**6. Management**

*Thymus*

**Table 2.**

*Masaoka-Koga staging system.*

Primary tumor (T)

Regional lymph nodes (N)

Distant metastases (M)

Prognostic stage groups

*TNM staging AJCC eighth edition.*

**TNM staging AJCC eighth edition**

**Masaoka-Koga stage** **Diagnostic criteria**

Stage IV a. Pleural or pericardial dissemination

TX Primary tumor cannot be assessed T0 No evidence of primary tumor

NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastases

N1 Metastases in anterior (perithymic) lymph nodes N2 Metastases in deep intrathoracic or cervical lymph nodes

M0 No pleural, pericardial, or distant metastases M1 Pleural, pericardial, or distant metastases

Stage I T1a,b N0 M0 Stage II T2 N0 M0 Stage IIIa T3 N0 M0 Stage IIIb T4 N0 M0

Stage IVa Any T N1

Stage IVb Any T N2

M1a separate pleural or pericardial nodules

T N M

N0–N1

Any N

M1b pulmonary intraparenchymal nodule or distant organ metastases

M0 M1a

M0–M1a M1b

encapsulated Stage II a. Microscopic transcapsular invasion

Stage I Macroscopically and microscopically completely

mediastinal pleura or pericardium

a. Without invasion in the great vessels b. With invasion in great vessels

b. Lymphogenous or hematogenous metastases

Stage III Macroscopic invasion into neighboring organs (i.e., pericardium, great vessels, lung)

T1 Tumor encapsulated or extending into the mediastinal fat may involve the mediastinal pleura T1a Tumor with no mediastinal pleural involvement T1b tumor with direct invasion of mediastinal pleura T2 Tumor with direct invasion of the pericardium (either partial or full thickness)

T3 Tumor with direct invasion into any of the following: lung, brachiocephalic vein, superior

T4 Tumor with invasion into any of the following: aorta, arch vessels, intrapericardial pulmonary artery, myocardium, or trachea esophagus

vena cava, phrenic nerve, chest wall, or extrapericardial pulmonary artery or veins

b. Macroscopic invasion into surrounding fatty tissue or grossly adherent to but not through

**80**

**Table 3.**

There are no phase III randomized, clinical trials on the treatment of thymoma and thymic carcinoma. Although they are two different entities, the general management per stage is almost the same. Surgery aimed at complete resection is the cornerstone of thymoma and thymic carcinoma management and should always be pursued.

All patients should be managed by a multidisciplinary team with experience in the management of thymoma and thymic carcinoma. The choice of treatment depends on resectability, stage, and whether or not myasthenia gravis is present. In all stages of thymoma and thymic carcinoma, resectability should be considered. When deemed possible in stages IIIb and IVa, surgery is part of a multimodality approach [25, 34–37].

An example of management according to stage could be as shown in **Table 4**. One should realize though that there is no advise based on phase III randomized controlled trails available and every case should be considered individually and there are different options, as discussed below.

## **6.1 Treatment thymoma**

## *6.1.1 Resectable disease*

Once complete resection of a thymoma is deemed possible, complete resection of the thymus, the tumor, and the invaded structures (including resection of the lung parenchyma or pericardium and vena cava reconstruction if necessary) is


#### **Table 4.**

*Treatment thymoma and thymic carcinoma according to stage.*

recommended [21, 25, 34, 36]. Preoperative evaluation for myasthenia gravis is advised. If this is diagnosed, treatment is essential, as myasthenia gravis can cause a postoperative myasthenic crisis or respiratory failure [38]. Thymoma Masaoka-Koga stages I and II have a 5-year survival rate of 100% after surgery [1].

