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ABSTRACT: Immunohistochemistry for PAX8 and GATA3 are sensitive markers for renal cell carcinoma and urothelial carcinoma, respectively. However, there are limited data on these markers in sarcomatoid renal cell carcinoma (SARCRCC) and sarcomatoid urothelial carcinoma (SARCUC). Tissue microarrays (TMAs) were constructed from 45 cases of SARCRCC and 45 cases of SARCUC of the lower urinary tract, with an additional 11 SARCUCs of the upper tract. PAX8 and GATA3 were also evaluated in TMAs from 161 sarcomas from other sites, 14 atypical epithelioid angiomyolipomas (AMLs) of the kidney, 23 bladder inflammatory myofibroblastic tumors (IMTs), and 2 bladder and 4 renal leiomyosarcomas. In the SARCRCC, PAX8 and GATA3 were positive in the sarcomatoid areas in 31 (69%) and 0 (0%) of cases, respectively. In the bladder SARCUC, GATA3 and PAX8 were positive in 14 (31%) and 2 (4%) of cases, respectively. Of the 11 SARCUCs of the upper urinary tract, 2 (18%) cases were PAX8 positive and 2 (18%) separate cases were GATA3 positive. Only 1 tumor present on the sarcoma TMAs, a Ewing sarcoma/primitive neuroectodermal tumor, was PAX8 positive, and all sarcomas were GATA3 negative. Of the AMLs, IMTs, and leiomyosarcoma, only 1 case of IMT showed moderate GATA3 positivity, and all were negative for PAX8. PAX8 can be used to distinguish SARCCRCC from atypical epithelioid AMLs and primary renal or retroperitoneal sarcomas. However, in a kidney/renal pelvic tumor, PAX8 shows overlap in staining between SARCUC and SARCRCC. GATA3 lacks sensitivity but is more specific for SARCUC.
Human pathology 02/2013; · 3.03 Impact Factor
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ABSTRACT: Inflammatory fibroid polyps (IFPs) are rare, benign tumors that can arise throughout the gastrointestinal tract. Although the molecular pathogenesis of these lesions has been well characterized, their morphologic features often vary. We report the clinicopathologic findings of the largest series of IFPs to date. A total of 83 IFPs seen at our institution were collected between 1999 and 2012. The specimens included 64 biopsies and 19 resections. A review of the clinical features identified a modest female predominance (47 women and 36 men) with patients ranging in age from 26 to 87 years (mean, 60 y). Involved sites included the esophagus (n=2), stomach (n=31; mainly antrum), small intestines (n=17), appendix (n=1), large intestines (n=31; majority within the rectosigmoid), and anal canal (n=1). Although most patients had a nonspecific presentation, those with small intestinal lesions frequently presented with intussusception. Grossly, the tumors ranged in size from 0.2 to 4.2 cm (mean, 1.7 cm). Histologically, IFPs were centered within the submucosa in all resection specimens, but mucosal extension was found in 74 of 83 (89%) cases. The tumors varied in both cellularity and degree of vascularity. However, the characteristic feature of perivascular onion skinning was present in only 54% (45/83) of the cases. In addition, a short fascicular growth pattern was also noted in 36% (30 of 83) of cases, whereas both features were present in 14 cases (17%). Eosinophils were present in 94% (78 of 83) of cases but varied widely in number from abundant (20/hpf) to sparse (1/hpf). Interestingly, in those cases with sparse eosinophils, prominent hyalinization was also present (11 of 78, 13%). In addition, although the majority of IFPs expressed CD34, 6 of 44 (14%) were negative. No associated dysplasia or malignancy was seen. IFPs represent a diverse set of submucosal-based lesions that commonly extend into the mucosa, making them amenable to endoscopic biopsy. Although their classic histologic features of perivascular onion skinning and predominance of eosinophils are well described, they may alternatively present with a short fascicular growth pattern, a sparse number of eosinophils, and prominent hyalinization.
