Thymoma ESMO 2008

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Thymic Malignancies

Egbert F. Smit, Dept. Pulmonary Diseases, Vrije Universiteit Medisch Centrum Amsterdam, The Netherlands

Thymoma A Rare Disease 3.32/1.000.000/year

de Jong et al. Eur. J. Cancer, 441,123,2008.

Thymoma: Where is the evidence? PUBMED search 1998-2008: Reviews: 203 hits Randomised controlled trials: 1 hit Clinical trial (Phase II studies): 9 hits

Cochrane data base: Systematic reviews: 1 hit

Practice Guideline: 1

Thymoma: Who is the expert?Can you tell us anything on diagnosis and treatment of thymoma?

Outline Clinical presentation Classification Treatment Surgery Radiotherapy Chemotherapy

Clinical Presentation 1/3 - 1/2 : asymptomatic mass (radiology) 40-50 years, no sex predisposition Local symptoms : cough, dyspnea, dysphagia, chest pain. Systemic symptoms : fever, weight loss, anorexia. Paraneoplastic syndromes 5-10%

Paraneoplastic Syndromes Pure red cell aplasia Neutrophil hypoplasia Pancytopenia Cushings syndrome Carcinoid syndrome DiGeorge syndrome Lambert-Eaton Syndrome Nephrotic syndrome SIADH Whipples disease Lupus erythematosis Pemphigus Scleroderma Polymyositis Polyneuritis Polyarthropathy Addisons disease Hypogammaglobulinemia

Myasthenia GravisTHYMOMA (8.5-15%) HYPERPLASIA (65%)

Age Mass CT density Calcification Position Thymectomy

40-50 yr (>30 y) Round >Muscle 20% Unilateral or midline Improves 25%

< 30 yr Elongated Fat

Bilateral Cure 30% Improves 70%

Thymoma usually presents as an anterior mediastinal mass.

Mediastinal Mass: Imaging CT-SCAN = Gold standard (91% sens., 97% spec.)- precise localization - near junction of heart and great vessels - round or oval with smooth or lobulated margins - protrusion to one or both sides of mediastinum - determination of nature and calcification (HU) - homogeneity: cystic (40%),nodular components necrotic (25%) - calcified (capsule) in 20% - contrast enhancement (vascular structures) - continuity with other structures/invasion

CT Findings: Thymoma

CT Findings: Thymoma

Size and Symptoms A case with severe myasthenia gravis

18FDG-PET

and Thymoma FDG PET useful in staging SUV predicts clinical behaviour In MG differentiation between hyperplasia and thymoma

Sung YM et al. J. Nucl. Med. 47,1628,2006

ANTERIOR MEDIASTINAL MASSTHYMUS Thymolipoma Thymic cyst Thymic hyperplasia Ectopic thyroid Ectopic adenoma Lipoma Thymoma Thymic CA Thymic carcinoid Substernal goiter carcinoma

THYROID PARATHYR OID FAT

Liposarcoma

ANTERIOR MEDIASTINAL MASSBenign LYMPH NODES Castlemans disease Mononuclueosis infectiosa Granuloma Malignant (Non) Hodgkins disease Metastatic carcinoma

GERM CELL RESTS

Teratoma

Seminoma Non Seminoma

OVERALL INCIDENCE OF MEDIASTINAL TUMORS/MASSESAdults Neurogenic Thymic Cysts Lymphoproliferative Germ cell Mesenchymal 23% 19% 18% 12% 12% 8% Children 39% 3%

Ref. : Shields TW. Mediastinal surgery 1991, pp. 111-117. Combining 9 series adults). Miscellaneous ( 600 children and 2200 8%

INCIDENCE OF ANTERIOR MEDIASTINAL TUMORSADULTS CHILDREN Thymic Lymphoproliferative Mesenchymal Germ cell 47 % 22 % 16 % 15 % 16% 45 % 15 % 24 %

Ref. : Mullen B et al, Ann Thorac Surg 1986 ; 42 : 338-45.

MEDIASTINAL MASS : DIAGNOSTIC APPROACHHistory & Physical Exam: signs & symptoms Laboratory tests Imaging techniques Tissue diagnosis: biopsy or excision (surgical)

MEDIASTINAL MASS : TISSUE DIAGNOSIS CT guided TTBX Bronchoscopy/Esophagoscopy Mediastinoscopy : cervical (Carlens) extended-substernal (Ginsberg) Mediastinotomy : anterior-parasternal (Chamberlain) VATS/Thoracoscopy Sternotomy Thoracotomy

Pleural and pericardial seedlings after previous biopsy

THYMUSThe thymus contains Epithelial elements Lymphoid elements Stroma Neuroendocrine cells Germ cells Corresponding tumour Thymoma Lymphoma Sarcomas Neuroendocrine tumours (carcinoids) Germ cell tumours

1999 WHO histological classification Basis : combination of morphology of neoplastic epithelial cells and ratio of these to non-neoplastic lymphoid cells Combination of letters and numbers Letters = tumour pattern Numbers = increasing epithelial/lymphocyte ratio and atypia

WHO classification A = atrophic, represents thymic cells of adult life B = bioactive, represents the biologically active organ of the foetus and infant C = carcinoma

The WHO Classification System:tnelodni evisser gga

A AB B1 B2 B3 C

Medullary Mixed type Predominant cortical Cortical Well diff. thymic ca. SCC, undiff. ca., lymphoepith.-like ca.

