Areas Of High-grade Dysplasia Research Articles

S3047 Intussusception: A Rare Presentation in the Proximal GI Tract

INTRODUCTION: Intussusception is a well-documented cause of bowel obstruction in pediatrics but is infrequently encountered in adults, accounting for less than 5% of all cases of intussusception. Typically observed in the small or large bowel, intussusception involving the stomach is rare. We present a unique case of gastro-gastric intussusception due to gastric adenocarcinoma arising in a pyloric gland adenoma with high grade dysplasia, with previous literature demonstrating only 5 other cases in the setting of an adenoma/adenocarcinoma. CASE DESCRIPTION/METHODS: A 57 year-old Caucasian female without significant past medical history presented with intermittent abdominal pain, nausea, vomiting, and weight loss for 3 months. Her labs on admission were notable for hypokalemia and hypomagnesemia, but were otherwise normal. A CT scan showed thickening of the gastric body with concern for gastro-gastric intussusception and underlying neoplasm (Figure 1). The surgical team requested an endoscopy by gastroenterology for biopsy and attempt at reduction, which confirmed the presence of gastric intussusception, beginning at 50 cm with a large, partially circumferential, frond-like mass noted in the gastric body, extending down into the intussusception. Multiple attempts were made to traverse the mass, but were unsuccessful and the pylorus was unable to be visualized nor was the intussusception able to be reduced. Multiple biopsies of the gastric mass were obtained during the procedure, demonstrating hyperplastic polyp tissue with low-grade dysplasia and negative for H. pylori (Figure 2). Two days later, the patient underwent a distal gastrectomy with Roux-en-Y gastrojejunostomy; intraoperative pathology revealed a hyperplastic polyp with high-grade dysplasia. Definitive pathology from the surgical specimen revealed a well-to-moderately differentiated adenocarcinoma arising from a 9 cm foveolar-type gastric adenoma with high-grade dysplasia and metastasis identified in 1 of 19 lymph nodes (Figure 3). DISCUSSION: Intussusception is rarely detected in the proximal GI tract, and when present, is most commonly seen in the setting of a surgical anastomosis, foreign body, or anatomic abnormality. This is the 1st documented case of gastro-gastric intussusception associated with a pyloric type adenoma with high grade dysplasia. Histology on endoscopic biopsies showed dysplasia without malignancy, highlighting that superficial biopsies may be misleading and a high index of suspicion for underlying malignancy should be maintained.Figure 1.: CT A/P with contrast shows thickening of the gastric body with concern for gastro-gastric intussusception and underlying neoplasm, no evidence of gastric obstruction or distant metastasis noted.Figure 2.: Superficial biopsy demonstrating adenomatous epithelium (pyloric gland type).Figure 3.: Invasive front of the tumor with overlying areas of high grade dysplasia.

Mutation Profiling of Premalignant Colorectal Neoplasia.

Accumulation of allelic variants in genes that regulate cellular proliferation, differentiation, and apoptosis may result in expansion of the aberrant intestinal epithelium, generating adenomas. Herein, we compared the mutation profiles of conventional colorectal adenomas (CNADs) across stages of progression towards early carcinoma. DNA was isolated from 17 invasive adenocarcinomas (ACs) and 58 large CNADs, including 19 with low-grade dysplasia (LGD), 21 with LGD adjacent to areas of high-grade dysplasia and/or carcinoma (LGD-H), and 28 with high-grade dysplasia (HGD). Ion AmpliSeq Comprehensive Cancer Panel libraries were prepared and sequenced on the Ion Proton. We identified 956 unique allelic variants; of these, 499 were considered nonsynonymous variants. Eleven genes (APC, KRAS, SYNE1, NOTCH4, BLNK, FBXW7, GNAS, KMT2D, TAF1L, TCF7L2, and TP53) were mutated in at least 15% of all samples. Out of frequently mutated genes, TP53 and BCL2 had a consistent trend in mutation prevalence towards malignancy, while two other genes (HNF1A and FBXW7) exhibited the opposite trend. HGD adenomas had significantly higher mutation rates than LGD adenomas, while LGD-H adenomas exhibited mutation frequencies similar to those of LGD adenomas. A significant increase in copy number variant frequency was observed from LGD through HGD to malignant samples. The profiling of advanced CNADs demonstrated variations in mutation patterns among colorectal premalignancies. Only limited numbers of genes were repeatedly mutated while the majority were altered in single cases. Most genetic alterations in adenomas can be considered early contributors to colorectal carcinogenesis.

