Thymic carcinoma has been recognized as an entity that is different. Treatment and Prognosis of Thymic Carcinoma. A Retrospective Analysis of 40 Cases

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1 3115 Treatment and Prognosis of Thymic Carcinoma A Retrospective Analysis of 40 Cases Kazuhiko Ogawa, M.D. 1 Takafumi Toita, M.D. 1 Takashi Uno, M.D. 2 Nobukazu Fuwa, M.D. 3 Yasumasa Kakinohana, Ph.D. 1 Minoru Kamata, M.D. 3 Kageharu Koja, M.D. 4 Takao Kinjo, M.D. 5 Genki Adachi, M.D. 1 Sadayuki Murayama, M.D. 1 1 Department of Radiology, University of the 2 Department of Radiology, Chiba University, School of Medicine, Chiba, Japan. 3 Department of Radiation Oncology, Aichi Cancer Center Hospital, Nagoya, Japan. 4 Second Department of Surgery, University of the 5 Department of Pathology, University of the BACKGROUND. Thymic carcinomas are rare neoplasms, and information regarding the results of treatment and possible prognostic factors in patients with these tumors is limited. METHODS. The records of 40 patients with histologically confirmed thymic carcinoma who were treated between 1984 and 1998 were reviewed. Twenty-seven patients were treated with surgical resection followed by radiotherapy with or without chemotherapy, and the remaining 13 patients were treated with radiotherapy with or without chemotherapy. The median follow-up time for the 13 surviving patients was 87 months (range, months). RESULTS. The 5-year and 10-year actuarial overall survival rates in all patients were 38% and 28%, respectively. On univariate analysis, complete resection, Karnofsky performance status (KPS), histology, and Masaoka stage at the time of diagnosis were found to have a significant impact on overall survival, whereas on multivariate analysis, complete resection, KPS, and histology were found to be significant prognostic factors. With regard to the degree of resection, 12 of 16 patients (75%) treated with complete resection were alive and free of disease at the time of last follow-up whereas 1 of 24 patients (4%) treated with incomplete resection or biopsy still was alive. Among 12 surviving patients treated with complete resection, 8 with resectable tumors at the time of presentation all had low-grade histology (squamous cell carcinoma) and were treated successfully with complete resection and postoperative radiotherapy with or without adjuvant chemotherapy. The remaining four patients with unresectable tumors at the time of presentation were treated successfully with neoadjuvant chemotherapy, complete resection, and postoperative radiotherapy. CONCLUSIONS. The results of the current study indicate that multimodal treatment, especially complete resection and postoperative radiotherapy with or without chemotherapy, is a curative therapy for thymic carcinomas. Cancer 2002;94: American Cancer Society. DOI /cncr KEYWORDS: thymoma, thymic carcinoma, radiation therapy, surgery, chemotherapy, multimodality treatments. Address for reprints: Kazuhiko Ogawa, M.D., Department of Radiology, University of the Ryukyus School of Medicine, 207 Uehara, Nishihara-cho, Okinawa, , Japan; Fax: (011) ; kogawa@med.u-ryukyu.ac.jp Received November 26, 2001; accepted January 15, Thymic carcinoma has been recognized as an entity that is different from thymoma, because of its obvious cytologic atypia, more invasive nature, and malignant behavior. 1 4 These tumors usually are advanced and have a higher recurrence rate and worse survival compared with the majority of thymomas. 5 The histologic classification of thymic carcinoma was proposed by Levine and Rosai 6 and revised by Suster and Rosai. 1 The tumors are classified broadly as being of low-grade and high-grade histology. Low-grade histology includes squamous cell carcinoma, mucoepidermoid carcinoma, and basaloid carcinoma. Those tumors with high-grade histology include lympho American Cancer Society

