Thymoma

Volume 49 Number 1 January 2001

Prognostic factors in thymoma

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Thymoma Analysis of Prognostic Factors Objective: We evaluated the prognostic factors for thymoma that remain controversial. Methods: We studied 72 consecutive patients treated for thymoma during the period between 1966 and 1997. Recurrence-free interval rates and overall survival rates calculated by the Kaplan-Meier method were compared using logrank test by the Masaoka stage, extent of surgical resection, histology, or associated disease(s). Multivariate analysis was performed using Cox’s proportional hazards model. Results: Thirty-two thymomas were at Masaoka stage I, 9 at stage II, 15 at stage III, and 16 were at stage IV. There were 56 complete resections, 7 incomplete resections (2 at stage III and 5 at stage IV), and 9 biopsies (1 at stage III and 8 at stage IV). Fortyone thymomas were cortical, 16 medullary, and 15 were mixed form. Association of myasthenia gravis was found in 20 patients, and pure red cell aplasia in 7. After an average follow-up period of 103 months, the recurrence-free 5-, 10-, 15-year interval rate was 89%, 80%, 80%, respectively, and overall 5-, 10-, 15-year survival rate was 86%, 71%, 59%, respectively. Factors influencing the recurrence-free interval and overall survival included the Masaoka stage, extent of surgical resection, and association with pure red cell aplasia. Multivariate analysis revealed stage IV tumor and association with pure red cell aplasia as risk factors for recurrence. Pure red cell aplasia indicated poor prognosis for overall survival. Conclusions: Masaoka stage, extent of surgical resection, and association with pure red cell aplasia were prognostic factors for thymoma. Multidisciplinary treatment for stage IV tumors and better control of pure red cell aplasia, if associated, should be investigated. (JJTCVS 2001; 49: 35–41) Key words: thymoma, prognostic factor, surgery, pure red cell aplasia Makoto Sonobe, MD, Masatsugu Nakagawa, MD, Masutaro Ichinose, MD, Naoyuki Ikegami, MD, Miyuki Nagasawa, MD, and Toru Shindo, MD.

T

Subjects and Methods

From the Department of Thoracic Surgery, Tenri Hospital, Nara, Japan. Received for publication January 15, 2000. Accepted for publication July 12, 2000. Address for reprints: Makoto Sonobe, MD, Department of Thoracic Surgery, Tenri Hospital, Mishima-cho 200, Tenri, Nara 632–8552, Japan.

Clinical and pathological data on 72 consecutive patients with thymoma, treated at our hospital during the period between 1967 and 1997, were reviewed. The tumors were histologically classified according to Marino and Müller-Hermelink,1 as cortical, medullary, or mixed form. Two cases of well-differentiated thymic carcinoma were excluded from this study. The tumors were staged according to Masaoka et al.2 Thymo-thymectomy through a median sternotomy was principally performed. In cases diagnosed as stage IV preoperatively, chemotherapy and/or radiotherapy were performed initially. According to the response to these treatments and the patient’s condition, surgical resection for the residual tumor was performed through median sternotomy with the assistance of lateral thoracotomy or thoracoscopy. Regardless of the Masaoka stage, patients with myasthenia gravis (MG) underwent extended thymo-thymectomy. On the initial surgical intervention, the extent of surgical resection was

hymoma is one of the common neoplasms among the anterior mediastinal tumors. As thymoma can present a malignant course, it has been treated as a malignant tumor. However, prognostic factors for thymoma are difficult to define and remain to be discussed. The reasons for this include that thymoma has a slow-growing tendency, it has histological polymorphism, and it is often associated with several types of autoimmune diseases that are occasionally critical. Therefore, in this retrospective study, we evaluated the impacts of several parameters on tumor recurrence and on overall survival in 72 patients with thymoma treated at our hospital.

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The Japanese Journal of Thoracic and Cardiovascular Surgery

Sonobe et al.

Table I.

