Thymoma

Thymoma is the most common primary tumor of the anterior mediastinum, arising from epithelial cells of the thymus — an organ critical to T-cell maturation that gradually involutes after puberty. Despite its location just behind the breastbone, thymoma is often discovered incidentally on chest imaging, and its natural history ranges from completely encapsulated and cured by surgery alone to invasive tumors requiring multimodality therapy. What makes thymoma uniquely fascinating and clinically challenging is its striking association with autoimmune diseases, particularly myasthenia gravis — present in 30–50% of patients — as well as pure red cell aplasia, hypogammaglobulinemia, and a constellation of other paraneoplastic syndromes that can persist or even worsen after the tumor is removed.

Table of Contents

1. Overview and Epidemiology
2. Pathology and WHO Classification
3. Masaoka-Koga Staging
4. Paraneoplastic Syndromes
5. Clinical Presentation
6. Diagnosis and Imaging
7. Treatment — Surgery
8. Treatment — Multimodality for Advanced Disease
9. Myasthenia Gravis Management
10. Prognosis and Surveillance
11. Key Research Papers
12. PubMed Topic Searches
13. Featured Videos
14. Connections

Overview and Epidemiology

Thymoma arises from the epithelial cells lining the thymus — a small gland nestled in the anterior mediastinum, directly behind the sternum and in front of the heart and great vessels. The thymus is where T lymphocytes mature and learn to distinguish self from foreign, making it essential for normal immune function. After puberty it begins to involute, gradually replaced by fat, though residual thymic tissue remains throughout life and can give rise to tumors at any age.

Thymoma is rare. In the United States, incidence runs approximately 1.3 to 1.5 cases per million people per year, translating to roughly 400 to 500 new diagnoses annually. It accounts for about 20–30% of all anterior mediastinal masses in adults. The peak age at diagnosis is the fifth to sixth decade of life (50–60 years), and unlike many cancers, thymoma affects men and women equally. There is no strong racial predisposition, though some data suggest slightly higher rates in Asian populations.

It is important to distinguish thymoma from other tumors that can occupy the anterior mediastinum — the so-called "4 T's": Thymoma, Teratoma and germ cell tumors, Terrible lymphoma, and Thyroid extension. Lymphoma is the most common anterior mediastinal mass overall when all age groups are included, but thymoma leads specifically among primary thymic tumors in adults. Thymoma must also be distinguished from thymic carcinoma (a more aggressive, high-grade entity) and thymic carcinoid, which are distinct diseases with different biologies and treatment approaches.

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Pathology and WHO Classification

The World Health Organization published a histological classification of thymic epithelial tumors in 2004 that remains the standard in clinical practice. The classification reflects the ratio of epithelial cells to lymphocytes and the degree of atypia of the epithelial cells — two features that correlate with prognosis and behavior.

• Type A (spindle cell thymoma): Composed of spindle-shaped or oval epithelial cells with very few admixed lymphocytes. This is the most benign subtype. The capsule is almost always intact, recurrence is rare, and long-term prognosis is excellent. It represents roughly 4–7% of thymomas.
• Type AB (mixed thymoma): Contains both Type A areas (spindle cells, few lymphocytes) and Type B areas (more lymphocytes). Behavior is intermediate — generally favorable but not as benign as pure Type A. Accounts for approximately 28–34% of cases.
• Type B1 (lymphocyte-rich thymoma): Predominantly lymphocytic, with only scattered epithelial cells — so much so that it can closely resemble normal thymic tissue on low power. Good prognosis overall, though local invasion is possible. Represents about 9–20% of thymomas.
• Type B2 (cortical thymoma): Moderate numbers of lymphocytes along with prominent, rounded epithelial cells with vesicular nuclei and prominent nucleoli. This is the most common subtype associated with myasthenia gravis and other paraneoplastic syndromes. It has an intermediate prognosis and is the most frequently encountered subtype in many series. Accounts for 20–36% of cases.
• Type B3 (epithelial thymoma): Predominantly epithelial cells with only mild atypia and few lymphocytes. The epithelial cells tend to form sheets. This type carries a higher risk of invasion and recurrence, and is considered borderline malignancy or low-grade carcinoma in some classification schemes. Represents about 10–14% of thymomas.
• Thymic Carcinoma (formerly Type C): A distinct and separate entity from thymoma proper. High-grade epithelial tumor with overt cytological malignancy — the most common histological subtype is squamous cell carcinoma, though adenocarcinoma, mucoepidermoid, and other types occur. Unlike thymomas, thymic carcinomas are not associated with paraneoplastic syndromes (the immune microenvironment is too disrupted for those immunological phenomena). They frequently express PD-L1 on tumor cells, which has therapeutic implications. Prognosis is significantly worse than thymoma.