Can we really continue to diagnose high grade dysplasia in Barrett’s esophagus in Europe without magnified virtual chromo-endoscopy?

Can we really continue to diagnose high grade dysplasia in Barrett’s esophagus in Europe without magnified virtual chromo-endoscopy?

Colonic polyp presenting as a tubulovillous adenoma and harbinger of high-grade neuroendocrine carcinoma: a unique presentation

High-grade neuroendocrine carcinomas (HGNEC) of the colon are rare. However, when they occur, there is evidence to support a strong association with tubulovillous/villous adenomas (TVA). We present a unique case of a colonic TVA associated with HGNEC in a 64-year-old woman with a large polypoid mass in the rectosigmoid colon diagnosed as TVA with high-grade dysplasia (HGD) on biopsy. Pathologic examination revealed a 4.8 cm friable polypoid mass composed of two morphologically distinct elements. The luminal portion of the tumor consisted of a TVA with areas of HGD. A distinct component was identified deeper to the adenoma, consisting of nested small-to-medium sized cells with increased nuclear-to-cytoplasmic ratio, nuclei exhibiting finely dispersed chromatin, inconspicuous nucleoli, patchy areas of necrosis, and increased mitotic figures. The two tumor components were closely apposed with focal areas of intermixing at their interface. Immunohistochemistry demonstrated diffuse positive staining of the deeper, nested neoplastic cells with synaptophysin, chromogranin, CD56 and CAM 5.2 and a perinuclear-dotlike pattern of pancytokeratin AE1/AE3 staining. The proliferation index was up to 90% (Ki-67). Given the overall findings, a diagnosis of HGNEC arising in a background of TVA was rendered. This unique case is one of the few reported cases of mixed adenoma HGNEC involving the colon. This case demonstrates possible pitfalls in diagnosis. Superficial biopsies often do not provide adequate representation of underlying neuroendocrine neoplasms. In this case, metastatic HGNEC was identified although initial biopsy revealed only TVA, suggesting that the two lesions were unrelated.

Comparative analysis of application of conventional colonoscopy and NBI colonoscopy for detection of early colorectal cancer

PURPOSE: Extending life expectancy is one of the major causes for increasing cancer incidence rate. The objective of the present investigation is to compare the diagnostic value of conventional and narrow band imaging (NBI) colonoscopy for the early diagnosis of colorectal cancer. MATERIAL AND METHODS: We examined 163 patients hospitalized in the First Clinic of Surgery, St. Marina University Hospital of Varna, for a period from 2010 to 2012 and compared the diagnostic modalities of conventional colonoscopy and NBI-colonoscopy. RESULTS: NBI colonoscopy with magnifying endoscopy had the potential to detect more lesions remaining not identified by conventional endoscopy. The relative share of newly-increased mucosal changes increased by 1.9 times (52%). The newly-diagnosed lesions were mostly small sized. We diagnosed by 2.7 times more lesions sized less than one mm as well as by two times, 1.7 and 1.3 times more lesions sized 1-3 mm, 3-5 mm and 5-9 mm, respectively. The method did not establish any new formations larger than one cm or more. The main part of the newly-detected lesions presented with non-specific inflammatory changes, i.e. by 9.2 times more often when compared to conventional endoscopy and represented hyperplastic/ inflammatory polyps by 2-3 times more often. In four new lesions there were either an early cancer, or areas of high-grade dysplasia while in 12 ones there was a low-grade dysplasia. CONCLUSION: NBI colonoscopy with magnifying endoscopy represents a reliable method for the diagnosis of small neoplasms of the colon. Scripta Scientifica Medica 2013; 45(2): 43-47.

SPILLED GALLSTONES AT LAPAROSCOPIC CHOLECYSTSECTOMY – A REASON FOR RE-OPERATION IN THOSE WITH INCIDENTAL GALLBLADDER CANCER?

IntroductionLaparoscopic Cholecystectomy is the gold standard treatment of symptomatic gallstone disease. Incidental gallbladder cancer is found in 0.6–2.1% of cases. Patients with Tis or T1a tumours generally undergo no further...

