Intratumoral genetic heterogeneity in Barrett adenocarcinoma

In 10 cases of Barrett adenocarcinoma, samples from 8 tumor areas (including superficial and deep from peripheral and central areas) and a regional lymph node metastasis were studied for amplification of c-myc, c-erbB-2, and EGFR. We analyzed loss of heterozygosity (LOH) at 3 loci (APC, MCC, and RB) and 2 anonymous microsatellite markers (D4S1652 and D18S474). We detected c-myc in variable fractions of tissue samples from 3 of 9 tumors; EGFR was amplified in 2 specimens from 1 tumor. One tumor demonstrated amplification of c-erbB-2 in all areas. LOH at the D4S1652, MCC, RB, APC, and D18S474 loci was found in 75% (3/4), 57% (4/7), 50% (4/8), 11% (1/9), and 0% (0/10) of informative cases, respectively. LOH generally was restricted to variable subpopulations of tumor cells within individual tumors. There was no obvious association of certain genetic alterations with topographically distinct tumor regions; however, superficial areas showed more frequent genetic alterations than areas from the deeply invading front. More aberrations were detected in the periphery than in the center. Barrett adenocarcinoma is characterized by marked intratumoral genetic heterogeneity, which must be considered when evaluating genetic alterations as indicators of response to therapy and prognosis.     

Combined tubular adenocarcinoma and hepatoid adenocarcinoma arising in Barrett esophagus

Hepatoid adenocarcinoma arising in the esophagus is extremely rare. To date, there are only 3 cases in the world English literature. We report the fourth case here. A 76-year-old Japanese man was admitted to our hospital because of the deterioration of nephritic syndrome. He presented with chest burn, and the endoscopic examination of upper digestive tract disclosed the tumor in the lower esophagus. The subtotal esophagectomy was undertaken because of esophageal cancer. The postoperative histologic examination showed the finding of combined tubular adenocarcinoma and hepatoid adenocarcinoma arising in Barrett esophagus. Immunohistochemically, hepatoid adenocarcinoma cells were positive for a-fetoprotein, hepatocyte, a1-antitrypsin, a1-antichymotrypsin, and CDX2, but negative for MUC5AC and MUC6. Esophageal hepatoid adenocarcinoma seems to be closely associated with Barrett esophagus and show the intestinal phenotype rather than gastric phenotype.     

HER-2/neu gene amplification by FISH predicts poor survival in Barrett's esophagus-associated adenocarcinoma

The HER-2/neu oncogene is localized to chromosome 17q and shares significant homology with the epidermal growth factor receptor. HER-2/neu protein overexpression has been associated with poor prognosis in a variety of tumors, but its significance in Barrett's esophagus-associated adenocarcinoma (BEAd) is unknown. Therefore, the aim of this study was to evaluate the prevalence and prognostic value of HER-2/neu gene amplification by fluorescence in situ hybridization (FISH) in 63 cases of BEAd. Routinely processed tissue sections from resection specimens of 63 patients with BEAd (M/F ratio, 10:1; mean age, 63 years) were assayed for HER-2/neu gene amplification by FISH using the Ventana unique sequence probe (Ventana Medical Systems, Inc, Tuscon, AZ). FISH results were correlated with the pathological features of the tumors and with patient survival. Clinical follow-up data were available for 54 patients (mean follow-up, 31 months [range, 1 to 152 months]). The HER-2/ neu gene was amplified in 12 of 63 (19%) cases. The presence of HER-2/neu gene amplification showed a trend toward a correlation with depth of tumor invasion (P = .07), lymph node metastasis (P = .13), and pathological stage (P = .14), but did not correlate with any of the other pathological features, such as degree of differentiation or tumor size. On both univariate and multivariate analysis, HER-2/neu gene amplification was associated with shortened survival (P = .03). HER-2/neu oncogene amplification, as determined by FISH, correlates with shortened patient survival and independently predicts poor outcome in patients with BEAd.     

Immunohistochemical investigation of tumorigenic pathways in small intestinal adenocarcinoma: a comparison with colorectal adenocarcinoma.

