Mediastinal masses and thymoma

• The mediastinum is the central compartment of the chest. Divided by the ITMIG CT-based scheme it has three parts: prevascular (anterior), visceral (middle) and paravertebral (posterior).
• A mass's compartment narrows the differential dramatically. About half of mediastinal masses are anterior, and in adults the "four T's" (thymoma, teratoma, thyroid tissue, terrible lymphoma) plus thymic lesions dominate there. ^[1]
• Thymoma is the commonest mass of the prevascular mediastinum in adults. It is slow-growing, histologically benign to low-grade malignant, but can invade and recur; its importance is its link to autoimmunity, especially myasthenia gravis.
• Imaging starts with contrast CT (sometimes MRI for cysts and fat). Biopsy is often not needed when CT in older adults with myasthenia gravis looks typical for thymoma; tissue is needed for unresectable, metastatic or atypical cases. ^[1]
• Surgery (complete thymectomy aiming for R0) is the main treatment. Stage, histology and completeness of resection drive prognosis, radiotherapy and chemotherapy afterwards.

By the end of this page you should be able to:

1. Divide the mediastinum by the ITMIG scheme and give the contents and typical lesions of each compartment.
2. Build a sensible differential for an anterior mediastinal mass using the four T's and the modern additions, and separate thymoma from thymic hyperplasia, germ cell tumours and lymphoma.
3. Explain the thymoma–myasthenia gravis, pure red cell aplasia and Good syndrome associations mechanistically, and the paraneoplastic percentages.
4. Interpret chest CT, MRI and PET findings in mediastinal masses and say when biopsy is needed and which technique to use.
5. Stage thymoma with Masaoka-Koga and TNM and use the stage to decide surgery, radiotherapy and chemotherapy.
6. Plan complete thymectomy, recognise its complications, and outline follow-up imaging for thymoma and thymic carcinoma.

The ITMIG scheme (2014) is based on landmarks visible on cross-sectional CT.^[6] It created a prevascular, visceral and paravertebral compartment. The prevascular compartment contains the thymus, fat and lymph nodes; the visceral compartment the heart, great vessels, trachea, oesophagus and nodes; the paravertebral compartment the spine and adjacent soft tissues.^[6]

Mediastinal masses are uncommon: they account for about 3% of thoracic tumours.^[1] Cross-sectional imaging first localises the mass to a compartment; this single step is the strongest clue to the diagnosis.^[6] About half of mediastinal masses are anterior (prevascular).^[1]

A benign mass is found in roughly two-thirds of all patients, but the proportion that is malignant is higher in the anterior compartment, at about 59%.^[1] The commonest anterior lesions give the classic mnemonic, and the modern expanded list is worth memorising in full:

For the visceral and paravertebral compartments the typical lists are shorter but important.^[6] Visceral compartment masses include lymphadenopathy (neoplastic or granulomatous), foregut duplication cysts, vascular lesions, oesophageal tumours and metastases. Paravertebral masses are dominated by neurogenic tumours (schwannoma, neurofibroma, malignant peripheral nerve sheath tumour), with meningocele, neurenteric cysts, extramedullary haematopoiesis and paraganglioma as alternatives.

Mediastinal tumours as a whole are rare. Thymic epithelial tumours (TETs), of which thymoma is the main member, have an overall incidence in the European Union of roughly 0.18 per 100 000 per year, of which thymoma is about 0.14 and thymic carcinoma about 0.01 per 100 000.^[5] Thymic tumours are most common in the fourth to sixth decades of life and show a slight male predominance (about 1.4 to 1) in older cohorts, though incidence patterns differ in younger Afro-American patients.^[5] There is no clear sex or race predilection for TET overall in many datasets, and no established environmental risk factor.^[2][1]

TETs make up about half of all anterior mediastinal masses^[5] and about 20% of all mediastinal neoplasms.^[2] Thymoma itself is the commonest prevascular mass in adults.^[2] Prognosis differs sharply by type: 5-year overall survival is roughly 80% for thymoma and 45% for thymic carcinoma.^[5]

No modifiable risk factor is established for thymoma. A set of well-described associations exists instead:

• Sporadic tumours are the rule; familial cases are uncommon.
• Thymoma, and TETs more generally, are associated with multiple endocrine neoplasia type 1: thymic carcinoid and thymoma have been described in MEN1 families.^[5]
• Patients with TET carry an increased risk of second malignancies, reported in the range 8 to 31%, particularly thymoma patients.^[5]
• Thymomas cause their most important morbidity not by invasion alone but through autoimmunity (see below).