In the case of an incomplete resection, postoperative radiotherapy (PORT), either on the primary tumor or on isolated metastasis, is recommended to reduce the risk of recurrence [35, 39]. In the past PORT was considered standard treatment for stage II completely resected tumors [7, 40]. Nowadays PORT in completely resected stages I and II WHO type A, AB, and B1 thymoma is not considered useful [10, 41–43]. Because of a high recurrence rate (even after R0 resection) PORT is advised for the higher stages and for WHO-type B2/3 thymoma and thymic carcinoma [21, 44], although the data are somewhat conflicting in this [7].

### *6.1.2 Potentially resectable disease*

More extensive thymomas can be initially irresectable but potentially resectable after neoadjuvant treatment. A multimodality approach containing neoadjuvant chemotherapy with or without postoperative radiotherapy should be used, depending on WHO type and resection margins [21, 35, 45–47].

Potential advantages of neoadjuvant chemotherapy are tumor downstaging and increasing the likelihood of complete resection. However, because the available data on chemotherapy in thymoma is based on small, phase II studies, there is no optimal chemotherapeutic regime established [21]. Potential disadvantages could be complications due to chemotherapy and longer operating time [48]. There is even some recent data suggesting that there is no overall survival benefit to be expected from neoadjuvant chemotherapy before surgery [48–50]. In the cases of extensive pleural disease, several institutions have reported small series of extrapleural pneumonectomy for stage IVA disease with excellent outcomes and low morbidity [51].

There are no RCT's available to settle this matter. For now, it is recommended to use neoadjuvant chemotherapy to downstage unresectable thymic malignancies before surgery [21]. Obviously, reevaluation after neoadjuvant therapy to determine whether or not the tumor responded sufficiently is mandatory. There is evidence supporting maximum debulking, combined with PORT and/or adjuvant chemotherapy, to benefit survival from a thymoma which turns out to be unresectable during surgery. This is, however, based on retrospective data, so selection bias could cloud this positive outcome [3, 52].

#### *6.1.3 Unresectable disease*

In the case of unresectable disease or the patients is inoperable due to condition or comorbidity, the possibility of radiation therapy should be assessed. If radiation is feasible, concurrent chemoradiation is advised. If radiation is not possible due to a too large field, palliative chemotherapy is recommended. But even in that setting, longterm disease control and survival can be sometimes pursued, and even a combination of radiation on the primary tumor combined with resection of metastasis could be considered [21].

**Chemotherapy** is the primary modality in systemic management of unresectable thymoma. Thymomas are known to be sensitive to chemotherapy, possible due to a "lymphocytic effect" of cytotoxic agents. Due to the rarity of the disease and surgery with or without PORT being the cornerstone of treatment, there are no randomized controlled trails available to select a preferred regime. Platinumbased combinations are standard of care, the most popular regimes being cisplatin with anthracycline and/or etoposide. The response rate range of these regimens is

**83**

*Thymoma and Thymic Carcinoma*

bicin/cyclophosphamide [21, 54].

opinion [21, 56, 57].

phase II data is available [60].

have a positive octreotide scan [64].

**6.2 Treatment thymic carcinoma**

*6.1.4 Recurrent disease*

safe [50, 65].

*DOI: http://dx.doi.org/10.5772/intechopen.87132*

between 25 and 100% [53]. The preferred regime by the NCCN is cisplatin/doxoru-

sis; conventional fractionation is appropriate for larger metastasis [21].

Stereotactic radiotherapy (SBRT) may be appropriate for limited focal metasta-

Response rates for second-line therapy range from 15 to 39% [55]. Pemetrexed and paclitaxel are considered the most efficacious in second-line treatment of thymic malignancies, although this is based on small phase II studies and expert

**Checkpoint inhibitors**. Programmed death ligand 1 (PD-L1) expression is high (82%) in thymoma, especially in WHO type B thymoma [58]. Even so, based on a phase II study on pembrolizumab (a humanized IgG4 antibody to PD-L1) in 33 thymic epithelial tumors (including 7 thymomas), immunotherapy is not recommended in thymoma. This is because of the high grade of immune-related events that was shown in seven thymoma patients during this study; 71% had grade 3 or higher immune-related adverse events (including myocarditis) [59]. Avelumab is a fully human IgG1 anti-PD-L1 antibody that showed less adverse events (38%) in a phase I trial (n = 7). However, it is currently under clinical development, and no

