Gastroesophageal junction hyperplastic (inflammatory) polyps: a clinical and pathologic study of 46 cases.

Hyperplastic (inflammatory) polyps (HPs) of the gastric corpus and antrum typically develop in association with chronic gastritis. However, little is known regarding the etiology, pathologic features, and natural history of HPs of the gastroesophageal junction (GEJ). We have noted, anecdotally, that GEJ HPs often occur in patients without gastric pathology. The aim of this study was to evaluate the clinical, pathologic, and outcome features of patients with HPs of the GEJ, and to compare the data with a control group of individuals with HPs in the gastric corpus or antrum. One hundred thirty-four consecutive polyps of the GEJ were identified by a 5-year search through the pathology files of a major tertiary-care hospital. Of these, 46 (36%) polyps from 46 patients met the pathologic criteria for HPs and formed the basis of this study. The 46 study patients, and their polyps, were evaluated for a wide variety of clinical, endoscopic, and pathologic features including outcome on follow-up endoscopy. The findings were compared with 46 HPs from 46 patients of the distal stomach (antrum or corpus) that were obtained randomly from the same 5-year period. Compared with patients with gastric antral or corpus HPs, patients with HPs of the GEJ were significantly younger in age (mean age, 55.9 y vs. 63.0 y; P=0.04). Pathologically, GEJ HPs showed a significantly higher rate of multilayered epithelium (P=0.06) and association with Barrett esophagus (BE) (P=0.0001) compared with distal gastric HPs. All BE-associated GEJ HPs were associated with either ultrashort (<1 cm) or short segment (1 to 3 cm) BE. All other pathologic variables, including intestinal metaplasia, were similar to those of distal gastric HPs. In a subanalysis, BE-associated GEJ HPs (33% of all GEJ HPs) showed a higher male to female ratio and a higher rate of intestinal metaplasia compared with all other HPs. Furthermore, none of the BE-associated GEJ HPs were associated with chronic active gastritis versus the non-BE-associated GEJ HPs, although this was not statistically significant. Only 1 HP (from the GEJ) from both the study and control groups was associated with a neoplasm (signet-ring cell carcinoma). On follow-up, 1 patient with a GEJ HP and 4 with distal gastric HPs developed recurrent HPs and none of the patients from either patient group developed dysplasia or carcinoma. In conclusion, unlike HPs of the gastric corpus or antrum, a significant proportion of HPs of the GEJ arise in association with BE and without gastric pathology. In patients with BE, the columnar-lined segment is often ultrashort, and thus, an HP may be the first clinical/endoscopic manifestation of that disorder.

Primary extragastrointestinal stromal tumor of the pleura: report of a unique case with genetic confirmation.

Gastrointestinal stromal tumors (GISTs), the most common mesenchymal neoplasms of the tubular gastrointestinal tract, usually originate in the wall of the stomach or small intestine. Most GISTs harbor oncogenic mutations in either the KIT or platelet-derived growth factor receptor alpha (PDGFRA) tyrosine kinase receptor genes and show differentiation along the lines of the interstitial cells of Cajal. Rarely, GISTs arise primarily in the omentum, mesentery, or retroperitoneum, at which sites they are referred to as "extragastrointestinal stromal tumors" (EGISTs). However, primary intrathoracic GIST arising in the pleura or lung has not been previously reported. We describe herein, a 62-year-old male who presented with a pleural-based mass unrelated to the esophagus that was morphologically typical of a spindle-cell GIST, showing strong immunoreactivity for KIT and DOG1, and harboring an exon 11 mutation in KIT. Ten years after resection, the tumor recurred as multiple masses in the pleura and mediastinum and was marginally reexcised. The patient was then treated with adjuvant imatinib mesylate with no evidence of further recurrences 13 months later. This seems to be the first EGIST arising above the diaphragm. This case shows a potential diagnostic pitfall with therapeutic consequences.

PAX8 Expression in well-differentiated pancreatic endocrine tumors: correlation with clinicopathologic features and comparison with gastrointestinal and pulmonary carcinoid tumors.