The American journal of surgical pathology 02/2013; · 4.06 Impact Factor
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ABSTRACT: Defects in telomere maintenance genes cause pathological telomere shortening, and manifest in syndromes which have prominent phenotypes in tissues of high turnover: the skin and bone marrow. Because the gastrointestinal (GI) epithelium has rapid turnover, we sought to determine whether telomere syndromes cause GI disease, and to define its prevalence, spectrum and natural history. We queried subjects in the Johns Hopkins Telomere Syndrome Registry for evidence of luminal GI disease. In sixteen percent of Registry subjects (6 of 38), there was a history of significant GI pathology, and 43 additional cases were identified in the literature. Esophageal stenosis, enteropathy and enterocolitis were the recurrent findings. In the intestinal mucosa, there was striking villous atrophy, extensive apoptosis, and anaphase bridging pointing to regenerative defects in the epithelial compartment. GI disease was often the first and most severe manifestation of telomere disease in young children. These findings indicate that telomere dysfunction disrupts the epithelial integrity in the human GI tract manifesting in recognizable disease processes. A high index of suspicion should facilitate diagnosis and management. © 2012 The Authors Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.
Aging cell 12/2012; · 7.55 Impact Factor
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ABSTRACT: Traditional serrated adenomas (TSAs) are a type of colorectal polyp with neoplastic potential. Immunohistochemical analysis and sequencing were performed on 24 TSAs from 23 patients to characterize the molecular genetics of TSAs. Abnormal Ki-67 and p53 labeling were observed in 7 (29%) of 24 and 6 (25%) of 24 TSAs, respectively; both types were significantly associated with the presence of conventional epithelial dysplasia (P = .0005 and P = .0001, respectively). Activating KRAS mutation was identified in 11 TSAs (46%) and was mutually exclusive with activating BRAF mutations, which were seen in 7 TSAs (29%). Abnormal p53 nuclear labeling in a TSA was significantly associated with BRAF mutation status (P = .04), whereas no relationship was found for β-catenin labeling patterns. The overall morphologic features of TSA do not correlate with the genetic status of the KRAS and BRAF genes. However, conventional epithelial dysplasia and abnormal p53 labeling in a TSA are seen more often in the setting of BRAF mutation.
American Journal of Clinical Pathology 09/2012; 138(3):356-66. · 2.60 Impact Factor
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ABSTRACT: Pleomorphic hyalinizing angiectatic tumor (PHAT) is a rare soft tissue tumor of low malignant potential, which most often arises in the lower extremities. To the best of our knowledge, there have been no prior descriptions of the imaging features of this neoplasm. In this case series, we report the imaging findings in three patients. Two patients had a lower extremity subcutaneous PHAT, while the third patient had an intramuscular upper extremity PHAT. While imaging features are variable, a diagnosis of PHAT should be considered when encountering an enhancing, subcutaneous tumor with ill-defined margins, particularly in the extremity.
Skeletal Radiology 06/2012; 41(12):1621-6. · 1.54 Impact Factor
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ABSTRACT: Epithelioid sarcomas (ES) are extremely rare soft tissue sarcomas. As such, their clinical behavior and response to treatment are poorly described in the literature.
We queried the centralized cancer registry and pathology archives at the Johns Hopkins Medical Institution and identified 22 patients with a diagnosis of ES. We excluded two patients because of inadequate data. A pathologist reviewed patient charts and reexamined available histological slides. This study was performed with institutional review board approval.
The median age at diagnosis was 27.8 y; most patients (75%) were male. Regional lymph node metastases were present in 10% of patients at presentation. The majority of tumors (57.9%) recurred and 35% recurred more than once, although the number of recurrences did not affect survival (P = 0.48). Patients did not experience a decrease in time to recurrence with increasing number of resections. The median time between resection and recurrence was 1.23 y and the maximum was 18.8 y. Median overall survival was 56.2 mo and 5-y survival was 92%.
Our study reveals that ES is an extremely rare tumor with a protracted and recurrent course, but overall survival may be more favorable than in the past. Patients benefit from aggressive and repeated resection. Epithelioid sarcoma is unique because it metastasizes to regional nodal basins. Extended surveillance is indicated, because recurrences can appear after decades of quiescence.
Journal of Surgical Research 05/2012; 177(1):116-22. · 2.25 Impact Factor
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Tomoharu Miyashita,
Furhawn A. Shah,
Guy P. Marti,
Todd D. Armstrong,
Jiaai Wang,
Pramod Bonde,
Michael K. Gibson,
Kiyoshi Yoshimura, Elizabeth A. Montgomery,
Mark Duncan,
Elizabeth M. Jaffee,
John W. Harmon
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ABSTRACT: Purpose We developed and evaluated a GM-CSF whole-cell tumor vaccine for esophageal cancer. Experimental design Cell lines derived from surgically induced rat reflux esophageal tumors were passaged invitro and transfected with GM-CSF.
