Thymoma and Thymic Carcinoma
BACKGROUND
What is the embryonic derivation of the thymus?
The embryonic derivation of the thymus is the 3rd pharyngeal pouch.
Where is the thymus located, and what is its function?
The thymus is in the ant mediastinum (MN), involved in the processing and maturation of T lymphocytes to recognize foreign antigens from “self” antigens.
What structures are located in the ant, middle, and post MN?
Anterior: LNs, thymus, mesenchymal tissues
Middle: heart and great vessels, trachea, esophagus, most mediastinal LNs, vagus and phrenic nerves
Posterior: paraspinal tissues, sympathetic and peripheral nerves
What proportion of tumors of the MN are malignant?
One-third of mediastinal tumors are malignant.
How prevalent is thymoma relative to other mediastinal tumors?
Thymoma comprises 20% of all mediastinal tumors but 50% of all ant mediastinal tumors.
What is the median age and sex predilection for thymomas?
The median age for thymomas is 40–60 yrs. There is no sex predilection (male = female).
Are thymomas common in children?
No. Thymomas are extremely rare in children, but if present they are extremely aggressive with poor survival.
Pathologically, what is the most important defining feature of thymomas?
Coexistence of nonneoplastic lymphoid cells with neoplastic epithelial cells (spindle to polygonal types)
How do thymic carcinomas differ from thymomas?
Much less prevalent (<1% of thymic tumors), very aggressive, with poorer survival (5-yr OS 30%–50%)
What are the WHO designations of thymomas vs. thymic carcinomas?
WHO type is based on shape and the lymphocyte/epithelial ratio.
WHO types A–AB: benign thymoma, medullary, spindle cell
WHO types B1–B3: malignant thymoma, lymphocytic, cortical, epithelial
WHO type C: highly malignant, thymic carcinoma, clear cell/sarcomatoid types
What is the LN metastatic rate of thymomas vs. thymic carcinomas?
Thymoma: ∼1%–2%
Thymic carcinoma: ∼30%
(Kondo K et al., Ann Thorac Surg 2003 [review of 1,320 pts with thymic tumors])
What is the hematogenous dissemination of thymomas vs. thymic carcinomas?
Thymoma: ∼1% (mostly to lung)
Thymic carcinoma: 12% (lung > bone, liver)
WORKUP/STAGING
What is the DDx of a mediastinal mass by location in the ant, middle, and post MN?
Anterior: thymoma, thymic carcinoma, carcinoid, germ cell tumors, lymphomas (Mnemonic: TTT: Thymoma, Teratoma, Terrible lymphoma)
Middle: cysts > lymphoma, teratomas > sarcomas (osteosarcoma, fibrosarcoma, angiosarcoma, rhabdomyosarcoma of the heart), granuloma
Posterior: neurogenic tumors (PNET, schwannoma, neurofibroma, neuroblastoma, ganglioneuroma), pheochromocytoma
What clinical presentations are common for pts with mediastinal tumors?
About one-half are diagnosed incidentally on imaging studies. The remainder present with local symptoms (cough, shortness of breath, pain, stridor, Horner, SVC syndrome) or as an association with myasthenia gravis (MG) if thymoma.
How do pts with thymomas or thymic carcinomas usually present?
50% are incidental findings; but if there are Sx, they reflect either locally advanced Dz, metastatic sequelae, or paraneoplastic disorders (in 50%–60% of thymomas but hardly seen in thymic carcinomas).
What paraneoplastic disorders are commonly seen in thymomas?
MG (35%–50% of cases), red cell aplasia (5%), immune deficiency syndromes such as hypogammaglobulinemia (5%), autoimmune disorders (collagen vascular, dermatologic, endocrine, renal Dz), and other malignancies (lymphomas, GI/breast carcinomas, Kaposi sarcoma)
What workup should be employed for a mediastinal mass?
Mediastinal mass workup: H&P (ask about B Sx [fever >38°C, drenching night sweats, weight loss >10% in preceding 6 mos] to r/o lymphoma, physical to assess nodal status, MG Sx), basic labs (LDH, ESR, AFP/HCG to r/o germ cell tumor as needed), imaging (PA/lat CXR, CT chest, MRI, PET if lymphoma suspected), Bx (FNA, but preferably Tru-Cut core Bx) or surgical (video-assisted thoracoscopic surgery, Chamberlain), PFTs to assess lung function
The Dx of thymoma is essentially established clinically if the pt presents in what way?
Ant mediastinal mass with Sx of MG, red cell aplasia, or hypogammaglobulinemia
Approximately what % of pts with thymoma present with MG?