PAX (paired box) genes encode a family of transcription factors that regulate organogenesis and cell-lineage specification in multiple organ systems. In the pancreas, PAX proteins play a critical role in islet cell differentiation. We recently observed that islet cells show strong, diffuse staining for PAX8 by immunohistochemistry. However, PAX8 expression has not previously been examined in pancreatic endocrine tumors (PETs). The purpose of this study was to evaluate PAX8 expression in PETs, and to correlate expression with clinical and pathologic features and behavior. PAX8 expression in other well-differentiated neuroendocrine tumors (WDNETs) was also studied. In total, 190 tumors were evaluated: 156 primary WDNETs (63 PETs, 31 ileal, 5 duodenal, 5 gastric, 19 appendiceal, 13 rectal, and 20 pulmonary carcinoid tumors) and 34 liver metastases (18 PETs and 16 ileal carcinoid tumors). PAX8 was positive in 42/63 (67%) primary PETs. Expression of PAX8 was significantly associated with WHO category 1.1 ("benign" behavior) compared with category 1.2 (uncertain behavior) or 2 (well-differentiated endocrine carcinoma) (positive in 100%, 64%, and 52% of tumors, respectively; P<0.05). PAX8-positive PETs were also significantly smaller and more often clinically functional; PAX8-negative tumors were more frequently associated with liver metastases. PAX8 expression was not associated with patient age, gender, MIB1 index, or lymph node metastases. PAX8 expression was detected in 0/20 (0%) pulmonary, 1/5 (20%) gastric, 5/5 (100%) duodenal, 0/31 (0%) ileal, 4/19 (21%) appendiceal, and 11/13 (85%) rectal carcinoid tumors. Among the liver metastases, PAX8 was positive in 9/18 (50%) metastatic PETs compared with 0/16 (0%) metastatic ileal carcinoid tumors. In summary, PAX8 is expressed in normal pancreatic islet cells and in a high proportion of primary and metastatic PETs. In the GI tract, PAX8 is positive in the majority of duodenal and rectal carcinoid tumors, and in a minor subset of appendiceal and gastric carcinoids. PAX8 expression is absent in ileal and pulmonary carcinoid tumors. PAX8 immunostaining may be helpful in determining the primary site for a WDNET metastatic to the liver, as ileal (PAX8 negative) and pancreatic (PAX8 positive) tumors most often present as a metastasis from an occult primary. PAX8 may also be a prognostic marker in PETs, as loss of expression is associated with malignant behavior.

Sox2 expression in pulmonary non-small cell and neuroendocrine carcinomas.

Sox2 is a transcription factor that regulates embryonic stem cell pluripotency and drives commitment of airway precursor cells to basal-type and neuroendocrine cells in the developing lung. In cancer, Sox2 has been associated with a "stemness" phenotype that predicts for poor outcomes. We examined Sox2 expression in pulmonary neoplasms with respect to tumor type and differentiation, in comparison with conventional markers. Immunohistochemistry for Sox2, p63, CK5/6, and thyroid transcription factor-1 was performed on 121 tumors, including 34 adenocarcinomas (ACA), 32 squamous cell carcinomas (SCC), 14 typical carcinoids, 12 atypical carcinoids, 14 large cell neuroendocrine carcinomas, and 15 small cell carcinomas. Sox2 was strongly, diffusely expressed in 91% of SCC and 21% of ACA. Ninety-four percent of SCC coexpressed Sox2 and p63; 1 case was only focally positive for p63 but diffusely positive for Sox2. Twenty-nine percent of ACA were at least focally p63+; 12% were Sox2+/p63+. All of the ACA diffusely positive for Sox2 were p63 negative. Among non-small cell lung carcinoma overall, there was a significant association between Sox2+/p63- expression and high-grade histology (P = 0.02). Strong Sox2 expression was detected in 23% of low-grade and 72% of high-grade neuroendocrine carcinomas (P = 0.0004). Sox2 is highly expressed in concert with p63 in most SCC, but may also influence tumor differentiation in both non-small cell lung carcinomas and pulmonary neuroendocrine tumors.

SOX2 is highly expressed in squamous cell carcinomas of the gastrointestinal tract.

