Thursday, November 30, 2017

HPHS JOURNAL WATCH: September - October 2017

American Journal of Surgical Pathology

The Almost-Normal Liver Biopsy: Presentation, Clinical Associations, and Outcome.
Czeczok TW, Van Arnam JS, Wood LD, et al. Am J Surg Pathol. 2017 Sep;41(9):1247-1253. 

Liver biopsy continues to serve an essential role in evaluating patients with abnormal liver enzymes and/or ascites.  However, a subset of these biopsies can appear almost normal on microscopic exam.  The investigators in this study sought to determine how frequently such almost-normal liver biopsies occur, and the clinical diagnoses associated with these biopsies, including follow-up data.  The frequency of almost-normal liver biopsies was 0.6% and 3.7% at two institutions; 97 patients and 97 total biopsies were included for study, with a median follow-up of 4.3 years (range 0-10 years).  This study determined that in 72% of patients, the most likely cause of abnormal clinical findings could be placed into one of eight categories: systemic autoimmune inflammatory conditions (18%), vascular/ischemic events (13%), metabolic syndrome (11%), drug reactions (8%), inflammatory conditions of the GI tract (7%), chronic liver disease (7%), biliary outflow impairment (3%), or miscellaneous (3%; Turner syndrome or familial Mediterranean fever).  The remaining 28% had no identifiable clinical association even after workup and on follow-up.  The results of this study can help clinicians and pathologists alike in shedding light on potential diagnostic considerations in patients with abnormal liver enzymes and/or ascites, but with nearly normal findings on liver biopsy.

Archives of Pathology and Laboratory Medicine

Practical Immunohistochemistry in Neoplastic Pathology of the Gastrointestinal Tract, Liver, Biliary Tract, and Pancreas
Wang HL, Kim CJ, Koo J, et al. Arch Pathol Lab Med. 2017 Sep;141(9):1155-1180.

This review discusses established and more recent immunohistochemical markers commonly used in daily practice and their diagnostic utility in GI and hepato-pancreato-biliary pathology.


Identification of an Immune-specific Class of Hepatocellular Carcinoma, Based on 
Molecular Features. 
Sia D, Jiao Y, Martinez-Quetglas I,et al. Gastroenterology. 2017;153(3):812-826.

This study determined gene expression pattern of inflammatory cells in HCC from 956 patients and correlated this with immune infiltrates and immune regulatory molecules determined by immunohistochemistry, in a training set of 228 HCC samples. We validated the correlation in a validation set of 728 tumor samples. Markers of inflammatory response were observed in 25% of HCCs with high expression of CD274 (PDL-1); these tumors had fewer chromosomal abnormalities. This category was labeled as ‘Immune class’ and had 2 subtypes: adaptive T-cell response group and exhausted immune response group. The latter was associated with expression of genes regulated by TGF-β1. There was no difference in numbers of mutations in the ‘Immune class’ compared to other HCCs. The authors speculate that agents that block regulatory pathways in T cells such as inhibitors of PDL-1 and TGF-β1 may be effective for ‘Immune class’ HCCs.

Risk of Hepatocellular Cancer in HCV Patients Treated With Direct-Acting Antiviral Agents. 
Kanwal F, Kramer J, Asch SM, et al. Gastroenterology. 2017;153(4):996-1005.

This is a retrospective study of 22,500 hepatitis C virus patients treated with DAA in 2015 (SVR 19,518; no SVR 2982). There were 271 new cases of HCC, of which 183 occurred in the setting of SVR. The risk of HCC was significantly lower with SVR (adjusted hazard ratio, 0.28, 95% CI=0.22-0.36), with highest incidence in cirrhosis cases after SVR compared to those without cirrhosis (adjusted hazard ratio, 4.73. 95% CI, 3.34-6.68).  Majority of HCC were stage 1 and less than 5 cm. The authors conclude that SVR reduces risk of HCC, and that DAA therapy does not increase risk of HCC. The risk of HCC remains high in cirrhosis cases, and ongoing surveillance is required. 

Risk for Hepatocellular Carcinoma After Hepatitis C Virus Antiviral Therapy With Direct-Acting Antivirals: Case Closed? (Editorial)
Maan R, Feld JJ. Gastroenterology. 2017 Oct;153(4):890-892.

The accompanying editorial is a nice discussion of the controversy about increased risk of HCC in hepatitis C patients treated with DAA agents. Contrary to early reports, data from 3 prospective French cohorts did not find an increase in HCC recurrence in patients with SVR and this studies supports these findings. There have been reports that HCC arising after DAA therapy are more aggressive, multifocal and clinically advanced. This study does not support these conclusions. 

Human Pathology

Histopathological evidence of neoplastic progression of von Meyenburg complex to intrahepatic cholangiocarcinoma.
Bhalla A, Mann SA, Chen S, et al. Hum Pathol. 2017;67:217-224.

