Saturday, May 26, 2018

HPHS Journal Watch: March/April 2018

American Journal of Surgical Pathology
MDM2 is an independent oncogene and also a negative regulator of p53. A recent whole-exome sequencing study identified MDM2 amplification in 5% of cholangiocarcinomas. The investigators sought to determine the frequency of MDM2-amplified intrahepatic cholangiocarciomas (iCCAs) and evaluate their clinicopathologic features. The study cohort consisted of surgical resections from Korean and Japanese patients. Tissue microarrays (TMAs) were constructed and tested for MDM2 amplification by in situ hybridization. Tumors that showed MDM2 amplification on TMA had whole tissue sections made and were re-tested to assess for heterogeneity in MDM2 amplification. In addition, all MDM2-amplified and 25 MDM2-nonamplified iCCAs were sequenced for KRAS and IDH1/2 mutations. All cases were tested for SMAD4 expression by immunohistochemistry.
MDM2-amplification was found only in iCCAs with large-duct type morphology and comprised 6% of cases; amplification was diffuse in 77% of iCCAs. KRAS and IDH1 mutations were only detected in MDM2-nonamplified iCCAs. Loss of SMAD4 expression was more frequent in MDM2-amplified iCCAs. Patients with MDM2-amplified iCCAs had a worse survival than those without MDM2-amplification (median survival 16 vs. 28 mo., median follow-up 39 mo.); however, when comparing only patients with large-duct type morphology iCCAs, MDM2-amplified and MDM2-nonamplified patients showed no statistically significant difference in survival. In summary, this study identified that MDM2-amplification is present in a subset of iCCAs and MDM2 inhibitor therapy may play a role in the future.

Liver Transplantation
This review summaries the use of radiation therapy for hepatocellular carcinoma, makes comparisons with other local ablative therapies, and addresses potential novel strategies for optimizing future utility.
Currently, normothermic machine perfusion (NMP) of donor livers using packed red blood cells and fresh frozen plasma is being used in clinical trials, and some suggest it will revolutionize organ transplantation. This paper discusses using NMP with a new synthetic solution created from a polymerized bovine hemoglobin-based oxygen carrier and a gelatin-based colloid suspension as an alternative to using scare and expensive human blood products. Included is a brief discussion, with photomicrographs, of NMP-related histopathologic ischemia-reperfusion injury changes.

This is a nice and fairly comprehensive review of the interplay between the gut microbiota and the liver in health and disease. 

Clinical Gastroenterology and Hepatology
Classically, in adults, the histologic findings of NASH include zone 3 steatosis, inflammation, and ballooned hepatocytes. In children, on the other hand, fatty liver disease may have fewer ballooned hepatocytes, more portal based inflammation, and can have zone 1 steatosis. The purpose of this study was to determine clinically relevant associations between zone 1 vs. zone 3 steatosis in children. Liver biopsies of 776 pediatric patients were scored for degree and location of steatosis, inflammation (lobular & portal), ballooned hepatocytes, and fibrosis.
19% had zone 1 steatosis, 31% had zone 3, and the remaining were panacinar (42%) or azonal (8%). Compared with children with zone 3 steatosis, those with zone 1 steatosis were younger, more likely to be Hispanic, have higher fasting triglyceride levels, male, and have higher AST. Children with zone 3 steatosis had higher waist circumference and blood pressure.
Biopsies with zone 3 steatosis had more ballooned hepatocytes than those with zone 1, higher NAFLD activity score, and NASH. Those with zone 1 steatosis had more portal inflammation and more fibrosis, with 2.34 times the odds of having advanced fibrosis compared to zone 3 steatosis patients.
In conclusion, zone 1 vs. zone 3 steatosis in pediatric NAFLD have informative risk differences in fibrosis and steatohepatitis, with zone 1 patients being more likely to be younger, Hispanic, and male; importantly they are more likely to have fibrosis.

The authors report a case of a 50-year-old woman presenting with concurrent erythema multiforme and autoimmune hepatitis. Despite the presence of several confounding factors, the authors do a convincing job of establishing the diagnosis. There is a brief discussion regarding the challenge of distinguishing lupus-related hepatitis from autoimmune hepatitis, and the clinical significance of doing so.

