Approach

Early-stage, discrete thymic tumors should be managed by an experienced thoracic surgeon. Locally advanced and metastatic thymic malignancies should be managed by a multidisciplinary team comprising medical oncologists, thoracic surgeons, radiation oncologists, pathologists, and radiologists. Patients with myasthenia gravis should have formal evaluation with neurology. Decision-making and interpretation with respect to radiologic features; pathologic diagnosis; surgical resectability; need and choice of neoadjuvant therapy; and postoperative radiation therapy (in patients with locally advanced and metastatic thymic malignancies) are complex and require discussion by a clinical care team with experience and expertise in treating these rare tumors.

There is little high-quality evidence to compare treatment options; case series, retrospective studies, and expert opinion, therefore, provide the basis for treatment.[39][40][41][42][43][44][45]​​​​​​​​​​​

Once a clinical diagnosis of a thymic tumor is made on chest computed tomography (CT), most thoracic surgeons judge resectability on the basis of tumor size, edge characteristics, apparent encapsulation, and symptoms (absence of symptoms favors an early-stage tumor). Small, noninvasive tumors are generally resected for both pathologic diagnosis and treatment, without preliminary biopsy. If lymphoma is a substantial possibility (due to young age) in a small invasive tumor, positron emission tomography (PET)/CT can be helpful to guide the biopsy versus resection decision. Thymic tumors that do not appear resectable with primary surgery require core needle biopsy to confirm the diagnosis, followed by consideration for neoadjuvant treatment, which usually consists of chemotherapy alone, although radiation therapy may also be given. After neoadjuvant therapy, operability of the tumor is reassessed from a repeat chest CT. Most are then eligible for resection. Patients with myasthenia gravis should have their therapy optimized before surgery.

Resectable tumor

Clinically encapsulated thymomas are resected for both pathologic diagnosis and treatment.[46] Total thymectomy (resection of the entire thymus gland) is recommended to assure wide resection margins and reduce risk of recurrence. However, there is evidence that thymomectomy (resection of thymoma with only partial thymectomy), with medium-term follow-up, may be appropriate for small tumors.[47][48][49][50][51][52][53]​​​​​​​​ Either of these procedures (total thymectomy vs. thymomectomy) can be performed by median sternotomy, video-assisted thoracoscopic surgery, or robotic-assisted thoracoscopic surgery. Experienced surgeons generally reserve median sternotomy for invasive tumors and large noninvasive tumors, although an exact size cutoff has not been definitively established. There is growing data indicating that, in specialized centers with experienced surgeons, a minimally-invasive approach for noninvasive thymoma is safe and can achieve the same oncologic outcomes compared to open surgery.[54][55]​​[56][57]​​[58][59][60][61][62]​​​​​​​​​ Macroscopically tumor-free resection margins must be achieved, and great care must be taken to maintain wide margins from the tumor, coming through tumor-free thymic tissue and/or mediastinal fat, widely, in all directions from the tumor. Operative morbidity and mortality are generally very low.

The pathology report, together with the surgeon's impression of completeness of resection, determine the need for adjuvant mediastinal radiation therapy. Any patient with a positive margin of resection should receive adjuvant radiation. Masaoka-Koga stage I tumors (encapsulated tumor with no evidence of invasion) are nearly always completely resected and do not require any adjuvant therapy (if negative margins are obtained). Masaoka-Koga stage II tumors (microscopic or macroscopic invasion into surrounding fat, but not invading through the mediastinal pleura or pericardium) are also almost always completely resected. The benefit of adjuvant radiation for Masaoka-Koga stage II tumors with a negative margin is controversial. Several case series suggest that radiation therapy does not always prevent relapses; that long-term freedom from relapse is possible without radiation therapy; and that the primary reason for treatment failure is disease in the pleura, which radiation therapy does not target.[63][64]​​ The complete resection status and the impression of the operating surgeon probably remain the best factors to consider when determining the need for adjuvant therapy in Masaoka-Koga stage II tumors. Radiation can be considered for high risk features such as close margin, high grade, or adherence to the pericardium.​[36][65]

Masaoka-Koga stage III tumors (invasion into local structures) are more likely to be incompletely resected and generally have close resection margins, even when officially pathologically "negative." Most patients with Masaoka-Koga stage III tumors are, therefore, referred for adjuvant radiation regardless of the official margin status and whether or not they received neoadjuvant chemotherapy.[66] Randomized evidence investigating the benefit of radiation therapy is lacking. Standard doses range from 45-60 Gy in the postoperative setting and 60-66 Gy in the definitive setting.[67]​ Elective nodal radiation is not standard.

