies found these three markers to be independently predictive of tumor biology and/or outcome.  Concerning CD155, Qu P. et al found that loss of CD155 expression by immunohistochemistry was associated significantly with “higher serum alpha-fetoprotein level (P = 0.016) and a higher incidence of portal vein tumour thrombus (P = 0.050)”. Also patients with retained expression of CD155 had “better overall survival after surgery than those with negative CD155 expression (P = 0.005)”.

Concerning Pygopus-2, Zhang S et al. reported that abnormal nuclear Pygopus-2 “… expression in HCC patients was associated with age (P = 0.025), tumour size (P = 0.005), intra- or extra-hepatic metastasis (P = 0.029), vascular invasion (P = 0.026) and tumour differentiation (P = 0.004)”, while patients with normal expression had better short term (1-year) and long term survival. A third marker, the B-cell receptor associated protein BAP31, operates at the level of endoplasmic reticulum (ER). The authors based their premises on recent report that ER stress was related to the hepatocellular carcinogenesis and development. Since BAP31 with EpCAM depletion had been reported to reduce cyclins D1 and E causing growth advantage the authors decided to investigate the role of BAP31. Using relative intensity of expression (rather than a positive-negative algorithm), the authors found that “decreased” expression of BAP31 correlated with poor overall survival.

It is difficult to say at these early stages how much a role, if any these prognostic markers will play in clinical management of hepatocellular carcinoma, but just like CK19 before them, they require continuing monitoring as confirmatory (or refuting) evidence unfolds.

Modern Pathology, June 2015 

DNAJB1-PRKACA is specific for fibrolamellar carcinoma 
Graham RP, et al. Mod Pathol. 2015 Jun;28(6):822-9.

In this study, RT-PCR and FISH assays to detect the rearrangements of PRKACA locus were performed on a total of 106 primary liver tumors to test the diagnostic specificity for fibrolamerllar hepatocellular carcinoma. RT-PCR was successful in 92% of tested fibrolamellar carcinoma cases (24/26) and the DNAJB1-PRKACA fusion transcript was not detected in other tumor types, including conventional hepatocellular carcinoma, cholangiocarcinoma, hepatic adenoma, and hepatoblastoma. In addition, FISH and RNA in situ hybridization displayed similar results. In summary, detection of DNAJB1-PRKACA fusion is sensitive and specific to support the diagnosis of fibrolamellar carcinoma.

Liver Transplantation, June 2015

Donation after Cardiac Death Liver Transplantation: Graft Quality Evaluation Based on Pretransplant Liver Biopsy.  
Xia W, et al.  Liver Transplantation.  2015 Jun;21(6):838-46.

Donation after cardiac death has been associated with inferior patient and graft survival.  Thus, many DCD livers are discarded due to concerns of inferiority.  In this study the authors assess the ability of liver biopsy to predict graft survival in 127 DCD liver transplants in China.  The biopsies were assessed for macrovesicular steatosis, hepatocyte swelling, hepatocyte vacuolation, hepatocyte necrosis, and sinusoidal neutrophilic infiltrate.  Factors associated with poor graft survival were macrovesicular steatosis greater than 20% [hazard ratio 2.9] and a sinusoidal neutrophilic infiltrate (> 2 sinusoidal neutrophils per high power field in the most affected area) [hazard ratio 6.9].  The donor characteristic that was associated with poor survival was a high total bilirubin.

Gut, May 2015

Pathobiology of Liver Fibrosis: A Translational Success Story.  
Ye YA, et al. Gut. 64(5):830-41.

In this review, Lee and colleagues discuss the recent developments in hepatic fibrosis with a particular focus on reversibility.  They discuss the cellular sources of fibrosis, the mechanism extracellular matrix deposition, and the pathways that lead to a fibrosis regression.  Antifibrotic therapies are also discussed.  This article may be of interest to those more interested in understanding the mechanisms of fibrosis and novel therapies aimed at reducing hepatic fibrosis.

Journal of Hepatology, June 2015

Increased risk of non-alcoholic fatty liver disease after diagnosis of celiac disease.
Reilly NR et al. Journal of Hepatology 2015; 62: 1405-1411.