The authors report an unusual case of hepatocellular carcinoma (HCC) presenting as a lateral eyebrow skin metastasis in an 83-year-old man who was subsequently found to have alcoholic cirrhosis. There is a brief discussion on the limited literature on HCC cutaneous metastases.

American Journal of Pathology
This study evaluated the differences in progenitor cell niche activation between primary sclerosing cholangitis (PSC) (n=20), primary biliary cholangitis (PBC) (n=20), and healthy livers (n=5). Ductular reaction, progenitor cell phenotype, and signaling pathways were investigated by IHC and immunofluorescence. Ductular reaction was found to be more expansive and more proliferative in PBC than PSC. Ductular reaction correlated with fibrosis and clinical prognostic risk scores both in PSC and PBC. The ductular phenotype was predominantly biliary in PBC, as compared to signs of hepatocyte commitment in PSC.

Small-RNA sequencing was used to profile miRNA expression in cirrhotic nodules (CNs), dysplastic nodules, early HCCs, and small progressed HCCs in 17 patients having chronic liver disease of various etiologies. An miRNA expression signature of 62 miRNAs distinguishing small progressed HCCs from matched CNs was identified. The authors suggest that identification of miRNAs discriminating CNs from neoplastic nodules may have relevant translational implications in early HCC diagnosis.

Modern Pathology
These authors shed much needed light on the difficult subject of diagnosing liver graft versus host disease by creating a three-tiered scoring system and histopathological algorithm. Their results show a high sensitivity, specificity and accuracy when compared to controls, including drug-induced liver injury cases. This is an exciting and “must read” paper.  

The aim of this study was to identify the relationship of xanthogranulomatous cholecystitis (XGC) with IgG4-related cholecystitis.  The histological features of 57 XGC cases were compared with those of 104 conventional chronic cholecystitis (CC) cases.  XGC cases showed increased gallbladder wall thickening and histiocytic infiltration as compared with CC cases.  XGC cases also more commonly showed dense lymphoplasmacytic infiltration, storiform fibrosis, and extensive IgG4+ plasma cell infiltration.  XGC demonstrated an increased mean number of IgG4+ plasma cells (35/hpf) as compared with CC (5/hpf) [p <0.001].  The XGC cases were further classified based on a cut-off of 50 IgG4+ plasma cells because this threshold was proposed for IgG4-related disease in the liver, pancreas, and bile duct.  IgG4-high XGC cases (n=16) had a mean number of 78 IgG4+ plasma cells compared to IgG4-low XGC cases (n =41) that had a mean number of 11 IgG4+ plasma cells.  Nine IgG4-high XGC cases (16%) had denser lymphoplasmacytic infiltration, fibrosis, and a higher IgG4/IgG ratio, suggesting that a subset of XGC cases share histological features with IgG4-related cholecystitis.  XGC cases with histological features suggestive of IgG4-related cholecystitis were also found to show clinical features such as extracholecystic involvement and mass-forming inflammation.  Of the nine IgG4-high XGC cases that had histologic features suggestive of an IgG4-related disease, only one case also had IgG4-related disease at another site.  The study findings suggest that XGC and IgG4-related cholecystitis have overlapping histologic features but are at best weakly associated with other typical organ manifestations of IgG4-related disease.

This is a prospective, biopsy-controlled, study conducted to compare 10 liver fibrosis markers in 289 patients [Enhanced Liver Fibrosis test (ELF), FibroTest, transient elastography, 2-D shear-wave elastography, and 6 indirect marker tests] in detection of advanced liver fibrosis (defined as Kleiner stage > F3).  The liver biopsy fibrosis stage was used as the reference standard.  The aim of the study was 1) to validate ELF in detection of advanced fibrosis in patients with alcoholic liver disease in primary and secondary health centers using a literature-established cutoff value of 10.5 as seen in the setting of NAFLD; and 2) to assess the diagnostic accuracy for significant fibrosis or cirrhosis and to determine whether combinations of fibrosis markers increases diagnostic yield.  The prevalence of advanced fibrosis by liver biopsy was 23% (66/289); 6% (8/128) in primary care and 36% (58/161) in secondary care. Both ELF and FibroTest identified advanced fibrosis with comparable high accuracy (AUROC of 0.92 and 0.90, respectively) in both primary and secondary care settings. ELF >10.5 correctly diagnosed advanced fibrosis in 79% of patients and absence of advanced fibrosis in 91%.  In the primary care setting, for an ELF score < 10.5, the negative predictive value to rule out advanced fibrosis was 98%, but the positive predictive value to affirm a diagnosis of advanced fibrosis was lower at 60%.  ELF better identified patients with advanced liver fibrosis than indirect markers.  However, combining ELF and FibroTest did not increase diagnostic yield of detecting advanced liver fibrosis and did not differ from transient elastography. The study suggests that ELF and FibroTest identified advanced liver fibrosis in alcoholic patients from primary and secondary care with high diagnostic accuracy (AUROC values of 0.90 or higher using biopsy as reference).