Locally advanced tumor

Once a tissue diagnosis of a locally advanced thymoma or thymic carcinoma is made, neoadjuvant chemotherapy is usually given if the tumor is thought to be resectable.[68][69][70][71]​ Definitive chemoradiation therapy may be used if the tumor is deemed unresectable from the start or after a trial of neoadjuvant chemotherapy.

Commonly utilized neoadjuvant chemotherapy regimens include: cisplatin plus doxorubicin plus cyclophosphamide; cisplatin plus etoposide; cisplatin plus vincristine plus doxorubicin plus cyclophosphamide; and carboplatin plus paclitaxel (especially for patients who are not candidates for cisplatin because of baseline hearing loss, renal insufficiency, or other comorbidities).[36][71][72]​​​​​ Response rates to neoadjuvant chemotherapy range from 40% to 100%, and pathologic complete responses have been observed in 6% to 40%. Complete resection is achievable in 20% to 80% of patients who receive this therapy. Occasionally, neoadjuvant chemotherapy plus radiation therapy is performed largely on the basis of institutional preference.[73]

Typically, patients receive 2 to 6 cycles of neoadjuvant therapy before surgery. Patients are then reevaluated for resection following repeat chest CT. Most will be able to undergo resection after neoadjuvant chemotherapy. The majority will then receive adjuvant mediastinal radiation therapy or combination postoperative radiation and chemotherapy, as some unresectable or partially resected tumors may benefit from a combined approach.

Some locally advanced thymic tumors remain unresectable following neoadjuvant chemotherapy. In cases where the disease is confined within a reasonable radiation portal, definitive thoracic radiation therapy can lead to prolonged progression-free survival.[66][74]

Recurrent tumor

In thymoma case series, the relapse rate is 10% to 20%, whereas in those with thymic carcinoma it is about 50%.[8][12][13][75] The time to relapse also differs: thymomas relapse at a median of 29 months after resection, whereas thymic carcinoma has a median relapse period of 19 months.[76] The most important factors associated with recurrence include stage, WHO histology, and completeness of resection. 

Thymoma tends to relapse in the chest, usually in the pleura (locoregional 87%; distant 13%), whereas thymic carcinoma tends to relapse at distant sites, particularly the lung, bone, brain, and liver (distant 60%; locoregional 40%).

Distant recurrences are usually treated with chemotherapy. Active chemotherapy agents include cisplatin, paclitaxel, etoposide, cyclophosphamide, doxorubicin, vincristine, ifosfamide, pemetrexed, and gemcitabine with or without capecitabine.[77][78]​​​​ Combination chemotherapy may also be utilized, and this may result in higher response rates. Targeted therapies and antiangiogenic agents are also options in the recurrent setting, including everolimus, sunitinib, and lenvatinib.[79][80][81] Octreotide, a somatostatin analog, is an alternative systemic therapy in recurrent thymoma. Most locoregional recurrences are treated in a multimodal fashion; resection, chemotherapy, and radiation are each often important components of therapy.[69][82][83][84]​​​​ Surgery is generally appropriate for disease that appears completely resectable.

Immunotherapy with pembrolizumab may be considered in patients with thymic carcinoma, however, it should be used cautiously due to the higher risk of immune-related adverse events.[36][85][86]​​ If used, it is often in the heavily-pretreated setting when other modalities may be limited, and after a thorough risk-benefit discussion is had with the patient. It is avoided in patients with thymoma.

With myasthenia gravis

Medical status should be optimized in patients with thymoma and myasthenia gravis before undergoing surgery because the stress of surgery can precipitate a myasthenic crisis, leading to respiratory failure.[87] As thymoma surgery is always elective, there is sufficient time to medically optimize status. See Myasthenia gravis (Treatment approach).

Post-treatment surveillance

Complete resection of thymoma yields excellent long-term survival overall. However, published studies have demonstrated that thymoma recurrence can occur at least up to 10 years following resection.[88][89][90]​​ Although data evaluating the optimal surveillance strategy are limited, National Comprehensive Cancer Network (NCCN) guidelines recommend a surveillance period of at least 10 years for thymoma, owing to the potential for late recurrence and 5 years for thymic carcinoma.[36]​ CT is the most common imaging modality utilized, although magnetic resonance imaging is a reasonable alternative for patients who wish to avoid radiation. NCCN guidelines recommend 6-monthly surveillance imaging for the first 2 years, followed by annual surveillance for the remaining period.[36]

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