The preneoplastic potential of Von Meyenburg complex (VMC) for intrahepatic cholangiocarcinoma (ICC) has been reported but remains controversial. This is a retrospective study of 86 resected cases of ICC. A morphologic association between VMC and ICC was observed in 35% of cases: VMC with low-grade biliary dysplasia in 24 cases and high-grade biliary dysplasia in 13 cases. The evolution was also supported by Ki67 and p53 immunostains. ICC associated with VMC had favorable histologic features such as small size, well to moderately differentiation, anastomosing glandular architecture, ductal carcinoma in situ–like growth pattern, peritumoral lymphocytic infiltrate, central fibrous scar, complete pushing border and low stage (T1). 


Systematic review of bariatric surgery liver biopsies clarifies the natural history of liver disease in patients with severe obesity.
Bedossa P, Tordjman J, Aron-Wisnewsky J, et al. Gut 2017;66:1688-1696. 

The authors analyzed 798 consecutive liver biopsies from patients undergoing morbid obesity surgery.  Histologic features were correlated with clinical, biological, anthropometrical, and body composition characteristics.  Patients who had normal liver biopsies tended to be significantly younger and had a different distribution of fat compared to those with steatosis and NASH (more peripheral and less truncal fat).  The presence of truncal fat correlated with severity of histologic disease.  Adipocyte size also correlated with liver disease, but only in females. The difference in fat distribution was not related to duration of obesity as this was similar across age groups (younger individual tended to have an earlier age of onset of obesity).  The authors conclude that young obese individual tend to store fat in subcutaneous tissues.  It is the shift of fat to visceral adipose tissue that correlates with liver damage.

Clinical Gastroenterology and Hepatology

Features and Treatment of Dapsone-Induced Hepatitis, Based on Analysis of 44 Cases and Literature Review
Devarbhavi H, Raj S, Joseph T, et al. Clin Gastroenterol Hepatol 2017;15:1805–1807.

Dapsone-induced hepatitis accounted for 5.2% of drug induced liver injury cases (44 cases among 850) in this study. The average length of treatment prior to onset of liver injury was approximately 34 days. Almost all of the patients also had skin rashes, fever, lymphadenopathy and eosinophilia. More than half also had jaundice. The liver injury pattern was mixed hepatitic/cholestatic in almost half of the cases, followed by hepatitic in 34%, and cholestatic in 16%. Acute liver failure occurred in 16%. 14% of patients died. In a literature review, liver was found to be the most common organ besides the skin to be affected by dapsone hypersensitivity syndrome. Latency period between treatment and dapsone induced hepatitis had a range of 7-150 days, with an average of 32 days. Hence, dapsone induced hepatitis occurs within the first month of therapy with a mixed hepatitic/cholestatic pattern of injury. Steroid treatment leads to lower mortality. 

Liver and Cardiovascular Damage in Patients With Lean Nonalcoholic Fatty Liver Disease, and Association With Visceral Obesity
Fracanzani AL, Petta S, Lombardi R, et al. Clin Gastroenterol Hepatol 2017;15:1604–1611.

Patients with BMI <25 who have non-alcoholic fatty liver disease are categorized as having “Lean NAFLD”. This study evaluated 143 “Lean NAFLD” Caucasian patients, including histology using classification from Kleiner, Brunt, et al. (Hepatology 2005;41:1313–1321). This group tended to be younger than NAFLD patients with BMI greater than 25. Having a waist circumference >102 cm for males or >88 cm for females was associated with a higher likelihood of having fibrosis score ≥2, among other factors, including diabetes and hypertension. 17% of the lean NAFLD group had severe liver disease, defined as having NASH and fibrosis score 2 or higher. Having GG PNPLA3 polymorphism was the only independent variable associated with NASH and significant fibrosis. A significantly higher prevalence of carriers of the TM6SF2 E167K variant was also found in the lean NAFLD patients. This variant is reported to be associated with decreased secretion of very-low-density lipoproteins, lower circulating lipids, more severe steatosis, inflammation, and NASH.


Uncommon Extrahepatic Metastases From Hepatocellular Carcinoma

Florimonte L, Iavarone M, Castellani M, et al. Hepatology 2017; 66(3): 986-988.

The authors report a case of a 56 year-old man with HBV-cirrhosis and multifocal HCC who underwent transplantation after downstaging of disease with radiofrequency ablation. Explant histology demonstrated residual disease with vascular invasion and six Edmondson grade 2 satellite nodules. Fifteen months post-transplant, the patient developed biopsy-proven metastases in the right ventricle and gluteus muscle, picked up by PET/CT scan. The authors suggest the utility of PET scan to pick-up distant metastasis in patients with high-risk features such as theirs: vascular invasion and multiple satellite nodules.

