eMedicine Specialties > General Surgery > Thorax

Thymoma

Quintessa Miller, MD, Staff Physician, Department of General Surgery, Keesler Air Force Base Medical Center
A Letch Kline, MD, Program Director, Department of Surgery, Keesler USAF Medical Center; Clinical Assistant Professor, Department of Surgery, Uniformed University of the Health Sciences

Updated: Jul 23, 2009

Introduction

Thymoma, the most common neoplasm of the anterior mediastinum, originates within the epithelial cells of the thymus.

The thymus is a lymphoid organ located in the anterior mediastinum. In early life, the thymus is responsible for the development and maturation of cell-mediated immunological functions. The thymus is composed predominantly of epithelial cells and lymphocytes. Precursor cells migrate to the thymus and differentiate into lymphocytes. Most of these lymphocytes are destroyed, with the remainder of these cells migrating to tissues to become T lymphocytes. The thymus gland is located behind the sternum in front of the great vessels (see images below and Images 1-2). It reaches its maximum weight at puberty and undergoes involution thereafter.

Anatomy of the thymus, with emphasis on the blood supply and relation to recurrent laryngeal and phrenic nerves.

Lateral view: The thymic arteries are derived from the adjacent internal mammary arteries; the inferior thymic vein empties into the innominate vein. The thymus gland's surrounding vascular and neural structures may be invaded during the spread of a thymoma.

History of the Procedure

A relationship between myasthenia gravis (MG) and thymomas was determined incidentally in 1939 when Blalock and coworkers reported the first excision of a thymic cyst in a 19-year-old girl with MG.¹ This patient achieved long-term remission; therefore, thymectomy became the definitive therapy for treatment of generalized MG.

Problem

No clear histologic distinction between benign and malignant thymomas exists. The propensity of a thymoma to be malignant is determined by the invasiveness of the thymoma. Malignant thymomas can invade the vasculature, lymphatics, and adjacent structures within the mediastinum. The 15-year survival rate of a person with an invasive thymoma is 12.5%, and it is 47% for a person with a noninvasive thymoma. Death usually occurs from cardiac tamponade or other cardiorespiratory complications.

Frequency

Thymoma, the most common neoplasm of the anterior mediastinum, accounts for 20-25% of all mediastinal tumors and 50% of anterior mediastinal masses.

Etiology

The etiology of thymomas has not been elucidated; however, it has been associated with various systemic syndromes. As many as 30-40% of patients who have a thymoma experience symptoms suggestive of MG. An additional 5% of patients who have a thymoma have other systemic syndromes, including red cell aplasia, dermatomyositis, systemic lupus erythematous, Cushing syndrome, and syndrome of inappropriate antidiuretic hormone secretion.

Presentation

Peak incidence of thymoma occurs in the fourth to fifth decade of life; mean age of patients is 52 years. No sexual predilection exists. Although development of a thymoma in childhood is rare, children are more likely than adults to have symptoms. Several explanations for the prevalence of symptoms in children have been proposed, including the following: (1) children are more likely to have malignancy, (2) lesions are more likely to cause symptoms by compression or invasion in the smaller thoracic cavity of a child, and (3) the most common location for mediastinal tumors in children is near the trachea, resulting in respiratory symptoms.

Four cases of patients who presented with severe chest pain secondary to infarction or hemorrhage of the tumor have been reported. Cases of invasion into the superior vena cava resulting in venous obstruction have also been reported.²  The clinician should be aware of these rare presentations of a thymoma.

Indications

Of patients with a thymoma, one third to one half are asymptomatic, and one third of patients present with local symptoms related to the tumor encroaching on surrounding structures. These patients may present with cough, chest pain, superior vena cava syndrome, dysphagia, and hoarseness if the recurrent laryngeal nerve is involved. One third of cases are found incidentally on radiographic examinations during a workup for MG.

Relevant Anatomy

The thymus gland is located behind the sternum in front of the great vessels and the pericardium. The gland can extend laterally to the phrenic nerves. The main blood supply is from the internal thoracic arteries; however, the thymus gland also is supplied with blood by the inferior thyroid and pericardiophrenic arteries. (See images below and Images 1-2.)

Anatomy of the thymus, with emphasis on the blood supply and relation to recurrent laryngeal and phrenic nerves.