Thymoma arises from thymic epithelial cells rather than lymphocytes. The thymus involutes after puberty and is replaced by fibrofatty tissue, so an apparent anterior mass in an older adult is more likely to be neoplastic. Histologic heterogeneity is common: a single thymoma often contains more than one WHO subtype, in roughly 10% increments, so a small biopsy can miss the higher-grade component.^[2]

The key pathophysiologic concept is central tolerance. In normal thymic medulla, self-reactive T cells are deleted by presentation of tissue-specific self-antigens driven by the AIRE gene. Thymomas, especially the cortical B-type thymomas, disrupt this architecture and inactivate AIRE-driven antigen expression, allowing autoreactive T cells to escape into the periphery.^[5] These autoimmune conditions therefore are not classical paraneoplastic syndromes that track tumour behaviour; they do not reliably wax and wane with tumour burden.^[5]

The autoimmune burden is large and specific:

• Autoimmune disorders occur in up to 30% of thymoma patients and around 3% of thymic carcinoma patients.^[5]
• Myasthenia gravis is the commonest. About 30 to 40% of thymoma patients experience symptoms suggestive of myasthenia gravis,^[2] and broader serologic cohorts report 30 to 50% of thymoma patients developing myasthenia gravis.^[1] Conversely, 10 to 30% of patients with myasthenia gravis harbour a thymoma,^[1] and 10 to 20% in a SEOM meta-analytic summary.^{[5] [3]}
• In cohorts of myasthenia gravis, about 10% have a thymoma overall (rising in late-onset AChR-positive disease); chest CT or MRI is therefore routine in myasthenia gravis to look for a thymoma.^[3]
• Pure red cell aplasia occurs in 5 to 15% of thymoma patients (StatPearls) or about 5% (ESMO); it is more common in older women and is often associated with spindle-cell (type A/AB) thymoma.^[2][4]
• Good syndrome (acquired hypogammaglobulinaemia) occurs in less than 5% of thymoma patients and in about 10% of patients with acquired hypogammaglobulinaemia; it, too, is usually tied to spindle-cell thymoma and does not resolve with thymectomy.^{[2] [4]}
• Other associations include thyroiditis, lupus, pemphigus, pernicious anaemia, haemolytic anaemia, pancytopenia, polymyositis, neuromyotonia (Isaacs syndrome), encephalomyelitis, giant cell myocarditis, glomerulopathy and colitis.^[5][2]
• Thymoma-associated multiorgan autoimmunity (TAMA) mimics graft-versus-host disease, with morbilliform rash, chronic diarrhoea and abnormal liver enzymes.^[2]

Mediastinal masses can be silent, compressive or systemic. The pattern is determined by location and biology, not by compartment alone.

• Asymptomatic incidental detection is common, especially for small thymomas on routine imaging.
• Local compression and invasion cause cough, chest pain, dyspnoea, stridor, dysphagia, hoarseness, SVC syndrome (facial and arm swelling, headache, visual disturbance), Horner syndrome, and phrenic nerve palsy. Cystic lesions can be mistaken for solid masses if they haemorrhage or become infected.
• Systemic B symptoms (fever, night sweats, weight loss) point to lymphoma or infection, although they can occur in any malignant anterior mass.
• Paraneoplastic features of thymoma (myasthenia gravis diplopia, ptosis, fatigable weakness; pure red cell aplasia; Good syndrome with recurrent infection) may be the presenting complaint.
• Red flags that need urgent action: SVC syndrome, signs of airway compromise, haemodynamic collapse, and new neurological deficits. Severe superior mediastinal obstruction can be life-threatening before tissue diagnosis.

