Therapy for thymic epithelial tumors

Thymoma is the most common tumor of the anterior mediastinum. This tumor is associated with unique paraneoplastic syndromes. The rarity of this tumor has somewhat obscured the optimal treatment for this disease. The World Health Organization classification system, which published in 1999, appears to be an advance in our understanding of thymoma. The Masaoka classification is now the most widely accepted and is an excellent predictor of the prognosis of thymoma. Now the International Thymic Malignancy Interest Group is currently engaged in the development of a validated formal TNM classification system for thymic malignancies. The optimal treatment of thymoma is performed according to its clinical stage. Surgery remains the mainstay of treatment for thymic epithelial tumors. Minimally invasive surgery including thoracoscopic surgery and robotic surgery for stage I and II thymomas is increasing now. The value of postoperative radiotherapy in completely resected stage II or III tumors is questionable. As thymomas have a moderate response rate to chemotherapy or radiotherapy, multimodality therapy involving surgery, chemotherapy and radiotherapy appears to increase the rate of complete resection and survival in the advanced (stage III and IV) thymomas.     

Comparison of stages I-II thymoma treated by complete resection with or without adjuvant radiation

BACKGROUND: Adjuvant radiation after resection of Masaoka stage II thymoma is widely advocated, but the evidence supporting it is controversial. Studies addressing this issue generally report few patients and lump all patients beyond stage I together in the analysis. METHODS: We retrospectively compared outcomes of stage I and II thymomas treated by resection alone with thymomas treated by resection plus radiation. Histology was re-reviewed to confirm pathologic staging and resection margin status. RESULTS: Between February 1992 and 2002, we performed 167 resections for thymoma. Of these, 70 patients were believed to have tumors in stage IIb or less intraoperatively, and all of these patients underwent complete resection. We reviewed the histopathology of 62 of 70 patients. Thirty thymomas demonstrated less than complete transcapsular microscopic invasion (stage I) and 40 thymomas demonstrated microscopic transcapsular invasion or macroscopic invasion into surrounding fatty tissue (stage II). Forty-seven patients underwent surgery without postoperative mediastinal radiotherapy. Dosages in the 23 radiated patients (3 stage I and 20 stage II) consisted of 45 to 55 Gy. Median follow-up was 70.3 months. Stage II patients who were radiated (n = 20) and those who were not radiated (n = 20) consisted of identical proportions in stages IIa and IIb. Two patients recurred (1 unradiated stage I patient and 1 radiated stage IIb patient). Overall 5-year survival rate was 91%. All who died were free of recurrence at time of death. Log-rank test showed no difference in Kaplan Meier survival curves (p = 0.32) between the radiated and unradiated groups. CONCLUSIONS: These data support the contention that margin-negative surgical resection alone is sufficient treatment for both stages I and II thymoma.     

Does surgical debulking for advanced stages of thymoma improve survival?

A best evidence topic in cardiothoracic surgery was written according to a structured protocol. The question addressed was 'Does surgical debulking for advanced stages of thymoma improve survival?' Altogether, only 17 papers were found using the reported search, of which only 10 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated; these studies have mainly reported the survival and recurrence rates after total vs subtotal resection of thymic tumours in patients receiving or not receiving adjuvant chemoradiotherapy. These studies confirmed that complete resection is the best prognostic factor in thymomas. With regard to subtotal tumour resection/debulking, we did not find any randomized controlled trials. The evidence on this topic is scarce and these 10 reported were retrospective reviews of the operative, histology and survival data of patients with thymoma who had subtotal vs partial resection for advanced stages of thymoma. Although debulking surgery for thymoma had positively affected survival, in six studies, the difference failed to reach statistical significance. Three of the studies, on the other hand, showed a higher survival rate in thymomas in which maximum debulking was performed and the treatment was followed by high-dose irradiation. None of these studies showed any benefit in debulking surgery for thymic carcinoma. Besides histology and tumour cell-type, other factors influencing survival included the tumour stage and the presence of symptoms such as myasthenia gravis as a warning sign at an early stage. Current evidence in the literature on the survival after debulking surgery for thymoma is contradictory, and most of the studies do not show any survival benefit after debulking for thymoma. However, debulking surgery minimizes the tumour size and area for irradiation postoperatively, hence it can result in less damage to the adjacent tissue during radiotherapy and may be considered for patients in advanced stages of thymoma in whom extensive radiotherapy will be required. In these cases, however, the risks of surgery followed by radiotherapy or radiotherapy alone should carefully be assessed prior to the initiation of treatment.     