PTU-172 C-Myc as a Biomarker in Barrett’S Oesophagus

IntroductionIdentifying Barrett’s oesophagus (BE) patients at risk of progressing to oesophageal adenocarcinoma (EA) remains a challenge. Diagnosis of low grade dysplasia is limited by considerable intra and inter-observer variability and...

Sa2005 C-Terminal SRC Kinase (CSK) As a Biomarker for Human Colonic Field Carcinogenesis

strict consensus diagnosis by expert pathologists [21 BE with no dysplasia (NDBE), 10 BE with low grade dysplasia (LGD), 13 BE with high grade dysplasia (HGD) and 8 EA]. Subsequent validation was performed on a BE tissue microarray (TMA) (60 NDBE, 19 LGD and 29 HGD), and EA TMA (n= 278). Results: Seventy eight genes were differentially expressed between NDBE and HGD. c-MYC was selected as a top target as the expression levels progressively increased with dysplasia stage and cancer with a fold change of 2.46 between NDBE and HGD. mRNA expression levels were significantly higher in HGD and EA compared to NDBE (p,0.0001). Immunostaining for MYC was positive in 25 out of 29 cases of HGD with a sensitivity 86% of and a specificity of 97 % (Table 1). 10 out of 19 LGD stained positive for MYC. 254 out of 278 (91%) EA cases showed significant cMYC protein expression. Among the 19 LGD samples, 9 had HGD in the BE segment and 7 of these were positive for c-MYC. Strong c-MYC staining was also observed in areas regarded as indefinite for dysplasia which were adjacent to areas of HGD. Conclusions: Immunohistochemistry for c-MYC is a promising molecular biomarker in Barrett's oesophagus. It could also enable better risk stratification in patients with samples in the LGD and indefinite categories.

Tu1214 The High Frequency of Adenomas Detected on Screening in Older Patients Warrants the Inclusion of This Cohort in National Programmes

Background: Colorectal cancer (CRC) is the second commonest malignancy in developed countries. The efficacy of CRC screening is well recognised, with many countries adopting a two stage approach with either gFOBT or FIT. Age is a recognised risk factor for CRC, yet the upper age limit for screening can vary substantially. Aim: To identify patterns of anatomical distribution and histological types of screening detected colorectal polyps in differnt age groups. Methods: A retrospective database review from Ireland's first FIT based pilot CRC screening programme over a two year period. In all, 9993 people between 5074 were invited, 51% (n=5063) participated and 10% (n=514) of FIT kits were positive and referred for colonoscopy. Subjects were excluded if they had a history of IBD, CRC or had undergone a colonoscopy within five years. Patient demographics, colonoscopy reports and histology results were recorded. Patients were divided into five age groups, 50-54, 55-59, 60-64, 65-69, and 70-74. Polyps were classified as either left sided (rectal,sigmoid,descending colon) or right sided (transverse colon, descending colon, caecum). Results: A total of 419 colonoscopies were performed, 409 (98%) were complete and 53% (n=216) had either a polyp or malignancy. There were 442 polyps diagnosed in 216 people, 32% (n=70) of people had more than one polyp. In all, 167 people had 318 adenomas. Of the adenomas, 59% (n=188) were tubular adenomas and 41% (n=130) were tubulovillous and 10% (n= 32) had areas of high grade dysplasia. Sixty seven (40%) of patients with adenomas were female and 38 (23%) were over 70 years of age. The incidence and distribution of adenomas according to age was n=6 (25%) and n=1 (14%) right sided for 50-54 years, n=30 (30%) and n=15 (29%) right sided for 55-59 age group, n=41 (41%) with n=29 (35%) right sided in the 60-64 age group, n=52 (49.5%) with n=31 (35%) right sided in the 65-69 age group and n=38 (47.5%) with n=29 (38%) right sided in the 70-74 age group. Conclusion: this study shows an increased incidence and preponderance of proximal adenomas with increasing age, highlighting that evaluation of the proximal colon is particularly important in elderly people. As 23% (n=38) of people with adenomaswere between 70-74, it would be appropriate to include this age group in future screening programmes.

Standard endoscopy with random biopsies versus narrow band imaging targeted biopsies in Barrett's oesophagus: a prospective, international, randomised controlled trial

BackgroundWhite light endoscopy with random biopsies is the standard for detection of intestinal metaplasia (IM) and neoplasia in patients with Barrett's oesophagus (BO). Narrow band imaging (NBI) highlights surface patterns...

