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 thumb 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 pleura 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])