Alexandros D. Polydorides

HER2/neu gene amplification and protein overexpression in gastric and gastroesophageal junction adenocarcinoma: a review of histopathology, diagnostic testing, and clinical implications.

Amplification of the human epidermal growth factor receptor 2/neu (HER2/neu) gene and overexpression of the HER2 protein (HER2) have been shown to occur in gastric and gastroesophageal junction adenocarcinoma in a number of studies. With a dismal survival rate, patients with these cancers stand to benefit from the identification of possible molecular targets such as HER2 for both prognostic and therapeutic purposes. Although these and other carcinomas that overexpress HER2 may have a poorer prognosis and exhibit resistance to conventional chemotherapy, they have also recently been shown to respond to targeted therapy with the anti-HER2 antibody trastuzumab. Here, we briefly review the molecular biology, histopathology, diagnostic techniques, and interpretation, as well as the clinical implications, of HER2 amplification/overexpression in gastric and gastroesophageal adenocarcinoma.

Colorectal dysplasia in chronic inflammatory bowel disease: pathology, clinical implications, and pathogenesis.

CONTEXTnColorectal cancer, the most lethal long-term complication of chronic inflammatory bowel disease (IBD), is the culmination of a complex sequence of molecular and histologic derangements of the intestinal epithelium that are initiated and at least partially sustained by chronic inflammation. Dysplasia, the earliest histologic manifestation of this process, plays an important role in cancer prevention by providing the first clinical alert that this sequence is underway and serving as an endpoint in colonoscopic surveillance of patients at high risk for colorectal cancer.nnnOBJECTIVEnTo review the histology, nomenclature, clinical implications, and molecular pathogenesis of dysplasia in IBD.nnnDATA SOURCEnLiterature review and illustrations from case material.nnnCONCLUSIONSnThe diagnosis and grading of dysplasia in endoscopic surveillance biopsies play a decisive role in the management of patients with IBD. Although interpathologist variation, endoscopic sampling problems, and incomplete information regarding the natural history of dysplastic lesions are important limiting factors, indirect evidence that surveillance may be an effective means of reducing cancer-related mortality in the population with IBD has helped validate the histologic criteria, nomenclature, and clinical recommendations that are the basis of current practice among pathologists and clinicians. Emerging technologic advances in endoscopy may permit more effective surveillance, but ultimately the greatest promise for cancer prevention in IBD lies in expanding our thus far limited understanding of the molecular pathogenetic relationships between neoplasia and chronic inflammation.

Evaluation of site-specific and seasonal variation in colonic mucosal eosinophils

Several systemic disorders and gastrointestinal diseases may be associated with increased colonic mucosal eosinophils, which may vary in number throughout the normal colon. Some investigators have proposed that colonic eosinophilia reflects allergen exposure, although this hypothesis has never been validated, and values quantifying the number of mucosal eosinophils that can be regarded as a normal finding are lacking. The aims of this study were to determine the number of intramucosal eosinophils normally present throughout the colon and evaluate the relationship between colonic eosinophilia and seasonal allergen exposure. Eosinophils in the crypt epithelium and lamina propria were evaluated in 198 mucosal biopsy specimens obtained from the ascending (n = 98) and descending (n = 100) colon of patients with normal colonoscopic examinations. The cases were stratified into 12 groups, reflecting the months during which the samples were obtained, and the mean number of mucosal eosinophils was determined for each group. Daily air pollen counts were recorded, and the mean determined for each month. Fifty-five percent of mucosal biopsy specimens from the ascending colon contained eosinophils in the crypt epithelium, compared with only 5% of biopsy specimens from the descending colon (P < .001). Lamina propria eosinophils were, on average, 3 times more numerous in the ascending compared with the descending colon (P < .001). Mucosal eosinophils were slightly more numerous in samples obtained in April and May, corresponding to periods of highest pollen counts, but this relationship was not significant (P > .05). We conclude that intramucosal eosinophils are commonly present in the proximal colon but show only mild fluctuations with ambient allergen exposure.

