Thymoma is a common disease in thoracic surgery and is now widely treated in various hospitals. When it comes to the accurate characterization and treatment plan for each type and stage of thymoma, the arguments put forward by various hospitals and research institutes in China and abroad vary greatly. Until now, the international physicians’ association has not been able to develop a unified treatment plan. In this article, we review the current status of thymoma treatment and its new developments in recent years for your reference.
Accurate concept
Thymoma is not a tumor of the thymus, but only a tumor of thymic epithelial origin. Thymic lymphocytes can give rise to Hodgkin’s lymphoma, thymic endocrine cells can give rise to thymic carcinoid tumors, small cell carcinomas, and other rare types such as lipomas, thymic cysts, and germ cell-derived tumors.
Ninety percent of all clinical thymic tumors are thymomas, but the two concepts should not be confused. Thymomas are slow growing and are called “inert tumors”. Because of the low recurrence rate of stage I and II thymoma after resection, the term “benign thymoma” has been used in the past, but now thymoma is considered to be a potentially malignant tumor and should be monitored.
Epidemiology
The annual incidence of thymoma in China is about 0.15%-0.17%, accounting for 0.2%-1.5% of all malignant tumors, and may be related to EBV infection, ionizing radiation, and genetic predisposition.
According to the National Cancer Institute (NCI), the incidence rate of men and women is basically equal, and the age of incidence is 40-60 years old, and the younger the age, the more malignant the tumor. In thoracic surgery, thymoma is the most common anterior mediastinal tumor, accounting for 47%-50% of all mediastinal tumors and 20% of all mediastinal tumors, of which 10% are located in the cervical or middle and posterior mediastinum.
Clinical presentation
Most of these patients are found during physical examination or treatment of other diseases. Most of them have Masaoka stage I-II tumors with intact envelope and small size. When thymoma enlarges, it will compress the surrounding organs and cause symptoms such as chest pain, chest tightness and cough.
When the tumor invades the superior vena cava, the recurrent laryngeal nerve, the phrenic nerve, the esophagus, the pericardium, and other important structures, severe complications such as facial edema, droopy eyelids, hoarseness, dysphagia, and pericardial compression may occur.
Paraneoplastic syndrome occurs in about 30% of thymoma patients, with myasthenia gravis (MG) being the most common, reported in 10%-50% of cases, and most often seen in type B2 thymoma. etc.
The thymus is an endocrine organ and a lymphoid organ, which is the site of T-lymphocyte maturation and participates in the autoimmune process, and may be the cause of thymoma complicated by paraneoplastic syndrome, the exact mechanism of which has not yet been fully elucidated.
Diagnosis and differential diagnosis
The diagnosis of thymoma mainly relies on chest CT, because the mediastinum is a collection of trachea, esophagus, heart and large blood vessels.
Enhanced CT of the chest is the most practical imaging method to diagnose thymoma. It can not only detect small-sized thymoma and identify its location, but also provide a good understanding of whether the envelope of thymoma is intact and the infiltration of the tumor into the surrounding organs, which can initially determine the benignity and malignancy, and guide the surgeon to formulate the surgical plan and suggest the structures that need attention to avoid misinjury during surgery.
Non-invasive thymoma appears as a round or round-like substantial mass with intact envelope, clear boundary and low density structure between it and surrounding structures, which can be easily removed completely. Invasive thymomas are irregular in shape, lobulated and infiltrative along the surrounding organ space, often with cystic necrosis and occasional calcification.
MRI has no significant advantage over CT. Fluorine-18-deoxyglucose (FDG) positron emission imaging can determine the malignancy of the tumor and detect metastases based on the degree of FDG uptake. The paraneoplastic syndrome suggests the possibility of thymoma, and some microscopic thymomas have been screened out as a result.
The diagnosis of thymoma requires pathology. Fine-needle aspiration biopsy (FNA) of tumors has been largely abandoned because of the low number of specimens and the low diagnostic rate, and interventional coarse needle biopsy or mediastinoscopic or thoracoscopic biopsy of tumors is the current mainstream method. Octreotidescanning has been reported occasionally, but it has not been promoted.
It should be emphasized that biopsy is only indicated for advanced thymomas with distant metastases or tumors encircling large blood vessels or trachea that have lost the opportunity for resection (as surgical skills improve, the rate of thymoma resection is gradually increasing and biopsy is decreasing.
Lymphoma, castle-man’sdisease, teratoma, intrathoracic goiter, and mediastinal lung cancer should be differentiated from thymoma. Lymphomas and giant lymphadenopathies originate in lymph nodes and can be located in other mediastinal subdivisions or in the hilum.