Histology Cortical form Medullary form Mixed form Associated diseases Myasthenia gravis Pure red cell aplasia

Histology of and diseases associated with the 72 patients, by the Masaoka stage Stage I (n = 32)

Stage II (n = 9)

Stage III (n = 15)

Stage IV (n = 16)

Total (%) (n = 72)

14 10 08

4 2 3

11 03 01

12 01 03

41 (57) 16 (22) 15 (21)

11 03

4 0

02 01

03 03

20 (28) 07 (10)

Table II. Extent of surgical resection and treatment modalities on initial treatment of the 72 patients

Complete resection Resection only Resection + rediation Resection + radiation + chemotherapy Incomplete resection Resection only Resection + radiation Resection + chemotherapy Resection + radiation + chemotherapy Biopsy Radiation Radiation + Chemotherapy

Stage I

Stage II

Stage III

Stage IV

Total (%)

32 32

9 5 4

12 07 05

3 1 1 1 5 2

56 (78)

defined as follows: macroscopically total resection was defined as “complete resection”, resection of more than 50% and less than 100% of the tumor volume as “incomplete resection”, resection of less than 50% of tumor volume or diagnostic biopsy excision as “biopsy”. No perioperative therapy was performed for stage I tumors. Patients with stage II tumors received routinely postoperative mediastinal irradiation of 50 Gy, after 1994. Postoperative chemotherapy and/or radiotherapy for patients with stage III and IV tumors was carried out preferentially. Chemotherapy before 1983 consisted of mainly intravenous cyclophosphamide. Cisplatin-containing chemotherapy was performed after 1984. Follow-up information until either death or completion of the study (December 1999) was obtained from medical records, questionnaires sent to patients, or by telephone interviews. The prognostic values of the Masaoka stage, extent of surgical resection, histological classification, association with MG, and of pure red cell aplasia (PRCA) were studied. Any difference in binary or ordinal variables was tested using the chi-square test. The relation between the clinical stage

02

07 (10)

01 01 01 01

2 1 8 1 7

09 (12)

and the extent of surgical resection was analyzed using Spearman’s rank correlation. Survival curves of the recurrence-free interval and of the overall survival were calculated using the Kaplan-Meier method, and they were statistically compared using the log-rank test. The endpoint of a recurrence-free interval was defined as the point of tumor recurrence or re-growth. Development of MG or PRCA without tumor recurrence or re-growth was not included as an endpoint of recurrence free-interval. Significant variables under this univariate method were tested by multivariate analysis using Cox’s proportional hazards model. Results were considered significant when the p value did not exceed 0.05. The statistical study was accomplished using the StatView software version 5.0. Results The ages of the patients at diagnosis ranged from 24 to 76 years, with a median of 56.5 years. There were 39 female and 33 male patients. Thirty-two thymomas were at Masaoka stage I, 9 at stage II, 15 at stage III, and 16 were stage at IV (Table I). The organs invaded by stage III tumors were the adjacent



37

Table III. Cause of death among the 72 patients, by the Masaoka stage

Total death Tumor-related Pure red cell aplasia-related Myasthenia gravis-related Treatment-related complication Miscellaneous diseases

Stage I

Stage II

Stage III

Stage IV

Total

4

1

5

3 1

1

9 5 1 1

20 05 05 03 01 06

1 1 3

3

Table IV. Recurrence-free interval rate, by the Masaoka stage, extent of surgical resection, histology, and associated diseases Prognostic factor Masaoka stage Stage I Stage II Stage III Stage IV Extent of surgical resection Complete Incomplete Biopsy Histology Cortical form Medullary form Mixed form Myasthenia gravis Absence Presence Pure red cell aplasia absence presence

Recurrence free interval (%) 5 years 10 years 15 years

p value (log-rank test) < 0.0001*

100.0 100.0 100.0 053.3

094.7 100.0 087.5 033.3

094.7 100.0 087.5 033.3

        

097.9 050.0 050.0

091.4 033.3 050.0

091.4 033.3

     

086.5 100.0 084.4

073.8 100.0 072.4

073.8 100.0 072.4

087.6 085.7

072.2 085.7

072.2 085.7

092.1 041.7

079.5

079.5

∼

∼

∼



 n.s. n.s.    n.s. 0.0006* < 0.0001* 

< 0.0001*  < 0.0001*  n.s. 0.3073, n.s.

0.3885, n.s.

