Thursday, May 23, 2019

HPHS Journal Watch: March/April 2019

American Journal of Surgical Pathology

Cholangiolocellular Carcinoma With “Ductal Plate Malformation” Pattern May Be Characterized by ARID1A Genetic Alterations
Sasaki M, Sato Y, Nakanuma Y. Am J Surg Pathol. 2019 Mar;43(3):352-360.

This study evaluated a number of genes for mutations and defects in protein expression in 77 primary liver tumors with a cholangiolocellular carcinoma (CLC) component. Tumors were further subdivided for analysis based on their proportion of a CLC component. The degree of ductal plate malformation (DPM) growth pattern in each tumor was also scored to determine any association with genetic alterations. The investigators found that loss of ARID1A expression was present in 20.8% of tumors with a CLC component and was seen more frequently in tumors with a higher proportion of a CLC component; 68.8% of this subset showed an extensive DPM-pattern. These findings suggest differences in CLC and provide data to support the possibility of molecular-morphologic classification of primary liver tumors in the future. More detailed information on additional genetic mutations and associations with morphologic findings are available in the manuscript.

Intrasinusoidal Spread of Hepatic Epithelioid Hemangioendothelioma: Implications for the Diagnosis in Minimal Samples
Agostini-Vulaj D, Pehlivanoglu B, Weiss SW, et al. Am J Surg Pathol. 2019 Apr;43(4):573-579

The authors examined 18 cases of hepatic epithelioid hemangioendothelioma (EHE) and found that 17 showed tumor cells within sinusoids that appeared histologically separate, but within 1 to 8 mm, from the main mass. These intrasinusoidal tumor cells did not have the classic epithelioid or dendritic cell appearance of EHE, but rather showed hyperchromatic, cerebriform-like nuclei with multinucleation that in some cases mimicked megakaryocytes in over one-third of cases. Pathologists should be mindful of this phenomenon, as needle biopsies may only sample the periphery of mass lesions. Recognition of these intrasinusoidal tumor cells in limited samples can prevent misdiagnosis as non-lesional hepatic parenchyma. Immunohistochemical stains for CAMTA1, ERG, and sometimes CAM5.2 can assist in highlighting tumor cells.

Clinical Gastroenterology and Hepatology

Nonalcoholic Steatohepatitis Is the Fastest Growing Cause of Hepatocellular Carcinoma in Liver Transplant Candidates
Younossi Z, Stepanova M, Ong JP, et al. Clin Gastroenterol Hepatol. 2019 Mar;17(4):748-755.

The authors used the Scientific Registry of Transplant Recipients (2002–2016) to estimate the trends in prevalence of HCC in liver transplant candidates with the most common types of chronic liver disease: alcoholic liver disease (ALD), chronic hepatitis B (CHB), chronic hepatitis C (CHC), and NASH. The proportions of HCC accounted for by CHC and ALD remained stable (both trend P > .10), the proportion of CHB decreased 3.1-fold (P < .0001), while the proportion of NASH in HCC increased 7.7-fold (from 2.1% to 16.2%; P < .0001). Over the study period, CHC was still the most common etiology for HCC (65%).

Cost Effectiveness of Transplanting HCV-Infected Livers Into Uninfected Recipients With Preemptive Antiviral Therapy
Bethea ED, Samur S, Kanwal F, et al. Clin Gastroenterol Hepatol. 2019 Mar;17(4):739-747.

Transplanting hepatitis C virus (HCV)-infected livers into HCV uninfected recipients is a controversial topic that is still not supported by current Guidelines. Direct-acting antivirals (DAAs) can be used to treat donor-derived HCV infection. The cost of DAA therapy may be a limitation. The authors evaluated the cost effectiveness of transplanting HCV-positive livers into HCV-negative patients with preemptive DAA therapy. Using a Markov-based mathematical model, they found that transplanting HCV-positive livers into HCV-negative patients with planned DAA therapy after transplantation was a cost-effective strategy that could improve health outcomes. It is important for pathologists who review liver transplant biopsies to be aware that under these circumstances, histopathologic features of HCV may still need to be evaluated.

Journal of Gastroenterology and Hepatology

Clinical and histopathological features of immunoglobulin G4‐associated autoimmune hepatitis in children
Aydemir Y, Akcoren Z, Demir H, et al. J Gastroenterol Hepatol. 2019 Apr;34(4):742-746.

They reviewed frequency and the characteristics of immunoglobulin G4 (IgG4)‐associated autoimmune hepatitis in 40 pediatric patients with autoimmune hepatitis who had liver biopsies. IgG4‐associated autoimmune hepatitis was defined as presence of more than 10 IgG4‐positive plasma cells/high‐power field. They found a positive correlation between IgG4‐positive plasma cell count and degree of portal (r: 0.406, P: 0.009) and lobular inflammation (r: 0.37, P: 0.019), grade of interface hepatitis (r: 0.33, P: 0.03), and fibrosis (r: 0.318, P: 0.046). Time required for normalization of liver transaminases and serum IgG level was significantly shorter in IgG4‐associated autoimmune hepatitis.

Journal of Hepatology

Fa(s)t assessment of the liver graft: Is it relevant?
Nahon P, Soubrane O. J Hepatol. 2019 Mar;70(3):346-347.

This editorial addresses the nuances in assessing the severity of fat involvement of liver grafts in transplantation, which in severe cases represents the main cause of donor livers being declined. It also emphasizes the yet unmet need for a fast, quantitative and reliable method to serve as an alternative to the current gold standard procedure of histological semi-quantitative evaluation performed on frozen biopsy section at the time of transplantation. Magnetic resonance spectroscopy, fibroscan devices, and user friendly non-invasive pocket spectrometer that can be administered by the harvesting surgeon to assess donor liver fat are being developed.