2 3116 CANCER June 15, 2002 / Volume 94 / Number 12 epithelioma-like carcinoma, small cell carcinoma, undifferentiated carcinoma, sarcomatoid carcinoma, and clear cell carcinoma. 1,7,8 Although surgical resection has been the first line of treatment of thymic carcinoma, radiotherapy and/or chemotherapy also have been utilized in cases that are unresectable. 1,7 9 However, information regarding treatment modalities and long-term prognosis has been limited by the rarity of this entity. In the current study, we reviewed a retrospective series of 40 patients with thymic carcinoma and indicated possible curative treatments in patients with these tumors. TABLE 1 Treatment Modalities in All 40 Patients with Thymic Carcinoma Treatment modalities No. of patients C SR RT 6 4 SR RT C 4 2 SR RT C RT 10 RT 3 Total CR: complete resection; C: chemotherapy; SR: surgical resection; RT: radiotherapy. No. of patients treated with CR MATERIALS AND METHODS A retrospective review of medical records identified 40 consecutive patients with histologically confirmed thymic carcinoma who were treated at the Department of Radiology, University of the Ryukyus Hospital, Chiba University Hospital, Aichi Cancer Center, and affiliated hospitals between The ages of the patients ranged from years (median, 55 years); 29 patients were male and 11 were female. At the time of presentation, an asymptomatic mass was present on the chest radiograph in 16 patients, symptoms of mediastinal compression (such as chest pain and dyspnea) were present in 16 patients, superior vena cava syndromes were present in 4 patients, hoarseness was present in 2 patients, and bloody sputum was present in 2 patients. None of these patients had concomitant paraneoplastic syndromes such as myasthenia gravis or pure red cell aplasia. All pathologic specimens and surgical reports were reviewed by a coauthor pathologist (K.T.). The criteria for the diagnosis of thymic carcinoma were those exhibiting clear-cut cytologic atypia and a set of cytoarchitectural features no longer specific to the thymus in the absence of a primary tumor at sites other than the anterior mediastinum, either at the time of presentation or at follow-up. The tumors were classified into squamous cell carcinoma (n 29 patients), small cell carcinoma (n 4 patients), undifferentiated carcinoma (n 4 patients), and lymphoepithelioma-like carcinoma (n 3 patients). Therefore, 29 patients had low-grade histology (squamous cell carcinoma) and the remaining 11 patients had high-grade histology. Pretreatment evaluation of the tumor was done by physical examination, chest radiography, chest computed tomography (CT) scan, abdominal CT scan, brain CT scan, abdominal ultrasonography, and bone scan. Clinical staging at the time of diagnosis was based on the criteria described by Masaoka et al. 10 The criteria used in this study are as follows. Stage I indicated macroscopically completely encapsulated disease and no microscopic capsular invasion. Stage II indicated 1) macroscopic invasion into surrounding fatty tissue or mediastinal pleura and/or 2) microscopic invasion into the capsule. Stage III indicated macroscopic invasion into neighboring organs (pericardium, great vessels, or lung). Stage IVA indicated pleural and/or pericardial dissemination of thymoma and Stage IVB indicated lymphogenous or hematogenous metastases. Seven patients had Stage II disease, 18 patients had Stage III disease, and 15 patients had Stage IV disease. Twenty-seven patients were treated with surgical resection (total resection in 16 patients and incomplete resection in 11 patients) followed by radiotherapy with or without chemotherapy. Of these 27 patients, 6 received neoadjuvant chemotherapy and 4 received adjuvant chemotherapy. The remaining 13 patients were treated with radiotherapy with or without chemotherapy (3 patients were treated with radiotherapy alone). The various treatment modalities are listed in Table 1. Radiotherapy was administered with a 60 Cobalt ( 60 CO) teletherapy unit or a 6-megavolt (MV) or 10-MV linear accelerator ( 60 Co teletherapy unit was used in 6 patients). Patients were treated with involved fields that covered the primary tumor or tumor bed with margins of approximately 1 2 cm. Patients were treated with anteroposterior opposed fields with the spinal cord dose limited to 45 grays (Gy) in all cases. Two anterior wedged portals or off-cord oblique opposed portals were used to boost the anterior mediastinum to higher doses. The total dose to the primary tumor or the tumor bed in all patients was Gy (median, 50 Gy). For 16 patients treated with complete resection, a total dose of Gy (median, 50 Gy) was administered. Daily fraction sizes of Gy, 5 days per week, were used. Twenty patients (50%) received various regimens of systemic chemotherapy during the initial treatment. Sixteen of 20 patients received a combination of cisplatin and the most used regimen was a combination of cisplatin,

