Serrated neoplasia of the colon: what do we really know?

Colonoscopy offers incomplete protection from colorectal cancer, particularly in the right colon. Part of this inadequacy may be related to serrated neoplasia. Serrated polyps of the colorectum are now understood to be a heterogeneous group of polyps, some of which are cancer precursors, such as the sessile serrated adenoma (SSA) and the traditional serrated adenoma (TSA). In contrast to conventional adenomas, there is limited published literature on the epidemiology and natural history of these lesions. Furthermore, existing guidelines regarding screening and surveillance practices for these polyps are based largely on expert opinion without firm evidence. In this review, we describe the current understanding of the molecular biology, histopathology, and endoscopic features of serrated neoplasia of the colorectum, with an emphasis on aspects relevant to the practicing gastroenterologist.

Focal fat masquerading as malignancy in the liver graft of a post-transplant patient.

BACKGROUND AND AIMS: Liver failure from non-alcoholic fatty liver disease (NAFLD) is an increasing indication for liver transplant and recurrence of fatty liver in transplanted grafts has been documented. Herein is described an atypical recurrence of steatosis as a de novo focal fatty lesion that mimicked a more ominous cancerous lesion. This presentation of recurrent NAFLD has not previously been described in the literature. METHODS: Chart review. RESULTS: Biopsy of an atypical lesion was found to be focal fat with surrounding steatohepatitis. CONCLUSIONS: Non-alcoholic fatty liver disease may recur after liver transplant and manifest as a focal fatty lesion. It is important to catalogue the atypical presentations of the increasingly common NAFLD developing in transplanted livers.

CD73 Maintains Hepatocyte Metabolic Integrity and Mouse Liver Homeostasis in a Sex-Dependent Manner.

BACKGROUND & AIMS: Metabolic imbalance and inflammation are common features of chronic liver diseases. Molecular factors controlling these mechanisms represent potential therapeutic targets. CD73 is the major enzyme that dephosphorylates extracellular adenosine monophosphate (AMP) to form the anti-inflammatory adenosine. CD73 is expressed on pericentral hepatocytes, which are important for long-term liver homeostasis. We aimed to determine if CD73 has nonredundant hepatoprotective functions. METHODS: Liver-specific CD73 knockout (CD73-LKO) mice were generated by targeting the Nt5e gene in hepatocytes. The CD73-LKO mice and hepatocytes were characterized using multiple approaches. RESULTS: Deletion of hepatocyte Nt5e resulted in an approximately 70% reduction in total liver CD73 protein (P < .0001). Male and female CD73-LKO mice developed normally during the first 21 weeks without significant liver phenotypes. Between 21 and 42 weeks, the CD73-LKO mice developed spontaneous-onset liver disease, with significant severity in male mice. Middle-aged male CD73-LKO mice showed hepatocyte swelling and ballooning (P < .05), inflammation (P < .01), and variable steatosis. Female CD73-LKO mice had lower serum albumin levels (P < .05) and increased inflammatory genes (P < .01), but did not show the spectrum of histopathologic changes in male mice, potentially owing to compensatory induction of adenosine receptors. Serum analysis and proteomic profiling of hepatocytes from male CD73-LKO mice showed significant metabolic imbalance, with increased blood urea nitrogen (P < .0001) and impairments in major metabolic pathways, including oxidative phosphorylation and AMP-activated protein kinase (AMPK) signaling. There was significant hypophosphorylation of AMPK substrates in CD73-LKO livers (P < .0001), while in isolated hepatocytes treated with AMP, soluble CD73 induced AMPK activation (P < .001). CONCLUSIONS: Hepatocyte CD73 supports long-term metabolic liver homeostasis through AMPK in a sex-dependent manner. These findings have implications for human liver diseases marked by CD73 dysregulation.

Intraosseous Rosai-Dorfman disease diagnosed by touch imprint cytology evaluation: A case series.

Sinus histiocytosis with massive lymphadenopathy, also known as Rosai-Dorfman disease (RDD) is a rare benign disorder that primarily affects the lymph nodes. Localized lymphadenopathy is the most common clinical manifestation of this disorder. However, RDD has been described in several extra-nodal sites including the head and neck region, soft tissue, skin, upper respiratory tract, gastro-intestinal tract and central nervous system (CNS). Involvement of the bone is considered very rare, occurring in less than 10% patients. RDD is one of the histiocytoses and the differential diagnosis includes entities such as Langerhans cell histiocytosis and Erdheim-Chester disease. In the rare intraosseous variant, the clinical and radiologic differential diagnosis is broader and includes neoplasms such as osteosarcoma and Ewing sarcoma. In this report, we describe three cases of extra-nodal, intraosseous RDD where touch imprint cytology played a crucial role in diagnosis. Two of the cases initially presented with involvement of the head and neck region and later developed intraosseous disease; while the third patient presented with primary bone involvement. The diagnosis was established by core biopsy with touch imprints of the bone lesions. The cytologic samples showed numerous histiocytes, often with neutrophils within their cytoplasm (emperipolesis) in addition to lymphocytes and plasma cells. The diagnosis of RDD was confirmed with appropriate immunohistochemical stains. Our account of these three cases of intraosseous Rosai-Dorfman disease highlights the role of cytology in the diagnosis of this rare entity.