WHO (World Health Organization) histological typing remains the standard, and is summarised here from StatPearls and SEOM.^[2][5]

These subtypes map to prognosis: thymomas B2 and B3 have worse overall survival than A, AB and B1, and thymic carcinoma is worse still.^[5] Immunohistochemistry supports the diagnosis: thymic epithelial cells are positive for keratins, p63, p40 and PAX8; CD5 and CD117 favour thymic carcinoma over other squamous lesions; CD20 can stain A/AB thymomas.^[2][5]

A thymoma itself usually appears on CT as a spherical or ovoid, encapsulated, off-midline soft-tissue lesion with homogeneous attenuation and enhancement; calcification (curvilinear along capsule, punctate or coarse) is common, and drop metastases may appear as pleural or pericardial nodules.^[6] Heterogeneity suggests necrosis, haemorrhage or cystic change.^[6]

The work-up is stepwise: chest radiograph (often the first clue), then contrast-enhanced CT of the chest (and abdomen, because the pleura is a common metastatic site), with MRI and PET as problem-solvers.^[6][5]

• CT chest with IV contrast is the standard for mediastinal masses and for thymoma staging. It defines size, location, morphology, density, fat, calcification, cystic change and relationship to the great vessels, pericardium and pleura.^[6][5] CT is superior or equal to MRI for most mediastinal problems.^[5]
• MRI is the better test for cystic lesions, thymic hyperplasia (chemical shift), complicated cysts and assessment of mediastinal invasion when surgery is being planned.^[5][6]
• PET-CT has low added value for thymoma detection (sensitivity 83%, specificity 58% for thymic masses in one summary) and is not generally recommended for routine thymic masses, but higher FDG uptake favours thymic carcinoma or carcinoid over well-differentiated thymoma; it is used for lymphoma staging and response.^[5][6]
• Thyroid scintigraphy and sestamibi scans localise functional thyroid and ectopic parathyroid tissue respectively.
• Pulmonary function tests and cardiac evaluation are part of surgical planning.^[2]

A biopsy is often the right move, but not always:

• In classic scenarios (adult 50 or older with myasthenia gravis, CT typical of thymoma; teratoma with characteristic fat and calcification; goitre continuous with the neck) a biopsy may be unnecessary, because CT plus clinical context is enough and needle biopsy carries risks including seeding.^[1]
• Biopsy is required when the mass is unresectable, neoadjuvant therapy is being considered, cancer is a different type than suspected, or surgery is too risky for age or co-morbidity.^[1][2]
• CT-guided percutaneous core needle biopsy has a sensitivity up to 90% for thymic tumours, whereas fine-needle aspiration is generally not recommended; surgical (thoracoscopic, cervical mediastinoscopy, Chamberlain) or endobronchial approaches are used when a percutaneous route is unsafe or uninformative.^[5][2]
• Pleural spaces should be respected to avoid tumour cell seeding.^[5]
• Laboratory context helps: germ cell markers (AFP, beta-hCG), LDH and a full blood count are essential in the young patient to exclude lymphoma and germ cell tumours before committing to surgery.^[1][2]

The visceral compartment contains both vascular and non-vascular structures; common lesions there are lymphadenopathy, foregut duplication cysts, oesophageal tumours, vascular lesions and mediastinal goitre extending into the chest. The paravertebral compartment is dominated by neurogenic tumours (schwannomas, neurofibromas, MPNSTs), plus meningoceles, neurenteric cysts and extramedullary haematopoiesis in haemolytic or myeloproliferative states.^[6]

There is no blood test that diagnoses thymoma. Diagnosis rests on imaging plus, where needed, histology. Staging uses two systems in parallel.