SOX2 is a high-mobility group box embryonic stem cell transcription factor that is expressed in the developing foregut and normal gastric epithelium and is downregulated in intestinal metaplasia of the stomach and esophagus. In addition, SOX2 colocalizes with p63 in the basal layer and plays a critical role in the maintenance of the stratified squamous epithelium of the esophagus. SOX2 expression in squamous cell carcinomas of the gastrointestinal tract has not been previously evaluated. The purpose of this study was to determine whether SOX2 is differentially expressed in squamous cell carcinomas versus adenocarcinomas of the esophagus and rectum/anal canal and to compare its expression to p63, cytokeratin 5/6, and CDX2. In total, 93 tumors were evaluated: 26 esophageal squamous cell carcinomas, 23 esophageal adenocarcinomas, 21 squamous cell carcinomas of the anal canal, and 23 rectal adenocarcinomas. SOX2 was expressed in 81% of esophageal squamous cell carcinomas and 91% of anal canal squamous cell carcinomas, compared to 13% and 17% of esophageal and rectal adenocarcinomas, respectively. p63 was expressed in 96% of esophageal squamous cell carcinomas and 100% of anal canal squamous cell carcinomas; the single squamous cell carcinoma negative for p63 was strongly positive for SOX2. Cytokeratin 5/6 was expressed in most esophageal and anal canal squamous cell carcinomas, but was also positive in 43% of esophageal adenocarcinomas and 13% of rectal adenocarcinomas. In summary, SOX2 is preferentially expressed in squamous cell carcinomas of the esophagus and anal canal compared to adenocarcinomas from these sites. SOX2 may be useful in an immunohistochemical panel to differentiate between squamous cell carcinomas and adenocarcinomas of the gastrointestinal tract.

Genomic characterization and expression of mouse prestin, the motor protein of outer hair cells.

We previously identified the gerbil gene (gPres) that encodes prestin, the putative motor protein responsible for outer hair cell (OHC) electromotility. Here we report the cloning and characterization of the complete genomic structure of the mouse Prestin (mPres) gene. We performed 5'- and 3'-RACE to determine the size and identity of the full-length mRNA transcript. The mPres gene encodes a protein 96% identical to the gPres gene product. The prestin open reading frames are 91% identical at the nucleotide level. Using an antibody raised against the N-terminus of gerbil Prestin, we observed mPrestin expression by immunofluorescence in the lateral membrane of mouse OHCs and found no detectable expression elsewhere in the organ of Corti. On the basis of the available genomic sequence from mouse Chromosome (Chr) 5, we concluded that the mPres gene is centromerically related to and resides within 19 kb of, the Reln gene. We were also able to characterize the exon/intron junctions of mPres by using cDNA/genomic sequence comparisons, as well as exon-exon PCR and sequencing. The mPres gene has 18 exons that encode protein and two exons in the 5' UTR. A CpG island, located at the start of exon 1, is a potential transcription start site. Sequence analysis of the ~500 bp upstream from exon 1 revealed multiple potential transcription factor binding sites, including both TATA and GC boxes, as well as other regulatory-element binding sites.

Identification of differentially expressed cDNA clones from gerbil cochlear outer hair cells.

In order to identify genes that are associated with outer hair cell(OHC)-specific function, a plasmid library enriched with OHC-specific gene products was constructed using single cell-type-specific complementary DNA (cDNA) and a PCR subtractive hybridization strategy. As a first step, we created separate OHC and inner hair cell (IHC) cDNA pools from individually collected cells using a nonspecific reverse transcription polymerase chain reaction. Next, the OHC cDNA was subtracted against IHC cDNA using a PCR-based subtractive technique. IHCs and OHCs share many common features, making IHC cDNA an ideal 'driver' to 'subtract away' common hair cell gene products and enrich differentially expressed cDNAs, including OHC-specific genes. The subtracted OHC cDNAs were then cloned to generate an OHC - IHC subtracted cDNA plasmid library. Finally, a differential screening procedure was performed, resulting in 477 differentially positive clones. After analysis of these 477 clones, 50 known genes were identified, including two previously known OHC-specific proteins: oncomodulin and the recently described motor protein prestin. An additional 84 novel clones were also found. As this library of cDNA fragments represents differentially expressed genes in OHCs, it can be used as starting material for isolation and characterization of a complete set of OHC gene products, an important step in investigating normal and abnormal cochlear function.