Lateral view: The thymic arteries are derived from the adjacent internal mammary arteries; the inferior thymic vein empties into the innominate vein. The thymus gland's surrounding vascular and neural structures may be invaded during the spread of a thymoma.

Contraindications

If the thymoma invades both phrenic nerves, do not resect either nerve; only debulk the area.

Workup

Laboratory Studies

• The diagnosis of a thymoma usually is clinically based on radiological findings. Laboratory studies generally are not indicated.

Imaging Studies

• Posteroanterior (PA) and lateral chest radiographs can detect most thymomas.
• On the PA view, the lesion typically appears as a smooth mass in the upper half of the chest, overlying the superior portion of the cardiac shadow near the junction of the heart and great vessels. The mass usually projects predominantly into one of the hemithoraces.
• On the right, the silhouette sign is present and the ascending portion of the aortic arch is obliterated. Conversely, if the thymoma is on the left, the silhouette sign is obscured and the aortic knob is identified behind the mass.
• Computed tomography (CT) scan may delineate a mass further or detect a smaller tumor missed on radiograph.
• ChestCT scan is the imaging procedure of choice in patients with MG.
• Thymic enlargement should be determined because most enlarged thymus glands on CT scan represent a thymoma.
• CT scan with intravenous contrast dye is preferred to show the relationship between the thymoma and surrounding vascular structures, to define the degree of its vascularity, and to guide the surgeon in removal of a large tumor, possibly involving other mediastinal structures. (See image below and Image 3).

This computed tomography (CT) scan clearly illustrates the mass in the right anterolateral mediastinum.

• A case report revealed that positron emission tomography (PET) scanning proved to be invaluable in confirming the diagnosis of an invasive malignant thymoma. Although CT scanning revealed evidence of an anterior mediastinal mass, the PET scan showed a hypermetabolic mass consistent with this location, thereby raising suspicion of malignancy. Subsequent resection of the mass revealed a minimally invasive thymoma due to capsular invasion. PET scanning should be added to the armamentarium as an available diagnostic modality to aid in staging and excluding extramediastinal involvement.³

Diagnostic Procedures

• Biopsy: If a patient presents with atypical features or is found to have an invasive tumor and is under consideration for induction therapy, obtaining preoperative biopsy is indicated. The limited anterior mediastinotomy (Chamberlain approach) is the standard approach that typically is performed over the projection of the tumor. A thoracoscopic approach for biopsy also can be used.
• Fine-needle aspiration: Controversy exits over the efficacy of fine-needle aspiration (FNA). FNA has been reported by some to be beneficial in making the diagnosis of a thymoma. Performing a core biopsy in conjunction with FNA is a modality that can increase the accuracy in differentiating thymomas from other neoplasms, such as lymphomas and germ cell tumors.

Histologic Findings

Traditionally, thymomas are classified into 3 histologic types based on the predominant cell type—lymphocytic, epithelial, and lymphoepithelial. A World Health Organization (WHO) classification has been developed. In a study conducted in Japan between 1973 and 2001 of a series of 100 resected thymomas, prognostic categories were distinguished using this WHO classification (Table 1).⁴

Table 1. World Health Organization Pathologic Classification and Associated Prognostic Categories

*Series of 100 thymomas resected in Japan between 1973 and 2001 using the WHO classification.

Staging

The Masaoka staging system of thymomas is the most commonly accepted system.

Table 2. Masaoka Staging System of Thymomas and Corresponding Therapy

Treatment

Medical Therapy

Chemotherapy

A few reports in the literature suggest that thymomas are chemosensitive tumors.⁵ Potential candidates for chemotherapy include approximately one third of the patients with an invasive thymoma that later metastasizes and all patients with stage IV disease. Fornasiero and colleagues reported successful cases and some long-term survivors following the administration of a regimen of cisplatin/vincristine/doxorubicin/cyclophosphamide for incompletely resected invasive thymomas or cases with unresectable disease.⁶ In 32 patients, a 47% complete and 90% overall response rate was noted with a median survival time of 15 months. A trial conducted by the European Organisation for Research and Treatment of Cancer reported that among 16 patients with recurrent or metastatic thymomas, 5 complete remissions and 4 partial remissions were observed. Median survival time in this study was 4.3 years.

