Publications by authors named "Michael S Torbenson"

140 Publications

Human liver organoids for disease modeling of fibrolamellar carcinoma.

Stem Cell Reports 2022 Aug 7;17(8):1874-1888. Epub 2022 Jul 7.

Laboratory of Cellular Biophysics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA. Electronic address:

Fibrolamellar carcinoma (FLC) is a rare, often lethal, liver cancer affecting adolescents and young adults, for which there are no approved therapeutics. The development of therapeutics is hampered by a lack of in vitro models. Organoids have shown utility as a model system for studying many diseases. In this study, tumor tissue and the adjacent non-tumor liver were obtained at the time of surgery. The tissue was dissociated and grown as organoids. We developed 21 patient-derived organoid lines: 12 from metastases, three from the liver tumor and six from adjacent non-tumor liver. These patient-derived FLC organoids recapitulate the histologic morphology, immunohistochemistry, and transcriptome of the patient tumor. Patient-derived FLC organoids were used in a preliminary high-throughput drug screen to show proof of concept for the identification of therapeutics. This model system has the potential to improve our understanding of this rare cancer and holds significant promise for drug testing and development.
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http://dx.doi.org/10.1016/j.stemcr.2022.06.003DOI Listing
August 2022

Eosinophilic Disorders of the Gastrointestinal Tract and Associated Abdominal Viscera: Imaging Findings and Diagnosis.

Radiographics 2022 Jul-Aug;42(4):1081-1102. Epub 2022 Jun 24.

From the Department of Radiology (M.Y., A.D.T.A., Z.S.K., M.L.W., J.P.H., S.P.S., J.L.F., S.K.V.) and Department of Laboratory Medicine and Pathology (M.S.T.), Mayo Clinic, 200 2nd St SW, Rochester, MN 55905; and Department of Diagnostic Imaging, National University Health System, Singapore (L.L.S.T.).

Eosinophilic gastrointestinal disorders (EGIDs) are inflammatory conditions of the gastrointestinal tract that are characterized by tissue eosinophilia and end-organ dysfunction or damage. Primary EGIDs are associated with atopy and other allergic conditions, whereas secondary EGIDs are associated with underlying systemic diseases or hypereosinophilic syndrome. Within the spectrum of EGIDs, eosinophilic esophagitis is the most prevalent. Eosinophilic gastroenteritis and eosinophilic colitis are relatively uncommon. Eosinophilic infiltration of the liver, biliary tree, and/or pancreas also can occur and mimic other inflammatory and malignant conditions. Although endoscopic evaluation is the method of choice for eosinophilic esophagitis, radiologic evaluation of the esophagus plays an important role in the assessment of disease severity. CT and MR enterography are the modalities of choice for demonstrating specific forms of eosinophilic gastroenteritis. CT and MRI are important in the detection of abdominal visceral involvement in EGIDs. Diagnosis is often challenging and relies on symptoms, imaging findings, histologic confirmation of tissue eosinophilia, and correlation with peripheral eosinophilia. Imaging is crucial for identifying characteristic organ-specific findings, although imaging findings are not specific. When promptly treated, EGIDs usually have a benign clinical course. However, a delayed diagnosis and associated surgical interventions have been associated with morbidity. Therefore, a radiologist's knowledge of the imaging findings of EGIDs in the appropriate clinical settings may aid in early diagnosis and thereby improve patient care. An overview of the clinical features and imaging findings of EGIDs and the eosinophilic disorders of associated abdominal viscera is provided. RSNA, 2022.
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http://dx.doi.org/10.1148/rg.220004DOI Listing
July 2022

MR elastography in primary sclerosing cholangitis: a pictorial review.

Abdom Radiol (NY) 2022 May 14. Epub 2022 May 14.

Department of Radiology, Mayo Clinic, Rochester, MN, USA.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by biliary ductal inflammation and fibrosis causing both intrahepatic and extrahepatic biliary strictures and dilatation. There is currently no effective medical treatment and the disease leads to cirrhosis and liver failure, with patients often requiring liver transplantation in end-stage disease. Liver fibrosis is one of the most important factors in determining patient outcome in PSC, and the diagnosis and monitoring of fibrosis are vital to patient care. MRI with magnetic resonance cholangiopancreatography is the non-invasive imaging modality of choice in PSC and is useful for the evaluation of parenchymal and biliary changes. Biliary ductal abnormalities, however, cannot always predict the presence of liver fibrosis and alternative means are needed. MR Elastography (MRE) is the most accurate non-invasive method for assessing liver fibrosis and is particularly helpful in PSC due to unique hepatic manifestations. Like other non-invasive modalities, MRE measures liver stiffness as an indirect method for assessing fibrosis. Given the ability of MRE to assess liver fibrosis and the importance of fibrosis in PSC patients, MRE can reliably predict patient outcome. In this pictorial review, we will review MR findings of PSC, with an emphasis on MRE, and demonstrate scenarios where MRE is particularly helpful in evaluating PSC patients.
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http://dx.doi.org/10.1007/s00261-022-03529-xDOI Listing
May 2022

Hepatic Adenomas in Patients 60 and Older Are Enriched for HNF1A Inactivation and Malignant Transformation.

Am J Surg Pathol 2022 06 6;46(6):786-792. Epub 2022 Apr 6.

Division of Anatomic Pathology, Mayo Clinic, Rochester, MN.

