Thymic Tumors

Epidemiology

Risk Factors

  • Far Eastern country? EBV
  • Childhood thymic XRT
  • MEN_syndrome I or II
  • Chromosomal abnormality? t(15:19) or deletion of short arm of chromo 6.

Associated Syndromes

  • Myasthenia_gravis
    • 30-50% thymoma present with myasthenia gravis
    • 15% myasthenia gravis have thymoma (Temes, 1999).
    • Cardiac myositis may cause heart failure, cardiac arrhythmia, and sudden death (Mygland, 2000; Agarwala, 1996).
  • Neuromyotonia can also be associated with thymoma. (Hart, 2000; Agarwala, 1996; Fauci, 1998).
  • Abnormality of the muscle fiber membrane leads to marked delay before the affected muscles can relax after a contractions; this leads to apparent muscle stiffness.
  • Lambert-Eaton myasthenic syndrome
  • Subacute sensory neuronopathy
  • Red cell aplasia
  • Immunodeficiency

Presentation and Evaluation

Anatomy

  • Anterior Mediastinum - heart and everything anterior to it.
  • Middle mediastinum - between, including the trachea and proximal bronchial tree, esophagus, mediastinal nodes, and portions of the central pulmonary vasculature.
  • Posterior mediastinum - spine and paravertebral gutters

Differential Diagnosis

Most Common Histology By Location

Location Histology in Order
Anterior Thymic tumors
lymphoma
germ cell tumor
carcinoma
Middle Bronchial cysts
enteric cysts
pericardial cysts
Posterior Neurogenic
esophageal
  • Thymic tumors are 50% of anterior mediastinal tumors

Most Common Histology By Age

Tumor Adults Children All Ages
Thymoma 31% (1) 28% (2) 23.3% (2)
Neurogenic 15% 47% (1) 25.3% (1)
Lymphoma 26% (2) 9% 15.3%
Germ cell tumor 15% 9% 12.2%

Pathology

General

  • thymus
  • Thymoma look similar to the normal cells of the thymus
  • However, the neoplastic cells of thymoas are epithelial cells

WHO Classification

Type Pathology OS-10
A Medullary thymoma
Spindle-cell thymoma
Benign clinical course
100%
AB Mixed thymoma 76%
B1 Lymphocyte-rich thymoma
Lymphocytic thymoma
Predominately cortical thymoma
Organoid thymoma
Moderate malignant clinical course
B2 Cortical thymoma 45%
B3 Epithelial thymoma
Atypical thymoma
Squamoid thymoma
Well-differentiated thymic carcinoma
45%
C Thymic carcinoma 28%
  • Series of 100 thymomas resected in Japan between 1973 and 2001 using the WHO classification.

Clinical Presentation

  • 30-40% are asympomatic and found as incidental
  • Some present with paraneoplastic syndromes; the most common is myasthenia gravis, which is seen in 45% of patients.

Routes of Spread

  • The predominant pattern of spread of thymomas is by direct invasion into adjacent organs.

Diagnostic Studies

  • rule out myasthenia gravis: muscle fatiguability especially up ward gaze of eyes.
  • rule out nonseminomatous germ cell tumors: AFP and beta-hCG
  • rule out metastatic diseases: Imaging studies of the body
  • confirm pathology with biopsy: CT or U/S guided FNA, bronchoscopy

Staging and Outcome

Prognostic Factors

  • invasiveness (stage)
  • completeness of surgical resection

Masaoka in 1981

Stage Description OS-5 [9]
Stage I Complete resection with no microscopic capsular invasion 100%
Stage II Macroscopic invasion into surrounding fatty tissue or mediastinal pleura or microscopic invasion into capsule 98%
Stage III Macroscopic invasion into neighboring organs (pericardium, great vessels, lungs) or intrathoracic mets, or both 88%
Stage IVa Pleural or pericardial dissemination 70%
Stage IVb Lymphogenous or hematogenous mets 50%
  • No AJCC staging in 6th ed.

Treatment

General

Adjuvant Therapy based on Stage, Histology and Surgery (does not include Thymic Carcinoma)

Stage Surgery Adjuvant Therapy
I-II Complete thymectomy (ie. R0 Resection, negative margins) No further treatment
II less than complete thymectomy post-op RT 50-60 Gy
III complete thymectomy post-op RT
III, IV initially unresectable MDACC regiment of chemotherapy and radiation [5]
  • MDACC regiment for unresectable Stage III, IV: neoadjuvant chemotherapy -> thymectomy-> postop XRT-> consolidative chemotherapy.
  • this regiment at time is extrapolated for "resectable" stage III patients.