Corticosteroids

Case reports have documented the administration of oral glucocorticoids resulting in regression of an invasive thymoma. In one case, the patient showed complete regression to the thymoma and associated symptoms and has remained without radiological recurrence after 12 months.⁷

Multidisciplinary approach

A multidisciplinary approach to therapy for unresectable thymomas has been advocated.⁸ In one trial conducted by the M.D. Anderson Cancer Center, a treatment regimen consisting of induction chemotherapy (ie, 3 courses of cyclophosphamide, doxorubicin, cisplatin, and prednisone), surgical resection, postoperative radiation therapy, and consolidation chemotherapy (ie, 3 courses of cyclophosphamide, doxorubicin, cisplatin, and prednisone) was tested.⁹

This study yielded encouraging results. Of 12 patients who underwent this treatment regimen, the disease had a complete response in 3 patients (25%), a partial response in 8 patients (67%), and a minor response in 1 patient (8%). Among 11 of these 12 patients (1 refused surgery), 9 (82%) had complete resections, and 2 (18%) who had been receiving radiation therapy and consolidation chemotherapy had incomplete resections. All 12 patients (100%) are alive at 7 years, and 10 of these patients (73%) are disease-free at 7 years. Therefore, the authors suggest that aggressive multimodal treatment is effective and may be curative in locally advanced, unresectable, malignant thymomas.

A study was conducted by Loehrer et al evaluating the effects of octreotide alone or with prednisone in 38 patients with advanced thymomas that expressed somatostatin receptors (ie, that were octreotide scan positive).¹⁰ The patients were given 0.5 mg subcutaneously 3 times daily. Four (10.5%) of the 38 patients had a partial response with octreotide treatment alone. In the 21 patients in whom prednisone (0.6 mg/kg daily) was added, 2 complete and 6 partial responses (38%) occurred. Combination therapy resulted in better progression-free survival than octreotide therapy alone. Octreotide therapy may be a valuable treatment to use in cases in which chemotherapy is ineffective.

Surgical Therapy

Initial management in most cases of thymomas is surgical.⁵ Surgical excision provides the histological characteristics of the tumor and provides staging information that is helpful in determining the need for adjuvant therapy. Small and encapsulated thymomas are excised for diagnosis and treatment. In the past, obtaining a preoperative biopsy of large invasive thymomas was shunned for fear of local implantation of tumor cells. Currently, biopsies are performed for these atypical tumors to discover the histology of the tumor and to ascertain its invasive potential.

A single-institution retrospective study was conducted of 5 patients with stage IVA treated with pleuropneumonectomy. The median survival was 86 months, and the Kaplan-Meier survival was 75% at 5 years and 50% at 10 years. There were no operative mortalities in this study. It has been suggested that, in select patients, this approach after a complete resection and neoadjuvant chemotherapy may be promising.¹¹

The prognosis of a person with a thymoma is based on the tumor's gross characteristics at operation, not the histological appearance. Benign tumors are noninvasive and encapsulated. Conversely, malignant tumors are defined by local invasion into the thymic capsule or surrounding tissue. The Masaoka staging system of thymomas is the most commonly accepted system. Although controversy exists pertaining to the use of postoperative radiation for invasive thymomas, the preponderance of evidence indicates that all thymomas, except completely encapsulated stage 1 tumors, benefit from adjuvant radiation therapy.¹²

Preoperative Details

Preoperative adjuvant radiation therapy has been used to increase the possibility of complete resection when CT scan suggests a tumor is very large or invasive. Although doses of 30-45 gray (Gy) have been used in this approach, complete responses rarely have been reported. One caveat to this therapy is that the patient is placed at increased risk for radiation pneumonitis because of the large size of ports required to cover the field.

Patients with a preoperative diagnosis of MG and a thymoma should optimize their medical condition prior to surgery by using cholinesterase inhibitors and plasmapheresis if indicated.

