|Year : 2013 | Volume
| Issue : 2 | Page : 235-239
Thymoma: Clinical experience from a tertiary care institute from North India
Narendra Kumar1, Ritesh Kumar1, Anjan Bera1, Sushmita Ghoshal1, Rakesh Kapoor1, BD Radotra2, Suresh Chander Sharma1
1 Department of Radiotherapy and Oncology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Pathology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
|Date of Web Publication||13-Jun-2013|
Department of Radiotherapy and Regional Cancer Center, Post Graduate Institute of Medical Education and Research, Chandigarh
Background: Thymomas are the most common tumors of the mediastinum. They have varied presentation ranging from asymptomatic incidental mediastinal masses to locally extensive tumor with compressive symptoms and distant metastases. The authors present our institute's experience in combined modality management of thymomas.
Materials and Methods: We retrospectively reviewed 36 patients of thymoma treated in our institute from January 2004 to December 2010. Clinical characteristics and treatment modality in form of surgery, radiotherapy (RT) and chemotherapy (CCT) were noted. Statistical analysis was done with regard to progression free survival (PFS) and overall survival (OS) using Kaplan-Meier survival analysis.
Results: A total of 17 patients had associated Myasthenia gravis and 3 patients had associated Cushing syndrome. Masaoka Stage 4a was the most common stage (13 patients) followed by stage 3 (10 patients), stage 2 (9 patients) and stage 1 (4 patients). Twenty seven patients underwent primary surgery, out of which 20 received adjuvant RT and five received both RT and CCT. Of nine non-surgical cases, four received only palliative RT whereas 5 received systemic CCT followed by local mediastinal RT. Overall, 23 patients had complete response while 13 had partial response. 1 patient had local recurrence. Three year PFS was 60% and 3 year OS was 83%.
Conclusions: Most common presentation in our series was locally advanced tumors. Most of these patients require adjuvant mediastinal radiation, which helps in significant loco-regional control. Systemic CCT benefits in inoperable, advanced and high-risk tumors. Risk-adapted and multimodality approach is the need of the hour to achieve good control rates while minimizing treatment related toxicity.
Keywords: Chemotherapy, radiotherapy, thymoma
|How to cite this article:|
Kumar N, Kumar R, Bera A, Ghoshal S, Kapoor R, Radotra B D, Sharma SC. Thymoma: Clinical experience from a tertiary care institute from North India. J Can Res Ther 2013;9:235-9
|How to cite this URL:|
Kumar N, Kumar R, Bera A, Ghoshal S, Kapoor R, Radotra B D, Sharma SC. Thymoma: Clinical experience from a tertiary care institute from North India. J Can Res Ther [serial online] 2013 [cited 2014 Oct 1];9:235-9. Available from: http://www.cancerjournal.net/text.asp?2013/9/2/235/113364
| > Introduction|| |
Thymoma is a neoplasm of the thymus originating from the gland's epithelial tissue. Thymomas are the most common anterior mediastinal neoplasm in adults and the most common tumor of the thymus.  The incidence is approximately 0.15 per 100,000 person years.  Thymomas are typically slow growing tumors that spread by local extension. Metastases are usually confined to the pleura, pericardium, or diaphragm, whereas extrathoracic metastases are uncommon.  Thymomas are frequently associated with different paraneoplastic syndromes (PNS).  There are classified into 5 WHO histological subtypes.  Different staging systems are used but the most widely used system is Masaoka-Koga staging system. ,, Surgery remains the cornerstone of treatment. Chemotherapy (CCT) and radiotherapy (RT) is used as an adjuvant in early stages and as neoadjuvant or palliatve therapy in advanced stages. Due to small number of cases, indolent nature and infrequent recurrences of this tumor, no study has definitively determined the optimal approach. We aimed to analyze the clinical, radiological, pathological characteristics, treatment regimens, and treatment outcomes of the thymoma cases in our institute. This is a retrospective chart review of patients of thymoma treated in our institute from 2004 to 2010.
