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Thymic Malignancies

Oncology

Authors

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Joseph D. Phillips, MD
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Matthew C. Carroll, MD
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Robin R. Cotter, MD
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Xavier P. Fowler, MD
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Michael J Wagner
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Introduction

Thymic tumors are exceedingly rare and account for only 0.2% to 1.5% of malignancies in the United States [1], with approximately 1000 cases per year in Europe [2]. Thymic carcinomas are more rare than thymomas, with an incidence of 0.2 to 0.5 per million [3].
Despite these overall low numbers, thymic tumors are the most common primary mediastinal tumor accounting for approximately 50% of anterior mediastinal masses [4].
The differential diagnosis of an anterior mediastinal mass includes primary thymic tumors, lymphoma (~20% of anterior mediastinal masses), germ-cell tumors (teratomas, seminomas, and non-seminomatous germ cell cancers), thyroid or parathyroid lesions, and metastases from other sites of disease. 
Thymomas and thymic carcinomas are derived from the thymic epithelium. The incidence of these tumors is approximately equal between men and women, and increases with age. The highest prevalence is in patients over 65 years and these tumors are rarely found in patients younger than 25 [1]. There is a reported increased prevalence of thymomas in patients of Asian, Pacific Island, and African decent, suggesting a potential genetic predisposition to thymoma in these groups [1].

Symptoms

Approximately half of thymomas are associated with paraneoplastic syndromes [5]. This is related to the role that the thymus plays in adaptive immunity, predisposing patients with thymomas to autoimmune disease [1].
In a study comparing patients with thymomas to healthy controls, those with a thymoma are more likely to have an autoimmune disease at some point during their lives (32.7% v 2.4%; P < .001)[6]. The most frequently associated are myasthenia gravis (24.5%), systemic lupus erythematosus (2.4%), and red cell aplasia (1.2%). 
Early stage thymomas are often asymptomatic and found incidentally on imaging. When they are symptomatic, thymomas most commonly cause respiratory symptoms such as cough, dyspnea, or pleuritic/substernal pain. As thymomas tend to spread via local expansion, advanced stage thymomas may present with symptoms related to invasion of local structures.
Superior vena cava syndrome can result in facial and upper extremity edema. Invasion of the phrenic nerve, recurrent laryngeal nerve, or sympathetic trunk may cause diaphragm paralysis, hoarseness, or Horner’s syndrome, respectively.  

Diagnostic Workup

CT imaging is the gold standard for characterizing anterior mediastinal masses. Initial evaluation should begin with a CT chest with intravenous contrast, which helps define the tumor’s relationship with the innominate vein and great vessels.  In some cases, MRI may be considered for further differentiation of tissue planes [7].
Thymomas are found anterior to the pericardium in the mid to upper substernal area. They are typically completely encapsulated, although 30-60% will show varying degrees of capsule invasion. Early stage thymomas are usually well circumscribed round or oval masses. 
Findings that are concerning for invasion include lobulated, irregular contours, calcifications, and low attenuation. More aggressive tumors may demonstrate hemorrhage or necrosis within the mass itself. Infiltration of adjacent structures can also be identified [8]. Imaging findings may aid in discriminating between stage I/II and III/IV disease, which is useful in determining which patients may benefit from neoadjuvant therapy [9].
Laboratory studies such as beta-human chorionic gonadotropin, alpha-fetoprotein, lactate dehydrogenase, anti-acetylcholine receptor antibody, complete blood count and thyroid function studies may be ordered as clinically indicated and may help narrow the differential diagnosis of the anterior mediastinal mass.
Tissue diagnosis is needed for the definitive diagnosis of thymoma. Small tumors without evidence of invasion are primarily resected and a pathologic diagnosis is subsequently established. Larger tumors not amenable to complete resection or with features that are concerning for local invasion require tissue diagnosis with either core needle biopsy or surgical biopsy prior to treatment [10]. 
The World Health Organization (WHO) classifies thymic tumors histopathologically as either type A, AB, B (B1-3), or Type C.
  • Type A and AB tumors are typically early stage, associated with myasthenia gravis and have a good prognosis.
  • Type B tumors tend to be more invasive and carry a moderate prognosis.
  • Type C tumors are thymic carcinomas. They are often aggressive with metastatic potential [11,12,13].

