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.