American Journal of Clinical Pathology

Portal Cavernoma Cholangiopathy: Histologic Features and Differential Diagnosis
Pittman ME, Kierans AS, Rao D, et al. Am J Clin Pathol. 2019 Mar(3):255-262.

This case series describes in detail the histopathological features of portal cavernoma cholangiopathy (PCC, formerly portal biliopathy), a type of biliary injury that occurs in association with a portal vein thrombus or cavernoma. Cases are noted to clinically mimic cholangiocarcinoma, cirrhosis, and may present as a hilar mass. Microscopic features are reminiscent of hepatoportal sclerosis and/or bile duct obstruction, and show obliterated or miniaturized portal veins, with ductular reaction, reactive epithelia atypia, and mixed inflammatory cell infiltrate and neutrophils.

Liver Transplantation

Not All Cellular Rejections Are the Same: Differences in Early and Late Hepatic Allograft Rejection
Jadlowiec CC, Morgan PE, Nehra AK, et al. Liver Transpl. 2019 Mar;25(3):425-435.

T cell–mediated rejection (TCMR) is common after liver transplantation (LT), and it is often thought to have a minimum impact on outcomes. The authors investigated the role of the timing of TCMR on patient and allograft survival and examined the risk factors for early and late TCMR. They reviewed protocol liver biopsies for 787 consecutive LT recipients with an 8.6‐year follow‐up. The incidence of early TCMR (≤6 weeks after LT) was 33.5% with nonalcoholic steatohepatitis patients having the lowest incidence. Younger recipient age (P < 0.01), number of human leukocyte antigen mismatches (P < 0.01), and use of deceased donor allografts (P = 0.01) were associated with increased risk of early TCMR, which had no impact on allograft (hazard ratio [HR], 1.02; 95% CI, 0.79‐1.32; P = 0.89) or overall survival (HR, 1.03; 95% CI, 0.78‐1.34; P = 0.86). Late TCMR (>6 weeks after LT) was less common (17.7%) and was associated with different risk factors. The majority of late TCMR (56.2%) episodes had no antecedent early TCMR, although moderate‐to‐severe early TCMR (HR, 2.85; 95% CI, 1.55‐5.23; P < 0.01) and steroid resistance (HR, 3.62; 95% CI, 1.87‐6.99; P < 0.01) were associated with late TCMR. Late TCMR increased risk of mortality (HR, 1.89; 95% CI, 1.35‐2.65; P = 0.001) and graft loss (HR, 1.71; 95% CI, 1.23‐2.37; P = 0.001). In summary, the majority of early TCMR episodes after LT are mild and do not appear to adversely impact long term patient or allograft survival, provided that they are treated adequately. By contrast, late TCMR may carry deleterious effects with associated long term risk of graft loss and decreased survival. The authors suggest that it is important to describe TCMR after LT in the context of its timing and histologic grade. Early moderate‐to‐severe or steroid‐resistant rejection may play a role in late TCMR as multiple or inadequately treated TCMR episodes are risk factors for chronic rejection. Patients with moderate‐to‐severe early TCMR are at an increased risk for late TCMR and warrant closer clinical follow‐up. The occurrence of late TCMR carries deleterious effects with increased long term risk of graft loss and decreased survival.


A phenotypical map of disseminated hepatocellular carcinoma suggests clonal constraints in metastatic sites
Martins-Filho SN, Alves VAF, Wakamatsu, et al. Histopathology. 2019 Apr;74(5):718-730.

Access to tissue in patients with hepatocellular carcinoma (HCC) is limited compared to other malignancies. This has precluded a thorough characterization of molecular drivers of HCC dissemination, particularly in relation to distant metastases. The authors evaluate 88 patients with HCC who underwent autopsy, including multiregional sampling of primary and metastatic sites totalling 230 nodules that were analyzed. The study included morphological assessment, immunohistochemistry and mutation status of the TERT promoter, which is the most frequently mutated gene in HCC. Immunohistochemistry (IHC) was performed for markers of hepatocyte differentiation (HepPar1 and arginase), WNT pathway (β‐catenin and glutamine synthetase), HCC progenitor cell features (K19, CD44 and EpCAM), markers of EMT (vimentin and claudin‐1) and cell proliferation (Ki67). Results for β‐catenin and glutamine synthetase IHC were combined as a proxy for WNT signaling pathway activation. Most of the patients were male (62 of 88, 70%), with background liver cirrhosis (79 of 88, 90%) due to hepatitis C virus (HCV) infection (47 of 88, 53%). The results of this study confirm a strong predilection of HCC for lung dissemination, including subclinical micrometastases (unrecognized during imaging and macroscopic examinations) in 30% of patients with disseminated disease. Size of dominant tumour nodule; multinodularity; macrovascular invasion; high histological, nuclear and architectural grades; and cellular crowding were associated with the presence of extrahepatic metastasis. Among the immunohistochemistry markers tested, metastatic nodules had significantly higher CK19 and EpCAM expression than primary liver tumors. Morphological and immunohistochemical features showed that metastatic HCC could be traced back to the primary tumour, sometimes to a specific hepatic nodule. Their study also illustrates how autopsies can go beyond their primary objective of defining the cause of death and help address biological questions.


Accuracy of the Liver Imaging Reporting and Data System in Computed Tomography and Magnetic Resonance Image Analysis of Hepatocellular Carcinoma or Overall Malignancy-A Systematic Review
van der Pol CB, Lim CS, Sirlin CB et al. Gastroenterology. 2019 Mar; 156(4):976-986.