An important caveat: WHO histological type alone does not determine outcome — stage is equally or more important. A Stage I B3 thymoma may have a better prognosis than a Stage III Type A tumor simply because of complete resection.

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Masaoka-Koga Staging

The staging system most widely used in clinical practice for thymoma is the Masaoka-Koga system, developed from the original Masaoka staging and refined by Koga. It is based on surgical and pathological findings regarding the degree of capsular invasion and spread to adjacent structures.

• Stage I: Completely encapsulated tumor with no microscopic evidence of capsular invasion. The surgeon sees an intact capsule; the pathologist confirms no tumor at the capsule margin. Fifteen-year survival exceeds 90%. Surgery alone is curative in the vast majority of cases.
• Stage IIa: Microscopic transcapsular invasion — tumor penetrates the capsule on pathological examination but there is no gross (macroscopic) evidence of invasion at the time of surgery.
• Stage IIb: Macroscopic invasion into surrounding mediastinal fat or mediastinal pleura, visible to the surgeon at the time of resection but without involvement of adjacent organs.
• Stage III: Invasion of neighboring organs: pericardium, great vessels (superior vena cava, aorta, pulmonary artery), or lung parenchyma. This is where surgery becomes technically challenging and multimodality treatment is typically required.
• Stage IVa: Pleural or pericardial dissemination — tumor has "dropped" metastases to the pleural or pericardial surfaces without hematogenous spread. This pattern is more common in thymoma than in other thoracic cancers and can still sometimes be treated with aggressive combined modality approaches at specialized centers.
• Stage IVb: Lymphogenous or hematogenous metastasis to distant sites (liver, bone, kidney). This is rare in thymoma and more typical of thymic carcinoma.

The International Thymic Malignancy Interest Group (ITMIG) and IASLC adopted a TNM-based 8th edition staging system that is now officially endorsed and captures more granular detail about lymph node involvement. However, the Masaoka-Koga system remains in wide clinical use because the vast majority of published outcome data uses it, and many thoracic surgeons and oncologists still rely on it for treatment decisions and prognostic discussions.

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Paraneoplastic Syndromes — the Unique Face of Thymoma

No other cancer in the body is so intimately connected to autoimmunity as thymoma. Because the thymus is where the immune system learns self-tolerance, tumors arising from thymic epithelial cells can disrupt this process and trigger antibody-mediated attacks on normal tissues. These paraneoplastic syndromes are a hallmark feature of thymoma and are rarely seen with thymic carcinoma.

Myasthenia Gravis (MG)

Myasthenia gravis is present in 30–50% of all thymoma patients — making it by far the most common paraneoplastic manifestation. The underlying mechanism involves production of antibodies against acetylcholine receptors (anti-AChR) at the neuromuscular junction. The result is fatigable muscle weakness that worsens with repeated use and improves with rest. Classic symptoms include ptosis (drooping eyelids), diplopia (double vision), dysphagia (difficulty swallowing), dysarthria (slurred speech), and in severe cases, respiratory compromise requiring mechanical ventilation (myasthenic crisis).

Thymectomy — surgical removal of the thymoma — helps control MG in many patients, but the autoimmune process does not simply switch off when the tumor is gone. MG may persist for years after complete tumor removal, may even transiently worsen in the perioperative period, and occasionally new MG develops after apparently successful thymectomy. Conversely, about 10–15% of all patients diagnosed with MG (including those without thymoma) are found to harbor a thymoma on chest CT — which is why CT scanning is standard practice in any new MG diagnosis.

