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.