Masaoka-Koga (clinical, and only assessable after resection for true accuracy) runs from completely encapsulated (stage I) through microscopic transcapsular invasion (IIA), gross capsular infiltration into adjacent fat (IIB), microscopic or macroscopic invasion of neighbouring structures (III), pleural/pericardial dissemination (IVA) to lymphogenous or haematogenous metastasis (IVB).^[5]

TNM (IASLC/ITMIG, 8th/9th edition) is the anatomic alternative, with T1-T4 for local invasion, N1 (anterior/perithymic) and N2 (deep/cervical) nodes, and M1a (pleural/pericardial nodules) versus M1b (pulmonary or distant). Stage groupings run I to IVB.^[2][5] The WHO classification correlates with both, with B3 thymoma and thymic carcinoma carrying higher risk of advanced stage.^[5]

Practical stage interpretation from StatPearls and SEOM data (5-year survival high in early disease, dropping with invasion) is summarised with the long-term imaging plans above.^[2][5]

Initial management aims to make the patient safe first (airway, SVC), to narrow the differential by compartment and imaging density, and to avoid unnecessary surgery.^[6]

For resectable TET, surgical resection is the cornerstone of treatment, and complete (R0) resection is the strongest modifiable prognostic factor.^[2][5] Complete thymectomy (tumour, residual thymus and perithymic fat) is generally preferred because local recurrence after incomplete excision is well described.^[4][5] Ten-year overall survival after surgery is roughly 90% for stage I, 70% for stage II, 55% for stage III and 35% for stage IVA disease, and patients who undergo complete resection do significantly better.^[5]

Resectability and approach.^[5][2]

• Median sternotomy is the standard approach. Minimally invasive (thoracoscopic/robotic) thymectomy is an option for presumed stage I or selected small stage II tumours without invasion of major structures, performed by fully trained thoracic surgeons.^[5][2]
• In widely invasive stage III or selected stage IVA disease, en-bloc removal of affected structures is undertaken, and induction chemotherapy may be discussed first.^[5]
• Phrenic nerve preservation does not alter survival but increases local recurrence risk, so the benefit must be weighed against myasthenia gravis burden in nerve-invasive disease.^[5]
• All affected areas with uncertain margins should be marked with clips to guide post-operative radiotherapy.^[5]
• Lymphadenectomy is recommended: N1 nodes as a minimum for all; N1 plus N2 (paratracheal, aortopulmonary window, subcarinal, cervical) for thymic carcinoma and thymoma invading mediastinal structures. Lymphatic spread is far more common in thymic carcinoma (about 20%) than in thymoma (about 3%).^[5][2]
• Surgery also has a role in resectable recurrent disease.^[5]

Perioperative optimisation in myasthenia gravis. No patient in myasthenic crisis should be operated on. Myasthenia gravis must be medically controlled before surgery; plasmapheresis is used around the operation and steroid doses minimised, with stress-dosing planned. Anaesthetic, neurology and surgical teams should agree the induction, intubation and extubation plan in advance.^[2]

Induction therapy for locally advanced disease. Two to four cycles of platinum-based induction chemotherapy are standard in stage III/IVA TETs not suitable for upfront resection, with a response rate around 70% and conversion to complete resection in at least half of responders.^[5] Surgery follows if complete resection becomes achievable. PAC (cisplatin 50 mg per m2, doxorubicin 50 mg per m2, cyclophosphamide 500 mg per m2 IV every 3 weeks) is the most common regimen, though carboplatin-paclitaxel and cisplatin-etoposide are alternatives.^[5] Concurrent chemoradiotherapy may give higher resection rates but greater toxicity.^[5]

Post-operative radiotherapy (PORT) is recommended in stage III disease, thymic carcinoma, and after R1 or R2 resection (starting within 3 months).^[5] For stage II thymoma it is considered with aggressive (B2/B3) histology or high-risk features. It is not recommended in stage I thymoma without capsular invasion, where studies show no survival benefit.^[2]

