Ogechukwu Eze

The Role of Epigenetic Alterations in Papillary Thyroid Carcinogenesis

Papillary thyroid carcinoma (PTC) accounts for over 80% of all thyroid malignancies. The molecular pathogenesis remains incompletely clarified although activation of the RET fusion oncogenes, and RAS and BRAF oncogenes, has been well characterized. Novel technologies using genome-wide approaches to study tumor genomes and epigenomes have provided great insights into tumor development. Growing evidence shows that acquired epigenetic abnormalities participate with genetic alterations to cause altered patterns of gene expression/function. It has been established beyond doubt that promoter cytosine methylation in CpG islands, and the subsequent gene silencing, is intimately involved in cancer development. These epigenetic events very likely contribute to significant variation in gene expression profiling, phenotypic features, and biologic characteristics seen in PTC. Hypermethylation of promoter regions has also been analyzed in PTC, and most studies have focused on individual genes or a small cohort of genes implicated in tumorigenesis.

Vanishing Thyroid Tumors: A Diagnostic Dilemma After Ultrasonography-Guided Fine-Needle Aspiration

BACKGROUND Fine-needle aspiration (FNA) is the most accurate and cost-effective method for evaluating thyroid nodules. However, FNA-induced secondary changes completely replacing thyroid tumors (vanishing tumors) may create a novel problem. In this study, we highlight the diagnostic and management issues associated with the unintended consequences of ultrasonography (US)-guided FNA. METHODS Fourteen thyroid glands (11 women and 3 men, ages 33-64 years) with vanishing tumors were prospectively identified between 2009 and 2012 upon surgical resection. Cytology and histopathology slides were reviewed, and second opinions were obtained when necessary. RESULTS The cytology of the 14 vanishing tumors was suspicious/positive for papillary thyroid carcinoma (PTC) in 5, indeterminate (atypia of unknown significance) in 5, benign in 2, follicular neoplasm in 1, and nondiagnostic in 1 nodule. Upon thyroidectomy, the vanishing tumors ranged in size from 0.4 to 3.5 cm (median 0.7 cm). Microscopically, the nodules showed cystic degeneration, organizing hemorrhage, granulation tissue, fibrosis, and microcalcifications. In seven tumors, a few residual malignant cells (PTC in five) or residual benign follicles (hemorrhagic cyst in two) at the periphery of the vanishing tumors helped with the final diagnosis. The remaining seven tumors were completely replaced by FNA-induced secondary changes, and had the cytology diagnosis of benign in one, follicular neoplasm in one, and suspicious/positive for PTC in five. Of the latter five, two showed additional separate foci of PTC, while three vanishing tumors (0.5, 1.2, and 1.6 cm) had no residual malignant cells and no additional carcinoma leading to a final diagnosis of negative for malignancy. CONCLUSIONS US-guided FNA may lead to complete obliteration of thyroid nodules, rendering final diagnosis upon thyroidectomy difficult or impossible. In these unusual circumstances, the possibility that the surgical pathology may be nonrepresentative should be considered if the cytologic features on FNA are sufficient by themselves to support a definitive diagnosis of PTC.

Definition of barrett esophagus in the United States: Support for retention of a requirement for goblet cells

Barrett esophagus (BE) predisposes patients to the development of esophageal adenocarcinoma (EAC). However, the global definition of BE is controversial. Pathologists in Europe and the United States require intestinal metaplasia (IM) within columnar-lined mucosa (CLM) in the tubular esophagus to diagnose BE, whereas in the UK and Japan only the presence of CLM is required. To aid in establishing an appropriate definition for BE, we evaluated whether IM accompanies EAC in a US patient cohort. We examined a series of 139 consecutive patients who underwent endoscopic mucosal resections or esophagectomies for EAC performed at a US tertiary care center. The resection specimens were evaluated for the presence (IM+) or absence (IM−) of IM within CLM. Ninety-seven (70%) patients were IM+. Tumors found in IM− patients tended to be advanced at the time of resection (57% pT3 or greater, IM−; 31% pT3 or greater, IM+; P=0.02) such that the tumor may have “overgrown” zones of IM. We hypothesized that changes as a result of neoadjuvant chemotherapy or radiation might mask preexisting IM. When evaluating this hypothesis, we found that 34 of 39 of treatment-naive patients were IM+. Two of the 5 IM− patients had prior IM+ biopsies resulting in 92% of treatment-naive patients who were IM+. In our US hospital population, CLM with IM in the tubular esophagus is found in association with EAC in 70% to 92% of patients. We believe that based on these data the United States definition of BE should continue to require the presence of IM.