3 Thymic Carcinoma/Ogawa et al FIGURE 1. Actuarial overall survival rate in all 40 patients with thymic carcinoma. doxorubicin, vincristine, and cyclophosphamide (ADOC). 11 To assess the prognostic factors for overall survival, the data were analyzed with respect to age, gender, Karnofsky performance status (KPS), histology, Masaoka stage at the time of diagnosis, complete resection, total dose, and use of chemotherapy. The median follow-up time of the 13 surviving patients was 87 months (range, months), and no patients were lost to follow-up. Overall survival rates were calculated actuarially according to the Kaplan Meier method 12 and were measured from the day of diagnosis. Differences between groups were estimated using the generalized Wilcoxon test. 13 Multivariate analysis was performed using the Cox regression model. 14 A probability level of 0.05 was chosen for statistical significance. Statistical analysis was performed using the SPSS software package (Version 6.1; SPSS, Inc., Chicago, IL). RESULTS Recurrences were observed in 27 of 40 patients (68%). Local recurrence was the most frequent site of first recurrence (15 patients) and 8 patients had distant metastases at the time of first recurrence (4 patients in the lung, 2 patients in the bone, 1 patient each in the lung and liver, and 1 patient in the lung and bone). Two patients developed recurrence at both the primary lesion and distant metastases (one in the lung and one in the bone) and the two patients had recurrence at both the primary lesion and extrathoracic lymph nodes. None of the 16 patients who were treated with complete resection followed by radiotherapy developed local (in-field) recurrence. Twenty-seven of 40 patients (68%) died during the period of this analysis, all of whom died of thymic carcinoma. The 5-year and 10-year actuarial overall survival rates in all patients were 38% and 28%, respectively (Fig. 1). The median survival time in those patients with low-grade histology was 29 months, and was 11 months in those patients with high-grade histology. On univariate analysis, complete resection, KPS, histology, and Masaoka stage at the time of diagnosis were found to have a significant impact on overall survival (Table 2). On multivariate analysis, complete resection, KPS, and histology were found to be significant prognostic factors (Table 3). Therefore, the results of these analyses indicated that complete resection, a KPS 70%, and low-grade histology were favorable prognostic factors for overall survival. Of those patients treated with complete resection, 12 of 16 patients (75%) were alive and free of disease at the time of last follow-up (follow-up range, months). Conversely, of the 24 patients treated with incomplete resection or biopsy, only 1 patient (4%) with low-grade histology who was treated with incomplete resection, postoperative radiotherapy, and adjuvant chemotherapy was alive with a follow-up of 57 months. Among 12 surviving patients treated with complete resection, 8 with resectable tumors at the time of presentation (Masaoka Stage II in 6 patients and Stage III in 2 patients) had low-grade histology and were treated successfully with complete resection and postoperative radiotherapy with or without adjuvant chemotherapy (follow-up range, months). The remaining 4 patients with unresectable tumors at the time of presentation (Masaoka Stage III) were treated successfully with neoadjuvant chemo-