CT shows homogeneous density of lymphoma, and enhancement shows mild enhancement and growth around blood vessels like “half-moon” sign, but it is not easy to compress blood vessels, which is different from invasive thymoma? Patients with intrathoracic goiter can often find an enlarged thyroid gland in the neck, and CT shows that the upper pole of the mass is connected to the thyroid gland in the neck, with uneven density and some with calcification. Mediastinal lung cancer tends to favor one side of the mediastinal pleura and has an irregular shape, although it is closely related to the mediastinum, it originates from the lung.
Tumor typing and staging
The histologic staging of thymoma was established by WHO in 1999 and is still used today. Type A thymoma: medullary or spindle cell thymoma; Type B1 thymoma: lymphocyte-rich thymoma; Type B2 thymoma: cortical thymoma; Type B3 thymoma: epithelial plastic or atypical or well-differentiated thymic carcinoma; Type AB thymoma: mixed thymoma; Type C thymoma: thymic carcinoma.
The mainstay of thymoma staging is the Masaoka staging, which was developed by WHO in 1999 and revised in 2004. The Haniuda classification focuses on the relationship of the tumor to surrounding structures (Table 1).
Treatment methods
I. Surgical resection
Surgical resection is the preferred treatment for thymoma, especially for stage I, II, and most stage III tumors, with an operative mortality rate of 0.7%-4.9%, averaging 2.5%.
The surgical resection rate of thymoma is high, and Kondo et al. reported that the resection rates of 1098 thymoma stages I, II, III, and IV were 100%, 100%, 85%, and 42%, respectively. Regnard et al. reported 10-year survival rates of 80%, 78%, 75%, and 42%, respectively, and 15-year survival rates of 78%, 73%, 30%, and 8%, respectively, for 307 cases of complete resection of thymoma, which is good compared with other types of malignant tumors.
Compared to complete resection, the 5-year survival rates for stage III and IV thymomas decreased to 93%, 64%, and 36% for complete resection, subtotal resection, and no surgery. Maggi et al. reported 5-year and 10-year survival rates of 80%, 59%, and 73% and 44% for complete and subtotal resection of invasive thymomas, respectively.
Minimally invasive surgery. VATS (videoassistedthoracicsurgery) thymoma resection is suitable for patients with thymoma bias on one side and is now widely performed. The advantages of minimally invasive surgery are less trauma, less intraoperative bleeding, less postoperative pain, and faster postoperative recovery, which basically achieve the effect of open-heart surgery.
Bilateral thoracic VATS surgery helps to remove the contralateral thymus and adipose tissue at the same time. In addition to the bilateral thoracic approach, there are also cervical-subxiphoid-thoracoscopic extended thymectomy, which is a complex procedure but has improved the rate of complete resection.
The da Vinci Surgical Robot operating system provides surgeons with high-definition magnified three-dimensional images, which is a category of minimally invasive surgery. Dong et al. reported 31 cases with an average operative time of 62 min, an average intraoperative bleeding of 54 ml, and a postoperative hospital stay of 5-19 days, all of which were successfully discharged with definite clinical results. The disadvantage of this procedure is that the robotic operating system is expensive and the learning period is long, which makes it difficult to be popularized.
Median sternal incision for thymoma resection + enlarged mediastinal fat clearance is considered by mainstream scholars to be the standard procedure for thymoma, especially for patients with stage III, 1V tumors or paraneoplastic syndromes such as MG. Arvind et al [2° reported that repair or replacement of the superior vena cava or cephalobrachial vein was associated with mechanical ventilation, graft thrombosis, and renal failure, but all patients survived at 18-24 months of follow-up.
Surgical treatment of tumor recurrence. Recurrence of thymoma is possible after complete resection regardless of stage, with 0.9%, 4.1%, 28.4%, and 34.3% for stages I, II, III, and IV, respectively. The average time to recurrence was found to be about 10 years for stage I tumors, 3 years for stages II, III, and IV, and about 5 years overall, with Yano et al. reporting a mean time to recurrence of 11.6-109.6 months and a mean of 36.4 months after surgery. In 81% of them, the recurrence was localized in the mediastinal region, 9% had distant metastases such as pleural, lung, liver, bone, and 11% had both. 50%-67% of patients with recurrence still had a chance for surgery, especially in patients with local recurrence, and reoperative resection was preferred, and the surgical approach was tailored to individual circumstances, with a complete resection rate of 45%-71%, averaging 62%.
The prognosis is better after complete resection, with a 5-year survival rate similar to that of patients without recurrence, and a 10-year survival rate of 53%-72%, which is significantly longer than that of patients without complete resection (90.9% vs. 44.7%).