0.0081*

*: The p value was less than 0.05 and considered significant. n.s.: not significant (The p value exceeded 0.05)

lungs in 10 cases, the pericardium in 8, the superior vena cava in 3, and the left pulmonary artery in 1. In stage IV thymomas, 13 showed pleural dissemination, 7 showed pericardial effusion, and 1 showed metastases to the pretracheal lymphnodes. Histologically, the cortical form was found in 41 patients, the medullary form in 16, and the mixed form in 15. There was no correlation between the tumor histology and the Masaoka stage (Chi-square test, p = 0.2161). Thirty-nine patients had autoimmune disease(s) that had a well-known association with thymoma. There were 20 patients with MG and 7 with PRCA. The proportions of stage I and II thymomas associated with MG (34% and 44%, respectively) were higher than those of stage III and IV (15% and 19%, respectively), but there was no significant correlation

between association with MG and Masaoka stage (Chisquare test, p = 0.2457). The histological type of PRCA-associated thymomas was cortical form in 6 patients and medullary form in 1. Although not shown in Table I, hypogammaglobulinemia was found in 16 patients, Hashimoto thyroiditis in 4, and idiopathic thrombocytic purpura in 1. The extent of surgical resection and treatment modality are shown in Table II. All of the stage I and II tumors, and 80% of the stage III tumors were completely resected. The extent of surgical resection had a significant correlation with the Masaoka stage (Spearman rank correlation test, rho = 0.694, p < 0.0001). No thirty-day operative mortality occurred. Three patients with MG required postoperative artificial ventilation for longer than 7 days because of

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Sonobe et al.

Table V.

Overall survival rate, by the Masaoka stage, extent of surgical resection, histology, and associated diseases

Prognostic factor Masaoka stage Stage I Stage II Stage III Stage IV Extent of surgical resection Complete Incomplete Biopsy Histology Cortical form Medullary form Mixed form Myasthenia gravis Absence Presence Pure red cell aplasia absence presence

5 years

Overall survival (%) 10 years 15 years

P value (log-rank test) 0.0003*

096.6 088.9 087.9 064.8

82.8 88.9 78.3 32.4

82.8 88.9 65.3 10.8

        

084.0 064.3 066.7

79.0 64.3 44.0

79.0 32.1 00.0

     

078.6 100.0 091.7

60.4 77.8 80.2

45.3 77.8 80.2

089.3 078.0

71.9 70.2

55.7 70.2

089.6 057.1

82.3 00.0

67.9 00.0

n.s. n.s. 0.0131*

    

n.s.

0.0015* 

0.0464*  0.0005*  n.s. 0.0943, n.s.

0.9083, n.s. < 0.0001*

*: The p value was less than 0.05 and considered significant. n.s.: not significant (The p value exceeded 0.05)

myasthenic crisis. One of them died at 46 days after surgery. The other 2 patients recovered completely. Follow-up data from the beginning of treatment until either death or completion of the study were obtained for all patients, except for one patient with a stage I tumor. The follow-up period ranged from 1 to 311 months, with an average of 103 months, and exceeded 120 months in 28 patients (39%). The 5-, 10-, and 15-year recurrence-free interval rate was 89%, 80%, and 80%, respectively. The overall survival rate was 86%, 71%, 59%, respectively. One patient (3.1%) with stage I tumor, 1 patient (6.7%) who had received complete resection and no adjuvant therapy for stage III tumor, and 10 (63%) with stage IV developed recurrence or tumor re-growth. In all patients, the initial recurrent lesion occurred in the thoracic cavity, and no distant metastasis was observed. Resection of the recurrent lesion was carried out for one patient at stage I, for one at stage III, and for 4 patients at stage IV. Three patients at stage IV received chemotherapy and radiotherapy for recurrent lesions. Three patients could not receive any treatment because of their poor condition. The causes of death are shown in Table III. Five patients with stage IV thymoma died by uncontrollable massive pleural effusion and/or ascites with dissemination. Five patients died by a complication caused by PRCA. In addition, 2 of 5 patients with