Staging

Thymomas have traditionally been classified by the Masaoka-Koga staging system, largely based on the locoregional characteristics of the tumor [14]. A TNM staging system was introduced in 2016 in the AJCC Cancer Staging Manual [16].
This TNM system is similar to the Masaoka-Koga system with the addition of incorporating the WHO histology classification system as tumors with aggressive histology characteristics are more likely to metastasize.  
Masaoka-Koga Staging System
Masaoka StageDefinition
Stage ICompletely encapsulated tumor without microscopic invasion of the capsule
Stage IIA: Microscopic transcapsular invasion
B: Macroscopic invasion into surrounding fatty tissue or grossly adherent to but not penetrating the mediastinal pleura or pericardium
Stage IIIMacroscopic invasion into neighboring organ
A: No invasion of great vessels
B: Invasion of great vessels
Stage IVA: Pleural or pericardial metastasis
B: Lymphogenous or hematogenous dissemination
Adapted from Koga et al 1994 [14] & Wright 2020 [13]
TNM Staging
Primary TumorDescription
TXPrimary tumor cannot be assessed
T0No evidence of primary tumor
T1Encapsulated or extending into the mediastinal fat, may involve the mediastinal pleura
A: No mediastinal pleura involvement
B: Invasion of the mediastinal pleura
T2Direct invasion of the pericardium
T3Invasion into lung, brachiocephalic vein, superior vena cava, phrenic nerve, chest wall or hilar (extra pericardial) pulmonary vessels 
T4Invasion into aorta, intrapericardial pulmonary artery, myocardium, trachea or esophagus 
Regional Lymph Nodes
NXRegional lymph nodes cannot be assessed 
N0No nodal involvement 
N1Anterior (perithymic) lymph node metastasis 
N2Deep intrathoracic or cervical lymph node metastasis
Distant Metastasis
M0No pleural, pericardial or distant metastasis
M1A: Separate pleural or pericardial nodule(s)
B: Pulmonary intraparenchymal nodule or distant organ metastasis 
Adapted from Wright 2020 [13], Ahmad 2020 [15], Amin et al 2017 [16] 

Management

Management of thymomas may include surgery, radiation, chemotherapy or a combination of these therapies. The treatment strategy is contingent upon the stage of the tumor and importantly the treatment of these patients should be guided by a multidisciplinary group.
Surgical Treatment
Surgery is the mainstay of treatment for thymoma when resection is deemed feasible. Resectability is determined primarily from imagining studies and patient co-morbidities as well as functional status. All stage I and some stage II/III tumors are amenable to resection. A multidisciplinary discussion is recommended prior to resection of stage ≥II cases [10].
An R0 resection is the goal in early-stage tumors as complete resection plays the strongest role in predicting disease-free recurrence [13]. There is no need for a biopsy prior to resection if imaging characteristics are consistent with a thymoma. Unresectable disease requires a core needle or surgical biopsy prior to the initiation of neoadjuvant treatment.
All patients undergoing surgical resection of a thymoma should be evaluated preoperatively for symptoms of myasthenia gravis [10]. If symptoms are present, the patient should be medically optimized prior to resection, as surgery can lead to myasthenic crisis in patients with uncontrolled symptoms. 
The traditional standard surgical approach in thymoma resection is a median sternotomy [17]. This approach provides access to the anterior mediastinum, lower neck, and bilateral pleural space. It is the ideal approach for large tumors as well as when the resection is anticipated to be difficult based on preoperative imaging suggesting invasion into surrounding structures. A minimally invasive approach is also an option for appropriately trained surgeons; Video-assisted thoracoscopic surgery (VATS) and robotic-assisted thoracic surgery have been utilized for many years. Although there is no long-term data given that this is a relatively recent surgical approach, early results suggest equivalent oncologic outcomes between open and minimally invasive approaches [13].
Traditional boundaries of the resection area for early stage tumors is the innominate vein superiorly, the phrenic nerves laterally, the diaphragm inferiorly, and the pericardium posteriorly. Regardless of approach, the goal of surgery is complete (R0) resection of the tumor and all thymic tissue, which should include the pericardium and/or lung resection as required.
A drain is typically placed in the anterior mediastinum at the completion of the case regardless of the surgical approach. This is usually removed early in the postoperative course (day 0 or 1) if the patient is recovering as expected. Patients with myasthenia gravis may require monitoring in an intensive care unit, particularly if they have a more urgent operation or poorly controlled symptoms. In general, other patients do not require more than standard postoperative monitoring.
Early mobilization, aggressive pulmonary hygiene and adequate pain control are key components of early postoperative care. Patients may be discharged when ambulating independently and pain is adequately controlled. Often those who undergo a minimally invasive approach can be discharged the day after surgery and in some cases even the same day.
Long term monitoring after surgery includes periodic CT scans of the chest with contrast; this is recommended annually for low-grade tumors and more frequently for tumors that are more aggressive [13]. 
Radiation strategies
External beam radiation therapy may be used as an adjunct in the treatment of thymic tumors, which are generally radiosensitive. Neoadjuvant radiation may be considered in the setting of imaging suggestive of locally invasive disease. Neoadjuvant therapy in this setting has been shown to increase the odds of complete resection and decrease the odds of local recurrence [18].
Following curative intent resection, tumor recurrence is most frequently local, suggesting a role for adjuvant radiation [19,20]. As such, radiation is also employed in the adjuvant setting when positive margins are present or in more advanced cancers (e.g. Masaoka stage III and IV) [21]. The benefits of adjuvant radiation are less clear for Masaoka stage II thymomas [22].
Finally, definitive radiation therapy can also be used in the setting of unresectable disease [23]. 
Chemotherapy strategies
Chemotherapy is also employed in a variety of settings including thymic tumors which are unresectable, incompletely resected, histologically aggressive, or recurrent. First-line combination chemotherapies all involving platinum-based agents are standard [24].
A variety of chemotherapy regimens may ultimately be employed – the details of these regimens are outside the scope of this chapter.
Consensus Guidelines for the Management of Thymomas [11]
StageTreatment Strategy
ISurgery: Complete surgical resection of the thymus gland. All mediastinal tissues bordered by the phrenic nerves laterally, the diaphragm inferiorly, the thyroid gland superiorly and the pericardium and great vessels posteriorly should be resected.

