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Thymoma

Thymoma

Chair

Dr. S. Lam
Respiratory Medicine, VGH

Members​

Thymomas are rare neoplasms that arise from tissue elements of the thymus and develop in the anterior mediastinum. Other anterior mediastinal tumours such as lymphoma, germ cell tumours and carcinoid tumours should be treated with protocols specific to that type.

Most thymomas are slow-growing tumours with a tendency to recur locally and seldom metastasise hematogenously. The majority of cases are cured. When thymoma is fatal, death is often caused by cardiorespiratory problems resulting from pericardial and pleural metastases.

Encapsulated thymic tumours are usually asymptomatic. Patients with invasive tumours may develop symptoms from a mediastinal mass. Compression of the trachea, bronchus, or lung may result in chest pain, cough or dyspnea. Thymomas can be associated with a variety of clinical syndromes such as myasthenia gravis, pure red cell aplasia, pancytopenia, hypogammaglobulinemia, collagen vascular disease and endocrinopathies. The frequency of association of myasthenia gravis and thymoma depends on selection factors associated with the series. It is estimated that 10% of patients with myasthenia gravis have thymoma and 30% of patients with thymoma have myasthenia gravis. Associated syndromes may but do not always improve with remission of the thymoma.

(Updated May 2001)

1. Demographics

Incidence
Thymic tumours are very uncommon in comparison with other thoracic tumours. Thymomas account for 17% - 30% of anterior mediastinal tumours. The incidence is 0.18 per 100,000 for men and 0.10 per 100,000 for women.

Age and Gender
Thymomas affect both sexes equally and are most often seen in the 5th and 6th decades of life.

Survival 
The long-term survival rate for completely resected non-invasive thymomas is over 95%. Completely excised capsular-invaded or minimally invasive tumours treated with postoperative radiotherapy should have a 5-year survival rate of approximately 80%. More extensive but non-metastatic tumours may have a 40-50% control rate. Metastatic and recurrent thymomas have variable virulence and may respond to systemic therapy. Median survival is 2-4 years and 5-year survival is 25-30%.

References: 

  1. Egea AM, Albasini JL, Paricio PP, et al. Prognostic factors of thymomas. Eur J Surg Oncol 1995;21:482-485  

  2. Maggi G, Casadio C, CavalloA, et al. Thymoma: results for 241 operated cases. Ann Thor Surg 1991;51:152-156.  

  3. Souadjian JV, Enriquez P, Silverstein MN, et al. The spectrum of diseases associated with thymoma. Arch Intern Med 1974;134:374

2. Predisposing Factors / Prevention

No predisposing factors or preventative strategies have been documented.

3. Screening / Early Detection

Patients with myasthenia gravis are routinely assessed for thymomas.

4. Diagnosis

4.1 Clinico-pathologic Considerations 
Thymomas are epithelial tumours that may or may not be extensively infiltrated by lymphocytes. True thymomas contain cytologically bland thymic epithelial cells and should be distinguished from thymic carcinomas that have malignant cytological characteristics and carry a poor prognosis. The terms invasive and noninvasive ​should be used to describe the behaviour of these tumours. Noninvasive thymomas have an intact fibrous capsule, are mobile and are easily resected. Invasive thymomas are malignant as evidenced by the finding of invasion of the tumour capsule or surrounding organs, or by the presence of a metastasis. About 30-40% of all thymomas are invasive.

Other anterior mediastinal tumours that need to be differentiated from thymoma include thymic carcinomas, germ cell tumours, lymphomas, carcinoids, and T-cell leukemias. Some mediastinal tumours can be difficult to categorise with standard pathology and it is crucial to distinguish potentially curable tumours such as thymoma, lymphoma and germ cell neoplasms. Special stains and tumour markers usually suffice but cytogenetic analysis may be required in some cases. Germ cell tumours characteristically have an isochromosome of the short arm of chromosome 12 (i[12p]) and lymphomas may have typical cytogenetic abnormalities.

Reference: 

  1. Kornstein MJ. Controversies regarding the pathology of thymomas. Path Ann 1992;27:1

4.2 Diagnostic Procedures 
Chest radiograph and CT of the chest are routine assessments. Magnetic resonance imaging may demonstrate invasion of pulmonary artery, innominate vein, or superior vena cava. The role of positon emission tomography scans has not been determined. Some cases are pathologically difficult and it is crucial to rule out germ cell tumours.

