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Outcomes of simultaneous resection of synchronous esophageal and extraesophageal carcinomas1
Outcomes of Simultaneous Resection of Synchronous Esophageal and Extraesophageal Carcinomas Satoshi Suzuki, MD, Tadashi Nishimaki, MD, Tsutomu Suzuki, MD, Tatsuo Kanda, MD, Satoru Nakagawa, MD, Katsuyoshi Hatakeyama, MD Adequate extent of surgical resection of simultaneous primary esophageal and extraesophageal carcinomas is controversial. STUDY DESIGN: Clinicopathologic records and treatment outcomes of 57 patients undergoing simultaneous resection of both synchronous esophageal and extraesophageal carcinomas (SC group) were reviewed and compared with those of 316 patients receiving esophagectomy for solitary esophageal carcinoma (EC group). RESULTS: Mortality and morbidity rates were 3.5% and 45.6% in the SC group, and 3.2% and 44.3% in the EC group, respectively. No significant difference was detected in either of the rates between the two patient groups. The overall 5-year survival rate of the SC group was 40%. Survival of the patients undergoing curative resection of both esophageal and extraesophageal tumors (n⫽30) was significantly better than that of the patients receiving palliative resection of at least one of the two tumors in the SC group (n⫽27)(5-year survival, 54.2% versus 19.9%, respectively)(p⬍0.01). Survival of the SC group patients undergoing curative resection of both tumors (n⫽30) did not differ from that of the EC group patients receiving curative esophagectomy (n⫽182)(5-year survival rates, 54.2% versus 60.0%, respectively). CONCLUSIONS: Simultaneous resection of synchronous esophageal and extraesophageal carcinomas can be safely performed, and complete tumor clearance of both tumors is needed for favorable longterm results. (J Am Coll Surg 2002;195:23–29. © 2002 by the American College of Surgeons) BACKGROUND:
No competing interests declared.
chronous cancer of the esophagus and other organs as 3.6% in Japan. Surgical treatment of both cancers can alter expected mortality, morbidity, and survival after the individual procedures. Therapeutic strategies for these scenarios have not been established, and the influence of multiple operations on outcomes remains unclear. The purpose of the present study was to compare outcomes of surgical resection of synchronous cancers of the esophagus and other organs with those of solitary esophageal cancer, and to determine the adequate extent of resection in patients with synchronous carcinomas of the esophagus and extraesophageal organs.
Received August 24, 2001; Revised January 2, 2002; Accepted January 29, 2002. From the First Department of Surgery, Niigata University School of Medicine, Niigata (S Suzuki, Nishimaki, T Suzuki, Kanda, Nakagawa, Hatakeyama), and the Department of Surgery, Tsuruoka Municipal Shonai Hospital, Yamagata (S Suzuki), Japan. Correspondence address: Satoshi Suzuki, MD, Department of Surgery, Tsuruoka Municipal Shonai Hospital, Baba-cho 2-1, Tsuruoka City, Yamagata, Japan 997-0035.
METHODS Between 1980 and 1995, 652 patients with carcinoma of the thoracic esophagus were admitted to the First Department of Surgery, Niigata University. Of those patients, esophageal resection was performed in 407 patients (62.4%).
Esophageal carcinoma carries a poor prognosis even after radical esophagectomy. Some recent studies have observed excellent 5-year survival rates of more than 40% in selected patients with esophageal cancer after extended radical esophagectomy combined with 3-field lymphadenectomy.1–3 But this procedure is highly invasive and places a maximal operative burden on patients, who are frequently compromised by poor nutrition. On the other hand, esophageal carcinoma frequently coincides with cancers of the extraesophageal organs.4,5 Nakayama and Abo6 have reported the incidence of syn-
© 2002 by the American College of Surgeons Published by Elsevier Science Inc.
