Assessment of Response to Transcatheter Arterial Chemoembolization with Doxorubicin-eluting Microspheres: Tumor Biology and Hepatocellular Carcinoma Recurrence in a 5-year Transplant Cohort.

Purpose To assess response to transcatheter arterial chemoembolization (TACE) based on immune markers and tumor biology in patients with hepatocellular carcinoma (HCC) who were bridged to liver transplantation, and to produce an optimized pretransplantation model for posttransplantation recurrence risk. Materials and Methods In this institutional review board-approved HIPAA-compliant retrospective analysis, 93 consecutive patients (73 male, 20 female; mean age, 59.6 years; age range, 23-72 years) underwent TACE with doxorubicin-eluting microspheres (DEB) (hereafter, DEB-TACE) and subsequently underwent transplantation over a 5-year period from July 7, 2011, to May 16, 2016. DEB-TACE response was based on modified Response Evaluation Criteria in Solid Tumors. Imaging responses and posttransplantation recurrence were compared with demographics, liver function, basic immune markers, treatment dose, and tumor morphology. Treatment response and recurrence were analyzed with uni- and multivariate statistics, as well as internal validation and propensity score matching of factors known to affect recurrence to assess independent effects of DEB-TACE response on recurrence. Results Low-grade tumors (grade 0, 1, or 2) demonstrated a favorable long-term treatment response in 87% of patients (complete response, 49%; partial response, 38%; stable disease [SD] or local disease progression [DP], 13%) versus 33% of high-grade tumors (grade 3 or 4) (complete response, 0%; partial response, 33%; SD or DP, 67%) (P < .001). Of the 93 patients who underwent treatment, 82 were followed-up after transplantation (mean duration, 757 days). Recurrence occurred in seven (9%) patients (mean time after transplantation, 635 days). Poor response to DEB-TACE (SD or DP) was present in 86% of cases and accounted for 35% of all patients with SD or DP (P < .001). By using only variables routinely available prior to liver transplantation, a validated model of posttransplantation recurrence risk was produced with a concordance statistic of 0.83. The validated model shows sensitivity of 83.6%, specificity of 82.6%, and negative predictive value of 98.4%, which are pessimistic estimates. Conclusion Response to DEB-TACE is correlated with tumor biology and patients at risk for posttransplantation recurrence, and it may be associated with HCC recurrence after liver transplantation. © RSNA, 2017 Online supplemental material is available for this article.

Outcomes utilizing imported liver grafts for recipients with hepatocellular carcinoma.

Liver transplantation (LT) offers the best chance of survival in selected patients with hepatocellular carcinoma (HCC). Wait-list mortality or dropout due to tumor progression can be significant, and therefore, timely transplantation is critical. Liver grafts discarded by outside organ procurement organizations are a potential source of grafts for low Model for End-Stage Liver Disease tumor patients. The primary aim of this study was to assess the disease-free and overall survival of patients with HCC transplanted with imported liver grafts (ILGs). Review of all patients transplanted for HCC between June 2005 and December 2014 was performed. Data on demographics, survival, and HCC recurrence were analyzed. During this time period, 59 out of 190 (31%) recipients with HCC received ILG. Of these 59 grafts, 54 were imported from within the region and 5 were from national offers (outside the region). The mean cold ischemia time for local liver grafts (LLGs) was 4.1 ± 1.5 hours versus 5.1 ± 1.4 hours for ILG (P < 0.001). The 1-, 3-, and 5-year patient survival was 90%, 85%, and 83% and 85%, 80%, and 79% for LLG and ILG (P = 0.08), respectively. The observed disease recurrence rate for both LLG and ILG recipients was equivalent. The median wait-list time for HCC recipients was 43 days (range, 2-1167 days). In conclusion, with careful graft assessment, the use of ILGs results in comparable outcomes following LT and no increased risk of HCC recurrence. Use of ILGs maximizes the donor pool and results in a higher rate of transplantation for HCC recipients. Liver Transplantation 23 299-304 2017 AASLD.

The chromophobe tumor grading system is the preferred grading scheme for chromophobe renal cell carcinoma.