The high rate of immune-related side effect was expected; the physiological role of the thymus is to induce tolerance to self-antigens and deletion of autoimmune T cells. In the normal thymus, PD-1/PL-D1 expression regulates this self-tolerant T-cell repertoire. It is thought that disruption of the PD-1/PDL-1 system could lead to significant alteration of the T-cell population and therefore cause autoimmune-

**Targeted therapies**. Although there is high epidermal growth factor receptor (EGFR) expression in immunohistochemical staining of thymic epithelial tumors (71% for thymoma and 53% for thymic carcinoma), there is no correlation between the EGFR status and EGFR mutations. Experience with targeted therapies in thymoma is very limited and based on a small number of heterogenic phase II studies, but as for now this shows that there is no place for EGFR inhibitors in the treatment of thymoma and thymic carcinoma [7]. KIT-inhibition (inhibition of a transmembrane type III tyrosine kinase receptor) may show some promises in thymic carcinomas, but as thymomas do not show c-KIT expression [62], KIT-inhibition is not effective. There is some phase II experience in insulin-like growth factor (IGFR) inhibitors in thymoma patients that have shown some promising results [63]. Octreotide (a somatostatin analog) plus prednisolone may be useful in patients who

The recurrence rate of thymoma after complete resection is 10–30%, and this can occur many years after initial treatment. Surgical resection of recurrent disease can be associated with long-term survival and should be considered for patients with recurrent thymoma. In pleural "drop" lesions, repeated resection is considered

Similar to thymoma, surgery aimed at complete resection is the cornerstone of thymic carcinoma treatment, and the principles of first-line treatment in resectable disease are more or less the same. Five-year survival rate of 100% is reported for completely resected stage I disease going down to 17% in stage IVb disease [66]. Patients with a thymic carcinoma have a high risk of recurrent disease. Therefore,

related adverse events in the case of checkpoint inhibition [61].

#### *Thymoma and Thymic Carcinoma DOI: http://dx.doi.org/10.5772/intechopen.87132*

*Thymus*

recommended [21, 25, 34, 36]. Preoperative evaluation for myasthenia gravis is advised. If this is diagnosed, treatment is essential, as myasthenia gravis can cause a postoperative myasthenic crisis or respiratory failure [38]. Thymoma Masaoka-

In the case of an incomplete resection, postoperative radiotherapy (PORT), either on the primary tumor or on isolated metastasis, is recommended to reduce the risk of recurrence [35, 39]. In the past PORT was considered standard treatment for stage II completely resected tumors [7, 40]. Nowadays PORT in completely resected stages I and II WHO type A, AB, and B1 thymoma is not considered useful [10, 41–43]. Because of a high recurrence rate (even after R0 resection) PORT is advised for the higher stages and for WHO-type B2/3 thymoma and thymic carci-

More extensive thymomas can be initially irresectable but potentially resectable after neoadjuvant treatment. A multimodality approach containing neoadjuvant chemotherapy with or without postoperative radiotherapy should be used, depend-

Potential advantages of neoadjuvant chemotherapy are tumor downstaging and increasing the likelihood of complete resection. However, because the available data on chemotherapy in thymoma is based on small, phase II studies, there is no optimal chemotherapeutic regime established [21]. Potential disadvantages could be complications due to chemotherapy and longer operating time [48]. There is even some recent data suggesting that there is no overall survival benefit to be expected from neoadjuvant chemotherapy before surgery [48–50]. In the cases of extensive pleural disease, several institutions have reported small series of extrapleural pneumonectomy for stage IVA disease with excellent outcomes and low morbidity [51]. There are no RCT's available to settle this matter. For now, it is recommended to use neoadjuvant chemotherapy to downstage unresectable thymic malignancies before surgery [21]. Obviously, reevaluation after neoadjuvant therapy to determine whether or not the tumor responded sufficiently is mandatory. There is evidence supporting maximum debulking, combined with PORT and/or adjuvant chemotherapy, to benefit survival from a thymoma which turns out to be unresectable during surgery. This is, however, based on retrospective data, so selection bias could

