Mounajjed, Taofic

Context.— Pulmonary carcinoids are classified as typical or atypical by assessing necrosis and mitoses, which usually cannot be adequately assessed on small biopsies. Ki-67 is not currently used to grade pulmonary carcinoids, but it may be helpful to determine preliminary grade in biopsies. However, the rate at which Ki-67 could underestimate or overestimate grade on small biopsies has not been well studied. Objective.— To compare Ki-67 labeling obtained on small biopsies to subsequent resection. Design.— Ki-67 was performed on paired biopsy and resection specimens from 55 patients. Slides were scanned using Aperio ScanScope. Labeling index was determined using automated hot spot and tumor tracing methods. Results.— The study included 41 typical and 14 atypical carcinoids. Atypical carcinoids were larger and had more distant metastases. Death from disease occurred in 3 patients (all had atypical carcinoids). Median hot spot Ki-67 labeling index was greater in resection compared with biopsy by 0.7% (P = .02). Median tumor tracing Ki-67 was lower in resection compared with biopsy by 0.5% (P < .001). Receiver-operating characteristic analysis showed similar hot spot Ki-67 cutoffs to predict atypical histology (3.5% for biopsy, 3.6% for resection; area under the curve [AUC], 0.75 and 0.74, respectively). Different optimal cutoffs were needed for tracing method based on biopsy (2.1%; AUC, 0.75) compared with resection (1.0%; AUC, 0.67). Conclusions.— Hot spot Ki-67 tends to underestimate grade on small biopsies, whereas grade is overestimated by tumor tracing. Hot spot Ki-67 cutoff of 3.5% predicted atypical histology for both biopsy and resection. Different biopsy and resection cutoffs were necessary for tumor tracing, which would make clinical implementation more difficult.

Disease monitoring in nonalcoholic steatohepatitis (NASH) is limited by absence of noninvasive biomarkers of disease regression or progression. We aimed to examine the role of multiparametric three‐dimensional magnetic resonance elastography (3D‐MRE) and magnetic resonance imaging proton density fat fraction (MRI‐PDFF) in the detection of NASH regression after interventions. This is a single‐center prospective clinical trial of 40 patients who underwent bariatric surgery. Imaging and liver biopsies were obtained at baseline and 1 year after surgery. The imaging protocol consisted of multifrequency 3D‐MRE to determine the shear stiffness at 60 Hz and damping ratio at 40 Hz, and MRI‐PDFF to measure the fat fraction. A logistic regression model including these three parameters was previously found to correlate with NASH. We assessed the model performance in the detection of NASH resolution after surgery by comparing the image‐predicted change in NAFLD activity score (delta NAS) to the histologic changes. A total of 38 patients (median age 43, 87% female, 30 of 38 with NAS ≥ 1, and 13 of 38 with NASH) had complete data at 1 year. The NAS decreased in all subjects with NAS ≥ 1 at index biopsy, and NASH resolved in all 13. There was a strong correlation between the predicted delta NAS by imaging and the delta NAS by histology (r = 0.73, P < 0.001). The strength of correlation between histology and the predicted delta NAS using single conventional parameters, such as the fat fraction by MRI‐PDFF or shear stiffness at 60 Hz by MRE, was r = 0.69 (P < 0.001) and r = 0.43 (P = 0.009), respectively. Conclusion: Multiparametric 3D‐MRE and MRI‐PDFF can detect histologic changes of NASH resolution after bariatric surgery. Studies in a nonbariatric setting are needed to confirm the performance as a composite noninvasive biomarker for longitudinal NASH monitoring.

