Thymoma and Thymic Carcinoma

WHAT ARE THYMOMA AND THYMIC CARCINOMA?

The thymus is a small organ that lies under the breastbone. It makes white blood cells called lymphocytes that travel through the body and fight infection.

Thymoma and thymic carcinoma are diseases in which cancer (malignant) cells are found in the tissues of the thymus. Thymomas are epithelial tumors of the thymus, which may or may not be extensively infiltrated by nonneoplastic lymphocytes. The term thymoma is customarily used to describe neoplasms that show no overt atypia of the epithelial component. A thymic epithelial tumor that exhibits clear-cut cytologic atypia and histologic features no longer specific to the thymus is known as a thymic carcinoma (also known as type C thymoma).

Invasive thymomas and thymic carcinomas are relatively rare tumors, together representing about 0.2% to 1.5% of all malignancies. Thymic carcinomas are rare and have been reported to account for only 0.06% of all thymic neoplasms. In general, thymomas are indolent tumors with a tendency toward local recurrence rather than metastasis. Thymic carcinomas, however, are typically invasive, with a high risk of relapse and death.

Most patients with thymoma or thymic carcinoma are aged 40 through 60 years. The etiology of these tumors is not known. In about half of cases, thymomas/thymic carcinomas are detected by chance with plain-film chest radiography. Ninety percent occur in the anterior mediastinum.



HOW TO DETECT THYMOMA AND THYMIC CARCINOMA?

Symptoms

The following symptoms suggest thymoma or thymic carcinoma:

A cough that won’t go away.
Pain in the chest.
Weakness in the muscles.
Approximately 30% of patients with thymoma/thymic carcinoma are asymptomatic at the time of diagnosis. In other cases, the presenting clinical signs of these tumors may include coughing, chest pain, and signs of upper airway congestion.

Paraneoplastic autoimmune syndromes associated with thymoma include myasthenia gravis, polymyositis, lupus erythematosus, rheumatoid arthritis, thyroiditis, and Sj?gren’s syndrome, among others. Autoimmune pure red cell aplasia and hypogammaglobulinemia each affect approximately 5% of patients with thymoma.

Thymoma-associated autoimmune disease involves an alteration in circulating T-cell subsets. In addition, B-cell lymphopenia has been observed in thymoma-related immunodeficiency, with hypogammaglobulinemia (Good syndrome) and opportunistic infection. In contrast to thymoma, the association of thymic carcinoma and autoimmune diseases is rare.

Approximately 47% of thymoma cases (excluding thymic carcinoma) were found to be associated with myasthenia gravis.

Stage

Histologic classification of thymoma is not sufficient to distinguish biologically benign thymomas from malignant thymomas. The degree of invasion or tumor stage is generally thought to be a more important indicator of overall survival.

Evaluating the invasiveness of a thymoma involves the use of staging criteria that indicate the presence and degree of contiguous invasion, the presence of implants, and lymph node or distant metastases regardless of histologic type. The following staging system is commonly employed and is shown below.



Thymoma Staging System

Stage
Description

I
Macroscopically, completely encapsulated; microscopically, no capsular invasion

II
Macroscopic invasion into surrounding fatty tissue or mediastinal pleura; microscopic invasion into capsule

III
Macroscopic invasion into neighboring organs (pericardium, lung, great vessels)

IVa
Pleural or pericardial dissemination

IVb
Lymphogenous or hematogenous metastases




For the purposes of treatment, these stages are grouped as either noninvasive or invasive.

Noninvasive

In noninvasive (stage I) disease, the tumor is limited to the thymus gland and has not involved other tissues. All of the tumor cells remain within a fibrous capsule that surrounds the tumor.

Invasive

In locally invasive (stage II) disease, the tumor has broken through the capsule and invaded the fat or pleura. In extensively invasive (stages III and IVa) disease, the tumor has spread contiguously from the thymus gland to involve other organs in the chest. Spread to organs in the abdomen or metastatic embolic spread (stage IVb) is unusual at the time of presentation.

Computed tomography (CT) may be useful in the diagnosis and clinical staging of thymoma, especially for noninvasive tumors. It is usually accurate in predicting tumor size, location, and invasion into vessels, the pericardium, and the lung. It cannot predict, however, invasion or resectability with accuracy. Appearance of the tumor on CT may be related to the World Health Organization histologic type. The smooth contours and a round shape are most suggestive of type A thymomas, whereas irregular contours are most suggestive of thymic carcinomas. Calcification is suggestive of type B thymomas.



HOW TO TREAT THYMOMA AND THYMIC CARCINOMA?

Most thymomas are diagnosed and staged at the time of surgical intervention. Surgical resection is the preferred treatment of patients who can tolerate surgery and have a mediastinal mass that is suspected of being a thymoma. A total thymectomy with complete resection of all tumor can be achieved in nearly all stage I and stage II patients and in 27% to 44% of stage III patients. Postoperative radiation therapy is generally employed for stage II and stage III patients. Patients with stage IVa disease can only rarely be resected completely and are usually offered debulking surgery and postoperative radiation therapy, with or without chemotherapy.

