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In comparison to squamous cell carcinoma of the esophagus, adenocarcinomas are relatively uncommon. Its notoriety is from its association with Barrett's esophagus.


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SYNONYMS Primary adenocarcinoma of the esophagus
INCIDENCE In the USA, 34% of all primary esophageal malignancies
80% of all carcinomas of the lower third
AGE-RANGE AND MEDIAN 20-90 years (Median 60 years)
Barrett's esophagus Same risk factors


BARRETT ESOPHAGUS Same risk factors
Do 40% of patients resected for barrett esophagus with high-grade dysplasia have unsuspected adenocarcinoma?

Tschanz ER.

Department of Pathology, University Hospitals, Geneva, Switzerland.
Arch Pathol Lab Med. 2005 Feb;129(2):177-80. Abstract quote

Results of studies conducted in the last 2 decades suggest that the detection of high-grade dysplasia in patients with Barrett esophagus is the harbinger of a synchronous adenocarcinoma, which remains undetected even by rigorous biopsy protocols but is discovered during resection of the esophagus.

The reported prevalence of synchronous carcinomas ranges from 0% to 75%. Other researchers maintain that appropriate surveillance programs can be used to detect carcinomas at a curable stage and to prevent unnecessary esophagectomies. Both logistical difficulties and potential methodological pitfalls have plagued many studies designed to investigate this issue. A large multicenter study that would stratify participants for hitherto unexplored variables (eg, age, gender, and ethnic background) may be required before the 40% occult cancer prevalence can be either confirmed or refuted. However, the large scale needed for such a study to provide reliable data and new developments in endoscopic imaging (eg, magnification endoscopy and optical coherence tomography) and endoscopic therapy (eg, mucosectomy) are likely to make such a study both ethically unacceptable and logistically and financially unfeasible.

Future research should utilize the combination of new endoscopic technologies with the continuing search for validated biomarkers that help predict the biological behavior of Barrett epithelium in individual patients, with a particular focus on the possible development of preneoplastic and neoplastic lesions.

Pathologists who chose to shift their focus from the traditional morphological investigation of dysplasia to the search for usable biomarkers can position themselves at the center of innovative research projects that could radically modify the management of patients with Barrett esophagus.

Adenocarcinoma in the distal esophagus with and without Barrett esophagus. Differences in symptoms and survival rates.

Johansson J, Johnsson F, Walther B, Willen R, Stael von Holstein C, Zilling T.

Department of Surgery, Lund University, Sweden.

Arch Surg 1996 Jul;131(7):708-13 Abstract quote

OBJECTIVE: To evaluate differences in clinical appearance and survival rates in patients operated on for adenocarcinoma in the distal esophagus with and without Barrett epithelium.

DESIGN: Prospective clinical study.

SETTING: University hospital, Sweden.

PATIENTS: Fifty-four patients with adenocarcinoma in the distal esophagus with (n = 17) or without (n = 37) Barrett epithelium.

INTERVENTION: Esophagectomy or total gastrectomy.

MAIN OUTCOME MEASURES: Preoperative symptoms, endoscopic results, and histological findings; postoperative morbidity, mortality, and survival rates.

RESULTS: The main indication for the endoscopic examination that revealed tumor in the group with Barrett esophagus was reflex-related symptoms in 6 patients (routine Barrett examination, n = 4; symptoms of reflux, n = 2), symptoms related to upper gastrointestinal tract bleeding in 6, and malignant symptoms in 5 (dysphagia, n = 4; weight loss, n = 1). In contrast, most patients in the cardia cancer group were admitted because of malignant symptoms (dysphagia, n = 26; epigastric pain, n = 9; and anemia, n = 2). Ten of 17 patients in the Barrett esophagus cancer group had tumors limited to the mucosa and submucosa only. In 1 patient the tumor grew into the muscular layer but not through it. In the remaining 6 patients the tumor did grow through the muscular layer and lymph node metastases were found. Wall penetration was found in 30 patients and metastases to lymph nodes in 29 patients in the cardia cancer group. The hospital mortality rate was 0 of 17 patients in the Barrett cancer group and 2 of 37 patients in the cardia cancer group. In the patients operated on for adenocarcinoma in the distal esophagus, a better long-term survival rate was seen in those with Barrett epithelium (50%) than in those without this metaplasia (10%) (log rank P = .005; X2 = 7.80).

CONCLUSIONS: Concomitant Barrett epithelium improved the prognosis for patients with adenocarcinoma in the distal esophagus. Probably the reason for this was a higher rate of early-stage disease, because symptoms of gastroesophageal reflux and other benign disorders, not dysphagia, were most common in patients with adenocarcinoma without Barrett epithelium in the distal esophagus.



Molecular genetic changes in metastatic primary Barrett's adenocarcinoma and related lymph node metastases: comparison with nonmetastatic Barrett's adenocarcinoma.

Walch AK, Zitzelsberger HF, Bink K, Hutzler P, Bruch J, Braselmann H, Aubele MM, Mueller J, Stein H, Siewert JR, Hofler H, Werner M.

Institutes of Pathology, GSF-National Research Center for Environment and Health, Neuherberg, Germany.

Mod Pathol 2000 Jul;13(7):814-24 Abstract quote

Lymph node metastasis is one of the strongest negative prognostic factors for patients with Barrett's adenocarcinoma (BCA). However, despite the importance of the metastatic process in BCA, the molecular basis of it remains poorly understood.

To search for cytogenetic events associated with metastasis in regional or distant lymph nodes in BCA, we investigated 8 primary BCA and their lymph node metastases and compared them with 18 nonmetastatic BCA. In metastatic primary BCA, we observed significantly more DNA gains on 3q (P = .013), 17q (P = .019), and 22q (P = .021) compared with nonmetastatic primary BCA. No statistically significant correlation could be observed between DNA copy number changes and the histopathologic stage, grade, or survival (P > .05). The most frequent alteration observed only in lymph node metastases but not in the related primary tumor was loss of 2q (5 of 8). Coamplification of 7p and chromosome 17 was found in 6 of 8 lymph node metastases. A comparison of DNA copy number changes between primary tumors and their corresponding metastases indicated a high degree of genetic heterogeneity. Fluorescence in situ hybridization analysis demonstrated the involvement of the Her-2/neu gene in primary BCA and its related lymph node metastases. Each of the investigated primary tumors and related lymph node metastases also showed striking heterogeneity with respect to Her-2/neu, with several areas displaying different levels of amplification.

In summary, our data indicate that DNA copy number changes on 2q, 3q, 7p, 17q, and 22q may be involved in the metastatic process in BCA. Furthermore, the striking genetic heterogeneity that we found between primary BCA and its lymph node metastases may underlie BCA's poor responsiveness to therapy and could help explain why prognostic biomarkers measured exclusively in primary tumors give an incomplete view of the biologic potential of BCA.

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

Varis A, Puolakkainen P, Savolainen H, Kokkola A, Salo J, Nieminen O, Nordling S, Knuutila S.

Department of Medical Genetics, Haartman Institute and Central Hospital, University of Helsinki, Helsinki, Finland.

Cancer Genet Cytogenet 2001 May;127(1):53-8 Abstract quote

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.

Intratumoral genetic heterogeneity in Barrett adenocarcinoma.

Owonikoko T, Rees M, Gabbert HE, Sarbia M.

Institute of Pathology, Heinrich-Heine-University, Dusseldorf, Germany.

Am J Clin Pathol 2002 Apr;117(4):558-66 Abstract quote

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.

Gene Amplification and Protein Overexpression of c-erb-b2 in Barrett Carcinoma and Its Precursor Lesions

Helene Geddert, MD, etal

Am J Clin Pathol 2002;118:60-66 Abstract quote

We examined 39 samples of metaplastic specialized epithelium (SE), 27 of low-grade dysplasia (LGD), 27 of high-grade dysplasia (HGD), and 46 of adenocarcinoma (CA) derived from Barrett esophagus for c-erb-b2 gene amplification using differential polymerase chain reaction and for overexpression of c-erb-b2 protein using immunohistochemical analysis.

Amplification of the c-erb-b2 gene was as follows: SE, 0.0%; LGD, 0.0%; HGD, 11.1%; and CA, 13.6%; and protein overexpression was as follows: SE, 0.0%; LGD, 7.4%; HGD, 18.5%; and CA, 21.7%. In 8 (89%) of 9 samples, c-erb-b2 gene amplification correlated with protein overexpression. The reverse was true in 8 (47%) of 17 samples: c-erb-b2 protein overexpression was proved with simultaneous gene amplification.

Amplification of c-erb-b2 is a late event in the carcinogenesis of Barrett esophagus. In contrast, protein overexpression appears more often and earlier. Besides gene amplification, other mechanisms to induce protein overexpression must exist.