The Liver Imaging Reporting and Data System (LI-RADS) categorizes observations from imaging analyses of high-risk patients based on the level of suspicion for hepatocellular carcinoma (HCC) and overall malignancy. However, the actual percentage of HCC and overall malignancy within each LI-RADS category is not known. The authors performed a systematic review to determine the percentage of observations in each LI-RADS category for computed tomography and magnetic resonance imaging that are HCCs or malignancies.  The authors searched the MEDLINE, Embase, Cochrane CENTRAL, and Scopus databases from 2014 through 2018 for studies that reported the percentage of observations in each LI-RADS v2014 and v2017 category that were confirmed as HCCs or other malignancies based on pathology, follow-up imaging analyses, or response to treatment (reference standard). Of 454 studies identified, 17 (all retrospective studies) were included in the final analysis, consisting of 2760 patients, 3556 observations, and 2482 HCCs. The pooled percentage of patients with HCC were 94% for patients who, on CT/MRI, had a lesion classified LR-5, 74% for LR-4, 38% for LR-3, 13% for LR-2, and 36% for LR-M. No malignancies were reported in the LR-1 category. Several potential variables associated with accuracy such as modality (CT vs. MRI) and lesion size could not be evaluated because of either lack of eligible studies or individual participant data. Understanding the accuracy of each LI-RADS category for liver cancer allows physicians to quantify and communicate risk associated with different findings on CT/MRI, allowing for more well-informed management decisions. LR 2 and 3 lesions had non-trivial cancer risks.

Human Pathology

Hepatic mast cell concentration directly correlates to stage of fibrosis in NASH
Lombardo J, Broadwater D, Collins R. et al. Hum Pathol. 2019 Apr;86:129-135.

Recent research has described an association between an increased concentration of mast cells in the liver and the severity of hepatic fibrosis in animal models. The role of mast cells in the liver with regard to fibrosis is not well understood. The authors retrospectively investigated whether a correlation exists between stages of fibrosis and mast cell concentrations. 106 tissue slides were collected from a large military hospital of known cases of unremarkable liver, non-alcoholic fatty liver disease (NAFLD), and each stage of NASH. Tryptase staining was used to highlight and quantify the mast cell concentration in each diagnostic category. Mast cells in five 400× fields (1 square mm) in both the periportal and parenchymal regions of each slide were counted.  The study demonstrated an increase in mast cells in NASH stage 3-4 fibrosis compared to unremarkable liver (35.48 versus 18.23, respectively, P < .001) and a direct correlation (r = 0.287) between the number of mast cells and the stage of fibrosis. Better characterization of the role of mast cells in the development of hepatic fibrosis may further develop our understanding of the pathophysiology of non-NASH NAFLD and NASH.

Steatotic and nonsteatotic scirrhous hepatocellular carcinomas reveal distinct clinicopathological features
Hatano M, Ojima H, Masugi  Y, et al. Hum Pathol. 2019 Apr;86:222-232.

The authors investigated the clinicopathological and molecular characteristics of scirrhous HCC.  120 resected HCC cases were evaluated, including tumor area containing fibrous stroma and the percentage of steatotic cells within the tumor.  37 cases with fibrous stroma making up > 50% of the largest tumor area were defined as scirrhous HCC (sHCC); the other 83 cases were categorized as common HCC (cHCC). Clinicopathologically, sHCC had fewer poorly differentiated tumors (p=0.037) and a higher percentage of cases with steatosis (p=.025) than cHCC.  sHCC cases were subsequently divided into two subgroups: those with > 5% steatotic cells (steatotic sHCC) and those with < 5% steatotic cells (nonsteatotic sHCC).  Steatotic sHCC tended to have a longer time to recurrence than nonsteatotic sHCC, and both sHCC subgroups exhibited different clinicopathologic and molecular features from cHCC.


Prevalence and burden of hepatitis D virus infection in the global population: a systematic review and meta-analysis
Chen HY, Shen DT, Ji D, et al. Gut 2019;68:512-521.

It is well known that Hepatitis D virus is a defective virus that completes its life cycle only with hepatitis B virus. However, there is limited data on the global burden of HDV infection. A systematic review found that 11% of HBsAg carriers (without histories of either intravenous drug use or high-risk sexual behaviour) were coinfected with Hepatitis D virus, which is twice previous estimates. A significantly higher HDV prevalence was noted in intravenous drug users (38%) and high-risk sexual behaviour (17%).  Clearly, coinfection with HDV needs to be actively considered by histopathologists, as well as other clinicians, in patients with HBV, especially those in high risk groups.

Prepared by:
Nafis Shafizadeh MD (Editor); Southern California Permanente Medical Group
Daniela Allende MD; Cleveland Clinic
Vishal Chandan MBBS; University of California Irvine
Robert Goldin MD; Imperial College, London
Bella Goyal MD; California Pacific Pathology Medical Group
Grace Guzman MD; University of Illinois
Mojgan Hosseini MD; University of California San Diego
Heather Stevenson-Lerner MD PhD; University of Texas
Eric Yee MD; University of Arkansas

Friday, May 3, 2019

President's Message April 2019

Dear Friends and Fellow Hepatophiles,

I would like to thank everyone who attended the HPHS reception at the USCAP meeting. We had a vibrant gathering and the room was packed within a few minutes. Hanlin and Ilke welcomed everyone at the door as part of the membership committee and the book raffle was a big hit as always. Thanks to all the authors who generously donated the books; I already have a few for the next year! Thanks also to all the executive members, Mike, Grace and Cindy for organizing the reception as well as to past president Isabel, who has been instrumental in the logistical aspects of the reception.

The companion society meeting was very well attended and I have received a lot of positive feedback about the speakers as well as the topics.

