Digestive Endoscopy

(2003)

15

, 266–269

Blackwell Science, LtdOxford, UKDENDigestive Endoscopy0915-56352003 Blackwell Science Asia Pty LtdOctober 2003154266269Original Article

RELAPSE AFTER EMR FOR ESOPHAGEAL CANCERY SHIMIZU Et al.

Correspondence: Yuichi Shimizu, Division of Endoscopy, HokkaidoUniversity Medical Hospital, Kita 15 jo Nishi 7 chome, Kitaku, Sapporo060-8638, Japan. Email: yshimizu@med.hokudai.ac.jp

Received 26 September 2002; accepted 3 March 2003.

ORIGINAL ARTICLE

RECURRENCE AFTER ENDOSCOPIC MUCOSAL RESECTION OF ESOPHAGEAL SQUAMOUS CELL CARCINOMA INVADING THE

MUSCULARIS MUCOSAE OR UPPER SUBMUCOSA

Y

UICHI

S

HIMIZU

,* H

IROYUKI

T

SUKAGOSHI

,

†

M

ASAHIRO

F

UJITA

,

‡

M

ASAO

H

OSOKAWA

,

§

M

OTOTSUGU

K

ATO

*

AND

M

ASAHIRO

A

SAKA

¶

*

Division of Endoscopy, Hokkaido University Medical Hospital, Departments of

†

Internal Medicine,

‡

Pathology and

§

Surgery, Keiyukai Sapporo Hospital and

¶

Third Department of Internal Medicine, Hokkaido University School of Medicine, Sapporo, Japan

Background

: Endoscopic mucosal resection (EMR) is recommended for cases of squamous cell carcinoma of the esoph-agus in which the tumor is confined to the lamina propria mucosa. However, EMR is often performed in patients whosetumors invade the muscularis mucosae (m3) or upper submucosa (sm1) to minimize surgical invasion, despite the increasedrisk of lymph node metastasis. We evaluated patients who were found to have distant or lymph node metastasis after EMRfor such lesions.

Methods

: Thirty-four consecutive patients with esophageal carcinoma invading m3 or sm1 who underwent EMR duringthe period from June 1992 through March 2001 (extended EMR group) were studied.

Results

: Five of these patients were found to have distant or lymph node metastasis on follow up. Patient 1 died of lungmetastasis 34 months after EMR. Patient 2 underwent chemotherapy because of an abnormally high value of squamouscell carcinoma (SCC) antigen. Patient 3 died of upper mediastinal lymph node metastasis 62 months after EMR. Patient4 underwent total gastrectomy because of gastric wall metastasis 41 months after EMR and underwent chemoradiotherapybecause of upper mediastinal lymph node metastasis 87 months after EMR. Patient 5 was found to have cardiac lymphnode metastasis by follow-up endoscopic ultrasonography examination 42 months after EMR and underwent curativelymph node dissection.

Conclusion

: It is unlikely that patient 1 and patient 2, both with probable distant metastasis, received inadequate treatment.Surgery with lymph node dissection usually cannot prevent distant metastasis. The patients with lymph node recurrence(patient 3 and patient 4) should have been followed up more carefully. We believe that patients with early lymph nodemetastasis, such as patient 5 in this study, should undergo curative surgical resection. Patients undergoing extended EMRshould be carefully followed up for a long period to enable early detection and treatment of lymph node metastasis.

Key words: endoscopic mucosal resection, esophageal carcinoma, metastasis, squamous cell carcinoma.

INTRODUCTION

Endoscopic mucosal resection (EMR) is now often used totreat early squamous cell carcinoma of the esophagusbecause of its minimal invasiveness and benefits in terms ofpatients' quality of life.

1,2

This procedure is currently recom-mended for tumors confined to the lamina propria mucosa,which are known to have a low risk of lymph node metasta-sis.

1–4

Subtotal esophagectomy with lymph node dissection isthe procedure of choice for patients with esophageal carci-nomas invading the muscularis mucosae or deeper.

3,5

How-ever, esophagectomy is very invasive and is associated withincreased morbidity and mortality,

3

particularly in elderlypatients and those with concurrent illness. Less invasivetreatment, such as EMR, is often used in such patients.

3,6

Wehave actively performed EMR in patients with esophageal

squamous cell carcinoma invading the muscularis mucosae(m3) or upper submucosa (sm1) for more than 5 years.

7

Inthe present study, we evaluated patients who were found tohave distant or lymph node metastasis after EMR for suchlesions in order to determine appropriate follow-up methods.