The association of celiac disease (CD) and non-alcoholic fatty liver disease (NAFLD) is unclear. This large population-based cohort study of 16,816 CD patients and 130,051 matched reference individuals with 10 years median follow-up reveals that individuals with CD have significantly higher risk of NAFLD compared to general population. Furthermore, their data indicates the risk of NAFLD is highest in children and is highly increased in the first year after the diagnosis of CD. The risk of NAFLD may persist over a long time (15 years).

Gastroenterology, June 2015

Features and Outcomes of 899 Patients With Drug-Induced Liver Injury: The DILIN Prospective Study. 
Chalasani N, et al.  Gastroenterology. 2015; 148(7):1340-1352.

This is an initial report from 1257 patients enrolled in a prospective study being done by Drug-Induced Liver Injury Network. DILI resulted in chronic liver disease in 17% of cases. Disease severity and mortality tended to be higher in patients with pre-existing disease.  Antimicrobial agents were the most common etiology for cases with a short latent period (≤7  days), while nitrofurantoin and minocycline were most commonly associated with long latency (>365 days). Cholestatic injury was more common in older individuals (>65 years)

β-Catenin Signaling and Roles in Liver Homeostasis, Injury, and Tumorigenesis.
Monga SP. Gastroenterology. 2015; 148(7):1294-1310.

β-catenin activation has been implicated in hepatocellular neoplasms including adenoma and carcinoma either through mutations/deletions in β-catenin or involvement of other members of the WNT signaling pathway. β-catenin interacts with a variety of transcription factors including T-cell factor, forkhead box protein O, and hypoxia inducible factor 1α, and can regulate the expression of many target genes. This extensive review discusses the role of β-catenin in metabolic zonation, and hepatocellular tumors.

Hepatology, May 2015

Hepatocyte Buds Derived from Progenitor Cells Repopulate Regions of Parenchymal Extinction in Human Cirrhosis

Stueck AE, Wanless IR. Hepatology 2015 May;61:1696-1707

The authors use immunohistochemistry for EpCAM, K19, CD34, glutamine synthetase and Ki-67 to investigate the origin of cells which repopulate the liver following parenchymal extinction lesions. Semiquantitative analysis of the morphologic sequence of hepatic “bud” maturation is described. The authors conclude that the stem/progenitor pathway is manifested by the bud sequence and that the majority of distal cholangiocytes have stem-like properties and the availability of bile ducts/or venous drainage are limiting facts for regeneration.

Hepatology, June 2015

Adaptive Remodeling of the Biliary Architecture Underlies Liver Homeostasis
Kaneko K, et al. Hepatology 2015 June;61:2056-2066.

The authors developed a novel imaging technique using infusion of ink containing carbon black into mice livers following various types of injury in order to visualize the global and fine-scale architecture of the regenerating biliary tree. They show the emergence and expansion of liver progenitor cells along with the structural transformation of the intrahepatic biliary tree. They conclude that the hepatobiliary system possesses structural flexibility and can remodel dynamically and adapt to various injury conditions.

Prepared by:
Rish Pai, MD, PhD; Mayo Clinic Arizona
Sanjay Kakar, MD; University of California, San Francisco
Cindy Guy, MD; Duke University
Wenqing Cao, MD; New York University
Jingmei Lin, MD, PhD; Indiana University
Oyedele Adeyi, MD; University of Toronto
Charles Lassman, MD; University of California, Los Angeles

Journals Reviewed
American Journal of Surgical Pathology, Modern Pathology, Histopathology, Human Pathology, American Journal of Clinical Pathology, Journal of Pathology, Archives of Pathology and Laboratory Medicine, Advances in Anatomic Pathology, Hepatology, Journal of Hepatology, Liver Transplantation, Gastroenterology, Gut, Clinical Gastroenterology and Hepatology, Journal of Gastroenterology and Hepatology, American Journal of Gastroenterology

Friday, June 19, 2015

President's Message June 2015

Dear Friends and Colleagues,

I hope everyone is doing well as the 2014-2015 academic year is about to end. Our Companion Meeting that was held during the USCAP Annual Meeting in Boston this past March was well-attended and a great success. We garnered high marks and positive feedback from the attendees. Congratulations are in order to all the speakers for this achievement.