Typical adjuvant doses are 45 to 50 Gy after R0 resection, 50 to 56 Gy for microscopic residual (R1) disease and 60 Gy for gross residual (R2) disease, delivered in 1.8 to 2 Gy fractions over 4 to 6 weeks.^[2][4][5] Late toxicities include pericarditis, pneumonitis, pulmonary fibrosis, accelerated coronary atherosclerosis and second malignancy, so risks and benefits need careful discussion.^[2]

For unresectable locally advanced disease, RT can be given concurrently with platinum-etoposide as definitive treatment (60 to 66 Gy) or as part of a sequential chemoradiotherapy strategy.^[5]

For metastatic disease not suitable for local treatment, platinum-based chemotherapy is standard, up to six cycles.^[5] ESMO similarly regards platinum-based chemotherapy as standard and lists options such as PAC, carboplatin-paclitaxel, cisplatin-etoposide, pemetrexed, gemcitabine with capecitabine, and everolimus targeted therapy for previously treated disease.^[4]

• Thymoma first-line: cyclophosphamide, doxorubicin and cisplatin (PAC regimens have higher response rates than non-anthracycline platinum combinations).^[2]
• Thymic carcinoma first-line: carboplatin, paclitaxel, with atezolizumab in some newer guidance.^[2]
• Selection of regimen depends on histology, cardiac function (anthracycline toxicity after mediastinal radiotherapy), and autoimmune status.
• PD-1/PD-L1 inhibitors are not recommended in thymoma because of severe immune-related adverse events; pembrolizumab and nivolumab have a limited, closely monitored role in thymic carcinoma, with myocarditis, myasthenia gravis and hepatitis as notable risks.^[2][5]
• Targeted options for pre-treated thymic carcinoma include lenvatinib, sunitinib and everolimus, with careful toxicity monitoring.^[2][5]

Treatment should be individualised by disease extent, symptom burden and performance status: radical intent includes surgery or radical radiotherapy for oligometastatic disease; metastatic or recurrent disease is managed with systemic therapy or palliative radiotherapy. Surgical resection is recommended for localised recurrence, including drop (pleural) metastases, because complete resection prolongs survival; more extensive recurrence is treated chemotherapeutically or with palliative radiotherapy.^[2]

Follow-up must be long, because thymoma can recur years later (mean time to recurrence 8 to 68 months, usually as pleural nodules).^[2] SEOM recommends:^[5]

• Baseline CT within 3 to 4 months of surgery.
• Completely resected stage I-II thymoma: annual CT for 5 years, then every 2 years. ^[5]
• Stage III-IV thymoma, thymic carcinoma or any R1/R2 resection: CT every 6 months for 3 to 5 years, then annually. ^[2][5]
• Continue surveillance for 10 to 15 years. ^[5]

A flare of autoimmune symptoms can mark recurrence, and prompt imaging is wise. Chest CT every 6 months for 2 years then annually for 10 years is a useful alternative framing for thymoma from StatPearls.^[2]

• Of the tumour: SVC syndrome, tracheal or oesophageal compression, Horner syndrome, phrenic nerve palsy, cardiac tamponade (rare, usually with invasive disease).
• Paraneoplastic: myasthenic crisis, pure red cell aplasia with transfusion dependence, Good syndrome with recurrent infection, TAMA.
• Of surgery: respiratory failure and prolonged ventilation (especially in myasthenia gravis), phrenic and recurrent laryngeal nerve injury, pleural effusion, pneumonia, atelectasis, pneumothorax, surgical site infection and mediastinitis.^[2]
• Of adjunctive therapy: radiation pericarditis, pneumonitis, pulmonary fibrosis; chemotherapy myelosuppression and cardiac toxicity (anthracyclines); immunotherapy pneumonitis, myocarditis and hepatitis in thymic carcinoma regimens.
• Long-term: second primary malignancies in about 17 to 28% after thymectomy.^[2]
• Autoimmune monitoring: AChR antibodies remain positive and need not be re-measured to track tumour; an AChR flare should, though, trigger imaging for recurrence.^[5]