Radiotherapy: Not recommended.

Systemic therapy: Not recommended.
IISurgery: Complete surgical resection as above.

Radiotherapy: Routine adjuvant radiation is not recommended for stage IIA. Adjuvant radiotherapy should be considered for high risk of local recurrence, close surgical margins, tumor adherent to the pericardium and WHO grade B type.

Systemic therapy: Not recommended.
IIIResectable/ Potentially Resectable Disease

Surgery: Surgery should be considered for stage IIIA disease either upfront or following neoadjuvant treatment. Stage IIIB disease should be considered for surgery following neoadjuvant therapy. If the tumor is found to be unresectable at the time of the operation, the operative strategy should switch to maximal debulking with clips left at the resection margins.

Neoadjuvant radiotherapy and systemic therapy: Chemoradiotherapy is often employed in this setting, although the best regimen and sequence has not yet been established.

Adjuvant radiotherapy and systemic therapy: Adjuvant radiotherapy is frequently used. There is not enough data to recommend adjuvant chemotherapy following resection.

Unresectable disease

Chemotherapy with or following radiotherapy is recommended.
IVResectable Stage IVA

Follow treatment guidelines established for Stage III disease. Surgery is only recommended if pleural and pericardial metastasis can be resected.

Unresectable Stage IVA

Chemotherapy with or following radiotherapy is recommended.

Stage IVB

Surgery: Not recommended.

Radiotherapy: Should be considered for life threatening situations or symptom palliation.

Systemic therapy: Recommended. 
Recurrent DiseaseSurgery: Should be considered for patients with localized disease.

Radiotherapy/Systemic therapy: Either may be considered appropriate alone or as combined therapy.

Controversies and Limitations

Given the overall rarity of thymic malignancies and the paucity of prospective randomized data, the topic has been more challenged by uncertainty rather than controversy. Specifically, further investigation is warranted for the role of adjuvant treatment in stage II disease, the sequence of multimodal treatment therapies, the utility of tumor debulking in metastatic disease and the optimal treatment strategy for recurrent disease [11].

Prognosis

Thymic tumors are typically slow growing without distant spread which accounts for their generally good prognosis. However, it is important to note that thymic carcinoma subtypes are much more likely to spread and carry a worse prognosis [25]. Five-year all-stage survival rates are around 78% and 40% for thymoma and thymic carcinoma respectively [26].
Amongst completely resected patients, one large study notes 10-year survival rates of 80%, 78%, 75%, and 42% for stages I, II, III, and IVa respectively [25,27]. While the data on prognostic factors has been debated over time, the most consistent prognostic factors appear to be tumor stage and ability to achieve complete resection [25].