4 3118 CANCER June 15, 2002 / Volume 94 / Number 12 TABLE 2 Univariate Analysis of Various Potential Prognostic Factors for Survival in Patients with Thymic Carcinoma Variable No. of cases OS 5-year rate (%) P value Complete resection Yes No KPS (%) Histology Low grade High grade Masaoka stage a II 7 86 III and IV Total dose of RT (Gy) Age (yrs) Gender Male Female Use of chemotherapy Yes No OS: overall survival; KPS: Karnofsky performance status; RT: radiotherapy; Gy: grays. a At the time of diagnosis. TABLE 3 Multivariate Analysis of Various Potential Prognostic Factors for Survival in Patients with Thymic Carcinoma Variable P value RR (95% CI) Complete resection ( ) KPS ( ) Histology ( ) Masaoka stage a 0.41 Total dose of RT 0.79 Age 0.24 Gender 0.13 Use of chemotherapy 0.32 RR: relative risk; 95% CI: 95% confidence interval; KPS: Karnofsky performance status; RT: radiotherapy. a At the time of diagnosis. therapy, complete resection, and postoperative radiotherapy (follow-up range, months). The histology of these four patients was squamous cell carcinoma in two patients, small cell carcinoma in one patient, and undifferentiated carcinoma in one patient. The chemotherapy regimens used for these four patients were the ADOC regimen in three patients and a cisplatin and etoposide regimen in one patient. DISCUSSION There is a general consensus that surgery is the treatment of first choice for thymomas, and the extent of surgery is a significant factor for survival. Therefore, many authors have recommended complete resection whenever possible. 15,16 Conversely, the efficacy of complete resection for thymic carcinoma remains unclear. Some reports have failed to show an improved survival in patients who undergo complete resection compared with those undergoing incomplete resection. 5,8 Others have indicated that the most important factor related to the prognosis of patients was the resectability of the tumor at surgery. 2,4 In the current study, the extent of surgery also was found to be a strong predictor of survival in patients with thymic carcinoma. Twelve of 16 patients (75%) who were treated with complete resection were alive and free of disease at the time of last follow-up, whereas only 1 of 24 patients (4%) treated with incomplete resection or biopsy was still alive. These results indicate that complete resection also is recommended in patients with thymic carcinoma, as well as those with thymoma. The histologic classification of thymic carcinoma has been important because of its prognostic significance. 1,3 Tumors in the high-grade histology group are characterized by an aggressive clinical course and a high incidence of local recurrence and distant metastases. Conversely, tumors in the low-grade histology group are characterized by a relatively favorable clinical course and a low incidence of local recurrence and distant metastases. 1 3,17 In the current study, the median survival time in patients with low-grade histology was 29 months, but was only 11 months in those patients with high-grade histology. Several reports also indicated median survivals of months in patients with low-grade histology compared with median survivals of months in patients with highgrade histology. 8,18 The reasons for such a good prognosis with low-grade tumors presumably are the high complete resection rate, the radiosensitivity of the tumor, and the tumor s indolent clinical course. 2,18 In the current study, of the 12 surviving patients treated with complete resection, 8 with resectable tumors at the time of presentation (Masaoka Stage II disease in 6 patients and Stage III disease in 2 patients) had lowgrade histology and were treated successfully with complete resection and postoperative radiotherapy with or without adjuvant chemotherapy. These results indicate that surgical resection and postoperative radiotherapy with or without adjuvant chemotherapy are the treatment of choice in patients with resectable thymic carcinoma with a low-grade histology. To our knowledge, a role for radiotherapy in the

5 Thymic Carcinoma/Ogawa et al treatment of thymic carcinoma has not been established; however, several authors have indicated that thymic carcinoma was as highly sensitive to irradiation as thymoma. 2,9 In the current study, no local recurrence was observed in patients treated with complete resection followed by radiotherapy with a median dose of 50 Gy. Postoperative radiotherapy with a total dose of 50 Gy appears to be effective in preventing local recurrence in patients treated with complete resection. Thymic carcinomas usually are invasive or metastatic at the time of diagnosis (Masaoka Stage III and Stage IV) and complete resection occasionally is impossible to achieve. The dismal prognosis of patients with advanced thymic carcinoma has made it necessary to experiment with new treatment modalities. 