Thanks to all the speakers for an outstanding session: Joe Misdraji (MGH), Bita Naini (UCLA), Andrew Bellizzi (U Iowa), Achim Weber (Zurich), Andrew Clouston (Brisbane) and Christine Sempoux (Lausanne). If you have any suggestions about the topics and speakers for next year’s meeting, please let me know.
A brief summary of the steatohepatitis survey was shared at the Hans Popper reception. The detailed results will be posted soon on the website and a notification will be sent to the members. Thanks again to the membership for their robust participation in the survey.

The committee chairs shared their annual reports in the Business meeting at the USCAP. The society’s activities including the Journal watch, case of the month and resident abstract award are going well, the
finances are sound, and the Twitter presence is growing. Please continue your active participation in the society’s activities.

Sanjay Kakar, MD
President, Hans Popper Hepatopathology Society

Interesting Case April 2019

Case contributed by:
Madhavi Rayapudi, MD and Stephen C. Ward, MD, PhD
Department of Pathology, Icahn School of Medicine at Mount Sinai, New
York, NY

Clinical History:
55 year old female with past medical history of IgG lambda multiple myeloma diagnosed 3 years prior. She is status post multiple treatments and is currently in remission. She presents now with intermittent high fevers, dry cough, and elevated liver enzymes - AST 247 (Ref range 15-37IU/L); ALT 280 (Ref range 15-56 IU/L); Alkaline phosphatase 145 (Ref range 48-118 U/L); Bilirubin 0.5 (Ref range 0.2-1.5MG/DL). Liver biopsy was performed.

Microscopic Findings:
Liver needle biopsy specimen shows multiple nonnecrotizing granulomas predominantly located within the hepatic parenchyma. Several granulomas contain a lipid droplet, some with a loose ring of fibrin around the fat droplets (best seen on Masson trichrome stain). Mild macrovesicular steatosis without significant ballooning degeneration is also seen.

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5
Granulomatous hepatitis with fibrin ring features secondary to immune checkpoint inhibitor toxicity.
The patient had been treated with venetoclax, ixazomib, dexamethasone, nelfinavir, and thalidomide. Immune checkpoint inhibitor therapy with anti-CTLA-4 agent ipilimumab and anti-PD-1 agent nivolumab was initiated three weeks prior to the biopsy. Following the biopsy the immune checkpoint inhibitor therapy was discontinued and liver enzymes returned to normal.

Immune checkpoint inhibitors have become standard of care in many types of malignancies; however, the underlying mechanism of hepatotoxicity is still not completely understood. In a retrospective study of 187 patients, an overall incidence of all grade hepatotoxicity with CTLA-4 inhibitors (e.g. ipilimumab) was 24%, 37% with PD-1 inhibitors (e.g. nivolumab), and 73% with the combination therapy (1). Immune check point inhibitor mediated hepatitis (ICIIMH) and idiopathic autoimmune hepatitis (iAIH) share some histologic similarities (2,3) but significant differences have also been described. ICIIMH was characterized by lobular hepatitis with abundant infiltration by CD3+ or CD8+ T-lymphocytes, while CD20+ or CD4+ lymphocytes were less likely to be seen in ICIIMH as compared to iAIH (4). Recently a granulomatous hepatitis with fibrin ring features has been described in patients treated with CTLA-4 inhibitors alone or in combination with PD-1 inhibitors. (5, 6). The granulomas consist of collections of epithelioid cells with a central lipid vacuole and a surrounding ring of fibrin. These cases also showed steatotosis with either spotty necrosis or perivenular confluent necrosis as well as central vein endotheliitis. Fibrin ring granulomas are not specific for immune checkpoint inhibitor toxicity. The differential diagnosis for fibrin ring granulomas also includes infection [Q fever (Coxiella burnetii), hepatitis A, visceral leishmaniasis, Epstein-Barr virus, toxoplasmosis, boutonneuse fever (Rickettsia conorii), staphylococcal infection, and salmonella], autoimmune (e.g. systemic lupus erythematosus), other drugs (e.g. allopurinol), Hodgkin disease, giant cell arteritis, metastases, as well as in the metabolic syndrome with hepatic steatosis, and mitochondrial injury (7, 8, 9).

1. Shah N, Puthiamadathil J, Serzan M, et al. Clinical Outcome of immune related hepatitis (IrHep) in patients with advanced melanoma (AM) treated with single agent or combination immune checkpoint inhibitors (ICI) [abstract]. Ann Oncol. 2018 Oct; 29(8):viii433.
2. Kleiner DE, Berman D. Pathologic changes in ipilimumab- related hepatitis in patients with metastatic melanoma. Dig Dis Sci. 2012; 57:2233–2240.
3. Johncilla M, Misdraji J, Pratt DS, et al. Ipilimumab-associated Hepatitis. Am J Surg Pathol. 2015 Aug 1;39(8):1075–1084
4. Zen Y, Yeh MM. Hepatotoxicity of immune checkpoint inhibitors: a histology study of seven cases in comparison with autoimmune hepatitis and idiosyncratic drug-induced liver injury. Mod Pathol 2018; 31:965–973.
5. De Martin E, Michot JM, Papouin B, et al. Characterization of liver injury induced by cancer immunotherapy using immune checkpoint inhibitors. J Hepatol. 2018 Jun 1; 68(6):1181–1190.
6. Everett J, Srivastava A, Misdraji J. Fibrin ring granulomas in checkpoint inhibitor-induced hepatitis. Am J Surg Pathol. 2017; 41: 134–137.
7. Lewis JH. Chapter 40. Granulomas of the liver. In: Schiff ER, Maddrey WC, Reddy KR, editors Schiff’s disease of the liver. 12th ed. Wiley-Blackwell New Jersey, USA. 2018. p. 1028–1052.
8. Aguilar-Olivos N, Del Carmen Manzano-Robleda M, Gutiérrez-Grobe Y, et al. Granulomatous hepatitis caused by Q fever: a differential diagnosis of fever of unknown origin. Ann Hepatol. 2013 Jan 15; 12 (1):138–141.
9. Joseph J. Jennings, Rohan Mandaliya, Ahmad Nakshabandi & James H. Lewis (2019) Hepatotoxicity induced by immune checkpoint inhibitors: a comprehensive review including current and alternative management strategies, Expert Opinion on Drug Metabolism & Toxicology, 2019 15:3, 231-244, DOI: 10.1080/17425255.2019.1574744