stage IV disease who died of thymoma could not receive intensive chemotherapy or radiotherapy because of severe anemia caused by PRCA. One patient with MG died from lung abscess during corticosteroid hormone treatment for deteriorating MG. Another patient died by respiratory failure caused by muscle weakness 8 years after surgery. One patient with a stage III tumor died by massive hemoptysis caused by radiation-induced pneumonitis. The statistical evaluation of related factors influencing the recurrence-free interval using the log-rank test revealed that the Masaoka stage, extent of surgical resection, and concomitant PRCA were each a significant predictor for tumor recurrence (Table IV). The overall survival and statistical evaluation are shown in Table V. The Masaoka stage, extent of surgical resection, and association with PRCA were again demonstrated each to be a significant factor for overall survival. Patients with a stage I, II, or III tumor had a significantly longer recurrence-free interval (p < 0.0001) and longer overall survival (p = 0.0003) compared with patients with a stage IV tumor. According to the extent of surgical resection, patients received complete resection had a lower recurrence rate (p < 0.0001) and a longer survival (p = 0.0013) compared with patients who underwent incomplete resection or biopsy. Patients with PRCA had a significantly higher


recurrence rate (p = 0.0081) and a decreased survival rate (p < 0.0001). The histological difference and association of MG had no correlation with tumor recurrence or overall survival. To determine which of these three factors had the predominant impact on prognosis, multivariate analyses were performed using Cox’s proportional hazards model. The Masaoka stage (stage I, II, and III vs. stage IV) was considered to be a strong risk factor for tumor recurrence (hazard ratio: 15.241, 95% confidential interval: 2.522–92.089, p = 0.0030). Association with PRCA (absence vs. presence) was also considered as an independent predictor for tumor recurrence (hazard ratio: 4.376, 95% confidential interval: 1.035–18.493, p = 0.0447). On the overall survival, only association with PRCA entered in regression (hazard ratio: 9.365, 95% confidential interval: 3.202–27.393, p < 0.0001). The extent of surgical resection (complete resection vs. incomplete resection or biopsy) had a marginal impact (hazard ratio: 2.846, 95% confidential interval: 0.866–9.360, p = 0.0850). When one of either the Masaoka stage or extent of surgical resection was excluded from the analysis, however, the other entered into the regression of the Cox model with strong influence because of the close association between both factors. Discussion Many prognostic factors of thymoma have been reported to date. They seem to be controversial, however, especially when we try to choose a treatment strategy for a given patient with thymoma, because some thymomas are highly sensitive to radiation, and some combination chemotherapy regimens have recently been reported. We have therefore attempted to evaluate the impacts of several predicting factors on tumor recurrence and on overall survival. The Masaoka stage was shown to be a strong risk factor for tumor recurrence and for overall survival with relation to the extent of surgical resection. The clinico-pathological stage of thymoma and extent of surgical resection generally relate to each other, and influence the decision regarding postoperative treatment. In our series, all of stage I and II thymomas were completely resected, and their recurrence rates and long-term survival rates were acceptable. In the literature, there is no doubt that complete resection plays a key role for treatment of stage I and II thymomas3–14 although postoperative mediastinal irradiation for stage


39

II tumors should be performed because of their higher local recurrence rate.11,14 The recurrence rate and the long-term survival rate of stage III thymomas were satisfactory in our series and were not different from those of stage I or II. The organs invaded by the tumor were mainly the adjacent lungs and pericardium that could be easily resected, and 12 (80%) of 15 patients with stage III tumors underwent complete resection. The high rate of complete resection in this series may explain the good prognosis.12,13 Generally, stage III tumors have a higher recurrence rate and the long-term survival is worse than for stage I or II.2,3,7,10,12,13 Even if the tumor is completely resected, postoperative irradiation5,6 and chemotherapy13 are recommended. Furthermore, for unresected or residual stage III tumors, irradiation and chemotherapy are considered essential.15,16 Venuta et al.9 and Shin et al.17 demonstrated the prognostic benefit of preoperative chemotherapy, surgery, and postoperative chemotherapy and irradiation. In our series, postoperative irradiation or chemotherapy was not carried out according to the protocol, and the effectiveness of these treatments for completely resected stage III tumor was not evaluated. However, one recurrence occurred in a patient who underwent complete resection without any adjuvant therapy. Complete resection for a stage III tumor should be attempted, and adjuvant therapy should be considered. It was pointed out from our data that stage IV tumors were correlated with incomplete resection or biopsy only and carried a high risk to recurrence and a poor long-term survival. Many studies have demonstrated the poor prognosis for patients with a stage IV tumor.2–7,9,10,13 As complete resection for stage IV thymomas is frequently impossible, multimodal treatment is necessary. Although no consensus on treatment modalities for a stage IV tumor has yet been achieved, irradiation and cisplatin-containing chemotherapy have played an important role. The potential benefit of preoperative chemotherapy, surgical resection, and postoperative irradiation and chemotherapy has been suggested.9,17,18 We have also started this multimodal approach (not included in this study). Further investigation should be performed to evaluate the effect of this treatment on prognosis. Control of pleural dissemination is important for patients with stage IV thymoma because massive pleural effusion due to pleural dissemination is often critical. Intraoperative pleurodesis using platinum-complex agents with distilled water has been performed in 2 patients with extensive dissemination and mas-