Clinical and biological significance of precursor lesions of intrahepatic cholangiocarcinoma.

Cholangiocarcinoma (CC) is primarily a malignant tumor of older adults most prevalent in Southeast Asia, where liver fluke infestation is high. However the etiology in western countries is unknown. Although the incidence of extrahepatic cholangiocarcinoma has remained constant, incidence of intrahepatic CC (ICC) which differs in morphology, pathogenesis, risk factors, treatment and prognosis is increasing. While this increase is associated with hepatitis C virus infection, chronic nonalcoholic liver disease, obesity, and smoking, the pathogenesis of ICC and molecular alterations underlying the carcinogenesis are not completely elucidated. Benign biliary lesions such as biliary intraepithelial neoplasia, intraductal papillary neoplasm of the bile duct, von Meyenburg complex or bile duct hamartoma, and bile duct adenoma have been associated with ICC. For each of these entities, evidence suggests or supports a role as premalignant lesions. This article summarized the important biological significance of the precursor lesions of ICC and the molecular mechanisms that may be involved in intrahepatic cholangiocarcinogenesis.

A Brief Review of the Controversial Role of Iron in Colorectal Carcinogenesis

Colorectal Cancer (CRC) is the second and third most common cancer in females and males worldwide, respectively. Major risk factors have been established for the development of CRC. These include susceptible genetics, increased age (50 years), male gender, and race. The role of environmental factors in CRC pathogenesis is evident but complex. Some environmental factors linked to CRC pathogenesis include diet, specifically red meat, refined grains and starches, sugars, fat, alcohol, and chemicals. Implicated chemicals include arsenic, chromium, nickel and iron. This article briefly reviews the evidence for the controversial role of iron in pathogenesis of CRC. Proposed mechanisms for iron carcinogenesis involve various genetic and metabolic pathways, illustrating the complex interplay of genetic and metabolic alterations in chemical carcinogenesis

Expression of VHL Causes Three-Dimensional Morphological Changes in Renal Cells Indicative of Proximal Tubule Differentiation.

Mutations in the von Hippel-Lindau (VHL) tumor suppressor gene are responsible for the VHL hereditary cancer syndrome, and are associated with the majority of clear cell renal cell carcinomas. In this study, scanning electron microscopy of VHL-negative renal carcinoma cells was utilized to examine the effects of VHL re-expression on the morphology of these cells. Significant differences were observed between the morphology of VHL-negative control cells and those with reintroduced VHL, with VHL expression mediating an apical surface that mounded upward, as opposed to the flat surfaces seen with VHL-negative cells. In long term cultures, rounded VHL-expressing cells grew in clusters on top the monolayer, and microvilli were observed on the apical face of these cells, in a manner suggestive of proximal tubule differentiation. In contrast, VHL-negative cells remained flat and did not develop microvilli in long-term cultures. Since VHL is a key member of an ubiquitin E3 ligase complex whose best known target is hypoxia-inducible factor alpha (HIF-α), we looked at the effects of HIF-α expression on cell morphology. Knockdown of HIF-2α in cells that only express this isoform had no effect on the morphology of the cells. These results indicate that VHL expression directs three dimensional morphological changes in renal cells indicative of differentiation, and while dysregulation of HIF-α may be necessary for tumorigenesis following VHL loss, it is not the major determinant of these VHL-mediated morphological changes.