Tuesday, April 9, 2019

HPHS Companion Meeting Presentations from USCAP 2019

Dr. Sanjay Kakar, current HPHS president, assembled and moderated an outstanding HPHS companion meeting at USCAP 2019.  Special thank you to each of the speakers for providing their expertise to our society and the hepatopathology community.  Click on the presentation titles below to view files:

Joseph Misdraji, MD, Massachusetts General Hospital, Harvard Medical School

Andrew Clouston, MBBS PhD FRCPA, Envoi Specialist Pathologists

Andrew Bellizzi, M.D., University of Iowa Hospitals and Clinics

Christine Sempoux, MD, PhD, Lausanne University Hospital

Tuesday, March 26, 2019

Congratulations to the Winners of 2019 HPHS Trainee Award

First Place Overall Winner of the 2019 HPHS Best Abstract Award
Trainee winner:  Dr. Wei Zheng, UCLA
OATP1B3 Is A Novel Immunohistochemical Marker to Discriminate Well Differentiated Hepatocellular Carcinoma from Its Benign Hepatocellular Mimickers

Wei Zheng, Alyssa M. Krasinskas, Wei Yue, Hanlin L. Wang
Dr. Hanlin Wang accepts the award on behalf of winner Dr. Wei Zhang
with HPHS Education Committee Chair Dr. Daniela Allende
First Runner Up
Trainee winner:  Dr. Catherine Forse, Cleveland Clinic
Reassessing the Histological Features Associated with Antibody-Mediated Rejection in Liver Transplant

Catherine L. Forse, Morteza Tarokh, Chao Tu, Bijan Eghtesad, Scott A. Robertson, Daniel E. Roberts, Lisa M. Yerian, Daniela Allende

Second Runner Up
Trainee winner:  Ram Al-Sabti , University of Chicago
Association of Histologic Features of Methotrexate Induced Hepatotoxicity with Clinical Risk Factors for Steatosis and Steatohepatitis

Ram Al-Sabti, Marcela A. Salomao, Rish Pai, Jerome Cheng, Maria Westerhoff, David Papke, Lei Zhao, Shaomin Hu, Nicole Panarelli, Katherine Boylan, John A. Hart
Dr. John Hart accepts the award on behalf of awardee Dr. Ram Al-Sabti
with HPHS Education Committee Chair Dr. Daniela Allende

HPHS Journal Watch: January / February 2019

Journal of Hepatology

Intra-tumoral tertiary lymphoid structures are associated with a low risk of early recurrence of hepatocellular carcinoma. 
Calderaro J, Petitprez F, Becht E, et al. Journal of Hepatology 2019;70:58–65.

In most cancers explored, tertiary lymphoid structures (TLS) supply a vital microenvironment for generating anti-tumor immune responses, and are linked with enhanced clinical outcomes in most cancers, but its role in HCC is not well defined.  In this retrospective pathological study of a series of 273 patients with HCC treated with surgical resection, intratumoral TLSs were found to be associated with a low risk of early relapse after surgical resection, suggesting that they reflect the existence of in situ effective anti-tumor immunity.  The pathological results were further validated by gene expression profiling using public data set (LCI cohort).  Learn more of the details of the study in the January 2019 issue. 

American Journal of Clinical Pathology

Unexpectedly High Prevalence of Cystoisospora belli Infection in Acalculous Gallbladders of Immunocompetent Patients. 
Noor M, Katzman PJ, Huber AR, et al. American Journal of Clinical Pathology 2019; 151: 100–107.

This study is a retrospective review of cholecystectomy specimens (n = 401) removed for various indications, and a prospective cohort of cholecystectomy specimens (n = 22) entirely submitted for histologic evaluation to determine the prevalence of C. belli.  C belli was identified in 39/401 (9.7%) of the retrospective cohort, and 6/22 (27.3%) of the entirely submitted specimens.  There was no correlations of presence of C belli with age, sex, clinical indication, and abnormalities of preoperative laboratory values.  The authors conclude that C belli resides in a latent state in the gallbladder and may be best considered a commensal organism.

Evaluation of Peritumoral Fibrosis in Metastatic Colorectal Adenocarcinoma to the Liver Using Digital Image Analysis. 
Waters KM, Cottrell TR, Besharati S, et al. American Journal of Clinical Pathology 2019, 151:226–230.

This study addresses the effect of peritumoral fibrosis to the assessment of native liver fibrosis in 25 cases of metastatic colonic adenocarcinoma to liver by digital image analysis.  The authors found that there was a 3.9 fold (range 0.9-18.6) median increase in fibrosis in the first 0.5 mm of peritumoral liver compared to distant liver. Fibrosis levels returned to baseline at median 2.5 mm (interquartile range 1.5-5.0 mm) from tumor.  The authors conclude that fibrosis is markedly increased in peritumoral liver. Fibrosis levels returned to baseline by 5 mm from tumor in approximately 75% of cases. Pathologists should be cautious of fibrosis in mass-directed liver biopsies without at least 5 mm of liver tissue distal to the mass.