Surgery

  • Complete en bloc surgical resection is the treatment of choice of all thymomas, regardless of invasiveness
  • A total thymectomy with complete resection of all tumor can be achieved in nearly all stage I and stage II patients and in 27% to 44% of stage III patients
  • For completely resected invasive tumors, recurrence rate can be as high as 30%. Adjuvant XRT for Stage III or IV can reduce risk to <10%.

Systemic Therapy

  • Reserved for locally advanced/metastatic disease
  • Cisplatin, doxorubicin, and cyclophosphamide have response rate > 50%
  • Improved overall survival with 5-yr OS 52.5%*
  • Concurrent chemoradiation can be used in selective cases
  • Potential candidates for chemotherapy include approximately one third of the patients with an invasive thymoma that later metastasizes and all patients with stage IV disease. [Fornasiero]
  • Other New Therapies include
    • Carboplatin & Paclitaxel
    • Octreotide [Loehrer]
    • erlotinib and bevacizumab
    • Imatinib (Gleevec)

Radiation Therapy

Stage II and III

  • Controversial area with some studies showing decreased local recurrence but others not.
  • Consider observation in completely resected patients as the largest study shows no benefit.
    • Study by Curran (1988) with 53 patients showed local control benefit in all stage II/III patients.[2]
    • The largest study 548 pts Kondo (2003) with stage II/III study showed no advantage to post-operative radiation.[9]
    • The therapy suggested splits the difference and recommends post-op RT for completely resected stage III but not stage II.

Example Fields for Stage III Thymoma

  • GTV + margin (4 cm cranial-caudal, 3 cm lateral margins)
  • Hemithorax irradiation is not considered to be standard in US, despite studies of improved RFS for completely resected stage II and III thymoma from Japan.

Unresectable

  • The role of preoperative and primary radiation therapy alone has fallen out of favor.[3]
  • Due to improved response rates to chemotherapy, most patient with advanced disease are treated with combined-modality approach.

Radiation doses[11]

Situation Dose
pre-op RT 45 Gy
post-op negative margins
or close margins
45 - 50 Gy
post-op microscopic residual 54 Gy
Gross residual 60 Gy or more

Studies

Patterns of Failure for Stage III Thymoma [11]

Location Tumor Bed Pleura Lung Distant
Failure Rate 23% 53% 8% 15%

Post-operative Radiation for Stage II and III
Curran (1988) [2]
Eligibility

  • 57 patient with Stage II or III with invasive thymomas

Results

Treatment Local failure rate
total resection without RT 53%
total resection with RT 0%
subtotal resection with RT 21%

Conclusion

  • need RT for all stage II/III

Kondo (2003) [9]
Eligibility

  • 247 stage II patient and 201 patient with III invasive thymomas

Results

Stage Treatment Local failure rate
II total resection without RT 1.6%
II total resection with RT 0%
III total resection without RT 3.1%
III total resection with RT 5.1%

Conclusion

  • No need RT for completely resected stage II/III

MD Anderson Protocol Lung Cancer (2004)[5]
Eligibility

  • Stage III/IV, unresectable
  1. Induction Chemotherapy
    • Cyclophosphamide 500 mg/m2 on day 1
    • doxorubicin 20 mg/m2 per day on days 1-3 via continuous infusion
    • cisplatin 30 mg/m2 per day on days 1-3 via
    • prednisone 100 mg/m2 per day days 1-5
    • repeat on 3-4 week interval
  2. Surgical Resection
  3. Radiation Therapy
    • 27% received 50 Gy
    • 73% received 60 Gy
  4. Consolidative Chemotherapy

Hemithorax Radiation
Uematsu[12]

  • 43 pts.
  • Doses used: 15 Gy in 15 fx to entire hemithorax (EH) and 40 Gy to Mediastinum (M)
  • 5 year relapse free survival 96% for EH-MRT and 74% for MRT (p = 0.03)
  • 5 year OS was 100% vs 66% NS

Studies of Doses and Control Rates for Unresectable Thymoma

Dose < 48 Gy 49-59 Gy > 59 Gy
Control Rates 49% 63% 80%

Studies: Gerein, Marks, Chahiniian, Ariaratnam, Arriagada, Kersh, Krueger

Chemotherapy
Fornasiero and colleagues (1991) a regimen of cisplatin /vincristine /doxorubicin/ cyclophosphamide for incompletely resected invasive thymomas or cases with unresectable disease.
90% response rate with a median survival time of 15 months.