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Of the 407 patients, 57 (14%) had a synchronous cancer of the extraesophageal organs. Histologically, 52 tumors (91.2%) were squamous cell carcinoma, 3 were adenocarcinoma, and 2 were undifferentiated carcinoma. Synchronous cancer was defined as a primary carcinoma of the extraesophageal organs detected within 1 year of diagnosis of esophageal carcinoma, based on the criteria reported by Warren and Gates.7 Treatment results of the 57 patients with synchronous esophageal and extraesophageal cancers (SC) were compared with those of 316 patients with solitary esophageal carcinoma (EC). Thirty-four of the 407 patients were excluded in this study because postoperative followup data were not available in these patients. Of the 316 tumors of the SC group, 291 (92.1%) were histologically squamous cell carcinoma, 16 were undifferentiated carcinoma, 4 were adenocarcinoma, 4 were adenosquamous carcinoma, and 1 was carcinosarcoma. In this study, the associated cancers in the SC group were diagnosed at the same time as the diagnosis of esophageal cancer, and all patients in the SC group underwent simultaneous resection of both lesions. Thirty-seven patients (64.9%) in the SC group and 202 (63.9%) in the EC group underwent extended radical esophagectomy with 3-field lymphadenectomy, respectively. Four patients in the SC group and 60 in the EC group had received preoperative radiotherapy or chemotherapy. Postoperative adjuvant therapy was administered to 26 patients in the SC group and 202 in the EC group: radiotherapy alone (50 Gy on average) was performed in 1 and 19; chemotherpy alone (cisplatin, vindesin, 5-fluorouracil, or tegafur, either alone or in combination) was given to 22 and 100; and chemoradiotherapy was performed in 3 and 83 in the SC group and in the EC group patients, respectively. Clinical and pathologic records were reviewed in all cases. Esophageal cancer was staged based on the TNM staging system of the International Union Against Cancer. Curative resection (R0) was defined as the absence of residual tumor, and palliative resection (R1 or R2) as the presence of residual tumor either grossly or histologically after resection. In the SC group, curative surgery was defined as cases in which R0 resections were performed for both esophageal and other carcinomas, and palliative surgery as cases in which palliative resection was performed for at least one of the synchronous cancers. Of the 37 patients in the SC group undergoing extended radical esophagectomy, 7 had palliative esophagectomy because of the presence of R1 disease after histologic
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examination of the resected specimens. Likewise, 20 of the 202 EC group patients were regarded as having palliative esophagectomy because of the presence of microscopic residual disease (R1). Early cancer of the stomach and colorectum is defined as a tumor confined to the mucosa or submucosa, regardless of the presence or absence of lymph node metastasis, based on the criteria of the Japanese Classification of Gastric Carcinoma9 and General Rules for Clinical and Pathological Studies of Cancer of the Colon, Rectum, and Anus10 Followup data were available for all patients. Patients were followed regularly at our institution or affiliated hospitals with routine physical and laboratory examinations after discharge. Serum tumor markers, including carcinoembryonic antigen, ␣-fetoprotein, and carbohydrate antigen 19-9 markers, were assessed every 2 to 3 months. Chest radiographs, ultrasonography, or CT scans were performed annually to detect possible disease recurrence. Other examinations, including scintigraphy, peritoneal aspiration cytology, and pleural aspiration cytology, were added when indicated. Differences in frequency were analyzed using a chisquare test or Fisher’s exact probability test for smaller numbers. Differences between means were assessed by Student’s t-test. Cumulative survival rates after surgery were examined using the Kaplan-Meier method. The equality of the survival curves was assessed using the generalized Wilcoxon test. A significant difference was defined as a two-sided p value less than 0.05. RESULTS Primary sites of extraesophageal cancers
The sites of synchronous carcinomas with esophageal carcinoma are summarized in Table 1. The most common site of the synchronous carcinomas was the stomach (59.6%), followed by the colon and rectum (12.3%). Of the 34 cases of gastric carcinoma and the 7 cases of colorectal carcinoma, 23 (67.6%) and 3 (42.9%), respectively, were early carcinomas. Triple cancers (esophagus, stomach, and colon) and quadruple cancers (esophagus, stomach, rectum, and colon) were found in one patient each. Clinicopathologic characteristics
Clinicopathologic features of the patients were compared between the SC and EC groups (Table 2). No significant differences were noted between the two
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groups with respect to age at esophagectomy, gender, primary site, and pathologic TNM stages of the esophageal carcinomas. The types of esophagectomy and reconstruction were compared between the SC and EC groups (Table 3). All patients underwent subtotal esophagectomy through a transthoracic or transhiatal approach, with simultaneous esophageal reconstruction. No major differences were detected in the type of esophagectomy between the two groups. Regarding the organs used as esophageal substitutes, the stomach was more commonly used in the EC group (87.0%) than in the SC group (64.9%) (p⬍0.001). Curative resection of both esophageal and extraesophageal synchronous carcinomas was performed in 30 patients (54.5%) in the SC group; 182 patients (57.6%) in the EC group underwent curative esophagectomy. There was no difference in quality of tumor clearance between the two groups. The types of resection of extraesophageal synchronous carcinomas in the 30 patients of the SC group undergoing curative resection are shown in Table 4. Of the 30 patients, 19 had simultaneous gastric carcinomas. Partial resection of the lesser curvature of the proximal stomach and gastric tube construction for an esophageal substitute using the rest of the stomach was performed in 11 patients, with small early gastric tumors occurring in this portion. The remaining eight patients underwent total gastrectomy with colonic (n⫽7) or jejunal (n⫽1) interposition because of the association of infiltrating gastric tumors requiring radical lymphadenectomy or large gastric tumors precluding tumor-free margins. On the other hand, the types of treatment of extraesophageal carcinomas in palliative cases in the SC group were varied: one patient with pharyngeal carcinoma underwent an intraoral resection, two patients with renal carcinoma underwent a nephrectomy, and a skin cancer patient underwent a tumor excision. Mortality and morbidity
Mortality rates were 3.5% in the SC group and 3.2% in the EC group. No notable difference was present in mortality rates between the two groups. Postoperative complications occurred in 26 patients (45.6%) of the SC group, but in 140 (44.3%) of the EC group. There was no marked difference in the overall incidence of operative complications between the two groups. The postoperative complication status is summarized and compared between the two groups in Table 5. Mean operative time and intraoperative blood loss were 345⫾115 minutes
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Table 1. Sites of Cancers Synchronous with Esophageal Cancer n (n ⴝ 59*)
Site
Stomach Colorectum Thyroid Lung Pancreas Kidney Bile ducts Liver Pharynx Prostate Urinary bladder Skin
34 (23) 7 (3) 5 3 2 2 1 1 1 1 1 1
Numbers in parentheses indicate cases of early cancers. *Triple and quadruple cancers are included, respectively.