Hepatic adenomas occur most commonly in women between the ages of 20 and 40 years, but rarely they occur in older aged persons, including those 60 years of age or older. This group of adenomas, however, has not been systemically examined. Twenty-six hepatic adenomas in persons 60 years of age or older were studied, along with a control group of 50 hepatic adenomas in persons aged 30 to 39. Hepatic adenomas in persons 60 or more years of age were found in 21 women and 5 men, while the control group had 44 women and 6 men. Subtyping the adenomas in persons 60 years or older showed the following results: 18 HNF1A-inactivated adenomas (69%), 4 inflammatory adenomas (15%), and 4 unclassified adenomas (15%). In contrast, the control group showed a significantly different pattern (P=0.003), with a greater percentage of inflammatory adenomas (28, 56%), fewer HNF1A-inactivated adenomas (8, 16%), and more unclassified adenomas (14, 28%). Atypia and malignant transformation within the hepatic adenomas was studied next. Of the hepatic adenomas in persons age 60 or greater, 3 (12%) showed atypical histologic features, and 6 (23%) had a malignant transformation. In contrast, for hepatic adenomas in the control group, only 4 (8%) adenomas showed atypical histologic features, and 3 (6%) had undergone malignant transformation. In addition, the hepatic adenomas that were atypical or showed early malignant transformation were less likely to have beta-catenin activation in patients over 60 (2/9 cases) compared with those between 30 and 39 years (5/7 cases). Myxoid change and heavy lipofuscin deposition were also more common in adenomas in older aged persons. In conclusion, hepatic adenomas in persons 60 years of age or older are enriched for HNF1A-inactivated adenomas and have a higher frequency of malignant transformation. Malignant transformation, however, is less likely to develop through activation of the beta-catenin pathway.
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http://dx.doi.org/10.1097/PAS.0000000000001892DOI Listing
June 2022

Neuropilin-1 deficiency in vascular smooth muscle cells is associated with hereditary hemorrhagic telangiectasia arteriovenous malformations.

JCI Insight 2022 05 9;7(9). Epub 2022 May 9.

Vascular and Interventional Radiology Translational laboratory, Division of Vascular and Interventional Radiology, Department of Radiology.

Patients with hereditary hemorrhagic telangiectasia (HHT) have arteriovenous malformations (AVMs) with genetic mutations involving the activin-A receptor like type 1 (ACVRL1 or ALK1) and endoglin (ENG). Recent studies have shown that Neuropilin-1 (NRP-1) inhibits ALK1. We investigated the expression of NRP-1 in livers of patients with HHT and found that there was a significant reduction in NRP-1 in perivascular smooth muscle cells (SMCs). We used Nrp1SM22KO mice (Nrp1 was ablated in SMCs) and found hemorrhage, increased immune cell infiltration with a decrease in SMCs, and pericyte lining in lungs and liver in adult mice. Histologic examination revealed lung arteriovenous fistulas (AVFs) with enlarged liver vessels. Evaluation of the retina vessels at P5 from Nrp1SM22KO mice demonstrated dilated capillaries with a reduction of pericytes. In inflow artery of surgical AVFs from the Nrp1SM22KO versus WT mice, there was a significant decrease in Tgfb1, Eng, and Alk1 expression and phosphorylated SMAD1/5/8 (pSMAD1/5/8), with an increase in apoptosis. TGF-β1-stimulated aortic SMCs from Nrp1SM22KO versus WT mice have decreased pSMAD1/5/8 and increased apoptosis. Coimmunoprecipitation experiments revealed that NRP-1 interacts with ALK1 and ENG in SMCs. In summary, NRP-1 deletion in SMCs leads to reduced ALK1, ENG, and pSMAD1/5/8 signaling and reduced cell death associated with AVM formation.
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http://dx.doi.org/10.1172/jci.insight.155565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9090252PMC
May 2022

Hemochromatosis.

Mayo Clin Proc 2022 02;97(2):423-424

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.

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http://dx.doi.org/10.1016/j.mayocp.2021.12.008DOI Listing
February 2022

Hepatocellular neoplasms with loss of liver fatty acid binding protein: Clinicopathologic features and molecular profiling.

Hum Pathol 2022 04 31;122:60-71. Epub 2022 Jan 31.

Department of Pathology, University of California, San Francisco, CA, 94143, USA. Electronic address:

HNF1A-inactivated hepatocellular adenomas (H-HCA) show steatosis, no atypia and loss of liver fatty acid binding protein (LFABP). LFABP loss also occurs in hepatocellular carcinoma (HCC). This study examines 68 LFABP-negative tumors: 33 typical H-HCA, 10 atypical hepatocellular neoplasms (AHN), 7 well-differentiated (WD) HCC, 18 moderately or poorly differentiated (MD/PD) HCC. Capture based sequencing was performed in 13 cases (8 AHN, 5 WD-HCC). Patients with HCA, AHN and WD-HCC were nearly all women. AHN and WD-HCC resembled H-HCA but had higher degree of atypia and/or reticulin loss. Variant features like inconspicuous fat (59% vs. 12%, p = 0.03), predominance of eosinophilic cells (59% vs. 21%, p = 0.01) and pseudoacini were more common in AHN and WD-HCC. Myxoid change and prominent lipofuscin were more common in WD-HCC (29% each) than H-HCA and AHN combined (2% and 7% respectively). Compared to WD-HCC, LFABP-negative MD/PD HCC were more commonly associated with male gender, viral hepatitis and cirrhosis. Biallelic HNF1A alterations were seen in all 13 (100%) sequenced cases. Additional mutations and/or copy number alterations were observed in 38% of AHN and 100% of WD-HCC. Diffuse glutamine synthetase (GS) staining was seen in 13% of cases, with no nuclear β-catenin or Wnt signaling alterations. In conclusion, variant features such as lack of fat, peliosis, myxoid change, pseudoacini and abundant lipofuscin are more common in AHN and/or WD-HCC. LFABP-negative MD/PD HCC have different clinicopathologic features compared to WD-HCC. The significance of diffuse GS in a subset of these cases is unclear.
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http://dx.doi.org/10.1016/j.humpath.2022.01.007DOI Listing
April 2022

Liver fibrosis quantification.

Abdom Radiol (NY) 2022 03 12;47(3):1032-1052. Epub 2022 Jan 12.