Regression of Hepatocellular Adenomas and Systemic Inflammatory Syndrome After Cessation of Estrogen Therapy
Sinclair M, Schelleman A, Sandhu D, et al. Hepatology 2017; 66(3): 989-991.

The authors report a case of a 43 year-old woman on OCPs who presented with generalized abdominal discomfort, debilitating fatigue, malaise, intermittent night sweats, and arthralgias. She was found to have an elevated ESR at 100 mm/hour, and an elevated C-reactive protein at 45 mg/L. MRI demonstrated multiple arterially enhancing liver lesions most consistent with hepatic adenomas, the largest of which was 8.5 cm. Biopsy was not performed. A diagnosis of adenoma-driven systemic inflammation was considered. OCP was discontinued. There was a steady decline in inflammatory makers and decrease in size of the liver lesions. Four years after OCP cessation, systemic symptoms had resolved, inflammatory markers had normalized, and the largest adenoma had shrunk to 4.2 cm. Although no biopsy was done, the authors suggest that the case represents another rare example of a systemic inflammatory syndrome associated with inflammatory-type hepatic adenoma (IHA), a syndrome believed to be associated with the interleukin-6 (IL-6) pathway activating mutations characteristic of such tumors.

Journal of Hepatology

Visualization of hepatitis E virus RNA and proteins in the human liver
Lenggenhager D, Gouttenoire J, Malehmir , et al. J Hepatol. 2017 (67); 471-479.

A panel of 12 commercially available antibodies against HEV open reading frame (ORF) 1-3 proteins were evaluated for immunohistochemistry (IHC) and two probes for in situ hybridization (ISH) in human FFPE tissues and HuH7 cells. ORF2 protein was detectable in both HEV protein expression cells and liver tissues of patients with hepatitis E. IHC for ORF2 revealed a patchy cytoplasmic, canalicular, and nuclear staining in liver specimens. Positive ORF2 IHC for HEV ORF2 protein in individual hepatocytes correlated with the detection of HEV RNA by ISH. The sensitivity and specificity of ORF2 IHC is comparable with HEV PCR.  ORF2 protein can be visualized in the liver of patients with hepatitis E. ORF2 IHC may be used to detect HEV in FFPE samples.

Histological subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour classification. 
Calderaro J, Couchy G, Imbeaud S, et al. J Hepatol. 2017 (67); 727-738. 

The correlation of phenotype with molecular features was investigated in 343 surgically resected HCC samples by pathological review, immunohistochemistry, gene expression profiling and sequencing. CTNNB1 mutations (40%) define a specific cholestatic well-differentiated subtype of HCC associated with Wnt/β-catenin activation. TP53 mutated HCC (21%) are poorly differentiated, highly proliferative and macrotrabecular-massive, and exhibited PI3K/AKT pathway activation. The scirrhous HCC subtype was characterized by TSC1/TSC2 mutation, lack of CTNNB1 mutations, and CK19 expression. The steatohepatitic subtype showed frequent IL-6/JAK/STAT activation without CTNNB1, TERT and TP53 pathway alterations.  A novel macrotrabecular-massive subtype of HCC (MTM-HCC) was identified during the pathological review characterized by a predominant (>50%) macrotrabecular growth pattern, more frequent in HBV infected patients, high AFP serum levels, histological features of aggressiveness (satellite nodules, macrovascular and microvascular invasion), and frequent TP53 mutations and FGF19 amplifications. Finally, integration of clinical, genetic, and pathological features showed phenotypically distinct tumour subclasses closely related to G1-G6 subgroups. 


Detection of Viral Hepatitis E in Clinical Liver Biopsies
Prost S, Crossan CL, Dalton HR, et al. Histopathology 2017 Oct;71:580-590.

Using in-situ hybridization and qPCR the authors examined 36 FFPE liver biopsies from 29 patients infected with viral hepatitis E. A brief review of hepatitis E virus (HEV) clinicopathologic findings is provided. The authors conclude that qPCR is more effective than in-situ RNA testing.

Mucinous Cystic Neoplasms of the Liver and Pancreas: Relationship between KRAS Driver Mutations and Disease Progression
Fujikura K, Akita M, Abe-Suzuki S, et al. Histopathology 2017 Oct;71:591-600.

Twenty five cases of mucinous cystic neoplasm (MCN) were sequenced for KRAS, GNAS, RNF43 and PIK3CA, including 17 MCN of the pancreas (MCN-P) and 8 MCN of the liver (MCN-L).  The molecular findings were correlated with the clinicopathologic features and immunohistochemistry findings. KRAS mutations were rare in MCNs with low grade dysplasia (5%), but were often detected in higher grade tumors (80%). The authors conclude that KRAS mutations appear to be major oncogenic drivers in both MCN-P and MCN-L. Within an individual case, an identical KRAS mutation was detected within the low grade and high grade dysplastic areas. The authors postulate that KRAS mutations within low grade dysplasia may lead to tumor progression, and preoperative testing could potentially contribute to patient management.