In the case of unresectable disease or the patients is inoperable due to condition or comorbidity, the possibility of radiation therapy should be assessed. If radiation is feasible, concurrent chemoradiation is advised. If radiation is not possible due to a too large field, palliative chemotherapy is recommended. But even in that setting, longterm disease control and survival can be sometimes pursued, and even a combination of radiation on the primary tumor combined with resection of metastasis could be

**Chemotherapy** is the primary modality in systemic management of unresectable thymoma. Thymomas are known to be sensitive to chemotherapy, possible due to a "lymphocytic effect" of cytotoxic agents. Due to the rarity of the disease and surgery with or without PORT being the cornerstone of treatment, there are no randomized controlled trails available to select a preferred regime. Platinumbased combinations are standard of care, the most popular regimes being cisplatin with anthracycline and/or etoposide. The response rate range of these regimens is

Koga stages I and II have a 5-year survival rate of 100% after surgery [1].

noma [21, 44], although the data are somewhat conflicting in this [7].

ing on WHO type and resection margins [21, 35, 45–47].

*6.1.2 Potentially resectable disease*

cloud this positive outcome [3, 52].

*6.1.3 Unresectable disease*

considered [21].

**82**

between 25 and 100% [53]. The preferred regime by the NCCN is cisplatin/doxorubicin/cyclophosphamide [21, 54].

Stereotactic radiotherapy (SBRT) may be appropriate for limited focal metastasis; conventional fractionation is appropriate for larger metastasis [21].

Response rates for second-line therapy range from 15 to 39% [55]. Pemetrexed and paclitaxel are considered the most efficacious in second-line treatment of thymic malignancies, although this is based on small phase II studies and expert opinion [21, 56, 57].

**Checkpoint inhibitors**. Programmed death ligand 1 (PD-L1) expression is high (82%) in thymoma, especially in WHO type B thymoma [58]. Even so, based on a phase II study on pembrolizumab (a humanized IgG4 antibody to PD-L1) in 33 thymic epithelial tumors (including 7 thymomas), immunotherapy is not recommended in thymoma. This is because of the high grade of immune-related events that was shown in seven thymoma patients during this study; 71% had grade 3 or higher immune-related adverse events (including myocarditis) [59]. Avelumab is a fully human IgG1 anti-PD-L1 antibody that showed less adverse events (38%) in a phase I trial (n = 7). However, it is currently under clinical development, and no phase II data is available [60].

The high rate of immune-related side effect was expected; the physiological role of the thymus is to induce tolerance to self-antigens and deletion of autoimmune T cells. In the normal thymus, PD-1/PL-D1 expression regulates this self-tolerant T-cell repertoire. It is thought that disruption of the PD-1/PDL-1 system could lead to significant alteration of the T-cell population and therefore cause autoimmunerelated adverse events in the case of checkpoint inhibition [61].

**Targeted therapies**. Although there is high epidermal growth factor receptor (EGFR) expression in immunohistochemical staining of thymic epithelial tumors (71% for thymoma and 53% for thymic carcinoma), there is no correlation between the EGFR status and EGFR mutations. Experience with targeted therapies in thymoma is very limited and based on a small number of heterogenic phase II studies, but as for now this shows that there is no place for EGFR inhibitors in the treatment of thymoma and thymic carcinoma [7]. KIT-inhibition (inhibition of a transmembrane type III tyrosine kinase receptor) may show some promises in thymic carcinomas, but as thymomas do not show c-KIT expression [62], KIT-inhibition is not effective. There is some phase II experience in insulin-like growth factor (IGFR) inhibitors in thymoma patients that have shown some promising results [63]. Octreotide (a somatostatin analog) plus prednisolone may be useful in patients who have a positive octreotide scan [64].