Metastatic Renal Cell Carcinoma to Hemangioblastoma in von Hippel-Lindau Disease

A case of metastatic renal cell carcinoma (RCC) to a capillary hemangioblastoma (HAB) of the central nervous system in a 52-year-old woman with von Hippel-Lindau (vHL) syndrome is described. We review the literature on metastatic RCC to HAB, summarize the histologic and immunohistochemical features that can distinguish between the 2 tumors, and comment on the significance of such a finding in terms of the clinical diagnosis of vHL. We found the expression of CAM 5.2, RCC antigen, and CD10 to be strong in RCC and absent in HAB and, conversely, staining with Leu-7, neural cell adhesion molecule, and inhibin-alpha was present in HAB but weak or absent in RCC. These antibodies can be used to differentiate these entities, provided one is astute in recognizing the possibility of their coexistence.

Large cell medulloblastoma with myogenic and melanotic differentiation: a case report with molecular analysis

We present a case of large cell medulloblastoma with myogenic and melanotic differentiation arising in the cerebellar vermis of a 2-year-old boy and following an aggressive clinical course. Histologic and immunohistochemical features of this tumor include primitive neuronal, rhabdomyoblastic, and pigmented epithelial elements, along with large cell features. Immunohistochemical and molecular data (c-myc gene amplification and the presence of isochromosome 17q) support the contention that this histologically diverse tumor represents a pattern of medulloblastoma with striated muscle and pigmented epithelial differentiation, rather than a teratoma or a cerebellar variant of melanotic neuroectodermal tumor of infancy (‘progonoma’).

Serrated colorectal polyps in inflammatory bowel disease.

Serrated colorectal polyps, which, besides hyperplastic polyps, comprise sessile serrated adenomas/polyps and traditional serrated adenomas, are presumptive precursors of at least 20% of sporadic colorectal carcinomas; however, their significance in patients with inflammatory bowel disease is unclear. We retrospectively evaluated 78 serrated polyps, removed over a 14-year period from 6602 inflammatory bowel disease patients undergoing endoscopic surveillance, with respect to morphologic, clinicopathologic, and molecular features, and compared rates of advanced neoplasia (high-grade dysplasia and carcinoma) development following the index serrated polyp diagnosis to reference inflammatory bowel disease cohorts without serrated polyps. Serrated polyps negative for dysplasia, which morphologically resembled sporadic sessile serrated adenoma/polyps, occurred mainly in females, in the proximal colon, and contained BRAF mutations. Serrated polyps with low-grade dysplasia resembled sporadic traditional serrated adenomas and occurred mainly in males, in the distal colon, and contained KRAS mutations. Serrated polyps indefinite for dysplasia were morphologically heterogeneous, but similar to serrated polyps positive for low-grade dysplasia with respect to male predominance, left-sided location, and KRAS mutation rates. Rates of prevalent neoplasia associated with serrated polyps positive for low-grade dysplasia, indefinite for dysplasia, and negative for dysplasia were 76, 39, and 11%, respectively (P<0.001). Actuarial 10-year rates of incident advanced neoplasia after an initial diagnosis of serrated polyp positive for low-grade dysplasia, indefinite for dysplasia, and negative for dysplasia were 17, 8, and 0%, respectively, the first and last being significantly different (P=0.02) and comparable to those of corresponding reference populations of inflammatory bowel disease patients with and without low-grade dysplasia at baseline, respectively. We conclude that in serrated polyps from inflammatory bowel disease patients, dysplasia grade correlates with morphology, sex, anatomic location, BRAF and KRAS mutation status, prevalent conventional neoplasia, and rates of advanced neoplasia development.

Chasing Colonic ”Polyps“Features That Predict Underlying Adenomas in Initially Nondiagnostic Endoscopic Biopsy Specimens

Initial tissue sections from biopsies of endoscopically apparent colonic polyps may not always demonstrate a lesion to account for the clinical findings. Studies have shown that deeper sections and/or reorientation reveal lesions in 10% to 31% of initially nondiagnostic cases. However, many are clinically inconsequential hyperplastic or inflammatory polyps, and, thus, exhaustive efforts to identify them may not be justified. The aim of this study was to identify clinical parameters that predict the detection of adenomas in initially nondiagnostic endoscopic biopsies of colonic polyps. We reoriented, reembedded, and obtained deeper tissue levels on 100 initially nondiagnostic biopsy specimens of clinically apparent polyps and found 9% to contain tubular adenomas. Only 3% of polyps smaller than 5 mm proved to be adenomas, compared with 22% of those 5 mm or larger (P < .01). We conclude that nondiagnostic biopsy specimens of polyps measuring 5 mm or more should be further evaluated because they are more likely to represent adenomas, whereas smaller lesions are usually clinically inconsequential.