Liver Transplantation 

Dropout Rate from the Liver Transplant Waiting List Because of Hepatocellular Carcinoma Progression in Hepatitis C Virus-Infected Patients Treated with Direct-Acting Antivirals
Zanetto A, Shalaby S, Vitale A, et al. Liver Transplantation. 2017 Sept;23:1103-1112.

As background information: Interferon-based therapies for HCV reduced the risk of HCC recurrence in patients who achieved a sustained virologic response (SVR).  Direct-acting antiviral (DAA)-based therapy has markedly increased the number of HCV patients who can achieve SVR, improves hepatocellular function and decreases the need for liver transplantation, however, questions remain whether DAAs are effective in the tertiary prevention of HCV-related HCC following definitive therapy of the tumor. 
This paper compared 23 patients with HCV-related HCC treated with DAAs and 23 HCV-HCC controls listed for liver transplantation, with a median follow up of 10 and 7 months, respectively. Although the cohorts were small and the follow up time short, the authors concluded that viral eradication using DAAs does not seem to be associated with an increased risk of dropout due to neoplastic progression in HCV-HCC patients awaiting LT.  

Determination of Hepatocellular Carcinoma Grade by Needle Biopsy is Unreliable for Liver Transplantation Candidate Selection
Court CM, Harlander-Locke MP, Markovic D, et al. Liver Transplantation. 2017 Sept;23:1123-1132.

This retrospective analysis included 965 patients undergoing liver transplantation for HCC over a >25 year period. Of those, 234 (24%) patients underwent preoperative needle biopsy (PNB) at a median of 280 days prior to transplantation. Grade of HCC in PNB had poor concordance to the final explant pathology HCC grade (κ = 0.22; p = 0.003), and low sensitivity (29%) and positive predictive value (35%) for identifying poorly differentiated tumors. Vascular invasion was predicted by explant pathologic grade (p < 0.001) but not PNB grade (p = 0.5). The final conclusions of this manuscript were that incorporation of PNB of HCC to guide transplant candidate selection appears unjustified.

Liver Transplantation (October edition).

This Supplemental Issue focused on Maximizing the Allograft Function. There are 3 sections: (1) Impact of Donors, (2) Allograft in the Peri-operative Period, and (3) Post Transplant Allograft Struggles. Although none of the papers are specifically focused on histopathology, each manuscript has high general knowledge value and is recommended reading for liver pathologists who sign out transplant cases.

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

Saturday, September 23, 2017

President's Message September 2017

Dear Friends and Colleagues:

In this president’s message we will consider one of the major functions of the office of the President—organizing the Hans Popper Hepatopathology companion meeting.

The President proposes topics and speakers to the Executive Committee, who provide feedback and additional suggestions before the agenda is finalized.  The topics are usually organized around a central theme.  For 2018, the theme will be Major challenges in liver pathology, with topics selected because they pose ongoing challenges, even to those with a lot of experience in diagnostic liver pathology.  Speakers are chosen because they have demonstrable expertise by way of experience and publications.  In many cases, there are multiple excellent speaker candidates, so other factors might be considered, such as geographic variation and if/when an individual spoke at the last Hans Popper companion meeting.  With the new SOPs, we try to hear a wider range of expert voices, selecting whenever possible speakers who have not given talks at the companion within the last three years.  Is there a topic you would be interested in?  Feel free to propose a topic or speaker by sending an email to the president.

Many of the speakers attend the annual Hans Popper Reception, which takes place on Saturday night before the companion meeting, and this is a great place to meet them informally. They are fun and interesting people!  If you get the chance, please take the opportunity to thank the speakers.  They do not receive honorarium or travel expenses with the new SOPs, but agree to speak because of their interest, expertise, and passion for liver pathology.

In the table below are the topics and speakers for the 2018 meeting.  I believe it will be an excellent session and hope you can attend.  

Please don’t forget to mark your calendars for the Hans Popper Reception in Vancouver (Saturday night)—location will be announced later.

Finally, at the reception we raffle off a handful of liver pathology books.  If you would like to donate a book, please send me an email (and the book) and I will get it to the reception.  It can be a book you wrote, or even one that you like a lot and think it would be a good addition to the raffle.


Michael Torbenson, MD
President, Hans Popper Society

HPHS JOURNAL WATCH: July - August 2017


De Marco L, Pellicano R. Gastroenterology. 2017 Jul;153(1):327.