Evaluation of p53 mutations in premalignant esophageal lesions and esophageal adenocarcinoma using laser capture microdissection.

Djalilvand A, Pal R, Goldman H, Antonioli D, Kocher O.

1Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Mod Pathol. 2004 Nov;17(11):1323-7. Abstract quote  

p53 mutations have been implicated in the development of esophageal malignancies.

The purpose of this study was to assess more accurately the incidence and types of p53 mutations in Barrett's esophagus (BE) with and without dysplasia and in esophageal adenocarcinoma, using pure preparations of epithelial cells obtained by laser capture microdissection (LCM). Assays were performed on paraffin-embedded tissue samples of normal antrum and premalignant and malignant esophageal samples from 57 patients, including 16 controls, 10 with BE metaplasia alone, 20 with BE-associated dysplasia, and 11 with BE-associated adenocarcinoma. All tissues were processed for LCM. DNA was extracted from isolated cells, and polymerase chain reaction (PCR) was performed using oligonucleutide primers for exons 5-8 of p53. PCR products were processed for DNA sequencing. p53 sequence abnormalities were identified in 2/16 cases of normal antrum and regenerative/chemical gastritis, 1/10 cases of BE, 1/20 cases of BE with dysplasia, and 2/11 cases of adenocarcinomas.

The abnormalities occurred in exons 7 and 8 in the form of point mutations. Our results, using LCM, show that p53 gene mutations are relatively rare in esophageal preneoplastic and neoplastic conditions. Only point mutations were detected, but no deletions/insertions were identified.

Expression of p53-related protein p63 in the gastrointestinal tract and in esophageal metaplastic and neoplastic disorders

Jonathan N. Glickman, MD, PhD
Annie Yang, BS
Aliakbar Shahsafaei, MSc
Frank McKeon, PhD
Robert D. Odze, MD, FRCP

Hum Pathol 2001;32:1157-116 Abstract quote

p63 is a p53-related DNA-binding protein that helps regulate differentiation and proliferation in epithelial progenitor cells. Its expression has never been evaluated in the human gastrointestinal tract.

The aim of this study was to evaluate the expression of p63 in the esophagus and related metaplastic and neoplastic disorders to gain insight into the pathogenesis of these processes. Of particular interest was the expression of p63 in Barrett esophagus (BE) and in BE-associated multilayered epithelium. Multilayered epithelium has been postulated to represent an early precursor to the development of BE primarily because it shares morphologic and immunophenotypic features of both squamous and columnar epithelium, and has been shown prospectively to be highly associated with BE. Routinely processed mucosal biopsy or resection specimens that contained normal esophageal squamous epithelium (n = 20), squamous dysplasia (n = 4), squamous cell carcinoma (n = 7), BE (n = 10), BE-associated multilayered epithelium (n = 13), esophageal mucosal gland ducts (n = 10), BE-associated dysplasia (n = 12), and BE-associated adenocarcinoma (n = 7) were immunostained for p63 to determine the extent and location of staining. p63 staining was compared with the staining patterns observed for p53, Ki 67 (proliferation marker), and cytokeratins (CKs) 13 (squamous marker), 14 (basal squamous marker), 8/18 (columnar marker), and 19 (basal/columnar marker). Expression of p63 messenger RNA (mRNA) isoforms was also analyzed by reverse-transcription polymerase chain reaction of freshly isolated tissues.

In the normal esophagus, p63 was expressed in the basal and suprabasal layers of the squamous epithelium and in basal cells that line the mucosal gland ducts but was negative in all other epithelia of the gastrointestinal tract, including the stomach, small intestine, and colon. Similarly, p63 was not expressed in BE, but it, was present in the basal layer of multilayered epithelium in 9 of 13 cases (69%). p63-positive cells in multilayered epithelium and in the mucosal gland duct epithelium were positive for CK8/18 (100%) and CK13 (67% and 30%, respectively) and negative for CK14 (0%), in contrast to p63-positive cells in squamous epithelium, which were positive for CK14 and CK13 (100%) but negative for CK8/18.

In neoplastic tissues, p63 was diffusely expressed in all cases of esophageal squamous cell dysplasia and carcinoma but was negative in all cases of esophageal and colorectal adenocarcinoma. The N isoform of p63 mRNA predominated in all benign and neoplastic squamous tissues examined. p63 may represent a marker of 2 distinct epithelial progenitor cells (basal squamous epithelium and gland duct epithelium) in the esophagus. P63 is upregulated in squamous neoplastic conditions and in this manner may play a role in squamous carcinogenesis.

These data also indicate that multilayered epithelium is phenotypically similar to, and may share a lineage relationship with, mucosal gland duct epithelium.


Variable depending on stage Early lesions may be indistinguishable from Barrett's
May progress to larger fungating and exophytic tumors
Adenocarcinoma arising from heterotopic gastric mucosa (Inlet patch) Inlet patch is a congenital condition occurring in about 4% of patients
Usually occurs in the upper 1/3 of the esophagus
Adenocarcinoma of submucosal glands Most resemble adenoid cystic carcinomas, see squamous cell carcinoma


Intestinal type Majority of adenocarcinomas, resembling adenocarcinoma of the colon
Adenosquamous carcinoma Coexisting adenocarcinoma and squamous cell carcinoma
Aggressive tumor
Choriocarcinoma of the esophagus Large fungating tumors with extensive hemorrhage and widespread mets
Serum markers elevated with HCG
Classic histology of choriocarcinoma

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

van Sandick JW, van Lanschot JJ, ten Kate FJ, Offerhaus GJ, Fockens P, Tytgat GN, Obertop H.

Department of Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Cancer 2000 Jun 1;88(11):2429-37 Abstract quote

BACKGROUND: 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.

METHODS: 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.

RESULTS: 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).

CONCLUSIONS: 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.

Prevalence and Significance of Prominent Mucin Pools in the Esophagus Post Neoadjuvant Chemoradiotherapy for Barrett's-Associated Adenocarcinoma.

Hornick JL, Farraye FA, Odze RD.

From the *Department of Pathology, Brigham and Women's Hospital, Harvard Medical School; and daggerSection of Gastroenterology, Boston Medical Center, Boston University School of Medicine; Boston, MA.

Am J Surg Pathol. 2006 Jan;30(1):28-35. Abstract quote  

Occasionally, patients with Barrett's-associated adenocarcinoma who received preoperative chemoradiotherapy (chemrad) show prominent mucin pools in their resection specimen, but the prognostic significance of this finding has never been investigated.

The purpose of this study was to evaluate the clinical and pathologic features, and prognostic significance, of prominent mucin pools in 21 patients identified from a cohort of 192 consecutive cancer patients (prevalence rate, 10.9%) who had an esophagectomy (post-chemrad) for adenocarcinoma. The clinical and pathologic features and follow-up data were evaluated in 21 patients with adenocarcinoma of the esophagus and with prominent mucin pools (male-to-female ratio, 21:0; mean age, 61 years) and compared with a control group of 19 consecutive chemrad-treated and stage-matched esophageal adenocarcinoma patients who had either minimal microscopic (9 cases) or no (10 cases), residual disease present in their resection specimen (male-to-female ratio, 18:1; mean age, 62 years). Of the 21 study patients, 7 (33%) had acellular mucin pools with no residual tumor, 7 (33%) showed rare isolated tumor cells within mucin pools, and 7 (33%) had acellular mucin pools with microscopic foci of residual adenocarcinoma in tissue adjacent to, but not within, mucin pools. In total, 2 cases (9%) showed mucin pools limited to the submucosa, 5 (24%) showed involvement of the muscularis propria, and 14 (67%) showed mucin pools within the muscularis propria and adventitia. Four cases (19%) showed involvement of the radial resection margin with acellular mucin pools.

Thirteen study patients (62%) contained acellular mucin pools within regional lymph nodes. A significantly higher proportion of patients with prominent mucin pools had mucinous adenocarcinoma prior to neoadjuvant therapy, compared with control patients without mucin pools (12 of 21 (57%) vs. 1 of 19 (5%), P < 0.001). Upon follow-up (mean, 27 months; range, 5-84 months), none of the study patients with prominent mucin pools died of disease (0%), in comparison to 5 of 19 (26%) control patients (mean follow-up, 27 months; range, 3-64 months) (P = 0.02). None of the patients who had acellular mucin pools involving the radial margin developed recurrence or metastasis or died of disease.

Prominent mucin pools in resection specimens from patients with Barrett's esophagus-associated adenocarcinoma who received preoperative chemrad are associated with mucinous tumors and are not associated with poor survival, even when acellular mucin pools involve the radial margin, and, thus, should not be interpreted as evidence of residual viable adenocarcinoma.


CDC2/CDK1 Expression in Esophageal Adenocarcinoma and Precursor Lesions Serves as a Diagnostic and Cancer Progression Marker and Potential Novel Drug Target.