Summary

  • Thymic malignancies are extremely rare.
  • Early stage thymomas are often asymptomatic and discovered incidentally on imaging.
  • Advanced stage thymomas may present with symptoms related to invasion of neighboring structures.
  • Approximately half of all thymomas are associated with a paraneoplastic syndrome; the most common association is myasthenia gravis.
  • CT chest with intravenous contrast is the gold standard for characterizing anterior mediastinal masses.
  • Tissue diagnosis with core needle or surgical biopsy is only necessary if the mass is deemed unresectable based on imaging findings.
  • Thymomas have traditionally been classified by the Masaoka-Koga staging system which describes thymomas based on locoregional characteristics. 
  • TNM staging incorporates the WHO histology classification system. 
  • Tumors with aggressive histology characteristics are more likely to metastasize.  
  • Treatment options include surgery, radiation, chemotherapy or a combination of these therapies. The treatment strategy is informed by the stage of the tumor. 
  • Complete surgical resection of the thymus and all mediastinal tissue is the mainstay of treatment for all stage I and amenable stage II/III disease.
  • Neoadjuvant radiotherapy can be considered for potentially resectable disease.
  • Radiotherapy and systemic therapy should be considered for unresectable disease.

References

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  2. Siesling S, van der Zwan JM, Izarzugaza I, Jaal J, Treasure T, Foschi R, et al. Rare thoracic cancers, including peritoneum mesothelioma. European Journal of Cancer (Oxford, England: 1990). 2012 May 1;48(7):949–60. 
  3. Marx A, Ströbel P, Badve SS, Chalabreysse L, Chan JKC, Chen G, et al. ITMIG consensus statement on the use of the WHO histological classification of thymoma and thymic carcinoma: refined definitions, histological criteria, and reporting. Journal of Thoracic Oncology: Official Publication of the International Association for the Study of Lung Cancer. 2014 May;9(5):596–611. 
  4. Strollo DC, de Christenson MLR, Jett JR. Primary Mediastinal Tumors. Part 1*. Chest. 1997 Aug;112(2):511–22.
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  9. Qu Y-J, Liu G-B, Shi H-S, Liao M-Y, Yang G-F, Tian Z-X. Preoperative CT findings of thymoma are correlated with postoperative Masaoka clinical stage. Academic Radiology. 2013 Jan 1;20(1):66–72. 
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  12. Marx A, Chan JKC, Chalabreysse L, Dacic S, Detterbeck F, French CA, et al. The 2021 WHO Classification of Tumors of the Thymus and Mediastinum: What Is New in Thymic Epithelial, Germ Cell, and Mesenchymal Tumors? Journal of Thoracic Oncology: Official Publication of the International Association for the Study of Lung Cancer. 2022 Feb 1;17(2):200–13.
  13. Wright C. Primary Tumors of the Thymus. In: Current Surgical Therapy, Thirteenth Edition. Elsevier; 2020. p. 885–89.
  14. 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. Pathology International. 1994 May 1;44(5):359–67. 
  15. Ahmad U. The eighth edition TNM stage classification for thymic tumors: What do I need to know? The Journal of Thoracic and Cardiovascular Surgery. 2020 Nov 12. 
  16. Amin et al. AJCC Cancer Staging Manual. 8th ed Springer International, 2017.
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  20. Liu J, Govindarajan A, Williams TM, Kim J, Erhunmwunsee L, Raz D, et al. An Updated Review on Radiation Treatment Management in Thymus Cancers. Clinical Lung Cancer. 2022 Jul 20.
  21. Lim YJ, Kim HJ, Wu H-G. Role of postoperative radiotherapy in nonlocalized thymoma. Journal of Thoracic Oncology. 2015Sep;10(9):1357–63. 
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  23. Modh A, Rimner A, Allen PK, Greenfield B, Marom EM, Rice D, et al. Treatment modalities and outcomes in patients with advanced invasive thymoma or thymic carcinoma. American Journal of Clinical Oncology. 2016Apr;39(2):120–5. 
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  27. Regnard J-F, Magdeleinat P, Dromer C, Dulmet E, De Montpreville V, Levi J-F, et al. Prognostic factors and long-term results after thymoma resection: A series of 307 patients. The Journal of Thoracic and Cardiovascular Surgery. 1996;112(2):376–84.