First, the GM-CSF whole cell vaccine was evaluated against subcutaneously transplanted esophageal tumor cells. In a subsequent
study, the vaccine was tested to see if it could reduce the incidence of cancer in the surgical reflux model. Results While subcutaneously transplanted tumor cells produced lasting tumors in PBS non-vaccinated placebo rats, transplanted tumors
regressed and were immunologically rejected in animals vaccinated prior to implantation. In the surgical reflux model, the
vaccine reduced the incidence of cancer from 17/23 (74%) in the controls to 6/16 (38%) in the vaccinated animals (P=0.046). Conclusions The GM-CSF whole cell tumor vaccine effectively promoted a strong immune response against subcutaneously transplanted tumors
and protected animals from developing esophageal cancer in the reflux model.
Digestive Diseases and Sciences 04/2012; 53(11):2858-2867. · 2.12 Impact Factor
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ABSTRACT: Gastric adenocarcinoma with chief cell differentiation (GA-CCD) has been reported as a new, rare variant of gastric adenocarcinoma. Only 12 cases in Japanese patients have been described to date, but they demonstrate distinct clinicopathologic features. To further characterize these lesions, we have collected 10 additional cases. Patients ranged in age from 44 to 79 years (mean, 64.2 y) with a relatively equal sex distribution (6 women and 4 men). Stratified by race, 4 patients were Hispanic, 2 were White, 2 were African American, 1 was Asian (Chinese), and the race was unknown for 1 patient. All patients presented with gastroesophageal reflux that prompted an endoscopic examination. The majority of GA-CCDs were identified in the fundus (7 of 10, 70%) and the remaining in the cardia (n=3). Grossly, they were solitary and polypoid, ranging in size from 0.2 to 0.8 cm (mean, 0.4 cm). Histologically, all cases were centered in the deep mucosa, with focal involvement of surface foveolar epithelium in 3 (30%) cases but not the submucosa. The tumors consisted of clustered glands and irregular branching cords of oxyntic epithelium. Thin wisps of radiating smooth muscle separated the epithelium, but desmoplasia was distinctly absent in all cases. The oxyntic mucosa was 1 to 2 cells thick and composed of a mixture of mucous neck, parietal, and chief cells. In 7 of 10 (70%) cases, chief cells were the predominant cell type, whereas the remaining 3 cases consisted primarily of mucous neck cells. The nuclei were mildly enlarged with slight nuclear pleomorphism, but no mitotic figures were identified. In addition, necrosis, lymphovascular invasion, and perineural invasion were absent. Immunohistochemically, GA-CCDs were diffusely positive for MUC6 (10 of 10, 100%) and negative for MUC5AC (0%) and MUC2 (0%). Ki-67 immunolabeling demonstrated variable expression, with the highest areas ranging from 0.2% to 10%. Clinical follow-up was available for 9 of 10 (90%) patients and ranged from 6 to 39 months. One patient had persistence of lesion at 6 months because of incomplete removal, whereas the other 8 were disease free. In summary, GA-CCDs are solitary, mucosal lesions of the gastric cardia/fundus that arise in patients from multiple ethnic backgrounds. Considering that patients within this study and those reported previously have had neither true recurrence nor progression of disease, these lesions are best regarded as benign. Consequently, the term GA-CCD is contradictory and we prefer the descriptive term "oxyntic gland polyp/adenoma" until further studies can clarify the pathogenesis of these lesions and their natural history.
The American journal of surgical pathology 03/2012; 36(7):1030-5. · 4.06 Impact Factor
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ABSTRACT: Cryotherapy is a method of endoscopic mucosal ablation that involves delivery of a cryogen to result in tissue destruction by extreme low temperature. Its effects are influenced by the dosage of cryogen and thawing of ice. There are limited data on the tissue effects of multiple freeze and thaw cycles of carbon dioxide (CO(2)) cryotherapy on GI tissues.
To investigate the extent of tissue injury due to escalating doses of CO(2) cryotherapy on the esophagus, stomach, and colon of pigs.
Animal experiment.
Varying doses of CO(2) cryotherapy with increasing number of freeze-thaw cycles were applied to each site. The animals were allowed to survive for 48 hours.
Depth of tissue injury assessed in blinded fashion by varying doses of cryotherapy on a defined area of porcine esophagus, stomach, and colon.