Lymfo

Epithelial component

Thymoma WHO B1

CD3 Lymphocytic component

CK5/6 Epithelial component

Thymoma WHO B3

Epithelial component

Mediastinal Carcinoid

gniniats 65 DC

Mediastinal Large B-cell lymphoma with sclerosis.

TH. Oo et al. J. Clin. Oncol. 21;4249,2003

Mediastinal Rhabdomyosarcoma arising in thymus

Panasuk et al. J. Clin. Oncol. 21,4455.2003

Survival according to the WHO classification.

Okumura et al. Cancer 95,420429,2002

Evidence Based Pathology Meta-analysis of all studies since 1997. Poor reproducibility Kappa stats: 0.49 for B types thymoma

No significant survival differences Type A/AB/B1 similar survival Type B2 and B3 different survival Regroup WHO classification?

Survival by stage could not be analyzed

Marchevsky et al. Cancer 112,2780,2008.

DISTINCTION BETWEEN BENIGN & MALIGNANT THYMOMACell of origin is epithelial Cannot be based on histology : most invasive thymomas are cytologically benign Malignant nature is determined by invasion (30%)

The Modified Masaoka Staging System:Stage I: Completely encapsulated tumor(40%) Stage II: Micro- or macroscopic invasion into adjacent mediastinal tissue (14%) Stage III: Macroscopic invasion into surrounding structures (34%) Stage IV-A: Distant pleural metastases (9%)

Survival according to the Masaoka staging systemN=282

Okumura et al. Cancer 94,624632,2002

Typical 10 - 20 yr. survival according to Masaoka stageStage I Stage II Stage III Stage IVa Stage IVb 90 - 100 % 90 - 100 % 50 - 90 % 0 - 30 % 0%

Survival according to Masaoka stage and pathology (WHO)

Chen et al. Cancer 95,420-429,2002

Pathology is an indpendent risk factor in Masaoka stage I and II

Chen et al. Cancer 95;420-429,2002

PROGNOSIS The 3 most important prognostic factors: complete resection, stage (Masaoka) WHO classification

Thymomas - treatment Surgery Chemotherapy Radiotherapy A combination of all three

THYMOMA: THERAPY Resectable disease Potentially resectable: operative exploration and resection Potentially resectable recurrences: operative exploration and resection Intraoperative irresectable: debulking (?)

Surgical approaches Median sternotomy

Surgical approaches"Clamshell" incision

Pathology: Type B2 thymoma microscopic invasion into fatty tissue

Survival according to type of resection.

Okumura et al. Cancer 94,624629,2002

Recurrent thymoma Can occur very late : mean time to recurrence of 84 86 mo in 2 studies 10 30 % after complete resection Survival curves after re-resection are not that different from "first time" ones

Thymoma: treatment of recurrences

Blumberg, Ann. Thor. Surg,1995.

sraey

THYMOMA: ROLE OF RADIOTHERAPY Radical postoperative (40-60 Gy, 1.8 2.0 Gy/d) in incompletely resected stage III-Iva Radical postoperative in completely resected stage III (30-58.7 Gy, 1.8 2.0 Gy/d) Radical postoperative in completely resected stage II debated.

Current Indications Radiotherapy (VUMc)Stage I Stage II Stage III Stage IV Never Only in high-risk cases (50 Gy) Routinely (50 Gy) In stage IVa, where feasible

noisicxe lacigrus etelpmoC secnerrucer lacigrus-tsoP esaesid elbareponI

Re-excision (if possible), followed by radiotherapy (when feasible) Chemotherapy, followed by one (or more) local treatments

Surgery vs surgery plus radiotherapy in completely resected Masaoka stage II

Singhal et al. Ann. Thor. Surg. 76,1635-1642,2003

Stage II Thymoma: Subgroups at high risk for recurrence Local recurrence in 20%. Local relapses increased in WHO subtypes B2-3. Microscopic invasion into fatty tissue or mediastinal pleura (Masaoka stage IIb): 40% 10year DFS Macroscopic invasion (Masaoka IIa): 70% 10-year DFS

Risk for Radiation Pneumonitis

Combined Modality Treatment In Stage III/IVa Thymoma. 45-50% irresectable disease at presentation. High-dose radiotherapy: 5-year survival 3050% Radical surgery & post-op RT, 5-year survival + 60%. Incomplete resection & post-op RT 50% local failures,, 5-year survival 30 - 40%. Cx-RT 5-year survival 53% Cx-RT-Surgery 5 year survival 70%

What Chemotherapy?

Single Agents in ThymomaAgent No. of patients 1 1 1 1 1 1 4 1 1 1 12 3 2 2 1 5 1 24 17 Steroids Cisplatin Maytansine Cisplatin Cisplatin Cisplatin Maytansine Cisplatin Cisplatin Cisplatin Steroids b Doxorubicin Vincristine Chlorambucil Nitrogen mustard Ifosfamide Steroids Cisplatin Cisplatinca b Corticotropic

Complete remission (%) 1 (100) 1 (100) 1 (100)a 2 (17) 2 (40) 6 (35)

Partial remission (%) 1 (100) 1 (100) 1 (100) 1 (100) 1 (100) 2 (50) 1 (100) 8 (67) 2 2 (40) 1 (100) 2 (8) 5 (29)

Duration of response (mos) 13 101 4 1 1.5, 4.5 201 2424 1

Survival (mos) 13 1

Reference Sofer et al., 1952 Talley et al., 1973 Jaffrey et al., 1980 Needles et al., 1981 Hetty and Arora, 19