Multimodality Treatment of Thymoma: A Prospective Study

Background. Thymomas are a heterogeneous group of tumors. Treatment of invasive lesions is not well standardized. The aim of this study is to propose a clinicopathologically based protocol for multimodality therapy.

Methods. Between 1965 and 1988, we operated on 83 patients with thymoma who did not receive standardized adjuvant therapy. In 1989, on the basis of the retrospective analysis of the data, we started a multimodality therapy protocol and used it for 65 patients. Twelve patients had medullary thymoma (11 stage I and 1 stage II), 13 had mixed type (6 stage I and 7 stage II), and 40 had cortical thymoma (4 stage I, 11 stage II, 12 stage III, and 13 stage IV). We considered three groups. Group I (n = 18 patients), benign thymoma, included stage I and II medullary and stage I mixed thymomas; radical resection with no adjuvant therapy was performed. Group II (n = 22), invasive thymoma, included stage I and II cortical and stage II mixed thymomas; postoperative chemotherapy plus radiotherapy was always administered. Group III (n = 25), malignant thymoma, comprised stage III and IV cortical thymomas and stage III mixed thymomas; resectable stage III lesions were removed, and highly invasive stage III and stage IV lesions underwent biopsy, neoadjuvant chemotherapy, and surgical resection; postoperative chemotherapy and radiotherapy was administered to all patients.

Results. The 8-year survival rate for patients in stages I, II, III, and IV was 95%, 100%, 92%, and 68%, respectively. Patients with medullary thymoma had a 92% 8-year survival rate; those with mixed type, 100%; and those with cortical thymoma, 85%. Group I had an 8-year survival rate of 94%; group II, 100%; and group III, 76%. Survival was compared with that of patients operated on before 1989: differences were not significant for group I; survival improved in group II (100% versus 81%; p = not significant); and group III showed significant improvement (76% versus 43%; p < 0.049).

Conclusions. Multimodality treatment with neoadjuvant chemotherapy and adjuvant chemotherapy plus radiotherapy may improve the results of radical resection and the survival of patients with invasive and malignant thymoma.     

Results from surgical treatment for thymoma. 43 years of experience.

OBJECTIVE: The biological behavior of thymoma and its prognosis after surgical intervention remain still controversial. The efficacy of surgical treatment for thymoma was investigated by examining long-term follow-up data. SUBJECTS AND METHODS: Follow-up data for patients undergoing surgical resection of histopathologically-confirmed thymoma between 1954 and 1997 were obtained and were retrospectively analyzed. Clinical staging was based on Masaoka's staging system, and histological classification on Rosai's proposed criteria. RESULTS: Data for 140 patients were collected. Sixty-four patients had stage I, 32 had stage II, 28 had stage III, and 16 had stage IV thymoma. There were significant differences in survival between patients with stage I and stage III, stage I and stage IV and stage II and stage III disease, but not between those with stage I thymoma and stage II thymoma. No significant difference in survival was observed between the 56 patients with myasthenia gravis (MG) and the 84 without MG. The 38 patients classified as having a predominantly-epithelial thymoma had a poorer prognosis than the 41 with a predominantly-lymphocytic thymoma. Until 1975, there were four patients with stage I thymomas who later showed recurrence, compared with 21 among those with stage II, III and IV diseases. Since 1976, extended thymectomy with thymomectomy under median sternotomy has been adopted as the standard operation for a thymoma, and there has been no recurrence in stage I patients. CONCLUSIONS: Patients with stage III or IV invasive thymoma have a poorer prognosis and a higher recurrence rate than those with encapsulated thymoma, and patients with a predominantly-epithelial thymoma have a poorer prognosis than those with a predominantly-lymphocytic thymoma. Extended thymectomy with thymomectomy under median sternotomy can be considered as adequate treatment for a stage I thymoma. Myasthenia gravis does not appear to affect the prognosis of patients with a thymoma.     

Which stages of thymoma benefit from adjuvant chemotherapy post-thymectomy?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was 'Which stages of thymoma benefit from adjuvant chemotherapy post thymectomy?' Altogether more than 150 papers were found using the reported search, of which only eight represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated; these studies have mainly reported the survival and recurrence rates of post-thymectomy patients who received adjuvant radiotherapy or chemoradiotherapy, and adjuvant radiotherapy alone was only used in a small group of patients in these studies. We did not find any randomized controlled trials comparing adjuvant chemotherapy with chemo/radiotherapy and, due to a very small incidence of this tumour, it is unlikely to see any trials in future. Studies were mainly retrospective or institutional reports and showed that, despite the high sensitivity of this tumour to chemotherapy agents and the use of chemotherapy as one of the main treatment modalities in the advanced stages of thymoma, current data are not supporting postoperative chemotherapy as a sole adjuvant treatment in advanced stages of thymoma. We conclude that, in patients with thymoma, surgical resection with or without radiation therapy is the gold standard treatment for early-stage disease (I and II). Adjuvant radiotherapy/chemoradiotherapy should be considered for Masaoka stage III (A and B) or above, and it is also advised to add adjuvant therapy for all patients with cortical fenestration, even in stages I and II. But there is no evidence that chemotherapy alone improves the survival in patients with completely resected stage III and IV thymomas and thymic carcinoma. In patients with extra-radiation field disease, however, the use of chemotherapy can potentially improve survival but no follow-up data on this group of patients are available.     