Anatomic Pathology Division, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

Liver fibrosis (LF) is the wound healing response to chronic liver injury. LF is the endpoint of chronic liver disease (CLD) regardless of etiology and the single most important determinant of long-term liver-related clinical outcomes. Quantification of LF is important for staging, to evaluate response to treatment and to predict outcomes. LF is traditionally staged by liver biopsy. However, liver biopsy is invasive and suffers from sampling errors when biopsy size is inadequate; therefore, non-invasive tests (NITs) have found important roles in clinical care. NITs include simple laboratory-based serum tests, panels of serum tests, and imaging biomarkers. NITs are validated against the liver biopsy and will be used in the future for evaluation of nearly all CLDs with invasive liver biopsy reserved for some cases. Both serum tests and some imaging biomarkers such as elastography are currently used clinically as surrogate markers for LF. Several other imaging biomarkers are still considered research and awaiting clinical application in the future. As the evaluation of imaging biomarkers will likely become the norm in the future, understanding pathogenesis of LF is important. Knowledge of properties measured by imaging biomarkers and its correlation with LF is important to understand the application of NITs by abdominal radiologists. In this review, we present a brief overview of pathogenesis of LF, spatiotemporal evolution of LF in different CLD, and severity assessment with liver biopsy. This will be followed by a brief discussion on properties measured by imaging biomarkers and their relationship to the LF.
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http://dx.doi.org/10.1007/s00261-021-03396-yDOI Listing
March 2022

PSMA as a Theranostic Target in Hepatocellular Carcinoma: Immunohistochemistry and Ga-PSMA-11 PET Using Cyclotron-Produced Ga.

Hepatol Commun 2022 05 15;6(5):1172-1185. Epub 2021 Nov 15.

Department of Radiology, Mayo Clinic, Rochester, MN, USA.

Prostate-specific membrane antigen (PSMA) is a validated target for molecular diagnostics and targeted radionuclide therapy. Our purpose was to evaluate PSMA expression in hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and hepatic adenoma (HCA); investigate the genetic pathways in HCC associated with PSMA expression; and evaluate HCC detection rate with Ga-PSMA-11 positron emission tomography (PET). In phase 1, PSMA immunohistochemistry (IHC) on HCC (n = 148), CCA (n = 111), and HCA (n = 78) was scored. In a subset (n = 30), messenger RNA (mRNA) data from the Cancer Genome Atlas HCC RNA sequencing were correlated with PSMA expression. In phase 2, Ga-PSMA-11 PET was prospectively performed in patients with treatment-naïve HCC on a digital PET scanner using cyclotron-produced Ga. Uptake was graded qualitatively and semi-quantitatively using standard metrics. On IHC, PSMA expression was significantly higher in HCC compared with CCA and HCA (P < 0.0001); 91% of HCCs (n = 134) expressed PSMA, which principally localized to tumor-associated neovasculature. Higher tumor grade was associated with PSMA expression (P = 0.012) but there was no association with tumor size (P = 0.14), fibrosis (P = 0.35), cirrhosis (P = 0.74), hepatitis B virus (P = 0.31), or hepatitis C virus (P = 0.15). Overall survival tended to be longer in patients without versus with PSMA expression (median overall survival: 4.2 vs. 1.9 years; P = 0.273). FGF14 (fibroblast growth factor 14) mRNA expression correlated positively (rho = 0.70; P = 1.70 × 10 ) and MAD1L1 (Mitotic spindle assembly checkpoint protein MAD1) correlated negatively with PSMA expression (rho = -0.753; P = 1.58 × 10 ). Of the 190 patients who met the eligibility criteria, 31 patients with 39 HCC lesions completed PET; 64% (n = 25) lesions had pronounced Ga-PSMA-11 standardized uptake value: SUV (median [range] 9.2 [4.9-28.4]), SUV 4.7 (2.4-12.7), and tumor-to-liver background ratio 2 (1.1-11). Conclusion: Ex vivo expression of PSMA in neovasculature of HCC translates to marked tumor avidity on Ga-PSMA-11 PET, which suggests that PSMA has the potential as a theranostic target in patients with HCC.
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http://dx.doi.org/10.1002/hep4.1861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9035563PMC
May 2022

Morphologic and Molecular Findings in Myxoid Hepatic Adenomas.

Am J Surg Pathol 2021 08;45(8):1098-1107

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.

Myxoid hepatic adenomas are a rare subtype of hepatic adenomas with distinctive deposition of extracellular myxoid material between the hepatic plates. A total of 9 cases were identified in 6 women and 3 men with an average of 59±12 years. The myxoid adenomas were single tumors in 5 cases and multiple in 4 cases. In 1 case with multiple adenomas, the myxoid adenoma arose in the background of GNAS-mutated hepatic adenomatosis. Myxoid hepatic adenomas had a high frequency of malignant transformation (N=5 cases). They were characterized at the molecular level by HNF1A inactivating mutations, leading to loss of LFABP protein expression. In addition, myxoid adenomas had recurrent mutations in genes within the protein kinase A (PKA) pathway or in genes that regulate the PKA pathway: GNAS, CDKN1B (encodes p27), and RNF123. In sum, myxoid adenomas are rare, occur in older-aged persons, have a high risk of malignant transformation, and are characterized by the combined inactivation of HNF1A and additional mutations that appear to cluster in the PKA pathway.
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http://dx.doi.org/10.1097/PAS.0000000000001711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8608350PMC
August 2021

Pediatric Hepatocellular Adenomas: The Influence of Age and Syndrome on Subtype.

Am J Surg Pathol 2021 12;45(12):1641-1647

Departments of Laboratory Medicine and Pathology.

