The thymus gland is an important immune organ in the body and is part of the lymphatic system whose function is to differentiate some lymphocytes into T-lymphocytes. The thymus, like other organs in the body, can develop benign or malignant tumors, the most common being thymoma. Other tumors or tumor-like diseases include: thymic carcinoma, thymic cyst, thymic lipoma, thymic hyperplasia, etc.
Introduction to the disease
The origin of the English word “thymus” is twofold, one is because the thymus looks like a plant thyme, and the other is that the word thymus is derived from the Greek word meaning center, heart, because early anatomy believed that the thymus was related to the heart.
The thymus is located in the anterior mediastinum and is generally divided into two asymmetrical lobes, connected by an isthmus in the middle, in the shape of an “H”. The thyroid gland is connected to the left and right lobes of the thyroid gland by the thyroid ligament. The lower pole is flat at the level of the 4th to 6th intercostal space and is covered by the pericardium and the great vessels at the base of the heart.
The thymus is covered by a fibrous envelope that extends to the interior of the thymus, forming fibrous tissue intervals that divide the thymus into lobules 0.5-2 mm in size, each lobule consisting of a cortex and a medulla, with the peripheral part of the lobule being cortical and dense with lymphocytes; the medulla is located in the center of the lobule, pale and with few lymphocytes, and the medullary area is connected to the medulla of the adjacent lobule.
Although the thymus is an important immune organ, it has largely degenerated by adulthood, and no changes in immune function have been observed in adults and children after thymectomy. Although there may be a decrease in lymphocyte counts and experiments in immunity, there is no specific clinical disease as a result.
Disease classification
The thymus, like other organs of the body, can develop benign or malignant tumors, the most common being thymoma. Other tumors or tumor-like diseases include: thymic carcinoma, thymic cyst, thymic lipoma, thymic hyperplasia, etc. There are several methods used to classify thymic tumors.
In the past, the most commonly used classification was that of Rosai and Levine, which named thymoma as the cellular component accounting for more than 80% of the tumor, and divided it into epithelial cell type, lymphocytic type and mixed epithelial lymphocytic type, but this classification is only suitable for the description of pathology, and no significant difference is found in the biological characteristics of the tumor, so this classification has been used less recently.
Another classification is the Muller-Hermelink method, which divides thymoma into cortical, medullary and mixed types, and the cortical type is divided into two subtypes: cortical-dominant type and “pure” cortical type. This classification has some theoretical advantages, but the biological characteristics and prognosis of different types of thymoma may be different.
Neither of these two classifications can accurately determine the benignity or malignancy of a tumor, so clinicians mostly use the classification based on the biological characteristics of the tumor, i.e., benign thymoma (also called non-invasive thymoma) and malignant thymoma (invasive thymoma). Benign thymoma has an envelope, does not invade surrounding tissues, and does not recur or metastasize after complete resection. Diagnosis of malignant thymoma: It mainly relies on intraoperative visual judgment that the tumor invades the surrounding tissues, such as pleura or pericardium, and recurrence or metastasis of the tumor is found during follow-up. Because histopathological examination often cannot distinguish between benign and malignant tumors, clinical advocates treat all thymomas with larger tumors as malignant.
In 1999, the World Health Organization made a new histologic classification of thymoma, which is briefly described as follows: Type A thymoma: a medullary or spindle cell thymoma; Type AB thymoma: a mixed thymoma; Type B thymoma: divided into three subtypes; Type B1 thymoma: a lymphocyte-rich thymoma, a lymphocytic thymoma, a cortical-dominant thymoma, or an organoid thymoma; Type B2 thymoma: a cortical thymoma; and Type B thymoma: a cortical thymoma. Type B3 thymoma: epithelial, atypical, squamous epithelial-like thymoma or well-differentiated thymic carcinoma. type C thymoma: thymic carcinoma, which is histologically more malignant than the other types of thymoma.
Clinical manifestations
Prevalent population
Thymoma occurs mainly in adults and is very rare in children. The average age of diagnosis is 45 to 52 years (5 to 80 years), slightly more common in women, and most often associated with myasthenia gravis.
Disease symptoms
1. 50% to 60% of patients are asymptomatic and are found incidentally during physical examination.
2.More than 25% of patients have local symptoms in the chest caused by tumor invasion or compression of adjacent mediastinal structures, including: cough, chest pain, dyspnea, dysphagia, and recurrent respiratory infections. Hoarseness and diaphragmatic paralysis are not common, but they mostly suggest the possibility of malignant spread.
3. Malignant thymoma metastases are mostly confined to the chest cavity and may be accompanied by pleural fluid, causing dyspnea, chest pain, chest discomfort and other symptoms. Only about 3% of malignant thymoma eventually metastasize outside the chest, and the metastatic site is most common in the skeletal system, causing related metastatic symptoms.
4. Systemic symptoms: 18% of patients with thymoma have general systemic symptoms, such as weight loss, fatigue, fever, night sweats and other non-specific symptoms. The concomitant symptoms of thymus disease are a complex group of systemic diseases, which may be complicated with thymoma by more than 30 diseases, the four most common ones being: myasthenia gravis, simple red blood cell aplastic anemia, hypogammaglobulinemia, and extrathymic malignancy. These diseases may occur simultaneously with thymoma, after resection, or many years before.
Complications
1. Myasthenia gravis: It is the most common complication of thymoma. About 1/3 of thymomas are complicated by myasthenia gravis, and conversely, 10% to 15% of patients with myasthenia gravis are accompanied by thymoma. It is believed that thymoma without MG tends to be more malignant than thymoma with MG and has a worse prognosis than the latter, which may be related to the fact that thymoma with MG is often detected early.