| > Materials and Methods|| |
We retrospectively reviewed the patients of thymoma from January 2004 to December 2010 treated in our institute. Total number of patients was 36. We reviewed the records of these patients to extract the following information : Age, sex, performance scale (PS), presence of paraneoplastic syndrome, histology, Masaoka stage, tumor size, extent of surgical resection, surgical margins, radiation (technique, total dose, dose per fraction, number of fractions), CCT (regimen, number of cycles), toxicity, response, recurrence, progression, metastases, and death. Operative notes were reviewed to determine intra-operative suspicion of invasion, gross tumor extension into adjoining structures, and completeness of resection. Pathology reports were obtained for all patients and the tumors were classified into five WHO histopathological classification subtypes.  Staging was based on the surgical and pathological criteria as per Masaoka-Koga staging system. , Surgery, RT, and CCT was used in the treatment in different settings as per the stage and high-risk features. In early stages (1 and 2), patients were primarily managed with surgery and adjuvant RT was given in cases with high-risk features (incomplete resection, positive margins, large size). In locally advanced stages (3 and 4), multimodality management was done and patients with poor PS and superior vena cava obstruction (SVCO) received palliative RT. The period between the first complaint and diagnosis was registered as symptom duration. Survival, recurrence and progression information were collected through chart review, patient or relative contact. Response evaluation was noted both clinically and radiologically and RECIST (Response Evaluation Criteria in Solid Tumors) criteria were applied.  SPSS (Statistical Package for Social Sciences) v 15 was used for statistical analysis. The Kaplan-Meier survival analysis was done for analyzing overall survival (OS) and progression free survival (PFS).
| > Results|| |
Patient characteristics are summarized in [Table 1]. Between January 2004 and December 2010, 36 patients of thymoma were registered in our department. The mean age of the patients was 40.83 years and ranges from 13 years to 65 years. 17 patients (47.2%) were males and 19 patients (52.8%) were females. Most of them were in ECOG PS 2 (28 patients). The median duration of symptoms was 6 months. PNS was associated in 20 patients with 17 having myasthenia gravis (MG) and 3 patients having Cushing syndrome. Cough was the most common presenting symptom manifesting in all patients followed by dyspnea in 30 patients (83.3%). 6 patients with symptoms of SVCO. Median size of the primary tumor was 8 cm and ranges from 3 cm to 17 cm. Masoka Stage 4a was the most common stage found in 13 patients (36.1%) followed by stage 3 in 10 patients (27.8%), stage 2 in 9 patients (25%) and stage 1 in 4 patients (11.1%). Histopathological analysis [Table 2] revealed B2 subtype as the most common subtype seen in 12 patients (33.3%). Other subtypes were B3, B1, AB and A seen in 7 (19.4%), 6 (16.7%), 6 (16.7%), and 5 (13.9%) patients respectively.
Treatment details are summarized in [Table 3]. Total of 27 patients (75%) underwent primary resection of the mediastinal mass whereas the rest 9 patients (25%) did not undergo any form of surgery. Of the 27 patients who underwent primary surgery, R0, R1, and R2 resections were observed in 13, 9, and 5 patients respectively. Of the primarily surgically resected patients, 2 did not receive any further adjuvant whereas 20 patients received adjuvant RT and 5 patients received both adjuvant RT and CCT. Of the 9 non-surgical patients, 5 were treated with primary CCT followed by localized mediastinal RT and the other 4 patients received only palliative localized mediastinal RT.
RT doses ranged from 30 Gy to 60 Gy with a median of 45 Gy. Palliative mediastinal RT was given in doses of 30 Gy in 10 fractions in 2 weeks. Radical RT doses delivered in doses of 45-60 Gy with higher doses in patients with R2 resections.
CCT was administered in 10 patients only with 5 patients in adjuvant settings and in other 5 patients as primary CCT. Two different CCT regimens were used, CAP regimen (cyclophosphamide, adriamycin, and cisplatin) in 6 patients and PE regimen (cisplatin and etoposide) in 4 patients. The CCT were given in 3 weekly intervals with a median 6 number of cycles.
There were no surgical complications in form of post-operative deaths or wound complications. Patients who underwent RT experienced 47.0% grade 1-2 esophagitis; 8.8% grade 1-2 pneumonitis; and no grade 3 or higher toxicity. CCT toxicity was seen in 30.0% of patients in form of grade 1-2 hematological toxicity. All patients completed treatment with no significant toxicity.