and 722⫾412mL in the SC group, and 342⫾99 minutes and 688⫾386mL in the EC group, respectively. No major difference was detected in these parameters between the two groups. Analysis of the 20 postoperaTable 2. Comparison of Clinicopathologic Characteristics Between Patients with Synchronous Esophageal and Extraesophageal Cancers and Those with Solitary Esophageal Cancer
Characteristics
Mean age (y) Gender Male Female Primary site of esophageal cancer Upper Middle Lower Pathologic stage of esophageal cancer 0 I II A II B III IV Unknown
SC (n ⴝ 57) (%)
65.9
EC (n ⴝ 316) (%)
63.5
p Value
ns
49 (86.0) 8 (14.0)
275 (87.0) 41 (13.0)
ns
3 (5.3) 26 (45.6) 28 (49.1)
30 (9.5) 150 (47.5) 136 (43.0)
ns
3 (5.3) 11 (19.3) 9 (15.8) 12 (21.1) 20 (35.1) 2 (3.5) 0 (0)
11 (3.5) 44 (13.9) 75 (23.7) 29 (9.2) 143 (45.3) 10 (3.2) 4 (1.3)
ns
EC, solitary esophageal carcinoma; ns, not significant (p ⬎ 0.05); SC, synchronous esophageal and extraesophageal carcinomas.
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Table 3. Operative Procedures for Esophageal Carcinoma SC (n ⴝ 57) Procedure
Approach Right thoracotomy Transhiatal Reconstruction organ Stomach Colon Jejunum
EC (n ⴝ 316)
n
%
n
%
p Value
37 20
64.9 35.1
232 84
73.4 26.6
ns
37 19 1
64.9 33.3 1.8
275 38 3
87.0 12.0 0.9
⬍0.001
EC, solitary esophageal carcinoma; ns, not significant (p ⬎ 0.05); SC, synchronous esophageal and extraesophageal carcinomas.
tive variables listed in Table 5 also revealed no substantial difference between the two groups. Longterm results
Excluding 2 operative deaths, 27 patients (49.1%) in the SC group died from recurrence of esophageal carcinoma. Only five patients (9.1%) in this group died from recurrence of extraesophageal cancer, including lung (n⫽2), stomach (n⫽1), bile duct (n⫽1), and kidney Table 4. Types of Resection of Extraesophageal Synchronous Carcinomas in SC Group Patients (n ⫽ 30) Undergoing Curative Resection Type
Stomach Total gastrectomy Local resection Colorectum Standard bowel resection Local excision Endoscopic mucosal resection Lung Lobectomy Thyroid Thyroidectomy Bile duct Pancreatoduodenectomy Pancreas Caudal pancreatectomy with splenectomy Liver Partial hepatectomy Prostate Castration Urinary bladder Transurethral resection Triple and quadruple cancers are included, respectively. SC, synchronous esophageal and extraesophageal carcinoma.
n
8 11 2 1 1 2 2 1
1 1 1 1
(n⫽1) tumors. The overall 5-year survival rate in the SC group was 40.0% (Fig. 1). The 5-year survival rate of the patients undergoing curative surgery was 54.2%; that of those undergoing palliative resection was 19.9%. A significant difference (p⬍0.01) was detected between the two survival curves. In contrast, there was no significant difference between the survival curves of the patients (n⫽30) in the SC group undergoing curative resection and those of the patients (n⫽182) in the EC group undergoing curative esophagectomy (Fig. 2). The 5-year survival rate of the latter patients was 60%. None of the patients in the SC group undergoing curative resection for stage 0 (n⫽3) and stage I (n⫽8) esophageal diseases died of tumor recurrence, and none of those in the EC group undergoing curative esophagectomy for stage 0 disease (n⫽11) died from recurrence. The survival curve of the patients undergoing simultaneous curative resection of stage II or stage III esophageal carcinomas and synchronous extraesophageal carcinomas (n⫽19) was not different from the survival curve of the patients undergoing curative esophagectomy for solitary stage II or stage III esophageal carcinomas (n⫽124). The respective 5-year survival rates were 30% and 48%. DISCUSSION It is well known that second primary carcinomas occasionally develop in extraesophageal sites of patients with esophageal cancer. Nakayama and Abo6 have reported that 251 (2.1%) and 136 (1.5%) of 11,732 patients with esophageal carcinoma had synchronous and metachronous cancers of other organs, respectively. In Japan, the most common site of concomitant carcinoma has been reported to be the stomach. In a nationwide study performed by the Japanese Society for Esophageal Diseases, gastric carcinoma was found as a second primary cancer
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Table 5. Postoperative Complications SC (n ⴝ 57) Category