This communication is in response to an article published by Elmasry et al (Gastroenterology 2017)regarding elevated ALT levels in patients with occult hepatitis C virus (HCV) infection (OCI) who had achieved sustained virologic response (SVR), after therapy with direct-acting antiviral (DAA). The authors point out 3 forms of OCI: (1) Undetectable HCV-RNA in serum and normal transaminases, but positive HCV-RNA in peripheral blood mononuclear cells or liver, (2) HCV-RNA undetectable in serum and persistent elevation of transaminases. In the study by Elmasry et al, 9 cases with SVR and elevated ALT had OCI, which led to the suggestion that these patients should receive additional antiviral therapy. IN this communication, the authors emphasize that evaluation for OCI and possibly additional treatment should also be considered for patients who have been treated for HCV prior to liver transplantation, and this can potentially reduce recurrent hepatitis C in the allograft liver. These reports to not mention liver histology, but the increasing recognition of OCI is interesting as persistent inflammation in the liver has been reported in many studies after SVR for hepatitis C. The correlation of histology with OCI is not fully understood as inflammatory changes are seen more often than detection of HCV-RNA in liver.

American Journal of Gastroenterology

Bugianese, E, et al. Am J Gastroenterol 2017;112:1277-1286.

The authors analyzed 288 consecutive Caucasian Italian overweight/obese children to determine any associations between clinical parameters and histologic features.  12.2% of this cohort was small for gestational age and this was associated with severe steatosis, portal inflammation, and NAS score ≥5.  Lobular inflammation and ballooning were similar between groups.  Children who were large for gestational age were more likely to have type 1 NAFLD (steatosis, ballooning, and/or perisinusoidal fibrosis without portal inflammation or periportal fibrosis) compared to children who were small for gestational age or appropriate for gestational age.

Journal of Hepatology

Urban TJ, Nicoletti P, et al. J Hepatol. 2017 (67); 137-144.

Minocycline drug-induced liver injury (DILI) can present with prominent autoimmune features. To determine the genetic characters of minocycline DILI, the authors studied 25 Caucasian patients with genome-wide genotyping and compared to unexposed population controls. HLA-B35:02 was identified as a potential genetic risk factor for minocycline DILI: 16% carrier rate in DILI compared to 0.6% in population control. This data was confirmed with sequence based genotyping. In addition, HLA docking study suggested that minocycline had the potential to bind HLA-B*35:02 antigen binding cleft. HLA-B35:02 may be useful diagnostic maker of minocycline DILI.

Patouraux S, Rousseau D, et al. J Hepatol. 2017 (67); 328-338.

The roles of CD44 in hepatic inflammation and fibrosis were studied in a mouse model of steatohepatitis and human tissues. Compared to wild type mice on methionine- and choline deficient diet (MCDD), CD44-/- mice showed significantly less liver inflammatory infiltrates (macrophages and neutrophils), CCL2/CCR2 expression, hepatocyte injury and fibrosis.  CD44 silencing strongly enhanced M2 macrophage polarization and decreased the expression of pro-inflammatory cytokines such as IL-6 and TNFα. Neutralization of CD44 corrected hepatic inflammation and liver injury induced by MCDD. In obesity patients, hepatic CD44 expression was upregulated and strongly correlated with macrophage recruitment and markers of inflammation including TNFα, IL1β, MCP1 and CCR2. Correction of NASH with Bariatric surgery was associated with less hepatic CD44 positive cells. Serum levels of CD44 increased with the severity of steatosis and NAFLD. The study suggests CD44 is a key player in NASH and a potential therapeutic target.

American Journal of Pathology
Labgaa I, Stueck A, Ward S. American Journal of Pathology 2017; 187(7): 1438-1444.

This is an excellent review and summary of the literature on both lymphoepithelioma-like hepatocellular carcinoma and lymphoepithelioma-like cholangiocarcinoma.

American Journal of Surgical Pathology

Yang Z, Klimstra DS, Hruban RH, Tang LH. Am J Surg Pathol. 2017 Jul;41(7):915-922.

The treatment of neuroendocrine tumors (NETs) can differ depending on the primary site of the tumor.  Therefore, identifying the site of origin for metastatic NETs can be important.  In patients with distant metastases, the liver is the most common site to be involved.  The authors compiled 85 cases of metastatic well-differentiated NETs to the liver and assessed the effectiveness of a panel of immunostains (TTF1, CDX2, ISL1, NKX2.2, PDX1) in predicting the site of origin.  Tissue from microarrays (42 cases) and whole sections (43 cases) were used in this study that included NETs from the pancreas (35%), small bowel (32%), rectum (8%), stomach (2%), bile duct (1%), lung (9%), and unknown origin (12%); the sites of origin were determined based on previous or concurrent pathologic specimens in 74% and the remainder were based on radiologic findings or clinical history.  The use of a 3-marker panel composed of TTF1, CDX2, and ISL1 gave a sensitivity of 63-89%, specificity of 94-100%, positive predictive value of 89-100%, and a negative predictive value of 84-96% in differentiating among sites of origin when grouped as small bowel, lung, and pancreas/rectum.  In examining the 12% of tumors of unknown origin, over half of the cases showed staining for at least one of these 3 markers and was suggestive of small bowel or pancreas/rectum as the primary site.  In conclusion, the authors propose using this 3-marker panel along with any clinical findings for predicting the site of origin of well-differentiated NETs to the liver.  NKX2.2 and PDX1 did not add any additional information regarding site of origin when used in conjunction with the proposed 3-marker panel. 

