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Purpose: This prospective phase II pilot study evaluated safety and efficacy of transarterial chemoembolization (TACE) with drug-eluting beads (DEBs) loaded with doxorubicin in patients with unresectable hepatocellular carcinoma (HCC).Methods: Twenty patients with unresectable HCC (75% Child's A, 95% Eastern Cooperative Oncology Group performance status 0 to 1, 60% Barcelona Clinic Liver Cancer C, tumor size 6.9 cm) underwent 34 DEB-TACE sessions. Primary endpoints were tumor response, assessed by contrast-enhanced magnetic resonance imaging at 1 month after treatment, using size (response evaluation criteria in solid tumors [RECIST]), contrast-enhancement (European Association for the Study of the Liver) and apparent diffusion coefficient values, and safety assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). Secondary endpoints included feasibility, progression-free survival, and overall survival.Results: DEB-TACE was successfully performed in 34 sessions and demonstrated a favorable safety profile. On initial (1 month) postprocedural magnetic resonance imaging, treated lesions had a mean decrease in size of 4% (P = 0.1129). Using RECIST, partial response was achieved in 2 patients (10%), and 18 patients (90%) had stable disease. Treated tumors demonstrated a mean decrease in contrast enhancement of 64% (P < 0.0001). By European Association for the Study of the Liver criteria, 12 patients (60%) had objective tumor response, and 8 (40%) had stable disease. No patients had progression of a treated lesion while undergoing treatment. At 6 months, the disease control rate was 95% using RECIST. Overall survival rates at 1 and 2 years were 65% and 55%, respectively; median overall survival was 26 months.Discussion: DEB-TACE is safe and effective in achieving local tumor control in patients with unresectable HCC. [ABSTRACT FROM AUTHOR]

Rationale: Obstructive sleep apnea is associated with insulin resistance and liver injury. It is unknown whether apnea contributes to insulin resistance and steatohepatitis in severe obesity.Objectives: To examine whether sleep apnea and nocturnal hypoxemia predict the severity of insulin resistance, systemic inflammation, and steatohepatitis in severely obese individuals presenting for bariatric surgery.Methods: We performed sleep studies and measured fasting blood glucose, serum insulin, C-reactive protein, and liver enzymes in 90 consecutive severely obese individuals, 75 women and 15 men, without concomitant diabetes mellitus or preexistent diagnosis of sleep apnea or liver disease. Liver biopsies (n = 20) were obtained during bariatric surgery.Measurements and Main Results: Obstructive sleep apnea with a respiratory disturbance index greater than 5 events/hour was diagnosed in 81.1% of patients. The median respiratory disturbance index was 15 +/- 29 events/hour and the median oxygen desaturation during apneic events was 4.6 +/- 1.8%. All patients exhibited high serum levels of C-reactive protein, regardless of the severity of apnea, whereas liver enzymes were normal. Oxygen desaturation greater than 4.6% was associated with a 1.5-fold increase in insulin resistance, according to the homeostasis model assessment index. Histopathology data suggested that significant nocturnal desaturation might predispose to hepatic inflammation, hepatocyte ballooning, and liver fibrosis. Fasting blood glucose levels and steatosis scores were not affected by nocturnal hypoxia. There was no relationship between the respiratory disturbance index and insulin resistance or liver histopathology.Conclusions: Hypoxic stress of sleep apnea may be implicated in the development of insulin resistance and steatohepatitis in severe obesity. [ABSTRACT FROM AUTHOR]