Cardiovascular Atrial fibrillation Paroxysmal atrial tachycardia Heart failure Other Pulmonary Pneumonia Pulmonary edema Lobar collapse Bronchial asthma Hydrothorax Pulmonary embolism Surgical Cervical anastomotic leak Cervical anastomotic stenosis Chylothorax Hemothorax Pneumothorax Wound dehiscence Other Infectious Wound infection Empyema Intraabdominal abscess Sepsis Enteritis Other Any of the above complications
EC (n ⴝ 316)
n
%
n
%
1 0 0 0
1.8 0.0 0.0 0.0
0 3 1 3
0.0 0.9 0.3 0.9
9 1 1 0 5 1
15.8 1.8 1.8 0.0 8.8 1.8
34 21 5 3 36 1
10.8 6.6 1.6 0.9 11.4 0.3
11 4 2 0 3 1 3
19.3 7.0 3.5 0.0 5.3 1.8 5.3
74 23 6 4 8 1 10
23.4 7.3 1.9 1.3 2.5 0.3 3.2
2 1 1 0 2 0 26
3.5 1.8 1.8 0.0 3.5 0.0 45.6
23 9 1 3 1 4 140
7.3 2.8 0.3 0.9 0.3 1.3 44.3
SC and EC groups were comparable (p ⬎ 0.05). EC, solitary esophageal carcinoma; SC, synchronous esophageal and extraesophageal carcinomas.
in 77% of 243 patients with both esophageal and extraesophageal carcinomas.6 The oropharyngolaryngeal region has also been reported to be a common site of occurrence of second primary cancer in patients with esophageal cancer. Goodner11 reported an incidence of 9.6% of such carcinomas in esophageal cancer patients suggesting the possibility of a common etiology between the two carcinomas12 In this study, simultaneous carcinomas occurring in extraesophageal sites were found in 14% of the patients undergoing esophagectomy for esophageal cancer. In accordance with previous reports,6 gastric cancer was the most common second primary cancer, followed by colorectal cancer. These results indicate the need for careful examination of these organs before esophageal resection
Figure 1. Survival after simultaneous resection of synchronous esophageal and extraesophageal carcinomas (n ⫽ 57).
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performed in patients, and does not lead to increased mortality and morbidity rates. For favorable longterm results, complete tumor resection of both tumors is necessary. Author Contributions
Study conception and design: S Suzuki, Nishimaki, T Suzuki Acquisition of data: S Suzuki, T Suzuki Analysis and interpretation of data: S Suzuki, Nishimaki, T Suzuki, Kanda, Nakagawa Drafting of manuscript: S Suzuki, Nishimaki Critical revision: Nishimaki, Hatakeyama Figure 2. Survival after curative surgery for solitary esophageal carcinoma (EC, n ⫽ 182) and simultaneous curative resection of synchronous esophageal and extraesophageal carcinomas (SC, n ⫽ 30). EC, esophageal carcinoma; SC, synchronous esophageal and extraesophageal carcinoma.
in patients with esophageal cancer. In contrast, carcinomas of the upper aerodigestive tract were rare in our series, which may reflect the higher incidence of gastric cancer in Japan,6,13,14 than in western countries. Adequate management of patients with synchronous extraesophageal carcinomas with esophageal carcinoma has been controversial. Some authors have insisted on separate resections and others have recommended simultaneous resection for these patients. In this series, mortality and morbidity rates were 3.5% and 45.6% in the SC group, and 3.2% and 44.3% in the EC group, respectively. No major difference was detected in either rate between the two patient groups. These results indicate that radical esophagectomy with simultaneous resection can be safely performed in most patients with synchronous esophageal and extraesophageal cancers, and does not necessarily lead to increased postoperative complications. There was no marked difference between the survival curves of the SC group patients undergoing curative resection and the EC group patients receiving curative esophagectomy. The survival curve of the patients undergoing curative resection of both carcinomas was notably better than that of those receiving palliative resection in this study. These results also support the need for complete tumor clearance of both carcinomas for favorable patient outcomes. In conclusion, simultaneous resection of synchronous esophageal and extraesophageal carcinomas can be safely
