Fibrolamellar carcinoma is a rare primary malignant liver neoplasm that usually affects adolescents and young adults with no underlying liver disease. Morphologically, the tumor cells resemble oncocytic hepatocytes arranged in cords with a stroma of lamellated collagen fibers. Immunohistochemical studies have found that fibrolamellar carcinomas express markers associated with both biliary (CK7 and epithelial membrane antigen) and hepatocytic (heppar-1and glypican-3) differentiation, as well as markers associated with hepatic progenitor cells (CK19 and EpCAM) and stem cells (CD133 and CD44). Genetic studies show fewer alterations compared with classic hepatocellular carcinoma. Pooled data from comparative genomic hybridization studies show that fibrolamellar carcinomas have fewer and less frequent genomic alterations when compared with classic hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma. Of the alterations seen in fibrolamellar carcinoma, the most frequent are gains in 1q and 8q (also frequently seen in other hepatic tumors) and loss of 18q. Fibrolamellar carcinoma also has less frequent methylation of tumor suppressor promoters compared with hepatocellular carcinoma and minimal alterations in mitochondrial DNA. Fibrolamellar carcinoma is associated with better survival than hepatocellular carcinoma and cholangiocarcinoma, presumably due to the young age of the patients and the lack of cirrhosis. These features make more aggressive surgical therapy possible. There is currently very little information on the effectiveness of chemotherapy for fibrolamellar carcinoma.

Plasma cell hepatitis (PCH) is characterized by plasma cell infiltration seen in allografts of patients who underwent liver transplantation (LT) for conditions other than autoimmune hepatitis. We identified 40 PCH patients who underwent LT for hepatitis C virus (HCV) by searching our pathology database (1994-2006) for the keywords liver allograft , lymphoplasmacytic , and plasma cell(s ). We selected 2 control patients who received LT for HCV for each PCH case. The control patients were matched according to date of LT and availability of biopsy material at the time interval to development of PCH in PCH patients. Explant and post-LT biopsy slides were blindly reviewed by 2 liver pathologists and the severity of the plasma cell infiltrate was scored. A score of 3 (plasma cells composing >30% of the infiltrate) defined PCH in allograft biopsies. Five random areas of dense inflammation were also examined in explant livers and the highest score was used. Poor outcome was defined as death or advanced fibrosis (stage ≥ 4 of 6). We found that PCH patients were more likely to have worse outcomes than control patients (65% versus 40%, P < 0.01), including increased mortality (50% versus 30%, P < 0.05). Kaplan-Meier survival analysis showed significantly worse survival for PCH patients from 4 to 10 years post-LT ( P < 0.05). Explants from 40% of PCH patients had a score of 3 compared to 18% of control patients ( P < 0.01). We found that the development of PCH is associated with poor outcome in patients undergoing LT for HCV. The association of significant plasma cell infiltrates in native livers of HCV patients developing PCH suggests that some patients may have a predisposition to developing PCH. Liver Transpl 15:1826-1833, 2009. © 2009 AASLD.

The SMAD4 tumor suppressor gene product inhibits transforming growth factor-β-mediated signaling and is mutated in ~10% of colorectal carcinomas. The prognostic significance of SMAD4 mutations has been controversial. We studied the pathological and clinical characteristics of SMAD4-mutated intestinal adenocarcinomas using a retrospective case-control study design. Cases and controls were identified among 443 primary adenocarcinomas that had undergone next generation DNA sequencing (NGS) with the Ion AmpliSeq Cancer Hotspot Panel v2, which evaluates 50 cancer-related genes. Twenty-eight SMAD4-mutated (SMAD4m) patients were matched 1:2 with 56 consecutive SMAD4 wild-type (SMAD4wt) control patients from the same analysis stream. Compared with the SMAD4wt controls, the SMAD4m tumors were of higher stage (P = 0.026) and were more likely to feature mucinous differentiation (P = 0.0000), to occur in the setting of Crohn’s disease (P = 0.0041), and to harbor concurrent RAS mutations (P = 0.0178). Tumor mucin content was significantly correlated with mutations involving the MH2 domain of the SMAD4 protein (P = 0.0338). Correspondence between mutation sites and morphology was demonstrated directly in a mixed adenocarcinoma and neuroendocrine tumor where SMAD4 mutations involving different protein domains were found in histologically disparate tumor regions despite both containing identical KRAS and TP53 mutations.