40

Sonobe et al.

sive pleural effusion.19 However, we have considered complete resection of a stage IV thymoma when we can expect to resect the thymoma completely and when the thymoma is not fully sensitive to chemotherapeutic agents. As Kirschner20 and Regard et al.21 suggested, we performed re-resection after chemotherapy for disseminated recurrent tumors that were relatively large in size but small in number in 3 patients. In 4 of these 5 patients, the pleural effusion was well controlled. Larger size series are required to define the prognostic significance of control of pleural dissemination. There have been conflicting reports regarding the prognostic impact of the histology of the thymoma. Predominantly epithelial-type thymomas based on Bernatz et al.22 have shown a poor prognosis because they tended to grow more invasively,3,4,8,10,12,23 and the cortical form on the Müller-Hermelink classification has been reported to have poor prognostic impact.5,15 On the contrary, several studies have reported that histological differences on the Bernatz classification3,7 or on the Müller-Hermelink classification23 did not influence prognosis. In our series, there was no prognostic difference according to the histology. The prognostic impact of each histological type may be not reflected in our series because 78% of the thymomas were completely resected. The influence of histological difference on unresected or incompletely resected thymomas may clarify the prognostic impact of histology. MG is the most common disease associated with thymomas, co-occurring in approximately 25% of patients. The development of perioperative preparations has remarkably decreased the morbidity and mortality of myasthenic crisis and has led to improvement in the prognosis of MG-associated thymomas. Many recent reports2–5,7,8,10,13 have revealed that the association with MG is no longer an adverse prognostic factor. Several reports have suggested that the existence of MG led to early detection of thymoma, which provided a better overall survival,6,11,23 although this tendency was not observed in our series. In our experience, only one patient with MG died of myasthenic crisis and no significant difference on prognosis was found between myasthenic thymomas and non-myasthenic thymomas. However, 2 patients without myasthenic crisis died of a MG-related complication. Infection under glucocorticoid administration and respiratory muscle weakness should still be monitored as a serious complication in the long-term management of MG.


The prognostic significance of PRCA on thymoma has not been fully evaluated because of its low incidence. Masaoka et al.24 and Maggi et al.6 suggested a poor prognosis of patients with thymoma associated with PRCA. Our series revealed a markedly adverse impact of PRCA on the prognosis of thymoma independently from other factors. Thymoma-associated PRCA is one of the acquired and secondary forms of PRCA, and its clinical presentations mimic the acquired sustained primary type. However, it has a worse prognosis.25 Although thymoma may induce immunological abnormalities such as B cell-mediated inhibition of erythropoiesis or T cell-mediated erythroid rejections,26 there is no definite evidence of etiological linkage between them. The therapeutic benefit of thymo-thymectomy on PRCA has been limited,24,27,28 and immunosuppressive treatment has not always been effective. Then thymoma-associated PRCA frequently runs a chronic course requiring repeated blood transfusions, resulting in hemochromatosis of multiple organs, such as the heart, liver, pancreas, and bone marrow. Chronic heart failure caused by cardiac hemochromatosis is a major cause of death. Before the clinical application of immunosuppressive treatment for PRCA, the average life expectancy of patients with secondary PRCA had been nearly 5 to 10 years from the diagnosis. In our series, only 2 of the 7 patients with PRCA received effective immunosuppressive treatment with predonisolone and cyclosporine A. Thus the poor overall survival in our series may simply have confirmed the poor prognosis of PRCA itself. Actually in our experience, 4 patients died of PRCA without tumor recurrence. However, patients with PRCA-associated tumor necessitating postoperative therapy are often intolerant to intensive chemotherapy and radiotherapy because of their severe anemia and hemochromatosis. Consequently, the perioperative treatment could be insufficient. In our series, all patients with a PRCA-associated stage IV thymoma developed recurrence, and this high recurrence rate may support our speculation. The poor performance status caused by severe anemia may also account for the worse overall survival, as described by Gripp et al.10 The application of effective treatment for PRCA is necessary in order to improve the prognosis of PRCA itself, and may enable patients with PRCA-associated thymoma to receive intensive chemotherapy and/or radiotherapy if needed. In conclusion, the Masaoka stage, the extent of surgical resection, and the association with PRCA were indicated each to be a prognostic factor. Surgery