PATIENTS AND METHODS

The criteria for selection of patients with esophageal carci-nomas invading m3 or sm1 for EMR were: (i) patients whohad increased operative risk because of concurrent illness;(ii) patients who had other non-esophageal advanced can-cers; (iii) patients who were older than 75 years; and (iv)patients who refused open surgery despite receiving anexplanation about the risk of cancer metastasis. Patients whohad evidence of lymph node metastasis were excluded.

Before treatment, endoscopic examinations and endo-scopic ultrasonography (EUS) (including use of a high-frequency catheter probe) were performed in all patients toevaluate the depth of cancer invasion, and EUS and com-puted tomography (CT) were performed to assess lymph

RELAPSE AFTER EMR FOR ESOPHAGEAL CANCER 267

node metastasis. Lymph nodes longer than 5 mm in shortestdimension that were spherical and had distinct borders onEUS and those longer than 10 mm in shortest dimension onCT were defined as metastatic lymph nodes.

8–12

The treat-ment strategy was decided on the basis of these findings aswell as the patient's condition and the patient's choice oftreatment methods.

During the period from June 1992 to March 2001, 137patients with squamous cell carcinoma of the esophagusunderwent EMR at Keiyukai Sapporo Hospital. Thirty-fourof those patients had histologically confirmed tumor invasionof m3 or sm1. Ten of those 34 patients received adjuvanttreatment (chemoradiotherapy) to prevent lymph nodemetastasis and distant metastasis. The above-mentioned 34patients were observed to assess the outcome (extendedEMR group).

Sixteen patients in the extended EMR group did notundergo surgical resection because of concurrent illness,their age, or other non-esophageal advanced cancer. Eigh-teen other patients received EMR because they refused opensurgery. No complication due to EMR arose in this group.

Lesion size (maximum dimension) ranged from 0.8 to 5.5 cm,2.3

±

1.2 cm (mean

±

SD).The study was approved by the ethics committee of our

institute, and informed consent for all procedures and forparticipation in this study was obtained from all subjects.

All resected specimens were cut into longitudinal slicesmeasuring 2–5 mm in width and were embedded in paraffin.Each slice was stained with hematoxylin-eosin and was ex-amined microscopically. The depth of cancer invasion wasclassified according to the criteria proposed by the JapaneseSociety for Esophageal Diseases.

13

All specimens werereviewed by a single pathologist. Characteristics of thepatients are shown in Table 1.

After treatment, all patients were monitored to detectlocal or distant recurrence every 3–6 months during the firstyear and annually afterward. Follow-up evaluations includedgastrointestinal endoscopy, CT of the chest and upper abdo-men, and percutaneous ultrasonography of the neck andupper abdomen. Endoscopic ultrasonography was also per-formed if clinically indicated.

RESULTS

Seven patients have died as of March 2002, within 2–62months after treatment. Two patients died of recurrentesophageal carcinoma, and five patients died of concurrentdiseases, including pulmonary failure, cardiac failure, cere-bral infarction and other primary cancers. Median follow upafter treatment in the other 27 patients was 49 months. Min-imum follow up was 12 months. Ten patients were followedup for more than 60 months. Among them, five were foundto have distant or lymph node metastasis during the follow-up period. Characteristics and outcomes of the patients areshown in Table 2. Patient 1 died of lung metastasis 34 monthsafter EMR. Patient 2 underwent chemotherapy because ofan abnormally high value of squamous cell carcinoma (SCC)antigen (79.0 ng/mL at 62 months after EMR). Patient 3 diedof upper mediastinal lymph node metastasis 62 months afterEMR. Patient 4 underwent total gastrectomy because of gas-tric wall metastasis 41 months after EMR and underwentchemoradiotherapy because of upper mediastinal lymphnode metastasis 87 months after EMR. Patient 5 was found

Table 1.

Characteristics of patients with squamous cell carci-noma of the esophagus invading the muscularis mucosal orupper submucosa

Extended EMRgroup (

n

=

34)

Age in years (mean

±

SD) 66.8

±

7.3Range 50–80

Sex (male : female) 32 : 2Tumor size in cm (mean

±

SD) 2.3

±

1.2Range 0.8–5.5

Tumor locationUpper 8Middle 16Lower 10

Tumor differentiationWell 10Moderately 23Poorly 1

Table 2.