Immunoglobulin G4-related disease (IgG4-RD) is a multiorgan immune-mediated disease that predominantly affects the biliary tract (IgG4-associated cholangitis) and pancreas (autoimmune pancreatitis). The sera of patients with IAC/AIP was compared control sera of patients with primary sclerosing cholangitis (PSC) and pancreatobiliary malignancies for reactivity against human H69 cholangiocyte lysates on immunoblot. The choice of PSC sera as one of the controls is interesting as it is recognized that in a subset of patients there is an overlap with IgG4-RD. Annexin A11 was identified as the main target antigen. Annexin A11-specific IgG4 and IgG1 antibodies were only detected in serum of patients with IgG4-RD and not in controls.  Epitope analysis showed that two annexin A11 epitopes targeted by IgG1 and IgG4 autoantibodies were shared between patients with IAC/AIP and IgG4 antibodies blocked binding of IgG1 antibodies to the shared annexin A11 epitopes. This suggests that IgG1-mediated pro-inflammatory autoreactivity against annexin A11 in patients with IgG4-RD may be attenuated by formation of annexin A11-specific IgG4 antibodies supporting an anti-inflammatory role of IgG4 in IgG4-RD.

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

Tuesday, May 8, 2018

President's Message April 2018

Dear Friends and Fellow Hepatophiles:

It is an honor to serve as President of the Hans Popper society following the footsteps of illustrious mentors and colleagues who have shepherded the society over the years. Thanks to Mike Torbenson for the outstanding leadership in the last two years.
It has been an eventful last couple of years for the Society. The reception that started off as a one-time tribute to Dr. Popper has now become a regular annual event, facilitating the members to interface with each other and grow as a society. Kudos to Isabel Fiel for the flawless organization of the receptions. Apart from the wonderful reception, the excellent companion society meeting contributed to the Society’s success during the recent USCAP meeting.

Another new endeavor this year was a membership survey on the use of special stains in liver biopsies. The results were presented at the reception and are available on the website. More practice-based surveys are planned for this year with the hope that the information will help members to be cognizant of the spectrum of practice in our field, enabling discussions and improvement in our respective practices.

The executive committee has also proposed a plan to publish guidelines/best practices articles on behalf of the society. The proposed guidelines for this endeavor have been posted on the website. Please review and provide your feedback in the comment region.

In keeping with the social media movement, the Society now has a Twitter handle. Thanks to Dora Lam-Himlin, our website committee chair, for enabling our entry into the digital age.

There are a lot of interesting posts on Twitter regarding events related to liver pathology and we currently have more than 200 followers. If you are at a national or international liver meeting, you can share new advances and ‘pearls’ with fellow members by posting on Twitter. Join the Twiterrati and become active hepatotweeps.
The academic presence of the Society will widen beyond the USCAP meeting with a joint session by Hans Popper Society and European Digestive Diseases working group at the 2018 European Society of Pathology meeting. We hope that this collaboration will continue in the future and our Society will have a regular presence at international meetings.

The society is engaged in several member-centric activities such as Journal Watch, Case of the Month and quarterly newsletters. If you are interested to contribute to these activities, join one of the committees, or would like to share ideas or feedback, please contact the committee chairs or any of the executive committee members. Your involvement is key to the success of the Society and I look forward to working with all of you in the coming year.