There was a dose-dependent relationship of CO(2) cryogen and depth of injury (P = .0001 and P = .002, respectively). In the stomach, the dose-response relationship was significant (P = .007), but the average grades of injury across the various doses were lower when compared with the esophagus at comparable cryogen doses (P = .0004). The estimated depth of tissue injury from the mucosal surface in the porcine esophagus and colon tissue ranged from 1.2 to 2.5 mm and 1.3 to 2.5 mm, respectively.
The study was performed in a normal porcine model.
There was a dose-dependent relationship between the dose of CO(2) cryotherapy and the depth of tissue injury in the porcine esophagus, stomach, and colon.
Gastrointestinal endoscopy 01/2012; 75(5):1062-7. · 6.71 Impact Factor
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ABSTRACT: Barrett esophagus is a metaplastic, premalignant lesion associated with approximately 0.5% annual incidence of progression to esophageal adenocarcinoma. Diagnosis and screening of Barrett esophagus and Barrett-related dysplasia relies on histologic evaluation of endoscopic mucosal biopsies, a process that is burdened with interobserver variability.
To review the histologic features and classification of Barrett esophagus and Barrett-related dysplasia, to discuss the underlying difficulties in diagnosis and pitfalls, and to provide a brief review of new developments related to therapeutic modalities for patients diagnosed with dysplasia.
Sources include a review of relevant literature indexed in PubMed (US National Library of Medicine).
In spite of interobserver variability, histologic assessment of dysplasia is currently the accepted method of surveillance, and subsequent patient management is dictated by this evaluation. Although not universal, endoscopic therapy is increasingly important in replacing esophagectomy for patients with high-grade dysplasia or early carcinoma.
Archives of pathology & laboratory medicine 10/2011; 135(10):1249-60. · 2.58 Impact Factor
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Christopher M Heaphy,
Andrea P Subhawong,
Seung-Mo Hong,
Michael G Goggins, Elizabeth A Montgomery,
Edward Gabrielson,
George J Netto,
Jonathan I Epstein,
Tamara L Lotan,
William H Westra, [......],
Janis M Taube,
Dinesh Rakheja,
Robert J Kurman,
T C Wu,
Richard B Roden,
Pedram Argani,
Angelo M De Marzo,
Luigi Terracciano,
Michael Torbenson,
Alan K Meeker
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ABSTRACT: Approximately 10% to 15% of human cancers lack detectable telomerase activity, and a subset of these maintain telomere lengths by the telomerase-independent telomere maintenance mechanism termed alternative lengthening of telomeres (ALT). The ALT phenotype, relatively common in subtypes of sarcomas and astrocytomas, has rarely been reported in epithelial malignancies. However, the prevalence of ALT has not been thoroughly assessed across all cancer types. We therefore comprehensively surveyed the ALT phenotype in a broad range of human cancers. In total, two independent sets comprising 6110 primary tumors from 94 different cancer subtypes, 541 benign neoplasms, and 264 normal tissue samples were assessed by combined telomere-specific fluorescence in situ hybridization and immunofluorescence labeling for PML protein. Overall, ALT was observed in 3.73% (228/6110) of all tumor specimens, but was not observed in benign neoplasms or normal tissues. This is the first report of ALT in carcinomas arising from the bladder, cervix, endometrium, esophagus, gallbladder, kidney, liver, and lung. Additionally, this is the first report of ALT in medulloblastomas, oligodendrogliomas, meningiomas, schwannomas, and pediatric glioblastoma multiformes. Previous studies have shown associations between ALT status and prognosis in some tumor types; thus, further studies are warranted to assess the potential prognostic significance and unique biology of ALT-positive tumors. These findings may have therapeutic consequences, because ALT-positive cancers are predicted to be resistant to anti-telomerase therapies.
