Dr S. Cohen, Thomas Jefferson University Hospital, Main Building, Suite 480, 132 South 10th Street, Philadelphia, PA 19147, USA. E-mail: email@example.com
Background Oesophageal adenocarcinoma is the sixth leading cause of cancer-related mortality worldwide. Previously, oesophageal cancer was mainly squamous cell, presenting late with dysphagia and weight loss.
Aims To examine the distribution of oesophageal cancer histopathology at a large, urban hospital; to determine the tumour stage and symptoms at presentation; and to evaluate the impact of endoscopic surveillance in Barrett's oesophagus.
Methods From 1999 to 2004, all patients diagnosed with oesophageal cancer were evaluated retrospectively for demographics and tumour stage at presentation using endoscopic ultrasonography and computerized tomography.
Results A total of 131 patients were included. 81% of tumours were adenocarcinomas; most localized to the distal oesophagus (97%). Patients presented with dysphagia (56%), pain (30%) and/or weight loss (16%). Irrespective of histology, locally advanced lesions accounted for most cases. Thirteen patients had lesions detected in Barrett's surveillance; these were early or intermediate stage in nine patients, but late stage in four patients.
Conclusions Adenocarcinoma has become the dominant histologic subtype, comprising 81% of proven malignancies. Despite a change in histopathology, most cancers are diagnosed at an advanced stage, presenting with dysphagia, pain and/or weight loss. Endoscopic surveillance of Barrett's oesophagus allows earlier diagnosis of cancer in most, but not all, patients.
With a sixfold increase in incidence over the past 3 decades, oesophageal adenocarcinoma is the fastest rising major malignancy in the US.1, 2 Overall, oesophageal cancer is the 8th leading cause of cancer death in American men, and the sixth leading cause of cancer death worldwide.1, 3 In 2005, 14 520 new cases, resulting in a high mortality of 13 570 deaths, are anticipated in the US.4
Greater than 90% of oesophageal cancers are either adenocarcinomas or squamous cell carcinomas. The incidence of oesophageal squamous cell carcinoma is decreasing and adenocarcinoma is increasing.5 Since 1975, the incidence of squamous cell carcinoma has decreased somewhat, while the rate of adenocarcinoma has increased 50% in black men and 450% in white men.1 The striking association between non-Hispanic–Caucasian males and oesophageal adenocarcinomas in the US is supported by the data from Scotland and the Netherlands.6 Although some of the change in epidemiology is because of trends in smoking, obesity, nutrition and medication usage, there is no well-established evidence that these trends are solely responsible for the change in the histologic pattern.6–8
Because of the advanced stage of most oesophageal tumours at the time of diagnosis, most patients complain of dysphagia alone or in combination with other symptoms. A multicentre survey of over 5000 oesophageal cancer patients in 1994 revealed that the most common symptoms of oesophageal cancer were dysphagia (74%), weight loss (57%), gastro-oesophageal reflux (21%), odynophagia (17%) and dyspnea (12%).9
The endoscopy unit of Thomas Jefferson University Hospital, located in Philadelphia, Pennsylvania, performs over 14 000 endoscopic procedures per year (the most on the East Coast of the US), and upper endoscopies account for 8000 of these procedures. Approximately, 400 patients are enrolled in an endoscopic surveillance programme at our institution for Barrett's oesophagus. The population of Philadelphia is 1.5 million persons, and the city is racially diverse – 45% Caucasian, 43% African–American and 5% Asian.
The purpose of this survey is to report the impact of recent changes in oesophageal cancer on clinical presentation, type of malignancy and stage in a large, urban US hospital setting.
Materials and methods
Oesophagogastroduodenoscopies performed at Thomas Jefferson University Hospital between October 1999 and October 2004 were retrospectively evaluated. All data were obtained from active patient charts. Patients with gastric tumours or a previous history of oesophageal cancer, chemoradiation or surgery were not included. Presenting symptoms, indication for endoscopy, gender, ethnicity and age were collected for the study population.