Circulating extracellular vesicles (EVs) are a novel and emerging biomarker for nonalcoholic steatohepatitis (NASH). It has been demonstrated that total circulating EVs and hepatocyte‐derived EVs are elevated in male mice with diet‐induced NASH. How hepatocyte‐derived EVs change over time and other cellular sources of EVs in NASH have not been determined. Our objective was to define the quantitative evolution of hepatocyte‐derived, macrophage‐derived, neutrophil‐derived, and platelet‐derived EVs in male and female mice with dietary NASH. Fluorescently labeled antibodies and a nanoscale flow cytometer were used to detect plasma levels of EVs. Asialoglycoprotein receptor 1 (ASGR1) and cytochrome P450 family 2 subfamily E member 1 (CYP2E1) are markers of hepatocyte‐derived EVs; galectin 3 is a marker of macrophage‐derived EVs; common epitope on lymphocyte antigen 6 complex, locus G/C1 (Ly‐6G and Ly‐6C) is a marker of neutrophil‐derived EVs; and clusters of differentiation 61 (CD61) is a marker of platelet‐derived EVs. Nonalcoholic fatty liver disease activity score (NAS) was calculated using hematoxylin and eosin‐stained liver sections, and magnetic resonance imaging (MRI) was used for measurement of the fat fraction and elastography. Hepatocyte‐derived EVs increased in both male and female mice at 12 and 10 weeks of feeding, respectively, and remained elevated at 24 weeks in both male and female mice and at 48 weeks in male mice and 36 weeks in female mice. Macrophage‐ and neutrophil‐derived EVs were significantly elevated at 24 weeks of dietary feeding concomitant with the histologic presence of inflammatory foci in the liver. In fat‐, fructose‐, and cholesterol‐ (FFC) fed male mice, platelet‐derived EVs were elevated at 12, 24, and 48 weeks, whereas in female mice, platelet derived EVs were significantly elevated at 24 weeks. Hepatocyte‐, macrophage‐ and neutrophil‐derived EVs correlated well with the histologic NAS. Conclusion: Circulating cell‐type‐specific EVs may be a novel biomarker for NASH diagnosis and longitudinal follow up.

Epithelioid hemangioendothelioma (EHE) is an uncommon low-grade malignant vascular tumor that may arise in soft tissue/bone or visceral sites such as the liver and lung. As this tumor exhibits epithelioid morphology, it frequently causes diagnostic confusion with other epithelioid vascular neoplasms as well as carcinoma. While 90% of classic EHE are driven by aWWTR1-CAMTA1fusion gene, a histologically distinctive subset of EHE has been recently shown to harbor a different fusion gene,YAP1-TFE3. This variant is likely underrecognized given its rarity and only recent description. Notably, EHE frequently involves the liver but only one case of hepaticYAP1-TFE3rearranged EHE has been reported to date. We present the second case ofYAP1-TFE3rearranged EHE affecting a 65-year-old woman and presenting as multiple liver masses, with characterization of the fusion gene at the transcriptomic and genomic levels. There are several educational points noted from this case.YAP1-TFE3rearranged EHE shows distinctly vasoformative foci, unlike classic EHE and mimicking angiosarcoma or epithelioid hemangioma. The tumors cells show a histiocytoid appearance with voluminous cytoplasm, similar to otherTFE3-rearranged tumors. Finally, in the liver, this tumor may in part mimic focal nodular hyperplasia of the liver which is an underrecognized diagnostic pitfall. This report highlights the key diagnostic and genetic features of this newly recognized variant of hepatic EHE to aid pathologists in appropriately classifying these tumors.

Hepatocellular adenomas (HCAs) often pursue an innocuous clinical course. Recent work has elucidated important subtypes of HCA and biomarkers to identify them, including HCA at an increased risk for malignant transformation. Another key complication of HCAs is the risk of spontaneous tumoral hemorrhage, which may be life-threatening. Identification of a predictive biomarker for this clinical complication would therefore be of clinical value. It has been suggested that Argininosuccinate Synthase 1 (ASS1) immunohistochemistry (IHC) identifies HCA with a high propensity for hemorrhage. The aim of our study was to validate ASS1 IHC as a predictive marker of hemorrhage. Eighty-nine HCAs were collected for ASS1 IHC and subtyped according to published criteria. Clinical records were examined for evidence of tumoral hemorrhage. Twenty-one (23.6%) HCAs were complicated by clinically detected hemorrhage and were more likely to be resected (P=0.0002). Hemorrhage complicated all WHO subtypes of HCA. There was no association between hemorrhage and HCA subtype (P=0.92). Neither the distribution of ASS1 expression nor the intensity of ASS1 expression compared to normal liver showed a significant association with hemorrhage (P=0.051 and 0.34). Interlaboratory comparison of 8 cases showed good agreement regarding the intensity (6/8 and 7/8) and distribution of staining (7/8 and 7/8) across 3 laboratories performing ASS1 IHC. In conclusion, all subtypes of HCA may be complicated by hemorrhage. ASS1 IHC expression did not correlate with hemorrhagic complications. Caution is prudent before routine implementation of ASS1 IHC in clinical practice.

