Esophageal adenocarcinoma is now the most common type of esophageal
cancer in the United States. Barrett’s esophagus and subsequent development of
dysplastic changes increase its risk of conversion to adenocarcinoma. Frequent
monitoring with endoscopic biopsies can detect adenocarcinoma in the very
early stages where treatment can be curative. We report an interesting case where
an initial metastatic disease had an excellent response to chemotherapy but later
another adenocarcinoma developed from the persistent Barrett’s dysplasia.
A 47-year-old Caucasian man presented with left sided supra-clavicular
lymphadenopathy. His other medical problems included hypertension, gout,
morbid obesity, obstructive sleep apnea and a long-standing history of
gastroesophageal reflux symptoms. He denied any history of dysphagia, weight
loss or loss of appetite. He was a farmer and had smoked heavily in the past with
decreased smoking for the past 10 years. He had moderate alcohol consumption
Clinical Medicine & Research
Volume 4, Number 3: 184-188
©2006 Marshfield Clinic
Received: May 5, 2006
Revised: July 19, 2006
Accepted: July 26, 2006
Hemender Singh Vats, MD
Department of General Internal Medicine
1000 North Oak Avenue
Esophageal Adenocarcinoma Arising from Barrett’s Dysplasia:
A Case Report of Double Occurrence and Prolonged
Survival after Chemotherapy
Hemender S. Vats, MD; Tarit K. Banerjee, MD, FACP; Jeffrey Resnick, MD; and Qaseem Khan, MD
Keywords: Barrett’s esophagus; Dysplasia; Esophageal adenocarcinoma; Gastroesophageal reflux disease
A relatively young patient with chronic gastroesophageal reflux disease (GERD),obesity,smoking,
and alcohol intake presented with widespread metastatic disease in lymph nodes,liver and lungs
from a lower esophageal adenocarcinoma extending into the gastroesophageal junction
associated with Barrett’s mucosa and dysplasia.A complete response was achieved with six cycles
of chemotherapy that sustained for more than 4 years without further recurrence.Unfortunately,
there was presence of esophageal metaplasia after complete response which eventually
converted to low to high grade dysplasia and ultimately to a second primary localized lower
esophageal adenocarcinoma that was treated with thoracoabdominal esophagectomy and
lymphadenectomy. No evidence of disease recurrence was seen 2 years later.The pathogenesis
of a recent increase in the incidence of GERD, Barrett’s esophagus and lower esophageal
adenocarcinoma are discussed. Surgery, radiotherapy and combination chemotherapy are
effective in the early stages leading to tumor shrinkage and prolongation of life and even cure in
some cases.Lower esophageal adenocarcinoma is frequently associated with Barrett’s high-grade
dysplasia. Since there has been a dramatic increase in the incidence of Barrett’s dysplasia,
appropriate surveillance with upper gastrointestinal endoscopy and preventive strategies,such as
the use of aspirin, cyclo-oxygenase II inhibitors and other nonsteroidal antiinflammatory drugs
known to be chemopreventive agents against colon,esophagus,gastric and bladder cancers,need
to be studied.
in his youth. There was a history of breast cancer in his
mother. His medications included allopurinol, losartan and
A biopsy of the supraclavicular lymph node revealed
metastatic large cell carcinoma,
adenocarcinoma. Detailed evaluation for the primary source
with computed tomography (CT) scans of the chest, abdomen
and pelvis revealed abnormal thickening of the lower
esophageal wall and extensive lymphadenopathy in the left
axillary, left supraclavicular, perihilar, hepatogastric,
perigastric, celiac, superior mesenteric and periaortic regions.
There was also evidence of hepatic metastases along with a
couple of right lung metastases (figure 1, column a).