Hepatic sinusoids are highly specialized microcirculatory conduits within the hepatic lobules that facilitate liver functions. The sinusoids can be affected by various disorders, including sinusoidal dilatation, sinusoidal obstruction syndrome (SOS), sinusoidal cellular infiltration, perisinusoidal infiltration, and endothelial neoplasms, such as hemangioendothelioma and angiosarcoma. While these disorders, particularly SOS and neoplasms, can be life threatening, their clinical manifestation is often nonspecific. Patients may present with right upper quadrant pain, jaundice, hepatomegaly, ascites, splenomegaly, and unexplained weight gain, although the exact manifestation depends on the cause, severity, and duration of the disease. Ultimately, invasive tests may be necessary to establish the diagnosis. A comprehensive understanding of imaging manifestations of various sinusoidal disorders contributes to early diagnosis and can help radiologists detect subclinical disease. Additionally, specific imaging features may assist in identifying the cause of the disorder, leading to a more focused and quicker workup. For example, a mosaic pattern of enhancement of the liver parenchyma is suggestive of sinusoidal dilatation; peripheral and patchy reticular hypointensity of the liver parenchyma on hepatobiliary MR images is characteristic of SOS; and associated diffuse multiple hyperintensities on diffusion-weighted images may be specific for malignant sinusoidal cellular infiltration. The authors provide an overview of the pathogenesis, clinical features, and imaging appearances of various hepatic sinusoidal disorders, with a special emphasis on SOS. © RSNA, 2024 Supplemental material is available for this article.

Fibrolamellar hepatocellular carcinoma (FLC) is a rare liver cancer that is driven by the fusion of DNAJB1 and PRKACA, the catalytic subunit of protein kinase A (PKA). PKA activity is controlled through regulatory proteins that both inhibit catalytic activity and control localization, and an excess of regulatory subunits ensures PRKACA activity is inhibited. Here, we found an increase in the ratio of catalytic to regulatory units in FLC patient tumors driven by DNAJB1::PRKACA using mass spectrometry, biochemistry, and immunofluorescence, with increased nuclear localization of the kinase. Overexpression of DNAJB1::PRKACA, ATP1B1::PRKACA, or PRKACA, but not catalytically inactive kinase, caused similar transcriptomic changes in primary human hepatocytes, recapitulating the changes observed in FLC. Consistently, tumors in patients missing a regulatory subunit or harboring an ATP1B1::PRKACA fusion were indistinguishable from FLC based on the histopathological, transcriptomic, and drug-response profiles. Together, these findings indicate that the DNAJB1 domain of DNAJB1::PRKACA is not required for FLC. Instead, changes in PKA activity and localization determine the FLC phenotype. Significance: Alterations leading to unconstrained protein kinase A signaling, regardless of the presence or absence of PRKACA fusions, drive the phenotypes of fibrolamellar hepatocellular carcinoma, reshaping understanding of the pathogenesis of this rare liver cancer., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background & Aims: The PTEN-AKT pathway is frequently altered in extrahepatic cholangiocarcinoma (eCCA). We aimed to evaluate the role of PTEN in the pathogenesis of eCCA and identify novel therapeutic targets for this disease., Methods: The Pten gene was genetically deleted using the Cre-loxp system in biliary epithelial cells. The pathologies were evaluated both macroscopically and histologically. The characteristics were further analyzed by immunohistochemistry, reverse-transcription PCR, cell culture, and RNA sequencing. Some features were compared to those in human eCCA samples. Further mechanistic studies utilized the conditional knockout of Trp53 and Aurora kinase A (Aurka) genes. We also tested the effectiveness of an Aurka inhibitor., Results: We observed that genetic deletion of the Pten gene in the extrahepatic biliary epithelium and peri-ductal glands initiated sclerosing cholangitis-like lesions in mice, resulting in enlarged and distorted extrahepatic bile ducts in mice as early as 1 month after birth. Histologically, these lesions exhibited increased epithelial proliferation, inflammatory cell infiltration, and fibrosis. With aging, the lesions progressed from low-grade dysplasia to invasive carcinoma. Trp53 inactivation further accelerated disease progression, potentially by downregulating senescence. Further mechanistic studies showed that both human and mouse eCCA showed high expression of AURKA. Notably, the genetic deletion of Aurka completely eliminated Pten deficiency-induced extrahepatic bile duct lesions. Furthermore, pharmacological inhibition of Aurka alleviated disease progression., Conclusions: Pten deficiency in extrahepatic cholangiocytes and peribiliary glands led to a cholangitis-to-cholangiocarcinoma continuum that was dependent on Aurka. These findings offer new insights into preventive and therapeutic interventions for extrahepatic CCA., Impact and Implications: The aberrant PTEN-PI3K-AKT signaling pathway is commonly observed in human extrahepatic cholangiocarcinoma (eCCA), a disease with a poor prognosis. In our study, we developed a mouse model mimicking cholangitis to eCCA progression by conditionally deleting the Pten gene via Pdx1-Cre in epithelial cells and peribiliary glands of the extrahepatic biliary duct. The conditional Pten deletion in these cells led to cholangitis, which gradually advanced to dysplasia, ultimately resulting in eCCA. The loss of Pten heightened Akt signaling, cell proliferation, inflammation, fibrosis, DNA damage, epigenetic signaling, epithelial-mesenchymal transition, cell dysplasia, and cellular senescence. Genetic deletion or pharmacological inhibition of Aurka successfully halted disease progression. This model will be valuable for testing novel therapies and unraveling the mechanisms of eCCA tumorigenesis., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Alcohol-associated liver disease (ALD) continues to be a global health concern, responsible for a significant number of deaths worldwide. Although most individuals who consume alcohol do not develop ALD, heavy drinkers and binge drinkers are at increased risk. Unfortunately, ALD is often undetected until it reaches advanced stages, frequently associated with portal hypertension and hepatocellular carcinoma (HCC). ALD is now the leading indication for liver transplant. The incidence of alcohol-associated hepatitis (AH) surged during the COVID-19 pandemic. Early diagnosis of ALD is therefore important in patient management and determination of prognosis, as abstinence can halt disease progression. The spectrum of ALD includes steatosis, steatohepatitis, and cirrhosis, with steatosis the most common manifestation. Diagnostic techniques including ultrasound, CT, and MRI provide useful information for identifying ALD and excluding other causes of liver dysfunction. Heterogeneous steatosis and transient perfusion changes on CT and MRI in the clinical setting of alcohol-use disorder are diagnostic of severe AH. Elastography techniques are useful for assessing fibrosis and monitoring treatment response. These various imaging modalities are also useful in HCC surveillance and diagnosis. This review discusses the imaging modalities currently used in the evaluation of ALD, highlighting their strengths, limitations, and clinical applications.