REFERENCES 1. Kato H, Watanabe H, Tachimori Y, Iizuka T. Evaluation of neck lymph node dissection for thoracic esophageal carcinoma. Ann Thorac Surg 1991;51:931–935. 2. Akiyama H, Tsurumaru M, Udagawa H, Kajiyama Y. Radical lymph node dissection for cancer of the thoracic esophagus. Ann Surg 1994;220:364–373. 3. Nishimaki T, Suzuki T, Suzuki S, et al. Outcomes of extended radical esophagectomy for thoracic esophageal cancer. J Am Coll Surg 1998;186:306–312. 4. Kuwano H, Morita M, Tsutsui S, et al. Comparison of characteristics of esophageal squamous cell carcinoma associated with head and neck cancer and those of gastric cancer. J Surg Oncol 1991;46:107–109. 5. Abemayor E, Moore DM, Hanson DG. Identification of synchronous esophageal tumors in patients with head and neck cancer. J Surg Oncol 1998;38:94–96. 6. Nakayama K, Abo S. Concurrent cancer of the esophagus in Japan. Int Adv Surg Oncol 1979;2:243–249. 7. Warren S, Gates O. Multiple primary malignant tumors. A survey of the literature and a statistical study. Am J Cancer 1932; 16:1358–1414. 8. Hermanek P, Sobin LH. TNM classification of malignant tumours. 4th ed. Berlin: Springer-Verlag; 1987:40–42. 9. Japanese Research Society for Gastric Cancer. Japanese classification of gastric carcinoma. First English edition. Tokyo: Kanehara & Co Ltd; 1995. 10. Japanese Society for Cancer of the Colon and Rectum. General rules for clinical and pathological studies on cancer of the colon, rectum and anus. 6th edition. Tokyo: Kanehara & Co Ltd; 1998. 11. Goodner JT. Cancer of the esophagus: its association with other primary cancers. Cancer 1956;9:1248–1252. 12. Tepperman BS, Fitzpatrik PJ. Secondary respiratory and upper digestive tract cancers after an oral cancer. Lancet 1981;2:547– 549. 13. Sales D, Levin B. Incidence, epidemiology, and predisposing factors. In: De Meester TR, Levin B, eds. Cancer of the esophagus. Orlando, FL: Grune & Straton; 1985:1–19. 14. Maeta M, Koga S, Adachi H, Izumi A. Esophageal cancer associated with primary early gastric cancer. Jpn J Surg 1983;13:96– 100.
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15. Uchida Y, Tomonari K, Murakami S, et al. Diagnosis and surgical treatment for esophageal cancer associated with simultaneous gastric cancer. J Jpn Soc Cancer Ther 1986;21:1292–1301. 16. Souquet J-C, Berger F, Bonvoisin S, et al. Esophageal squamous cell carcinoma associated with gastric adenocarcinoma. Cancer 1989;63:786–790.
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17. Katayanagi N, Muto T, Tanaka O, et al. Study on esophageal cancer associated with other primary cancers. Jpn J Gastroenterol Surg 1991;24:968–976. 18. Satoh H, Isono K, Onoda S. Concurrent cancer of the esophagus and other organs. The Saishin Igaku 1985;40:1629– 1633.
No competing interests declared.
chronous cancer of the esophagus and other organs as 3.6% in Japan. Surgical treatment of both cancers can alter expected mortality, morbidity, and survival after the individual procedures. Therapeutic strategies for these scenarios have not been established, and the influence of multiple operations on outcomes remains unclear. The purpose of the present study was to compare outcomes of surgical resection of synchronous cancers of the esophagus and other organs with those of solitary esophageal cancer, and to determine the adequate extent of resection in patients with synchronous carcinomas of the esophagus and extraesophageal organs.
Received August 24, 2001; Revised January 2, 2002; Accepted January 29, 2002. From the First Department of Surgery, Niigata University School of Medicine, Niigata (S Suzuki, Nishimaki, T Suzuki, Kanda, Nakagawa, Hatakeyama), and the Department of Surgery, Tsuruoka Municipal Shonai Hospital, Yamagata (S Suzuki), Japan. Correspondence address: Satoshi Suzuki, MD, Department of Surgery, Tsuruoka Municipal Shonai Hospital, Baba-cho 2-1, Tsuruoka City, Yamagata, Japan 997-0035.
METHODS Between 1980 and 1995, 652 patients with carcinoma of the thoracic esophagus were admitted to the First Department of Surgery, Niigata University. Of those patients, esophageal resection was performed in 407 patients (62.4%).
Esophageal carcinoma carries a poor prognosis even after radical esophagectomy. Some recent studies have observed excellent 5-year survival rates of more than 40% in selected patients with esophageal cancer after extended radical esophagectomy combined with 3-field lymphadenectomy.1–3 But this procedure is highly invasive and places a maximal operative burden on patients, who are frequently compromised by poor nutrition. On the other hand, esophageal carcinoma frequently coincides with cancers of the extraesophageal organs.4,5 Nakayama and Abo6 have reported the incidence of syn-
© 2002 by the American College of Surgeons Published by Elsevier Science Inc.