Esophagogastroduodenoscopy (EGD) revealed a friable
ulcerated exophytic growth 5 cm in length in the lower third
of the esophagus extending into the gastroesophageal
junction. The proximal and mid esophagus, stomach and
duodenum were normal. A biopsy of the mass confirmed
poorly differentiated invasive adenocarcinoma along with the
presence of Barrett’s high-grade dysplasia (figure 2a). The
histology of the metastatic lymph node and esophageal mass
Based on the biopsy findings of the esophageal mass and the
imaging studies, a diagnosis of metastatic (stage IV)
adenocarcinoma of the lower third of the esophagus was
made, and the patient was treated with three cycles of
5-fluorouracil (24-hour infusion daily for 4 days via Hickman
catheter and ambulatory pump), cisplatin and paclitaxel (3-hour
infusions of each) every 3 weeks. Three additional cycles
using carboplatin as 30-minute infusions replacing cisplatin
due to poor tolerance were administered. After six cycles of
chemotherapy, there was a complete response in measurable
disease clinically and radiologically (figure 1, columns a and
b). A repeat EGD, after completion of chemotherapy, also
demonstrated the complete response endoscopically with
presence of a benign nodule 0.5 cm at the gastroesophageal
junction. Biopsy revealed intestinal metaplasia but no
dysplasia or malignancy (figure 2b).
The patient underwent surveillance with EGD and CT scans,
as follow-up, and there was no evidence of recurrence of
malignancy. However, Barrett’s esophagus persisted and
subsequent biopsies continued to demonstrate dysplastic
changes (figure 2c and 2d). The average length of the Barrett’s
segment was 5-7 cm. The grading of dysplasia, over time,
changed from focal high-grade changes to diffuse high-grade
with ulceration. As initial presentation showed diffusely
metastatic disease, surgical treatment was not initially
considered. After 4 years in complete remission, and with
worsening Barrett’s dysplastic changes in the lower
esophagus, a surgical consultation was obtained. Surgical
treatment was not recommended as there was no malignancy.
However, photodynamic therapy was considered, but the
patient preferred to have further surveillance.
The patient’s EGD at 4 years after initial diagnosis
demonstrated the presence of Barrett’s esophagus along with
a mass measuring 4-5 cm in the lower third of the esophagus
and at a location different from the first mass. A biopsy of this
second mass confirmed intramucosal adenocarcinoma arising
in Barrett’s metaplasia and high-grade dysplasia (figure 2e).
Endoscopic ultrasonography confirmed a lower third
esophageal mucosal mass extending 35-40 cm from the
incisor with no invasion of the muscularis propria or evidence
of spread into the esophageal wall. There was no
lymphadenopathy or evidence of distant metastases by CT
scan, endoscopic ultrasonography and the positron emission
Figure 1. Computed tomographic (CT) images of chest and
abdomen in (column a) prechemotherapy and (column b)
postchemotherapy period (5 months after initial diagnosis)
demonstrating the excellent response to chemotherapy. Row 1,
Axillary lymphadenopathy. Row 2, Lower esophageal thickening.
Row 3, Liver metastases. Row 4, Periaortic lymphadenopathy.
Subsequent CT scans did not reveal any evidence of visceral
or lymph node malignancy.
Vats et al.
CM&R 2006 : 3 (September)
Esophageal adenocarcinoma from Barrett’s dysplasia
CM&R 2006 : 3 (September)
tomography scan. The positron emission tomography scan,
however, demonstrated uptake in the lower esophageal mass.
The patient was diagnosed with a second de novo
adenocarcinoma of the lower third of the esophagus, which
was staged as cT1 N0 M0 (stage I) disease.
The patient subsequently underwent distal esophagectomy
(up to the level of the azygous vein), esophagogastric
anastomosis and pylorotomy by thoracoabdominal approach
with periesophageal and perigastric lymph node dissection.
Cervical esophagogastric anastomosis was not achievable due
to the patient’s obesity. Pathology demonstrated intramucosal
adenocarcinoma with no submucosal, lymphatic, lymph node
or vascular invasion, and was staged as pT1b N0 disease
(figure 2f). The surgical margins of resection were free of
malignancy but were involved by Barrett’s metaplasia with
low- and high-grade dysplasia. Because of the early stage of
this second malignancy, no adjuvant therapy was
Subsequent follow-up for 24 months postsurgery with EGD
has not demonstrated recurrence of Barrett’s dysplasia or
malignancy. He continues to have symptoms from
gastroesophageal reflux disease (GERD) that is relieved by
taking a proton pump inhibitor.
