H.H. Gregg Professor of Oncology
Director, IU Simon Cancer Center
Associate Dean for Cancer Research
Indiana University School of Medicine
Diagnosis and Staging
Patients who present with an anterior mediastinal mass have a unique differential diagnosis, each of which has vastly different treatment options. This includes: germ cell cancer, Hodgkin and non-Hodgkin lymphoma, substernal thyroid (benign and malignant) disorders, and thymic tumors. The most common of these tumors are thymic malignancies (thymoma and thymic carcinoma), which typically present with signs and symptoms of paraneoplastic syndromes, especially myasthenia gravis (which presents in up to 30 percent of patients), hypogammaglobulinemia or pure red cell aplasia.
By the time of adulthood, the thymus gland has accomplished its principal goal to establish a competent immune repertoire and begins to atrophy. This process leaves a thymus gland that is much smaller and more infiltrated with adipocytes than found at infancy. In some cases, thymic hyperplasia or lymphoid hyperplasia may be confused with a thymoma, but is associated with reactive stress such as burns or chemotherapy in young adults or generalized growth associated with myasthenia gravis. Indeed, 85 percent of patients with myasthenia gravis have associated thymic hyperplasia.
Thymic malignancies typically present with a mass on chest x-ray that can fill the superior mediastinum space (best seen on a lateral chest x-ray). Computerized tomography will confirm this mass that may range from a small, round, or oval mass to a large mass that drapes over one side or the other of the middle mediastinal structures.
What is Unique About Thymoma?
Thymomas are indolent and rare tumors. About 30 to 50 percent of these tumors have an abnormality in the immune systems. This may be manifested with autoimmune syndromes such as myasthenia gravis, red cell aplasia, hypogammaglobulinemia, or the presence of unusual infection.
About 20 percent of patients with thymoma will have other malignancies that either precede or follow diagnosis of thymoma. Thus lifelong follow-up of patients is needed. Thymoma and thymic carcinoma may also present with pleural metastases, one of the few tumors to metastasize in such a fashion.
How to Make Diagnosis?
In a patient with a small well-circumscribed mass whose appearance is consistent with a thymoma, we may recommend that he or she go directly to thoracotomy to completely resect the tumor without a preoperative biopsy.
In patients with bulkier tumors, a core biopsy should be performed to make a definitive diagnosis. Care should be taken not to allow spillage of tumor through pleura. Fine needle aspiration is discouraged because of false-positive and false-negative biopsies for which the different diagnosis includes thymic malignancies (thymoma or thymic carcinoma); lymphoma (Hodgkin's and NHL); goiter, thymic cyst; and primary mediastinal germ cell tumors. The latter can be diagnosed without tissue diagnosis in patients presenting with large masses and markedly elevated β-subunit HCG and/or alpha-fetoprotein.
In Patients With Limited Stage Disease, How Do You Treat?
For these patients with early stage disease, I recommend surgical resection. For elderly patients or those with co-morbid illnesses, observation with serial CT scans of the mediastinal mass may also be appropriate. For those undergoing a RO resection (negative margins), even with capsular invasion (Stage II), I no longer recommend postoperative radiotherapy. However, I would consider postoperative radiotherapy if the surgical margins are positive.
The role of adjuvant chemotherapy is uncertain at best with no data demonstrating improvement in survival. I do not generally recommend adjuvant chemotherapy for these patients.
The most important part of the evaluation is to determine whether the patient has disease that can be completely resected. For patients with clinical Stage I or II disease (and without other contraindications), surgical resection (typically through a median sternotomy) is primary treatment. I typically recommend a median sternotomy as this affords the best opportunity for a RO resection.
Some investigators promulgate use of video-assisted thoracoscopy. Long-term follow-up using this is lacking, but because of the predilection of thymic tumors to spread along the pleura, I discourage this approach for most patients except those with small circumcised tumors.
What is Appropriate for More Advanced Disease?
For patients with bulky or clinically invasive disease (clinical Stage III) in which complete resection is uncertain, I recommend preoperative chemotherapy. A "meta-analysis" of prospective trials using anthracycline-based therapy (e.g., PAC, ADOC) demonstrates objective response rates of 75 percent or more.
Thus, tumors have a high likelihood to regress, thus making a subsequent RO resection more likely. Radiation is typically reserved for the postoperative setting.
In patients with Stage IVA (pleural metastases) or IVB (visceral metastases), chemotherapy is the first-line therapeutic approach. Having said this, it is important to recognize two points:
First, chemotherapy is not curative. Chemotherapy does have high response rates and prolongs disease-free survival, but it is not curative alone.
Second, patients with thymoma have a prolonged survival. Indeed, more than 25 percent of patients with Stage IV disease survive 10 or more years, even with little chemotherapy intervention. Thus, delayed institution of chemotherapy in patients with Stage IV disease is a reasonable alternative until either symptomatic or more volumetric growth is seen.
What Choice of Chemotherapy?
As mentioned above, I typically recommend anthracycline-based chemotherapy for first-line therapy (e.g., PAC (cisplatin, doxorubicin, cyclophosphamide). In second-line therapy or later, I typically use monotherapy.
A number of drugs have single-agent activity including paclitaxel, pemetrexed, gemcitabine, etoposide, ifosfamide, fluorouracil plus leucovorin (or capecitabine), octreotide plus prednisone (if octreotide scan is positive), or investigational agents (belinostat, a histone deacetylate inhibitor, was recently found to have some activity).
I typically treat patients for a maximum duration of four to six months, recognizing that many tumors are indolent and if responsive, I can always return to that agent.
In Patients with Advanced Disease, How Long Do You Treat?
As mentioned above, a variety of regimens are used. We typically would use PAC for four cycles and then stop if an excellent response is seen, and if the surgeon feels he or she can completely resect the tumor, then we would consider that option. The balance of the morbidity and mortality of aggressive surgical options need to be weighed carefully with the patient.
In patients with recurrent disease, I typically use single-agent chemotherapy for four to six months maximum and wait for future signs of progression.