Subtyping hepatic adenomas is important for patient management due to differing complication risks. Immunohistochemical staining with C-reactive protein (CRP) and serum amyloid-A (SAA) is widely accepted as a surrogate for molecular classification to identify inflammatory hepatocellular adenomas. Limited data, however, has been published on how these 2 stains compare for sensitivity. We conducted a large, multicenter, retrospective study to examine the sensitivity and staining characteristics of CRP and SAA in inflammatory hepatic adenomas, with focal nodular hyperplasia (FNHs) as a control group. Inflammatory adenomas were identified in 133 patients (average age 37 years, 109 were female). In all, 69.9% of cases were resection specimens and 90.2% of all cases showed positive staining for both CRP and SAA; 10 (7.5%) were positive for CRP only and 3 (2.3%) were positive for SAA only. CRP was more sensitive than SAA (97.74% vs. 92.48%, P -value = 0.0961) and showed more extensive and intense staining, with a significantly higher modified H-score ( P <0.001). Focal nodular hyperplasia can also show positive CRP and SAA staining but with a lower modified H-score ( P <0.0001). Based on beta-catenin and glutamine synthetase staining, 26 of inflammatory adenomas also had beta-catenin activation (19.5%). All 3 cases with positive SAA and negative CRP staining were beta-catenin activated. In contrast, the proportion of cases that were CRP positive and SAA negative was similar regardless of beta-catenin activation. The data affirms the strategy of using both CRP and SAA immunostains for hepatic adenoma subtyping and raises the awareness of the highly variable nature of SAA staining characteristics., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Hepatic angiosarcomas are aggressive malignant tumors of the liver with variable morphology. One of the rare morphologies is that of the sinusoidal growth pattern, which is challenging to diagnose because of its subtle imaging and morphologic findings. This retrospective study characterizes the clinical, histologic, and immunohistochemical features of sinusoidal hepatic angiosarcomas. Thirteen cases were included in the study, comprising 12 (92.3%) needle core biopsies and 1 wedge biopsy; one of the needle biopsies also had a subsequent resection specimen available for review. Multiple biopsies were needed to make the diagnosis in 4 cases. At least moderate sinusoidal dilatation was seen in 53.8% of cases. Increased cellularity within the sinusoids was seen at both low-power and high-power magnification (69.2% and 84.6%, respectively). Cytologic atypia ranged from mild to marked. Multinucleated tumor cells were present in most cases (10/13 cases) but were often sparse. Mitotic activity was identified in 5/13 cases. ERG immunostains were more reliable than CD31 and CD34 in identifying the tumor cells. Ki-67 proliferative index ranged from 5% to 30%. p53 immunostains were available in 9 cases and c-MYC in 7 cases; they were positive in 62.5% and 33.3% of cases, respectively and had a mutually exclusive staining pattern. In summary, this rare pattern of hepatic angiosarcoma is challenging to diagnose but has distinctive morphologic findings that can be supplemented with immunostains to establish the diagnosis., Competing Interests: Conflicts of Interest and Source of Funding: Supported by a P50 CA210964 grant (M.S.T.). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background/aim: Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare tumor presenting in younger patients without chronic liver disease. Up to 80-100% develop recurrent disease, necessitating additional surgery or systemic treatment. Systemic options and pre-clinical treatment studies are lacking. We previously described patient-derived xenograft (PDX) development, allowing for pre-clinical studies. Herein, we develop FLHCC PDX models and utilize these to define tumor characteristics and determine the efficacy of systemic agents., Materials and Methods: Primary and lymph node metastatic tumor tissues were obtained at the time of FLHCC resection in two patients. Tumor lysates were screened for protein upregulation. Cell lines were generated from metastatic and primary tumor tissue. The viability of the cell lines was assessed after treatment with temsirolimus, gemcitabine/oxaliplatin, and FOLFIRINOX. Two PDX models were developed from metastatic tissue. For in vivo studies, tumor-bearing mice were treated with temsirolimus, FOLFIRINOX, and Gemcitabine/oxaliplatin., Results: PDX models were successfully generated from metastatic FLHCC, which closely recapitulated the original tumor. Upregulation of mTOR was seen in metastatic tissue compared to primary tumors. Cell lines from metastatic tissue demonstrated significant sensitivity to temsirolimus. In vivo testing of PDX models demonstrated a significant response to single-agent temsirolimus with minimal toxicity., Conclusion: Herein, we demonstrate the feasibility of developing PDX models that closely recapitulate FLHCC. Upregulation of mTOR was seen in metastatic tissue compared to primary tissue. The efficacy of mTOR inhibition with temsirolimus treatment suggests that the upregulation of the mTOR pathway may be a significant mechanism for growth in metastatic lesions and a potential target for therapeutics., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