Approximately 400,000 cases of esophageal cancer are
diagnosed annually world wide.1Of these approximately
14,250 are diagnosed in the United States with 13,570 people
estimated to die from the disease in 2005.2However, the
incidence of squamous cell esophageal carcinoma has
decreased in the western hemisphere.7
The prognosis for esophageal cancer is dismal, although the
5-year survival has modestly improved from 5% to 15% in the
past three decades. Systemic metastatic disease is present in
50% of patients at the time of diagnosis, and the majority of
the remaining group having localized regional disease at
diagnosis will ultimately develop systemic metastases.8
However, 3-year survival rates range from 44% to 63% in
patients with localized cancer (stage I and IIA) and from 6%
to 10% in those with involvement of regional lymph nodes
(stage IIB and III).9The prognosis is extremely bleak in
recurrent and advanced metastatic disease with most patients
dying within 2 years in this stage.10It is believed that chronic
GERD exposes lower esophageal mucosa to gastric acid and
bile, resulting in lower esophageal epithelium change from
squamous to intestinal columnar type (metaplasia).
Subsequently with genetic changes in P53 and P16, the
epithelium becomes dysplastic and later may progress into
Ordinarily, locally advanced disease can cause dysphagia,
anemia due to ulceration, weight loss, food sticking in
esophagus, regurgitation and aspiration pneumonia, though
our patient did not have any of these symptoms. Obesity,
smoking, alcohol intake and GERD were his predisposing
factors, and he presented with distant metastatic disease in the
lymph nodes, lungs and liver.
Lower esophageal adenocarcinoma is commonly associated
with Barrett’s metaplasia, dysplasia and disease extension
into the gastroesophageal junction.12Although Helicobacter
pylori is known to be present in gastric adenocarcinoma and
gastric lymphoma, it is usually found with lower incidence in
GERD.13-15Current debate is taking place over whether
eradication of H. pylori by antibiotics after treatment of
peptic ulcer disease may be giving rise to increased incidence
of GERD and Barrett’s esophagus.15
Figure 2. (a) Invasive poorly differentiated adenocarcinoma
arising at the lower end of the esophagus. There is a solid
proliferation of highly atypical epithelial cells with some gland
formation. Note the surface ulcer with fibrinous exudate. (b)
Postchemotherapy endoscopic biopsy (8 months after initial
diagnosis). Cardiac-type mucosa with intestinal metaplasia,
consistent with Barrett’s esophagus. There is no evidence of
dysplasia. Note the accompanying squamous re-epitheliazation.
(c) Endoscopic biopsy of lower esophagus 15 months after
completion of chemotherapy demonstrated high-grade dysplasia.
The glands show architectural complexity (manifesting as
crowding) with nuclear stratification and hyperchromasia. (d)
Thirty-months postchemotherapy. High-grade dysplasia persists.
(e) Three and one-half years after chemotherapy intramucosal
adenocarcinoma was found in the background of high-grade
dysplasia. The lower aspect of the figure shows an elongated
nest of neoplastic cells invading the lamina propria. (f)
Intramucosal adenocarcinoma in esophagectomy specimen. The
high-grade dysplasia is accompanied by neoplastic cells
infiltrating the lamina propria and muscularis mucosa. Despite
extensive sampling of the lesion for histologic evaluation, there
was no involvement of the submucosa.
Treatment options for advanced esophageal cancer have
changed considerably over the past two decades. Initially
surgery alone was the gold standard of treatment (5-year
survival rate of 15% to 20%) for early stage esophageal
cancer.16However, chemotherapy and radiotherapy, in both
pre- and postoperative phases, have started to improve
treatment outcomes. Radiation therapy in the adjuvant or
neoadjuvant setting has been shown to reduce the incidence
of local recurrence but does not provide any improvement in
survival.16Combined chemo-radiation as a definitive therapy
has been demonstrated to be effective.16The results of its use
have been subjected to various randomized controlled trials
comparing this with chemotherapy or radiation therapy alone,
with or without surgery. The Radiation Therapy Oncology
Group 8501 trial showed progression free survival is better
with chemo-radiation as compared to radiation alone.17,18The
intergroup trial has shown that a higher dose of radiation does
not improve survival in combination with chemotherapy.19
Use of neoadjuvant chemotherapy has shown variable results
in different studies. A randomized study conducted by the
Medical Research Council of the United Kingdom reported a
significant benefit in overall survival for patients who
received preoperative chemotherapy.20A retrospective
comparison of neoadjuvant chemo-radiation versus surgery
alone showed dramatic improvement in survival in stage II or
III lower esophageal and gastroesophageal junction
adenocarcinoma with preoperative chemo-radiation.21On the
other hand, the North American Intergroup trial by Kelsen et
al did not report any significant survival benefit with
Combined use of chemotherapy and radiation before surgery
in locally advanced disease has been studied in various trials.