Molecular imaging via novel application of fluorescent lectins permits rapid endoscopic identification of dysplasia in barrett's oesophagus

IntroductionEarly detection of oesophageal adenocarcinoma (AC) or high grade dysplasia (HGD) improves prognosis but may missed at endoscopy.HypothesisGlycosylation alterations in the progression to AC could be detected using lectins to...

KRAS Mutation Analysis Helps to Differentiate Between Pulmonary Metastasis from Colon Adenocarcinoma In Situ and Primary Lung Adenocarcinoma

A 69-year-old woman never-smoker was noted to have a solitary 4-cm lesion in the left upper lobe on routine preoperative chest x-ray before elective hip replacement. Chest computed tomography redemonstrated the spiculated 4 3.3-cm lesion. Positron emission tomography-computed tomography confirmed that the lesion was fluorodeoxyglucose-avid with no other sites of fluorodeoxyglucose avidity (Figure 1). The patient underwent a core needle biopsy of the lung lesion showing a cytokeratin (CK) 20 and caudal type homeobox transcription factor 2–positive adenocarcinoma, which was negative for CK7 and thyroid transcription factor-1. The expected immunohistochemical markers for a primary lung adenocarcinoma are CK7 and thyroid transcription factor-1, whereas the usual markers for a primary colorectal adenocarcinoma are CK20 and caudal type homeobox transcription factor 2. The patient underwent a video-assisted thoracoscopic lobectomy and mediastinal lymphadenectomy revealing a 3.8-cm adenocarcinoma with the same histologic (Figure 2A) and immunophenotype (Figure 3) as the previous biopsy. One inferior mediastinal lymph node (level 9L) was also involved with tumor, and levels 5, 10L, 11L, and 12L nodes were negative for disease. A colonoscopy, upper endoscopy, and capsule video enteroscopy did not show any evidence of a primary tumor. Seven years before the discovery of the lung mass, she had a 2-cm sigmoid adenoma with areas of high-grade dysplasia (Figure 2B) and carcinoma in situ resected endoscopically in a piecemeal fashion. Her resected lung tumor was sent for genetic testing and found to harbor a Kirsten ras sarcoma viral oncogene homolog (KRAS) gene codon 12 GGT to GTT (glycine to valine) missense mutation (KRAS G12V). The tumor was wild-type for the epidermal growth factor receptor gene. Given there was no evidence of primary colorectal tumor on endoscopy, the archived, paraffin-embedded sigmoid adenoma was also genotyped and found to carry the same KRAS codon 12 GTT transversion. This suggested that the lung tumor was a late recurrence from the original KRAS mutant sigmoid carcinoma in situ. She was subsequently found to have multiple new pulmonary lesions.

Total Gastrectomy for Gastric Dysplasia in a Patient With Attenuated Familial Adenomatous Polyposis Syndrome

A 31-year-old woman was referred to our institution in June 2007 for evaluation of moderate gastric dysplasia in the setting of numerous fundic gland polyps. The patient’s family is known to carry a mutation associated with attenuated familial adenomatous polyposis (AFAP), and her siblings and mother have clinical manifestations of the disease. Before her referral, the patient had annual screening colonoscopy and upper endoscopy starting at age 17 years. Her surveillance colonoscopies never demonstrated more than a single adenomatous polyp that was resected endoscopically. In contrast, on initial upper endoscopy, she was found to have numerous small polyps involving the majority of her stomach. Biopsy of these small polyps demonstrated fundic gland-type polypsis characterized by cystically dilated and irregularly budded fundic glands. Subsequently, an upper endoscopy in April 2007 showed at least three dominant polypoid lesions within this carpet of small fundic gland polyps along the greater curvature of the stomach, each measuring approximately 3 cm in diameter. Pathological analysis of these areas revealed multiple fundic gland polyps with adenomatous features and mild to moderate dysplasia. Computed tomography of the abdomen and pelvis revealed thickening of the anterior wall of the stomach and antrum, but found no other appreciable lesions within the peritoneal cavity. (Fig 1, white arrow) After preoperative evaluation, she underwent a total gastrectomy with roux-en-y esophagojejunostomy with feeding jejunostomy in early July 2007. Exploratory laparotomy revealed no evidence of extra-gastric disease. After resection, the stomach was found to have a 17 16 cm area with numerous small polyps studding the mucosal surface. (Fig 2) She had an uneventful postoperative course and was discharged 10 days after the operation requiring jejunostomy tubefeeding. Final pathologic evaluation showed fundic gland-type gastric polyposis with multiple areas of high grade dysplasia in a background of patchy low grade dysplasia. (Fig 3, 400 ) Fortunately, there were no areas containing invasive carcinoma. Familial adenomatous polyposis (FAP) is a rare, but wellcharacterized autosomal dominant condition in which affected individuals develop hundreds of colonic polyps beginning in adolescence and early adulthood (age 20 to 30 years). FAP is caused by mutations in the adenomatous polypsis coli (APC) tumor suppressor gene on chromosome 5q. AFAP differs from FAP in that patients clinically develop fewer colonic polyps ( 100) and at a later age (30 to 40 years) than patients with full-blown FAP. Genetically, germline APC mutations in the first four coding exons, in the alternatively spliced region