Refractory inflammatory bowel disease: is there a role for Epstein–Barr virus? A case controlled study using highly sensitive EBV encoded small RNA1 In Situ hybridization

A potential role for viral infections has been implicated in inflammatory bowel disease (IBD) unresponsive to medical treatment. It is well known that Epstein-Barr virus (EBV) infection can elicit a brisk mononuclear response in the gastrointestinal tract. The aim of this study was to further evaluate the role of EBV in patients with refractory IBD and compare them with nonrefractory IBD cases. Surgically resected colonic specimens from 67 patients with refractory IBD (62 with ulcerative colitis, 3 patients with Crohn disease, and 2 patients with indeterminate colitis) were retrieved. Twelve colectomy specimens from patients with ulcerative colitis who had undergone resections for dysplasia or endometriosis were included as controls. Highly sensitive EBV-encoded small RNA1 (EBER-1) in situ hybridization was performed on a representative block from each specimen. EBER-1 reactivity was graded as absent, focal, or diffuse. EBV was detected in 60% (40/67) of patients with refractory IBD compared with 25% (3/12) of the control group (P < .05). Focal EBER-1 positivity was present in 45% of cases of refractory IBD compared with 25% of controls. Diffuse EBER-1 reactivity was seen in 15% of cases of refractory IBD (10/67); none of the samples from the control group contained diffuse EBER-1 positivity. There was a positive correlation between EBER positivity and depth of inflammation and mucosal ulceration in patients with refractory IBD. Our findings suggest a potential role for EBV infection in patients with refractory IBD.

Frequency and pathological characteristics of drug-induced liver injury in a tertiary medical center

Drug-induced liver injury (DILI) accounts for approximately 10% of acute hepatitis cases. DILI can arise as idiosyncratic or intrinsic injury from hundreds of drugs, herbals, and nutritional supplements and is essential to recognize as one of the differential diagnoses of hepatitis in a liver biopsy. The purpose of this study is to investigate the frequency and pathological characteristics of DILI related to the variety of hepatotoxic agents. We searched our pathology database for all patients with hepatitis diagnosed on liver biopsy from January 2012 to May 2016, and selected patients with a diagnosis of DILI. Electronic medical records were reviewed for patient medication list, history of herbal medicine or supplement use, and pre-biopsy liver function test (LFT) results. Clinical and pathologic correlation was used to determine the causative or related agents for DILI. We then assessed histopathologic features of liver injury and categorized biopsy findings as primarily bile duct injury, lobular/portal hepatitis, or mixed changes. Six hundred four total liver biopsies for hepatitis or liver injury were identified, of which 70 cases (11.6%) carried the diagnosis of DILI confirmed by clinical correlation. The most common etiologies associated with DILI were supplements and herbal products (31.4%), antimicrobials (14.3%), chemotherapeutics (11.4%), antilipidemics (7.1%) and immunomodulatory agents (7.1%). LFT results positively correlated with histological findings. Nutritional/herbal supplements have emerged as one of the major hepatotoxicity agents. DILI can manifest as predominantly hepatitis, bile duct injury or combination. Histological pattern recognition in the liver biopsy may help identify specific hepatotoxic agents causing DILI.

A rare case of Crohn’s ileitis in a patient with constitutional mismatch repair deficiency

Constitutional mismatch repair deficiency (CMMRD), a variant of Lynch syndrome, is a rare disease characterized by café-au-lait spots, oligopolyposis, glioblastoma and lymphoma. A 24-year-old male, under surveillance for CMMRD, developed Crohn’s ileitis after total colectomy with end ileostomy for colorectal cancer and failed to respond to oral corticosteroids. The patient underwent induction and maintenance of remission with vedolizumab infusions. We report the first patient with CMMRD developing Crohn’s disease. The choice of immunosuppressive therapy in these patients is challenging and needs to be made according to their risk for malignancy.