2, simple red blood cell aplastic anemia: the exact relationship between thymoma and simple red blood cell aplastic anemia is not very clear, but about 30% of patients can get complete remission of anemia after a long time after thymoma removal. Patients with thymoma may also have other hematologic disorders including leukopenia and thrombocytopenia, T-lymphocytosis, lymphocytic leukemia, and multiple myeloma.
3. Hypo-Υglobulinemia: 4% to 12% of thymoma patients have combined hypo-Υglobulinemia, usually with recurrent bacterial infections, viral infections, and mycobacterial infections. Thymoma resection is not effective in raising immunoglobulin levels.
Diagnosis and differentiation
1.Radiological examination: Chest plain film and chest CT are the most common means to detect and determine thymic tumors. 80% of thymomas are located in the anterior mediastinum at the heart base, and 80% of their tumors can cover the hilum. The vast majority are located in the anterior superior or superior mediastinum, and the rest are located in the neck, hilum, intrapulmonary, posterior mediastinum, etc.
2.Biopsy: It is generally believed that invasive biopsy is not recommended for anterior mediastinal tumors because: imaging combined with tumor markers can basically confirm the diagnosis of anterior mediastinal tumors; biopsy destroys the envelope of non-invasive thymoma and turns it into invasive thymoma; needle aspiration biopsy often cannot collect enough specimens for immunohistochemical examination. However, it is also believed that needle aspiration or VATS biopsy can be considered when it cannot be differentiated from other malignant tumors or when there are symptoms.
3. Other tests: All patients suspected of thymoma should be examined for acetylcholine antibodies, blood tests, AFP, β-hCG and LDH to exclude anemia, myasthenia gravis and germ cell tumors. Other diseases to be differentiated include: lymphoma, aortic aneurysm, teratoma, etc.
Disease Staging
Most thymomas are slow growing tumors with an intact envelope and can be cured by excision. The proportion of invasive (malignant) thymomas reported in the literature varies widely, ranging from 5% to 50%. The average time from diagnosis to recurrence after treatment for malignant thymomas is generally 6 years, so it is believed that thymomas should be followed up for a long time.
Staging: The so-called tumor staging is an artificial division into 4 stages according to the extent and degree of tumor invasion. The clinical and pathological staging of thymoma is based on Bergh’s staging in 1978, modified by Masaoka in 1981 as the standard clinical staging system, and further modified in 1995 by giving.
Stage I: intact pericardium visible to the naked eye, without microscopic extrapericardial invasion.
Stage II: microscopic invasion of the pericardium or invasion of the mediastinal adipose tissue or mediastinal pleura seen by the naked eye.
Stage III: invasion of adjacent structures (e.g., pericardium, great vessels, or lungs) seen by the naked eye; or focal tumor tissue found within the remaining normal thymic tissue.
Stage IVA: pleural cavity dissemination (pleural or pericardial metastases).
Stage IVB: lymphatic or hematogenous metastases with extrathoracic dissemination (bone metastases are the most common).
Survival period: Stage I is the so-called non-invasive thymoma, and the 10-year survival rate of thymoma is 86%-100%; after stage II, all thymomas are invasive, and the 10-year survival rate of stage II thymoma is 60%-84%; the 10-year survival rate of stage III thymoma is 21%-77%; the 10-year survival rate of stage IVa thymoma is 26%-47%.
Surgical treatment
Surgical resection is the preferred treatment option for thymoma and should be performed as soon as it is detected. It is suitable for stage I-III thymoma. Patients with severe myasthenia gravis now have minimal operative mortality, almost dependent on mortality from mechanical assisted ventilation. radiotherapy is not required after stage I surgery, unless tumor resection is incomplete. Preoperative invasion of adjacent organs (stage III) may be considered after preoperative radiotherapy or chemotherapy before surgery.
Comparison of surgical methods
The disadvantage of this surgery is that it is very traumatic and slow to recover, but the advantage is good intraoperative exposure, so it is only used for some stage III patients. Nowadays, thoracoscopic surgery is more often used. The advantages are: minimally invasive, beautiful, fast recovery, and complete removal of tumor, so it is suitable for all stage I and II patients and some stage III patients. There are many disadvantages of neck incision, such as poor intraoperative visualization and incomplete resection, so it is only used occasionally in conjunction with thoracoscopic surgery. The lateral open chest incision has been replaced by thoracoscopic surgery in most cases, and is only used in isolated cases when a huge tumor protrudes into one side of the chest cavity.
Radiation therapy
The value of adjuvant radiation therapy for aggressive thymoma has been proven and has been used as a routine postoperative treatment.
Chemotherapy
Thymoma has been clearly recognized as a chemotherapy-sensitive tumor in the last decade, but the optimal regimen and the definitive role of chemotherapy are unclear because of the low incidence of thymoma, which limits credible clinical trials in large groups. A cisplatin-based combination chemotherapy regimen is currently considered the most effective. Hormonal therapy has also been used clinically.
Treatment options
Stage IV thymoma: Chemotherapy is preferred. Surgery may be considered for stage IVA thymoma if the initial chemotherapy is effective. Trial of thoracic radiotherapy as combined treatment can also be considered. Relapsed thymoma that is resistant to chemotherapy can be treated with palliative radiotherapy as appropriate.
Local recurrence and distant metastasis: Stage I and II thymoma can also recur locally, up to 12% of non-invasive thymoma recurrence, but 0% to 5% are also reported. 13% of stage II, 29% of which have no adjuvant therapy after surgery. Stage II recurrence rates of 28% to 33% have also been reported. If possible, all of them should be resected twice. Most of the patients with satisfactory results of secondary surgery can still survive for a long time and need to add radiotherapy after surgery. Chemotherapy is preferred for distant metastases.