Small intestinal adenocarcinoma is an uncommon neoplasm morphologically similar to or indistinguishable from colorectal adenocarcinoma. Although much has been learned about genetic pathways critical to colorectal tumorigenesis, little is known about molecular alterations involved in the development of small intestinal adenocarcinoma. In this study, we immunohistochemically compared non-ampullary small intestinal adenocarcinomas with sporadic colorectal adenocarcinomas for the expression of several proteins known to serve pivotal roles in colorectal tumorigenesis. These included adenomatous polyposis coli and beta-catenin involved in the Wnt signaling pathway, and DNA mismatch repair enzymes hMLH1, hMSH2 and hMSH6 involved in the microsatellite instability pathway. The expression of two important tumor suppressors, p53 and RB, was also examined. The results show that complete loss of adenomatous polyposis coli immunoreactivity, presumably resulting from its gene mutations, was observed in eight of 26 (31%) small intestinal adenocarcinomas and 36 of 51 (71%) colorectal adenocarcinomas (P = 0.0008). Nuclear localization of beta-catenin, an indirect evidence of deregulated Wnt signaling pathway, was observed in 5 (19%) small intestinal adenocarcinomas and 36 (71%) colorectal adenocarcinomas (P<0.0001). Total lack of nuclear staining for one or more of the DNA mismatch repair enzymes occurred in a similar low frequency in both small intestinal and colorectal adenocarcinomas, seen in two of 25 (8%) and 10 of 47 (21%) cases, respectively (P = 0.1958). The frequencies of aberrant p53 and RB expression were also similar between small intestinal and colorectal adenocarcinomas. These observations indicate that defects in the Wnt and microsatellite instability pathways occur in over 90% of colorectal adenocarcinomas, but in only 40% of small intestinal adenocarcinomas. Small intestinal tumorigenesis appears to follow a distinct, yet unidentified, molecular pathway(s) from its colorectal counterpart despite their morphologic similarity.     

Frequent c-myc amplification in high-grade dysplasia and adenocarcinoma in Barrett esophagus

Barrett esophagus (BE) is a condition in which the normal squamous epithelium of the esophagus is replaced by a metaplastic columnar epithelium. BE is a premalignant lesion that represents the initial step in a metaplasia-dysplasia-carcinoma sequence. In the present study, amplification of the proto-oncogene c-myc was determined by means of differential polymerase chain reaction analysis of metaplastic specialized epithelium, low-grade dysplasia, high-grade dysplasia, and invasive adenocarcinoma obtained by microscopic dissection of 43 esophagectomy specimens. Amplification of c-myc was found in none of 29 specialized epithelial specimens, none of 23 low-grade dysplasia specimens, 6 of 24 high-grade dysplasia specimens, and 17 of 39 adenocarcinoma specimens. Our data indicate that amplification of c-myc is a late event in the metaplasia-dysplasia-carcinoma sequence in BE. Furthermore, determination of c-myc amplification may help identify high-risk patients who would benefit from intensified endoscopic surveillance or from immediate treatment.     

Basal cell adenocarcinoma in minor salivary glands

Basal cell adenocarcinoma is a rare and relatively recently characterized malignant salivary gland tumour, the malignant counterpart of basal cell adenoma. Diagnosis depends on finding features similar to adenoma but with an infiltrative growth pattern and exclusion of adenoid cystic carcinoma, sialoblastoma and basaloid squamous carcinoma. Basal cell adenocarcinoma is very rarely reported in minor salivary glands. We report three cases of basal cell adenocarcinoma affecting the labial, buccal and palatal minor salivary glands. One recurred following complete removal but with lesional disruption and further local wide excision appeared curative. A further lesion failed to recur in 5 years' follow-up despite marginal excision and a third after 3 years' follow-up. Basal cell adenocarcinoma is considered a low-grade malignancy, and in the minor glands wide excision and radiotherapy are recommended. However, the reported lesions appear to have a more indolent behaviour than previously reported lesions in minor glands.     

Cardiac rather than intestinal-type background in endoscopic resection specimens of minute Barrett adenocarcinoma