Abstract Objectives To examine the immunohistochemical and ultrastructural features of hepatocellular cytoplasmic globules in venous outflow impairment (VOI). Methods Sixty-four liver core biopsies were screened. Patients with α-1 antitrypsin (AAT) deficiency were excluded. All biopsies were stained with H&E, Masson trichrome, periodic acid-Schiff with diastase digestion (PAS-D), phosphotungstic acid hematoxylin (PTAH), complement protein 4d (C4d) immunostain, and AAT immunostain. Electron microscopy was also performed. Results Hepatocellular globules were identified in 8% of in-house cases. Causes of VOI included heart failure and Budd-Chiari syndrome. The hepatocellular cytoplasmic globules showed size variability, random distribution, and positivity for PAS-D, PTAH, and AAT. C4d was inconsistently positive. Electron microscopy showed that the globules were lysosome-bound inclusions containing microfibrillar material and fibrinogen. Conclusions PAS-D–positive hepatocellular globules occur in VOI. They cross-react with AAT but have different appearance, localization, and ultrastructural composition from globules in AAT deficiency.

ABSTRACT Objectives Albumin messenger RNA (mRNA) expression is a marker of hepatocellular differentiation. Most published data are from review of tissue microarrays, and albumin in situ hybridization (ISH) expression across several tumor types is incompletely characterized. Methods Sections from 221 tumors were evaluated for albumin mRNA. Immunohistochemistry was used to confirm diagnoses. Albumin ISH was performed according to manufacturer-provided instructions. Fifty-nine cases were evaluated with both commercial ISH assays. Results Albumin mRNA was detected in all hepatocellular carcinomas (HCCs) and 81% of intrahepatic cholangiocarcinomas. Lung (20%), gallbladder (39%), hepatoid pancreatic (n = 1 of 1) adenocarcinoma, breast invasive ductal carcinoma (18%), yolk sac tumor (25%), and acinar cell carcinoma (29%) showed expression. Both assays were concordant in 93% of cases. Conclusions Albumin ISH was expressed in all HCCs studied. It was also positive in intrahepatic cholangiocarcinoma and patchy positive in gallbladder adenocarcinoma and a subset of other neoplasms, which can be a potential pitfall.

The lack of reliable, noninvasive methods to diagnose early nonalcoholic steatohepatitis (NASH) is a major unmet need. We aimed to determine the diagnostic accuracy of three‐dimensional magnetic resonance elastography (3D‐MRE), with shear stiffness measured at 60 Hz, damping ratio at 40 Hz, and magnetic resonance imaging proton density fat fraction (MRI‐PDFF) in the detection of NASH in individuals undergoing bariatric surgery. Obese adults at risk for NASH were enrolled between 2015 and 2017 (prospective cohort, n = 88) and 2010 and 2013 (retrospective cohort, n = 87). The imaging protocol consisted of multifrequency 3D‐MRE (mf3D‐MRE) with shear waves delivered at different frequencies to explore parameters that best correlated with histologic NASH, and MRI‐PDFF to estimate steatosis. The prospective cohort was used to establish the optimal mf3D‐MRE technical parameters for NASH detection. The two cohorts were then combined to derive predictive models of NASH and disease activity by nonalcoholic fatty liver disease activity score (NAS) using the three imaging parameters that correlated with NASH. A total of 175 patients (median age 45, 81% women, and 81 [46%] with histologic NASH) were used for model derivation. From the complex shear modulus output generated by mf3D‐MRE, the damping ratio at 40 Hz and shear stiffness at 60 Hz best correlated with NASH. The fat fraction obtained from MRI‐PDFF correlated with steatosis ( P < 0.05 for all). These three parameters were fit into a logistic regression model that predicted NASH with cross‐validated area under the receiver operating characteristic curve (AUROC) = 0.73, sensitivity = 0.67, specificity = 0.80, positive predictive value = 0.73 and negative predictive value = 0.74, and disease activity by NAS with cross‐validated AUROC = 0.82. Conclusion: The mf3D‐MRE allows identification of imaging parameters that predict early NASH and disease activity. This imaging biomarker represents a promising alternative to liver biopsy for NASH diagnosis and monitoring. The results provide motivation for further studies in nonbariatric cohorts.