Hansel DE, Dhara S, Huang RC, Ashfaq R, Deasel M, Shimada Y, Bernstein HS, Harmon J, Brock M, Forastiere A, Washington MK, Maitra A, Montgomery E.

From the Departments of *Pathology, daggerBiology, paragraph signSurgery, and #Oncology, Johns Hopkins University School of Medicine, Baltimore, MD; double daggerDepartment of Pathology, University of Texas Southwestern Medical Center, Dallas, TX; section signDepartment of Surgery, Kyoto University, Kyoto, Japan; parallelDepartment of Pediatrics and Cancer Center, University of California San Francisco, San Francisco, CA; and **Department of Pathology, Vanderbilt University, Nashville, TN.
Am J Surg Pathol. 2005 Mar;29(3):390-399. Abstract quote  

Esophageal adenocarcinoma arises through well-defined precursor lesions (Barrett esophagus), although only a subset of these lesions advances to invasive adenocarcinoma. The lack of markers predicting progression in Barrett esophagus, typical presentation at advanced stage, and limitations of conventional chemotherapy result in >90% mortality for Barrett-associated adenocarcinomas.

To identify potential prognostic markers and therapeutic targets, we compared gene expression profiles from Barrett-associated esophageal adenocarcinoma cell lines (BIC1, SEG1, KYAE, OE33) and normal esophageal epithelial scrapings utilizing the Affymetrix U133_A gene expression platform.

We identified 560 transcripts with >3-fold up-regulation in the adenocarcinoma cell lines compared with normal epithelium. Utilizing tissue microarrays composed of normal esophageal squamous mucosa (n = 20), Barrett esophagus (n = 10), low-grade dysplasia (n = 14), high-grade dysplasia (n = 27), adenocarcinoma (n = 59), and node metastases (n = 27), we confirmed differential up-regulation of three proteins (Cdc2/Cdk1, Cdc5, and Igfbp3) in adenocarcinomas and Barrett lesions. Protein expression mirrored histologic progression; thus, 87% of low-grade dysplasias had at least focal surface Cdc2/Cdk1 and 20% had >5% surface staining; 96% of high-grade dysplasias expressed abundant surface Cdc2/Cdk1, while invasive adenocarcinoma and metastases demonstrated ubiquitous expression. Esophageal adenocarcinoma cell lines treated with the novel CDC2/CDK1 transcriptional inhibitor, tetra-O-methyl nordihydroguaiaretic acid (EM-1421, formerly named M4N) demonstrated a dose-dependent reduction in cell proliferation, paralleling down-regulation of CDC2/CDK1 transcript and protein levels.

These findings suggest a role for CDC2/CDK1 in esophageal adenocarcinogenesis, both as a potential histopathologic marker of dysplasia and a putative treatment target.

Identical cytokeratin expression pattern CK7+/CK20- in esophageal and cardiac cancer: etiopathological and clinical implications.

Driessen A, Nafteux P, Lerut T, Raemdonck DV, De Leyn P, Filez L, Penninckx F, Geboes K, Ectors N.

1Department of Pathology, University Hospital Maastricht, The Netherlands.
Mod Pathol. 2004 Jan;17(1):49-55. Abstract quote  

Surgical treatment and prognosis is different in esophageal, cardiac and distal gastric adenocarcinomas. Determination of the origin, in particular of adenocarcinomas situated at the gastroesophageal junction, may be difficult. It has been suggested that esophageal adenocarcinomas are characterized by a specific cytokeratin pattern, namely the CK7+/CK20- pattern. According to the same authors, this cytokeratin pattern is absent in gastric adenocarcinomas.

The aim of our study is to evaluate if this cytokeratin pattern CK7+/CK20- is absent in cardiac and distal gastric adenocarcinomas. Therefore, we evaluated the combined immunohistochemical expression of CK7 and CK20 on paraffin-embedded material of 214 resection specimens for adenocarcinoma, comprising 66 esophageal, 73 cardiac and 75 distal gastric adenocarcinomas (UICC-classification). The adenocarcinomas were subtyped into intestinal- and diffuse-type according to the Lauren classification. The immunohistochemical staining was considered as positive if 50% or more of the tumor cells were stained. Statistical analysis has been performed applying the chi(2)-test. The tumors situated at the gastroesophageal junction, esophageal as well as cardiac adenocarcinomas, showed predominantly a CK7+/CK20- expression pattern (67 vs 68%), whereas this cytokeratin pattern is rather uncommon in distal gastric adenocarcinomas (31%, P<4 x 10(-5)). Independent of their localization, intestinal- as well as diffuse-type adenocarcinomas have a similar cytokeratin pattern. Our data show that the combined expression of CK7 and CK20 is different for the adenocarcinomas situated on both sides of the gastroesophageal junction compared to the distal gastric adenocarcinomas.

However, in contrast to data in the literature, the combined expression of CK7 and CK20 has a low specificity in the distinction between esophageal and cardiac adenocarcinomas. This may suggest a similar origin (cell lineage) and thus may have an impact on therapeutic strategies.

Cytokeratin expression in adenocarcinomas of the esophagogastric junction: a comparative study of adenocarcinomas of the distal esophagus and of the proximal stomach.

Taniere P, Borghi-Scoazec G, Saurin JC, Lombard-Bohas C, Boulez J, Berger F, Hainaut P, Scoazec JY.

Am J Surg Pathol 2002 Sep;26(9):1213-21 Abstract quote

Adenocarcinomas of the esophagogastric junction form a heterogeneous group of tumors. We aimed to evaluate the value of the expression pattern of cytokeratins 7, 19, and 20 for their diagnosis and classification.

A total of 85 cases of adenocarcinoma of the distal esophagus and 67 cases of adenocarcinoma of the proximal stomach, defined on strict topographical criteria, were investigated. About 90% of the adenocarcinomas of distal esophagus were positive for cytokeratins 7 and 19, in contrast to <45% of the adenocarcinomas of proximal stomach (p <0.01); 17.6% of the adenocarcinomas of the distal esophagus and 55.2% of the adenocarcinomas of the proximal stomach expressed cytokeratin 20 (p <0.01); and 74.1% of the adenocarcinomas of the distal esophagus and 23.8% of the adenocarcinomas of the proximal stomach had a CK7+/CK20- immunophenotype (p <0.01). In intestinal-type tumors a CK7+/CK20- immunophenotype had a sensitivity of 76.5%, a specificity of 84.5%, and a predictive positive value of 87.3% for the diagnosis of adenocarcinoma of the distal esophagus.

Cytokeratin patterns are different in adenocarcinomas of the distal esophagus and in adenocarcinomas of the proximal stomach. A CK7+/CK20- pattern is highly suggestive of an esophageal origin and may be helpful for the correct classification of esophagogastric adenocarcinomas.


HIGH GRADE DYSPLASIA Invasion is the only reliable differentiating feature
Presence of single cells or small clumps of cells infiltrating the lamina propria, muscularis mucosae, or submucosa

Hyperplastic Polyps of the Esophagus and Esophagogastric Junction Histologic and Clinicopathologic Findings

Susan C. Abraham, M.D.; Vikesh K. Singh, M.D.; John H. Yardley, M.D.; Tsung-Teh Wu, M.D., Ph.D.

From the Division of Gastrointestinal/Liver Pathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A. therapy. Four patients (15%) had Barrett's esophagus, three of whom had or developed dysplastic Barrett's mucosa. These results underscore the pathogenesis of esophageal/EGJ region hyperplastic polyps as a mucosal regenerative response to surrounding mucosal injury. Careful clinical history and biopsy of the nonpolypoid mucosa are essential for determining the clinicopathologic context in which the polyps have developed.

Am J Surg Pathol 2001;25:1180-1187 Abstract quote

Hyperplastic polyps of the esophagus and esophagogastric junction region (EGJ) are uncommon lesions characterized by hyperplastic epithelium (foveolar-type, squamous, or both) with variable amounts of inflamed stroma. They have been reported almost exclusively in the radiologic and clinical literature as occurring predominantly in association with gastroesophageal reflux disease (GERD). Comprehensive histologic and clinicopathologic evaluation of these polyps, their association with background mucosal pathology, and their association with Barrett's esophagus has not been previously performed.

We studied 30 hyperplastic polyps from 27 patients and characterized the histologic, endoscopic, and clinical features of both the polyps and the background esophagus. Hyperplastic polyps were most common in the region of the EGJ (67%), followed by the distal esophagus (30%) and mid-esophagus (3%). Most (80%) were composed of predominantly cardiac-type mucosa, predominantly squamous mucosa (17%), or an admixture (3%). Intestinal metaplasia of the polyp was present in only 7% and low-grade dysplasia in only 3%. In the majority of cases (67%) hyperplastic polyps were associated with concurrent or recent ulcers or erosive esophagitis. In most cases (48%) esophageal injury was associated with GERD, but other potential etiologies included medications, infection, anastomotic or polypectomy sites, vomiting, and photodynamic therapy. Four patients (15%) had Barrett's esophagus, three of whom had or developed dysplastic Barrett's mucosa.