Clinical and pathologic predictors of survival in patients with thymic tumors

BACKGROUND: The aim of this study is to evaluate the impact of thymectomy in patients with thymic neoplasms and to identify clinical and histopathological factors associated with improved long-term outcome of surgery. METHODS: We treated 74 patients between February 1987 and July 1993. There were 29 total and 36 simple thymectomies. These last cases, all non-myasthenic, had benign thymomas (n=30) but 6 had thymic carcinomas. Nine tumors were no-resected (5 thymomas and 4 thymic carcinomas). Minimum follow-up by Department of Thoracic Surgery Istituto Nazionale Tumori was 60 months after thymectomy. We divided the specimens according to Marino and Muller-Hermelink's classification: 54 thymomas, 18 thymic carcinomas and 2 no-diagnosis specify thymomas. There were 53 stage I, 1 stage II, 13 stage III, 5 stage IVa and 2 stage IVb according to Masaoka. RESULTS: Forty-six patients with treated thymoma were alive without disease at the end of follow-up, the remaining 8 died from recurrence in 6, a new tumor in 1 and a heart attack in the last. Of 18 thymic carcinomas 9 were alive at the end of follow-up (1 with recurrence), only 4 dead from recurrence. The actuarial survival of patients with thymomas was 88.5% at 5 years, (73.6% in cortical type, 85.7% in medullary type, 93.9% in mixed type, 100% in predominantly cortical type). Myasthenia gravis didn't influence the survival: 87.3 (no MG) vs 90%. Advanced stage thymomas significantly increased the risk of death from early stage I: 32.4 vs 100% at 5 years. In thymic carcinoma patients with well-differentiated thymic carcinoma (WDTC) died less than others: the actuarial probability of survival at 5 years was 90 vs 68%. CONCLUSIONS: Thymectomy was the best treatment to long term outcome. In our experience, survival was related to histotype and to local extension of tumor.     

Spindle cell and mixed spindle/lymphocytic thymomas: an integrated clinicopathologic and immunohistochemical study of 81 cases

Forty-three cases of spindle cell thymoma (medullary, WHO type A) and 38 cases of mixed spindle/lymphocytic thymoma (WHO type AB) were studied for their clinicopathologic and immunohistochemical characteristics. Three histologic patterns of spindle cell thymoma were observed: short-spindled (57%), long-spindled (31%), and micronodular (12%). The short-spindled variant was composed of oval to short spindle cells commonly arranged in a hemangiopericytic or microcystic pattern. The long-spindled variant chiefly consisted of fibroblast-like epithelial cells mimicking fibrohistiocytic neoplasms. The micronodular variant was characterized by small nests of short spindle cells dispersed among a lymphoid stroma with frequent germinal centers. All kinds of spindle cell could be admixed with lymphocyte-rich "cortex"-like areas to constitute mixed spindle/lymphocytic thymomas. Immunohistochemically, the epithelial cells in up to 70% of the short-spindled and long-spindled variants of spindle cell thymoma and 90% of mixed spindle/lymphocytic thymomas were positive for CD20, whereas the epithelial cells in all micronodular spindle cell thymomas were negative. All of the spindle cell thymomas and most of the mixed spindle/lymphocytic thymomas in this study were found in stages I and II. Follow up of the patients did not disclose relapse or mortality directly resulting from the tumors. However, the prognosis of stage I and II spindle cell and mixed spindle/lymphocytic thymomas did not significantly differ from those of stage I and II thymomas of other types by a stage-matched survival analysis. Our data showed that spindle cell and mixed spindle/lymphocytic thymomas are distinctive in histologic pattern and immunohistochemical profile. When interpreted within the context of staging, spindle cell and mixed spindle/lymphocytic thymomas presenting in stages I and II most likely behave in an indolent fashion.     