MYC proto-oncogene dysregulation alters metabolism, translation, and other functions in ways that support tumor induction and maintenance. Although Myc +/- mice are healthier and longer-lived than control mice, the long-term ramifications of more complete Myc loss remain unknown. We now describe the chronic consequences of body-wide Myc inactivation initiated postnatally. "MycKO" mice acquire numerous features of premature aging, including altered body composition and habitus, metabolic dysfunction, hepatic steatosis, and dysregulation of gene sets involved in functions that normally deteriorate with aging. Yet, MycKO mice have extended lifespans that correlate with a 3- to 4-fold lower lifetime cancer incidence. Aging tissues from normal mice and humans also downregulate Myc and gradually alter many of the same Myc target gene sets seen in MycKO mice. Normal aging and its associated cancer predisposition are thus highly linked via Myc., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Newer radiotherapy techniques, such as stereotactic body radiation, have been increasingly used as part of the treatment of cholangiocarcinomas, particularly as a bridge to liver transplantation. Although conformal, these high-dose therapies result in tissue injury in the peritumoral liver tissue. This retrospective study characterized the morphologic changes in the liver after stereotactic body radiation in a series of liver explant specimens with perihilar cholangiocarcinoma. The morphologic changes in the irradiated zone were compared against the nonirradiated background liver parenchyma to control for chemotherapy-related changes. Of the 21 cases studied, 16 patients (76.2%) had underlying primary sclerosing cholangitis, and 13 patients (61.9%) had advanced liver fibrosis. The average duration between completion of radiotherapy and liver transplantation was 33.4 weeks (range: 6.29 to 67.7). Twelve patients (57.1%) had no residual tumor in the liver. The most frequent histologic changes in the peritumoral irradiated liver tissue were sinusoidal congestion (100%), sinusoidal edematous stroma (100%), and hepatocellular atrophy (100%), followed by partial/complete occlusion of central veins (76.2%), sinusoidal cellular infiltrates (76.2%), and hepatocyte dropout (66.7%). The findings in the radiated areas were more extensive than in the background liver ( P <0.01). Sinusoidal edematous stroma was striking and dominated the histologic findings in some cases. Over time, there was less sinusoidal congestion but more hepatocyte dropout (r s =-0.54, P =0.012 and r s =0.64, P =0.002, respectively). Uncommon findings, such as foam cell arteriopathy in the liver hilum, were also observed. In summary, postradiation liver specimens have distinctive morphologic findings., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Fibrolamellar hepatocellular carcinoma (FLC) is a usually lethal primary liver cancer driven by a somatic dysregulation of protein kinase A. We show that the proteome of FLC tumors is distinct from that of adjacent nontransformed tissue. These changes can account for some of the cell biological and pathological alterations in FLC cells, including their drug sensitivity and glycolysis. Hyperammonemic encephalopathy is a recurrent problem in these patients, and established treatments based on the assumption of liver failure are unsuccessful. We show that many of the enzymes that produce ammonia are increased and those that consume ammonia are decreased. We also demonstrate that the metabolites of these enzymes change as expected. Thus, hyperammonemic encephalopathy in FLC may require alternative therapeutics.