Patients were clinically staged according to the tumour-node-metastasis (TNM) criteria of the American Joint Committee on Cancer (AJCC)Cancer Staging Manual, using endoscopic ultrasonography (EUS) and computerized tomography.10 Endoscopy was performed by three endoscopists using Olympus radial endoscopic ultrasound equipment. The location of the mass within the oesophagus was recorded; the proximal, middle and distal locations were roughly defined as 21–26, 26–32 and 32–40 cm from the mouth, respectively. If the gastric cardia was free of tumour, endoscopic criteria were employed to distinguish oesophageal from gastro-oesophageal junctional or gastric cardia lesions.
Radiographic studies were reviewed by two specialized body imaging radiologists. Three-phase computerized tomography of the thorax and abdomen was performed using a Philips Mx8000 multislice scanner after the administration of oral and i.v. contrast media. Pathologic stage of disease, including tumour histology, grade and site, was reported for all patients. Oesophageal specimens were reviewed by two gastrointestinal pathologists.
These data were also recorded for a separate cohort of Barrett's oesophagus patients (defined as intestinal metaplasia with goblet cells present on oesophageal biopsy) in an endoscopic surveillance programme. Endoscopic surveillance was performed according to the guidelines of the American Gastro-oenterological Association, with the presence of Barrett's oesophagus upon screening endoscopy for gastro-oesophageal reflux symptoms as the indication for surveillance.11 All patients in the surveillance group had long segment Barrett's oesophagus.
This study is intended as a descriptive survey of disease characteristics and patterns of diagnosis of oesophageal cancer.
* Expressed as a percentage of all patients. Cancer, all oesophageal cancer; adeno, symptomatic oesophageal adenocarcinoma; SCC, oesophageal squamous cell carcinoma; BE, oesophageal adenocarcinoma found during surveillance endoscopy for Barrett's oesophagus.
Number of patients (n)
Median age (years, range)
Gender (%, male/female)*
The age at initial presentation of each type of oesophageal cancer was similar (median 66 years). Overall, men outnumbered women by a ratio of 3.4:1, however the ratio of men to women with adenocarcinoma, 4.9:1, was much greater than the ratio of men to women with squamous cell carcinoma, 1.2:1. Although most patients in this study were non-Hispanic–Caucasians, a significantly greater proportion of adenocarcinoma patients compared with squamous cell carcinoma patients were of this ethnicity. Patients found to have oesophageal tumours during surveillance endoscopy for Barrett's oesophagus mirrored the adenocarcinoma subgroup in both ethnicity and gender distributions.
Oesophageal cancer histopathology
More than 97% of the 131 patients with malignant histology were diagnosed with adenocarcinomas or squamous cell carcinomas (Figure 1). A total of 106 patients (81%) had adenocarcinomas, 22 patients (17%) had squamous cell carcinomas, and the remaining three patients had an undifferentiated carcinoma, a malignant melanoma and a malignant gastrointestinal stromal tumour.
At the time of diagnosis, dysphagia, pain and weight loss were the most frequent reported symptoms among oesophageal cancer patients. The presentations were similar in patients with both histologic types of oesophageal cancer; 72 patients (55%) reported dysphagia, 38 (29%) reported pain and 20 (15%) reported weight loss. Thirteen patients (10%) presented for surveillance endoscopy of Barrett's oesophagus. Less commonly, patients reported, in descending order of frequency, emesis, gastrointestinal bleeding, an incidental mass, anaemia, cough, fatigue, anorexia and hoarseness.
Site of cancer
The overwhelming majority of symptomatic adenocarcinomas and cancers found during surveillance for Barrett's oesophagus were located in the distal oesophagus or gastro-oesophageal junction (Table 2). The remaining lesions in these groups were located in the middle oesophagus. Squamous cell carcinomas were distributed throughout the oesophagus.