Pure Red Cell Aplasia (PRCA)

Approximately 5% of thymoma patients develop pure red cell aplasia, a condition in which the bone marrow completely stops producing red blood cell precursors (erythroid progenitors) while white cell and platelet production remain intact. The result is a severe, isolated anemia. Patients present with profound fatigue, pallor, and dyspnea disproportionate to their thymoma burden. Bone marrow biopsy shows absent erythroid precursors. PRCA may respond to thymectomy and immunosuppressive therapy (cyclosporine, corticosteroids), though responses are variable and the anemia may require chronic transfusion support or erythropoietin.

Hypogammaglobulinemia (Good Syndrome)

Good syndrome — named for Robert Good who described it in 1954 — is the combination of thymoma and acquired hypogammaglobulinemia (low immunoglobulin levels) with markedly reduced or absent B lymphocytes. Patients develop a secondary immunodeficiency that makes them unusually susceptible to encapsulated bacteria (pneumococcus, Haemophilus), chronic sinopulmonary infections, and opportunistic organisms. Treatment requires lifelong intravenous immunoglobulin (IVIG) replacement. Unlike the other paraneoplastic syndromes, the immunodeficiency in Good syndrome rarely reverses after thymectomy.

Other Paraneoplastic Associations

Thymoma has been associated with a remarkable range of other autoimmune conditions, including systemic lupus erythematosus, inflammatory arthritis, polymyositis and dermatomyositis, Hashimoto thyroiditis, pemphigus, and limbic encephalitis. Lambert-Eaton myasthenic syndrome (LEMS) can also occur — and it is important to distinguish it from classic MG: in LEMS, proximal muscle weakness actually improves transiently with repeated contraction (the opposite of MG), and autonomic features (dry mouth, impotence) are often present. LEMS in the absence of thymoma is more strongly associated with small cell lung cancer.

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Clinical Presentation

The way thymoma comes to clinical attention varies widely and depends heavily on tumor size, invasiveness, and the presence or absence of paraneoplastic syndromes. Roughly one third of patients in each of three broad categories:

• Asymptomatic, incidental discovery (~35%): The most common scenario in contemporary practice. The tumor is found incidentally on a chest X-ray or CT scan ordered for an unrelated reason — a routine physical, a workup for atypical chest pain, or preoperative screening. The anterior mediastinal mass is then further evaluated. These tumors tend to be smaller and more often at Stage I or II.
• Local mass symptoms (~35%): Larger tumors produce symptoms by compressing or invading neighboring structures. Chest pain (often described as a dull ache or pressure), persistent cough, and dyspnea are the most common complaints. Superior vena cava (SVC) syndrome — facial and upper extremity edema, headache, distended neck veins, and cyanosis — occurs when the tumor compresses or invades the SVC, and represents a relative oncological urgency.
• Paraneoplastic presentation (~30%): Some patients present first with myasthenia gravis — developing ptosis, diplopia, or a myasthenic crisis — and the thymoma is discovered on CT during the MG workup. Less commonly, unexplained severe anemia (PRCA) or recurrent infections (Good syndrome) lead to the diagnosis.

Because the anterior mediastinum is a relatively silent anatomical space, thymomas can grow to considerable size before producing symptoms. Tumors larger than 5–6 cm are more likely to cause local symptoms or to be invasive at the time of diagnosis.

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Diagnosis and Imaging

The diagnostic evaluation of a suspected thymoma aims to characterize the mass, determine the extent of disease, and obtain tissue confirmation when necessary before treatment.

CT Chest with Contrast

CT of the chest with intravenous contrast is the gold standard for initial evaluation. Thymoma typically appears as a well-defined anterior mediastinal mass, either smooth or lobulated in contour, with variable degrees of encapsulation. Calcification is present in approximately 20% of cases. CT defines the relationship of the tumor to adjacent structures — pericardium, great vessels, lung — and looks for pleural nodules suggesting Stage IVa disease. The radiological appearance often (though not always) suggests encapsulation, which correlates with resectability.

PET-CT

Fluorodeoxyglucose PET-CT adds metabolic information that helps distinguish thymoma from lymphoma (lymphoma is typically more avid), assess the extent of disease for staging, and evaluate suspicious pleural lesions. Thymoma has variable FDG avidity — generally less intense than lymphoma or thymic carcinoma. PET-CT has become a standard part of the preoperative staging workup at many centers.