Clinical Gastroenterology and Hepatology

Freeman AJ, Ng VL, Harpavat S, et al. Clin Gastroenterol Hepatol. 2017 Jul;15(7):1133-1135.

The authors evaluate the utility of gamma glutamyltransferase (GGT) as a potential marker of disease progression for patients affected by biliary atresia who survive without liver transplant. Thrombocytopenia is a recognized surrogate marker for disease progression and portal hypertension. The authors find that a GGT level ≥100 U/L at 2 years of age correlated with progressive decline in platelet counts at 4, 5, and 6 years of age. In comparison, having a GGT level < 100 U/L predicted a low risk of developing subsequent thrombocytopenia. The potential ramifications of this finding is that GGT levels obtained at age 2 may predict the development of thrombocytopenia, a feature of portal hypertension. If these findings are validated with further long term studies, such patients may need additional monitoring or closer follow up in consideration of therapeutic intervention.

Jacobson IM, Washington MK, Buti M, et al. Clin Gastroenterol Hepatol. 2017 Jul;15(7):1087-1094.e2.

Some chronic hepatitis B patients continue to have abnormal levels of alanine aminotransferase (ALT) despite antiviral therapy. This study of chronic hepatitis B patients treated with tenofovir showed 18% to continue to have increased ALT level at year 5, despite long term tenofovir disoproxil fumarate treatment. Grade 1 steatosis (34% to <66%), pretreatment HBeAg seropositivity, and younger age were the main factors associated with increased ALT at year 5. Compared to patients who achieve normalized ALT levels (n=384), those with persistently elevated ALT (n=18) were less likely to achieve virologic suppression and less likely to have cirrhosis regression at year 5 (80% vs 47%). In addition, in the group with persistently elevated ALT, HBeAg+ patients with steatosis on baseline biopsy had a higher frequency of progressing in steatosis over 5 years. The correlation between ALT abnormality and steatosis was not related to PNPLA3 genotype status.

Whitcomb E, Choi W, Jerome K, et al. Clin Gastroenterol Hepatol. 2017 Aug;15(8):1279-1285.

Hepatitis C infection is now curable, as defined by the absence of detectable serum HCV RNA after treatment completion. This study evaluated liver biopsies from patients who received liver transplant for chronic hepatitis C. Even after sustained virologic response (SVR) to antiviral therapy, ~70% of liver biopsies showed histologic features of active HCV infection, posing a potential pitfall of misdiagnosis to pathologists unaware of treatment status. PCR results, however, were negative for HCV in the liver tissue after sustained virological response, despite the histologic findings of hepatitis C infection. Of interest, approximately 30% of the patients had an increase in fibrosis stage in subsequent biopsy. This study characterizes the persistent histologic features of HCV in post-SVR allograft liver biopsies, although PCR is negative for hepatitis C virus in the tissue. Pathologists should avoid incorrect diagnosis of recurrent or persistent HCV in these patients who have completed therapy successfully. Nevertheless, the progression of fibrosis in a subset of these patients raises the question of what may be causing increase in disease stage, whether it be low but undetectable levels of persistent virus or other mechanisms such as idiopathic post-transplant hepatitis.


Kim YJ, Rhee H, Yoo JE, et al. Histopathology. 2017 Aug;71(2):217-226.

The authors use immunohistochemistry including keratins and markers of stemness (K19, K7, EpCAM, and NCAM), inflammation and inflammatory signaling (CD163, CD68, and pSTAT3), proliferation (Ki-67), and fibroblast activation protein (FAP) to mark cancer-associated fibroblasts (CAFs) on 17 scirrhous HCCs and 6 fibrolamellar carcinomas to evaluate differences in the supporting stroma/tumor microenvironment.

Liver Transplantation

Bajaj JS, Fagan A, Sikaroodi M et al. Liver Transpl. 2017 Jul;23(7):907-914.

The effects of liver transplantation on the gut microbial composition were evaluated and correlated with cognitive function and health-related quality of life measures in patients with cirrhosis.

Perito ER, Vase T, Ramachandran R et al. Liver Transpl. 2017 Jul;23(7):957-967.