Many publications focusing on the background or original mucosa of Barrett adenocarcinoma have maintained that adenocarcinoma arises in intestinal-type mucosa with goblet cells in the columnar-lined esophagus, and this has become a central dogma. The mucosa on each side of a series of 141 minute esophageal adenocarcinomas (almost all of which were mucosal carcinomas) resected by endoscopic mucosal resection was recorded as the background mucosa. All 141 cases had endoscopic evidence of an esophageal origin, and for 113 of them, histologic evidence of an esophageal origin was also available. The mucosae were classified into 4 types--squamous, cardiac, fundic, and intestinal--based on routine histology and immunohistochemical staining. The present joint pathologic examination of the background mucosa of Barrett adenocarcinoma conducted by Japanese and German pathologists and gastroenterologists found that more than 70% of primary small adenocarcinomas (<2 cm) of the esophagus were adjacent to cardiac/fundic-type rather than intestinal-type mucosa. Moreover, intestinal metaplasia was not observed in any areas of the endoscopic mucosal resection specimens in 64 (56.6%) of the 113 cases. In other words, there was no evidence to support the previously held view that Barrett adenocarcinoma is nearly always accompanied and preceded by intestinal-type mucosa. Our study has demonstrated a close relationship between esophageal adenocarcinoma and cardiac-type mucosa. Therefore, it is not proven histogenetically that the background mucosa of esophageal adenocarcinoma is the intestinal type. Also, it seems better to define Barrett esophagus as metaplastic columnar-lined esophagus alone, without requiring the presence of goblet cells, in accordance with histogenetic and practical standpoints.     

DNA copy number profiling in esophageal Barrett adenocarcinoma: comparison with gastric adenocarcinoma and esophageal squamous cell carcinoma.

We screened 18 specimens of Barrett adenocarcinoma for genetic alterations using comparative genomic hybridization (CGH) to analyze DNA copy number changes. The most common gains were at 20q (56%) and 17q (39%). High-level amplifications were observed in the same chromosomes. The most common losses were in chromosomes 4 (22%) and 5 (22%). Other recurrent changes were gains of chromosomes 8, 10q, and 13. We compared the copy number changes in Barrett adenocarcinoma and those previously reported in the intestinal type of stomach carcinoma. The similarities we found suggest a common molecular pathogenesis, whereas dissimilarities seen between Barrett adenocarcinoma and esophageal squamous cell carcinoma are in keeping with a well-known different etiology.     

Beta-catenin expression and its association with prognostic factors in adenocarcinoma developed in Barrett esophagus

The majority of the adenocarcinomas arising in Barrett esophagus manifest clinically at an advanced stage and have a poor prognosis. As a result of this poor prognosis, much attention has been directed toward the exploration of markers for neoplastic progression in Barrett esophagus. The objective of the present study was to determine the expression of beta-catenin by immunohistochemical analysis in 70 adenocarcinomas developed in Barrett esophagus and to examine its relationship to various prognostic factors currently in use. Abnormal beta-catenin expression, consisting of the loss of membranous staining and the appearance of the nuclear staining, was found in 43 cases (61%). Of patients with the 43 tumors showing abnormal beta-catenin expression, 25 (58%) survived more than 1 year. In contrast, only 7 (26%) of 27 patients with tumors showing normal beta-catenin expression survived longer than 1 year. Most of the superficial (Tis-T1) tumors (83% [10/12]) exhibited abnormal beta-catenin expression compared with only 53% (31/58) in the T2-T3 group. These results suggest a possible correlation among beta-catenin expression, tumor stage, and length of survival as prognostic factors in patients with adenocarcinoma in Barrett esophagus.     

Prognostic significance and effect of chemoradiotherapy on microvessel density (angiogenesis) in esophageal Barrett's esophagus-associated adenocarcinoma and squamous cell carcinoma.

Previous studies have shown that intratumoral microvessel density (IMD) correlates with clinical outcome in a variety of human neoplasms, such as those that arise in the breast, colon, and stomach, suggesting that angiogenesis is important in cancer progression. The aims of this study were to evaluate the prognostic utility of IMD in esophageal Barrett's-associated adenocarcinoma (AdCa) and squamous cell carcinoma (SCC), and to determine the effect of preoperative chemoradiotherapy (chemrad) on this process. Tissue sections of tumor from 67 patients with esophageal carcinoma (45 with Barrett's-associated AdCa, 22 with SCC) were stained with the vascular marker CD31. The IMD was calculated by evaluating at least 5 different 200 x fields of tumor hot spot areas to obtain the mean microvessel count (MVC). The data then were correlated with the clinical and pathological features, chemrad status, and patient survival. The MVC was significantly higher in AdCa (143 +/- 63.2) compared with SCC (77.2 +/- 38.6, P = 0.0001). In AdCa, no correlation was noted between the MVC and any of the clinical or pathological features, including chemrad status. In contrast, in SCC, a statistically significant higher MVC was detected in patients who did not receive chemrad (97.2 +/- 37.3) compared with those who did (48.3 +/- 15.9, P = .002) and in tumors that were larger in size (P = .02). However, the MVC did not correlate with survival in either AdCa or SCC (P > .05). The degree of angiogenesis is not a significant prognostic indicator in either esophageal AdCa or SCC. Preoperative chemrad has a positive effect on reducing the degree of angiogenesis in esophageal carcinoma, particularly SCC.     