Tumour markers are not usually elevated in thymomas. Nevertheless, in view of the differential diagnosis of an anterior mediastinal mass (particularly in young males), it would be wise to check beta HCG, alpha fetoprotein, and CEA.

Histologic diagnosis is essential in planning treatment. Fine needle aspiration or needle biopsy usually provide sufficient information for the diagnosis. Mediastinoscopy, anterior mediastinotomy, and video-assisted thoracic surgery may have specific indications, but are rarely necessary in establishing the diagnosis. Consideration should be given to obtaining diagnostic material suitable for cytogenetic studies in appropriate cases.

References: 

  1. Graeber GM, Shriver CD, Albus RA, et al. The use of computed tomography in the evaluation of mediastinal masses. J Thorac Cardiovasc Surg 1986:91:662  

  2. Pearson FG. Mediastinal masses diagnosis: invasive techniques. Semin Thorac Cardiovasc Surg 1992;4:23.

5. Staging

​5.1 Classific​ation Criteria

Although there is no standardised UICC staging system, the system cited by Masaoka, 1981 is commonly employed.

Stage I
Intact capsule or growth within the capsule

Stage II​
Invasion into surrounding fatty tissue or mediastinal pleura

Stage II A:
microscopic invasion through capsule

Stage II B:
macroscopic and microscopic invasion through capsule

Stage III
Macroscopic invasion into neighbouring organs (pericardium, great vessels, lung)

Stage IVA
Pleural or pericardial dissemination

Stage IVB
Lymphogenous or hematogenous metastasis

Reference: 

  1. Masaoka A, Monden Y, Nakahara K, et al: Follow-up study of thymomas with special reference to their clinical stages. Cancer 1981;48:2485-2492.

5.2 Staging ​Diagram

Click to enlarge - Thymoma Staging Diagram 

Click for larger image

6. Management

Referral Information for the New Patient Visit 


Patients not previously seen at the BCCA may be referred to a cancer center for consultation and management by contacting the Admitting Department of the geographically appropriate center. The availability of relevant operative, pathology and imaging laboratory reports will be requested so that these can be obtained prior to the patient being seen, together with the relevant slides and radiographs for review. The courtesy of a brief referring letter or phone call is appreciated.

Best Practice Guidelines 

Stage I


Complete resection of a well-encapsulated, non-invasive thymoma is usually curative, with a risk of local recurrence of less than 2%. In patients with myasthenia gravis, operative mortality can now be minimised with close attention to respiratory support when planning surgical treatment. There is no role for radiotherapy unless a non-invasive thymoma is incompletely resected.

Stage II

Surgery
En bloc surgical resection of the tumour with intact capsule is standard. The surgeon must carefully assess the tumour during the operation in an attempt to identify any invasive qualities, and should mark areas that are suspicious for invasion in an effort to guide the pathologist's microscopic description and the radiation oncologist's adjuvant therapy.

Radiotherapy 
The value of adjuvant radiation therapy in invasive thymomas is well documented and should be included in the treatment regimen regardless of the completeness of tumour resection. In a review of 115 completely resected invasive thymomas (Curran et al. 1988), a recurrence rate of 5% was documented when adjuvant radiation therapy was employed; this increased to 28% without adjuvant radiotherapy.

Chemotherapy  
Adjuvant chemotherapy has not been reported in stage II thymoma. Radiotherapy is the treatment of choice when the area at risk of recurrence can be encompasses within a reasonable radiotherapy volume. In cases where the surgeon identifies pleural invasion (Stage IIB) such that the pleural space is judged to be at risk of drop metastases, the area at risk extends outside a reasonable radiotherapy volume. In such cases, adjuvant chemotherapy may be a consideration particularly in young or fit patients. Complex cases are ideal for multi-disciplinary review at lung conference.

Stage III

Surgery 
When invasion of neighbouring organs is identified intra-operatively, aggressive resection including lung, pleura, phrenic nerve, pericardium, and great vessels is occasionally necessary. Adjuvant thoracic irradiation may be guided if areas at high risk of recurrence are marked with surgical clips. The role of subtotal resection or debulking procedures in advanced, unresectable stage III disease is uncertain.

When invasion of adjacent organs is identified before surgery, preoperative downstaging with chemotherapy or chemoradiation should be considered. After pre-operative therapy, definitive local surgery should be performed 4 to 6 weeks after the final cycle of chemotherapy.