The prevalence, persistence and association of post-transplant steatosis and chronic liver damage were evaluated in children in this single center study with long-term follow up.

Kasahara M, Sakamoto S, Sasaki K et al. Liver Transpl. 2017 Aug;23(8):1051-1057.

In this study, the authors report their experience with 12 children <3 months of age who underwent liver transplantation at a single center. The overall cumulative 10-year patient and graft survival rates were both excellent at 90.9%.

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

Interesting Case September 2017

Clinical History:
The patient is a 27-year-old male with a history of right lower extremity osteosarcoma, status post above-knee amputation and chemotherapy that resulted in severe cardiomyopathy requiring a cardiac transplant.  Subsequently, he developed monomorphic post-transplant lymphoproliferative disorder (PTLD), diffuse large B-cell type, involving the GI tract, bone, and lymph nodes which had been in remission for the past 4 years. He was also being followed for a small lesion in the left lobe of the liver. He presented to the hospital for acute onset of jaundice with a peak bilirubin of 10.0. Due to concern for a recurrence of PTLD, a biopsy of the liver lesion was performed.

Imaging Findings:
MRI of the abdomen initially demonstrated a T2 hyperintense round lesion (1.0 cm) with thin peripheral enhancement. A CT abdomen performed a year later showed that the lesion had slowly increased in size measuring 1.7 x 1.4 x 1.4 cm. The findings were nonspecific and a wide clinical differential was considered, including a simple cyst, infection, metastatic disease, and PTLD.

Figure 1: H&E 100x 
Figure 2: H&E 200x

Figure 3: Smooth muscle actin 100x

Figure 4: Desmin 100x

Figure 5: EBER 100x

Liver Biopsy Findings:
The liver biopsy showed spindled tumor cells arranged in short intersecting fascicles. The tumor cells were bland, demonstrating elongated nuclei with blunted ends and abundant eosinophilic cytoplasm. No significant cytologic atypia was identified. Mitotic activity and tumor necrosis were not conspicuous. The background liver was unremarkable.
Immunohistochemical stains demonstrated that tumor cells were diffusely positive for smooth muscle actin (SMA) and patchy positive for desmin. In situ hybridization for Epstein-Barr virus encoded RNA (EBER) was strongly and diffusely positive in the tumor cells. 

EBV-associated smooth muscle tumor

Epstein-Barr virus (EBV)-associated smooth muscle tumor is a rare neoplasm that is most commonly seen in immunocompromised patients, including those with organ transplants, HIV/AIDS, and congenital immunodeficiency1. The lesions can involve a variety of anatomic sites and multifocal tumors are thought to be due to multiple infections rather than metastatic disease2. In post-transplant recipients, the most common locations of tumor occurrence are the liver, lungs, larynx, pharynx, gastrointestinal tract, spleen, kidneys and central nervous system.  Histopathologic features may vary in terms of cellular atypia, mitotic activity, and necrosis, however unlike conventional smooth muscle tumors, these features do not correlate well with tumor behavior.
Local surgical resection, reduced immunosuppression, and chemotherapeutic approaches have been used in the treatment of these tumors. Most patients succumb to infectious complications or underlying disease rather than tumor progression, however HIV associated tumors and tumors of the CNS have been reported to have the worst prognoses. 
Histologic features
The histologic features of these tumors include spindled cells arranged in fascicles. Tumor cells have eosinophilic cytoplasm with elongated, blunt-ended nuclei. Two unique histologic features have been described, which include a variable number of intratumoral lymphocytes and occasional primitive round cell areas. Histopathologic features may vary in terms of cellular atypia, mitotic activity, and necrosis. 
Ancillary testing
The critical ancillary diagnostic finding is positive in situ hybridization for EBER. The tumor cells are positive for SMA and may be positive for desmin. They are negative for S100, HMB45, CD34, CD117, and HHV-8. 
Differential diagnosis
These tumors demonstrate a relatively bland spindle cell proliferation, and the morphologic differential diagnosis includes mesenchymal tumors such as solitary fibrous tumor, leiomyoma, schwannoma, neurofibroma, angiomyolipoma, gastrointestinal stromal tumor, and inflammatory myofibroblastic tumor3.  Due to the patient’s clinical history of post-organ transplant immunosuppression, Kaposi sarcoma and mycobacterial spindle cell pseudotumor may also be considered. In this case, the tumor cells were diffusely and strongly positive for EBER and SMA, which confirmed the diagnosis. 
In conclusion, EBV-associated smooth muscle tumor is a rare lesion that can occur in the liver of immunocompromised patients. In situ hybridization for EBER confirms the diagnosis. The patient has undergone partial left liver resection of the lesion and is currently doing well. His hyperbilirubinemia resolved without elucidation of a definitive etiology, but it was thought not to be related to the tumor.