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Of the 407 patients, 57 (14%) had a synchronous cancer of the extraesophageal organs. Histologically, 52 tumors (91.2%) were squamous cell carcinoma, 3 were adenocarcinoma, and 2 were undifferentiated carcinoma. Synchronous cancer was defined as a primary carcinoma of the extraesophageal organs detected within 1 year of diagnosis of esophageal carcinoma, based on the criteria reported by Warren and Gates.7 Treatment results of the 57 patients with synchronous esophageal and extraesophageal cancers (SC) were compared with those of 316 patients with solitary esophageal carcinoma (EC). Thirty-four of the 407 patients were excluded in this study because postoperative followup data were not available in these patients. Of the 316 tumors of the SC group, 291 (92.1%) were histologically squamous cell carcinoma, 16 were undifferentiated carcinoma, 4 were adenocarcinoma, 4 were adenosquamous carcinoma, and 1 was carcinosarcoma. In this study, the associated cancers in the SC group were diagnosed at the same time as the diagnosis of esophageal cancer, and all patients in the SC group underwent simultaneous resection of both lesions. Thirty-seven patients (64.9%) in the SC group and 202 (63.9%) in the EC group underwent extended radical esophagectomy with 3-field lymphadenectomy, respectively. Four patients in the SC group and 60 in the EC group had received preoperative radiotherapy or chemotherapy. Postoperative adjuvant therapy was administered to 26 patients in the SC group and 202 in the EC group: radiotherapy alone (50 Gy on average) was performed in 1 and 19; chemotherpy alone (cisplatin, vindesin, 5-fluorouracil, or tegafur, either alone or in combination) was given to 22 and 100; and chemoradiotherapy was performed in 3 and 83 in the SC group and in the EC group patients, respectively. Clinical and pathologic records were reviewed in all cases. Esophageal cancer was staged based on the TNM staging system of the International Union Against Cancer. Curative resection (R0) was defined as the absence of residual tumor, and palliative resection (R1 or R2) as the presence of residual tumor either grossly or histologically after resection. In the SC group, curative surgery was defined as cases in which R0 resections were performed for both esophageal and other carcinomas, and palliative surgery as cases in which palliative resection was performed for at least one of the synchronous cancers. Of the 37 patients in the SC group undergoing extended radical esophagectomy, 7 had palliative esophagectomy because of the presence of R1 disease after histologic
J Am Coll Surg
examination of the resected specimens. Likewise, 20 of the 202 EC group patients were regarded as having palliative esophagectomy because of the presence of microscopic residual disease (R1). Early cancer of the stomach and colorectum is defined as a tumor confined to the mucosa or submucosa, regardless of the presence or absence of lymph node metastasis, based on the criteria of the Japanese Classification of Gastric Carcinoma9 and General Rules for Clinical and Pathological Studies of Cancer of the Colon, Rectum, and Anus10 Followup data were available for all patients. Patients were followed regularly at our institution or affiliated hospitals with routine physical and laboratory examinations after discharge. Serum tumor markers, including carcinoembryonic antigen, ␣-fetoprotein, and carbohydrate antigen 19-9 markers, were assessed every 2 to 3 months. Chest radiographs, ultrasonography, or CT scans were performed annually to detect possible disease recurrence. Other examinations, including scintigraphy, peritoneal aspiration cytology, and pleural aspiration cytology, were added when indicated. Differences in frequency were analyzed using a chisquare test or Fisher’s exact probability test for smaller numbers. Differences between means were assessed by Student’s t-test. Cumulative survival rates after surgery were examined using the Kaplan-Meier method. The equality of the survival curves was assessed using the generalized Wilcoxon test. A significant difference was defined as a two-sided p value less than 0.05. RESULTS Primary sites of extraesophageal cancers
The sites of synchronous carcinomas with esophageal carcinoma are summarized in Table 1. The most common site of the synchronous carcinomas was the stomach (59.6%), followed by the colon and rectum (12.3%). Of the 34 cases of gastric carcinoma and the 7 cases of colorectal carcinoma, 23 (67.6%) and 3 (42.9%), respectively, were early carcinomas. Triple cancers (esophagus, stomach, and colon) and quadruple cancers (esophagus, stomach, rectum, and colon) were found in one patient each. Clinicopathologic characteristics
Clinicopathologic features of the patients were compared between the SC and EC groups (Table 2). No significant differences were noted between the two
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groups with respect to age at esophagectomy, gender, primary site, and pathologic TNM stages of the esophageal carcinomas. The types of esophagectomy and reconstruction were compared between the SC and EC groups (Table 3). All patients underwent subtotal esophagectomy through a transthoracic or transhiatal approach, with simultaneous esophageal reconstruction. No major differences were detected in the type of esophagectomy between the two groups. Regarding the organs used as esophageal substitutes, the stomach was more commonly used in the EC group (87.0%) than in the SC group (64.9%) (p⬍0.001). Curative resection of both esophageal and extraesophageal synchronous carcinomas was performed in 30 patients (54.5%) in the SC group; 182 patients (57.6%) in the EC group underwent curative esophagectomy. There was no difference in quality of tumor clearance between the two groups. The types of resection of extraesophageal synchronous carcinomas in the 30 patients of the SC group undergoing curative resection are shown in Table 4. Of the 30 patients, 19 had simultaneous gastric carcinomas. Partial resection of the lesser curvature of the proximal stomach and gastric tube construction for an esophageal substitute using the rest of the stomach was performed in 11 patients, with small early gastric tumors occurring in this portion. The remaining eight patients underwent total gastrectomy with colonic (n⫽7) or jejunal (n⫽1) interposition because of the association of infiltrating gastric tumors requiring radical lymphadenectomy or large gastric tumors precluding tumor-free margins. On the other hand, the types of treatment of extraesophageal carcinomas in palliative cases in the SC group were varied: one patient with pharyngeal carcinoma underwent an intraoral resection, two patients with renal carcinoma underwent a nephrectomy, and a skin cancer patient underwent a tumor excision. Mortality and morbidity
Mortality rates were 3.5% in the SC group and 3.2% in the EC group. No notable difference was present in mortality rates between the two groups. Postoperative complications occurred in 26 patients (45.6%) of the SC group, but in 140 (44.3%) of the EC group. There was no marked difference in the overall incidence of operative complications between the two groups. The postoperative complication status is summarized and compared between the two groups in Table 5. Mean operative time and intraoperative blood loss were 345⫾115 minutes
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Table 1. Sites of Cancers Synchronous with Esophageal Cancer n (n ⴝ 59*)
Site
Stomach Colorectum Thyroid Lung Pancreas Kidney Bile ducts Liver Pharynx Prostate Urinary bladder Skin
34 (23) 7 (3) 5 3 2 2 1 1 1 1 1 1
Numbers in parentheses indicate cases of early cancers. *Triple and quadruple cancers are included, respectively.