Tubulovillous adenoma of anal canal: A case report

Tumors arising from the anal canal are usually of epithelial origin and are mostly squamous cell carcinoma or basal cell carcinoma. We present a case of benign anal adenomas arising from the anus, an extremely rare diagnosis. A 78-year-old white man presented with rectal bleeding of several months duration. Examination revealed a 4 cm friable mass attached to the anus by a stalk. At surgery, the mass was grasped with a Babcock forceps and was resected using electrocautery. Microscopic examination revealed a tubulovillus adenoma with no areas of high grade dysplasia or malignant transformation. The squamocolumnar junction was visible at the edges of the lesion confirming the anal origin of the tumor. We believe the tubulovillus adenoma arose from either an anal gland or its duct that opens into the anus. Although seen rarely, it is important to recognize and treat these tumors at an early stage because of their potential to transform into adenocarcinoma.

BRCA-Mutation–Associated Fallopian Tube Carcinoma

To compare clinical and histologic features between fallopian tube cancers in women with germline BRCA mutations and sporadic cases. Twenty-eight patients with fallopian tube cancer had BRCA mutation testing using multiplex polymerase chain reaction and protein truncation testing. Histologic slides were reviewed by 2 pathologists, and immunohistochemical staining for p53, ki67, estrogen receptor, and progesterone receptor was performed on carcinomas and dysplastic and benign tubal epithelia. Twelve of 28 (43%) women had BRCA mutations: 11 BRCA1, 1 BRCA2. Excluding 4 cases found at prophylactic surgery, the median age of diagnosis of BRCA mutation carriers was 57 years compared with 65 years among sporadic cases (P = .09). Patients with BRCA-associated fallopian tube cancer had a median survival time of 68 months compared with 37 months when compared with sporadic cases (P = .14). Both groups had predominantly advanced stage, high grade, serous fallopian tube cancers. No patient had exclusively proximal disease. Occult fallopian tube cancer diagnosed at prophylactic surgery in BRCA mutation carriers was exclusively distal. "Skip" areas of high-grade dysplasia were only seen in 2 patients, both of whom were BRCA mutation carriers. There were no differences in the immunohistochemical staining for p53, ki67, estrogen receptor or progesterone receptor in carcinomas and dysplastic or benign epithelia of patients with or without BRCA mutations. Overexpression of p53 was commonly seen in fallopian tube cancers and dysplastic epithelium, but rarely noted in benign epithelium. Fallopian tube cancer is part of the BRCA mutation phenotype and seems to share many clinical features with sporadic fallopian tube cancers, including no exclusively proximal disease. The presentation of BRCA-associated fallopian tube cancers may, however, occur at a younger age and have an improved survival.