PURPOSE: The prognostic usefulness of the Fuhrman nuclear grading system has been questioned for chromophobe renal cell carcinoma due to its frequent nuclear and nucleolar pleomorphism. Chromophobe tumor grade, a novel 3-tier tumor grading system based on geographic nuclear crowding and anaplasia, was recently reported to be superior to the Fuhrman system. We compared the 2 scoring systems in a large sporadic chromophobe renal cell carcinoma cohort to determine which grading scheme provides the most predictive assessment of clinical risk. MATERIALS AND METHODS: We identified a total of 84 cases of sporadic chromophobe renal cell carcinoma in 82 patients from a total of 2,634 cases (3.2%) spanning 1989 to 2010. A subset of 11 tumors had secondary areas of sarcomatoid transformation. All cases were reviewed for Fuhrman nuclear grade and chromophobe tumor grade according to published parameters by an expert genitourinary pathologist blinded to clinicopathological information. RESULTS: The distribution of Fuhrman nuclear grades 1 to 4 was 0%, 52.4%, 32.9% and 14.7% of cases, and the distribution of chromophobe tumor grades 1 to 3 was 48.8%, 36.5% and 14.7%, respectively. Metastasis developed in 20 patients (24.4%). Survival analysis revealed statistically significant differences in recurrence-free survival when adjusted for chromophobe tumor grade and Fuhrman nuclear grade. Chromophobe tumor grade showed a slightly higher AUC for recurrence-free survival and overall survival than the Fuhrman nuclear grading system. Neither chromophobe tumor grade nor Fuhrman nuclear grade was retained as an independent predictor of outcome in multivariate modeling when patients with sarcomatoid lesions were excluded. CONCLUSIONS: Chromophobe tumor grade effectively stratifies patients with chromophobe renal cell carcinoma across all grading levels. Since it does not rely on nuclear features, it avoids the hazard of overestimating the malignant potential of chromophobe renal cell carcinoma. Overall chromophobe tumor grade has higher predictive accuracy than the Fuhrman nuclear grading system.

Reflex high risk HPV testing in atypical squamous cells, cannot exclude high grade intraepithelial lesion: a large institution's experience with the significance of this often ordered test.

OBJECTIVE: Cervical cytology specimens diagnosed with ASC-H consist of squamous cells with equivocal cytology for high-grade dysplastic lesions. We reviewed our cases of ASC-H with reflex HPV testing to evaluate this patient population. STUDY DESIGN: We retrospectively identified patients with ASC-H in Pap smears over a 3-year period. Reflex high-risk (HR) HPV DNA testing was performed by request. Follow-up results and smear characteristics were evaluated. RESULTS: HR HPV DNA testing was positive in 60 of 82 (73%) cases tested. The risk of high grade cervical intraepithelial neoplasia (CIN) on follow-up after a positive HPV test with ASC-H is 68.3%. The risk of high grade CIN after a negative HPV test with ASC-H is 58.3%. High grade CIN lesions were found in 20% HPV-negative patients. The cellularity of atypical cells in Pap smears was not helpful in analyzing differences in HPV-positive and HPV-negative ASC-H. CONCLUSION: The risk of high grade dysplasia after an ASC-H Pap diagnosis was high irrespective of the reflex HPV test results in our patient population. Therefore, our findings support the continued utilization of the current ASCCP guidelines of colposcopy and caution when utilizing reflex HR HPV testing in the colposcopy triage ASC-H patients.

Ultrasound Stratification of Hepatic Steatosis Using Hepatorenal Index.

Hepatorenal index (HRI) has been shown to be an effective, noninvasive ultrasound tool to screen patients for those with or without >5% hepatic steatosis. OBJECTIVE: The aim of this study was to further refine this HRI tool in order to stratify patients according to their degree of liver steatosis and give direction as to which patients should undergo random liver biopsy. METHODS: We conducted a retrospective review of 267 consecutive patients from 2015 to 2017 who had abdominal ultrasounds and a subsequent random liver biopsy within one month. The HRI was calculated and compared with the percent steatosis as assessed by histology. RESULTS: An HRI of ≤1.17 corresponds with >95% positive predictive value of ≤5% steatosis. Between HRI values 1.18 and 1.39, performance of steatosis prediction is mixed. However, for values <1.37 there is an increased likelihood of steatosis ≤5% and likewise the opposite for values >1.37. An HRI of ≥1.4 corresponds with >95% positive predictive value of ≥10% steatosis. CONCLUSION: HRI is an accurate noninvasive tool to quantify degree of steatosis and guide who should undergo random liver biopsy, potentially significantly reducing the total number of necessary liver biopsies.