American Journal Of Pathology 08/2011; 179(4):1608-15. · 4.89 Impact Factor
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Hector Alvarez,
Joanna Opalinska,
Li Zhou,
Davendra Sohal,
Melissa J Fazzari,
Yiting Yu,
Christina Montagna, Elizabeth A Montgomery,
Marcia Canto,
Kerry B Dunbar, [......],
K H Ramesh,
Linda Cannizzaro,
J Mollenhauer,
Reid F Thompson,
Masako Suzuki,
Stephen Meltzer,
Ari Melnick,
John M Greally,
Anirban Maitra,
Amit Verma
PLoS Genetics 05/2011; 7(5). · 8.69 Impact Factor
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Hector Alvarez,
Joanna Opalinska,
Li Zhou,
Davendra Sohal,
Melissa J Fazzari,
Yiting Yu,
Christina Montagna, Elizabeth A Montgomery,
Marcia Canto,
Kerry B Dunbar, [......],
Linda Cannizzaro,
J Mollenhauer,
Reid F Thompson,
Masako Suzuki,
Stephen J Meltzer,
Stephen Meltzer,
Ari Melnick,
John M Greally,
Anirban Maitra,
Amit Verma
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ABSTRACT: Although a combination of genomic and epigenetic alterations are implicated in the multistep transformation of normal squamous esophageal epithelium to Barrett esophagus, dysplasia, and adenocarcinoma, the combinatorial effect of these changes is unknown. By integrating genome-wide DNA methylation, copy number, and transcriptomic datasets obtained from endoscopic biopsies of neoplastic progression within the same individual, we are uniquely able to define the molecular events associated progression of Barrett esophagus. We find that the previously reported global hypomethylation phenomenon in cancer has its origins at the earliest stages of epithelial carcinogenesis. Promoter hypomethylation synergizes with gene amplification and leads to significant upregulation of a chr4q21 chemokine cluster and other transcripts during Barrett neoplasia. In contrast, gene-specific hypermethylation is observed at a restricted number of loci and, in combination with hemi-allelic deletions, leads to downregulatation of selected transcripts during multistep progression. We also observe that epigenetic regulation during epithelial carcinogenesis is not restricted to traditionally defined "CpG islands," but may also occur through a mechanism of differential methylation outside of these regions. Finally, validation of novel upregulated targets (CXCL1 and 3, GATA6, and DMBT1) in a larger independent panel of samples confirms the utility of integrative analysis in cancer biomarker discovery.
PLoS Genetics 03/2011; 7(3):e1001356. · 8.69 Impact Factor
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ABSTRACT: Gastrointestinal (GI) tract involvement by Langerhans cell histiocytosis (LCH) is a rare condition. It is typically noted in male patients with systemic disease and is associated with both poor prognosis and high morbidity. The incidence peaks in childhood. However, a limited number of cases have been reported in adults. To further characterize this disease process, we collected 24 cases of GI tract LCH from 12 patients. The patients included 2 children (4 mo and 2.3 y) and 10 adults (40 to 77 y; mean, 58.4 y), with a female predominance (9 of 12, 75%). Both children presented with failure to thrive, bloody diarrhea, and anemia. In contrast, 5 of 10 (50%) adults were asymptomatic and the rest had unrelated symptoms. Endoscopically, the pediatric patients showed the involvement of the duodenum and multiple colonic sites. However, 8 of 10 (80%) adults presented with a solitary polyp, primarily involving the colorectum (7 of 8, 88%). The lesions ranged in size from 0.1 to 0.8 cm (mean, 0.4 cm), and were predominantly intramucosal (18 of 24, 75%) with either a marginated (14 of 24, 58%) or infiltrative (10 of 24, 42%) growth pattern. Microscopic features were similar to those of LCH found elsewhere, although some cases differed by showing prominent lymphocytes (12 of 24, 50%) rather than eosinophils and large nucleoli (2 of 24, 8%). Reactive overlying mucosal and entrapped epithelial changes (10 of 24, 42%), mucosal ulceration (3 of 24, 13%), focal necrosis (1 of 24), and multinucleated giant cells (1 of 24) were also identified. Mitotic figures were absent. On immunohistochemistry, all lesions expressed the S-100 protein and CD1a. Follow-up information was available for 11 (92%) patients ranging from 2 months to 5.3 years (mean, 1.8 y). One pediatric patient was lost to follow-up. However, the other patient developed multisystem disease and died 1 year after the initial diagnosis. Two adult patients developed cutaneous disease, 2 months and 2 years after the initial diagnosis, 1 of whom had multifocal colonic disease. On the basis of this study, GI tract LCH lesions present in both children and adults with a female predominance. Consistent with earlier reports, pediatric cases are associated with systemic disease and poor prognosis. However, in adults, LCH is typically encountered as an incidental, solitary polyp. Rare cases of systemic disease may occur and, therefore, close follow-up may be warranted.