A prospective clinicopathological and endoscopic evaluation of flat and depressed colorectal lesions in the United Kingdom

Objectives Flat and depressed colorectal lesions are now reported in Western populations. The malignant potential, anatomical distribution, and other clinicopathological features have not been established in this group. This study aimed to assess prospectively the prevalence, clinicopathological, and endoscopic features of flat and depressed colorectal lesions in the United Kingdom. Methods A single endoscopist performed colonoscopy on 850 consecutive patients presenting for routine colonoscopy. All endoscopies were performed using a high magnification colonoscope with chromoscopy to facilitate detection of flat and depressed colorectal lesions. Results A total of 458 flat lesions were identified. Of these, 173 (38%) were hyperplastic and 285 (62%) adenomatous or beyond. Of the 173 hyperplastic flat lesions, 162 (94%) were located in the recto-sigmoid region. Of the 267 adenomas, 66 (25%) had areas of high grade dysplasia (HGD), with 54/66 (82%) being present in the right colon. Flat lesions <8 mm in diameter was more likely to contain HGD than those <8 mm ( p < 0.001). Nine of the 10 (90%) flat invasive adenoacarcinomas were in the right colon and all had a depressed morphological component. In contrast, HGD was observed in 58/466 (12%) of protuberant (sessile/pedunculated) adenomas of which 95% (55/58) were located in the left colon. In addition, HGD was present in 17% of all sessile adenomas versus 44.6% of flat lesions >8 mm in diameter ( p = 0.001). Of the 14 protuberant carcinomas, 13/14 (93%) were in the left colon. Synchronous lesions were found in 96/816 (12%) of cases. Of the 816 patients with two or more left-sided protuberant adenomas <8 mm (with or without HGD), 89 (11%) had one or more flat lesions in the right colon with HGD. Conclusions Flat adenomas and carcinomas have a high malignant potential compared to protuberant lesions and have a propensity for developing in the right hemi-colon. Total colonoscopy is required to detect such lesions, as only 18% of flat lesions would be in reach of the flexible sigmoidoscope.

Pathology of early invasive adenocarcinoma of the esophagus or esophagogastric junction: implications for therapeutic decision making.

As an alternative to surgical resection, endoscopic treatment modalities are being explored for the treatment of patients with early esophageal carcinoma. This study aimed to evaluate patterns of local growth and regional dissemination of early adenocarcinoma of the esophagus or esophagogastric junction, as these pathologic features may contribute to rational therapeutic decision making. Among 173 patients who underwent esophageal resection for invasive adenocarcinoma (1993-1998), 32 (19%) had early stage cancer (pT1). Clinical records, pathology reports, and original slides of the surgically resected esophagus were reviewed in each case. In 12 patients tumor invasion was limited to the mucosa, whereas in 20 patients the tumor showed infiltration of the submucosa. All cancers were associated with intestinal metaplasia. Areas of high grade dysplasia accompanied 27 of the 32 cancers (84%). Intramucosal cancer had no lymph node metastasis but presented as multifocal disease in 42% of cases and extended under preexisting squamous mucosa in 17% of cases. In submucosal cancer, lymph node metastases were present in 30% of cases. Disease specific 3-year survival for patients with intramucosal cancer was 100% and for those with submucosal cancer 82% (P = not significant). Based on the local growth pattern of intramucosal adenocarcinoma of the esophagus or esophagogastric junction, endoscopic treatment of patients with this disease should be applied with caution. For submucosal carcinoma, surgery is the mainstay of treatment, as lymph node metastasis is frequently present. Both subclassifications of early cancer show a favorable outcome after esophagectomy.

3442 Role of high resolution endoscopic imaging using optical coherence tomography (oct) in patients with barrett's esophagus (be).

OCT, a novel technique for high resolution endoscopic imaging clearly delineates microscopic mucosal and submucosal structures of the GI tract. Aim: To study the ability of OCT to identify and characterize BE. Methods: OCT images were obtained using an endoscopic OCT probe (2.4 mm dia, 0.5 mm focal distance)in patients undergoing surveillance EGD for BE. Images were captured digitally and were objectively rated in terms of clarity, resolution, ease of identification of BE and to determine whether areas of dysplasia could be identified. Four quadrant large particle biopsies were taken from the area of BE at 2 cm intervals and were correlated with OCT images. Results:8 patients with BE (mean age 62.5 years, 6 men) were studied. Mean length of BE was 7.7 (SE 2.2) cms; 3 patients had focal areas of high grade dysplasia. During OCT imaging squamous epithelium and Barrett's epithelium could be readily distinguished. Also, areas with Barrett's epithelium lacked the characteristic thick, dark band which is seen with stratified squamous epithelium. The esophageal mucosa was significantly thicker in the areas of Barrett's epithelium (mean thickness 0.6 mm vs. 0.4 mm, p