These results underscore the pathogenesis of esophageal/EGJ region hyperplastic polyps as a mucosal regenerative response to surrounding mucosal injury. Careful clinical history and biopsy of the nonpolypoid mucosa are essential for determining the clinicopathologic context in which the polyps have developed.

Adenocarcinoma of the Esophagus and Gastric Cardia: Two Diseases or One?

Sanjay Kakar, MD; Lawrence J. Burgart, MD

From the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.

Pathol Case Rev 2002;7:43-47 Abstract quote

Adenocarcinomas situated near the gastroesophageal junction can be classified as esophageal, cardial or subcardial depending on the anatomic location of the tumor. There is debate about the pathogenesis of adenocarcinoma arising in the proximal stomach/cardia. Do such neoplasms parallel the distal stomach, arising because of chronic gastritis related to Helicobacter pylori? Or are they similar to adenocarcinomas of the distal esophagus, developing in mucosa injured by chronic gastroesophageal reflux.

This review describes the molecular profiles of adenocarcinomas at three sites—esophagus, gastroesophageal junction (including gastric cardia) and distal stomach—to see whether junctional neoplasms have a constellation of genetic abnormalities more like those arising in Barrett’s esophagus or those of the stomach. This approach depends on the premise that differences in molecular pathogenesis reflect differences in the inciting insult rather than regional variations in the underlying mucosa. This premise is supported by experience at other sites (e.g., liver) where specific molecular abnormalities are associated with specific etiologic agents, and by the commonality of the precursor lesion (intestinal metaplasia) in the esophagus and stomach, which should largely negate differences of underlying mucosa. The literature indicates that adenocarcinoma of the proximal stomach/cardia demonstrates a pattern of genetic abnormality, which is intermediate between those of distal cancer and Barrett’s-type cancer.

Our interpretation is that cardia adenocarcinomas can and do arise as a result of either mechanism. The possibility that both mechanisms may contribute to individual tumors can not be excluded by these data. Pathogenetic mechanisms unique to cardia adenocarcinomas have not been described.


PROGNOSIS Stage is the most factor
Significance of the Depth of Tumor Invasion and Lymph Node Metastasis in Superficially Invasive (T1) Esophageal Adenocarcinoma.

Liu L, Hofstetter WL, Rashid A, Swisher SG, Correa AM, Ajani JA, Hamilton SR, Wu TT.

From the Departments of *Pathology, daggerThoracic and Cardiovascular Surgery, and double daggerGI Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX.
Am J Surg Pathol. 2005 Aug;29(8):1079-1085. Abstract quote  

Superficially invasive esophageal adenocarcinomas are a heterogeneous group of tumors, including tumors invading into mucosa and submucosa. The prognostic significance of the depth of tumor invasion and lymph node status in this group of patients remain unclear.

We evaluated 90 consecutive patients with resected T1 adenocarcinoma of esophagus or esophagogastric junction. The T1 tumors were classified into four groups based on the depth of invasion: T1a, invading into lamina propria; T1b, into muscularis mucosae; T1c, into superficial submucosa; and T1d, into deep submucosa. The depth of tumor invasion was compared with clinicopathologic features. The depth of tumor invasion was significantly associated with the presence of lymph node metastasis (36% in T1d, 8% in T1c, 12% in T1b, and 0% in T1a; P < 0.001) and with tumor size (76% > 1.2 cm in T1d, 75% in T1c, 35% in T1b, and 25% in T1a; P < 0.001). The 5-year recurrence-free and overall survivals were significantly better in patients with tumors confined to mucosa (100% and 91%, respectively) than invasive into submucosa (60% and 58%; P = 0.0005 and P = 0.02, respectively).

Lymph node metastasis was associated with tumor recurrence (P = 0.01) but not overall survival. Lymphovascular invasion was associated with both tumor recurrence (P = 0.001) and overall survival (P < 0.001) and was an independent prognostic factor in multivariate analysis (P = 0.04).

Our study indicated evaluation of depth of tumor invasion, status of lymph nodes, and lymphovascular invasion is important in resected superficially invasive esophageal adenocarinoma and may provide supportive information for the decision about postoperative adjuvant therapy.

Outcome of surgical treatment of adenocarcinoma in Barrett's oesophagus.

Menke-Pluymers MB, Schoute NW, Mulder AH, Hop WC, van Blankenstein M, Tilanus HW.

Department of Surgery, University Hospital, Rotterdam-Dijkzigt, The Netherlands.

Gut 1992 Nov;33(11):1454-8 Abstract quote

A retrospective study was performed of an 11 year period (1978-88) to analyse the survival of 112 patients (85 men and 27 women, mean age 63 years) with adenocarcinoma in a columnar lined (Barrett's) oesophagus in respect of surgical treatment, tumour staging, and histological grading.

Presenting symptoms were dysphagia (60%) and pain (25%). Only six patients were previously known to have a columnar lined oesophagus. Eighty five patients (76%) underwent partial resection of the oesophagus and cardia. Postoperative mortality was 6%. After resection (n = 85), the 5 year survival was 24%. Survival was significantly better for patients without regional lymph node metastases (stage 0, I, IIA (n = 61): 5 year survival 30%) and even better if the tumour was restricted to the submucosa (stage 0, I (n = 12): 5 year survival 63%). Survival was not influenced by the histological grade of the tumour.

Staging based on infiltration of the oesophageal wall and lymph node spread is valuable in determining the prognosis for patients with adenocarcinoma in Barrett's oesophagus.

Prognostic factors of resected adenocarcinoma of the esophagus.

Holscher AH, Bollschweiler E, Bumm R, Bartels H, Hofler H, Siewert JR.

Department of Surgery, Technische Universitat Munchen, Klinikum rechts der Isar, Germany.

Surgery 1995 Nov;118(5):845-55 Abstract quote

BACKGROUND. The main purpose of this study was to determine prognostic factors in patients with surgical treatment of adenocarcinoma of the esophagus.

METHODS. Within a 12.5-year period, esophageal adenocarcinoma was resected in 165 patients by radical transhiatal esophagectomy (n = 134) or transthoracic en bloc esophagectomy (n = 31). Tumors were analyzed according to the 1992 UICC classification with respect to pTNM stage, residual tumor (R) status, grading, and ratio of infiltrated to resected lymph nodes (lymph node ratio); both univariate and multivariate analysis of prognostic factors were performed.

RESULTS. The 30-day mortality rate was 6.1%. A complete removal of the tumor was achieved in 83% of the patients. Lymph node metastases were not detected in mucosal cancer (pT1a) but were detected in 18% of submucosal cancer (pT1b), 77% of pT2, 83% of pT3, and 96% of pT4. The overall 5-year survival rate was 34%; for patients without postoperative residual tumor (R0) it was 41%, and for those without lymph node metastases (pN0, R0) 63%. The 5-year survival rate for patients (pN1) with less than 30% invaded lymph nodes was 45%, compared with 0% for more than 30% invaded nodes. Independent prognostic factors for R0 resected patients excluding postoperative fatal outcome were pT and lymph node ratio.

CONCLUSIONS. Long-term survival after resection of esophageal adenocarcinoma is mainly associated with complete tumor removal, limited esophageal wall penetration, and ratio of infiltrated to removed lymph nodes of less than 0.3.


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

Osterheld MC, Bian YS, Bosman FT, Benhattar J, Fontolliet C.

Institute of Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

Am J Clin Pathol 2002 Mar;117(3):451-6 Abstract quote

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.

Endoglin (CD105) and vascular endothelial growth factor as prognostic markers in esophageal adenocarcinoma.

Saad RS, El-Gohary Y, Memari E, Liu YL, Silverman JF.

Department of Pathology, Allegheny General Hospital, Drexel University College of Medicine, Pittsburgh, PA 15213, USA.

Hum Pathol. 2005 Sep;36(9):955-61 Abstract quote.  

Endoglin (CD105), a member of transforming growth factor beta1 receptor complex, has been shown to be a more useful marker to identify tumor angiogenesis than panendothelial markers such as CD31.