35%–50%. Conversely, 10%–15% of pts with MG have thymoma.
What are the pathogenesis, presentation, Dx, and Tx of MG?
Autoantibody to the acetylcholine receptor at the postsynaptic endplate. Pts present with easy fatigability, ptosis, and diplopia (worse with movement, whereas the opposite is true for Lambert-Eaton). Dx is by the Tensilon test (edrophonium). Tx is by anticholinesterase (pyridostigmine) or thymectomy (reverses in 40% of pts with thymoma).
What is the Modified Masaoka system used to stage thymomas?
Stage I: fully encapsulated, no microscopic capsular invasion
Stage IIA: microscopic invasion into capsule
Stage IIB: macroscopic invasion into surrounding fat or mediastinal pleura
Stage III: macroscopic extension to surrounding organs (lung, pericardium) without great vessel invasion (A) or with great vessel invasion (B).
Stage IVA: pleural or pericardial dissemination
Stage IVB: +LN or DM
Is there controversy regarding the Masaoka staging system for thymoma?
Yes. UCLA retrospective meta-analysis of ∼2,500 patients showed no difference in DFS or OS between stages I and II patients (Gupta R, Arch Pathol Lab Med 2008)
What are the 5-yr survival rates for thymomas based on the Masaoka staging?
5-yr survival for thymomas (Masaoka staging):
Stage I: 95%
Stage II: 90%
Stage III: 60%
Stage IV: 11%–50%
What is the 5-yr survival rate of invasive vs. noninvasive thymomas?
Invasive: 50%
Noninvasive: 70%
What are the most important prognostic factors for thymomas?
The Masaoka stage and completeness of resection are the most important prognostic factors for thymomas.
Based on modern surgical series, what are the rates of complete resection, the recurrence rate, and 5-yr OS based on Masaoka staging?
Kondo et al. reported outcomes for 1,320 pts. The % of complete resection, % of recurrence, and 5-yr OS, respectively, were as follows:
Stage I: 100%, 1%, 100%
Stage II: 100%, 4%, 98%
Stage III: 85%, 28%, 89%
Stage IVA: 42%, 34%, 71%
(Ann Thorac Surg 2003)
Is the Masaoka staging useful for thymic carcinoma?
Controversial. Although the Masaoka staging is also applied for thymic carcinomas, a MSKCC series of 43 patients failed to find association of Masaoka staging with survival. (Blumberg D, J Thorac Cardiovasc Surg 1998)
What are the most important prognostic factors for thymic carcinomas?
The completeness of resection, invasion of innominate vessels, and presence of LN mets are the most important prognostic factors for thymic carcinomas.
What is the 5-yr survival rate for thymic carcinoma?
The 5-yr OS for thymic carcinoma is 20%–30%.
TREATMENT/PROGNOSIS
What is the most important modality in the management of thymomas?
Surgery is the mainstay of Tx, with complete resection being the primary goal. The outcome is fully dependent on the extent and completeness of the resection, regardless of stage or histology. Surgical clips can help identify areas difficult to resect or possible residual Dz. It may even be reasonable to resect pleural mets since prolonged survival is possible.
What is the usual approach for the surgical management of thymomas?
Median sternotomy, but more extensive resections may be required depending on the stage at presentation, including partial or total pneumonectomy or pericardiectomy.
In a thymoma pt with MG, what should be done preoperatively?
Signs + Sx should be controlled medically prior to undergoing surgical resection.
How is thymic carcinoma generally managed?
If possible, max surgery → CRT postoperatively. If inoperable, consider induction therapy with chemo, RT, or combination CRT.
When is adj radiotherapy a reasonable indication for the management of thymic malignancies?
Adj radiotherapy should be considered with stages III–IVA, +/close margins, or any thymic carcinoma.
Is adj radiotherapy necessary for a stage II thymoma after complete resection?
This is controversial. It initially was recommended based on a classic review (Curran W et al., JCO 1988) in 103 pts with thymomas, finding that pts without PORT had ↑LR (6 of 19 pts for stage II) vs. no LR in PORT (0 of 1 pt for stage II, 0 of 4 pts for stage III). More recent data out of the Massachusetts General Hospital (Mangi A et al., Ann Thorac Surg 2002) and Japan (Haniuda M et al., Ann Surg 1996) showed that PORT may not be necessary after complete resection for stage II pts. Haniuda et al. demonstrated that stage II thymoma with macroscopic adherence to the pleura did benefit from PORT (LR 36% vs. 0%), but PORT was not useful for microscopic invasion of the pleura or pericardium.