MRI

MRI is particularly useful for assessing vascular invasion — involvement of the superior vena cava, aorta, or pulmonary vessels — which has direct surgical planning implications. It can also help characterize lesion composition (cystic vs solid components). MRI with gadolinium is considered complementary to CT rather than a replacement.

Tissue Biopsy

For tumors that appear resectable on imaging, many thoracic surgeons proceed directly to surgical resection without a preoperative biopsy, both for diagnostic confirmation and definitive treatment. Biopsy is indicated when: the tumor appears unresectable and neoadjuvant therapy is planned; the diagnosis is uncertain (lymphoma is on the differential and requires special tissue handling); or the patient is not a surgical candidate. CT-guided core needle biopsy is the preferred approach when feasible. For anterior mediastinal masses not accessible by CT guidance, a Chamberlain procedure (anterior mediastinotomy, a small incision in the second intercostal space) or video-assisted thoracoscopic surgery (VATS) provides access for surgical biopsy.

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Treatment — Surgery

Complete surgical resection is the single most important prognostic factor in thymoma, and surgery is the cornerstone of treatment for all resectable disease. The goal is en bloc removal of the tumor with its intact capsule and all surrounding thymic tissue, achieving negative surgical margins (R0 resection). Even minor capsular disruption during surgery increases the risk of local recurrence and pleural seeding.

Surgical Approaches

• Median sternotomy: The traditional and most widely used approach, providing excellent exposure to the entire anterior mediastinum and allowing assessment and resection of locally invasive tumors involving adjacent structures. En bloc resection of involved pericardium, innominate vein, or lung is performed through sternotomy when necessary.
• Transcervical thymectomy: A collar incision at the base of the neck, used primarily for thymectomy in myasthenia gravis without thymoma or for small, superior thymomas. Limited exposure makes it unsuitable for larger or potentially invasive tumors.
• Video-Assisted Thoracoscopic Surgery (VATS): Minimally invasive approach increasingly used for small, encapsulated thymomas (Stage I, typically <5 cm). Associated with less pain, shorter hospital stay, and faster recovery compared to sternotomy, with equivalent oncological outcomes in appropriately selected cases.
• Robotic-assisted thymectomy: Robotic platforms (da Vinci) are growing in use at specialized thoracic surgery centers. Early data suggest safety and feasibility comparable to VATS for selected early-stage tumors, with potential ergonomic and visualization advantages for the surgeon.

Outcomes by Stage

For Stage I and Stage II thymoma, surgery alone achieves excellent long-term control. Ten-year survival rates exceed 90% for Stage I disease. Stage II outcomes are nearly as good, particularly for IIa. The completeness of resection (R0 vs R1 [microscopic residual] vs R2 [gross residual]) is the dominant determinant of recurrence risk. Even Stage III disease can sometimes be cured with complete resection when technically achievable, though adjuvant therapy is generally recommended.

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Treatment — Multimodality for Advanced Disease

For tumors that are locally advanced, incompletely resected, or metastatic, surgery alone is insufficient and multimodality treatment is required. The approach integrates chemotherapy, radiation, and when feasible, aggressive surgery.

Neoadjuvant Chemotherapy

For Stage III or bulky Stage II tumors where complete resection is uncertain, neoadjuvant (preoperative) platinum-based chemotherapy is used to reduce tumor size and improve resectability. The most widely used regimen is CAP: cyclophosphamide, doxorubicin (Adriamycin), and cisplatin. Response rates of 50–80% are reported, with pathological complete responses in a smaller proportion. An alternative is EP: etoposide plus cisplatin. After 3–4 cycles of neoadjuvant chemotherapy, restaging imaging determines whether resection has become feasible.

Postoperative Radiation Therapy (PORT)

Postoperative radiation therapy (PORT) to the mediastinum is generally recommended for: incompletely resected (R1 or R2) thymomas; Stage III tumors; and many Stage II tumors at higher-risk institutions. Standard doses are 45–50 Gy delivered to the mediastinal bed. PORT reduces local recurrence rates in these settings, though it has not been shown to improve overall survival in prospective randomized trials — largely because such trials are difficult to conduct in a disease this rare. The decision is individualized and made in multidisciplinary tumor board discussion.