Medical Treatment
Loehrer et al evaluating the effects of octreotide alone or with prednisone in 38 patients with advanced thymoma that expressed somatostatin receptors (ie, that were octreotide scan positive).
The patients were given 0.5 mg subcutaneously TID. Four (10.5%) of the 38 patients had a PR with octreotide treatment alone. In the 21 patients in whom prednisone (0.6 mg/kg daily) was added, 2 complete and 6 partial responses (38%) occurred. Combination therapy resulted in better progression-free survival than octreotide therapy alone.

Thymic Carcinoma

  • Thymic carcinoma look very different from the normal cells of the thymus, grow more quickly, and have usually spread to other parts of the body when the cancer is found
  • Same staging is used as for Thymoma altough it is not ver prognostic
  • Grade of the the tumor is most prognostic for Thymic carcinoma
Stage OS-5
I/II 88%
III 50%
IV 40%

Treatment

  • surgical resection, postoperative radiation, and chemotherapy is generally recommended.
Bibliography
1. Ciernik IF, Meier U, Lütolf UM: Prognostic factors and outcome of incompletely resected invasive thymoma following radiation therapy. J Clin Oncol 12 (7): 1484-90, 1994.
2. P Curran WJ Jr, Kornstein MJ, Brooks JJ, Turrisi AT 3rd. Invasive thymoma: the role of mediastinal irradiation following complete or incomplete surgical resection. J Clin Oncol. 1988 Nov;6(11):1722-7. PMID: 3183702.
3. Gunderson L, Tepper J: Clinical Radiation Oncology. 2nd ed. China: Elsevier 2007.
4. Jackson MA, Ball DL: Post-operative radiotherapy in invasive thymoma. Radiother Oncol 21 (2): 77-82, 1991.
5. Kim ES, Putnam JB, Komaki R, Walsh GL, Ro JY, Shin HJ, Truong M, Moon H, Swisher SG, Fossella FV, Khuri FR, Hong WK, Shin DM. Phase II study of a multidisciplinary approach with induction chemotherapy, followed by surgical resection, radiation therapy, and consolidation chemotherapy for unresectable malignant thymomas: final report. Lung Cancer. 2004 Jun;44(3):369-79. PMID: 15140551
6. Loehrer PJ Sr, Kim K, Aisner SC, 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 12 (6): 1164-8, 1994.
7. Fornasiero A, Daniele O, Ghiotto C, et al.: Chemotherapy for invasive thymoma. A 13-year experience. Cancer 68 (1): 30-3, 1991.
8. Haniuda M, Miyazawa M, Yoshida K, Oguchi M, Sakai F, Izuno I, Sone S. Is postoperative radiotherapy for thymoma effective? Ann Surg. 1996 Aug;224(2):219-24. PMID: 8757387
9. Kondo K, Monden Y. Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan. Ann Thorac Surg. 2003 Sep;76(3):878-84; discussion 884-5. PMID: 12963221
10. Mornex F, Resbeut M, Richaud P, 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 32 (3): 651-9, 1995.
11. Myojin M, Choi NC, Wright CD, Wain JC, Harris N, Hug EB, Mathisen DJ, Lynch T, Carey RW, Grossbard M, Finkelstein DM, Grillo HC. Stage III thymoma: pattern of failure after surgery and postoperative radiotherapy and its implication for future study. Int J Radiat Oncol Biol Phys. 2000 Mar 1;46(4):927-33. PMID: 10705015
12. Uematsu M, Yoshida H, Kondo M, Itami J, Hatano K, Isobe K, Ito H, Kobayashi K, Yamaguchi Y, Kubo A. Entire hemithorax irradiation following complete resection in patients with stage II-III invasive thymoma. Int J Radiat Oncol Biol Phys. 1996 May 1;35(2):357-60. PMID: 8635944
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