The society membership voted upon the proposed modifications to the HPHS By-Laws during the Business Meeting that immediately followed the Companion Meeting. One of the changes that was approved included formalizing the creation of a Website Committee. Its inaugural chair, Arief Suriawinata, reported that the Interesting Case Series published in both the Newsletter and the HPHS website resulted in a record number of web visits (page views). As an aside, as of today, June 15, 2015, per Arief, there have been 16,742 visits to the website. This huge increase is mainly due to the Case Series that is being made available to the general public.

This Case Series section would not have been possible without the Education Committee’s dedication and resolve to generate interesting cases under the leadership of Oyedele Adeyi and the section editor, Cynthia Guy. In addition to the Cases, a new section, Journal Watch, was proposed by Dele Adeyi, which the Exec Com approved today. This will commence in the next issue of the Newsletter. This tremendous accomplishment is giving greater visibility to liver pathology and our Society. This Newsletter would not be possible without the Newsletter Committee chaired by Bita Naini and its very active members, Steve Ward, Erin Rubin and Cynthia Behling, who have worked very hard to keep this Newsletter coming out on a regular basis.

The Membership Committee members chaired by Maha Guindi were kept busy as the USCAP meeting was approaching because applications for membership were at an all-time high this year. A total of 22 were approved for membership (11 regular, 10 associate and 1 international). The By-Laws were also modified to include deliberations for membership to occur quarterly or even on a rolling basis as the need arises. This will hopefully result in keeping a potential member to be interested in the society and not wait for several months before a decision is made.

The HPHS was involved in putting together the liver pathology program at the Asia Pacific International Academy of Pathology that was held in Brisbane two weeks ago. The speakers included Yoh Zen, Yasuni Nakanuma, Young-Nyun Park, Andrew Clouston and Anthony Chan. This was also a successful meeting.

I am lucky to have the help and counsel from the other members of the Executive Committee: Michael Torbenson (incoming President), Matthew Yeh (Past President) and Grace Kim (Secretary-Treasurer) who work diligently behind the scenes but equally share in the responsibilities and challenges of keeping our Society flourishing.

The next newsletter will be published in three months and there will be more to come. I wish everyone a great summer.


M. Isabel Fiel, M.D.
Hans Popper Hepatopathology Society

Interesting Case June 2015 #1

Case History: 

A 47 year old man with a past medical history of diabetes, hypertension, and obesity presented with abdominal pain, abdominal distension, and lower extremity swelling. A multiphase MRI of the liver revealed multiple calcified and non-calcified hypoenhancing masses, more confluent in, and involving most of, the right hepatic lobe. Smaller discrete lesions were seen in the left lobe, measuring up to 4.1 cm. The right portal vein showed findings suspicious for tumor thrombus. Needle-core biopsies were performed.

Figure 1: 4x, 1st biopsy core.

Figure 2: 10x, 1st biopsy core.

Figure 3: 20x, 1st biopsy core.

Figure 4: 40x, 1st biopsy core.

Figure 5: 40x, 1st biopsy core.

Figure 6: CD34, 1st biopsy core.

Figure 7: 10x, 2nd biopsy core.

Figure 8: 40x, 2nd biopsy core.

Figure 9: CD34, 2nd biopsy core.

Figure 10: CD34, 2nd biopsy core.
In addition to the CD34 immunohistochemistry (IHC) stain shown, the lesional cells were positive for CD31 and Factor VIII.


Epithelioid Hemangioendothelioma


Epithelioid Hemangioendothelioma (EHE) is a rare, low grade vascular malignancy that was first recognized as a distinct clinicopathologic entity in the early 1980s in the soft tissues and lung. In the latter organ it was originally referred to as intravascular bronchioloalveolar tumor (IVBAT). It is now known to occur in many sites, including the liver.