We investigated endoglin and vascular endothelial growth factor (VEGF) expression as possible prognostic markers in esophageal adenocarcinoma. Surgical specimens from 75 patients with esophageal adenocarcinoma treated with esophagectomy were immunostained for endoglin, CD31, and VEGF. We also included 10 cases of Barrett's esophagus with high-grade dysplasia and 10 cases with Barrett's esophagus low-grade dysplasia. Positively stained microvessels (MVs) were counted in hot spots at magnification of x400. Results were expressed as the highest number of MV identified. For VEGF, intensity of staining was scored on 3-tiered scale. Endoglin demonstrated significantly more vessels than the CD31 (mean, 28.9 +/- 13.2 versus 19.0 +/- 9.4, P < .001). Both endoglin and CD31 MV counts showed significant correlation with stage of the disease (r = 0.59, P < .001; r = 0.52, P < .001, respectively) and patient survival (log rank P < .01). Only endoglin MV count was significantly correlated with the presence of angiolymphatic invasion (r = 0.34, P < .05) and lymph node (LN) metastases (r = 0.48, P < .001). Univariate analysis showed that endoglin MV count is an independent prognostic factor. Endoglin showed a significant increase in MV count in Barrett's esophagus with high-grade dysplasia when compared with Barrett's esophagus low-grade dysplasia (P < .01), whereas CD31 did not show any significant difference. VEGF was expressed in 48 (64%) of 75 cases of adenocarcinoma and was significantly correlated with angiolymphatic invasion, LN metastases, and survival.

In conclusion, endoglin is a specific and sensitive marker for tumor angiogenesis. Endoglin staining also showed prognostic significance with positive correlation with the presence of angiolymphatic invasion, LN metastases, tumor stage, and survival.
Overexpression of decoy receptor 3 in precancerous lesions and adenocarcinoma of the esophagus.

Li H, Zhang L, Lou H, Ding I, Kim S, Wang L, Huang J, Sant'agnese PA, Lei JY.

Department of Pathology, Zhengzhou University School of Medicine, Henan, China.
Am J Clin Pathol. 2005 Aug;124(2):282-7. Abstract quote  

Overexpression of decoy receptor (DcR) 3 protein, a recently discovered member of the tumor necrosis factor receptor superfamily, was examined in 40 esophagogastrectomy specimens containing areas of Barrett esophagus (n = 27), low-grade dysplasia (n = 27), high-grade dysplasia or carcinoma in situ (n = 22), and esophageal adenocarcinoma (EAC; n = 28) with immunohistochemical analysis.

The results revealed significantly more overexpression of DcR3 in high-grade dysplasia or carcinoma in situ and EAC than in benign esophageal mucosa (both P < .0001), Barrett esophagus (both P < .001), and low-grade dysplasia (P < .01 and P = .033, respectively). Low-grade dysplasia also showed significant overexpression of DcR3 compared with benign esophagus (P < .05) but not with Barrett esophagus (P > .05). DcR3 overexpression seems to negatively correlate with the grade of EAC.

Our results suggest that overexpression of DcR3 protein might aid in the diagnosis of high-grade dysplasia or carcinoma in situ and EAC and also might serve as a potential therapeutic target.

Prevalence and location of nodal metastases in distal esophageal adenocarcinoma confined to the wall: implications for therapy.

Nigro JJ, Hagen JA, DeMeester TR, DeMeester SR, Peters JH, Oberg S, Theisen J, Kiyabu M, Crookes PF, Bremner CG.

University of Southern California, Department of Surgery, Los Angeles, Calif.90033-4612, USA.

J Thorac Cardiovasc Surg 1999 Jan;117(1):16-23; discussion 23-5 Abstract quote

OBJECTIVE: The purpose of this study was to characterize the prevalence and location of regional lymph node metastases in adenocarcinoma confined to the esophagal wall, to determine the extent of dissection required, and to investigate the applicability of nonoperative therapy.

METHODS: Histologic evaluation of the resected specimens after en bloc esophagogastrectomy with mediastinal and abdominal lymphadenectomy was performed on 37 patients with adenocarcinoma confined to the esophageal wall. Follow-up was complete in all patients (median 24 months).

RESULTS: Fifteen patients (41%) had intramucosal tumors. Twelve (32%) had submucosal tumors and 10 (27%) had muscular invasion. The prevalence of regional lymph node metastases (15/37 patients, 41%) increased progressively with depth of tumor invasion, with involved nodes identified in 80% of patients with muscular invasion. Lymph node metastases were also more common at distant node stations in intramuscular tumors (5/10, 50%). Actuarial survival for the entire group was 63% at 5 years. Recurrence was identified in 6 of the 37 patients (16%), with the risk of recurrence correlating with tumor depth.

CONCLUSIONS: Tumor depth is a strong predictor of the probabilities of regional lymph node metastases, the likelihood of involvement of distant node groups, and the risk of recurrence. Patients with invasion of the muscular wall are at particularly high risk. En bloc esophagectomy with mediastinal and abdominal lymphadenectomy has the highest likelihood of achieving an R0 resection. The long-term survival and low recurrence rate achieved with an en bloc esophagectomy emphasizes the importance of an aggressive lymph node dissection to remove all potentially involved nodes.

Node status in transmural esophageal adenocarcinoma and outcome after en bloc esophagectomy.

Nigro JJ, DeMeester SR, Hagen JA, DeMeester TR, Peters JH, Kiyabu M, Campos GM, Oberg S, Gastal O, Crookes PF, Bremner CG.

University of Southern California, Departments of Surgery and Cardiothoracic Surgery, Los Angeles, CA, USA.

J Thorac Cardiovasc Surg 1999 May;117(5):960-8 Abstract quote

OBJECTIVE: Adenocarcinoma has replaced squamous cell as the most common esophageal cancer in the United States. The purpose of this study was to determine the prevalence and location of lymph node metastases, the feasibility of performing an R0 resection, and disease recurrence and survival in patients with transmural adenocarcinoma of the lower esophagus and gastroesophageal junction.

METHODS: Forty-four patients with transmural adenocarcinoma underwent en bloc esophagectomy with systematic thoracic and abdominal lymphadenectomy. They were followed up for a median of 23 months.

RESULTS: Actuarial survival for the entire group was 26% at 5 years. The most important predictors of the likelihood of recurrent disease and 5-year survival were the presence and number of lymph node metastases and the ratio of involved to total removed nodes. Seven patients (16%) were found to have no lymph node metastases and had an 85% 5-year survival. In contrast, patients with more than 4 involved nodes or a node ratio greater than 0.1 had a high likelihood of recurrence and death. Location of involved lymph nodes did not predict the likelihood of recurrence or death. Despite all patients having transmural tumors, recurrence within the field of the en bloc resection occurred in only 1 patient (2%).

CONCLUSIONS: En bloc esophagectomy in patients with transmural esophageal adenocarcinoma is required to obtain the survival benefit of an R0 resection, to adequately assess lymphatic tumor burden, and to be able to predict the likelihood of recurrence and death and thereby guide the use of postoperative adjuvant therapy.

Ratio of invaded to removed lymph nodes as a prognostic factor in adenocarcinoma of the distal esophagus and esophagogastric junction.

Saha S, Dehn TC.

Department of Surgery, Royal Berkshire Hospital, Reading, UK.

Dis Esophagus 2001;14(1):32-6 Abstract quote

This study examined the influence of nodal harvest and the proportion of positive nodes on survival in 59 patients with adenocarcinoma of the distal esophagus and esophagogastric junction undergoing esophagectomy with curative intent.

A total of 754 lymph nodes were harvested (median 13, range 0-28). Two hundred and twenty-eight positive nodes were found on histology (median 4, range 1-23) in 43 (79%) patients with a higher incidence from T3/T4 than T1/T2 lesions (P < 0.003). Overall 1- and 3-year survival rates were 73% and 47% respectively. Node positivity increased with increased total nodal harvest, but was not influenced by the site of tumors or surgical approaches. There was no survival benefit for patients with <20% over >20% nodal positivity (P=0.31). Only negative lateral resection margin emerged as a significant factor in both univariate (P < 0.01) and multivariate analysis (P < 0.05).

We conclude that the degree of nodal positivity in adenocarcinoma is less important than resection margin status as a prognostic factor.

The pattern of metastatic lymph node dissemination from adenocarcinoma of the esophagogastric junction.

Dresner SM, Lamb PJ, Bennett MK, Hayes N, Griffin SM.

Northern Esophago-Gastric Cancer Unit, Royal Victoria Infirmary, Newcastle upon Tyne, UK.

Surgery 2001 Jan;129(1):103-9 Abstract quote

BACKGROUND: The incidence of adenocarcinoma of the esophagogastric junction is rapidly increasing, and the extent of lymphadenectomy for such tumors remains controversial. The aim of this study was to identify the pattern of dissemination by examination of all lymph nodes retrieved from resected tumors of the esophagogastric junction.

METHODS: The endoscopic and pathologic reports of patients who underwent RO resection for adenocarcinoma of the esophagogastric junction between January 1996 and November 1999 were examined. Patients with type 1 tumors (distal esophagus) underwent subtotal esophagectomy with 2-field lymphadenectomy. Patients with type 2 (gastric cardia) tumors underwent transhiatal D2 total gastro-esophagectomy. Lymph node groups were dissected from the main specimens and examined separately.