The American journal of surgical pathology 02/2011; 35(2):305-10. · 4.06 Impact Factor
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Harry H Yoon,
Paul J Catalano,
Kathleen M Murphy,
Todd C Skaar,
Santosh Philips,
Mark Powell, Elizabeth A Montgomery,
Michael J Hafez,
Steven M Offer,
Geoffrey Liu,
Stephen J Meltzer,
Xifeng Wu,
Arlene A Forastiere,
Al B Benson,
Lawrence R Kleinberg,
Michael K Gibson
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ABSTRACT: Recent data in esophageal cancer suggests the variant allele of a single-nucleotide polymorphism (SNP) in XRCC1 may be associated with resistance to radiochemotherapy. However, this SNP has not been assessed in a histologically homogeneous clinical trial cohort that has been treated with a uniform approach. In addition, whether germline DNA may serve as a surrogate for tumor genotype at this locus is unknown in this disease. Our objective was to assess this SNP in relation to the pathologic complete response (pCR) rate in subjects with esophageal adenocarcinoma who received cisplatin-based preoperative radiochemotherapy in a multicenter clinical trial (Eastern Cooperative Oncology Group 1201). As a secondary aim, we investigated the rate of allelic imbalance between germline and tumor DNA.
Eighty-one eligible treatment-naïve subjects with newly diagnosed resectable esophageal adenocarcinoma received radiotherapy (45 Gy) concurrent with cisplatin-based chemotherapy, with planned subsequent surgical resection. The primary endpoint was pCR, defined as complete absence of tumor in the surgical specimen after radiochemotherapy. Using germline DNA from 60 subjects, we examined the base-excision repair SNP, XRCC1 Arg399Gln, and 4 other SNPs in nucleotide excision (XPD Lys751Gln and Asp312Asn, ERCC1 3' flank) and double-stranded break (XRCC2 5' flank) repair pathways, and correlated genotype with pCR rate. Paired tumor tissue was used to estimate the frequency of allelic imbalance at the XRCC1 SNP.
The variant allele of the XRCC1 SNP (399Gln) was detected in 52% of subjects. Only 6% of subjects with the variant allele experienced a pCR, compared to 28% of subjects without the variant allele (odds ratio 5.37 for failing to achieve pCR, p = 0.062). Allelic imbalance at this locus was found in only 10% of informative subjects, suggesting that germline genotype may reflect tumor genotype at this locus. No significant association with pCR was noted for other SNPs.
Assessed for the first time in a prospective, interventional trial cohort of esophageal adenocarcinoma, XRCC1 399Gln was associated with resistance to radiochemotherapy. Further investigation of this genetic variation is warranted in larger cohorts. In addition, these data indicate that germline genotype may serve as a surrogate for tumor genotype at this locus.
BMC Cancer 01/2011; 11:176. · 3.01 Impact Factor
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Mashaal Dhir,
Shinichi Yachida,
Leander Van Neste,
Sabine C Glöckner,
Jana Jeschke,
Emmanouil P Pappou, Elizabeth A Montgomery,
James G Herman,
Stephen B Baylin,
Christine Iacobuzio-Donahue,
Nita Ahuja
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ABSTRACT: The diagnosis of sessile serrated adenomas (SSAs) is challenging, and there is a great deal of interobserver variability amongst pathologists in differentiating SSAs from hyperplastic polyps (HPPs). The aim of this study was (i) to assess the utility of epigenetic changes such as DNA methylation in differentiating SSAs from HPPs and (ii) to identify common methylation based molecular markers potentially useful for early detection of premalignant neoplastic lesions of gastrointestinal tract. A total of 97 primary patient adenoma samples were obtained from The Johns Hopkins Hospital pathology archive with IRB approval and HIPAA compliance. We analyzed the promoter associated CpG island methylation status of 17 genes using nested multiplex methylation specific PCR (MSP). Methylation of CDX2, hMLH1 and TLR2 was detected in SSAs and SSAs with dysplasia but not in HPPs. A subset of genes including EVL, GATAs (4 and 5), HIN-1, SFRPs (1, 2, 4 and 5), SOX17 and SYNE1 were methylated frequently in all premalignant gastrointestinal adenomas including tubular adenomas, villous adenomas, SSAs and SSAs with dysplasia but infrequently in non-premalignant polyps such as HPPs. Methylation of CDX2, hMLH1 and TLR2 may be of diagnostic utility in differentiating, histologically challenging cases of SSAs from HPPs. Genes such as EVL, GATAs, HIN-1, SFRPs, SOX17 and SYNE1, which are frequently methylated in all types of tested premalignant adenomas, may be useful as biomarkers in stool-based strategies for early detection of these adenomas and CRCs in future.