Intraoperative Details

Although the preferred approach is a median sternotomy providing adequate exposure of the mediastinal structures and allowing complete removal of the thymus, the cervical approach also is adequate. If the tumor is small and appears readily accessible, perform a total thymectomy with contiguous removal of mediastinal fat. If the tumor is invasive, perform a total thymectomy in addition to en bloc removal of involved pericardium, pleura, lung, phrenic nerve, innominate vein, or superior vena cava. Resect one phrenic nerve; however, if both phrenics are involved, do not resect either nerve, and debulk the area. Clip areas of close margins or residual disease to assist the radiation oncologist in treatment planning.

Controversy about whether biopsy versus subtotal excision is superior for treating unresectable tumors exists. Some studies have supported subtotal excision, while others have shown no difference between the 2 modalities. A generally accepted rule is that patients with invasive or residual disease should receive adjuvant therapy.

Postoperative Details

Radiation therapy

Adjuvant radiation therapy⁵ in completely or incompletely resected stage III or IV thymomas is considered a standard of care. The use of postoperative radiation therapy in stage II thymomas has been more questionable. Thymomas are indolent tumors that may take at least 10 years to recur; therefore, short-term follow-up will not depict relapses accurately. Furthermore, the gross appearance of tumor invasiveness is subjective, depending on the opinion of the surgeon. In one report at Massachusetts General Hospital, 22% of patients (5 out of 23) with stage II disease developed recurrence, leading to a proposed recommendation that postoperative radiation be instituted in all patients with stage II thymoma.¹³

In a study conducted by Curran and colleagues, of 21 patients with stage II and III disease who did not undergo postoperative (total resection) radiation therapy, 8 had recurrence in the mediastinum.¹⁴ The 5 patients who received adjuvant radiation did not have recurrences. A series from Memorial Sloan Kettering Cancer Center, however, showed that adjuvant radiation therapy did not improve survival or decrease recurrence in stage II and III disease.¹⁵ To reduce the incidence of local relapse, perform postoperative adjuvant radiation therapy in patients without completely encapsulated stage I tumors.

Follow-up

Relapse after primary therapy for a thymoma may occur after 10-20 years. Therefore, long-term follow-up probably should continue to be performed throughout the patient's life.

Complications

Complications (eg, radiation pericarditis, radiation pneumonitis, pulmonary fibrosis) following postoperative radiation therapy have been reported. Clinicians must consider carefully the risk versus benefit ratio of adjuvant radiation therapy because deaths from these complications have been reported.

Outcome and Prognosis

Prognosis is worse for patients with symptomatic thymomas because these patients are more likely to have a malignant thymoma. The single most important factor predicting the outcome of patients with thymomas is evidence of invasion. Assess histologic characteristics, such as microscopic capsular¹² invasion. The surgeon should perform a gross inspection. Cellular characteristics are inconsequential because they have no impact on patient treatment. Because of the well-documented propensity for late recurrences, discuss long-term survival in terms of a 10-year follow-up after treatment of the thymoma. A study conducted by the MemorialSloanKetteringCancerCenter (1995) reported 5-year and 10-year survival rates to corresponding stages of thymomas.¹⁵

Thymomas have been associated with the development of second malignancies. In a review of the Surveillance, Epidemiology, and End Results (SEER) database of thymoma cases in the United States (1973-1988), 849 cases were identified, of which 66 were found to have second malignancies. In this study, there was an excess occurrence of non-Hodgkin lymphoma and soft tissue sarcomas but no other specific cancers. Notably, an increase in digestive system cancers (colon/rectum, stomach, esophagus, liver/biliary tract) occurred; however, these increases where not statistically significant.

Table 3. Survival of Thymoma by Stage: The Memorial Sloan Kettering Experience

Future and Controversies

With the advent of video-assisted minimally invasive surgery, many of the traditional thoracic procedures have been abandoned. Cases of video-assisted thoracoscopy have been described; however, no long-term results are available. Roviaro et al performed video thoracoscopy on 6 patients with thymomas; however, they did not describe the extent of resection, size of tumor, or stage of tumor, and long-term follow-up data are unavailable.¹⁷ Kaiser advocated the use of transcervical dissection in conjunction with video thoracoscopy, allowing better exposure.¹⁸ Mack presented a series of photographs of thymus glands removed using thoracoscopy.¹⁹ These photographs confirmed the thymus gland can be resected completely by experienced surgeons. Long-term follow-up data are required to determine the true efficacy of this procedure compared with traditional thymectomy.

