Radiation Oncology/Thymoma/Overview

Thymoma Overview

Epidemiology

• Arises from thymus epithelial cells
• Mostly considered indolent, but does have potential for local invasion, pleural dissemination, and distant metastases
• Malignant thymoma (see below, but in the SEER study defined as microscopic or macroscopic evidence of invasion) is rare; there were 849 cases in US SEER database between 1973-1998 (incidence 0.15/100,000)
• Age typically 40-60 years; though highest incidence in 70's
• M:F ~1:1
• 20% of primary mediastinal neoplasms in adults
• Risk factors:
  • Myasthenia gravis in 35-50% (conversely, 75% patients with MG have thymus abnormalities, of these 85% have hyperplasia and 15% have thymoma)
  • Red cell aplasia in 5%
  • Hypogammaglobulinemia in 5%
  • Ionizing radiation
• Clinical presentation:
  • ~1/3 asymptomatic, found incidentally on CXR
  • ~1/3 local symptoms (chest pain, neck mass, SVC syndrome
  • ~1/3 concurrent diagnosis with myasthenia gravis

• SEER; 2003 (1973-1998) PMID 12712448 -- "Malignant thymoma in the United States: demographic patterns in incidence and associations with subsequent malignancies." (Engels EA, Int J Cancer. 2003 Jul 1;105(4):546-51.)
  • Population study. Malignant thymoma (vs. benign thymoma and possibly vs. thymic carcinoma) reviewed. 849 cases (0.15/100,000). Male slightly more than females. Highest incidence in Pacific Islanders (0.49/100,000)
  • Follow-up malignancies: Sarcoma 11.1x, NHL 4.7x (all after RT), GI cancers 1.8x

Anatomy

• Mediastinum borders
  • Superior: thoracic inlet
  • Inferior: diaphragm
  • Anterior: sternum
  • Posterior: vertebral column
  • Lateral: parietal pleural
• Thymoma typically presents in the anterior/superior mediastinum
• Spread is mainly local invasion; pleural mets may occur in more advanced disease

Histology

• Thymus is unique among human organs because its "normal" appearance varies considerably depending on age of the patient
  • At birth, weight is 10-35gm
  • Functional maturity during childhood/adolescence, with weight 20-50gm
  • In adults, progressive atrophy of thymic tissue, and replacement with fat
  • In elderly, weight 5-15gm
• Two predominant cell types in normal thymus
  • Thymic epithelial cells
  • Lymphocytes (T-cell lineage)
• Thymus anatomy
  • Two fused lobes, comprising of multiple lobules
  • Each lobule has an outer cortex and inner medulla
• Thymic epithelial tumors arise from thymic epithelial cells, but due to the role of thymus in lymphocyte maturating, they may predominately contain lymphocytes
• There are multiple classifications of thymic epithelial tumors, making things confusing for clinicians
  • The WHO 1999/2004 morphologic classification is the most commonly accepted, and has been shown to have correlation with clinical behavior and outcome
  • A proposal has been made for a more simplified classification parallel to other carcinomas (thymoma, atypical thymoma, thymic carcinoma)

Bernatz Classification System for Thymoma (1961)

• Spindle Cell (favorable outcome)
• Lymphocytic
• Epithelial (aggressive)
• Mixed (aggressive)

WHO Classification of Thymic Epithelial Tumors (1999/2004) - based on shape and lymphocyte/epithelial ratio

• Thymoma (Type A, B, and AB)
  • Type A - Spindle/ovoid shape, homogeneous neoplastic cells, few lymphocytes; equivalent to "spindle cell tumor"
  • Type AB - Mix of Type A and Type B, with foci rich in lymphocytes
  • Type B - Round/polygonal shape, with varying proportion of lymphocytes/epithelial cells, and increasing degree of atypia
    • Type B1 - Resembles normal thymus, with areas resembling both cortex and medulla. Few neoplastic epithelial cells, predominance of lymphocytes; equivalent to "lymphocyte-rich tumor"
    • Type B2 - Increased number of epithelial thymic cells, among populations of lymphocytes; equivalent to "mixed tumors"
    • Type B3 - Predominately neoplastic epithelial cells, more atypia, with few lymphocytes
• Thymic carcinoma (Type C)
  • Over features of malignancy independent of shape, no immature lymphocytes
  • Multiple histologic subtypes

Suster and Moran (1999) - based on degree of differentiation; PMID 16627265

• Thymoma - well differentiated
• Atypical thymoma - moderately differentiated
• Thymic carcinoma - poorly differentiated