Table 2. Tumour site and clinical stage at presentation
Adeno, % (n = 93)
SCC, % (n = 22)
BE, % (n = 13)
* Clinical stage determined by endoscopic ultrasonography (EUS) and radiography: AJCC stage groupings: stage 0, Tis N0 M0; stage I, T1 N0 M0; stage IIA, T2 N0 M0 or T3 N0 M0; stage IIB, T1 N1 M0 or T2 N1 M0; stage III, T3 N1 M0 or T4 any N M0; stage IV, any T any N M1.10
Adeno, symptomatic oesophageal adenocarcinoma; SCC, oesophageal squamous cell carcinoma; BE, oesophageal adenocarcinoma found during surveillance endoscopy for Barrett's oesophagus.
Cancer stage at presentation
The stage at initial presentation of symptomatic oesophageal cancer was similar for adenocarcinomas and squamous cell carcinomas. For adenocarcinomas, endosonography revealed one of 93 patients (1%) with an in situ lesion, 11 patients (12%) with T2 tumours, 73 patients (79%) with T3 tumours and nine patients (10%) with T4 tumours. For squamous cell carcinomas, three of 22 patients (14%) had T2 tumours, 12 patients (55%) had T3 tumours, four patients (18%) had T4 tumours and one patient (5%) could not be evaluated because of oesophageal obstruction. Most patients with locoregional lymph node metastases had bulky T3 or T4 tumours, and 10% of symptomatic patients had distant metastases (M1) at the time of initial endosonographic evaluation. Most symptomatic oesophageal cancer patients were clinically staged with intermediate or advanced disease (stage IIA, IIB, III and IV).
Adenocarcinoma of the oesophagus: comparison of the stage for symptomatic presentation vs. cancers detected during endoscopic surveillance of Barrett's oesophagus
Thirteen patients that underwent surveillance for Barrett's oesophagus had oesophageal cancer visible at endoscopy, and over 75% of these masses were located in the distal oesophagus. By EUS, two of 13 patients (15%) had T1 tumours, seven patients (54%) had T2 tumours, three patients (23%) had T3 tumours, and one patient (8%) had a T4 tumour. Most of the Barrett's oesophagus patients with N1 disease had T3 or T4 tumours, and 15% of patients had distant metastatic disease (M1). Endosonographic staging demonstrated a greater proportion of Barrett's oesophagus patients with early lesions compared with the total oesophageal adenocarcinoma population (Figure 2). In contrast to symptomatic oesophageal carcinoma patients, the majority of patients in the surveillance group were clinically staged with early or intermediate disease (stage I, IIA and IIB).
The results of this study indicate that oesophageal adenocarcinoma has become the predominant oesophageal cancer, but both the site and stage of this cancer at presentation are unchanged from historical controls.1, 2, 12, 13 Patients had representative demographics compared with prior reports, with a median age at diagnosis of 66 years and a preponderance of non-Hispanic–Caucasian males.
Dysphagia, whether isolated or in concert with other symptoms, continues to be the chief symptom of oesophageal cancer. The most common symptoms in our patient group at the time of oesophageal cancer diagnosis were dysphagia, pain and weight loss, consistent with previous reports.9 Further, oesophageal cancer remains a malignancy that most often presents symptomatically. This pattern of symptoms is representative of advanced, bulky tumours that obstruct the oesophagus, diminishing its function and causing pain.
The increasing incidence of gastro-oesophageal reflux disease and Barrett's oesophageal mucosal changes has triggered a parallel increase in the incidence of oesophageal adenocarcinomas. In 1975, approximately 75% of oesophageal cancer cases in the US were squamous cell carcinomas and 25% were adenocarcinomas. In 1988, oesophageal squamous cell carcinomas outnumbered adenocarcinomas 2:1, and during the period of 1992–1994, the incidence of oesophageal adenocarcinomas overtook squamous cell carcinomas in the US by 1.2:1.7, 13 Prospective trials conducted in the late 1990s indicate that oesophageal adenocarcinomas surpassed squamous cell carcinomas in the UK and Australia by almost 2:1.14, 15 Our results demonstrate that since 1999, oesophageal adenocarcinoma has been overwhelmingly more prevalent than squamous cell carcinoma in a large, tertiary care hospital in the US, outnumbering it 4.9:1.