After treatment completion, patients were assessed for response both clinically and radio logically. 19 patients (52.8%) were asymptomatic and 17 patients (47.2%) had significant improvement in symptoms. As per the RECIST criteria, 23 patients (63.9%) had complete response (CR) and the rest 13 patients (36.1%) had partial response (PR). One patient had local recurrence. Three year OS of all patients was 83% [Figure 1] and 3 year PFS was 60% [Figure 2]. The mean OS was 75 months and the mean PFS was 51 months.
| > Discussion|| |
Thymomas are the most common tumor of the thymus and account for 50% of the anterior mediastinal masses.  However, thymomas are rare human neoplasms accounting for less than 0.5% of all cancers. As a consequence of their rarity, knowledge regarding these tumors is mainly based on case reports or small retrospective series. We here present our institute's experience in management of thymomas using the three therapeutic modalities - Surgery, RT and CCT in different combinations.
Thymomas are typically slow growing tumors that spread by local extension. Metastases are usually confined to the pleura, pericardium, or diaphragm, whereas, extra-thoracic metastases are uncommon.  Thymomas are classified into five WHO histopathological subtypes.  Different staging systems are used but the most widely used system is Masaoka-Koga staging system, based on the pre-operative and histopathological findings. ,,
Surgery is the cornerstone of the management of thymomas, initially being useful for precise histopathological diagnosis and staging, and in most cases providing the first-line therapeutic modality.  For resectable tumors, immediate and complete surgical resection is advocated. During surgery, a careful examination of the mediastinum and pleural cavities, followed by evaluation of macroscopic capsular invasion, peritumoral and pleural adhesions, and involvement of surrounding tissues is necessary. Careful exploration of the mediastinal pleura, especially in the costodiaphragmatic sinuses, may detect droplet metastasis.  Areas of uncertain margins are marked with clips to allow precise delivery of post-operative RT. Microscopically negative margin, microscopically positive margin, and gross residual tumors are designated as R0, R1, and R2 resection respectively. In our series, 27 patients (75%) underwent surgical resection, of which 9 had R1 resections and 5 had R2 resections.
RT is used in the treatment of thymomas in adjuvant, neoadjuvant, definitive or palliative settings. Post-operative RT is recommended in incompletely resected thymomas.  Completely resected stage 2 and 3 also benefit from adjuvant RT to reduce local recurrence rates. Evolving trends for locally advanced tumors include multimodal chemoradiation strategies. Current modalities of RT for thymoma include the use of multi-field arrangement conformal RT and three dimensional treatment planning. A total RT dose ranging from 40 Gy to 60 Gy is advocated, including a boost on the tumor bed in incompletely resected or non-resected lesions, with a standard fractionation scheme consisting in daily doses from 1.8 Gy to 2 Gy over a period of 4-6 weeks.  The benefit of RT dose escalation on local control has not clearly been established. Arriagada et al. reported similar local control rates with total doses inferior to 48 Gy or superior to 60 Gy.  However, Mornex et al. in a French series, reported high-local recurrence rates after adjuvant RT delivered to median doses of 45-50 Gy in stage 3-4 resected tumors.  This led most investigators to increase RT doses to 60-65 Gy, which is nowadays possible with conformal radiation planning systems. RT in definitive setting have been reported in few small series, most of included patients with various tumor stages, heterogeneous performance status, different RT doses and techniques. Overall, local control rates ranges from 45% to 50%. Patients with poor performance status and advanced diseases with compressive symptoms are given palliative RT in doses of 30 Gy in 10 fractions or 20 Gy in five fractions. In this series, adjuvant RT was given in 25 patients out of 27 patients who underwent surgery. The dose ranged from 45 Gy to 60 Gy with a median of 45 Gy. Of the 9 patients who did not underwent surgical resection, 4 received palliative RT in doses of 30 Gy in 10 fractions, whereas, the rest 5 patients were managed with primary CCT followed by localized mediastinal RT. The overall median RT dose was 45 Gy.
The toxicity of RT depends on the amount of normal tissues included in the radiation portal, and mainly consists of acute pneumonitis, esophagitis and pericarditis, and late coronary disease and pulmonary fibrosis.  No appreciable acute grade 3-4 toxicity was observed in this series and all patients completed their treatment without treatment breaks.
