Thymoma

Overview

• Origin: the thymus has 2 main cell types, epithelial cells and lymphocytes; both thymomas and thymic carcinomas arise from thymic epithelial cells.
• Thymoma: abundant immature lymphocytes (T cells), relatively indolent. Most common thymic malignancy.
• Thymic carcinoma: scant lymphocytes, behaves like other carcinomas. Worse prognosis; more often has nodal and distant hematogenous mets (lung, liver, bone) than thymoma. Subtypes: squamous (most common), adenocarcinoma, NUT carcinoma, salivary-gland-like, undifferentiated, NOS.
• NUT carcinoma: BRD4::NUTM1 (or BRD3::NUTM1) fusion; BRD4/BRD3 are BET-family genes, NUTM1 (formerly NUT) is the non-BET fusion partner. Very rare, aggressive midline tumor. Historical mOS ~5 to 7 mo (6.7 mo Bauer 2012, 6.5 mo Chau 2020); case series 2-yr OS ~30%.
• Anterior mediastinal mass, "4 Ts" mnemonic: Thymoma, Teratoma (germ cell), Thyroid, Terrible lymphoma (and sometimes "C" for Carcinoid).

Paraneoplastic syndromes

• Myasthenia gravis (MG): anti-AChR (acetylcholine receptor) antibodies.
  • ~30 to 50% of thymomas have MG (more common in thymoma, rare in thymic carcinoma).
  • >60% of MG pts have benign thymic (follicular) hyperplasia; separately, ~10 to 15% of MG pts have a thymoma.
  • ~10 to 15% of MG pts have a thymic malignancy.
  • MG often improves after thymectomy (definitive in many cases).
• Pure red cell aplasia (PRCA): T-cell-mediated suppression of erythroid progenitors, in ~2 to 5% of thymomas (rare in thymic carcinoma). Thymectomy alone resolves only ~25 to 38%; most need immunosuppression (usually cyclosporine).
• Hypogammaglobulinemia (Good syndrome): recurrent sinopulmonary infections; persists after surgery, IVIG required.
• Other autoimmune: SLE, polymyositis, dermatomyositis, autoimmune cytopenias.

Diagnosis

• Histology varies by WHO type: A spindle-oval epithelial cells with few lymphocytes; AB mixed, type A areas plus lymphocyte-rich areas; B1/B2 epithelioid epithelial cells with abundant immature TdT+ thymocytes; B3 epithelial-rich with few thymocytes.
• IHC: cytokeratin (AE1/AE3, CK7) distinguishes thymoma from nonepithelial malignancies; PAX8+, TTF-1−. CD5+ supports thymic carcinoma.
• Upfront resection if resectable (analogous to testicular ca, do not biopsy first). Well-defined anterior mediastinal mass in thymic bed, negative tumor markers, LN−, no continuity with thyroid.
• If unresectable or poor surgical candidate: CT-guided core needle biopsy via anterior approach; avoid transpleural route to prevent pleural/mediastinal tract seeding.

Staging: Masaoka-Koga and AJCC/UICC 9th ed (supersedes 8th): T1a <=5 cm vs T1b >5 cm, mediastinal pleura dropped, lung/phrenic-nerve invasion now T2 (was T3)

Treatment

• Upfront surgery, complete thymectomy via median sternotomy (or VATS/robotic for selected stage I/II).
• Adjuvant therapy by margin/stage:
  • R0 + completely encapsulated (stage I): surveillance.
  • R0 + capsular invasion or stage II to IV: consider adjuvant RT.
  • R1 (microscopic +): adjuvant RT (thymoma); RT +/- chemo (thymic carcinoma).
  • R2 (gross residual): adjuvant RT +/- chemo (thymoma); RT + chemo (thymic carcinoma).
  • Surveillance: contrast CT q6mo × 2 yrs, then annually × 5 yrs (thymic carcinoma) or × 10 yrs (thymoma).
  • Poor prognostic factors: ↑ WHO histologic type (B3), tumor >10 cm, tracheal/vascular compression, age <30, R1/R2 margins, thymic carcinoma histology.

• Neoadjuvant chemo (CAP, cisplatin/doxorubicin/cyclophosphamide; or EP, cisplatin/etoposide) to ↑ chance of R0 resection → consider surgery if resectable. Controversial; benefit not proven by RCT.

• Thymoma 1L: CAP +/- prednisone, or cisplatin/etoposide +/- ifosfamide, or ADOC (CAP + vincristine).
• Thymic carcinoma 1L: carboplatin + paclitaxel.
• Refractory / 2L+:
  • Lenvatinib (REMORA phase 2): ORR 38%, mPFS 9.3 mo in pretreated thymic carcinoma. NCCN-listed; most active TKI in thymic carcinoma.
  • Sunitinib (Rajan phase 2): ORR 26%, mPFS 7.2 mo in thymic carcinoma. Less active in thymoma.
  • Pembrolizumab (Giaccone phase 2): ORR 23% in thymic carcinoma; ↑↑ immune-related AE rate (myocarditis, myositis, hepatitis), caution in thymoma especially with MG.
  • Lenvatinib + pembrolizumab (PECATI phase 2, ESMO 2024): pretreated B3-thymoma/thymic ca, 5-mo PFS rate 88.4%, mPFS 14.9 mo. Promising; manageable tox.
  • Everolimus (RADD phase 2, Zucali JCO 2018): mPFS 10.1 mo overall (thymoma 16.6 mo, thymic ca 5.6 mo).
  • Octreotide +/- prednisone: for octreoscan+ thymomas.
  • Other 2L+ single agents: pemetrexed, gemcitabine +/- capecitabine, 5-FU/leucovorin, paclitaxel, etoposide, ifosfamide.
  • IO caution: pembrolizumab can trigger fulminant myocarditis/myositis in thymoma, screen for MG, monitor closely, avoid in pts with active autoimmune syndromes.

High-yield pearls

• Thymoma + MG: MG often improves post-thymectomy; ~30 to 50% of thymomas have MG.
• Avoid pembrolizumab in thymoma with active autoimmune disease (myocarditis/myositis risk).
• Lenvatinib is the most active TKI in thymic carcinoma (REMORA).
• PECATI (lenvatinib + pembrolizumab), emerging combination for refractory disease.
• Surgery first if resectable (like testicular ca); avoid biopsy when possible (tract seeding).
• Anterior mediastinal mass DDx, 4 Ts.
• PRCA (~2 to 5% of thymomas) and hypogammaglobulinemia (Good syndrome) are other high-yield thymic paraneoplastic syndromes.