• Osaka; 2002 PMID 11857293 -- "The World Health Organization histologic classification system reflects the oncologic behavior of thymoma: a clinical study of 273 patients." (Okumura M, Cancer. 2002 Feb 1;94(3):624-32.)
  • Retrospective. 273 with thymoma (no thymic carcinoma).
  • Invasive by class: A 11%, AB 42%, B1 47%, B2 69%, B3 85%
  • Great vessel invasion by class: A 0%, AB 4%, B1 7%, B2 17%, B3 19%
  • 20-year OS: A 100%, AB 87%, B1 91%, B2 59%, B3 36%
  • By Masaoka stage: I 89%, II 91%, III 49%, IV 0%
  • Multivariate predictors: Masaoka and WHO class; not related R-status, great vessel involvement
  • Conclusion: WHO histologic appearance reflects oncologic behavior

Work-Up

• CT scan
• MRI yield over CT minimal
• Serum AFP and b-HCG to rule out germ cell tumors

• UCLA; 2008 -- PMID 18517274 -- "Evidence-based pathology and the pathologic evaluation of thymomas: transcapsular invasion is not a significant prognostic feature." (Gupta R, Arch Pathol Lab Med. 2008 Jun;132(6):926-30.)
  • Meta-analysis. 21 retrospective publications, 2451 cases (Stage I 1419, Stage II 1032)
  • Outcome: No difference in DFS or OS for Stage I and Stage II
  • Conclusion: Evaluation of transcapsular invasion is of no clinical value in tumors that lack invasion of neighboring organs or the pleurra

• MSKCC; 1999 (1949-1993) PMID 9475524 -- "Thymic carcinoma: current staging does not predict prognosis." (Blumberg D, J Thorac Cardiovasc Surg. 1998 Feb;115(2):303-8; discussion 308-9.)
  • Retrospective. 43 patients, Masaoka Stage I 7%, Stage II 35%, Stage III 47%, Stage IVA 11%. Well-differentiated 16/43, type II malignant thymomas 27/43
  • Outcome: OS 5-years 65%, 10-years 35%; recurrence rate 65% and 75%
  • Predictors: multivariate only invasion of innominate vessels, not age, sex, size, or Masaoka stage
  • Conclusion: high rate of recurrence; invasion of the innominate vessels poor sign. Masaoka staging not useful for thymic carcinoma, only for thymoma
  • Masaoka comment: PMID 10047676

Treatment Overview

• Total thymectomy with en bloc removal of all affected structures is the surgical procedure of choice. Degree of resection appears to affect prognosis (GTR > STR > biopsy alone)
• Patients with Stage I disease and R0 resection do not need adjuvant treatment
• Adjuvant treatment of patients with Stage II disease is controversial; adjuvant RT may be indicated
  • Recent pathological meta-analysis (see above, PMID 18517274) suggests that there is no difference in outcome between Stage I and IIa
  • If pleural invasion (T2b), should consider RT
  • If close (<1mm) surgical margin, can consider RT
  • If "higher" grade (e.g. WHO B3), can consider RT
• Adjuvant RT appears indicated with Stage III/IVA or subtotal resection (R1 or R2)
  • NCCN Adjuvant Guidelines (2012) - Conventional fractionation (1.8-2Gy per fraction)
    • 45-50 Gy for clear margins
    • 54 Gy for residual microscopic disease
    • 60 Gy for gross residual disease
  • NCCN for Unresectable Disease - 60-70 Gy with conventional fractionation (1.8-2Gy per fraction)

Adjuvant Radiation Therapy

Randomized

• Peking; 1999 (China)(1981-1996) PMID 11593579 -- "Postoperative radiotherapy for stage I thymoma: a prospective randomized trial in 29 cases." (Zhang H, Chin Med J (Engl). 1999 Feb;112(2):136-8.)
  • Randomized. 29 patients, Stage I, age <65 years. Arm 1) surgery alone vs. Arm 2) surgery + adjuvant RT. RT AP and/or two anterior oblique wedge fields. If lymphocytic predominant, used 50 Gy/25 fractions, if epithelial/mixed used 60 Gy/30 fractions.
  • Outcome: No recurrence or metastases in either group; 10-year OS surgery 92% vs. surgery + RT 88% (NS)
  • Conclusion: Adjuvant RT not necessary for Stage I thymoma