Sanjay Kakar, MD
President, Hans Popper Society

Friday, May 4, 2018

Interesting Case: April 2018

Case submitted by
Kalpesh Patel M.D. 1, Cassandra Gandle M.D. 2, Sadhna Dhingra M.D. 3
1. Department of Gastroenterology, Baylor College of Medicine, Houston TX
2. Department of Internal Medicine, Baylor College of Medicine, Houston TX
3. Department of Pathology and Immunology, Baylor College of Medicine, Houston TX

A 55 year-old Hispanic woman with rheumatoid arthritis, chronic back pain, disc prolapse and multiple surgeries on chronic opiate use, presents with chronic abdominal pain and rectal bleeding. Her gastric emptying studies were normal. Rectal bleeding was mild and secondary to hemorrhoids. Laboratory studies showed normal liver function tests, including normal transaminases and normal alkaline phosphatase. Urinalysis on multiple occasions over the past 3 years showed trace proteinuria. She underwent an esophagogastroduodenoscopy to rule out chronic pancreatitis.

Endoscopic findings for esophagus, stomach and duodenum were normal. There were no endoscopic changes in common bile duct and pancreas. Endosonographic imaging showed diffuse abnormal echotexture in the left lobe of the liver. This was characterized by a hyperechoic appearance. EUS-FNA (fine needle biopsy) of the liver was performed.

The liver biopsy showed multifocal amorphous globular eosinophilic deposits in a perivenular (zone 3) and portal/periportal distribution. These deposits were congophilic (congo red stain) and showed apple green birefringence on polarizing microscopy. The deposits also displayed fluorescence on fluorescent microscopy using Texas Red filter. The background liver parenchyma was unremarkable. No steatosis, lobular or portal inflammation was seen. No portal fibrosis was seen. The tissue was sent to Mayo Clinic Laboratories for mass spectroscopic analysis for accurate identification of amyloid. However, the amyloid deposition was minimal and insufficient for the mass spectroscopy to be performed. The diagnosis was based on the morphology and pattern of distribution.


Liver is a frequent site of amyloid deposition in systemic amyloidosis. The most common type of amyloid deposition is AL (light chain-associated) amyloid or SAA (serum amyloid A) amyloid. We report a case of incidental hepatic ALECT2 in a hispanic female with clinical history significant for rheumatoid arthritis (RA). RA is a chronic inflammatory disease, which is usually associated with acute phase reactant serum amyloid A deposition in organs. Our patient had normal liver function tests and underwent an EUS-guided liver biopsy for abnormal echotexture while being evaluated for abdominal pain. The diagnosis of ALECT2 was made based on the morphology and pattern of distribution of amyloid deposition in the liver. Pure globular hepatic amyloid is specific for LECT2 amyloid. 1 Immunostain for LECT 2 using mouse monoclonal IgG antibody is highly specific and sensitive.

Leucocyte cell-derived chemotaxin 2 (LECT 2) is a relatively recently described amyloid protein first recognized in the international classification of amyloidosis in 2010. 2 It’s deposition was first described in the kidneys in 2008. 3 Although, abnormal amyloid bodies were noted in liver by Livni et al 4 as early as 1977, hepatic “globular’ amyloid deposition was first described in 1981. 5 The clinical significance of these deposits was unknown at the time of first description, and it was considered not to be distinctive from other systemic amyloidosis. 5, 6 In 2007, Makhlouf and Goodman, 7 reported globular hepatic amyloid in 9.6% of cases with hepatic amyloidosis, and hypothesized that this may represent an early form of liver involvement in generalized amyloidosis. Subsequently, the first case of hepatic ALECT2 was reported in 2014. 8 Chandan et al (2015) 1 reported that globular hepatic amyloid is highly sensitive and specific for ALECT2.
ALECT2 is associated with a distinctive clinical and pathological profile. It occurs in Hispanic patients with a median age range of 60.5 years and has female predilection. It has also been reported in other ethnic groups such as Punjabis (ethnic group in India and Pakistan), Arabs, Israelis, Native Americans and First Nation People from British Columbia. 9 The most common site of deposition is kidney and liver, but rare cases have been reported in spleen, small bowel, pancreas, gallbladder, parathyroid, prostate and lung. 10, 11 In contrast to AL amyloidosis or SAA amyloidosis, the presence of hepatic ALECT 2 is incidental, and not associated with abnormal liver function tests. 12 The pathogenesis of ALECT2 is unknown. The LECT2 protein is secreted by hepatocytes by the activation of LECT 2 gene present on chromosome 5q31.1. It is hypothesized that constitutive activation of gene or activation secondary to hepatocellular damage leads to secretion of LECT 2.