En bloc Extended Total Thymectomy and Extrapleural Pneumonectomy in Masaoka stage IVA Thymomas

Background  

Surgical excision is the primary treatment for a thymoma. However, for advanced thymoma that extends to within the thoracic cavity and for recurrent cases with pleural dissemination (Masaoka stage IVA), the appropriate treatment is controversial. We evaluated the safety of surgery and outcomes of seven patients that underwent an en bloc extended total thymectomy and extrapleural pneumonectomy for stage IVA thymomas.     

Recurrence of stage I thymoma 32 years after total excision

Malignant thymomas are invasive and recur frequently, but noninvasive thymomas rarely do so. We report on a case of recurrent thymoma in a 50-year-old white man, 32 years after total excision of a stage I thymoma. We stress the importance of long-term follow-up in all patients.     

Thymoma: results of 241 operated cases

Clinical and histopathological aspects of 241 thymomas were reviewed. One hundred sixty of the patients with thymoma had myasthenia gravis and 15 had other autoimmune diseases; 55% of the thymomas were encapsulated and 45% invasive. Operation was radical resection in 87.5% of the patients, subtotal resection with residual tumor in 8.7%, and simple biopsy in 3.7%. A tumor relapse was observed in 24 patients (10%): 2 (1.5%) of 133 with encapsulated thymomas and 22 (20.4%) of 108 with invasive thymomas; among these patients, a relapse was found in 20.6% of the patients who received radiotherapy postoperatively and in 24.6% who did not. Adverse prognostic factors were clinical stage IVa (multiple pleural nodes), not feasible resection (for technical reasons), inoperable tumor relapse, and association with one of the following autoimmune diseases: pure red cell aplasia, hypogammaglobulinemia, and lupus erythematosus. Conversely, myasthenia gravis is now a curable disease; it contributes to early discovery of associated thymoma, thus allowing a better survival for patients with thymoma who have myasthenia gravis compared with patients with thymoma but without myasthenia gravis (p less than 0.05). Postoperative radiotherapy does not seem necessary after removal of encapsulated thymomas, but it is advisable in case of invasive thymomas, regardless of the extent of the resection.     

Infrasternal mediastinoscopic surgery for anterior mediastinal masses

Background Infrasternal mediastinoscopic surgery is a new alternative to the thoracoscopic approach for patients with anterior mediastinal masses.Methods We applied this technique to 18 thymectomies, one thymomectomy, and one cystectomy in a total of 20 patients with anterior mediastinal masses and then assessed the surgical results.Results Infrasternal mediastinoscopic surgery was accomplished in 18 of the 20 patients (90%). The pathological diagnoses included 13 Masaoka stage I thymomas, one stage II thymoma, two stage III thymomas, one thymic cyst, one pericardial cyst, one thymic granuloma, and one mature teratoma. Two patients with stage III thymoma required conversion to sternotomy, one for invasion into the innominate vein and the other for invasion into the pericardium. There was no surgically related mortality or complications in any patients.Conclusion Infrasternal mediastinoscopic surgery is safe and feasible for stage I thymoma and other benign tumors in the anterior mediastinum.     

Management of myasthenic patients with thymoma

Myasthenia gravis (MG) associated with thymomas differs from nonthymomatous MG, and thymomas associated with MG are also different from non-MG thymomas. According to the World Health Organization classification, the incidence of MG in thymomas was the highest in the subtypes B2, B1, and AB. Transsternal approach is still regarded as the gold standard for surgical treatment of thymomas. Less-invasive techniques of thymectomy are promising, but it is too early to estimate their real oncological value. In the series including more than 100 patients, the prognosis for survival is better in patients with thymomas associated with MG than in those with non-MG thymomas, and the prognosis for patients with MG associated with thymoma is worse than that for patients with nonthymomatous MG.     

Number of recurrent lesions is a prognostic factor in recurrent thymoma

In advanced stage thymomas, recurrence is not uncommon but prognostic factors in recurrent thymoma have not been determined and standardized treatment for recurrence has not yet been established. A retrospective analysis was conducted on 24 thymoma patients who underwent treatment for recurrence in our institution to determine the prognostic factors for overall survival. Recurrence of thymoma appeared 11.6-109.6 months after the primary operation (34.6±25.7 months). Pleural disseminated recurrence was common (n=21) as the primary recurrent lesions. Single or combined modality therapy was performed in 19 patients; surgical resection in 12, radiotherapy in 10, and chemotherapy in six patients. A third surgical resection was performed in two patients. There was no difference in overall survival between the groups with or without treatment nor in those with or without resection. Old age and chemotherapy were factors for poorer prognosis. Patients with one or two recurrent lesions detected on CT examinations showed better prognosis. Prognosis in thymoma patients with recurrence was reviewed in the present study. Patients with a small number of recurrent lesions showed better prognosis irrespective of the treatment.     