Sa1827 Diagnostic Accuracy of a Novel Low Cost Microendoscope for the Detection of Barrett's Neoplasia: A Prospective, Single-Center Trial

istry (IHC). IECs were isolated and fractionated into cytosolic and nuclear fractions. p53 levels were assessed using WB and RT-PCR. Cleaved caspase-3 protein levels were assessed by WB. Target genes of p53 including survivin, p21, and Perp were measured using RTPCR. Results: WB of purified IECs 5 days after ICR revealed that nuclear p53 levels in the ICR mice were decreased compared to sham operated mice. Survivin, which is repressed by p53 transcription, was increased by RT-PCR (2-fold) and most dramatically by IHC with (3-5 fold) more survivin positive IEC staining through the lower to mid crypt regions in the ICR mice. We next examined other p53 target genes. Perp and p21 mRNA showed a 1.5 and 2 fold respective decreases in the RT-PCR of WT ICR as compared to sham surgery. Cleaved caspase-3 protein levels demonstrated a 2-fold decrease in the WT ICR as compared to sham surgery.Conclusions : The post-surgical epithelial responses after intestinal resection continue to be poorly understood. We demonstrated the importance of the down-regulation of p53 after ICR. As expected, survivin levels increased in the ICR mouse consistent with the notion that p53 repression and survivin induction contribute to the expanded surface area in ICR mice.

Su2011 Diagnostic Yield and Clinical Impact of a Low-Cost Microendoscope in the Early Diagnosis of Barrett's Associated Neoplasia: A Prospective, Single-Center Randomized Controlled Trial

G A A b st ra ct s Additionally, differentiated IMFEN-iRFP neurons were triggered by electrical field stimulation to produce transient relaxation of bioengineered IAS constructs. Conclusion: Our results suggest that IM-FEN-iRFPs are detectable in the near IR range (710nm), and that iRFP expression does not inhibit IM-FEN ability to differentiate into neurons. This is the first instance where NIR proteins have been used to label neural cells. By labeling progenitor cells with NIR proteins, in vivo imaging can be optimized in the biologically clear window (700-1000nm). This work was supported by NIH R01DK071614 and the Wake Forest Institute for Regenerative Medicine Team Pilot grant.

Eosinophilic Esophagitis and Esophageal Granular Cell Tumor: An Unexpected Association.

Esophageal granular cell tumors (GCTs) are rare. Eosinophilic esophagitis (EoE) is an immune-mediated disease characterized by esophageal eosinophilia despite proton pump inhibitor (PPI) therapy. Given that GCTs occur at sites of scarring and inflammation, we sought to determine the prevalence of EoE in patients with esophageal GCTs. Our center’s pathology database was searched for GCT specimens from 1995 to 2014. Slides were blindly rereviewed. GCTs were scored for atypical cytological features. Presence and number of eosinophils in the tumor and the surrounding esophageal epithelium and any EoE features were recorded. Medical records were reviewed. From >30,000 esophageal cases, 23 esophageal GCTs were identified, with 18 available for review (16 adult, 2 pediatric). Median patient age was 38.7 years. Four adults had esophageal intraepithelial eosinophilia (peak 38 to 68 eosinophils/high power field [HPF]); 2 confirmed to have EoE, 1 with PPI-responsive esophageal eosinophilia, and 1 had not received PPI therapy. Both pediatric cases had confirmed EoE (peak 24 and 34 eosinophils/HPF). In total, 12/18 GCTs had intratumoral eosinophilia (peak 1 to 16 eosinophils/HPF). All 6 cases with esophageal eosinophilia had intratumoral eosinophilia. Two GCTs displayed atypical cytologic features. Esophageal eosinophilia was present in 25% of adult and 100% of pediatric GCTs, the majority confirmed to have EoE. Overall, 67% of cases had intratumoral eosinophilia and 2 had atypical features. On the basis of these findings, we propose evaluating surrounding tissue for eosinophilia when esophageal GCT is diagnosed, and adding GCT as a potential complication of untreated EoE. Research for an immunologic link between EoE and esophageal GCTs is needed.