Clinicopathologic and molecular analysis of high-grade dysplasia and early adenocarcinoma in short- versus long-segment Barrett esophagus

Barrett esophagus, especially dysplastic Barrett mucosa, has been regarded as a preneoplastic lesion for esophageal adenocarcinoma. However, the etiology and pathogenesis of dysplasia and early adenocarcinoma in short- (SSBE) and long- (LSBE) segment Barrett esophagus have not been studied in detail. The aims of this study were to clarify clinicopathologic and genetic differences between high-grade dysplasia (HGD) and early adenocarcinoma in SSBE versus LSBE. We analyzed the clinicopathologic features from 47 patients (19 SSBE [<3 cm] and 28 LSBE [> or =3 cm]) with esophagectomy for HGD/T1 adenocarcinoma. Allelic losses on chromosomes 3p (FIHT), 5q (APC), 9p (p16), and 17p (p53) were compared in 12 HGD and 9 T1 tumors from 19 cases of SSBE and in 23 HGD and 15 T1 tumors from 28 cases of LSBE. Patients with SSBE were more likely to be smokers than were patients with LSBE (94.7% v 57.1%; P =.004). HGD or T1 tumors arising from SSBE were less likely to show adjoining nondysplastic Barrett mucosa than those from LSBE (73.6% v 100%; P =.02). LSBE more frequently showed a circumferential pattern of Barrett mucosa than did SSBE (96.4% v 47.3%; P =.0002). Chromosomal allelic losses on 3p, 5q, 9p, and 17p were detected in 19% (4 of 21), 43% (15 of 35), 40% (14 of 35), and 48% (16 of 33) of HGD, respectively, and 26% (5 of 19), 35% (8 of 23), 35% (8 of 23), and 57% (13 of 23) of T1 tumor, respectively. There were no significant differences in allelic loss of 3p, 5q, 9p, or 17p in HGD or T1 tumors from SSBE versus LSBE. These results suggest that both HGD and early adenocarcinoma in SSBE and LSBE may occur through similar genetic alterations, whereas there are some clinicopathologic differences between SSBE and LSBE. HUM PATHOL Copyright 2001 by W.B. Saunders Company     

Prevalence and characteristics of Barrett esophagus in patients with adenocarcinoma of the esophagus or esophagogastric junction

The prevalence and characteristics of Barrett esophagus in patients with adenocarcinoma of the esophagus or esophagogastric junction are uncertain. We studied 61 consecutive esophagogastrectomy specimens with adenocarcinoma, which were subjected to extensive histopathologic examination. Barrett esophagus was found in 64% of the cases (39 of 61), but had been recognized in only 38% of the patients with Barrett-associated carcinoma who had undergone preoperative endoscopy with biopsy (13 of 34). The median extent of Barrett esophagus with adenocarcinoma was 5 cm (range, 1 cm to 12 cm), and distinctive-type ("specialized") Barrett mucosa predominated (35 of 39; 90%). The Barrett adenocarcinomas were centered in the distal esophagus 2 cm +/- 0.3 cm above the esophagogastric junction. The patients with Barrett adenocarcinoma showed a striking predominance of white men (34 of 39; 87%) in contrast to gastric adenocarcinoma cases (21 of 69; 30%) and to Barrett patients without carcinoma or dysplasia (75 of 149; 50%), but similar to patients having adenocarcinoma of the esophagus or esophagogastric junction without demonstrable Barrett esophagus (16 of 22; 73%). Our findings suggest that most adenocarcinomas of the esophagus or esophagogastric junction are Barrett carcinomas, rather than gastric cardiac cancers or other types of esophageal adenocarcinoma; most Barrett adenocarcinomas occur in short segments of Barrett esophagus, which may be difficult to detect at endoscopy; and white men with Barrett esophagus may constitute a clinically identifiable at-risk group suitable for surveillance.     