Chemotherapy 
During the past decade, thymoma has clearly been identified as a chemosensitive tumour. The optimal regimen and precise role of chemotherapy continues to be uncertain because the low incidence of thymomas limits feasibility of large clinical trials.

Cisplatin containing combination chemotherapy regimens appear to be the most active. The PAC regimen consisting of cisplatin, doxorubicin, and cyclophosphamide (Loehrer et al. 1994) and etoposide plus cisplatin (Giaccone et al. 1996) are capable of inducing responses in the majority of patients with advanced disease with some complete responses. Neoadjuvant chemotherapy with PAC before resection of locally advanced cases is associated with a high response rate but the majority of patients had histologically viable tumour in the resection specimen and received post-operative radiotherapy (Rea et al. 1993). Theoretically, risk of tumour dissemination outside the mediastinum at the time of surgery should be diminished if a higher proportion of patients were downstaged to pT0. A higher pT0 rate should be possible when combined chemoradiation is given before surgery. Preoperative thoracic irradiation given concurrently with cisplatin plus etoposide has been widely used in the combined modality therapy of stage III NSCLC (Albain et al. 1995) with acceptable risk of toxicity and promising results. A similar model of treatment may be suitable for stage III thymoma when initial complete resection appears unlikely.

Radiotherapy 
Adjuvant radiotherapy after resection is standard in cases where ​the risk for recurrence is judged to reside within a reasonable radiotherapy volume.

Thoracic irradiation delivered concurrently with cisplatin plus etoposide should be delivered in the same fashion described for Stage III NSCLC (at Lung page, click on 6.Management).

Stage IV and Recurrent Thymoma  

Chemotherapy 
Etoposide plus cisplatin or the PAC regimen induce responses in more than half of advanced cases with median survival of 3-4 years and 5-year survival of 20-30%. Concurrent chemoradiation should not be considered for patients with disease not encompassable within a reasonable radiotherapy volume.

Surgery and Radiotherapy
Surgery may be considered in Stage IVA thymomas that respond well to initial chemotherapy. Such cases are appropriate for lung conference.

Thoracic irradiation as a consolidative therapy after good chemotherapy response of stage IV thymomas should be considered on a case by case basis. Recurrent thymoma that is resistant to chemotherapy may be appropriate for palliative radiotherapy.

References: 

  1. McKenna WG, Bonomi P, Barnes MM, et al. Malignancies of the thymus. In:Roth JA, Ruckdeschel JC, Weisenburger TH: Thoracic Oncology. Philadelphia, Pa, WB Saunders Co 1989, pp 466-477.  

  2. Shamji F, Pearson FG, Todd TRJ, Ginsberg RJ, Ilves R, Cooper JD. Results of surgical treatment of thymoma. J Thorac Cardiovasc Surg 1984;87:43.  

  3. Curran WJ, Kornstein MJ, Brooks JJ, et al. Invasive thymoma: the role of mediastinal irradiation following complete or incomplete surgical resection. J Clin Oncol 1988;6:1722-1727.  

  4. Pollack A, Komaki R, Cox JD, et al. Thymoma: treatment and prognosis. Int J Radiol Oncol Biol Phys 1992;23:1037  

  5. Loehrer PJ, Kim K, Aisner SC, et al. Cisplatin plus doxorubicin plus cyclophosphamide in metastatic or recurrent thymoma: final results of an intergroup trial. J Clin Oncol 1994;12:1164-1168  

  6. Giaccone G, Ardizzoni A, Kirkpatrick A, et al. Cisplatin and etoposide combination chemotherapy for locally advanced or metastatic thymoma: a phase II study of the European Organization for Research and Treatment of Lung Cancer Cooperative Group. J Clin Oncol 1996;14:814-820.  

  7. Rea F, Sartori F, Loy M, et al. Chemotherapy and operation for invasive thymoma. J Thorac Cardiovasc Surg 1993;106:543-549.  

  8. Albain K, Rusch V, Crowley J, et al. Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 1995;13:1880-92.

Follow-up

 
For patients with invasive thymoma in complete remission after definitive treatment, follow-up should include clinical examination and chest radiographs every four months for two years, every six months until five years and annually thereafter. The rationale of this follow-up is that recurrent thymomas can occasionally achieve long lasting second remissions with salvage therapy. Thymoma patients treated palliatively should have follow-up based on symptomatology and treatment modality used. The BCCA doctor in charge should explicitly clarify the physician in charge of palliative patient follow-up.

SOURCE: Thymoma ( )
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