CCT in thymomas is preferred in locally advanced, unresectable and metastatic disease.  The common drugs with good response rates include cisplatin, adriamycin, etoposide, cyclophosphamide, and ifosfamide. Current standard regimens include the following : c0 yclophosphamide, adriamycin, cisplatin (CAP);  cisplatin and etoposide (PE);  adriamycin, cisplatin, vincistine, cyclophosphamide (ADOC);  and etoposide, ifosfamide, cisplatin (VIP).  Response rates range between 32% and 92%, including 10-43% of complete responses.  Adjuvant CCT has been reported to favorably influence survival in stage 3 and 4a resected thymomas. CCT is also used as the initial treatment of stage 3 and 4a unresectable thymomas.  The main objective is to reduce the tumor volume to allow subsequent surgery with higher chances of achieving negative margins, or to deliver RT sparing more normal tissues. There is a high-response rates to neoadjuvant CCT, ranging from 77% to 100%, associated with survival rates ranging from 77% to 95%. Thus currently, multimodal approach is preferred in locally advanced thymoma, combining all the three modalities i.e., CCT, surgery and RT. , For stage 4b thymomas with disseminated disease, CCT only is preferred with local RT for palliation of local symptoms.  10 patients received CCT in this series, 6 with CAP regimen and 4 with PE regimen.
Thymomas are associated with PNS in 50-70% of cases.  The most common PNS associated are MG (30-50%), Cushing syndrome, pure red blood cell aplasia, hypogammaglobulinemia, limbic encephalitis ,and rheumatoid arthritis. In this series, PNS was associated in 20 patients, 17 having MG and 3 having Cushing syndrome. MG is presently regarded as a favorable factor influencing outcome, as it may lead to an earlier disclosure of the tumor.  Thymectomy and chemoradiation has been reported to improve symptoms of MG in 50-60% of cases, with achievement of complete remission in 8-30% of cases. Other PNS (pure red blood cell aplasia, hypogammaglobulinemia and stiff-person disease) also improve with treatment of thymic tumors.
Late recurrences occurring more than 5-10 years after resection are not uncommon in thymoma. Recurrences are usually loco-regional. , One patient recurred in the present series and the recurrence was local. Recurrences are managed actively using the three modalities - Surgery, RT and CCT. High-response rates with good 5 year survival rates were obtained in small retrospective series.
Prognostic factors predicting recurrence was evaluated by Detterbeck et al. in a systemic review.  The significant factors were Masaoka Stage and completeness of resection. Other factors such as age, sex, size of tumor, and PNS were not statistically significant in multivariate analysis.
The management of thymoma is a paradigm of co-operation between clinicians, surgeons, and pathologists from establishing diagnosis to organizing the therapeutic strategy and evaluating the prognosis. With new techniques and drugs, there is a significant improvement of therapeutic standard and thymic tumors represent a model of therapeutic implementation and achievement in oncology.
| > References|| |
|1.||Detterbeck FC, Parsons AM. Thymic tumors. Ann Thorac Surg 2004;77:1860-9. |
|2.||Cowen D, Hannoun-Levi JM, Resbeut M, Alzieu C. Natural history and treatment of malignant thymoma. Oncology (Williston Park) 1998;12:1001-5. |
|3.||Regnard JF, Magdeleinat P, Dromer C, Dulmet E, de Montpreville V, Levi JF, et al. Prognostic factors and long-term results after thymoma resection: A series of 307 patients. J Thorac Cardiovasc Surg 1996;112:376-84. |
|4.||Suster S, Moran CA. Thymoma classification: Current status and future trends. Am J Clin Pathol 2006;125:542-54. |
|5.||Masaoka A, Monden Y, Nakahara K, Tanioka T. Follow-up study of thymomas with special reference to their clinical stages. Cancer 1981;48:2485-92. |
|6.||Koga K, Matsuno Y, Noguchi M, Mukai K, Asamura H, Goya T, et al. A review of 79 thymomas: Modification of staging system and reappraisal of conventional division into invasive and non-invasive thymoma. Pathol Int 1994;44:359-67. |