Prior reports indicate that the dominant site of oesophageal adenocarcinomas is the distal oesophagus or gastro-oesophageal junction in 75% of cases, whereas squamous cell carcinomas distribute evenly in the middle and distal thirds of the oesophagus.2 Our results agree that the vast majority of oesophageal adenocarcinomas occur in the distal third of the oesophagus, and squamous cell carcinomas localize with equal frequencies to the middle and distal thirds of the oesophagus. This distribution reflects the underlying oesophageal adenocarcinoma pathophysiology.
Tumours of the oesophagus are staged using the TNM classification, according to the characteristics of the lesion, locoregional lymph node involvement and distant metastases.10 The most accurate and cost-effective approach to oesophageal cancer staging is the combination of computerized tomography and endosonography.12, 16–19 However, positron emission tomography, in conjunction with EUS and computerized tomography, has recently been demonstrated to improve detection of systemic metastases, and may soon supplement the standard staging regimen for oesophageal cancer.20, 21
By treatment modality, patients are traditionally classified as resectable if the malignancy has not invaded the muscularis propria and is without locoregional lymph node involvement or distant metastases (stages 0 and I).10, 14 Lesions that extend past the muscularis propria and/or involve locoregional lymph nodes, but are without distant metastases and/or malignant celiac lymphadenopathy (stages IIA, IIB and III without adjacent soft tissue invasion) are sometimes resectable, but require neoadjuvant radio-chemotherapy.15, 21 Tumours with regional organ invasion and/or celiac lymph node or distant metastatic involvement are not resectable, and these patients are candidates for palliative therapy (stage III with adjacent soft tissue or organ invasion, IVA and IVB). In addition, palliative surgery, brachytherapy or stenting are sometimes performed for obstructive symptoms. The stage at presentation is thought to be similar for both oesophageal adenocarcinomas and squamous cell carcinomas.1 Unfortunately, many patients with oesophageal cancer present with unresectable lesions or metastatic disease, and the survival rate for this group is poor.12, 13 In this study, most patients had advanced disease at initial presentation by endosonographic, radiographic and histologic criteria, consistent with historical controls. Patients with either oesophageal adenocarcinoma or squamous cell carcinoma continue to present symptomatically at roughly the same stage, with most having stage IIA, IIB, III or IV disease. These tumours are often unresectable or require neoadjuvant chemoradiation prior to surgery, and carry a poor prognosis.
Barrett's oesophagus occurs in 5–8% of patients with gastro-oesophageal reflux disease, and has an annual rate of neoplastic transformation of 0.5%.22 It is believed that surveillance endoscopy every 2–3 years in Barrett's oesophagus patients without dysplastic lesions, and more often if low-grade dysplasia is present, may represent the appropriate management of these patients.23, 24 Those patients initially found to have high-grade dysplastic lesions are best suited for interventions.13 It is unclear whether surveillance endoscopy for Barrett's oesophagus identifies less advanced lesions than in patients that do not undergo surveillance.25 Our results indicate that endoscopic surveillance of Barrett's oesophagus patients does yield less advanced oesophageal carcinomas than in patients that present with symptoms of malignant oesophageal disease, with a significantly greater proportion of lesions confined to the oesophagus. Although the sample size of patients that underwent surveillance endoscopy for Barrett's oesophagus was small, it appears that this strategy is important in the detection of early stage oesophageal adenocarcinomas prior to nodal metastasis. This trend toward earlier diagnosis was not seen in all patients.
In summary, oesophageal carcinoma epidemiology displays a striking increase in the incidence of adenocarcinomas within the distal third of the oesophagus. This cancer correlates strongly with non-Hispanic–Caucasian ethnicity and male gender. Most tumours cause symptoms of advanced disease at the time of diagnosis, and are found to be deeply invasive and/or metastatic by EUS and computerized tomography, characteristics associated with a poor outcome. Surveillance endoscopy for Barrett's oesophagus is an important procedure to reduce the mortality of oesophageal adenocarcinomas, but large, prospective, controlled clinical trials are vital to definitively evaluate this approach.
This study received no external funding or industry support.