1. Dekate J, Chetty R. Epstein-Barr virus-associated smooth muscle tumor. Arch Pathol Lab Med. 2016;140(7):718-22.
2. Deyrup AT, Lee VK, Hill CE, et al. Epstein-Barr virus-associated smooth muscle tumors are distinctive mesenchymal tumors reflecting multiple infection events: a clinicopathologic and molecular analysis of 29 tumors from 19 patients. Am J Surg Pathol. 2006;30(1):75-82.
3. Burt A, Portman B, Ferrell L. MacSween’s Pathology of the Liver. 6th ed. Edinburgh: Churchill Livingston Elsevier; 2012. Chapter 14, Tumours and tumour-like lesions of the liver; p. 818-819.

This case was submitted by:
Katherine E. Boylan, MD, Resident, Department of Pathology, University of Utah, Salt Lake City, UT
Mazdak Khalighi, MD, Assistant Professor, Department of Pathology, University of Utah, Salt Lake City, UT
Eric Swanson, MD,  Assistant Professor,  Department of Pathology, University of Utah, Salt Lake City, UT

Wednesday, September 6, 2017

In Memoriam Lina Popper

Lina Popper passed away on August 15, 2017 in her Manhattan home at age 100. She was the wife of the eminent physician Dr. Hans Popper, the pathologist who is credited with originating modern liver research and who was a founder and the first academic dean of Mount Sinai Hospital's Medical School, now the Icahn School of Medicine at Mount Sinai. Long revered in the medical community, Lina traveled with her husband to medical meetings all over the world and was a constant and respected presence in the research community long after his 1988 death. She was born in Vienna, Austria to Paul Billig and Rosa Dym Billig on July 4, 1917. She fled the Nazis in 1938 for Chicago. There she met and married Hans, a fellow Viennese immigrant. She was President of the local PTA every year their children were in school in Chicago. They moved in 1957 to New York City, where she lived the rest of her life. She was an early volunteer at the Transplant Living Center at Mount Sinai. Her love of the arts made her a strong supporter and patron of New York's cultural offerings, including opera, classical music, art, education, environmental issues, and Jewish activities. Her day was never complete until she had attended a cultural event with a friend, and she finished The New York Times crossword puzzles every day in pen well into her 90's. Her loving family survives: sons Frank, a Rutgers University and Princeton University professor of city planning, and Charles, a psychiatrist at McLean Hospital and Harvard University Medical School; daughter-in-law and partner Deborah Popper and Leland Perry; grandchildren Joanna and Nicholas, married to Amy Haley; and great- grandchildren Hazel and Celia. The family would appreciate donations to the Visiting Doctors Program at Mount Sinai, a valuable service that provided medical care for Lina at home in the final years.

Wednesday, August 16, 2017

GI/Liver Pathology Fellowship

University of California, Davis School of Medicine (Sacramento, CA)

The University of California, Davis, Department of Pathology and Laboratory Medicine is seeking candidates for its non-ACGME-certified Surgical Pathology Fellowship for the 2018-19 and 2019-2020 academic years.  Sub-specialty emphasis in either GI or GYN pathology is available (limited to one each per year).

UC Davis offers a one-year Surgical Pathology fellowship program which is designed to prepare the fellow as a diagnostic expert in the interpretation of surgical pathology specimens. Expertise will include; intra-operative consultations (frozen section interpretation), gross examination, biopsy diagnosis/interpretation and appropriate work-up of cancer resections. The fellow in Surgical Pathology will develop an analytical approach to diagnoses, which include the appropriate use of ancillary techniques  (electron microscopy, immunohistochemistry and molecular pathology). Training in this program will encompass consultation to health care staff, residents, pathologists and clinicians including tumor boards and other conferences. Participation in a research project, or in a LEAN/ CQI project is expected. The fellow will also participate in departmental teaching activities for residents and medical students. At completion, the successful fellow should be able to demonstrate the knowledge, poise, maturity and communication skills to effectively function at the level of junior staff/faculty.

The Program Director will select from resident applicants who have preferably had four or more years of training with two years anatomic pathology and two years clinical pathology experience.  Completed applications consist of the following and must be free of gaps of time, whether professional or personal: CV/Resume/CAP standardized form; personal statement, three letters of recommendation (one must be from your Residency Program Director), please address to John Bishop, M.D., Director, Surgical Pathology Fellowship; and your letter of interest or intent. Applicants must be licensed in California in the spring prior to their start date.  Please submit application materials to Residency & Fellowship Program Coordinator, Anna Gutierrez at

For additional information, please visit our website at  

John W. Bishop, M.D.
HSC Professor of Pathology and Vice Chair for Clinical Services
UCDMC Pathology
4400 V St, Suite 1116
Sacramento, CA 95817