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., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary liver cancer that affects primarily adolescents and young adults. It is associated with a poor overall prognosis. There is a need to better define risk factors, but small sample size has limited such studies. An FLC patient registry now provides data sufficient for statistically robust inferences. We leveraged a unique patient community-based FLC registry to analyze the prognostic impact of demographic and clinical characteristics evident at diagnosis. Variables were analyzed using Cox proportional hazards regression to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). In multivariable models of 149 patients (88 females and 61 males), female gender was associated with statistically significant improved survival with HR of 0.52 (95% CI 0.29-0.93). Factors evident at diagnosis that are associated with worse survival included the presence of 10 or more tumors within the liver (HR 7.1; 95% CI 2.4-21.04), and metastases at diagnosis (HR 2.17; 95% CI 1.19-3.94). Positive lymph nodes at diagnosis, despite being found significantly associated with worse survival in a univariate analysis, did not remain significant when adjusted for covariates in a multivariable analysis. We found no statistically significant effect of age at diagnosis nor tumor size at diagnosis on survival. Female gender may confer a favorable prognosis in FLC. Established high-risk prognostic factors that we confirmed in this Registry included the diagnostic presence of numerous intrahepatic tumors, and metastases. This is the first study derived from a FLC patient community-based registry, and highlights how registries of rare tumors can empower patients to meaningfully advance clinical and scientific discoveries., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Historically, radiation therapy was not considered in treatment of liver tumors owing to the risk of radiation-induced liver disease. However, development of highly conformed radiation treatments such as stereotactic body radiation therapy (SBRT) has increased use of radiation therapy in the liver. SBRT is indicated in treatment of primary and metastatic liver tumors with outcomes comparable to those of other local therapies, especially in treatment of hepatocellular carcinoma. After SBRT, imaging features of the tumor and surrounding background hepatic parenchyma demonstrate a predictable pattern immediately after treatment and during follow-up. The goals of SBRT are to deliver a lethal radiation dose to the targeted liver tumor and to minimize radiation dose to normal liver parenchyma and other adjacent organs. Evaluation of tumor response after SBRT centers on changes in size and enhancement; however, these changes are often delayed secondary to the underlying physiologic effects of radiation. Knowledge of the underlying pathophysiologic mechanisms of SBRT should allow better understanding of the typical imaging features in detection of tumor response and avoid misinterpretation from common pitfalls and atypical imaging findings. Imaging features of radiation-induced change in the surrounding liver parenchyma are characterized by a focal liver reaction that can potentially be mistaken for no response or recurrence of tumor. Knowledge of the pattern and chronology of this phenomenon may allay any uncertainty in assessment of tumor response. Other pitfalls related to fiducial marker placement or combination therapies are important to recognize. The authors review the basic principles of SBRT and illustrate post-SBRT imaging features of treated liver tumors and adjacent liver parenchyma with a focus on avoiding pitfalls in imaging evaluation of response. Online supplemental material is available for this article. © RSNA, 2022.