RESULTS: One hundred and four type 1 and 48 type 2 tumors were studied. Median nodal recovery was 23 lymph nodes (type 1, 22 lymph nodes; type 2, 23 lymph nodes). Seventy-eight percent of the type 1 tumors with nodal metastases had dissemination in both the abdomen and mediastinum. The common abdominal sites were the paracardiac and the left gastric stations. Within the mediastinum, paraesophageal, paraaortic and tracheobronchial metastases were more often encountered. Type 2 tumors had positive lymph nodes most frequently in the left and right paracardiac, lesser curve (N1 group), and left gastric (N2 group) territories. Nodal status correlated with increasing depth of tumor invasion (P =.002).

CONCLUSIONS: The pattern of nodal dissemination for cardia tumors concurs with that described by other studies. The current definition of nodal fields in the abdomen and mediastinum for esophageal tumors relates to experience with squamous carcinomas. Our results demonstrate a different pattern of dissemination for junctional esophageal adenocarcinomas. The nodal stations to be resected in radical lymphadenectomies for such tumors should be redefined.

5 Year Survival 25%

Prognosis of early esophageal cancer. Comparison between adeno- and squamous cell carcinoma.

Holscher AH, Bollschweiler E, Schneider PM, Siewert JR.

Department of Surgery, Technische Universitat Munchen, Germany.

Cancer 1995 Jul 15;76(2):178-86 Abstract quote

BACKGROUND. The purpose of this study was to compare the prognosis of patients with T1 squamous cell carcinoma (SCC) with those with T1 adenocarcinoma of the esophagus and to explain prognostic differences by an analysis of clinicopathologic characteristics.

METHODS. Seventy-seven patients with early esophageal cancer who underwent esophagectomy and lymphadenectomy from 1982 to 1993 were included in the study. Clinical and histopathologic characteristics, patterns of lymph node metastasis, results of surgery, and long term prognosis of 47 patients with SCC were compared with 30 patients with adenocarcinoma; a multivariate analysis of various prognostic factors was performed.

RESULTS. The groups with adenocarcinoma and SCC were comparable regarding age, postoperative 90-day mortality (6.6% vs. 8.5%), infiltration of submucosa (74.5% vs. 80%), and rate of lymph node metastasis (17% vs. 16.6%). Cancer limited to the mucosa was not associated with lymph node metastasis in either group, whereas submucosal spread showed lymph node involvement in 21% of patients with adenocarcinoma and 26% of those with SCC. The 5-year survival rate of patients with complete tumor removal was superior for those with adenocarcinoma (82.5%) compared with those with SCC (59.2%) (P < 0.03). Multivariate analysis indicated that the histopathologic type (adenocarcinoma vs. SCC) was the only independent prognostic factor. The unfavorable prognosis of patients with T1 SCC was due to a higher recurrence rate and the more frequent development of second primary tumors (21% vs. 0%).

CONCLUSIONS. The prognosis of patients with early esophageal cancer depends on the histologic tumor type. Patients with T1 SCC should be examined for another primary cancer before surgery and during follow-up.

Metastasis In general, behave similar to squamous cell carcinoma of the esophagus
Tend to spread proximally in the submucosal lymphatics and present in the resection margin in 1/3 of cases
Lymph node mets common in 75% of cases
Invasion into the tracheobronchial tree
Excellent Interobserver Agreement on Grading the Extent of Residual Carcinoma After Preoperative Chemoradiation in Esophageal and Esophagogastric Junction Carcinoma: A Reliable Predictor for Patient Outcome.

Departments of *Pathology daggerBrigham and Women Hospital, Boston MA double daggerMayo Clinic, Rochester, MN section signUniversity of Pittsburgh, Pittsburgh, PA parallelDepartments of Thoracic and Cardiovascular Surgery paragraph signGI Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX.

Am J Surg Pathol. 2007 Jan;31(1):58-64 Abstract quote

The extent of residual carcinoma in resected esophageal cancer specimens after preoperative chemoradiation is a predictor of survival according to 3 groups: P0 (0% residual carcinoma), P1 (1% to 50% residual carcinoma), and P2 (>50% residual carcinoma). However, the interobserver variation and reliability of this classification has not been evaluated among different pathologists.

Histologic hematoxylin and eosin-stained slides from 60 coded cases of esophageal adenocarcinomas treated with preoperative chemoradiation followed by esophagectomy were independently reviewed by 6 pathologists from 4 different institutions for extent of residual carcinoma and ypT stage. Interobserver agreement was analyzed by kappa (kappa) statistics, and grading of extent of residual carcinoma and ypT stage based on individual and consensus gradings were correlated with patients' survival.

The interobserver agreement was excellent for extent of residual carcinoma (kappa=0.84, Kendall's W=0.92; P<0.000001) and was good for ypT stage (kappa=0.71, Kendall's W=0.88; P<0.000001). Agreement was excellent for all categories of residual carcinoma: P0 (kappa=0.87), P1 (kappa=0.81), and P2 (kappa=0.85). Extent of residual carcinoma was a significant predictor for overall survival based on individual pathologist grading (all P values <0.03), and consensus grading (13 P0, 32 P1, and 15 P2), P=0.004; independent of ypT and ypN stages in multivariate analysis (P=0.02).

Our results indicate that after preoperative chemoradiation in esophageal cancer there is excellent interobserver agreement among pathologists on grading extent of residual carcinoma. The extent of residual carcinoma is a reliable and reproducible predictor of survival; this grading system may allow a novel and early means of comparing outcomes after different neoadjuvant treatment regimens.
Adjuvant chemotherapy and radiotherapy
Histopathologic Aspects of Photodynamic Therapy for Dysplasia and Early Adenocarcinoma Arising in Barrett's Esophagus.

Ban S, Mino M, Nishioka NS, Puricelli W, Zukerberg LR, Shimizu M, Lauwers GY.

From the Departments of *Pathology, Gastrointestinal Pathology Service, and double daggerMedicine (Gastrointestinal Unit), Massachusetts General Hospital, Boston, MA; and daggerDepartment of Pathology, Saitama Medical School, Saitama, Japan
Am J Surg Pathol. 2004 Nov;28(11):1466-1473. Abstract quote  

The efficacy of photodynamic therapy (PDT) is currently evaluated for the treatment of superficial neoplasms arising in Barrett's esophagus (BE). An accurate assessment of this technique requires the evaluation of biopsies before and after treatment. However, despite the importance of pathology, only a limited number of studies have systematically assessed the mucosal changes after PDT.

To evaluate mucosal changes after PDT, and pathologic variables that may impact on the success of this therapy, we analyzed the pre- and post-PDT biopsies of a cohort of patients treated by this modality. Thirty-three patients (mean age, 71 years) with high-grade dysplasia (HGD) and/or intramucosal carcinoma (IMC) arising in BE and followed up after PDT using Porfimer sodium form the basis of this study. In all patients, a review of all pre- and post-PDT biopsies was performed. The variables recorded included the histologic grade and architecture of neoplasms, the distribution of neoplasms, and squamous re-epithelialization. IMC and HGD coexisted in the pre-PDT biopsies of 18 patients (54.5%). IMC and HGD showed a prominent tubular proliferation in 14 patients and displayed a papillary pattern (at least partially) in 19 patients. In post-PDT, patches of specialized columnar epithelium were buried under squamous epithelium in 17 patients (51.5%), and foci of dysplasia/carcinoma covered by squamous epithelium were found in 9 patients (27.3%). HGD and/or IMC were eradicated in 17 patients (eradicated group) and persisted in 16 patients (persistent group). In the persistent group, grade and architecture were unchanged after PDT in 62.5% and 87.5% of patients, respectively. The persistent group was characterized by: 1) a more frequent papillary architecture (P < 0.05), and 2) a diffuse distribution of the neoplasms on pre-PDT biopsies (P = 0.05). Singularly, the persistent neoplastic lesions were observed in the distal esophagus (P < 0.05).

A systematic histopathologic evaluation allowed us to draw attention to the fact that distally located and papillary-type neoplasia seem resistant to PDT. The higher than expected incidence of buried residual neoplastic epithelium should also be emphasized since it represents a risk for undetected growth of malignancy.

Radical esophageal resection for adenocarcinoma arising in Barrett's esophagus.

Collard JM, Romagnoli R, Hermans BP, Malaise J.

Department of Surgery, Louvain Medical School, Brussels, Belgium.

Am J Surg 1997 Sep;174(3):307-11 Abstract quote

BACKGROUND: Esophagectomy with extensive lymph node dissection is the best way to give Barrett's patients with locally advanced adenocarcinoma a good chance of cure.

MATERIAL AND METHODS: Fifty-five patients underwent subtotal (n = 47) or distal (n = 8) esophagectomy for Barrett's adenocarcinoma (n = 43) or high-grade dysplasia (HGD) (n = 12). Thirteen patients (23.6%) never had had any reflux symptom before disclosure of the neoplastic lesion, and 20 patients (36.4%) had esophageal shortening. Ro resections (n = 50) included removal of the esophageal tube en bloc with the locoregional lymph nodes.