and 722⫾412mL in the SC group, and 342⫾99 minutes and 688⫾386mL in the EC group, respectively. No major difference was detected in these parameters between the two groups. Analysis of the 20 postoperaTable 2. Comparison of Clinicopathologic Characteristics Between Patients with Synchronous Esophageal and Extraesophageal Cancers and Those with Solitary Esophageal Cancer
Characteristics
Mean age (y) Gender Male Female Primary site of esophageal cancer Upper Middle Lower Pathologic stage of esophageal cancer 0 I II A II B III IV Unknown
SC (n ⴝ 57) (%)
65.9
EC (n ⴝ 316) (%)
63.5
p Value
ns
49 (86.0) 8 (14.0)
275 (87.0) 41 (13.0)
ns
3 (5.3) 26 (45.6) 28 (49.1)
30 (9.5) 150 (47.5) 136 (43.0)
ns
3 (5.3) 11 (19.3) 9 (15.8) 12 (21.1) 20 (35.1) 2 (3.5) 0 (0)
11 (3.5) 44 (13.9) 75 (23.7) 29 (9.2) 143 (45.3) 10 (3.2) 4 (1.3)
ns
EC, solitary esophageal carcinoma; ns, not significant (p ⬎ 0.05); SC, synchronous esophageal and extraesophageal carcinomas.
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Table 3. Operative Procedures for Esophageal Carcinoma SC (n ⴝ 57) Procedure
Approach Right thoracotomy Transhiatal Reconstruction organ Stomach Colon Jejunum
EC (n ⴝ 316)
n
%
n
%
p Value
37 20
64.9 35.1
232 84
73.4 26.6
ns
37 19 1
64.9 33.3 1.8
275 38 3
87.0 12.0 0.9
⬍0.001
EC, solitary esophageal carcinoma; ns, not significant (p ⬎ 0.05); SC, synchronous esophageal and extraesophageal carcinomas.
tive variables listed in Table 5 also revealed no substantial difference between the two groups. Longterm results
Excluding 2 operative deaths, 27 patients (49.1%) in the SC group died from recurrence of esophageal carcinoma. Only five patients (9.1%) in this group died from recurrence of extraesophageal cancer, including lung (n⫽2), stomach (n⫽1), bile duct (n⫽1), and kidney Table 4. Types of Resection of Extraesophageal Synchronous Carcinomas in SC Group Patients (n ⫽ 30) Undergoing Curative Resection Type
Stomach Total gastrectomy Local resection Colorectum Standard bowel resection Local excision Endoscopic mucosal resection Lung Lobectomy Thyroid Thyroidectomy Bile duct Pancreatoduodenectomy Pancreas Caudal pancreatectomy with splenectomy Liver Partial hepatectomy Prostate Castration Urinary bladder Transurethral resection Triple and quadruple cancers are included, respectively. SC, synchronous esophageal and extraesophageal carcinoma.