Hepatocellular adenomas are rare in children. A large study focused on pediatric patients has not been undertaken. A natural language search was performed at 5 institutions for hepatocellular adenomas in patients younger than 21 years old. Clinical characteristics as well as immunohistochemical staining profile was reviewed and adenomas subtyped per standard classification. Patients were divided into prepubescent and postpubescent age group. Thirty-one patients were included. Eleven (35%) were male and 10 (32%) were prepubescent. Fifteen (54%) of 28 patients with known clinical histories had adenomas associated with a syndrome. The percentage of the different adenoma subtypes was: 16% β-catenin activated, 10% combined inflammatory and β-catenin activated, 29% HFN1α-inactivated, 35% inflammatory, and 10% unclassified subtype by immunohistochemical staining. Interestingly 53% of patients with syndromes were male, while 85% of patients in the nonsyndromic group were female. The total number of β-catenin activated tumors was greater in the syndromic group (5/15, 33%) and prepubescent group (5/10, 50%) than in the nonsyndromic group (2/13, 16%) and postpubescent group (3/21, 14%), P=0.4 and 0.07, respectively. Inflammatory type adenoma was more frequent in the postpubescent (10/21, 48%) than in the prepubescent group (1/10, 10%), P=0.06, trending toward significance. Pediatric patients with hepatocellular adenomas frequently have syndromes, especially in the prepubescent group. In patients with syndromes a greater percentage of adenomas were β-catenin activated. In patients without a known syndrome the distribution of hepatocellular adenoma subtypes appears similar to adults.
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http://dx.doi.org/10.1097/PAS.0000000000001763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8608351PMC
December 2021

Identification of Novel Therapeutic Targets for Fibrolamellar Carcinoma Using Patient-Derived Xenografts and Direct-from-Patient Screening.

Cancer Discov 2021 10 14;11(10):2544-2563. Epub 2021 Jun 14.

Pediatric Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.

To repurpose therapeutics for fibrolamellar carcinoma (FLC), we developed and validated patient-derived xenografts (PDX) from surgical resections. Most agents used clinically and inhibitors of oncogenes overexpressed in FLC showed little efficacy on PDX. A high-throughput functional drug screen found primary and metastatic FLC were vulnerable to clinically available inhibitors of TOPO1 and HDAC and to napabucasin. Napabucasin's efficacy was mediated through reactive oxygen species and inhibition of translation initiation, and specific inhibition of eIF4A was effective. The sensitivity of each PDX line inversely correlated with expression of the antiapoptotic protein Bcl-xL, and inhibition of Bcl-xL synergized with other drugs. Screening directly on cells dissociated from patient resections validated these results. This demonstrates that a direct functional screen on patient tumors provides therapeutically informative data within a clinically useful time frame. Identifying these novel therapeutic targets and combination therapies is an urgent need, as effective therapeutics for FLC are currently unavailable. SIGNIFICANCE: Therapeutics informed by genomics have not yielded effective therapies for FLC. A functional screen identified TOPO1, HDAC inhibitors, and napabucasin as efficacious and synergistic with inhibition of Bcl-xL. Validation on cells dissociated directly from patient tumors demonstrates the ability for functional precision medicine in a solid tumor..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8734228PMC
October 2021

Sulfatase 2 (SULF2) Monoclonal Antibody 5D5 Suppresses Human Cholangiocarcinoma Xenograft Growth Through Regulation of a SULF2-Platelet-Derived Growth Factor Receptor Beta-Yes-Associated Protein Signaling Axis.

Hepatology 2021 09 24;74(3):1411-1428. Epub 2021 May 24.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.

Background And Aims: Existing therapeutic approaches to treat cholangiocarcinoma (CCA) have limited effectiveness, prompting further study to develop therapies for CCA. We report a mechanistic role for the heparan sulfate editing enzyme sulfatase 2 (SULF2) in CCA pathogenesis.

Approach And Results: In silico analysis revealed elevated SULF2 expression in human CCA samples, occurring partly through gain of SULF2 copy number. We examined the effects of knockdown or overexpression of SULF2 on tumor growth, chemoresistance, and signaling pathway activity in human CCA cell lines in vitro. Up-regulation of SULF2 in CCA leads to increased platelet-derived growth factor receptor beta (PDGFRβ)-Yes-associated protein (YAP) signaling activity, promoting tumor growth and chemotherapy resistance. To explore the utility of targeting SULF2 in the tumor microenvironment for CCA treatment, we tested an anti-SULF2 mouse monoclonal antibody, 5D5, in a mouse CCA xenograft model. Targeting SULF2 by monoclonal antibody 5D5 inhibited PDGFRβ-YAP signaling and tumor growth in the mouse xenograft model.

Conclusions: These results suggest that SULF2 monoclonal antibody 5D5 or related agents may be potentially promising therapeutic agents in CCA.
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http://dx.doi.org/10.1002/hep.31817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9075007PMC
September 2021

Hepatocellular carcinoma: making sense of morphological heterogeneity, growth patterns, and subtypes.

Hum Pathol 2021 06 30;112:86-101. Epub 2020 Dec 30.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA. Electronic address:

Hepatocellular carcinomas are not a homogenous group of tumors but have multiple layers of heterogeneity. This heterogeneity has been studied for many years with the goal to individualize care for patients and has led to the identification of numerous hepatocellular carcinoma subtypes, defined by morphology and or molecular methods. This article reviews both gross and histological levels of heterogeneity within hepatocellular carcinoma, with a focus on histological findings, reviewing how different levels of histological heterogeneity are used as building blocks to construct morphological hepatocellular carcinoma subtypes. The current best practice for defining a morphological subtype is outlined. Then, the definition for thirteen distinct hepatocellular carcinoma subtypes is reviewed. For each of these subtypes, unresolved issues regarding their definitions are highlighted, including recommendations for these problematic areas. Finally, three methods for improving the research on hepatocellular carcinoma subtypes are proposed: (1) Use a systemic, rigorous approach for defining hepatocellular carcinoma subtypes (four-point model); (2) Once definitions for a subtype are established, it should be followed in research studies, as this common denominator enhances the ability to compare results between studies; and (3) Studies of subtypes will be more effective when morphological and molecular results are used in synergistic and iterative study designs where the results of one approach are used to refine and sharpen the results of the other. These and related efforts to better understand heterogeneity within hepatocellular carcinoma are the most promising avenue for improving patient care by individualizing patient care.
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http://dx.doi.org/10.1016/j.humpath.2020.12.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9258523PMC
June 2021

Hepatocellular neoplasms arising in genetic metabolic disorders: steatosis is common in both the tumor and background liver.