Characteristics of five patients who were found to have distant or lymph node (LN) metastasis on follow up

Case Age Morphologicaltype

Depth ofinvasion

Tumordifferentiation

Recurrentpattern

Period to recurrence

Treatment Outcome

1 75 years 0–IIa

+

IIc sm1 Moderately Lung metastasis 30 mo None 34 mo dead2 64 years 0–IIc sm1 Moderately Abnormally high

value of SCCantigen

56 mo Chemoradiotherapy 84 mo alive

3 62 years 0–IIc sm1 Moderately Upper mediastinalLN metastasis

50 mo Chemoradiotherapy 62 mo dead

4 72 years 0–IIc m3 Moderately Gastric wallmetastasis

41 mo Total gastrectomy 94 mo alive

Upper mediastinalLN metastasis

87 mo Chemoradiotherapy

5 78 years 0–IIc m3 Moderately Cardiac LNmetastasis

42 mo LN dissection 54 mo alive

sm1, tumors invading the upper submucosa; m3, tumors invading the muscularis mucosae; mo, months.

268 Y SHIMIZU

ET AL.

to have cardiac lymph node metastasis (diameter, 1.1 cm) byfollow-up EUS examination 42 months after EMR andunderwent curative lymph node dissection (Figs 1,2).

DISCUSSION

Numerous studies on esophageal squamous cell carcinomahave shown that lesions confined to the lamina propriamucosa have a minimal risk of lymph node or distantmetastasis.

2–4

In contrast, lymph node metastasis occurs in10–15% of cases with invasion of m3 or sm1.

2–4

These findingshave led to recommended indications for EMR. Convention-ally, the use of EMR was limited to carcinoma in situ andtumors invading the lamina propria of the esophagus.

1–3

Tumors invading m3 or deeper were indications for esoph-agectomy.

3,5

However, more than 85% of patients withtumors extending to m3 or sm1 actually do not require lymphnode dissection. Moreover, improved systems for EUS nowenable us to undergo preoperative detection of 50–80% ofmetastatic lymph nodes.

8–10

Thus, EMR provides an adequateextent of resection for many patients with esophageal tumorsinvading m3 or sm1 who have no evidence of lymph nodemetastasis.

Pulmonary complications, recurrent laryngeal nerve paral-ysis, and other problematic symptoms often occur in patientswho undergo subtotal esophagectomy. Some patients diebecause of such complications.

3

Esophagectomy also nega-tively affects patients' quality of life, and can cause swallow-ing disturbances, aspiration pneumonia and malnutrition.

3

Minimally invasive treatment may, therefore, be better forpatients with early esophageal carcinoma who are elderly,have comorbidity or refuse invasive surgery.

We previously reported that there was no significant dif-ference in overall survival distributions, notably 5-year sur-vival rates, between the extended EMR group and patientswith tumor in the same stage who underwent surgical resec-tion, despite the inclusion of many poor-risk patients in theformer group.

7

These groups also had similar cause-specific

Fig. 1.

Endoscopic image showing slightly depressed type(0–IIc type) reddish carcinoma of the esophagus (case 5 inTable 2). The patient underwent endoscopic mucosal resection.Histologically, the tumor invaded the muscularis mucosae.

Fig. 2.

(a) Endoscopic ultrasonographic image showing acardiac lymph node of a patient 29 months after endoscopicmucosal resection. (b) Endoscopic ultrasonographic imageshowing the same cardiac lymph node as that presented inFig. 2a. The diameter of the lymph node increased from 4 mmto 11 mm over a period of 11 months, and was diagnosed as ametastatic lymph node. Lymph node dissection was performedand histological examination confirmed the diagnosis ofmetastatic lymph node.

a

b

RELAPSE AFTER EMR FOR ESOPHAGEAL CANCER 269

5-year survival rates.

7

Although further study is required, theresults indicate a good survival distribution in the extendedEMR group.

As for the five patients who were found to have metastasisafter extended EMR, it is unlikely that patient 1 and patient2, both with probable distant metastasis, received inadequatetreatment. Surgery with lymph node dissection usually can-not prevent distant metastasis. Radical surgery does notalways result in complete cure. The patients with lymph noderecurrence (patient 3 and patient 4) did not undergo follow-up examination for more than 1 year, and lymph nodemetastasis in those patients were already advanced at thetime of detection. We believe that patients with early lymphnode metastasis, such as patient 5 in this study, shouldundergo curative surgical resection. We recommend thatpatients undergoing extended EMR be followed up by CT,EUS and percutanous ultrasonography every 6 monthsfor at least 5 years after EMR. Patients with early lymphnode metastasis should undergo surgical resection orchemoradiotherapy.

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