RESULTS: An invasive carcinoma was found in the resected specimen of 4 of the 12 patients operated on for HGD. Two of the 5 patients whose metaplasia was surveyed endoscopically were operated on for an advanced lesion (T2N1, T3N1) because they had not strictly complied with the proposed schedule. One of the 4 patients whose HGD was followed up endoscopically until disclosure of deeper mucosal invasion had positive lymph nodes at operation. The prevalence of early lesions (Tis, T1, T2, No) was 7.4% in patients with tumor-related symptoms versus 85.7% in those having unrelated symptoms (P = 0.0000), which resulted in a 5-year survival rate of 33.8% and 82.4%, respectively (P = 0.0012). Five-year survival rate after Ro resection made for invasive carcinoma was 59.3% (all cases), 73.1% (No), 61.5% (< or =5 positive lymph nodes), and 0% (>5 positive lymph nodes).

CONCLUSIONS: High-grade dysplasia is an indication for esophageal resection. Early detection of the neoplastic transformation of Barrett's metaplasia prior to the onset of obstructive symptoms gives the best chance of cure. Esophagectomy with radical lymph node clearance is capable of curing a large proportion of the patients having no or a limited number of metastatic lymph nodes.

Limited resection for early adenocarcinoma in Barrett's esophagus.

Stein HJ, Feith M, Mueller J, Werner M, Siewert JR.

Chirurgische Klinik und Poliklinik, and the Institut fur Pathologie und Pathologische Anatomie, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany.

Ann Surg 2000 Dec;232(6):733-42 Abstract quote

OBJECTIVE: To assess the extent of disease in patients with pT1 esophageal adenocarcinoma and to evaluate the feasibility and outcomes of a limited surgical approach.

SUMMARY BACKGROUND DATA: Radical esophagectomy with systematic lymphadenectomy is widely advocated as the treatment of choice in patients with early adenocarcinoma of the distal esophagus. This approach, however, is associated with substantial complications and long-term side effects. The extent of resection necessary to achieve cure in such patients is not clear.

METHODS: Seventy-one patients with pT1 adenocarcinoma of the distal esophagus underwent transmediastinal or transthoracic esophagectomy with two-field lymphadenectomy. Twenty-four patients with uT1N0 tumors underwent a limited resection of the distal esophagus and esophagogastric junction, regional lymphadenectomy, and reconstruction by interposition of an isoperistaltic pedicled jejunal segment. The two groups were compared for extent and multicentricity of the primary tumor and associated high-grade dysplasia, pattern of lymph node metastases, complications, deaths, and outcome of surgical treatment.

RESULTS: Multicentric tumor growth or associated high-grade dysplasia was observed in 60.6% of the resection specimens. Complete resection of the tumor and the entire segment with intestinal metaplasia was achieved in all patients, irrespective of the surgical approach. Patients undergoing limited resection had fewer complications. Lymph node metastases or micrometastases were present in none of the 38 patients with tumors limited to the mucosa (pT1a) versus 10 of the 56 (17.9%) patients with tumors invading the submucosa (pT1b). Distant lymph node metastases occurred only in patients with more than three positive regional lymph nodes. Lymph node metastases were prognostic, but the pT1a/pT1b category and the surgical approach were not. The mean Gastrointestinal Quality of Life Index after limited resection did not differ from that of healthy controls: 20 of the 24 patients were completely asymptomatic.

CONCLUSIONS: In patients with early adenocarcinoma in the distal esophagus, resection of the distal esophagus and esophagogastric junction, with regional lymphadenectomy and jejunal interposition, is an attractive limited surgical alternative to radical esophagectomy.

Adenocarcinoma of the esophagogastric junction: results of surgical therapy based on anatomical/topographic classification in 1,002 consecutive patients.

Rudiger Siewert J, Feith M, Werner M, Stein HJ.

Chirurgische Klinik und Poliklinik and Institut fur Pathologie und Pathologische Anatomie, Klinikum rechts der Isar, Technische Universitat Munchen, Munich, Germany.

Ann Surg 2000 Sep;232(3):353-61 Abstract quote

OBJECTIVE: To assess the outcome of surgical therapy based on a topographic/anatomical classification of adenocarcinoma of the esophagogastric junction.

SUMMARY BACKGROUND DATA: Because of its borderline location between the stomach and esophagus, the choice of surgical strategy for patients with adenocarcinoma of the esophagogastric junction is controversial.

METHODS: In a large single-center series of 1,002 consecutive patients with adenocarcinoma of the esophagogastric junction, the choice of surgical approach was based on the location of the tumor center or tumor mass. Treatment of choice was esophagectomy for type I tumors (adenocarcinoma of the distal esophagus) and extended gastrectomy for type II tumors (true carcinoma of the cardia) and type III tumors (subcardial gastric cancer infiltrating the distal esophagus). Demographic data, morphologic and histopathologic tumor characteristics, and long-term survival rates were compared among the three tumor types, focusing on the pattern of lymphatic spread, the outcome of surgery, and prognostic factors in patients with type II tumors.

RESULTS: There were marked differences in sex distribution, associated intestinal metaplasia in the esophagus, tumor grading, tumor growth pattern, and stage distribution between the three tumor types. The postoperative death rate was higher after esophagectomy than extended total gastrectomy. On multivariate analysis, a complete tumor resection (R0 resection) and the lymph node status (pN0) were the dominating independent prognostic factors for the entire patient population and in the three tumor types, irrespective of the surgical approach. In patients with type II tumors, the pattern of lymphatic spread was primarily directed toward the paracardial, lesser curvature, and left gastric artery nodes; esophagectomy offered no survival benefit over extended gastrectomy in these patients.

CONCLUSION: The classification of adenocarcinomas of the esophagogastric junction into type I, II, and III tumors shows marked differences between the tumor types and provides a useful tool for selecting the surgical approach. For patients with type II tumors, esophagectomy offers no advantage over extended gastrectomy if a complete tumor resection can be achieved.

Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction.

Macdonald JS, Smalley SR, Benedetti J, Hundahl SA, Estes NC, Stemmermann GN, Haller DG, Ajani JA, Gunderson LL, Jessup JM, Martenson JA.

St Vincent's Comprehensive Cancer Center, New York, USA.

N Engl J Med 2001 Sep 6;345(10):725-30 Abstract quote

BACKGROUND: Surgical resection of adenocarcinoma of the stomach is curative in less than 40 percent of cases. We investigated the effect of surgery plus postoperative (adjuvant) chemoradiotherapy on the survival of patients with resectable adenocarcinoma of the stomach or gastroesophageal junction.

METHODS: A total of 556 patients with resected adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to surgery plus postoperative chemoradiotherapy or surgery alone. The adjuvant treatment consisted of 425 mg of fluorouracil per square meter of body-surface area per day, plus 20 mg of leucovorin per square meter per day, for five days, followed by 4500 cGy of radiation at 180 cGy per day, given five days per week for five weeks, with modified doses of fluorouracil and leucovorin on the first four and the last three days of radiotherapy. One month after the completion of radiotherapy, two five-day cycles of fluorouracil (425 mg per square meter per day) plus leucovorin (20 mg per square meter per day) were given one month apart.

RESULTS: The median overall survival in the surgery-only group was 27 months, as compared with 36 months in the chemoradiotherapy group; the hazard ratio for death was 1.35 (95 percent confidence interval, 1.09 to 1.66; P=0.005). The hazard ratio for relapse was 1.52 (95 percent confidence interval, 1.23 to 1.86; P<0.001). Three patients (1 percent) died from toxic effects of the chemoradiotherapy; grade 3 toxic effects occurred in 41 percent of the patients in the chemoradiotherapy group, and grade 4 toxic effects occurred in 32 percent.

CONCLUSIONS: Postoperative chemoradiotherapy should be considered for all patients at high risk for recurrence of adenocarcinoma of the stomach or gastroesophageal junction who have undergone curative resection.

Long-term survival following induction chemoradiotherapy and esophagectomy for esophageal carcinoma.

Lew JI, Gooding WE, Ribeiro U Jr, Safatle-Ribeiro AV, Posner MC.

Department of Surgery, The University of Chicago Hospitals, and the Pritzker School of Medicine, 5841 S Maryland Ave, MC 5031, Chicago, IL 60637, USA.

Arch Surg 2001 Jul;136(7):737-42; Abstract quote

HYPOTHESIS: Long-term survival is rare in patients treated for esophageal carcinoma. Several clinical trials suggest the possibility of prolonged survival in patients who undergo induction chemoradiotherapy plus esophagectomy.

DESIGN: Prospective uncontrolled study.