Hum Pathol 2021 02 24;108:93-99. Epub 2020 Nov 24.

University of Washington, Department of Laboratory Medicine and Pathology, Seattle, WA 98195, United States; University of Washington, Department of Medicine, Seattle, WA 98195, United States. Electronic address:

Hepatocellular neoplasms can develop in multiple genetic metabolic disorders. While there have been rare case reports, clinical and pathological characterizations have not been systematically performed. We conducted a retrospective study in 9 patients with these rare genetic metabolic disorders, including glycogen storage disease type 1, ornithine carbamyl transferase deficiency, hereditary tyrosinemia type 1, and Navajo neurohepatopathy, who developed hepatocellular neoplasms. Our results show that steatosis is a common finding in both tumor (6/9 cases, 67%) and background liver parenchyma (8/9 cases, 89%), underlying a possible role for steatosis in tumorigenesis in these genetic metabolic disorders. Our findings also raise a consideration of underlying genetic metabolic disorder when young patients with hepatocellular neoplasm show steatosis in both the tumor and background liver.
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http://dx.doi.org/10.1016/j.humpath.2020.11.012DOI Listing
February 2021

Aberrant keratin expression is common in primary hepatic malignant vascular tumors: A potential diagnostic pitfall.

Ann Diagn Pathol 2020 Dec 15;49:151589. Epub 2020 Aug 15.

Department of Pathology and Laboratory Medicine, University of California-Irvine, CA, United States of America. Electronic address:

Malignant vascular neoplasms such as epithelioid hemangioendothelioma (EHE) and angiosarcoma (AS) can arise within the liver. The aim of this study was to study the expression of keratins CK7, AE1/AE3 and OSCAR in primary hepatic EHE and AS. 9 cases of hepatic EHE and 13 cases of hepatic AS were stained with ERG, CK7, keratin AE1/AE3 and keratin OSCAR. Their expression was graded as 1+ (1-25% of tumor cells positive), 2+ (26-50%), 3+ (51-75%) or 4+ (>75%). ERG was positive in all 9 (100%) EHEs and all 13 (100%) ASs. CK7 was positive in 5/9 (56%) EHEs (2, 1+; 1, 2+; 1, 3+; 1, 4+) and 1/13 (8%) AS (2+). Keratin OSCAR was positive in 6/9 (67%) EHEs (5, 1+; 1, 2+) and 4/13 (31%) ASs (2, 1+; 1, 2+; 1, 4+). Keratin AE1/AE3 was positive in 6/9 (67%) EHEs (3, 1+; 3; 2+) and 4/13 (31%) ASs (2, 1+; 1, 2+; 1, 4+). Overall, 6/ 9 (67%) EHEs were positive for at least one keratin marker, of which 5 were positive for all 3 keratins (AE1/AE3, OSCAR and CK7) while 1 was positive only for 2 keratins (OSCAR and AE1/AE3). 4/13 (31%) of ASs were positive for both keratins OSCAR and AE1/AE3, of which 1 case was also positive for CK7. Aberrant keratin expression is common in primary hepatic EHEs (67%) and ASs (31%). Awareness of this diagnostic pitfall is important for avoiding misdiagnosis of these primary hepatic malignant vascular tumors as carcinomas.
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http://dx.doi.org/10.1016/j.anndiagpath.2020.151589DOI Listing
December 2020

Amyloid-like Fibronectin Deposits in the Liver: A Novel Morphologic Finding.

Am J Surg Pathol 2021 02;45(2):205-208

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.

Amyloid deposits in the liver are recognized by their hematoxylin and eosin (H&E) findings, consisting of acellular eosinophilic deposits in various compartments of the liver parenchyma, including the stroma, vessels, and rarely the hepatocytes. H&E findings that suggest amyloid are then confirmed by Congo red stains and subtyped when clinically needed. Two cases are reported with sinusoidal deposits of acellular material that closely mimicked amyloid on H&E, but were Congo red negative. Mass spectrometry-based proteomic analysis identified the material as fibronectin. In 1 case, the deposits were located in the sinusoids of a well-differentiated hepatocellular carcinoma and in 1 case in the sinusoids of a benign liver.
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http://dx.doi.org/10.1097/PAS.0000000000001585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796990PMC
February 2021

Carboxypeptidase A1 and regenerating islet-derived 1α as new markers for pancreatic acinar cell carcinoma.

Hum Pathol 2020 09 21;103:120-126. Epub 2020 Jul 21.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, United States.

Acinar cell carcinoma (ACC) is a rare tumor that differentiates toward pancreatic acinar cells and shows evidence of pancreatic enzyme production. Mixed acinar-neuroendocrine carcinoma (MANC) is defined as having more than 30% of both acinar and neuroendocrine cell types as per immunohistochemistry analysis. Trypsin is currently the most commonly used stain for acinar differentiation. In this study, we investigate the utility of two novel markers, carboxypeptidase A1 (CPA1) and regenerating islet-derived 1α (REG1a), in diagnosing ACC/MANC. Immunohistochemical staining for CPA1 and REG1a was performed on 14 cases of ACC and 5 cases of MANC as well as on 80 other pancreatic tumors including 20 cases each of ductal adenocarcinoma, well-differentiated neuroendocrine tumor, mucinous cystic neoplasm, and solid pseudopapillary tumor. All ACCs and MANCs were positive for CPA1 (all diffuse) and REG1a (12 diffuse, 4 patchy, and 3 focal). A diffuse or patchy staining pattern was significantly more common in ACC/MANC cases (100% diffuse/patchy for CPA1 and 84% for REG1a) than in other pancreatic tumors (5% diffuse/patchy for CPA1 and 7.5% for REG1a), with a P-value of <0.0001 for both CPA1 and REG1a. The sensitivity and specificity of diffuse/patchy staining for CPA1 and REG1a in diagnosing pancreatic ACC/MANC were 100% and 95% for CPA1 and 84% and 93% for REG1a, respectively. In conclusion, CPA1 and REG1a are sensitive markers for ACC that can be used as additional acinar cell differentiation markers to help in the diagnosis of pancreatic ACC and MANC. A negative result for CPA1 virtually excludes ACC/MANC.
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http://dx.doi.org/10.1016/j.humpath.2020.07.019DOI Listing
September 2020