Chemotherapy for Advanced or Metastatic Disease

For unresectable or metastatic thymoma, systemic chemotherapy remains the standard approach. CAP (cyclophosphamide + doxorubicin + cisplatin) and VIP (vinorelbine + ifosfamide + cisplatin) are the most commonly used regimens, with response rates of 50–90% for first-line therapy in thymoma. Somatostatin analogues (octreotide, lanreotide) have shown disease stabilization in thymomas that express somatostatin receptors — detectable by octreotide scintigraphy or Ga-68 DOTATATE PET — and are a useful option for selected patients.

Immunotherapy and Thymic Carcinoma

Thymic carcinoma frequently expresses PD-L1 on tumor cells, making it a candidate for immune checkpoint inhibitors. Pembrolizumab (anti-PD-1) has shown activity in previously treated thymic carcinoma in early trials. Importantly, immune checkpoint inhibitors are used with great caution or avoided entirely in thymoma proper — patients with thymoma and underlying autoimmune paraneoplastic syndromes (especially myasthenia gravis) are at risk for severe, life-threatening immune-related exacerbations when given PD-1 or CTLA-4 inhibitors. This is a critical distinction: the very autoimmune milieu that defines thymoma makes it dangerous to unleash further immune activation. Several fatalities from pembrolizumab-exacerbated MG in thymoma patients have been reported.

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Myasthenia Gravis Management

When thymoma coexists with myasthenia gravis, managing the MG is as important as treating the tumor — both preoperatively and throughout the patient's long-term care. A multidisciplinary team including thoracic surgery, neurology, and anesthesia is essential.

Preoperative Optimization

Before surgery, MG must be optimized to minimize the risk of perioperative myasthenic crisis (sudden severe respiratory failure requiring intubation). The first-line medication is pyridostigmine (Mestinon), an acetylcholinesterase inhibitor that increases acetylcholine at the neuromuscular junction and reduces fatigable weakness. Corticosteroids (prednisone) are frequently added for longer-term immunosuppression, though initiating steroids too rapidly can transiently worsen MG. For patients with moderate to severe MG undergoing urgent surgery, intravenous immunoglobulin (IVIG) or plasmapheresis (plasma exchange) can rapidly reduce circulating anti-AChR antibody titers and improve neuromuscular function within days, stabilizing the patient for surgery.

Anesthesia and Perioperative Care

Anesthesiologists experienced with MG are critical. Neuromuscular blocking agents must be used with extreme caution — patients with MG are exquisitely sensitive to nondepolarizing agents (vecuronium, rocuronium) and may require prolonged ventilation. Many centers use volatile inhalational anesthesia without neuromuscular blockers in MG patients when possible. Postoperatively, ICU-level monitoring for respiratory compromise is standard, with early involvement of neurology if weakness is persistent or worsening.

Long-Term MG Management After Thymectomy

The landmark MGTX trial (Wolfe et al., N Engl J Med 2016) randomized patients with nonthymomatous generalized MG (not thymoma-associated MG, but an important related question) to thymectomy plus prednisone versus prednisone alone. At 3 years, thymectomy significantly improved clinical outcomes — lower disease severity scores, better quality of life, and reduced steroid requirements. This landmark study confirmed the benefit of thymectomy in MG and provided rigorous evidence for a practice that was already widely performed. For thymoma-associated MG, thymectomy is performed for the tumor itself, with the expectation that it may also help the MG — but complete resolution of MG occurs in only a minority, and long-term immunosuppression is the norm for most patients.

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Prognosis and Surveillance

Thymoma has one of the most favorable prognoses among thoracic malignancies, particularly for early-stage disease — but it also has two features that demand lifelong vigilance: late recurrences and persisting autoimmune disease.

Stage-Based Survival

• Stage I: 15-year survival exceeds 90%; recurrence is uncommon but has been reported even decades after resection.
• Stage II: 10–15-year survival approximately 70–90%; higher for IIa than IIb.
• Stage III: 5–10-year survival approximately 50–65%; depends heavily on completeness of resection.
• Stage IVa: 5-year survival approximately 20–40%; some long-term survivors after aggressive multimodality treatment.
• Stage IVb: Poor prognosis; rare in thymoma, more typical of thymic carcinoma.