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., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

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. Online supplemental material is available for this article. © RSNA, 2022.

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., Competing Interests: Conflicts of Interest and Source of Funding: M.S.T. received grant support: P50 CA210964. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

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.

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 68 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, 68 Ga-PSMA-11 PET was prospectively performed in patients with treatment-naïve HCC on a digital PET scanner using cyclotron-produced 68 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 -5 ) and MAD1L1 (Mitotic spindle assembly checkpoint protein MAD1) correlated negatively with PSMA expression (rho = -0.753; P = 1.58 × 10 -6 ). Of the 190 patients who met the eligibility criteria, 31 patients with 39 HCC lesions completed PET; 64% (n = 25) lesions had pronounced 68 Ga-PSMA-11 standardized uptake value: SUV max (median [range] 9.2 [4.9-28.4]), SUV mean 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 68 Ga-PSMA-11 PET, which suggests that PSMA has the potential as a theranostic target in patients with HCC., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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. This article is highlighted in the In This Issue feature, p. 2355 ., (©2021 The Authors; Published by the American Association for Cancer Research.)

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., (© 2021 by the American Association for the Study of Liver Diseases.)

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., Competing Interests: Conflicts of Interest and Source of Funding: M.S.T. and S.M.S. provided by the Mayo Clinic Hepatobiliary SPORE (P50 CA210964). For the remaining authors none were declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Steatosis is the most important prognostic histologic feature in the setting of liver procurement. The currently utilized diagnostic methods, including gross evaluation and frozen section examination, have important shortcomings. Novel techniques that offer advantages over the current tools could be of significant practical utility. The aim of this study is to evaluate the accuracy of surface color spectrophotometry in the quantitative assessment of steatosis in a murine model of fatty liver. C57BL/6 mice were divided into a control group receiving normal chow (n = 19), and two steatosis groups receiving high-fat diets for up to 20 weeks-mild steatosis (n = 10) and moderate-to-severe steatosis (n = 19). Mouse liver surfaces were scanned with a hand-held spectrophotometer (CM-600D; Konica-Minolta, Osaka, Japan). Spectral reflectance data and color space values (L*a*b*, XYZ, L*c*h*, RBG, and CMYK) were correlated with histopathologic steatosis evaluation by visual estimate, digital image analysis (DIA), as well as biochemical tissue triglyceride measurement. Spectral reflectance and most color space values were very strongly correlated with histologic assessment of total steatosis, with the best predictor being % reflectance at 700 nm (r = 0.91 [0.88-0.94] for visual assessment, r = 0.92 [0.88-0.95] for DIA of H&E slides, r = 0.92 [0.87-0.95] for DIA of oil-red-O stains, and r = 0.78 [0.63-0.87] for biochemical tissue triglyceride measurement, p < 0.0001 for all). Several spectrophotometric parameters were also independently predictive of large droplet steatosis. In conclusion, hepatic steatosis can accurately be assessed using a portable, commercially available hand-held spectrophotometer device. If similarly accurate in human livers, this technique could be utilized as a point-of-care tool for the quantitation of steatosis, which may be especially valuable in assessing livers during deceased donor organ procurement., (© 2021. The Author(s), under exclusive licence to United States and Canadian Academy of Pathology.)