An analysis of these studies shows that although there is no
significant improvement in median survival, there is
improved resectability, decreased local recurrence and better
symptom relief.21,23A study by Walsh et al,24including only
adenocarcinoma patients, found a significant improvement in
survival with use of neoadjuvant chemo-radiation and surgery
versus surgery alone.
For patients with metastatic disease who are considered
incurable by surgery, palliative chemotherapy, radiation
therapy and deployment of stents can markedly improve
symptoms of dysphagia, pain and bleeding, and leads to
improvement in functional quality of life.10,16,25
We report a case of widely metastatic lower esophageal
adenocarcinoma that was treated initially with chemotherapy.
Single-agent chemotherapy with 5-fluorouracil, cisplatin/
carboplatin, paclitaxel, docetaxel, irinotecan, vinorelbine and
vindesine can give rise to 15% to 35% variable responses and
improvement of survival. A combination chemotherapy of
5-fluorouracil plus cisplatin and paclitaxel gave 48%
responses.26In our patient there was a dramatic, complete
response to combination chemotherapy of 5-fluorouracil,
paclitaxel and cisplatin/carboplatin chemotherapy with no
endoscopic, radiologic or histologic evidence of cancer which
was sustained for more than 4 years after initial diagnosis.
Because of poor tolerance, cisplatin was replaced by
carboplatin during later cycles. Serial endoscopies and
biopsies continued to show Barrett’s esophagus with evidence
of dysplasia. Subsequent follow-up demonstrated progression
of dysplasia and ultimately development of adenocarcinoma
arising de novo from the dysplastic epithelium. There was no
evidence of any distant metastases on the second occurrence.
At this time the patient was treated as stage I cancer by distal
esophagectomy and lymphadenectomy, and 2 years after
surgery there is no evidence of recurrence of either of the two
This case represents a unique combination of an initial
excellent response to chemotherapy in widely metastatic
disease followed by development of a second de novo primary
adenocarcinoma, in a morphologically different location from
the first tumor, due to persistence of Barrett’s dysplastic
changes. This case also emphasizes the importance of close
follow-up of patients with Barrett’s high-grade dysplasia with
serial endoscopies and biopsies in order to establish an early
diagnosis and definitive treatment.
A dysplastic change in Barrett’s epithelium is a pre-malignant
condition. It is possible Barrett’s dysplasia and lower
esophageal adenocarcinoma is increasing due to an increased
incidence of GERD. Endoscopic surveillance at regular
intervals may detect early stage, curable, malignant
transformation of dysplasia. The effectiveness of aspirin,
nonsteroidal antiinflammatory drugs and cyclo-oxygenase II
inhibitors in decreasing the incidence of malignant
transformation from dysplasia needs to be studied.4
The authors thank Marshfield Clinic Research Foundation for
its support through the assistance of Alice Stargardt and
Linda Weis in the preparation of this manuscript.
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Hemender S. Vats, MD, Department of General Internal
Medicine, Marshfield Clinic, 1000 North Oak Avenue,
Marshfield, WI 54449
Tarit K. Banerjee, MD, FACP, Department of
Hematology/Oncology, Marshfield Clinic, 1000 North Oak
Avenue, Marshfield, WI 54449
Jeffrey Resnick, MD, Department of Pathology, Marshfield
Laboratories, 1000 North Oak Avenue, Marshfield, WI 54449
Qaseem Khan, MD, Department of Hematology/Oncology,
Marshfield Clinic, 1000 North Oak Avenue, Marshfield, WI
Esophageal adenocarcinoma from Barrett’s dysplasia
CM&R 2006 : 3 (September)