Prognosis rests on three factors: completeness of resection (R0 the strongest favourable marker), Masaoka stage, and histology (B2/B3 worse than A/AB/B1; thymic carcinoma much worse than thymoma).^[2][5] Older age and great-vessel invasion worsen recurrence-free survival. High-risk recurrence profiles (T2/T3 B2 or B3 thymoma, all thymic carcinomas, neuroendocrine tumours) usually declare within the first 3 to 6 years.^[2]

There is no screening programme for mediastinal masses. General preventive advice is non-specific: treat prolonged SVC/airway symptoms as emergencies, investigate an unexplained mediastinal widening, and in patients with myasthenia gravis arrange chest CT at diagnosis and after any change in symptoms. There is no evidence that screening changes outcomes.

• Pregnancy: Mediastinal masses in pregnancy raise anaesthetic and airway concerns; multidisciplinary management is needed. Elective imaging after delivery is often safe for a stable mass; biopsy decisions weigh fetal safety.
• Children: Neuroblastoma, germ cell tumours and lymphomas dominate; thymoma is rare in children. In younger patients, suspect an inherited or familial form (for example MEN1) when thymic tumour appears early.
• Older adults: Fibrofatty replacement means an apparent thymic mass in older adults is more likely neoplastic than hyperplasia, and surgical risk is higher.
• Immunocompromised patients: Good syndrome and pure red cell aplasia do not resolve with surgery; plan immunoglobulin replacement and haematology follow-up.

• Contrast CT is not always available. A plain chest radiograph followed by ultrasound-guided or surgical biopsy is a fallback, but CT localisation by compartment is the decision-making step that should be secured if possible.^[6]
• Where CT is available, a single contrast study usually both localises and stages the mass.
• Needle biopsy may not be available; anterior mediastinotomy or thoracoscopy then becomes the diagnostic route.
• Curative thymectomy, lymphadenectomy, radiotherapy and PAC chemotherapy require referral to a centre with thoracic surgery, medical oncology and radiation oncology.
• Laboratory planning: AFP and beta-hCG are cheap and high-yield to exclude germ cell disease in young patients.
• Histology should be obtained and reported in 10% increments for thymoma subtypes so that staging and radiotherapy thresholds can be applied.
• Long-term CT surveillance may be impractical; plain radiographs at longer intervals plus symptom review is a pragmatic substitute when CT access is limited.

• The ITMIG scheme divides the mediastinum into prevascular, visceral and paravertebral compartments; localising a mass to a compartment is the first and most useful diagnostic step.
• About half of mediastinal masses are anterior (prevascular); the four T's (thymoma, teratoma, thyroid, terrible lymphoma) remain the teaching core, with thymic cysts, thymic hyperplasia and parathyroid among the modern additions.
• Thymoma is the commonest prevascular mass in adults, accounting for about 20% of mediastinal neoplasms, and occurs in the fourth to sixth decades.
• Thirty to forty percent of thymoma patients have myasthenia gravis; up to 30% of thymoma patients have an autoimmune disorder, and only 3% of thymic carcinoma patients do.
• Pure red cell aplasia occurs in 5 to 15% of thymoma patients (ESMO quotes about 5%), and Good syndrome in under 5%; both are more common with spindle-cell (A/AB) thymoma.
• Ten to thirty percent of patients with myasthenia gravis have a thymoma; chest CT or MRI is routine in myasthenia gravis.
• CT with contrast is the standard imaging first test; MRI solves cyst and fat questions, and PET helps distinguish thymic carcinoma from thymoma but is not routine.
• A biopsy is not always needed for a typical thymoma in an older patient with myasthenia gravis, but is needed for atypical, unresectable or non-thymoma masses.
• Complete (R0) thymectomy is the treatment of choice for resectable thymoma; median sternotomy is standard, with minimally invasive approaches for early disease.
• Follow-up is long: completely resected stage I-II thymoma annually for 5 years then every 2 years; III-IV or R1/R2 disease every 6 months for 3 to 5 years, then annually, for 10 to 15 years.