Biopsy Specimens From Allograft Liver Contain Histologic Features of Hepatitis C Virus Infection After Virus Eradication.

BACKGROUND & AIMS: Most patients, even those who have received a liver transplant, achieve a sustained virologic response (SVR) to therapy for hepatitis C virus (HCV) infection. Little is known about the histologic features of liver biopsy specimens collected after SVR, particularly in patients who have received a liver transplant. We aimed to better characterize the histologic features of allograft liver biopsy specimens from patients who achieved SVR to anti-HCV therapy after liver transplantation. METHODS: We performed a retrospective analysis of 170 allograft liver biopsy specimens from 36 patients who received a liver transplant for chronic HCV infection, had recurrent HCV infection after transplantation, and subsequently achieved SVR (collected from 1999 through 2015 at 4 medical centers). SVR was defined as an undetectable serum HCV RNA level 24 weeks after completion of HCV treatment. A total of 65 biopsy specimens were post-SVR (at least 1 post-SVR from each patient; some biopsy specimens were collected at later time points from a subset of patients). We performed polymerase chain reaction analysis for HCV RNA on a subset of the biopsy specimens (28 collected before SVR and 32 after SVR). RESULTS: Of the 65 post-SVR biopsy specimens, 45 (69%) had histologic features of active HCV infection. Of the initial post-SVR biopsy specimens collected from each of the 36 patients, 32 (89%) showed these changes. For patients with more than 1 post-SVR biopsy specimen, 6 (46%) had no change in fibrosis between biopsies, and fibrosis worsened for 3 patients (23%) based on their most recent biopsy. The HCV RNA level was undetectable in 31 of the 32 biopsy specimens analyzed by polymerase chain reaction. CONCLUSIONS: In a retrospective analysis of allograft liver biopsy specimens from patients who achieved SVR after a liver transplant for chronic HCV infection, histologic changes associated with active HCV were present in 69% and fibrosis continued to progress in 23%, despite the lack of detection of HCV RNA. Pathologists should be aware of patients' SVR status when analyzing liver biopsy specimens to avoid diagnoses of chronic HCV-associated hepatitis. Because of the persistent inflammatory activity and fibrosis after SVR, clinicians should continue to monitor patients carefully after SVR to anti-HCV therapy.

Safety and efficacy of EMR for sporadic, nonampullary duodenal adenomas: a single U.S. center experience (with video).

BACKGROUND AND AIMS: EMR is increasingly used for resection of sporadic, nonampullary duodenal adenomas (SNDAs), but there are no guidelines for the management of these lesions. The aims of this study were to evaluate the safety and efficacy of EMR exclusively for SNDAs and to determine the factors predictive of outcomes. METHODS: We performed a retrospective review of patients with SNDAs referred for endoscopic therapy from 2006 to 2013. The outcomes studied were successful endoscopic resection, major adverse events, early and late recurrences, and clinical remission. RESULTS: Sixty-eight patients with SNDAs were included and 51 (75%) underwent EMR. The mean adenoma size was 22.0 ± 8.9 mm. Successful resection was achieved in 49 of 51 patients (96.1%), and major adverse events were noted in 8 of 51 patients (15.7%). Early and late recurrences were noted in 25.6% and 5.2% of patients, respectively, and were treated endoscopically. Clinical remission was achieved in 89.7% of patients after a median follow-up of 15 months. Presence of villous histology was associated with increased recurrence (P = .019), but no association of recurrence was noted with other endoscopic features or resection technique. Large adenoma size (P = .0057) and need for intraprocedural hemostasis (P = .006) were associated with increased adverse events, but no association of adverse events was noted with location or resection technique. CONCLUSIONS: Large duodenal adenomas can be effectively managed with EMR at a referral center with experienced endoscopists. However, EMR has a significant recurrence rate, especially early recurrence, and the risk of adverse events is not negligible. Endoscopic therapy is successful in managing recurrent adenomas.

Mass-spectrometry-based quantitation of Her2 in gastroesophageal tumor tissue: comparison to IHC and FISH.