Its histologic features are quite distinctive in the liver. In hepatic EHE the tumor is often multifocal, with calcifications seen radiographically. They are firm, white to yellow, with ill-defined borders. Tumor cells are both dendritic and epithelioid in various proportions. The spindle cells are irregularly shaped and elongated. Epithelioid cells are rounder with more abundant eosinophilic cytoplasm. Small papillations or tufts of tumor cells may be seen within thin-walled vascular spaces. Abortive vascular differentiation is typically seen, with tumor cell cytoplasm containing a single vacuole representing a capillary luminal space — so-called “blister cells.” Tumor cells lie within a variably myxoid to fibrous stroma. The tumor often infiltrates hepatic vein and portal vein branches, leading to Budd-Chiari syndrome as a possible presentation. The tumor tends to grow around and leave pre-existing hepatic structures intact, particularly at the periphery of tumor nodules. In these areas, only subtle infiltration of tumor cells may be seen within sinusoids, in an otherwise architecturally normal liver, something which can be particularly treacherous in small liver biopsies.

On core biopsy material, the differential diagnosis can be separated into two distinct categories:

  1. the lesion is clearly neoplastic but the histogenesis of the tumor is not obvious
  2. fibrosis vs. EHE.

In the first setting, the lesion is sufficiently cellular and atypical to be clearly neoplastic, and the differential diagnosis often includes carcinomas such as hepatocellular carcinoma, cholangiocarcinoma, or metastatic carcinoma. IHC stains for vascular markers (CD34, CD31, Factor VIII, FLI1), are typically positive in EHEs and negative in carcinomas. Patchy keratin staining can be seen in some tumor cells of EHE, or in entrapped hepatocytes or bile ducts, and care should be taken not to misdiagnose a carcinoma.

In the second setting, the tumor is hypocellular and has a fibrotic stroma, and can closely mimic fibrosis or confluent necrosis with drop-out. In this setting, the tumor can be very difficult to diagnose on limited core biopsy material. One can look for focal areas of greater cytologic atypia, or areas of sinusoidal infiltration of tumor cells. A vascular IHC stain can be helpful to highlight such infiltration, keeping in mind not to misinterpret capillarization of sinusoids, which can be seen in various settings.

The largest series on hepatic EHE is from the AFIP, in which 137 cases were described. It typically occurs in middle-aged adults (though rare cases in children have been reported), with a slight female predominance. It presents with non-specific symptoms such as abdominal pain, nausea and vomiting, hepatosplenomegaly, or as Budd-Chiari syndrome, or as an incidental finding. It is slowly progressive and treated with excision, or transplantation in advanced cases. In this presented case, the patient was immediately referred for liver transplantation. Because the tumor grows so slowly, transplantation can still be performed in the presence of extra-hepatic disease. Overall 5-year survival rate is 43-55%.

More recently, a characteristic translocation has been reported: t(1;3)(p36.3;q25), resulting in a WWTR1-CAMTA1 fusion. This translocation has been shown to occur in the majority of EHEs of various sites, and not in their histologic mimics. A smaller subset of EHEs show a YAP1-TFE3 fusion. A recent study showed a high sensitivity and specificity for a CAMTA1 IHC stain, suggesting its possible utility as a diagnostic marker.


Antonescu CR, et al. Novel YAP1-TFE3 fusion defines a distinct subset of epithelioid hemangioendothelioma. Genes Chromosomes Cancer 2013; 52: 775-784.
Errani C, et al. A Novel WWTR1-CAMTA1 Gene Fusion is a Consistent Abnormality in Epithelioid Hemangioendothelioma of Different Anatomic Sites. Genes Chromosomes Cancer 2011; 50: 644-653.
Makhlouf HR, Ishak KG, Goodman ZD. Epithelioid hemangioendothelioma of the liver: a clinicopathologic study of 137 cases. Cancer 1999; 85: 562-582.
Mehrabi A, et al. Primary malignant hepatic epithelioid hemangioendothelioma: a comprehensive review of the literature with emphasis on surgical therapy. Cancer 2006; 107: 2108-2121.
Shibuya R, et al. CAMTA1 is a useful immunohistochemical marker for diagnosing epithelioid hemangioendothelioma. Histopathology 2015 Apr; doi 10.1111/his.12713.