Radiotherapy and chemotherapy
Most scholars previously believed that thymoma is sensitive to radiotherapy and can benefit patients. There is a consensus that adjuvant radiotherapy after complete thymectomy does not reduce the recurrence rate and does not improve progression-free survival (PFS) or overall survival (OS). A Meta-analysis of 592 cases concluded that postoperative radiotherapy had no therapeutic benefit for complete resected stage II tumors, and Utsumi et al. reported that postoperative radiotherapy was not recommended for stage I and II thymomas in 324 cases. However, Mornex et al. reported that postoperative radiotherapy for stage II thymoma reduced the recurrence rate from 30% to 5%.
The National Cancer Network guidelines recommend postoperative radiotherapy for patients with stage II and above, with a recommended dose of 50-60 Gy for patients with complete resection. postoperative radiotherapy for patients with incomplete resection is a necessary adjuvant therapy that has been clinically proven to prolong survival and is widely accepted. the National Cancer Network guidelines recommend a dose of radiotherapy greater than 60 Gy for these patients, using 3D conformal radiotherapy or intensity-modulated radiotherapy. For stage III and IVa thymoma, preoperative radiotherapy can shrink the tumor and lead to the chance of surgery.
Preoperative induction chemotherapy can improve the rate of surgical resection, and preoperative induction chemotherapy with ADOC regimen (Adriamycin + cis-K + vincristine + cyclophosphamide) has been reported to have an efficiency of 62%-100%, complete resection rate of 43%-69%, and complete pathological remission rate of 8%-31%. Kim et al. reported 77% efficiency with CAP (cyclophosphamide + adriamycin + cisplatin + prednisone), 76% complete resection rate, 38% pathological remission rate, and median survival time over 5 years. For stage HI, IV and progressive thymomas, platinum-based combination chemotherapy is currently more effective, and commonly used regimens include CAP and EP (etoposide + cis-K). The efficiency of chemotherapy with CAP regimen is reported to be 50%, with a median survival time of 11.8 months; the efficiency of chemotherapy with EP regimen is 56%, with a median survival time of 4.3 years; the efficiency of chemotherapy with AD0C regimen is 90%, with a median survival time of 15 months; and the efficiency of chemotherapy with PC (paclitaxel + carboplatin) regimen is 35%. There are few large-scale prospective randomized clinical trials, and the best chemotherapy regimen needs to be discovered.
Signaling pathways and targeted therapy
The signaling pathway and targeted drug research of thymoma epithelial tumor is a hot topic in recent years, the related genes are epidermal growth factor receptor (EGFR), Kit, vascular endothelial growth factor (VEGF), Kras, human epidermal growthfactorreceptor, EGFR (HER1,ErbB1), located on human chromosome 7 (7p11.2), is a class of tyrosine kinase receptors (RTKs) that are widely distributed in various tissues and organs. EGFR gene activation can promote cell proliferation, affect cell motility and adhesion, and is closely associated with tumors.
In a study of 227 thymomas and 41 thymic carcinomas, the average EGFR immunohistochemical positivity rate was 70% in thymomas and 53% in thymic carcinomas, and Girard, Suzuki, and Ionescu et al. further showed that the strength of EGFR expression or amplification correlated with tumor grade, which could be used to confirm the degree of tumor differentiation.
Few large cases of thymoma EGFR mutations have been reported, with only 3 mutations found in 158 thymomas in one study, and they were not associated with high gene expression. A clinical trial of 26 patients with thymoma treated with the EGFR inhibitor gefitinib resulted in one partial remission, 15 stable, and no complete remissions.
Kit, a transmembrane growth factor with TK activity, is highly expressed in gastrointestinal mesenchymal tumors and is effectively treated with the Kit inhibitors imatinib and sunitinib. A study found a mean immunohistochemical positivity rate of 2% in 291 thymomas and a high rate of 79% in 97 thymic carcinomas, with significant differences between the two. The results of the Kit mutation rate study were discouraging, with 70 thymomas showing a mutation rate of only 7 percent. One study showed 7 B3 thymomas treated with imatinib, with 2 stable and 5 progressive.
In conclusion, patients with thymoma can still achieve good results with aggressive and rational combination therapy. Further attention is needed in the future basic and clinical work.
(1) To implement preoperative induction radiotherapy before surgery for patients who cannot be treated surgically.
(2) To improve and promote minimally invasive surgery to remove the tumor and clear the adipose tissue in the mediastinal area.
(3) To explore the molecular mechanism of thymoma producing paraneoplastic syndrome.
(4) To seek the most reasonable treatment mode for each stage of tumor.
(5) To elucidate the mechanism of thymoma genetically, to clarify the signaling pathways and to develop the corresponding targeted therapeutic drugs.