Hepatic Focal Nodular Hyperplasia.

Mayo Clin Proc 2020 07;95(7):1557-1558

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.

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http://dx.doi.org/10.1016/j.mayocp.2020.05.021DOI Listing
July 2020

Ki-67 "hot spot" digital analysis is useful in the distinction of hepatic adenomas and well-differentiated hepatocellular carcinomas.

Virchows Arch 2021 Feb 25;478(2):201-207. Epub 2020 Jun 25.

Department of Laboratory Medicine and Pathology, Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA.

This study aims to investigate the utility of digital protocols for Ki-67 immunohistochemistry quantitative analysis ("hot spot" method) in the setting of well-differentiated hepatocellular neoplasms. Resection cases of typical hepatic adenomas (HAs) (n = 40), atypical HAs (n = 9), and well-differentiated hepatocellular carcinomas (WD HCCs) (n = 56) were selected. HAs were further classified by immunohistochemistry using antibodies against liver fatty acid binding protein, glutamine synthetase, B-catenin, hepatic serum amyloid A, and C-reactive protein. Ki-67 proliferative index by immunohistochemistry was evaluated in all cases by digital analysis using a modified neuroendocrine tumor "hot spot" protocol. The proliferative rate of HAs (typical, median 1.2% (range 0-7.4%) and atypical, median 1.0% (range 0.3-3%)) was significantly lower than that of WD HCCs (median 4.5%, range 0-49.8%) (P < 0.0001). Only a few (7.5%) of the adenomas (all inflammatory/telangiectatic type) had proliferative rates higher than 4%, compared to most (51%) of HCCs. Ki-67 is a potentially useful adjunct marker in the evaluation of WD hepatocellular neoplasms, as "hot spot" proliferative rates are consistently very low in HAs but vary significantly in WD HCCs.
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http://dx.doi.org/10.1007/s00428-020-02868-8DOI Listing
February 2021

Biliary tract cancer patient-derived xenografts: Surgeon impact on individualized medicine.

JHEP Rep 2020 Apr 16;2(2):100068. Epub 2020 Jan 16.

Department of Surgery, Mayo Clinic, Rochester, MN.

Background & Aims: Biliary tract tumors are uncommon but highly aggressive malignancies with poor survival outcomes. Due to their low incidence, research into effective therapeutics has been limited. Novel research platforms for pre-clinical studies are desperately needed. We sought to develop a patient-derived biliary tract cancer xenograft catalog.

Methods: With appropriate consent and approval, surplus malignant tissues were obtained from surgical resection or radiographic biopsy and implanted into immunocompromised mice. Mice were monitored for xenograft growth. Established xenografts were verified by a hepatobiliary pathologist. Xenograft characteristics were correlated with original patient/tumor characteristics and oncologic outcomes. A subset of xenografts were then genomically characterized using Mate Pair sequencing (MPseq).

Results: Between October 2013 and January 2018, 87 patients with histologically confirmed biliary tract carcinomas were enrolled. Of the 87 patients, 47 validated PDX models were successfully generated. The majority of the PDX models were created from surgical resection specimens (n = 44, 94%), which were more likely to successfully engraft when compared to radiologic biopsies ( = 0.03). Histologic recapitulation of original patient tumor morphology was observed in all xenografts. Successful engraftment was an independent predictor for worse recurrence-free survival. MPseq showed genetically diverse tumors with frequent alterations of . Sequencing also identified worse survival in patients with tumors containing tetraploid genomes.

Conclusions: This is the largest series of biliary tract cancer xenografts reported to date. Histologic and genomic analysis of patient-derived xenografts demonstrates accurate recapitulation of original tumor morphology with direct correlations to patient outcomes. Successful development of biliary cancer tumografts is feasible and may be used to direct subsequent therapy in high recurrence risk patients.

Lay Summary: Patient biliary tract tumors grown in immunocompromised mice are an invaluable resource in the treatment of biliary tract cancers. They can be used to guide individualized cancer treatment in high-risk patients.
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http://dx.doi.org/10.1016/j.jhepr.2020.100068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066236PMC
April 2020

Intestinal Spirochetosis.

Mayo Clin Proc 2020 02;95(2):427-428

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.

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http://dx.doi.org/10.1016/j.mayocp.2019.12.003DOI Listing
February 2020

Recurrent Rearrangements in PRKACA and PRKACB in Intraductal Oncocytic Papillary Neoplasms of the Pancreas and Bile Duct.

Gastroenterology 2020 02 31;158(3):573-582.e2. Epub 2019 Oct 31.

Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.

Background & Aims: Intraductal oncocytic papillary neoplasms (IOPNs) of the pancreas and bile duct contain epithelial cells with numerous, large mitochondria and are cystic precursors to pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCA), respectively. However, IOPNs do not have the genomic alterations found in other pancreatobiliary neoplasms. In fact, no recurrent genomic alterations have been described in IOPNs. PDACs without activating mutations in KRAS contain gene rearrangements, so we investigated whether IOPNs have recurrent fusions in genes.