Contributed by:
Nafis Shafizadeh, MD
Southern California Permanente Medical Group

Woodland Hills Medical Center

Interesting Case June 2015 #2

Case History: 

A 62 year old woman with a history of renal cell carcinoma removed years ago presented with a 2.4 cm liver mass found in CT during follow-up. A partial hepatectomy was performed.

Laboratory values: 

ALT, AST, alkaline phosphatase and bilirubin were normal. There is no prior history of liver disease.

Gross examination of the liver resection: 

Cut section reveals a 2.4 cm circumscribed mass with a gray-brown focally spongy appearance.

Figure 1

Figure 2

Figure 3, CD31 immunohistochemistry

Final diagnosis: 

Hemangioma, anastomosing type.


Hepatic hemangioma is a common benign vascular neoplasm in both infants and adults that shares the same growth pattern and prognosis as its cutaneous counterpart. Based on its distribution, hemangioma can be classified as focal, multifocal, or diffuse.  Most hepatic hemangiomas are of the cavernous type followed by the capillary type. Capillary hemangioma, including lobular capillary hemangioma (also known as pyogenic granuloma) commonly presents on the skin and mucosa, although rare liver or gastrointestinal tract examples have been reported. Capillary hemangioma is composed of a lobular proliferation of vascular channels with plump endothelial cells lining the vascular channels. Anastomosing hemangiomas in the liver, as seen in this case, are rare hepatic vascular neoplasms characterized by an interconnecting sinusoidal-like pattern of tightly packed capillary channels. The tumor appears well circumscribed grossly with a gray-brown focally spongy appearance in the liver. Low-power magnification shows a well-demarcated lesion with lobular architecture in the liver. At higher magnification the tumors consists of anastomosing sinusoidal capillary-sized vessels with scattered hobnail endothelial cells within a framework of non-endothelial supporting cells. No mitotic figures or necrosis are observed. Mild cytologic atypia is appreciated. Immunohistochemical stain for CD31 is diffusely positive.

The primary differential diagnosis of anastomosing hemangioma is angiosarcoma. Angiosarcoma of the liver and gastrointestinal tract is rare and behaves aggressively. The overall survival is poor and patients rapidly develop metastases and usually die within 6–12 months. Accurate diagnosis can be challenging, particularly if the patients have no history of exposure to specific toxins including thorium dioxide, arsenicals, and vinyl chloride monomer. Distinguishing anastomosing hemangioma from a well-differentiated angiosarcoma is challenging especially on small biopsies. Histologically, branching, jagged, slit-like vascular channels with prominent cytological alterations and a diffuse infiltrating border is characteristic of angiosarcoma, in contrast to the sharp demarcation, mild cytological atypia, and lack of mitotic figures in anastomosing hemangioma. The absence of multilayering of endothelial cells, high grade cytologic atypia, and mitotic activity coupled with circumscribed borders favor a benign process. Awareness of this entity and attention to cytological features and the overall lobular architecture are essential to avoid diagnostic errors.

In summary, anastomosing hemangiomas in the liver is a rare entity and leads to concern for angiosarcoma. Awareness of this entity can minimize a misdiagnosis of angiosarcoma and avoid unnecessary aggressive treatment.