Chromosomal Imbalances in Barrett's Adenocarcinoma and the Metaplasia-Dysplasia-Carcinoma Sequence

To characterize cytogenetic alterations found in Barrett's adenocarcinoma (BA) and, more importantly, its premalignant stages, we studied chromosomal imbalances in various lesions in the histologically proposed metaplasia-dysplasia-carcinoma sequence using comparative genomic hybridization (CGH). Using 30 esophageal adenocarcinoma resection specimens, we were able to study 30 areas of Barrett's adenocarcinoma and 8 lymph node metastases (LN). In addition, we investigated 25 premalignant lesions adjacent to BA derived from a subset of 14 resection specimens including 11 areas of high grade dysplasia (HGD), 8 areas of low grade dysplasia (LGD), and 6 areas of intestinal metaplasia (IM), which were laser-microdissected and studied with CGH. To validate the CGH findings, fluorescence in situ hybridization analysis on 13 BA with probes specific for HER-2/neu and 20q13.2 were performed. The chromosomal alterations most often identified in BA were: gains on 8q (80%), 20q (60%), 2p, 7p and 10q (47% each), 6p (37%), 15q (33%) and 17q (30%). Losses were observed predominantly on the Y-chromosome (76%), 4q (50%), 5q and 9p (43% each), 18q (40%), 7q (33%) and 14q (30%). High-level amplifications were observed on 8q23-qter, 8p12-pter, 7p11-p14, 7q21-31, 17q11-q23. Recurrent chromosomal changes were also identified in metaplastic (gains on 8q, 6p, 10q, losses on 13q, Y, 9p) and dysplastic epithelium (gains on 8q, 20q, 2p, 10q, 15q, losses on Y, 5q, 9p, 13q, 18q). Novel amplified chromosomal regions on chromosomes 2p and 10q were detected in both Barrett's adenocarcinoma and premalignant lesions. An increase of the average number of detected chromosomal imbalances from IM (7.0 +/- 1.7), to LGD (10.8 +/- 2.2), HGD (13.4 +/- 1.1), BA (13.3 +/- 1.4), and LN (22 +/- 1.2) was seen. Although the detection of common chromosomal alterations in premalignant lesions and adjacent carcinomas suggest a process of clonal expansion, the occurrence of several chromosomal changes in an apparently random order relative to one another is striking evidence that clonal evolution is more complex than would be predicted by linear models. This is probably a reflection of the existence of many divergent neoplastic subpopulations and highlights one of the main problems associated with surveillance of Barrett's patients, namely sampling error.

Endoscopic mucosectomy: an alternative treatment for superficial esophageal cancer.

Recent trends in the management of superficial esophageal cancer consist of improved detection, pretherapeutic staging and reliable criteria for curative endoscopic therapy. The endoscopic treatment is legitimate when the cancer is at an early stage, intra-epithelial or microinvasive (m1 or m2) and N0. Submucosal cancer should not be treated with a curative intent by endotherapy. Concerning squamous cell cancer, the oriental and occidental pathologists include high-grade dysplasia in the same group as intramucosal cancer. The distinction is however maintained for adenocarcinoma in the Barrett's esophagus. Indications of endoscopic rather than surgical treatment rely on: (1) the small size of the tumor (not more than 2 cm in diameter); (2) the endoscopic morphology in the type 0 of the Japanese classification with the flat subtypes IIa and IIb rather than type IIc--there is high risk of submucosal invasion for the polypoid (type I) or ulcerated superficial cancer (type III); and (3) the endoscopic ultrasound staging, with confirmed integrity of the hyperechoic submucosal layer. The high-frequency (20 MHz) miniprobe is preferred to the standard (7.5 MHz) instrument. The elective procedure for tumor eradication is endoscopic mucosectomy. The technique is associated with a 6.8% risk of severe complications (hemorrhage or perforation) and a recurrence rate of 3%-7%. The 5-year survival rate is similar to that of surgery (over 80%). In the small group of patients with superficial esophageal cancer (less than 10% of the disease) endoscopic treatment may now be proposed in about 30% of cases, surgery is preferred for submucosal cancer and for neoplasia with a large surface. Areas of high-grade dysplasia in the Barrett's esophagus offer a new and increasing sector of indications. The concurrent endoscopic procedure of destruction--photodynamic therapy--is preferred for the destruction of lesions with poorly delineated limits.