Noninvasive Thymoma and Thymic Carcinoma

Standard treatment options

Surgical resection: Complete resection of a well-encapsulated, noninvasive thymoma is usually curative, with a risk of local recurrence of less than 2%. In patients with myasthenia gravis, operative mortality can be minimized with close attention to respiratory support when planning surgical treatment.
Radiation therapy is not indicated following complete resection of a well-encapsulated thymoma. Radiation therapy should be considered, however, in rare cases when a noninvasive thymoma is incompletely resected, and when the patient is a poor surgical risk.
Invasive Thymoma and Thymic Carcinoma

Operable

En bloc surgical resection if possible. In patients with myasthenia gravis, operative mortality can be minimized with close attention to respiratory support when planning surgical treatment.
Following surgical resection, radiation therapy is generally recommended whether or not the surgical resection has been complete, especially for stage III and stage IVa patients. Retrospective clinical studies show improved local control and survival with the addition of postoperative radiation therapy.
Inoperable (stages III and IV with vena caval obstruction, pleural involvement, pericardial implants, etc.)

Radiation therapy: In patients who have residual macroscopic tumor following biopsy or attempted resection, radiation therapy has been reported to achieve local control in 60% to 90% of cases. Because of an increased risk of radiation-induced injury, doses greater than 60 Gy should be avoided. Overall 5-year survival rates of approximately 50% are reported for patients with unresectable stage III tumors. It is uncertain whether patients who undergo tumor debulking have a better prognosis than those who undergo biopsy only.
Chemotherapy: Transient partial responses have been reported with single-agent doxorubicin, maytansine, cisplatin, ifosfamide, and corticosteroids. It is important to remember, however, that corticosteroids and many chemotherapeutic agents are lympholytic; shrinkage of thymic tumors with substantial lymphoid cell infiltration may reflect shrinkage of the nonmalignant components of the tumors rather than the malignant epithelial components.
Combination chemotherapy has been reported to produce both complete and partial remissions.
In a series of 30 patients with stage IV or locally progressive recurrent tumor following radiation therapy, the PAC regimen (cisplatin, doxorubicin, cyclophosphamide) achieved a 50% response rate, including 3 complete responses. The median duration of response was 12 months, and 5-year survival was 32%.In another series, the ADOC regimen (doxorubicin, cisplatin, vincristine, cyclophosphamide) produced a 92% response rate (34 of 37 patients), including complete responses in 43% of patients.
A study of combined chemotherapy with cisplatin and etoposide produced responses in 9 out of 16 patients treated, with a median response duration of 3.4 years and a median survival of 4.3 years. In yet another study, 9 of 28 patients with invasive thymoma or thymic carcinoma who received 4 cycles of etoposide, ifosfamide, and cisplatin at 3-week intervals had partial responses. The median duration of response was 11.9 months (range, <1-26 months), and the median overall survival was 31.6 months. The 1-year and 2-year survival rates were 89% and 70%, respectively.
A retrospective analysis of 17 patients treated with cisplatin alone or in combination with prednisone revealed an overall response rate of 64%.Cisplatin alone (50 mg/m2 every 21 days), however, was associated with a partial response rate of only 10% (2 of 20 patients) in a phase II study. Treatment with single-agent ifosfamide was associated with 5 complete responses and 1 partial response in 13 patients with advanced thymoma in another prospective study.
Neoadjuvant chemotherapy followed by resection: One series of 16 patients with stages III or IVa disease were treated with initial ADOC chemotherapy. All patients achieved a clinical response to chemotherapy. Eleven patients had residual histologic tumor and received postoperative radiation therapy. The median survival of the entire group was 66 months.
Combined chemotherapy and radiation therapy for unresectable tumors. An intergroup study of patients with unresectable disease who received cisplatin, doxorubicin, and cyclophosphamide followed by thoracic radiation reported a 5-year survival rate of 52%.
Recurrent Thymoma and Thymic Carcinoma

Standard treatment options (in order of decreasing effectiveness):

Repeat surgical resection, particularly for local recurrences and, in some cases, pleural and pericardial implants. Postoperative radiation therapy has been used for patients with incomplete resections and has been employed in selected patients following complete resection of recurrent thymoma. Radiation therapy (when possible, based on previous treatment).
Corticosteroids in unresectable tumors that have not responded to radiation therapy.
Chemotherapy: Combination chemotherapy has been reported to produce complete and partial remissions; some of the complete remissions have been pathologically confirmed at subsequent surgery. In a series of 30 patients with stage IV or locally progressive recurrent tumor following radiation therapy, the PAC regimen (cisplatin, doxorubicin, cyclophosphamide) achieved a 50% response rate, including 3 complete responses. The median duration of response was 12 months, and 5-year survival was 32%.


HOW ABOUT THE PROGNOSIS OF THYMOMA AND THYMIC CARCINOMA?

The prognosis of this tumor is related with its staging.It is reported 5-year survival rates of 96% for stage I disease, 86% for stage II disease, 69% for stage III disease, and 50% for stage IV disease. In a large retrospective study involving 273 cases of thymoma, 20-year survival rates (as defined by freedom from tumor death) according to the staging system were reported to be 89% for stage I disease, 91% for stage II disease, 49% for stage III disease, and 0% for stage IV disease.

Thymoma has been associated with an increased risk for second malignancies, which appears to be unrelated to thymectomy, radiation therapy, or a clinical history of myasthenia gravis. Because of this increased risk for second malignancies and the fact that thymoma can recur after a long interval, it has been recommended that surveillance should be lifelong. The measurement of interferon-alpha and interleukin-2 antibodies has been reported to be helpful in identifying patients with a thymoma recurrence.