is the mainstay of treatment for patients with thymoma and complete resection should be attempted whenever possible. Multidisciplinary treatment should be investigated for stage IV thymomas. Better control of associated PRCA is necessary to improve the prognosis of a PRCA-associated thymoma.


14.

15.

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long-term results after thymoma resection: a series of 307 patients. J Thorac Cardiovasc Surg 1996; 112: 376–84. Haniuda M, Miyazawa M, Yoshida K, Oguchi M, Sakai F, Izuno I, et al. Is postoperative radiotherapy for thymoma effective? Ann Surg 1996; 224: 219–24. Martinez LQ, Wilkins W, Choi N, Efird J, Hug E, Harris NL. Thymoma: histologic subclassification is an independent prognostic factor. Cancer 1994; 74: 606–17. Fornasiero A, Daniele O, Ghiotto C, Piazza M, FioreDonati L, Calabro F, et al. Chemotherapy for invasive thymoma: a13-year experience. Cancer 1991; 68: 30– 3. Shin DM, Walsh GL, Komaki R, Putnam JB, Nesbitt J, Ro JY, et al. A multidisciplinary approach to therapy for unresectable malignant thymoma. Ann Intern Med 1998; 129: 100–4. Macchiarini P, Chella A, Ducci F, Rossi B, Testi C, Bevilacqua G, et all. Neoadjuvant chemotherapy, surgery, and postoperative radiation therapy for invasive thymoma. Cancer 1991; 68: 706–13. Sonobe M, Nakagawa M, Ikegami N, Suzumura Y, Nagasawa M, Shindo T. Two cases of intraoperative intrathoracic hypotonic chemotherapy for stage IVa thymoma with pleural effusion (Eng abstr). J Jpn Assn Chest Surg 1998; 12: 623–8. Kirschner PA. Reoperation for thymoma: report of 23 cases. Ann Thorac Surg 1990; 49: 550–5. Regnard JF, Zinzindohoue F, Magdeleinat P, Guibert L, Spaggiari L, Levasseur P. Results of re-resection for recurrent thymomas. Ann Thorac Surg 1997; 64: 1593–8. Bernatz PE, Harrison EG, Clagett OT. Thymoma: a clinicopathologic study. J Thorac Cardiovasc Surg 1961; 42: 424–44. Wilkins KB, Sheikh E, Green R, Patel M, George S, Takano M, et al. Clinical and pathological predictors of survival in patients with thymoma. Ann Surg 1999; 230: 562–74. Masaoka A, Hashimoto T, Shibata K, Yamanaka Y, Nakamae K, Iizuka M. Thymomas associated with pure red cell aplasia: histologic and follow-up studies. Cancer 1989; 64: 1872–8. Clark DA, Dessypris EN, Krantz SB. Studies on pure red cell aplasia: XI. result of immunosuppressive treatment of 37 patients. Blood 1984; 63: 277–86. Erslev AJ, Soltan A. Pure red cell aplasia: a review. Blood Reviews 1996; 10: 20–8. Mamiya S, Itoh T, Miura AB. Acquired pure red cell aplasia in Japan. Eur J Haematol 1997; 59: 199–205. Mukaida T, Aoe M, Yamashita M, Date H, Ando A, Shimizu N: Four cases of thymoma associated with pure red cell aplasia (Eng abstr). J Jpn Assn Thorac Surg 1997; 45: 96–101.