ALECT2 (globular amyloid) is a recently described distinctive subtype of amyloid. This is seen in predominantly in Hispanic population with a male to female ratio of 0.6:1. It is an incidental finding in the liver biopsies. The amyloid deposition can be minimal/minute in some cases, and in this situation the demonstration of apple green birefringence of congophilic material by polarizing microscopy can be quite challenging. In this situation, congo red fluorescence using Texas Red filter increases the diagnostic yield. 13 Based on the current literature, at the time of reporting of this case, hepatic ALECT2 is not associated with clinically significant liver disease. However, in kidneys it is associated with slowly progressive chronic renal disease without systemic disease. Therefore, a nephrology consultation may be a consideration when this is first detected in liver biopsies. Knowledge and identification of this specific amyloid is important to avoid unnecessary administration of toxic therapeutic drugs for AL or AA amyloid.

1. Chandan VS, Shah SS, Lam-Himlin DM, Petris GD, Mereuta OM, Dogan A, Torbenson MS, Wu TT. Globular hepatic amyloid is highly sensitive and specific for LECT2 amyloidosis. Am J Surg Pathol. 2015 Apr;39(4):558-64.
2. Sipe JD, Benson MD, Buxbaum JN, Ikeda S, Merlini G, Saraiva MJ, Westermark P. Amyloid fibril protein nomenclature: 2010 recommendations from the nomenclature committee of the International Society of Amyloidosis. Amyloid. 2010 Sep;17(3-4):101-4.
3. Benson MD, James S, Scott K, Liepnieks JJ, Kluve-Beckerman B. Leukocyte chemotactic factor 2: A novel renal amyloid protein. Kidney Int. 2008 Jul;74(2):218-22.
4. Livni N, Behar AJ, Lafair JS. Unusual amyloid bodies in human liver. Ultrastructural and freeze-etching studies. Isr J Med Sci. 1977;13:1163–1170.
5. French SW, Schloss GT, Stillman AE. Unusual amyloid bodies in human liver. Am J Clin Pathol. 1981 Mar;75(3):400-2.
6. Kanel GC, Uchida T, Peters RL. Globular hepatic amyloid--an unusual morphologic presentation. Hepatology. 1981 Nov-Dec;1(6):647-52.
7. Makhlouf HR, Goodman ZD. Globular hepatic amyloid: an early stage in the pathway of amyloid formation: a study of 20 new cases. Am J Surg Pathol. 2007 Oct;31(10):1615-21
8. Damlaj M, Amre R, Wong P, How J. Hepatic ALECT-2 amyloidosis causing portal hypertension and recurrent variceal bleeding: a case report and review of the literature. Am J Clin Pathol. 2014 Feb;141(2):288-91
9. Nasr SH, Dogan A, Larsen CP. Leukocyte Cell-Derived Chemotaxin 2-Associated Amyloidosis: A Recently Recognized Disease with Distinct Clinicopathologic Characteristics. Clin J Am Soc Nephrol. 2015 Nov 6;10(11):2084-93.
10. Said SM, Sethi S, Valeri AM, Chang A, Nast CC, Krahl L, Molloy P, Barry M, Fidler ME, Cornell LD, Leung N, Vrana JA, Theis JD, Dogan A, Nasr SH. Characterization and outcomes of renal leukocyte chemotactic factor 2-associated amyloidosis. Kidney Int. 2014 Aug;86(2):370-7.
11. Khalighi MA, Yue A, Hwang MT, Wallace WD. Leukocyte chemotactic factor 2 (LECT2) amyloidosis presenting as pulmonary-renal syndrome: a case report and review of the literature. Clin Kidney J. 2013 Dec;6(6):618-21.
12. Mereuta OM, Theis JD, Vrana JA, Law ME, Grogg KL, Dasari S, Chandan VS, Wu TT, Jimenez-Zepeda VH, Fonseca R, Dispenzieri A, Kurtin PJ, Dogan A. Leukocyte cell-derived chemotaxin 2 (LECT2)-associated amyloidosis is a frequent cause of hepatic amyloidosis in the United States. Blood. 2014 Mar 6;123(10):1479-82.
13. Clement CG, Truong LD. An evaluation of Congo red fluorescence for the diagnosis of amyloidosis. Hum Pathol. 2014 Aug;45(8):1766-72