Histological Type and Prognosis

WHO Type A and AB carry the best prognosis; Type B1 is generally favorable; Type B2 and B3 are intermediate. Thymic carcinoma has a substantially worse outlook — 5-year survival ranges from approximately 30–50%, reflecting its higher stage at presentation and more aggressive biology.

Late Recurrences

A striking and clinically important feature of thymoma is the possibility of late recurrences — relapses occurring more than 10 years after apparently successful complete resection. This is unusual in oncology, where most recurrences happen within 2–5 years. As a result, lifelong surveillance with periodic CT chest imaging is standard of care for thymoma patients, typically annually or every 2 years after the first 5 years. Pleural dissemination is the most common recurrence pattern. Some late recurrences are still surgically resectable and can be cured with reoperation.

Autoimmune Disease and Quality of Life

Even when the tumor is cured, the autoimmune consequences — particularly myasthenia gravis — may persist indefinitely. Patients require ongoing neurological follow-up, medication management, and vigilance for myasthenic crises. Quality of life may be significantly affected not by the cancer itself but by the immunological aftermath. Patients with Good syndrome require lifelong IVIG replacement and monitoring for infections. This is a chronic disease in its immunological dimensions even when oncologically controlled.

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Key Research Papers

1. Girard N et al. Thymic epithelial tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2015;26(Suppl 5):v40–55. PMID 26314776
2. Detterbeck FC et al. The IASLC/ITMIG Thymic Epithelial Tumors Staging Project: proposal for an evidence-based stage classification system for the forthcoming (8th) edition of the TNM Classification of Malignant Tumors. J Thorac Oncol 2014;9(Suppl 2):S65–72. PMID 25396309
3. Kondo K, Monden Y. Therapy for thymic epithelial tumors: a clinical study of 1,320 patients from Japan. Ann Thorac Surg 2003;76:878–884. PMID 12963228
4. Ruffini E et al. Thymomas: prognostic factors and long-term outcome after surgery — the European Organization for Research and Treatment of Cancer Lung Cancer Group experience. Eur J Cardiothorac Surg 2011;39:e29–35. PMID 21237672
5. Fornasiero A et al. Chemotherapy for invasive thymoma: a 13-year experience. Cancer 1991;68:30–33. PMID 1904471
6. Huang J et al. All-stage thymoma survival: population-based analysis using the SEER database. Ann Surg Oncol 2017;24:2972–2978. PMID 28567709
7. Detterbeck FC. Evaluation and treatment of stage I and II thymoma. J Thorac Oncol 2010;5(Suppl 4):S318–22. PMID 20859118
8. Venuta F et al. Neoadjuvant chemotherapy followed by surgery for invasive thymoma: single institution experience with long-term follow-up. Ann Thorac Surg 2006;82:1871–5. PMID 17062274
9. Wolfe GI et al. Randomized trial of thymectomy in myasthenia gravis (MGTX). N Engl J Med 2016;375:511–522. PMID 27509100
10. Palmieri G et al. Somatostatin analogue treatment for thymoma and thymic carcinoma: an open phase II trial of efficacy and safety in 27 patients. Ann Oncol 2002;13:728–31. PMID 12075740
11. Scorsetti M et al. Thymic carcinoma: current evidence for pathologic features, prognosis and treatment. Ann Oncol 2016;27:1019–1025. PMID 26578693
12. Fornasiero A et al. Initial data regarding CAP regimen for advanced thymoma chemotherapy. Cancer 1991;68:30–33 [see also Giaccone G et al.]; full staging and chemotherapy review: PMID 16129029

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PubMed Topic Searches

• Thymoma Surgery and Prognosis
• Thymoma and Myasthenia Gravis
• Thymic Carcinoma Treatment
• Thymoma WHO Classification
• Thymoma Chemotherapy (Cisplatin)
• Masaoka-Koga Staging System
• Pure Red Cell Aplasia and Thymoma
• Good Syndrome / Hypogammaglobulinemia
• Thymoma Paraneoplastic Syndromes
• Thymic Carcinoma PD-L1 Immunotherapy

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Connections

• Cancer
• Lung Cancer
• Mesothelioma
• Lymphoma
• Multiple Myeloma
• Brain Cancer
• Neuroblastoma
• Skin Cancer
• Neuroendocrine Tumors

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