Retrospective

• Indiana University/SEER; 2010 (1973-2005) PMID 19427738 -- "Postoperative radiotherapy after surgical resection of thymoma: differing roles in localized and regional disease." (Forquer JA, Int J Radiat Oncol Biol Phys. 2010 Feb 1;76(2):440-5. Epub 2009 May 8.)
  • SEER database analysis. 901 patients with thymoma or thymic carcinoma, surgically resected; excluded patients dying within 3 months after surgery. SEER localized (Masaoka Stage I) stage 275 (31%), regional (Masaoka Stage II-III) stage 626 (69%). Post-op RT in 65%
  • Outcome:
    • SEER localized disease - Radiation may cause adversely impact 5-year cause-specific survival (CSS) PORT 91% vs. No PORT 98% (SS).
    • SEER regional disease - 5-year CSS 91% vs 86% (NS); 5-year OS 76% vs 66%
  • Conclusion: Postop RT no benefit in Masaoka Stage I, but possible OS benefit in Stage II-III

• Israel; 2007 (1984-2003) PMID 17762439 -- "Adjuvant radiotherapy for thymic epithelial tumor: treatment results and prognostic factors." (Kundel Y, Am J Clin Oncol. 2007 Aug;30(4):389-94.)
  • Retrospective. 47 thymic tumors treated by adjuvant RT (thymoma 78%, thymic carcinoma 12%; Stage II 70%, Stage III 26%, Stage IVA 4%). RT dose 26-60 Gy. Median F/U 10.6 years
  • Outcome: 5-year OS 73% (thymoma 77% vs. thymic carcinoma 33%, SS), DFS 67%, median time-to-recurrence 8.3 years
  • Stage II 5-year OS: RT dose <=45 Gy 59% vs. >45 Gy 100%; DFS 37% vs. 100%
  • Predictors: lower disease stage (II vs. III/IV), surgery (resection vs. bx), higher RT dose (<=45 vs. >45 Gy). Thymic carcinoma histology no impact on OS, only DFS
  • Conclusion: Post-op RT should be >45 Gy, may improve DFS and OS, especially stage II

• Okinawa; 2002 (Japan)(1979-1998) PMID 11920495 -- "Postoperative radiotherapy for patients with completely resected thymoma: a multi-institutional, retrospective review of 103 patients." (Ogawa K, Cancer. 2002 Mar 1;94(5):1405-13.)
  • Retrospective. 103 patients, completely resected thymoma + adjuvant RT. Masaoka Stage I 17%, Stage II 59%, Stage III 24%. RT median 40 Gy, 51% IFRT vs. 49% whole mediastinum. No chemo. Median F/U 9.3 years
  • Outcome: 10-year OS 81%, Stage I 100%, Stage II 90%, Stage III 48%
  • Recurrence: Stage I 0%, Stage II 10%, Stage III 44%; no recurrence in-field, 70% within pleura. If no pleural invasion initially, 0% pleural failure; but if pleural invasion initially, then 38% pleural failure. No dose-response seen (<40 Gy vs. 40 Gy vs. >40 Gy)
  • Conclusion: RT to 40 Gy effective, if pathologic pleural invasion, mediastinal RT insufficient

• FNCLCC; 1995 PMID 7790251 "Radiotherapy and chemotherapy for invasive thymomas: a multicentric retrospective review of 90 cases." (Mornex, Int J of Radiat Onc, Biol, Phys. 1995; 32(3): 651-9)
  • Retrospective review of 90 cases tx'd with incomplete surgery or bx alone, GETT III-IVa. Pts received surgery + xrt (median 50 Gy to tumor bed + margin, 2/3 tx'd to supraclav).
  • Cumulative local control at 8.5 yrs was 66%; if subtotal resection local control at 5yr 64% vs 39% if bx alone. Conclusion: Need >50 Gy given the high rate of local failure w/ +margins/bx alone.

• Fox Chase; 1988 PMID 3183702 -- "Invasive thymoma: the role of mediastinal irradiation following complete or incomplete surgical resection." (Curran, JCO 1988; 6(11): 1722-7)
  • Retrospective. 103 patients with thymoma. Masaoka Stage I 42%, Stage II 20%, Stage III 35%, Stage IV 3%
  • 5-year outcome: OS Stage I 67%, Stage II 86%, Stage III 69%; RFS 100%, 58%, 53%
  • Recurrences: R0 Stage I 0%; R0 Stage II-III no RT 53% vs. +RT 0%; also compared with R1/R2 Stage II-III +RT 21%. Recurrence rate for entire cohort: no RT 28% vs. +RT 5%
  • Conclusion: R0 resection alone inadequate in Stage II-III

Review

• MGH; 2007 PMID 17570676 -- "Management of thymomas." (Wright CD, Crit Rev Oncol Hematol. 2007 Jun 12 [Epub ahead of print])