Methods: We analyzed 20 resected pancreatic IOPNs and 3 resected biliary IOPNs using a broad RNA-based targeted sequencing panel to detect cancer-related fusion genes. Four invasive PDACs and 2 intrahepatic CCAs from the same patients as the IOPNs, were also available for analysis. Samples of pancreatic cyst fluid (n = 5, collected before surgery) and bile duct brushings (n = 2) were analyzed for translocations. For comparison, we analyzed pancreatobiliary lesions from 126 patients without IOPN (controls).

Results: All IOPNs evaluated were found to have recurring fusions of ATP1B1-PRKACB (n = 13), DNAJB1-PRKACA (n = 6), or ATP1B1-PRKACA (n = 4). These fusions also were found in corresponding invasive PDACs and intrahepatic CCAs, as well as in matched pancreatic cyst fluid and bile duct brushings. These gene rearrangements were absent from all 126 control pancreatobiliary lesions.

Conclusions: We identified fusions in PRKACA and PRKACB genes in pancreatic and biliary IOPNs, as well as in PDACs and pancreatic cyst fluid and bile duct cells from the same patients. We did not identify these gene fusions in 126 control pancreatobiliary lesions. These fusions might be used to identify patients at risk for IOPNs and their associated invasive carcinomas.
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http://dx.doi.org/10.1053/j.gastro.2019.10.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010554PMC
February 2020

The Role of Magnetic Resonance Elastography in the Diagnosis of Noncirrhotic Portal Hypertension.

Clin Gastroenterol Hepatol 2020 12 17;18(13):3051-3053.e2. Epub 2019 Oct 17.

Department of Radiology, Mayo Clinic, Rochester, Minnesota. Electronic address:

Portal hypertension (PH) is defined as abnormal elevation of portal venous pressure with cirrhosis accounting for 90% of cases and 10% of cases classified as noncirrhotic PH (NCPH). The differentiation of cirrhotic PH (CPH) from NCPH is difficult (Supplementary Figure 1), with recent research efforts focusing on noninvasive evidence of increased hepatic stiffness. Magnetic resonance elastography (MRE) is an established imaging technique in the assessment of hepatic stiffness, and is now the most efficacious, noninvasive method to assess for hepatic fibrosis. The aim of this study was to assess the ability of magnetic resonance imaging (MRI) and MRE to differentiate between CPH and NCPH.
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http://dx.doi.org/10.1016/j.cgh.2019.10.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946339PMC
December 2020

Standardising the interpretation of liver biopsies in non-alcoholic fatty liver disease clinical trials.

Aliment Pharmacol Ther 2019 11 3;50(10):1100-1111. Epub 2019 Oct 3.

London, ON, Canada.

Background: There is substantial variation in how histologic definitions and scoring systems of non-alcoholic fatty liver disease (NAFLD) are operationalised.

Aim: To develop a consensus-based framework for standardising histologic assessment of liver biopsies in clinical trials of NAFLD.

Methods: An expert panel of 14 liver pathologists and three hepatologists was assembled. Using modified RAND/University of California Los Angeles appropriateness methodology, 130 items derived from literature review and expert opinion were rated by each panel member on a 1-9 scale. Disagreement was defined as ≥5 ratings in the lowest (1-3) and highest (7-9) categories. Items were classified as inappropriate (median 1-3.5 without disagreement), uncertain (median 3.5-6.5 or any median with disagreement) or appropriate (median 6.5-9 without disagreement). Survey results were discussed as a group before voting.

Results: Current measures of disease activity and fibrosis may not fully capture important features of non-alcoholic steatohepatitis (NASH). Alternative methods to evaluate ballooning degeneration are needed. Panellists were uncertain whether portal inflammation, degree of steatosis and Mallory-Denk bodies are important measures of disease activity. Furthermore, it was felt that current staging systems do not capture the full spectrum of fibrosis in NASH. A consensus definition and sub-stages for bridging fibrosis are needed. The severity of perisinusoidal fibrosis should be captured at all stages. Lastly, a method to evaluate features of fibrosis regression should be developed.

Conclusion: The operating properties of the modifications proposed should be evaluated prospectively to determine reliability and responsiveness.
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http://dx.doi.org/10.1111/apt.15503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817398PMC
November 2019

Magnetic Resonance Elastography of Liver in Light Chain Amyloidosis.

J Clin Med 2019 May 23;8(5). Epub 2019 May 23.

Department of Radiology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.

In this paper, we present our preliminary findings regarding magnetic resonance elastography (MRE) on the livers of 10 patients with systemic amyloidosis. Mean liver stiffness measurements (LSM) and spleen stiffness measurements (SSM) were obtained. Magnetic resonance imaging (MRI) images were analyzed for the distribution pattern of amyloid deposition. Pearson correlation analysis was performed in order to study the correlation between LSM, SSM, liver span, liver volume, spleen span, spleen volume, serum alkaline phosphatase (ALP), N-terminal pro b-type natriuretic peptide (NT pro BNP), and the kappa and lambda free light chains. An increase in mean LSM was seen in all patients. Pearson correlation analysis showed a statistically significant correlation between LSM and liver volume ( = 0.78, = 0.007) and kappa chain level ( = 0.65, = 0.04). Interestingly, LSM did not correlate significantly with SSM ( = 0.45, = 0.18), liver span ( = 0.57, = 0.08), or serum ALP ( = 0.60, = 0.07). However, LSM correlated significantly with serum ALP when corrected for liver volume (partial correlation, = 0.71, = 0.03) and NT pro BNP levels (partial correlation, = 0.68, = 0.04). MRI review revealed that amyloid deposition in the liver can be diffuse, lobar, or focal. MRE is useful for the evaluation of hepatic amyloidosis and shows increased stiffness in hepatic amyloidosis. MRE has the potential to be a non-invasive quantitative imaging marker for hepatic amyloidosis.
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http://dx.doi.org/10.3390/jcm8050739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572504PMC
May 2019

Anastomosing hemangioma of the liver: a case series.