1. Kulungowski AM, Alomari AI, Chawla A, Christison-Lagay ER, Fishman SJ. Lessons from a liver hemangioma registry: subtype classification. J Pediatr Surg. Jan 2012;47(1):165-170. 
2. Dickie B, Dasgupta R, Nair R, et al. Spectrum of hepatic hemangiomas: management and outcome. J Pediatr Surg. Jan 2009;44(1):125-133. 
3. Abaalkhail F, Castonguay M, Driman DK, Parfitt J, Marotta P. Lobular capillary hemangioma of the liver. Hepatobiliary Pancreat Dis Int. Jun 2009;8(3):323-325. 
4. Nishiyama N, Mori H, Kobara H, et al. Bleeding duodenal hemangioma: morphological changes and endoscopic mucosal resection. World journal of gastroenterology : WJG. Jun 14 2012;18(22):2872-2876. 
5. Giaccaglia V, Stefanuto A, Cavallotti C, Quintiliani A, Stipa F. Transanal excision of rectal pyogenic granuloma: case report and literature review. Surg Laparosc Endosc Percutan Tech. Apr 2011;21(2):e91-92. 
6. Santos J, Ruiz-Tovar J, Lopez A, Arroyo A, Calpena R. Simultaneous massive low gastrointestinal bleeding and hemoperitoneum caused by a capillary hemangioma in ileocecal valve. International journal of colorectal disease. Oct 2011;26(10):1363-1364. 
7. Nagoya H, Tanaka S, Tatsuguchi A, et al. Rare cause of obscure gastrointestinal bleeding due to pyogenic granuloma in the ileum detected by capsule endoscopy and treated with double balloon endoscopy. Dig Endosc. Jan 2010;22(1):71-73. 
8. Park SY, Park CH, Lee WS, Kim HS, Choi SK, Rew JS. Pyogenic granuloma of the duodenum treated successfully by endoscopic mucosal resection. Gut Liver. Mar 2009;3(1):48-51. 
9. Shibuya T, Osada T, Mitomi H, et al. Jejunal capillary hemangioma treated by using double-balloon endoscopy (with video). Gastrointest Endosc. Sep 2010;72(3):660-661. 
10. Benevento A, Boni L, Dionigi G, Besana Ciani I, Danese E, Dionigi R. Multiple hemangiomas of the appendix and liver. J Am Coll Surg. Nov 2003;197(5):860-861. 
11. Lin J, Bigge J, Ulbright TM, Montgomery E. Anastomosing hemangioma of the liver and gastrointestinal tract: an unusual variant histologically mimicking angiosarcoma. The American journal of surgical pathology. Nov 2013;37(11):1761-1765. 
12. Brown CJ, Falck VG, MacLean A. Angiosarcoma of the colon and rectum: report of a case and review of the literature. Diseases of the colon and rectum. Dec 2004;47(12):2202-2207. 
13. Maluf D, Cotterell A, Clark B, Stravitz T, Kauffman HM, Fisher RA. Hepatic angiosarcoma and liver transplantation: case report and literature review. Transplantation proceedings. Jun 2005;37(5):2195-2199. 
14. Alrenga DP. Primary angiosarcoma of the liver. Review article. Int Surg. Apr 1975;60(4):198-203. 
15. Elliott P, Kleinschmidt I. Angiosarcoma of the liver in Great Britain in proximity to vinyl chloride sites. Occupational and environmental medicine. Jan 1997;54(1):14-18. 
16. Bhati CS, Bhatt AN, Starkey G, Hubscher SG, Bramhall SR. Acute liver failure due to primary angiosarcoma: A Case Report and Review of the Literature. World J of Surg Oncol. 2008;6:104.

Contributed by:
Jingmei Lin, MD, PhD
Department of Pathology and Laboratory Medicine
Indiana University School of Medicine

Friday, March 27, 2015

Congratulations to Winners of 2015 HPHS Trainee Award!

Winner of The 2015 HPHS Best Abstract
Dr. Emily Waterhouse & Dr. David Solomon (UCSF,  faculty sponsor. Linda Ferrell):
Validation of an RT-PCR assay for detection of recurrent DNAJB1-PRKACA fusion transcripts in fibrolamellar hepatocellular carcinoma

Drs. Fiel, Waterhouse, Solomon and Adeyi

First Runner-up Abstract
Dr.  Christos Tsokos,  UCSF (faculty sponsor Gregor Krings):
Telomerase Reverse Transcriptase Promoter Mutations (mTERTp) in Combined Hepatocellular(HCC)-Cholangiocarcinoma(CC; cHCC-CC) Support Clonal and HCC-like Origin for Both Components

Drs. Fiel, Tsokos and Adeyi

Second Runner-up Abstract
Dr. Dana Balitzer,  UCSF (Faculty sponsor -  Sanjay Kakar):
Autoimmune Hepatitis: Review of Validity of Histologic Features Included in the Simplified Criteria Proposed by the International Autoimmune Hepatitis Group (IAIHG)

Drs. Fiel, Balitzer and Adeyi