Hepatocyte paraffin 1 antigen as a biomarker for early diagnosis of Barrett esophagus

We evaluated hepatocyte paraffin 1 (HepPar1) antigen expression, a sensitive marker of small intestinal differentiation, in combination with morphologic features to demonstrate intestinal differentiation in cases equivocal for Barrett esophagus (BE). Clinicopathologic features and HepPar1 expression were recorded for 54 BE cases, 45 consistent with reflux esophagitis (RE) cases, and 65 "suspicious" for BE (SBE) cases. The SBE category included RE cases with 2 or more morphologic changes associated with BE or metaplastic reaction to injury (eg, multilayered epithelium, squamous islands, goblet cell mimickers, pancreatic metaplasia). HepPar1 was expressed in all 54 BE cases, 4 of 45 RE cases, and 24 of 65 SBE cases. In SBE cases, 2 or more morphologic changes were associated with HepPar1 expression in 37% of cases (24/65), 3 or more features in 59% (13/22), and 4 or more features in 100% (4/4) (P ≤ .004). The combination of certain morphologic changes and HepPar1 expression in clinically suspicious distal esophageal biopsy cases without goblet cells supports the presence of evolving intestinal metaplasia.     

Beta-catenin expression as a prognostic indicator in cervical adenocarcinoma

The purpose of this study was to assess the prognostic influence of beta-catenin expression by immunohistochemistry in patients with cervical adenocarcinomas. The study group comprised of 51 patients who underwent total hysterectomy for cervical cancer. The median follow-up was 39 months (range 1-138 months). beta-catenin was expressed strongly on the membranes of normal cervical epithelial and glandular cells. Uniform membranous beta-catenin staining localized to intercellular borders was observed in 35% of tumors, whereas 65% of tumors demonstrated an abnormal pattern of reduced or aberrant beta-catenin expression (i.e., cytoplasmic and/or nuclear staining patterns). Abnormal beta-catenin immunoreactivity was associated statistically with advanced pathologic stage (p=0.018). The 10-year disease-free survival was 51.0% in patients with preserved expression of beta-catenin. On the other hand, a poorer prognosis was noted in the group with abnormal expression of beta-catenin with a 10-year disease-free survival of 43.4%. By multivariate analysis, low pathologic stage (stages I and II, p=0.001) and preservation of beta-catenin expression (p=0.012) were independently favorable prognostic factors. Our results indicate that changes in beta-catenin expression occur during the progression of cervical adenocarcinoma to an invasive phenotype. These results suggest that beta-catenin is an important intercellular adhesion molecule. Assessment of beta-catenin immunoreactivity may be a useful prognostic tool in cervical adenocarcinoma complementary to established prognostic factors. Furthermore, we developed a strategy for choosing biomarkers representing the steps in malignant progression in an effort to identify patients with occult metastases who will need adjuvant therapy and spare women from unnecessary interventions.     

Defective signal transduction--a common pathway for cellular dysfunction in HIV infection?

Qualitative defects in immune responsiveness after human immunodeficiency virus (HIV) infection have been well characterized and may play a key role in the development of HIV disease. However, no clear picture of the underlying mechanism of the functional deficiencies has yet emerged. In this article, Anthony Pinching and Keith Nye suggest that HIV or HIV proteins can sabotage transmembrane signalling and that this is of primary importance to the alterations in immune responsiveness.     

Polymorphous low grade adenocarcinoma of minor salivary gland: a clinicopathologic and comparative immunohistochemical study

Retrospective review of seven cases of polymorphous low grade adenocarcinoma (PLGA) revealed that the original histologic diagnosis in five instances was mixed tumor (four benign and one malignant). Comparison of PLGA tumors with eleven representative cases of benign pleomorphic adenoma of minor salivary gland (BPA) showed marked similarity in cytologic features. PLGA and BPA also exhibited similar mucohyaline and/or fibromyxoid stromal components. In contrast, tumor margins of the two neoplasms were quite different; margins of PLGA were consistently infiltrative, whereas those of BPA were generally well circumscribed and encapsulated. Immunophenotypic comparison confirmed the glial fibrillary acidic protein (GFAP) positivity in BPA reported by others, whereas cases of PLGA were uniformly nonreactive with this antibody. Although previous reports have emphasized the histologic similarities of PLGA and adenoid cystic carcinoma, our findings indicate that differentiation of PLGA from BPA may represent a more common diagnostic problem. Awareness of comparative histologic features is important in the differential diagnosis of these minor salivary gland neoplasms. Also, monoclonal GFAP may be useful in distinguishing cases of PLGA from BPA where histologic features are otherwise similar.