International Journal of Cancer 12/2010; 129(8):1889-98. · 5.44 Impact Factor
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Alvarez Hector, Elizabeth A Montgomery,
Collins Karikari,
Marcia Canto,
Kerry B Dunbar,
Jean S Wang,
Georg Feldmann,
Seung-Mo Hong,
Michael C Haffner,
Alan K Meeker, [......],
Pingyu Ding,
Dane Goff,
Rajinder Singh,
Juan Carlos Roa,
Arivusudar Marimuthu,
Gregory J Riggins,
James R Eshleman,
Barry D Nelkin,
Akhilesh Pandey,
Anirban Maitra
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ABSTRACT: Esophageal adenocarcinoma (EAC) arises in the backdrop of reflux-induced metaplastic phenomenon known as Barrett esophagus. The prognosis of advanced EAC is dismal, and there is an urgent need for identifying molecular targets for therapy. Serial Analysis of Gene Expression (SAGE) was performed on metachronous mucosal biopsies from a patient who underwent progression to EAC during endoscopic surveillance. SAGE confirmed significant upregulation of Axl "tags" during the multistep progression of Barrett esophagus to EAC. In a cohort of 92 surgically resected EACs, Axl overexpression was associated with shortened median survival on both univariate (p < 0.004) and multivariate (p < 0.036) analysis. Genetic knockdown of Axl receptor tyrosine kinase (RTK) function was enabled in two EAC lines (OE33 and JH-EsoAd1) using lentiviral short hairpin RNA (shRNA). Genetic knockdown of Axl in EAC cell lines inhibited invasion, migration, and in vivo engraftment, which was accompanied by downregulation in the activity of the Ral GTPase proteins (RalA and RalB). Restoration of Ral activation rescued the transformed phenotype of EAC cell lines, suggesting a novel effector mechanism for Axl in cancer cells. Pharmacological inhibition of Axl was enabled using a small molecule antagonist, R428 (Rigel Pharmaceuticals). Pharmacological inhibition of Axl with R428 in EAC cell lines significantly reduced anchorage-independent growth, invasion and migration. Blockade of Axl function abrogated phosphorylation of ERBB2 (Her-2/neu) at the Tyr877 residue, indicative of receptor crosstalk. Axl RTK is an adverse prognostic factor in EAC. The availability of small molecule inhibitors of Axl function provides a tractable strategy for molecular therapy of established EAC.
Cancer biology & therapy 11/2010; 10(10):1009-18. · 2.64 Impact Factor
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ABSTRACT: The role of proton pump inhibitors in Barrett's metaplasia and esophageal adenocarcinoma has been an area of controversy.
We evaluated the effectiveness of the proton pump inhibitor rabeprazole as a chemoprevention agent in a surgical rat reflux model of esophageal cancer.
The rat reflux model was created by performing a jejuno-esophagostomy on Sprague-Dawley rats. The surgery promoted the reflux of gastro-duodenal contents into the esophagus. Rabeprazole sodium (Eisai, Tokyo, Japan) was dissolved in 0.9% physiological saline to a desired concentration of 1.5% (W/V). Beginning 4 weeks post-surgery, all animals were administered either 0.2 ml per 100 g body weight injections of rabeprazole or equivalent injections of saline 3 days per week into the subcutaneous tissue of the back. Forty animals were killed 40 weeks after surgery and their esophagi were examined. Of these, 23 were included in the control group, while the remaining 17 were subjected to rabeprazole.
While 74% (17/23) of the controls developed esophageal cancer, animals administered rabeprazole had an incidence of cancer of 29% (5/17) (p < 0.05, Fisher's exact test). Barrett's metaplasia was found on 100% (23/23) of the rats in the placebo group, but there was a protective effect in the rabeprazole group with 65% (11/17) of the rats displaying signs of Barrett's metaplasia (p < 0.05, Fisher's exact test). All of the rats developed proliferative hyperplasia.
Rabeprazole protected against the development of esophageal cancer in a clinically relevant surgical reflux model. Rabeprazole warrants further investigation for potential clinical use as a chemoprevention agent.