n
8 11 2 1 1 2 2 1
1 1 1 1
(n⫽1) tumors. The overall 5-year survival rate in the SC group was 40.0% (Fig. 1). The 5-year survival rate of the patients undergoing curative surgery was 54.2%; that of those undergoing palliative resection was 19.9%. A significant difference (p⬍0.01) was detected between the two survival curves. In contrast, there was no significant difference between the survival curves of the patients (n⫽30) in the SC group undergoing curative resection and those of the patients (n⫽182) in the EC group undergoing curative esophagectomy (Fig. 2). The 5-year survival rate of the latter patients was 60%. None of the patients in the SC group undergoing curative resection for stage 0 (n⫽3) and stage I (n⫽8) esophageal diseases died of tumor recurrence, and none of those in the EC group undergoing curative esophagectomy for stage 0 disease (n⫽11) died from recurrence. The survival curve of the patients undergoing simultaneous curative resection of stage II or stage III esophageal carcinomas and synchronous extraesophageal carcinomas (n⫽19) was not different from the survival curve of the patients undergoing curative esophagectomy for solitary stage II or stage III esophageal carcinomas (n⫽124). The respective 5-year survival rates were 30% and 48%. DISCUSSION It is well known that second primary carcinomas occasionally develop in extraesophageal sites of patients with esophageal cancer. Nakayama and Abo6 have reported that 251 (2.1%) and 136 (1.5%) of 11,732 patients with esophageal carcinoma had synchronous and metachronous cancers of other organs, respectively. In Japan, the most common site of concomitant carcinoma has been reported to be the stomach. In a nationwide study performed by the Japanese Society for Esophageal Diseases, gastric carcinoma was found as a second primary cancer
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Table 5. Postoperative Complications SC (n ⴝ 57) Category
Cardiovascular Atrial fibrillation Paroxysmal atrial tachycardia Heart failure Other Pulmonary Pneumonia Pulmonary edema Lobar collapse Bronchial asthma Hydrothorax Pulmonary embolism Surgical Cervical anastomotic leak Cervical anastomotic stenosis Chylothorax Hemothorax Pneumothorax Wound dehiscence Other Infectious Wound infection Empyema Intraabdominal abscess Sepsis Enteritis Other Any of the above complications
EC (n ⴝ 316)
n
%
n
%
1 0 0 0
1.8 0.0 0.0 0.0
0 3 1 3
0.0 0.9 0.3 0.9
9 1 1 0 5 1
15.8 1.8 1.8 0.0 8.8 1.8
34 21 5 3 36 1
10.8 6.6 1.6 0.9 11.4 0.3
11 4 2 0 3 1 3
19.3 7.0 3.5 0.0 5.3 1.8 5.3
74 23 6 4 8 1 10
23.4 7.3 1.9 1.3 2.5 0.3 3.2
2 1 1 0 2 0 26
3.5 1.8 1.8 0.0 3.5 0.0 45.6
23 9 1 3 1 4 140
7.3 2.8 0.3 0.9 0.3 1.3 44.3
SC and EC groups were comparable (p ⬎ 0.05). EC, solitary esophageal carcinoma; SC, synchronous esophageal and extraesophageal carcinomas.
in 77% of 243 patients with both esophageal and extraesophageal carcinomas.6 The oropharyngolaryngeal region has also been reported to be a common site of occurrence of second primary cancer in patients with esophageal cancer. Goodner11 reported an incidence of 9.6% of such carcinomas in esophageal cancer patients suggesting the possibility of a common etiology between the two carcinomas12 In this study, simultaneous carcinomas occurring in extraesophageal sites were found in 14% of the patients undergoing esophagectomy for esophageal cancer. In accordance with previous reports,6 gastric cancer was the most common second primary cancer, followed by colorectal cancer. These results indicate the need for careful examination of these organs before esophageal resection
Figure 1. Survival after simultaneous resection of synchronous esophageal and extraesophageal carcinomas (n ⫽ 57).
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performed in patients, and does not lead to increased mortality and morbidity rates. For favorable longterm results, complete tumor resection of both tumors is necessary. Author Contributions
Study conception and design: S Suzuki, Nishimaki, T Suzuki Acquisition of data: S Suzuki, T Suzuki Analysis and interpretation of data: S Suzuki, Nishimaki, T Suzuki, Kanda, Nakagawa Drafting of manuscript: S Suzuki, Nishimaki Critical revision: Nishimaki, Hatakeyama Figure 2. Survival after curative surgery for solitary esophageal carcinoma (EC, n ⫽ 182) and simultaneous curative resection of synchronous esophageal and extraesophageal carcinomas (SC, n ⫽ 30). EC, esophageal carcinoma; SC, synchronous esophageal and extraesophageal carcinoma.
in patients with esophageal cancer. In contrast, carcinomas of the upper aerodigestive tract were rare in our series, which may reflect the higher incidence of gastric cancer in Japan,6,13,14 than in western countries. Adequate management of patients with synchronous extraesophageal carcinomas with esophageal carcinoma has been controversial. Some authors have insisted on separate resections and others have recommended simultaneous resection for these patients. In this series, mortality and morbidity rates were 3.5% and 45.6% in the SC group, and 3.2% and 44.3% in the EC group, respectively. No major difference was detected in either rate between the two patient groups. These results indicate that radical esophagectomy with simultaneous resection can be safely performed in most patients with synchronous esophageal and extraesophageal cancers, and does not necessarily lead to increased postoperative complications. There was no marked difference between the survival curves of the SC group patients undergoing curative resection and the EC group patients receiving curative esophagectomy. The survival curve of the patients undergoing curative resection of both carcinomas was notably better than that of those receiving palliative resection in this study. These results also support the need for complete tumor clearance of both carcinomas for favorable patient outcomes. In conclusion, simultaneous resection of synchronous esophageal and extraesophageal carcinomas can be safely
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