A Case of Advanced Esophageal Cancer with Extensive Lymph Node Metastases Successfully Treated with Multimodal Therapy Kaori Shigemitsu 1 , Yoshio Naomoto 1 , Yasuhiro Shirakawa 1 , Minou Haisa 1 , Mehmet Gunduz 2 and Noriaki Tanaka 1 Departments of 1 Gastroenterological Surgery, Transplant and Surgical Oncology and 2 Oral Pathology and Medicine, Graduate School of Medicine and Dentistry, Okayama University, Okayama, Japan For reprints and all correspondence: Kaori Shigemitsu, Department of Gastroenterological Surgery, Transplant and Surgical Oncology, Graduate School of Medicine and Dentistry, Okayama University, 251 Shikata-cho, Okayama City, Okayama 700-8558, Japan Received February 14, 2002; accepted May 14, 2002 Advanced esophageal cancer patients with extensive lymph node metastases show extremely poor prognosis and the long-term outcome is poorer with the involvement of more lymph nodes. We report here a long-surviving case of advanced esophageal cancer with histologically 34 lymph node metastases, in which surgical resection with three-field lymphadenectomy fol- lowed by adjuvant chemotherapy and radiotherapy was performed. A 53-year-old male was diagnosed as advanced middle esophageal cancer with multiple regional lymph node metas- tases such as paraesophageal, pretracheal, tracheobronchial and bifurcational lymph nodes and three intramural metastatic lesions. Subtotal esophagectomy with three-field lymphade- nectomy was performed for the tumor. Histopathologically, the tumor was poorly differ- entiated squamous cell carcinoma and 34 lymph nodes including ligamentum arteriosum lymph nodes and pretracheal lymph nodes were proved to be metastatic. Numerous tumor cells were found in the lymphatic vessels near the metastatic lymph nodes. Chemotherapy [3000 mg of 5- fluorouracil (5-FU), 50 mg of cisplatin (CDDP) and 30 mg of methotrexate (MTX)] was admin- istered in two courses, followed by radiation therapy (field size 21 20 cm in mediastinum, 10 MV X-rays, 2 Gy/fr, 5 fr/week, total 46 Gy). Subsequently, 1000 mg of 5-FU and 200 mg of CDDP were administered every 34 months without any significant toxicities. The patient has been alive and well without recurrence for 5 years following operation. For treatment of advanced esophageal cancer with extensive lymph node metastases, a wide resection of the tumor and regional lymph nodes should be performed, followed by adjuvant chemotherapy and radiotherapy. Key words: esophageal cancer lymph node metastasis adjuvant therapy multimodal therapy INTRODUCTION Esophageal cancer is most often found as advanced cancer with metastatic lesions, with extremely poor patient prognosis. In recent years, several strategies involving combination therapy have been tried to improve this prognosis (1,2), but with little success. In this paper, we report a case of advanced esophageal cancer with histological metastasis of 34 lymph nodes, who showed a good response to 5-fluorouracil (5-FU), cisplatin (CDDP) and methotrexate (MTX) combination chemotherapy followed by radiotherapy after curative resec- tion. He has been alive and well for 5 years after surgery. CASE REPORT A 53-year-old male was referred to our hospital for further examination of X-ray abnormalities including elevated lesion in the esophagus. On admission, he was 168 cm tall and weighed 56 kg, and no specific clinical findings were noted. There were no abnormal findings in laboratory data except for slight elevation of C-GTP. Tumor markers on admission were carcinoembryonic antigen (CEA) 2.29 ng/ml and squamous cell carcinoma antigen (SCC) 0.72 ng/ml. Endoscopy revealed an elevated lesion 3134 cm from the incisor teeth, at the left-anterior wall of the middle esophagus (Fig. 1a). An unstained area delineated the lesion and the sur- rounding flat lesion on iodine staining (Fig. 1b). We diagnosed the tumor as type Ip (polypoid type) + 0IIc (slightly depressed type), according to endoscopic classification based on the Guide Lines for Clinical and Pathologic Studies of the Japanese Society for Esophageal Disease (3). Three lesions detected 27 and 29 cm from the incisor teeth were suspected to Jpn J Clin Oncol 2002;32(8) 311 be intramural metastases. Specimens taken from the tumor revealed poorly differentiated squamous cell carcinoma. Radiological examination of the upper gastrointestinal tract showed an elevated lesion, measuring 3.0 2.4 cm, with uneven surface and distinct margins (Fig. 2). Another smaller elevation was detected in its proximal region. Cervical and chest computed tomography (CT) images sug- gested multiple regional lymph nodes, such as paraesophageal lymph nodes (Fig. 3a and b), pretracheal lymph nodes (Fig. 3a and 3c), tracheobronchial lymph nodes (Fig. 3c) and bifurca- tional lymph nodes (Fig. 3c), to be metastatic. Figure 1. (a) An elevated lesion 3134 cm from the incisor teeth, at the left-anterior wall of the middle esophagus. (b) An unstained area delineated the lesion and the surrounding flat lesion on iodine staining. Figure 2. Radiological examination of the upper gastrointestinal tract showed an elevated lesion, measuring 3.0 2.4 cm, with uneven surface and distinct margins. Figure 3. (a) Cervical and chest CT images suggested the paraesophageal lymph nodes and pretracheal lymph nodes to be metastatic. (b) Paraesophageal lymph nodes swelled to be metastatic. (c) Pretracheal, bifurcational and tracheobronchial lymph nodes swelled to be metastatic. 