5,19 Recently, a good response rate to chemotherapy has been reported in the literature 7,20,21 and multimodal strategies have been advocated. 5,8,9,19 Lucchi et al. reported the results of multimodality treatment including neoadjuvant chemotherapy, surgery, and postoperative radiotherapy. 19 Seven patients with Masaoka Stage III tumors responded to neoadjuvant chemotherapy, and surgical resection was complete in four cases. Of these 4 patients, 3 still were alive and free of disease with a follow-up of months. In the current study, 4 patients with unresectable tumors at the time of presentation underwent complete resection with a good response using neoadjuvant chemotherapy, and all 4 patients were alive and free of disease with a follow-up of months. To our knowledge no recommended regimen of chemotherapy has been clearly established, although some authors have advocated a cisplatin- and/or doxorubicinbased combination. 7,9,11,18,20,22 For advanced tumors that appear to be unresectable at the time of presentation, preoperative shrinkage of the thymic carcinoma by means of neoadjuvant chemotherapy may improve the resectability and, therefore, the survival rate. Further prospective studies with a greater number of patients and also with different chemotherapeutic regimens are necessary to validate this treatment modality. REFERENCES 1. Suster S, Rosai J. Thymic carcinoma. A clinicopathologic study of 60 cases. Cancer. 1991;67: Shimosato Y, Kameya T, Nagai K, Suemasu K. Squamous cell carcinoma of the thymus. An analysis of eight cases. Am J Surg Pathol. 1977;1: Truong LD, Mody DR, Cagle PT, Jackson-York GL, Schwartz MR, Wheeler TM. Thymic carcinoma. A clinicopathologic study of 13 cases. Am J Surg Pathol. 1990;14: Tsuchiya R, Koga K, Matsuno Y, Mukai K, Shimosato Y. Thymic carcinoma: proposal for pathological TNM and staging. Pathol Int. 1994;44: Blumberg D, Burt ME, Bains MS, et al. Thymic carcinoma: current staging dose not predict prognosis. J Thorac Cardiovasc Surg. 1998;115: Levine GD, Rosai J. Thymic hyperplasia and neoplasia: a review of current concepts. Hum Pathol. 1978;9: Weide LG, Ulbright TM, Loehrer PJ Sr., Williams SD. Thymic carcinoma. A distinct clinical entity responsive to chemotherapy. Cancer. 1993;71: Hsu CP, Chen CY, Chen CL, et al. Thymic carcinoma. Ten years experience in twenty patients. J Thorac Cardiovasc Surg. 1994;107: Yano T, Hara N, Ichinose Y, Asoh H, Yokoyama H, Ohta M. Treatment and prognosis of primary thymic carcinoma. J Surg Oncol. 1993;52: Masaoka A, Monden Y, Nakahara K, Tanioka T. Follow-up study of thymomas with special reference to their clinical stages. Cancer. 1981;48: Fornasiero A, Daniele O, Ghiotto C, et al. Chemotherapy for invasive thymoma. A 13-year experience. Cancer. 1991;68: Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53: Gehan E. A generalized Wilcoxon test for comparing arbitrarily single-censored samples. Biometrika. 1965;52: Cox DR. Regression models and life tables. J R Stat Soc. 1972;34: Graeber GM, Tamim W. Current status of the diagnosis and treatment of thymoma. Semin Thorac Cardiovasc Surg. 2000;12: Ogawa K, Uno T, Toita T, et al. Postoperative radiotherapy for completely resected thymoma: a multiinstitutional retrospective review of 103 patients. Cancer. 2002;94: Hartmann CA, Roth C, Minck C, Niedobitek G. Thymic carcinoma. Report of five cases and review of the literature. J Cancer Res Clin Oncol. 1990;116: Chang HK, Wang CH, Liaw CC, et al. Prognosis of thymic carcinoma: analysis of 16 cases. J Formos Med Assoc. 1992; 91: Lucchi M, Mussi A, Basolo F, Ambrogi MC, Fontanini G, Angeletti CA. The multimodailty treatment of thymic carcinoma. Eur J Cardiothorac Surg. 2001;19: Dy C, Calvo FA, Mindan JP, et al. Undifferentiated epithelialrich invasive malignant thymoma: complete response to cisplatin, vinblastine, and bleomycin therapy. J Clin Oncol. 1988;6: Carlson RW, Dorfman RF, Sikic BI. Successful treatment of metastatic thymic carcinoma with cisplatin, vinblastine, bleomycin, and etoposide chemotherapy. Cancer. 1990;66: Loehrer PJ Sr., Jiroutek M, Aisner S, et al. Combined etoposide, ifosfamide, and cisplatin in the treatment of patients with advanced thymoma and thymic carcinoma: an intergroup trial. Cancer. 2001;91: