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Background

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

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)
SEX (MALE:FEMALE) 3-7:1
GEOGRAPHIC DISTRIBUTION 80% whites

 

EPIDEMIOLOGIC ASSOCIATIONS CHARACTERIZATION
Barrett's esophagus Same risk factors

 

DISEASE ASSOCIATIONS CHARACTERIZATION
Barrett's esophagus Same risk factors

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.

 

PATHOGENESIS CHARACTERIZATION
Barrett's 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.

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.

 

GROSS APPEARANCE/CLINICAL VARIANTS CHARACTERIZATION
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

 

HISTOLOGICAL TYPES CHARACTERIZATION
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.

 

SPECIAL STAINS/IMMUNOPEROXIDASE/OTHER CHARACTERIZATION
Cytokeratin positive  

 

DIFFERENTIAL DIAGNOSIS DIFFERENTIATING FEATURES
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.

 

PROGNOSIS AND TREATMENT CHARACTERIZATION
PROGNOSIS Stage is the most factor

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.

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
TREATMENT Surgical
Adjuvant chemotherapy and radiotherapy

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.

Tumors of the Esophagus and Stomch in Atlas of Tumor Pathology. Fascicle 18. Third Series. AFIP. 1996.


Commonly Used Terms

Barrett's esophagus
Esophagus
GERD


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