312 Multimodal therapy for esophageal cancer Based on these findings, the case was classified as a T3N1M0, Stage III advanced esophageal cancer, according to the TNM Classification of Malignant Tumors (4). On thoracotomy, the tumor was located mainly at the middle esophagus and direct invasion of the surrounding tissue could not be identified. Metastases into multiple lymph nodes, including No. 106 pre (pretracheal lymph nodes) and No. 103 (peripharyngeal lymph nodes), according to the Guide Lines for Clinical and Pathologic Studies of the Japanese Esophageal Cancer Society (3), were suspected. Accordingly, subtotal esophagectomy with three-field lymphadenectomy was per- formed and with reconstruction with a gastric tube via the retromediastinal route. The tumor was 3.5 2.6 cm in diameter and presented as type 1p (Fig. 4), and three intramural metastatic lesions were revealed. Histopathological examination showed a poorly differentiated squamous cell carcinoma, pT3, INF >, ly2, v1, pN4(2c), according to the Guide Lines (3). One of two har- vested nodes of light cervical esophageal lymph nodes (No. 101L), one of two light supraclavicular lymph nodes (No. 104L), one of three right recurrent nerve lymph nodes (No. 106 recR), four of four left recurrent nerve lymph nodes (No. 106 recL), four of four upper thoracic paraesophageal lymph nodes (No. 105), 13 of 17 No. 106 pre (Fig. 5a), two of two left tra- cheobronchial lymph nodes (No. 106 tbL), two of six middle thoracic paraesophageal lymph nodes (No. 108) and six of six ligamentum arteriosum lymph nodes (No. 113) were positive for metastasis (Fig. 6). Tumor cells were found in the lym- phatic vessels near the metastatic lymph nodes (Fig. 5b) and intramural metastatic lesions. Four weeks after surgery, the patient was treated with a course of 5-FU at 1000 mg/day on days 13, together with CDDP at 50 mg/day on day 1 and MTX at 30 mg/day on day 1, and received the same course 2 weeks later. From the 67th postoperative day, he received radiotherapy for bilateral supra- clavicular and superior mediastinal nodes (field size 21 20 cm, 10 MV X-rays, 2 Gy/fr, 5 fr/week), a total dose of radio- therapy of 46 Gy. After this therapy, mild leukopenia falling to 3200/l and mild anorexia developed but no serious side effects were observed. After discharge, the patient was treated with a course of 5-FU at 500 mg/day on days 1 and 2, together with CDDP at 20 mg/day on day 1. This combination chemo- therapy was continued further with close follow-up examina- tions and such treatment was repeated every 34 months without any severe adverse effects. The patient has remained alive and well 5 years after surgery without an apparent recur- rent tumor. DISCUSSION Stage IV esophageal cancer usually shows a very poor progno- sis and cases with long-term survival have rarely been reported (5). In our institute, between 1990 and 1998, 179 patients with primary esophageal cancer underwent esophagectomy. Among them, 5-year survival rate of 28 stage IVa cases (15.9%) was 14.9%. Moreover, only two cases among 15 pN4 cases sur- vived for four or more years. It has been reported that the number of nodes involved influ- ences patient survival independently. Kawahara et al. (6) and Kimura et al. (7) reported that the long-term outcome was poorer with the involvement of more lymph nodes and that the 5-year survival rate was significantly poor in patients with four or more metastatic lymph nodes. In the latest edition of the Guide Lines for Clinical and Pathologic Studies of the Japa- nese Society for Esophageal Diseases (3), the degree of lymph node metastasis was modified by the number of metastatic Figure 4. The tumor was 3.5 2.6 cm in diameter and presented as type 1pl. Figure 5. Histological findings. (a) Pretracheal lymph nodes were found to be metastatic. (b) Tumor cells in lymphatic vessels were revealed. Jpn J Clin Oncol 2002;32(8) 313 lymph nodes to define new pN categories: the degree of lymph node metastasis of carcinomas with 47 metastatic regional nodes as the number with one added to the number of meta- static lymph nodes group and with eight or more metastatic regional nodes as the number with two added. Clinical results for esophageal cancer have become rela- tively more favorable than those for other gastrointestinal cancers. Several drugs such as CDDP, mytomycin C, vindesine, MTX and 5-FU have shown antitumor activity against esopha- geal cancer, with a response rate of over 20% in single-agent therapy (2). Although combinations of these drugs have pro- vided response rates of 4060%, most of them were limited to partial response and did not improve survival (2,8). 5-FU and CDDP are the two basic agents in combination chemotherapy for esophageal cancer and the reported objective response rates have been 3560% (911). In loco-regional esophageal cancer, chemotherapy, mostly a combination of 5-FU with CDDP (9,10), together with radiation therapy (12,13) has curative potential. However, for patients with metastatic disease, chemotherapy yields few complete response results and hence is unlikely to have any impact on survival (14). Therefore, a standard therapy for metastatic esophageal carcinoma has yet to be established. In the present case, postoperative histopathological exami- nations showed 34 lymph nodes with metastasis among 49 harvested nodes and the case was considered to have a poor prognosis. 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