#### *6.1.4 Recurrent disease*

The recurrence rate of thymoma after complete resection is 10–30%, and this can occur many years after initial treatment. Surgical resection of recurrent disease can be associated with long-term survival and should be considered for patients with recurrent thymoma. In pleural "drop" lesions, repeated resection is considered safe [50, 65].

#### **6.2 Treatment thymic carcinoma**

Similar to thymoma, surgery aimed at complete resection is the cornerstone of thymic carcinoma treatment, and the principles of first-line treatment in resectable disease are more or less the same. Five-year survival rate of 100% is reported for completely resected stage I disease going down to 17% in stage IVb disease [66]. Patients with a thymic carcinoma have a high risk of recurrent disease. Therefore,

some centers offer PORT (with or without chemotherapy) regardless of stage and resection margins [3, 21]. The available data is yet again limited, and there are indications that adjuvant therapy is not beneficial in R0-resected stage I thymic carcinoma [21, 42, 67].

**Chemotherapy**. Thymic carcinomas respond less to chemotherapy than thymomas. Carboplatin/paclitaxel has the highest response rate in patients with thymic carcinoma, but even so this is only 22–36% [21, 55]. Response rates for second-line chemotherapy in thymic carcinoma are even worse (4–12%) [55].

**Checkpoint inhibitors**. Second-line treatment with pembrolizumab showed promising results in a phase II trial containing 40 patients with thymic carcinoma. There was an ORR of 22.5%, and the median duration of response was 22 months. While less in thymomas, there was still a high rate of immune-related adverse events (15%), including two cases of severe myocarditis [59]. A recently published study on nivolumab in thymic carcinoma patients showed no objective response in 15 patients, although 5 patients showed stable disease for more than 24 weeks [68].

**Targeted therapies**. The same as in thymoma, experience with targeted therapies in thymoma is very limited and based on small phase II studies and individual case reports. Sunitinib may be beneficial for patients with a c-KIT mutation, although the mutation rate is rare <10% [10, 69]. IGFR inhibition and octreotide did not show any activity in thymic carcinoma, in contrast to thymomas [63, 64].

#### **6.3 Follow-up**

After primary resection, expert opinion on follow-up consists of a CT scan every 6 months for 2 years, then annually for 5 years for thymic carcinoma and annually for 10 years for thymomas [21], although an exceptional case of late recurrence has been reported [70].

### **7. Conclusion**

Thymomas and thymic carcinomas are rare mediastinal tumors, and although the course of a thymoma can be indolent, they can indeed be locally invasive and metastasize. Thymic carcinomas more often are disseminated at presentation. Therefore, both are considered malignant. Forty to fifty percent of thymomas are related to autoimmune paraneoplastic syndromes, the most common being myasthenia gravis. Resection of the thymus can also act as treatment for the paraneoplastic syndrome. However, thymic treatment does not always resolve those paraneoplastic syndromes.

Because of the improved representation of the N-stage and correlation to prognosis, rather than surgical resectability, we recommend the AJCC eighth TMN classification.

There is no phase III data available on the management of thymic epithelial tumors. Surgery is considered the cornerstone of thymoma and thymic carcinoma management in resectable disease and even in recurrent disease. Neoadjuvant treatment and PORT should be considered according to stage.

In metastatic disease chemotherapy containing an anthracycline is advised. For recurrent metastatic disease sunitinib and octreotide, among other things, could be considered. A special note on checkpoint inhibitors should be made. Although they do show promising results in thymic carcinoma, the rate of immune-related adverse events is too high to consider this a valuable option for the treatment of thymoma right now.