American Journal of Gastroenterology

Diagnosis and Management of Primary Biliary Cholangitis.
Younossi ZM, Bernstein D, Shiffman ML, et al. Am J Gastroenterol. 2019; 114 (1):48-63.

This paper provides a good general review of PBC.  With reference to liver biopsy,  it supports the current consensus that the diagnosis  of PBC does not require liver biopsy and that the diagnosis is based on clinical and laboratory tests. It is, however, indicated when the diagnosis of PBC is uncertain or where another superimposed diagnosis (most commonly non-alcoholic fatty liver disease) is suspected. It is essential if an overlap syndrome is suspected because of clinical and laboratory features of AIH.


Clinical Manifestations and Outcomes of Patients with Sarcomatoid Hepatocellular Carcinoma
Liao SH, Su TH, Jeng YM, et al. Hepatology 69(1): 209-221.

This study examines 40 cases of sarcomatoid HCC and compares them to 160 cases of non-sarcomatoid HCC. The sarcomatoid group had significantly shorter median recurrence-free and overall survival. Sarcomatoid histology was an independent factor for all-cause mortality and tumor recurrence, and was associated with atypical imaging patterns.

Hepatocellular Carcinoma as a Complication of Vascular Disease of the Liver After Fontan Procedure
Mazzarelli C, Cannon MD, Hudson Mark, et al. Hepatology 69(2): 911-913.

The authors report 3 cases of HCC occurring in patients 17-18 years after Fontan procedure as children. None of the patients had features of advanced liver disease. They suggest further studies are needed on this rare, late complication of Fontan procedure.

Antiprogrammed Cell Death-1 Immunotherapy-Related Secondary Sclerosing Cholangitis
Ogawa K, Kamimura K, Terai S. Hepatology 69(2): 914-916.

The authors report a case of secondary sclerosing cholangitis due to PD-1 immunotherapy with pembrolizumab. The case adds to the list of immune-mediated adverse events that can occur in the setting of immunotherapy.


Histology of portal vascular changes associated with idiopathic non-cirrhotic portal hypertension: nomenclature and definition.
Guido M, Alves VAF, Balabaud C; et al, International Liver Pathology Study Group. Histopathology 2019 Jan;74(2):219-226.

Idiopathic non-cirrhotic portal hypertension (INCPH) is a vascular liver disease of unknown etiology, characterized by clinical signs of portal hypertension (PH) in the absence of cirrhosis. As much uncertainty exists about INCPH pathophysiology, and as no definite diagnostic tests are available, liver biopsy is an essential tool for achieving a definite diagnosis. The histological   diagnosis of INCPH is not always straightforward. The terminology and dentition are ambiguous, which adds complexity to the already complex clinicopathological scenario. An   international study group of liver pathologists and hepatologists pursued a consensus on nomenclature for the portal vascular lesions of INCPH.  The authors describe the portal and periportal changes in INCPH, characterized by portal vein narrowing, portal vascular spaces directly abutting the hepatic parenchyma at the limiting plate, increase in the number of portal vascular spaces and abnormal spaces immediately adjacent to a portal tract. The authors aim at simplification and providing a basis for standardization, proposing a nomenclature that is intended to be descriptive enough to be used without pathophysiological implications. 

Human Pathology

Somatic HNF1A mutations in the malignant transformation of hepatocellular adenomas: a retrospective analysis of data from MSK-IMPACT and TCGA.
Hechtman JF, Abou-Alfa GK, Stadler ZK, et al. Hum Pathol 2019 Jan;83:1-6.

Mutations of HNF1A gene are well documented in hepatocellular adenoma. The role of HNF1A mutations in hepatocellular carcinoma remains to be determined. In this study, all hepatocellular neoplasms evaluated by Memorial Sloan Kettering-Integrated Mutational Profiling of Actionable Clinical Targets assay or the Cancer Genome Atlas sequencing, and cases reported in the literature, were queried for HNF1A mutations. 11 of 672 (1.6%) HCCs harbored HNF1A mutations. 3 of these 11 HCCs arose in a background of adenomatosis. Information on pre-existing adenoma for the remaining cases (8) was not available. Their findings suggest that malignant transformation of HNF1A-mutated hepatocellular adenoma occurs, albeit infrequently.


Epidemiology and Management of Hepatocellular Carcinoma. 
Kulik L, El-Serag HB. Gastroenterology. 2019 Jan;156(2):477-491.

A review of the emerging data on the risk and determinants of HCC in these conditions and the implications of HCC surveillance.

Genomic Medicine and Implications for Hepatocellular Carcinoma Prevention and Therapy.
Dhanasekaran R, Nault JC, Roberts LR, et al. Gastroenterology. 2019 Jan;156(2):492-509.

A review of recent advances in genomics which have increased our understanding of the mechanisms by which hepatitis B virus, hepatitis C virus, alcohol, fatty liver disease, and other environmental factors.

Targeted and Immune-Based Therapies for Hepatocellular Carcinoma.
Greten TF, Lai CW, Li G, et al. Gastroenterology. 2019 Jan;156(2):510-524.

Provides a summary of the targeted and immune-based agents in trials of patients with advanced hepatocellular carcinoma and discusses the future of these strategies for liver cancer.

Journal of Gastroenterol and Hepatology

Biliary transporter gene mutations in severe intrahepatic cholestasis of pregnancy: Diagnostic and management implications
Yeap SP, Harley H, Thompson R, et al. Journal of Gastroenterology and Hepatology 2019, 34: 425–435

Five women with a total of 8 pregnancies with Intrahepatic cholestasis were included in the study.
Two cases showed biallelic heterozygosity for several ABCB11 mutations, one was homozygous for an ABCB4mutation and a fourth case was heterozygous for another ABCB4 mutation.