Studies have investigated the molecular changes in thymomas. In one study, 10 out of 12 thymomas exhibited epidermal growth factor receptor (EGFR) expression. This information would be useful in selecting patients that may benefit from EGFR inhibitors as part of their treatment regimen. Other areas of investigation include apoptosis-related markers, such as p63, a member of the p53 family. p63 was found to be expressed in virtually all thymomas. Further research pertaining to the biology of thymomas will allow more adequate approaches to treatment.

Multimedia

Media file 1: Anatomy of the thymus, with emphasis on the blood supply and relation to recurrent laryngeal and phrenic nerves.

Media file 2: Lateral view: The thymic arteries are derived from the adjacent internal mammary arteries; the inferior thymic vein empties into the innominate vein. The thymus gland's surrounding vascular and neural structures may be invaded during the spread of a thymoma.

Media file 3: This computed tomography (CT) scan clearly illustrates the mass in the right anterolateral mediastinum.

References

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Keywords

thymoma, thymus, myasthenia gravis, thymus gland, myasthenia, thymectomy, thymic carcinoma, anterior mediastinal tumor, thymic tumor, thymus tumor, anterior mediastinal neoplasm, mediastinal tumor, mediastinal neoplasm, thymic neoplasm, thymus neoplasm

Contributor Information and Disclosures

Author

Quintessa Miller, MD, Staff Physician, Department of General Surgery, Keesler Air Force Base Medical Center
Quintessa Miller, MD is a member of the following medical societies: American College of Surgeons and National Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

A Letch Kline, MD, Program Director, Department of Surgery, Keesler USAF Medical Center; Clinical Assistant Professor, Department of Surgery, Uniformed University of the Health Sciences
A Letch Kline, MD is a member of the following medical societies: American College of Chest Physicians, American College of Surgeons, American Medical Association, American Society for Parenteral and Enteral Nutrition, Association for Surgical Education, Southeastern Surgical Congress, and Southwestern Surgical Congress
Disclosure: Nothing to disclose.

Medical Editor

Juan B Ochoa, MD, Assistant Professor, Department of Surgery, University of Pittsburgh
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Michael A Grosso, MD, Consulting Staff, Department of Cardiothoracic Surgery, St Francis Hospital
Michael A Grosso, MD is a member of the following medical societies: American College of Surgeons, Society of Thoracic Surgeons, and Society of University Surgeons
Disclosure: Nothing to disclose.

CME Editor

Paolo Zamboni, MD, Professor of Surgery, Chief of Day Surgery Unit, Chair of Vascular Diseases Center, University of Ferrara, Italy
Paolo Zamboni, MD is a member of the following medical societies: American Venous Forum and New York Academy of Sciences
Disclosure: Nothing to disclose.

Chief Editor

John Geibel, MD, DSc, MA, Vice Chairman, Professor, Department of Surgery, Section of Gastrointestinal Medicine and Department of Cellular and Molecular Physiology, Yale University School of Medicine; Director of Surgical Research, Department of Surgery, Yale-New Haven Hospital
John Geibel, MD, DSc, MA is a member of the following medical societies: American Gastroenterological Association, American Physiological Society, American Society of Nephrology, Association for Academic Surgery, International Society of Nephrology, New York Academy of Sciences, and Society for Surgery of the Alimentary Tract
Disclosure: AMGEN Royalty Other

Related eMedicine topics:
Myasthenia Gravis [Emergency Medicine]
Myasthenia Gravis [Neurology]
Myasthenia Gravis [Ophthalmology]
Surgery of the Thymus Gland
Thymoma [Pediatrics: General Medicine]
Thymic Tumors
Thymus, Lesions

Clinical guidelines:
The management of thymoma: guideline recommendations. Program in Evidence-based Care - State/Local Government Agency [Non-U.S.].  2008 Sep 26.  41 pages.  NGC:006749

Clinical trials:
Belinostat in Treating Patients With Recurrent or Metastatic Thymoma and Thymic Carcinoma That Cannot be Removed by Surgery

Efficacy of Octreotide Treatment in Patients With Primary Inoperable Thymoma

Paclitaxel and Cisplatin for Thymic Neoplasm

Preoperative Treatment of Patients With High Risk Thymoma

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