Northern Italy in the American South: Assessing interobserver reliability within the Milan System for Reporting Salivary Gland Cytopathology.

BACKGROUND: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) has been proposed to standardize salivary gland fine-needle aspiration (FNA) diagnoses. This study assessed salivary gland FNA results and risk of malignancy (ROM) rates at the University of North Carolina as well as the interobserver reliability (IOR) of the atypia of undetermined significance (AUS) and salivary gland neoplasm of uncertain malignant potential (SUMP) categories. METHODS: The electronic medical record was searched for FNA cases from 2010 to 2017 with subsequent surgical resections. Histologic diagnosis was used for gold-standard comparison. The original cytologic results were then converted into MSRSGC categories (nondiagnostic, nonneoplastic, AUS, benign neoplasm, SUMP, suspicious, and malignant). For the assessment of IOR, 23 cases were selected with enrichment for cases diagnosed as AUS (n = 11) or SUMP (n = 9). Six boarded cytopathologists and 1 cytopathology fellow assessed representative slides and provided an MSRSGC diagnosis for each case. Fleiss' κ coefficients were calculated to determine IOR. RESULTS: The ROM was 33% for both AUS and SUMP cases; however, the risk of neoplasia was 56% for AUS cases and 100% for SUMP cases. Fleiss' κ for the AUS category was 0.217 (P < .05), and Fleiss' κ for the SUMP category was 0.024 (P = .74). CONCLUSIONS: In this study assessing the IOR of MSRSGC categories, fair agreement and slight agreement were found for the AUS and SUMP categories, respectively. Observers preferentially used the AUS or benign neoplasm category for SUMP cases, perhaps because of unfamiliarity with SUMP as a diagnostic option. The initial adoption of a new reporting system will require a quality assessment to ensure that the system is reliable and useful for clinicians. Cancer Cytopathol 2018;126:390-6. © 2018 American Cancer Society.

Comprehensive analysis of The Cancer Genome Atlas reveals a unique gene and non-coding RNA signature of fibrolamellar carcinoma.

Fibrolamellar carcinoma (FLC) is a unique liver cancer primarily affecting young adults and characterized by a fusion event between DNAJB1 and PRKACA. By analyzing RNA-sequencing data from The Cancer Genome Atlas (TCGA) for >9,100 tumors across ~30 cancer types, we show that the DNAJB1-PRKACA fusion is specific to FLCs. We demonstrate that FLC tumors (n = 6) exhibit distinct messenger RNA (mRNA) and long intergenic non-coding RNA (lincRNA) profiles compared to hepatocellular carcinoma (n = 263) and cholangiocarcinoma (n = 36), the two most common liver cancers. We also identify a set of mRNAs (n = 16) and lincRNAs (n = 4), including LINC00473, that distinguish FLC from ~25 other liver and non-liver cancer types. We confirm this unique FLC signature by analysis of two independent FLC cohorts (n = 20 and 34). Lastly, we validate the overexpression of one specific gene in the FLC signature, carbonic anhydrase XII (CA12), at the protein level by western blot and immunohistochemistry. Both the mRNA and lincRNA signatures support a major role for protein kinase A (PKA) signaling in shaping the FLC gene expression landscape, and present novel candidate FLC oncogenes that merit further investigation.

Metastatic melanoma in an esophagus demonstrating Barrett esophagus with high grade dysplasia.

BACKGROUND: Metastatic melanoma involving the esophagus is rare; the occurrence of metastatic melanoma in a background of Barrett esophagus is rarer still. We report a case of an 80 year-old male who presented to our institution for workup of Barrett esophagus with high-grade dysplasia and who proved to have metastatic melanoma occurring in the background of Barrett esophagus, the first report of this kind, to our knowledge, in the English literature. CASE PRESENTATION: An 80 year-old Caucasian male was diagnosed at an outside institution with Barrett's esophagus with high grade dysplasia and presented to our institution for therapy. The patient underwent endoscopic mucosal resection using a band ligation technique of an area of nodularity within the Barrett esophagus. Microscopic examination demonstrated extensive Barrett esophagus with high-grade dysplasia as well as a second tumor which was morphologically different from the surrounding high-grade dysplasia and which was positive for S-100, HMB 45 and Melan-A on immunohistochemistry, consistent with melanoma. Further workup of the patient demonstrated multiple radiologic lesions consistent with metastases. Molecular studies demonstrated that the melanoma was positive for the 1799T>A (V600E) mutation in the BRAF gene. The overall features of the tumor were most consistent with metastatic melanoma occurring in a background of Barrett esophagus with high-grade dysplasia. CONCLUSION: This case demonstrates a unique intersection between a premalignant condition (Barrett esophagus with high grade dysplasia) and a separate malignancy (melanoma). This report also shows the utility of molecular testing to support the hypothesis of primary versus metastatic disease in melanoma.