Archives of Pathology and Laboratory Medicine

Colorectal Liver Metastases. A Pathologist’s Guide to Creating an Informative Report and Improving Patient Care.
Moreno Prats M, Sasatomi E1, Stevenson HL. Arch Pathol Lab Med. 2019 Feb;143(2):251-257.

The authors review the important pathologic elements for reporting colorectal cancer (CRC) liver metastases as well as background changes that can be seen in the liver, including those following chemotherapy for CRC.

Calcifying Nested Stromal-Epithelial Tumor of the Liver: An Update and Literature Review
Benedict M, Zhang X. Arch Pathol Lab Med. 2019 Feb;143(2):264-268.

This is a resident short review that covers the clinical, radiologic, behavioral, and pathologic findings as well as the differential diagnosis and treatment of calcifying nested stromal-epithelial tumor of the liver.

Prepared by (in alphabetical order):
Daniela Allende MD (Editor), Cleveland Clinic
Vishal Chandan, MBBS; University of California Irvine
Robert Goldin MD; Imperial College, London
Bella Goyal, MD; California Pacific Pathology Medical Group
Grace Guzman MD; University of Illinois
Mojgan Hosseini MD; University of California San Diego
Nafis Shafizadeh MD; Southern California Permanente Medical Group
Maria Westerhoff MD; University of Michigan
Eric Yee MD; University of Arkansas for Medical Sciences

Wednesday, March 6, 2019

HPHS Reception at USCAP 2019

Please join us at the USCAP for the 2019 annual Hans Popper Hepatopathology Society reception!  Enjoy some light food and excellent company.   A short, informal program and the book raffle starts a few minutes after 6, but please join us at any time between 6 and 8. 

Date:  Saturday, March 16
Time:  6-8 PM
Location: Magnolia 2 room of the Gaylord National Resort & Convention Center

Tuesday, February 5, 2019

President's Message January 2019

Dear friends and fellow hepatophiles,

New year greetings to all. The Society is gearing up for the USCAP meeting and we are looking to welcome everybody to the Hans Popper reception. The details will be posted on the website and the HPHS twitter account later this month. Come to share a drink with the fellow members and friends, and make sure you stay for the book raffle. The Hans Popper Companion Society meeting will be held in the morning on Sunday March 17, and we have an excellent line-up of national and international speakers for the session.

In the past few newsletters, I’ve focused on the important role played by different committees and introduced you to members and committee chairs. Towards the end of this academic cycle, I would like to thank the Executive committee for leading the Society. Grace Kim as the Secretary-Treasurer has spearheaded major changes in the last few years that has led to the growth of the society to more than 100 members. Mike Torbenson continues as Past President after his excellent two-year stint as President, and is currently leading efforts to organize the HPHS reception and the joint session with our transatlantic colleagues at the European Congress of Pathology. Cindy Guy as Vice President has been overseeing the Education committee with its important roles in Journal Watch and Trainee Abstract Award.

would like to thank everyone who responded to the steatohepatitis survey. We have received more than a hundred responses. The results are being tabulated and will soon be shared on the website as well as at the HPHS reception.

The Society is doing well and we are currently in a healthy financial situation. The dues statements for 2019 have been sent. Please pay your dues in a timely fashion to enable smooth functioning of the Society. The financial details and reports from HPHS committees will be shared in the Business meeting at noon following the Companion Society session at the USCAP meeting. I am looking forward to seeing you all in March.

Sanjay Kakar, MD
President, Hans Popper Hepatopathology Society

Interesting Case: January 2019

Case contributed by:
Phoenix D. Bell, MD, MS and Michael G. Drage, MD, PhD
University of Rochester Medical Center, Rochester, NY

Clinical History
A 3-year-old female with a past medical history of autism spectrum disorder and global developmental delay presented with several month history of decreased appetite, fatigue, and abdominal distension. A palpable abdominal mass was noted on physical exam. There was no history of nausea, abdominal pain, constipation, vomiting, or diarrhea. Serum alpha feto-protein (AFP), carcinoembryonic antigen (CEA), and beta-HCG were within normal limits.

Imaging Findings
An abdominal x-ray was performed, which showed striking hepatomegaly. Ultrasound demonstrated a multicystic mass (17.7 x 16.3 x 12.6 cm) in the right upper quadrant with thick septations and internal debris. MRI revealed mass effect on the adjacent structures, including upward displacement of the right hemidiaphragm and compression of the right kidney (Figures 1 and 2). 

Figure 1

Figure 2
Gross and Microscopic Findings
The patient underwent partial liver resection and gross examination showed an 18 x 17 x 5 cm, pink-purple cystic lesion. The cut surfaces were gray-white to pink-yellow with numerous cystic spaces up to 13.5 cm in greatest dimension and cross-sections revealing smaller intramural cysts (Figures 3 and 4). A portion of the specimen was sent for cytogenetic analysis, which failed due to lack of metaphase spreads. Microscopic examination revealed that the lesion was composed of a bland spindle cell population (Figure 5) within a variably loose, edematous, myxoid to hyalinized stroma with scattered ectatic thin-walled vessels, and occasional entrapped large biliary structures, the latter surrounded by dense concentric fibrosis (Figure 6).  Grossly appreciated cystic structures were not lined by epithelium, and contained degenerated blood or bile (Figure 7), the latter often with xanthomatous reaction at the periphery (Figure 8).  Cords of benign hepatocytes were prominent at the periphery of the lesion (Figure 9). 