An immunohistochemical study of thymic epithelial tumors. III. The distribution of interdigitating reticulum cells and S-100 beta-positive small lymphocytes

We report an immunohistochemical study of the distribution and number of interdigitating reticulum cells (IDC) and S-100 beta-positive small lymphocytes (S-100 beta + lymphocytes) in 53 thymomas and 11 thymic carcinomas. All 53 thymomas showed the presence of IDC in the tumor parenchyma. In most cases of predominantly lymphocytic and mixed-type thymoma, IDC clustered in areas, that corresponded to locations that had medullary differentiation and contained accumulated mature lymphocytes. By contrast, in most of the predominantly epithelial-type thymomas, IDC were scattered rather than forming clusters. The distribution and number of IDC were correlation with the histological type of thymoma but not with invasiveness. In thymic carcinomas, IDC were scattered in tumor nests. In 47 of the 53 thymomas (89%), infiltrating S-100 beta + lymphocytes were readily recognized. The remaining six cases without S-100 beta + lymphocytes were noninvasive thymoma. We conclude that the degree of S-100 beta + lymphocyte infiltration is correlated with the stage of thymoma and may be a marker of thymoma malignancy.     

Current status of the diagnosis and treatment of thymoma

Although thymomas are rare neoplasms, they are the most common tumor of the anterior mediastinum in adults. Preferred therapy for these neoplasms is complete surgical resection. If a thymoma cannot be completely resected, postoperative radiotherapy may produce satisfactory results in controlling the tumor. Significant 5- and 10-year survival rates have been recorded for patients with advanced thymomas who have been treated by radiation therapy alone. Chemotherapy may be used in patients with unresectable thymomas as well, but the results are less promising than with radiotherapy. Combinations of radiotherapy and chemotherapy used on patients with unresectable thymomas have produced encouraging results. Surveillance of patients with thymoma should be prolonged because late recurrence (more than 5 years after initial therapy) can be expected in a significant minority of patients. Aggressive therapy of late recurrence, including resection of new tumor masses and pleural metastases, has yielded successive disease-free intervals that validate persistent treatment.     

Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan

BACKGROUND: Surgery remains the mainstay of treatment for thymic epithelial tumors, and radiation and chemotherapy also have been applied widely as adjuvant and palliative procedures. METHODS: We compiled records of 1,320 patients with thymic epithelial tumors who were treated from 1990 to 1994 in 115 institutes certified as special institutes for general thoracic surgery by The Japanese Association for Chest Surgery. RESULTS: Patients with stage I thymoma were treated with only surgery, and patients with stage II and III thymoma and thymic carcinoid underwent surgery and additional radiotherapy. Patients with stage IV thymoma and thymic carcinoma were treated with radiation or chemotherapy. The Masaoka clinical stage is an excellent predictor of the prognosis of thymoma and thymic carcinoma, but not thymic carcinoid. In stage III and IV thymoma, the 5-year survival rates of total resection, subtotal resection, and inoperable groups were 93%, 64%, and 36%, respectively. On the other hand, in thymic carcinoma, the 5-year survival rates of total resection, subtotal resection, and inoperable groups were 67%, 30%, and 24%, respectively. Prophylactic mediastinal radiotherapy could not prevent local recurrences effectively in patients with totally resected stage II and III thymoma. Adjuvant therapy including radiation or chemotherapy did not improve the prognosis in patients with totally resected III and VI thymoma and thymic carcinoma. CONCLUSIONS: Total resection is the most important factor in the treatment of thymic epithelial tumors. There is value in debulking surgery in invasive thymoma, but not in thymic carcinoma. We doubt that adjuvant therapy is valuable for patients with totally resected invasive thymoma and thymic carcinoma.     

Good syndrome coexisting with leukopenia

A 61-year-old man was admitted to our hospital for further examinations of a mediastinal mass. He had underwent an extended thymothymectomy, and had a tumor that was diagnosed as a type B1 thymoma, according to the World Health Organization. One year after surgery he was admitted again for recurrent diarrhea and pneumonia. Laboratory data revealed severe hypogammaglobulinemia with leukopenia. He was diagnosed with Good syndrome with leukopenia. Regular gamma globulin and figrastim injections were successful in keeping the patient symptom free. The prognosis of patients with Good syndrome and leukopenia is very poor; therefore, immediate diagnosis is important. The development of infectious diseases in a patient with thymoma or after the resection of thymoma mandates early and comprehensive immunologic investigation.