Abdom Radiol (NY) 2019 08;44(8):2781-2787

Department of Radiology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.

Purpose: To report imaging and pathologic features of five pathologically proven anastomosing hemangiomas of the liver (AHL).

Methods: A retrospective review for AHL was conducted using our institutional database from 6/2004 to 3/2018. Histology proven AHL with radiologic imaging available for review were included. A total of five patients who met our criteria were identified from our institutional database. Computed tomography, ultrasound, and magnetic resonance imaging findings, including location, size, attenuation/signal intensity, enhancement characteristics, and additional imaging data were reviewed. The clinical and pathological data were also reviewed.

Results: The imaging characteristics of AHL are variable, but features such as peripheral or diffuse hyperintensity on diffusion weighted imaging, arterial hyperenhancement without globular interrupted enhancement, and persistent enhancement without complete filling in the delayed phases were more characteristic of AHL. Imaging also demonstrated a lack of aggressive features.

Conclusions: AHL present a diagnostic dilemma as they can mimic more malignant lesions, such as angiosarcoma, both on imaging and at pathology. While the imaging characteristics of AHL are variable, there are some features which can help distinguish AHL from other liver lesions. When the diagnosis of anastomosing hemangioma is known, the management of choice is primarily surveillance, as intervention can cause unnecessary morbidity, and no degeneration to malignancy has been identified to date.
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http://dx.doi.org/10.1007/s00261-019-02043-xDOI Listing
August 2019

Angiosarcoma of the Liver: Clinicopathologic Features and Morphologic Patterns.

Am J Surg Pathol 2019 05;43(5):581-590

Division of Anatomic Pathology, Mayo Clinic, Rochester, MN.

Angiosarcoma is a rare malignant neoplasm of the liver. The various morphologic patterns seen with angiosarcomas of the liver have not been systematically studied and their recognition remains a major diagnostic challenge. In order to provide more comprehensive data on the morphologic patterns, angiosarcomas that had been diagnosed between 1996 and 2016 at a large medical referral center were reviewed. The major growth patterns were classified as sinusoidal (non-mass forming) versus mass forming. The mass-forming cases were further subdivided into epithelioid, spindled, or vasoformative. The study identified 21 patients with primary hepatic angiosarcoma: 13 men and 8 women. The ages ranged from 26 to 89 years. Seventeen angiosarcomas were mass-forming tumors, of which 9 showed predominantly vasoformative growth. Most of these vasoformative cases (6/9) were composed of small vessels, 2 cases had slit-like vascular spaces, and one case showed a mixture of small and large vessels. There were 7 mass-forming angiosarcomas without vasoformation: 3 had an epithelioid morphology and 4 were composed primarily of spindled cells. The final mass-forming tumor showed a mixture of vasoformative and nonvasoformative areas. Four of 21 cases were non-mass forming and showed either diffuse sinusoidal infiltration (N=2) or prominent peliotic changes (N=2). Finally, 3 uncommon patterns were identified. One case showed nodules of spindle cells arranged in prominent whorls in a background of loose connective tissue with abundant inflammation. A second case arose in the setting of the Blue Rubber Bleb Nevus Syndrome and showed numerous tumor nodules with an architectural pattern that resembled infantile hemangioma, some with areas of atypia consistent with malignant transformation to angiosarcoma. The third unusual pattern showed multiple nodules of thin walled large caliber vascular proliferations, some of which showed atypia that reached the level of angiosarcoma. The results from this study indicate that the majority of hepatic angiosarcomas are mass forming (two third of cases), a pattern that is recognizable on H&E when vasoformative, but can mimic carcinoma or undifferentatied sarcomas when nonvasoformative (one third of cases). The sinusoidal patterns are particularly challenging and are frequently missed on initial review. Finally, we describe several unsual patterns of angiosarcoma. Awareness of these classic and rare morphologic patterns can help make the diagnosis of angiosarcoma.
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http://dx.doi.org/10.1097/PAS.0000000000001228DOI Listing
May 2019

Identification of key challenges in liver pathology: data from a multicenter study of extramural consults.

Hum Pathol 2019 05 8;87:75-82. Epub 2019 Mar 8.

Department of Pathology, University of Washington Medical Center, Seattle, WA, USA.

Extramural consultation for challenging pathology cases is an important part of patient care. The specific reasons why liver cases are submitted in consultation are poorly understood. To study patterns in extramural consultation, data were gathered from 1360 liver/GI/pancreatobiliary consults submitted to 7 academic centers. Liver cases comprised 40% of consults and are the focus of this paper. They were submitted for questions on medical (61%) and tumor pathology (39%). A preliminary diagnosis was provided by the referring pathologist in 65% of cases. The most common questions in medical liver pathology were on general classification of a hepatitic pattern of injury (37%), primary biliary cirrhosis (14%), fatty liver disease (13%), autoimmune hepatitis (12%), and etiology of cirrhosis (10%). Most tumor consults were submitted for classification (83%). The most common final tumor consultant diagnoses for benign tumors were hepatic adenoma or focal nodular hyperplasia (52%) and for malignant tumors were metastatic malignancies (47%), hepatocellular carcinoma (32%), or cholangiocarcinoma (8%). For cases submitted with a diagnosis of malignancy, the diagnosis was concordant (43% of cases), concordant but with a generic diagnosis for which a more specific diagnosis could be rendered (37%), or discordant with a major change in diagnosis from malignant to benign or change in tumor type (17%). In conclusion, analysis of consult patterns identifies challenging areas in medical and tumor liver pathology, areas that benefit from consult services and can be focused on by continuing medical educational activities.
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http://dx.doi.org/10.1016/j.humpath.2019.03.001DOI Listing
May 2019
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