Meta-analysis (Korst RJ et al., Ann Thorac Surg 2009): 1981–2008 systematic review of 13 studies, 592 pts, ∼42% had surgery + PORT. The LR rate did not benefit from PORT for stages II–III thymoma (OR 0.87 for both stages II–III, p = 0.69).
Forquer JA et al.: 901 pts, SEER data 1973–2005; 92% thymoma, 8% thymic carcinoma (TC); localized Dz in 274 pts, regional Dz in 626 pts. 5-yr OS benefited from surgery + PORT for regional Dz (76% vs. 66%, p = 0.01); for localized Dz, surgery alone was more favorable (98% vs. 91% [PORT], p = 0.03). (IJROBP 2009)
Current recommendation for adj RT for stages II–III thymoma: +/close margin (<1 mm), gross fibrous adhesion to pleura, or ↑ WHO grade (B3) tumors (Wright CD et al., Hem Oncol 2008)
What should the postop target volume include?
The postop target volume should include the entire bed of resection and any involved organs. It is imperative to have a preop CT scan available to help delineate tumor bed volumes. Also, information from operative and pathology reports may help determine areas that might have had adherent, invasive Dz. For high-risk disease, consider elective LN coverage.
What are the RT doses used for the postop management of thymic malignancies?
Depends on the extent of resection:
If R0: 45–54 Gy
If R1: 55–60 Gy
If R2: 60–70 Gy
When should postop concurrent chemotherapy be considered with RT for the management of thymic malignancies?
Per NCCN 2014, thymoma with gross residual Dz (R2 resection) or thymic carcinoma with R1-R2 resection
What are some management approaches for unresectable thymic tumors?
Management approaches for unresectable thymic tumor:
1. Induction chemo → RT only
2. Induction chemo → surgery → PORT
3. Induction RT/CRT → surgery → ± more RT
What are the results of definitive RT for unresectable thymic tumors?
RT can be used as the sole modality, with 5-yr OS 50%–87%. Surgery should be done whenever possible, however, since resectability is still the most important prognostic factor.
Given the good response rates seen with platinum-based chemo, what is the current preferred Tx paradigm for unresectable thymic malignancy?
Unresectable thymic malignancy Tx paradigm:
1. Chemo → RT (no surgery) (Loehrer PJ et al., JCO 1997). Cisplatin/doxorubicin/cyclophosphamide (PAC) 2–4 cycles → RT to ≥54 Gy to primary + regional LN. 5-yr OS was 53%.
2. Chemo → surgery (if possible) → PORT (MDACC: Shin DM et al., Ann Int Med 1998). 3 cycles induction chemo (Cytoxan/Adriamycin/cisplatin [CAP] + prednisone) → max surgery → RT. 7-yr follow-up showed 100% OS and 73% DFS.
What RT dose can be used for the neoadjuvant management of unresectable thymomas?
24–30 Gy with chemo → surgery → then consideration for more RT depending on resection status
What are the 1st-line combination chemo regimens used for the management of thymic malignancies?
CAP +/– prednisone; VP-16/ifosfamide/cisplatin (VIP); cisplatin/VP-16 (EP); carboplatin/Taxol; cisplatin/Adriamycin/vincristine/Cytoxan (ADOC); Cytoxan/Adriamycin/vincristine/prednisone (CHOP)
What are the typical response rates with induction chemo for the management of thymic malignancies?
Typical response rates with induction chemo are 50%–60%.
TOXICITY
What is the follow-up for pts who have had a complete resection of a thymoma?
Completely resected thymoma follow-up: H&P + annual CT chest
Is 5 yrs of follow-up sufficient for a pt treated for thymomas?
No. Late recurrences can occur at >10 yrs. Pts need lifelong follow-up.
What are the expected early and late toxicities after adj RT for the management of thymic tumors?
Early: skin reaction, fatigue, dysphagia/odynophagia, cough
Late: RT pneumonitis/fibrosis, pericarditis, esophageal stricture, myelitis
What are the dose-limiting structures and dose limits when the MN is irradiated?
Lung: RT alone → V20 <40%; CRT → V20<35%, V5<65%, mean lung dose <20 Gy (per NCCN 2014)
Heart: V40 <50% (V40 <40% if CRT)
Spinal cord: ≤45 Gy
Esophagus: Ideally, the mean dose of RT to the esophagus should be <34 Gy. Try to minimize the V60 as much as possible (V60 <33%, V50 <50%, ≤45 Gy to the entire esophagus, max dose point <70 Gy).
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