Digestive Diseases and Sciences 10/2010; 56(5):1309-14. · 2.12 Impact Factor
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ABSTRACT: Clear cell change is seen in <1% of colonic tubular adenomas (TAs) and remains incompletely characterized. Associated adenocarcinomas can also demonstrate a clear cell phenotype. Eleven TAs with at least focal clear cell change with or without associated invasive adenocarcinoma, from 10 patients were studied. The lesions were stained with periodic acid-Schiff (PAS)/PAS-diastase and immunolabeled with antibodies to MUC2, MUC5AC, MUC6, CK7, CK20, and CDX2. Eight of 11 (77%) TAs with clear cell change had focal to extensive high-grade dysplasia. Two were associated with invasive clear cell adenocarcinoma. The adenomas and adenocarcinomas ranged from 0.5 to 3.5 cm. PAS/PAS-diastase stains showed minimal PAS(+) material in the clear cells. On immunohistochemical studies, the clear cells had decreased MUC2 labeling compared with the surrounding conventional adenoma in 9 of 11 (88%) cases, including the 2 clear cell adenocarcinomas. In 3 of the 11 lesions, the background TA showed at least focal MUC5 immunoreactivity, their associated clear cell area had decreased MUC5 labeling in all 3 cases. No immunoreactivity to MUC6 was observed in the background TAs and clear cells in all cases. Compared with background TA, both increased and decreased expression of CK7, CK20 (in quantity), and CDX2 (in intensity) were observed in the clear cells of TAs and adenocarcinomas. One of the clear cell adenocarcinomas was CK20, CK7, CDX2 and the other was CK20, CK7, CDX2-focal positive. Thus, although the clear cells have different MUC protein profiles than the background adenomatous epithelium, invasive clear cell adenocarcinomas retained the typical CK20(+)/CK7(-) profile of conventional adenocarcinomas. Our results indicate that clear cell adenocarcinomas can be primary to the colorectum with identifiable precursors. Awareness of them and their immunoprofile allows distinction from clear cell lesions from other sites.
The American journal of surgical pathology 09/2010; 34(9):1344-50. · 4.06 Impact Factor
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ABSTRACT: Granular cell tumor (GCT) is commonly located in the subcutaneous tissue and oral cavity, and uncommon in the gastrointestinal tract, in which the majority arises in the esophagus with over-representation in African Americans (AA). However, experience with GCTs of the colorectum is quite limited. We report the clinicopathologic features of 1 of the largest series to date of colorectal GCTs. We reviewed the clinical features of 26 colorectal GCTs seen at our institution between the years 1995 to 2009, which included 24 biopsies, 1 low anterior resection, and 1 colectomy. Review of the clinical features of all 26 cases from 24 patients identified an equal gender distribution (12 males and 12 females), with patients ranging in age from 31 to 60 years (mean, 49.8 y; median, 51.5 y) with a modest White predominance (15/24, 63%; our overall patient population is 67% White). The majority of colorectal GCT involved the right colon (19/26, 73%) ranging in size from 0.2 to 1.8 cm (mean 0.6 cm). Most neoplasms were encountered on routine colonoscopy (14/24, 64%), however 3 patients presented with hematochezia, 3 with changing bowel habits, 2 with Crohn disease, 1 with diverticular disease, and 1 with appendicitis. Of the 20 cases available for histologic review, the tumors were noted to either be infiltrative (12/20, 60%) or marginated (8/20, 40%) involving either the mucosa (7/20, 35%), submucosa (10/20, 50%), or both (3/20, 15%). The microscopic features were similar to those of GCTs found elsewhere, but many of the neoplasms differed by displaying nuclear pleomorphism (8/20, 40%), lymphoid cuffs (9/20, 45%), and focal calcification (7/20, 35%). Some had reactive mucosal surface changes (7/20, 35%), including 1 initially misdiagnosed as a tubular adenoma. Neither mitoses nor necrosis were identified. On immunochemistry, 18 of the neoplasms were stained for S-100 and all cases showed positive staining. Follow-up information was available for 19 patients (19/24, 79%) with 2 documented occurrences of regrowth at the prior cecal biopsy site owing to incomplete excision, but no metastases. Although infrequently found in the colorectum, colorectal GCT typically presents incidentally on routine colonoscopy and involves the right colon; it is not over-represented in AA patients. GCTs can have both an infiltrative or marginated growth pattern with a subset displaying nuclear pleomorphism, a lymphoid cuff, focal calcification, and reactive mucosal surface changes, which in our experience, may lead to misdiagnosis on colorectal mucosal biopsies. Although GCTs were benign tumors in this series, if incompletely excised regrowth of the lesion may occur and therefore, follow-up may be warranted.
The American journal of surgical pathology 08/2010; 34(8):1186-92. · 4.06 Impact Factor