Process Variation Detection using Missing Data in a Multihospital Community Practice Anatomic Pathology Laboratory.

OBJECTIVES: Barcode-driven workflows reduce patient identification errors. Missing process timestamp data frequently confound our health system's pending lists and appear as actions left undone. Anecdotally, it was noted that missing data could be found when there is procedure noncompliance. This project was developed to determine if missing timestamp data in the histology barcode drive workflow correlated with other process variations, procedure noncompliance, or is an indicator of workflows needing focus for improvement projects. MATERIALS AND METHODS: Data extracts of timestamp data from January 1, 2018, to December 15, 2018 for the major histology process steps were analyzed for missing data. Case level analysis to determine the presence or absence of expected barcoding events was performed on 1031 surgical pathology cases to determine the cause of the missing data and determine if additional data variations or procedure noncompliance events were present. The data variations were classified according to a scheme defined in the study. RESULTS: Of 70,085, there were 7218 cases (10.3%) with missing process timestamp data. Missing histology process step data was associated with other additional data variations in case-level deep dives (P < 0.0001). Of the cases missing timestamp data in the initial review, 18.4% of the cases had no identifiable cause for the missing data (all expected events took place in the case-level deep dive). CONCLUSIONS: Operationally, valuable information can be obtained by reviewing the types and causes of missing data in the anatomic pathology laboratory information system, but only in conjunction with user input and feedback.

Interleukin-33 / Cyclin D1 imbalance in severe liver steatosis predicts susceptibility to ischemia reperfusion injury.

Transplanting donor livers with severe macrosteatosis is associated with increased risk of primary non-function (PNF). The purpose of this study was to identify steatosis-driven biomarkers as a predisposition to severe liver damage and delayed recovery following ischemia reperfusion injury. Wistar rats were fed a methionine- and choline-deficient (MCD) diet for up to three weeks to achieve severe macrosteatosis (>90%). Animals underwent diet withdrawal to control chow and/or underwent ischemia reperfusion and partial hepatectomy injury (I/R-PHx) and reperfused out to 7 days on control chow. For animals with severe macrosteatosis, hepatic levels of IL-33 decreased while Cyclin D1 levels increased in the absence of NF-κB p65 phosphorylation. Animals with high levels of nuclear Cyclin D1 prior to I/R-PHx either did not survive or had persistent macrosteatosis after 7 days on control chow. Survival 7 days after I/R-PHx fell to 57% which correlated with increased Cyclin D1 and decreased liver IL-33 levels. In the absence of I/R-PHx, withdrawing the MCD diet normalized IL-33, Cyclin D1 levels, and I/R-PHx survival back to baseline. In transplanted grafts with macrosteatosis, higher Cyclin D1 mRNA expression was observed. Shifts in Cyclin D1 and IL-33 expression may identify severely macrosteatotic livers with increased failure risk if subjected to I/R injury. Clinical validation of the panel in donor grafts with macrosteatosis revealed increased Cyclin D1 expression corresponding to delayed graft function. This pre-surgical biomarker panel may identify the subset of livers with increased susceptibility to PNF.

Hepatic YAP1-TFE3 Rearranged Epithelioid Hemangioendothelioma.

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 a WWTR1-CAMTA1 fusion 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 hepatic YAP1-TFE3 rearranged EHE has been reported to date. We present the second case of YAP1-TFE3 rearranged 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-TFE3 rearranged 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 other TFE3-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.

Liver transplantation and the management of progressive familial intrahepatic cholestasis in children.

Progressive familial intrahepatic cholestasis (PFIC) is a constellation of inherited disorders that result in the impairment of bile flow through the liver that predominantly affects children. The accumulation of bile results in progressive liver damage, and if left untreated leads to end stage liver disease and death. Patients often present with worsening jaundice and pruritis within the first few years of life. Many of these patients will progress to end stage liver disease and require liver transplantation. The role and timing of liver transplantation still remains debated especially in the management of PFIC1. In those patients who are appropriately selected, liver transplantation offers an excellent survival benefit. Appropriate timing and selection of patients for liver transplantation will be discussed, and the short and long term management of patients post liver transplantation will also be described.