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9
Hepatic mesenchymal hamartoma

Hepatic mesenchymal hamartoma (HMH) represents 8% of primary liver tumors in children, and is the second most common benign pediatric liver tumor after infantile hemangioma [1-4]. Approximately 80% of MH present within the first two years of life as an asymptomatic, enlarging abdominal mass [5-7].  Approximately 75% occur in the right lobe [8].  Radiologic studies show variable solid and cystic components [5, 7]. Liver function tests are usually unremarkable[9]; however, there may be mild elevations in AFP[10]. Grossly, sectioning reveals soft cut surfaces with single to multiple cysts, which may contain clear-yellow to bilious fluid or gelatinous material [5, 6]. HMH has variable histologic features, which including areas of normal hepatic parenchyma separated by areas of spindled cells in a myxoid, collagenous, or hyalinized background[11]. The stroma contains interspersed elongated and clustered biliary ducts and numerous cystic spaces lacking an epithelial lining [3, 5]. A subset of HMH are discovered in adults, whose tumors show a greater tendency to be solid, densely fibrotic, and paucicellular [12], suggesting either involution of a long-standing lesion, or a different biology. 
Occasionally, HMH may present as a solid lesion in children, altering the differential. Mixed epithelial-mesenchymal hepatoblastoma (HB), demonstrates radiologic and histologic overlap, particularly in areas of bland hepatocytes in a background of spindled cells. Elevated AFP and the presence of calcifications distinguish the latter from HMH [1, 2, 6].
Because of the age distribution and predilection for the right lobe, HMH was initially considered a developmental abnormality.  Recent evidence has confirmed its neoplastic etiology.  First, there are reports of synchronous or metachronous occurrence of HMH with undifferentiated embryonal sarcoma (UES), both of which share recurrent chromosomal rearrangements involving 19q13, with a translocation partner located at 11q11-3.  In one case of concurrent HMH/UES, the lesions were contiguous and shared identical rearrangement in the stromal component [3], likely reflecting a somatic process. Dysregulated imprinting has also been proposed as a potential mechanism of tumorigenesis, based on observations that a subset of cases show evidence of androgenetic/biparental mosaicism [13], and interestingly, occasional cases are reported in patients with Beckwith-Wiedemann syndrome [14].  Although benign, HMH causes significant mass effect [14]. Complete resection is curative [1, 7]; liver transplant may be considered for unresectable cases [9, 11].

Learning Points
  • MH is a rare tumor most often found in the pediatric population, which presents as an enlarging abdominal mass.
  • Mixed epithelial-mesenchymal hepatoblastoma may demonstrate radiologic and histologic overlap with MH.
  • Recent studies demonstrate that MH is a neoplastic process, rather than a developmental abnormality

Note: This case was presented in part at the College of American Pathologists Annual Meeting (Poster #94; Oct 21, 2018). 


1.         Bahador, A., et al., Mesenchymal Hamartoma Mimicking Hepatoblastoma. International Journal of Organ Transplantation Medicine, 2014. 5(2): p. 78-80.
2.         Kim, S.H., et al., Radiological Spectrum of Hepatic Mesenchymal Hamartoma in Children. Korean Journal of Radiology, 2007. 8(6): p. 498-505.
3.         Mathews, J., E.J. Duncavage, and J.D. Pfeifer, Characterization of translocations in mesenchymal hamartoma and undifferentiated embryonal sarcoma of the liver. Experimental and Molecular Pathology, 2013. 95: p. 6.
4.         Ishak, K.G., Z.D. Goodman, and J.T. Stocker, Tumors of the liver and intrahepatic bile ducts. 3rd Series. 2001, Washington D.C.: Armed Forces Institute of Pathology. 356.
5.         Liao, W., et al., A 4 and a half years old boy with mesenchymal hamartomas in the left lateral lobe of the liver: A case report and literature review. Medicine, 2017. 96(31): p. e7281.
6.         Patel, S.R., et al., Benign Hepatic Mesenchymal Hamartoma (HMH) – A Case Report. Journal of Clinical and Diagnostic Research : JCDR, 2014. 8(3): p. 119-120.
7.         Rosado, E., et al., Mesenchymal hamartoma of the liver - a case report and literature review. Journal of Radiology Case Reports, 2013. 7(5): p. 35-43.
8.         Stringer, M.D. and N.K. Alizai, Mesenchymal hamartoma of the liver: a systematic review. Journal of Pediatric Surgery, 2005. 40(11): p. 1681-1690.
9.         Li, J., et al., Liver transplantation for a giant mesenchymal hamartoma of the liver in an adult: Case report and review of the literature. World journal of gastroenterology, 2015. 21(20): p. 6409-6416.
10.       Iacob, E.R., et al., Mesenchymal hamartoma of the left liver lobe in an 18-month-old female patient. Rom J Morphol Embryol, 2016. 57(2 Suppl): p. 841-847.
11.       Koganti, S.B., V.M. Thumma, and B. Nagari, Mesenchymal Hamartoma of the Liver: Complete Excision Always Necessary. Case Rep Surg, 2017. 2017: p. 8314102.
12.       Cook, J.R., J.D. Pfeifer, and L.P. Dehner, Mesenchymal hamartoma of the liver in the adult: Association with distinct clinical features and histological changes. Human Pathology, 2002. 33(9): p. 893-898.
13.       Lin, J., et al., Occult Androgenetic-Biparental Mosaicism and Sporadic Hepatic Mesenchymal Hamartoma. Pediatric and Developmental Pathology, 2011. 14(5): p. 360-369.
14.       Pan, E.T., et al., Liver transplantation as definitive treatment of an unresectable mesenchymal hamartoma in a child with Beckwith-Wiedemann Syndrome. Journal of Surgical Case Reports, 2017. 8: p. 1-3.