BACKGROUND: Trastuzumab has shown a survival benefit in cases of Her2-positive gastroesophageal cancer (GEC). Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) currently determine eligibility for trastuzumab-based therapy. However, these low-throughput assays often produce discordant or equivocal results. METHODS: We developed a targeted proteomic assay based on selected reaction monitoring mass spectrometry (SRM-MS) and quantified levels (amol/µg) of Her2-SRM protein in cell lines (n = 27) and GEC tissues (n = 139). We compared Her2-SRM protein expression with IHC/FISH, seeking to determine optimal SRM protein expression cutoffs in order to identify HER2 gene amplification. RESULTS: After demonstrating assay development, precision, and stability, Her2-SRM protein measurement was observed to be highly concordant with the HER2/CEP17 ratio, particularly in a multivariate regression model adjusted for SRM expression of the covariates Met, Egfr, Her3, and HER2 heterogeneity, as well as their interactions (cell lines r (2) = 0.9842; FFPE r (2) = 0.7643). In GEC tissues, Her2-SRM protein was detected at any level in 71.2 % of cases. ROC curves demonstrated that Her2-SRM protein levels have a high specificity (100 %) at an upper-level cutoff of >750 amol/µg and sensitivity of 75 % at a lower-level cutoff of <450 amol/µg for identifying HER2 FISH-amplified tumors. An "equivocal zone" of 450-750 amol/µg of Her2-SRM protein was analogous to IHC2+ but represented fewer cases (9-16 % of cases versus 36-41 %). CONCLUSIONS: Compared to IHC, targeted SRM-Her2 proteomics provided more objective and quantitative Her2 expression with excellent HER2/CEP17 FISH correlation and fewer equivocal cases. Along with its multiplex capability for other relevant oncoproteins, these results demonstrate a refined HER2 protein expression assay for clinical application.

RUNX2 quadruplication: additional evidence toward a new form of syndromic craniosynostosis.

The RUNX2 transcription factor regulates osteoblast differentiation. Its absence, as with cleidocranial dysplasia, results in deficient bone formation. However, its excess seems to follow a dose response of over ossification. RUNX2 duplications (3 copies) are exceedingly rare but have been reported to cause craniosynostosis. There are no existing reports of quadruplications (4 copies). We present a case study of a boy with an atypical skull deformity with pan-craniosynostosis whose microarray analysis revealed 4 copies of a 1.24-Mb region from 6p12.3 to 6p21.1 containing the RUNX2 gene. Further characterization of this osteogenic pathway may aid in our understanding of the pathogenesis and subsequent prevention and treatment of syndromic craniosynostosis.

Morphologic and Molecular Findings in Myxoid Hepatic Adenomas.

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.

Toxic Epidermal Necrolysis with Gastrointestinal Involvement: A Case Report and Review of the Literature.

Gastrointestinal involvement is a rare complication of toxic epidermal necrolysis syndrome (TENS) that results in sloughing of the intestinal epithelium. Prior case reports have noted the potential susceptibility of the entire gastrointestinal tract, from oropharynx and esophagus to sigmoid colon and rectum. Given its infrequency, the effect of gastrointestinal involvement on the treatment and prognosis of TENS is poorly understood. Here, the authors report a case of gastrointestinal symptoms in a patient diagnosed with toxic epidermal necrolysis, likely representing gastrointestinal involvement. In addition, the authors describe the histopathologic and endoscopic characteristics of the involved mucosa, clinical course, and present a review of the literature of this rare but potentially impactful complication of TENS.

Crohn enteritis-associated small bowel adenocarcinomas exhibit gastric differentiation.

Primary small bowel adenocarcinoma is rare. Although generally similar to colonic adenocarcinoma, some small bowel adenocarcinomas exhibit unique morphologic features, particularly those arising in association with Crohn disease. In this study, 15 sporadic small bowel adenocarcinomas and 11 Crohn enteritis-associated small bowel adenocarcinomas were examined for histology and immunohistochemical profile including cytokeratins (CK) 7 and 20, intestinal markers CDX2 and MUC2, and gastric epithelial markers MUC5AC and MUC6. We found that Crohn enteritis-associated small bowel adenocarcinomas frequently resemble gastric tubular adenocarcinoma histologically. In addition, when compared to sporadic small bowel adenocarcinoma, the former expressed MUC5AC and MUC6 with much higher frequency (82% vs. 7% and 73% vs. 0%, respectively). Ten of 11 Crohn enteritis-associated small bowel adenocarcinomas (91%) were positive for at least one gastric-type marker (MUC5AC or MUC6). Expression of CK7 was also more frequent in Crohn enteritis-associated small bowel adenocarcinoma (73% versus 27%) while expression of CK20 was less frequent (64% vs. 100%). There was no difference between sporadic and Crohn enteritis-associated small bowel adenocarcinoma in expression of CDX2 (100% vs. 91%) and MUC2 (93% vs. 73%). These observations suggest that there is a difference in the morphologic and immunohistochemical characteristics of sporadic versus Crohn enteritis-associated small bowel adenocarcinoma, particularly in their expression of gastric-type mucin. The findings also suggest that gastric differentiation in Crohn enteritis-associated small bowel adenocarcinoma is related to gastric metaplasia, a common phenomenon in Crohn disease.