|7.||Yamakawa Y, Masaoka A, Hashimoto T, Niwa H, Mizuno T, Fujii Y, et al. A tentative tumor-node-metastasis classification of thymoma. Cancer 1991;68:1984-7. |
|8.||Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47. |
|9.||Murakawa T, Nakajima J, Kohno T, Tanaka M, Matsumoto J, Takeuchi E, et al. Results from surgical treatment for thymoma. 43 years of experience. Jpn J Thorac Cardiovasc Surg 2000;48:89-95. |
|10.||Falkson CB, Bezjak A, Darling G, Gregg R, Malthaner R, Maziak DE, et al. The management of thymoma: A systematic review and practice guideline. J Thorac Oncol 2009;4:911-9. |
|11.||Huang J, Detterbeck FC, Wang Z, Loehrer PJ Sr. Standard outcome measures for thymic malignancies. J Thorac Oncol 2010;5:2017-23. |
|12.||Arriagada R, Bretel JJ, Caillaud JM, Garreta L, Guerin RA, Laugier A, et al. Invasive carcinoma of the thymus. A multicenter retrospective review of 56 cases. Eur J Cancer Clin Oncol 1984;20:69-74. |
|13.||Mornex F, Resbeut M, Richaud P, Jung GM, Mirabel X, Marchal C, et al. Radiotherapy and chemotherapy for invasive thymomas: A multicentric retrospective review of 90 cases. The FNCLCC trialists. Fédération Nationale des Centres de Lutte Contre le Cancer. Int J Radiat Oncol Biol Phys 1995;32:651-9. |
|14.||Loehrer PJ Sr, Kim K, Aisner SC, Livingston R, Einhorn LH, Johnson D, et al. Cisplatin plus doxorubicin plus cyclophosphamide in metastatic or recurrent thymoma: Final results of an intergroup trial. The Eastern Cooperative Oncology Group, Southwest Oncology Group, and Southeastern Cancer Study Group. J Clin Oncol 1994;12:1164-8. |
|15.||Giaccone G, Ardizzoni A, Kirkpatrick A, Clerico M, Sahmoud T, van Zandwijk N. Cisplatin and etoposide combination chemotherapy for locally advanced or metastatic thymoma. A phase II study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 1996;14:814-20. |
|16.||Fornasiero A, Daniele O, Ghiotto C, Sartori F, Rea F, Piazza M, et al. Chemotherapy of invasive thymoma. J Clin Oncol 1990;8:1419-23. |
|17.||Loehrer PJ Sr, Jiroutek M, Aisner S, Aisner J, Green M, Thomas CR Jr, et al. Combined etoposide, ifosfamide, and cisplatin in the treatment of patients with advanced thymoma and thymic carcinoma: An intergroup trial. Cancer 2001;91:2010-5. |
|18.||Berruti A, Borasio P, Gerbino A, Gorzegno G, Moschini T, Tampellini M, et al. Primary chemotherapy with adriamycin, cisplatin, vincristine and cyclophosphamide in locally advanced thymomas: A single institution experience. Br J Cancer 1999;81:841-5. |
|19.||Yokoi K, Matsuguma H, Nakahara R, Kondo T, Kamiyama Y, Mori K, et al. Multidisciplinary treatment for advanced invasive thymoma with cisplatin, doxorubicin, and methylprednisolone. J Thorac Oncol 2007;2:73-8. |
|20.||Lucchi M, Ambrogi MC, Duranti L, Basolo F, Fontanini G, Angeletti CA, et al. Advanced stage thymomas and thymic carcinomas: Results of multimodality treatments. Ann Thorac Surg 2005;79:1840-4. |
|21.||Venuta F, Rendina EA, Longo F, De Giacomo T, Anile M, Mercadante E, et al. Long-term outcome after multimodality treatment for stage III thymic tumors. Ann Thorac Surg 2003;76:1866-72. |
|22.||Monden Y, Nakahara K, Kagotani K, Fujii Y, Masaoka A, Kawashima Y. Myasthenia gravis with thymoma: Analysis of and postoperative prognosis for 65 patients with thymomatous myasthenia gravis. Ann Thorac Surg 1984;38:46-52. |
|23.||de Perrot M, Liu J, Bril V, McRae K, Bezjak A, Keshavjee SH. Prognostic significance of thymomas in patients with myasthenia gravis. Ann Thorac Surg 2002;74:1658-62. |
|24.||Monden Y, Nakahara K, Iioka S, Nanjo S, Ohno K, Fujii Y, et al. Recurrence of thymoma: Clinicopathological features, therapy, and prognosis. Ann Thorac Surg 1985;39:165-9. |
|25.||Ruffini E, Mancuso M, Oliaro A, Casadio C, Cavallo A, Cianci R, et al. Recurrence of thymoma: Analysis of clinicopathologic features, treatment, and outcome. J Thorac Cardiovasc Surg 1997;113:55-63. |
|26.||Detterbeck F, Youssef S, Ruffini E, Okumura M. A review of prognostic factors in thymic malignancies. J Thorac Oncol 2011;6:S1698-704. |
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]