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., (Copyright © 2020. Published by Elsevier Inc.)

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., Competing Interests: Conflicts of Interest and Source of Funding: M.S.T. received grant support (P50 CA210964). For the remaining authors none were declared., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

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., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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.

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., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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). 1 , 2 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. 3,4 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. 5-8 The aim of this study was to assess the ability of magnetic resonance imaging (MRI) and MRE to differentiate between CPH and NCPH., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

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 ( p  = 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 CDKN2A, SMAD4, NRG1, TP53 . 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., Competing Interests: The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2020 The Authors.)

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., (© 2019 John Wiley & Sons Ltd.)

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.

Appendix pathology represents uncommonly encountered specimens with unique diagnostic challenges. To delineate common knowledge gaps, extramural consults submitted to seven institutions between 2016-2017 were reviewed. All appendix consults were resections (100%, n = 43), and the majority were directed for consultation by the originating pathologist (95%, n = 41) with no additional studies performed by the consultant (65%, n = 28). This study was dominated by inquiries related to low grade appendiceal mucinous neoplasms (44%, n = 19) and goblet cell carcinoid related neoplasms (19%, n = 8). Of the 43 appendiceal consults, 19 were submitted by the contributing pathologist as low grade appendiceal mucinous neoplasm, but only half of these were diagnosed by the consultant as such (n = 9). Low grade appendiceal mucinous neoplasm-related consultation themes included diverticular disease, criteria for invasion, high grade atypia, extra-appendiceal mucin, and staging. Examples of major disagreements that were downgraded included consults submitted as low grade appendiceal mucinous neoplasm and diagnosed by the consultant as serrated polyp (n = 3), appendicitis (n = 1), and benign appendix (n = 1). Examples of major disagreements-upgraded included cases submitted as low grade appendiceal mucinous neoplasm and diagnosed by the consultant as low grade appendiceal mucinous neoplasm with high-risk features (n = 2) and mucinous adenocarcinoma (n = 2). One case contained both a major disagreement-upgrade (low grade appendiceal mucinous neoplasm changed to high grade appendiceal mucinous neoplasm) and a major disagreement-downgrade (pT3 changed to Tis). Of the 15 cases diagnosed by the consultants as low grade appendiceal mucinous neoplasm, submitted diagnoses included low grade appendiceal mucinous neoplasm (n = 9), adenocarcinoma (n = 5), and one case was submitted without a diagnosis. For goblet cell carcinoid-related consults, the usual inquiry related to distinguishing goblet cell carcinoid from goblet cell carcinoid with adenocarcinoma (adenocarcinoma ex-goblet cell carcinoid). Of the 38 overall consults with a submitted diagnosis, 53% (n = 20) were disagreements, and most of these were major disagreements-downgraded (n = 13).

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 ( r = 0.78, p = 0.007) and kappa chain level ( r = 0.65, p = 0.04). Interestingly, LSM did not correlate significantly with SSM ( r = 0.45, p = 0.18), liver span ( r = 0.57, p = 0.08), or serum ALP ( r = 0.60, p = 0.07). However, LSM correlated significantly with serum ALP when corrected for liver volume (partial correlation, r = 0.71, p = 0.03) and NT pro BNP levels (partial correlation, r = 0.68, p = 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.

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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.

Hamartomas and malformations of the liver are rare and can lead to diagnostic challenges. Most present as mass lesions that can mimic true neoplasms of the liver on imaging and sometimes on histology, one example being focal nodular hyperplasia. The primary cell type in the hamartomas and malformations can be biliary, vascular, or hepatic. Biliary lesions include bile duct hamartomas and simple liver cysts. Other cystic malformations include the ciliated hepatic foregut cysts and mesothelial cysts. Vascular malformations include telangiectasias, arteriovenous malformations, and hereditary lymphedema. Malformations composed primarily of hepatocytes include accessory lobes and focal nodular hyperplasia. All of these entities are discussed, with a focus on the diagnostic histological findings., (Copyright © 2018 Elsevier Inc. All rights reserved.)