**85**

**Author details**

Annette Rebecca Bijsmans and Robin Cornelissen\*

provided the original work is properly cited.

Erasmus MC Cancer Institute, Rotterdam, The Netherlands

\*Address all correspondence to: r.cornelissen@erasmusmc.nl

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Thymoma and Thymic Carcinoma*

*DOI: http://dx.doi.org/10.5772/intechopen.87132*

ter and more treatment options in the future.

The lack of phase III level evidence due to the rarity of the disease calls for collaboration in research to improve the quality and impact of thymic malignancy treatment. Such efforts are currently underway, and hopefully this will lead to bet-

#### *Thymoma and Thymic Carcinoma DOI: http://dx.doi.org/10.5772/intechopen.87132*

*Thymus*

carcinoma [21, 42, 67].

24 weeks [68].

**6.3 Follow-up**

been reported [70].

paraneoplastic syndromes.

**7. Conclusion**

classification.

some centers offer PORT (with or without chemotherapy) regardless of stage and resection margins [3, 21]. The available data is yet again limited, and there are indications that adjuvant therapy is not beneficial in R0-resected stage I thymic

chemotherapy in thymic carcinoma are even worse (4–12%) [55].

**Chemotherapy**. Thymic carcinomas respond less to chemotherapy than thymomas. Carboplatin/paclitaxel has the highest response rate in patients with thymic carcinoma, but even so this is only 22–36% [21, 55]. Response rates for second-line

**Checkpoint inhibitors**. Second-line treatment with pembrolizumab showed promising results in a phase II trial containing 40 patients with thymic carcinoma. There was an ORR of 22.5%, and the median duration of response was 22 months. While less in thymomas, there was still a high rate of immune-related adverse events (15%), including two cases of severe myocarditis [59]. A recently published study on nivolumab in thymic carcinoma patients showed no objective response in 15 patients, although 5 patients showed stable disease for more than

**Targeted therapies**. The same as in thymoma, experience with targeted therapies in thymoma is very limited and based on small phase II studies and individual case reports. Sunitinib may be beneficial for patients with a c-KIT mutation, although the mutation rate is rare <10% [10, 69]. IGFR inhibition and octreotide did not show any activity in thymic carcinoma, in contrast to thymomas [63, 64].

After primary resection, expert opinion on follow-up consists of a CT scan every 6 months for 2 years, then annually for 5 years for thymic carcinoma and annually for 10 years for thymomas [21], although an exceptional case of late recurrence has

Thymomas and thymic carcinomas are rare mediastinal tumors, and although the course of a thymoma can be indolent, they can indeed be locally invasive and metastasize. Thymic carcinomas more often are disseminated at presentation. Therefore, both are considered malignant. Forty to fifty percent of thymomas are related to autoimmune paraneoplastic syndromes, the most common being myasthenia gravis. Resection of the thymus can also act as treatment for the paraneoplastic syndrome. However, thymic treatment does not always resolve those

Because of the improved representation of the N-stage and correlation to prognosis, rather than surgical resectability, we recommend the AJCC eighth TMN

There is no phase III data available on the management of thymic epithelial tumors. Surgery is considered the cornerstone of thymoma and thymic carcinoma management in resectable disease and even in recurrent disease. Neoadjuvant treat-

In metastatic disease chemotherapy containing an anthracycline is advised. For recurrent metastatic disease sunitinib and octreotide, among other things, could be considered. A special note on checkpoint inhibitors should be made. Although they do show promising results in thymic carcinoma, the rate of immune-related adverse events is too high to consider this a valuable option for the treatment of thymoma

ment and PORT should be considered according to stage.

**84**

right now.

The lack of phase III level evidence due to the rarity of the disease calls for collaboration in research to improve the quality and impact of thymic malignancy treatment. Such efforts are currently underway, and hopefully this will lead to better and more treatment options in the future.