SETTING: University hospital.

PATIENTS AND METHODS: Forty-four patients with carcinoma of the esophagus or gastroesophageal junction were prospectively entered into a phase II trial of preoperative 5-fluorouracil, cisplatin, and interferon alfa with concurrent external beam radiotherapy before esophagectomy. Curative resection was performed on 36 of 41 patients who completed the induction chemoradiotherapy.

RESULTS: Of the 44 patients, 17 are alive at a median follow-up of 50 months. Of these 17 patients, 15 show no evidence of recurrent disease. Of the 14 patients with long-term survival (> or =3 years), 1 patient died of disease, and another patient is alive with disease. The remaining 12 patients are alive and disease-free (median follow-up, 54 months). Six patients have survived longer than 4 years and 3 patients longer than 5 years. Subsequent primary tumors have developed in 2 patients. One patient had a recurrence at 11 months following initiation of treatment and remains disease-free 43 months postresection of a single brain metastasis. Standard clinicopathologic parameters (age, sex, histologic findings, chemoradiotherapy regimen, and clinical and pathologic stages) were not significantly associated with a survival time of 3 years or longer (Fisher exact test, 2-tailed). Although not significant, p 53 mutational status suggested long-term survival. In 11 of 14 patients who are alive with no history of recurrence, p53 genotyping demonstrated no point mutations in 10 patients. Median survival time for the long-term survivors has not been reached.

CONCLUSIONS: Long-term survival can be achieved in patients with esophageal carcinoma who undergo induction chemoradiotherapy and esophagectomy. Recurrence is unlikely in patients who survive for 3 years or longer after undergoing this multimodality treatment.

A three-step strategy of induction chemotherapy then chemoradiation followed by surgery in patients with potentially resectable carcinoma of the esophagus or gastroesophageal junction.

Ajani JA, Komaki R, Putnam JB, Walsh G, Nesbitt J, Pisters PW, Lynch PM, Vaporciyan A, Smythe R, Lahoti S, Raijman I, Swisher S, Martin FD, Roth JA.

Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

Cancer 2001 Jul 15;92(2):279-86 Abstract quote

BACKGROUND: Patients with locoregional carcinoma of the esophagus or gastroesophageal junction have a poor survival rate after surgery. Preoperative chemotherapy or chemoradiotherapy has not improved the outcome for these patients. Our study was designed to assess the feasibility of preoperative induction combination chemotherapy in addition to chemoradiotherapy to improve the curative resection rate, local control, and survival.

PATIENTS AND METHODS Patients having histologic proof of localized carcinoma (either squamous cell carcinoma or adenocarcinoma) of the esophagus or gastroesophageal junction underwent full classification including endoscopic ultrasonography (EUS). Patients first received up to two courses of induction chemotherapy consisting of 5-fluorouracil at 750 mg/m(2)/day as continuous infusion on Days 1--5, cisplatin at 15 mg/m(2)/day as an intravenous bolus on Days 1--5, and paclitaxel at 200 mg/m(2) as a 24-hour intravenous infusion on Day 1. The second course was repeated on Day 29. This was followed by radiotherapy (45 grays in 25 fractions) and concurrent admission of 5-fluorouracil (300 mg/m(2)/day as a continuous infusion 5 days/week) and cisplatin (20 mg/m(2) on Days 1--5 of radiotherapy). After chemoradiotherapy, patients underwent surgery. The feasibility of this approach, curative resection rates, patient survival, and patterns of failure were assessed.

RESULTS: Thirty-seven of 38 patients enrolled were evaluable for toxicity and survival. Adenocarcinoma and distal esophageal location of carcinoma were observed frequently. Thirty-five (95%) of the 37 patients underwent surgery, all of whom had an R0 (curative) resection. A pathologic complete response was noted in 11 (30%) of the 37 total patients. In addition, 5 patients (14%) had only microscopic carcinoma. According to EUS classification, 31 (89%) of the 35 patients who underwent surgery had a T3 carcinoma whereas according to pathologic classification only 3 (9%) had a T3 carcinoma (P

CONCLUSIONS: These data show that the three-step strategy of preoperative paclitaxel-based induction chemotherapy then chemoradiotherapy followed by surgery is feasible and appears quite active in patients having locoregional carcinoma of the esophagus or gastroesophageal junction. Future investigations should focus on substituting cisplatin with less toxic agents and including more systemic therapy with newer classes of agents.

Exclusive radical surgery for esophageal adenocarcinoma.

Collard JM.

Department of Surgery, Louvain Medical School, Brussels, Belgium.

Cancer 2001 Mar 15;91(6):1098-104 Abstract quote

BACKGROUND: Because very poor survival rates were reported after exclusive nonradical surgery, the current opinion in the medical community is that very few esophageal adenocarcinoma patients can anticipate long-term survival after esophagectomy. In the current study the ability of exclusive radical surgery including very extended lymph node dissection to provide a substantial percentage of patients with long-term survival was examined.

METHODS: Radical esophagectomy (including removal of the esophageal tube, excision of the potentially involved locoregional lymph nodes, and skeletization of the nonresectable vital organs in the mediastinum and upper abdomen) was attempted in 183 consecutive patients with either Barrett (n = 77) or non-Barrett (n = 106) adenocarcinoma of the esophagus or cardia. Esophagectomy was subtotal (neck anastomosis) or distal (chest anastomosis) in 103 patients and 80 patients, respectively.

RESULTS: Radical esophagectomy (Ro resection) was feasible in 137 patients (75%) whereas 46 patients (25%) in whom a part of the neoplastic process was not resectable (R1 or R2 resection) underwent a palliative esophagectomy. The 5-year survival, including in-hospital deaths (4.3%), was 35.3% for the whole series, 48% after Ro resection, and 0% after R1 or R2 resection. The 5-year survival rate after any R resection was 57.2% in patients with Barrett adenocarcinoma compared with 20% in patients with non-Barrett adenocarcinoma (P < 0.0001) because of a higher prevalence of nontransmural tumors (Tis through T2, N0) in the former group (56.5%) compared with the latter group (6.6%) (P < 0.0001). The 5-year survival was related closely to the magnitude of both wall penetration and extraesophageal neoplastic spread (Ro, Tis-T1-T2, N0 = 83.5% vs. Ro, T3, N0 = 44.4% vs. Ro, any T, N1 < 5 metastatic lymph nodes = 37% vs. Ro, any T, N1 > or = 5 metastastic lymph nodes = 6.8% vs. R1, R2 = 0%; P < 0.0001).

CONCLUSIONS: Exclusive radical esophagectomy provides a chance of long-term survival in 35% of esophageal adenocarcinoma patients in whom it is attempted and nearly 50% of those patients in whom it is feasible. The presence of a small number of metastatic lymph nodes does not appear to preclude a long-term favorable outcome.

Superficial adenocarcinoma of the esophagus.

Rice TW, Blackstone EH, Goldblum JR, DeCamp MM, Murthy SC, Falk GW, Ormsby AH, Rybicki LA, Richter JE, Adelstein DJ.

Department of Thoracic and Cardiovascular Surgery, The Center for Swallowing and Esophageal Disorders, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.

J Thorac Cardiovasc Surg 2001 Dec;122(6):1077-90 Abstract quote

OBJECTIVE: Experience with treatment and outcome of superficial adenocarcinoma of the esophagus is limited. The purpose of this study was to evaluate the results of surgical management and identify predictors of survival.

METHODS: Between September 1985 and December 1999, 122 patients underwent resection. Eighty-nine percent were men (mean age 63 +/- 10 years; range 35-83 years). Sixty (49%) patients were in endoscopic surveillance programs and 48 (39%) had the preoperative diagnosis of high-grade dysplasia. Forced expiratory volume in 1 second was less than 2 L in 12 (12%). Seventy-five (61%) patients underwent transhiatal esophagectomy. Pathologic stage was N1 in 8 (7%). Pulmonary complications necessitating reintubation (respiratory failure) occurred in 10 (8%) patients. Time-related survival models were developed for decision-making (preoperative), prognosis (operative), and hospital care (postoperative).

RESULTS: Operative mortality was 2.5%. Survival at 1, 5, and 10 years was 89%, 77%, and 68%. Preoperative decision-making factors associated with ideal outcome were 1-second forced expiratory volume of more than 2 L, surveillance, preoperative diagnosis of high-grade dysplasia, and planned transhiatal esophagectomy. Prognosis was decreased in younger patients and in those with N1 disease. Postoperative respiratory failure increased mortality.

CONCLUSIONS: Surgery is the treatment of choice for superficial adenocarcinoma of the esophagus. The ideal patient has a preoperative diagnosis of high-grade dysplasia found at surveillance, good pulmonary function, and undergoes a transhiatal esophagectomy. Discovery of N1 disease or development of postoperative respiratory failure reduces the benefits of surgery.

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