thymoma esmo 2008

Thymic Malignancies

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

Amsterdam, The Netherlands

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

Thymoma – A Rare Disease

• 3.32/1.000.000/year

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• Cushing’s syndrome• Carcinoid syndrome• DiGeorge syndrome• Lambert-Eaton

Syndrome• Nephrotic syndrome

• SIADH• Whipple’s disease• Lupus erythematosis• Pemphigus• Scleroderma• Polymyositis• Polyneuritis• Polyarthropathy• Addison’s disease• Hypogammaglobulinemia

Myasthenia Gravis

THYMOMA (8.5-15%)

HYPERPLASIA(65%)

Age 40-50 yr (>30 y) < 30 yr

Mass Round Elongated

CT density >Muscle Fat

Calcification 20%

Position Unilateral or midline

Bilateral

Thymectomy Improves 25% Cure 30%Improves 70%

Thymoma usually presents as an anterior mediastinal mass.

• 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

Mediastinal Mass: Imaging

CT Findings: Thymoma

CT Findings: Thymoma

Size and Symptoms – A case with severe myasthenia gravis

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

18FDG-PET and Thymoma

• FDG PET useful in staging

• SUV predicts clinical behaviour

• In MG differentiation between hyperplasia and thymoma

ANTERIOR MEDIASTINAL MASS

THYMUS

THYROID

PARATHYROID

FAT

ThymolipomaThymic cystThymic hyperplasiaEctopic thyroid

Ectopic adenoma

Lipoma

ThymomaThymic CAThymic carcinoidSubsternal goiter carcinoma

Liposarcoma

ANTERIOR MEDIASTINAL MASS

Benign Malignant

LYMPH NODES Castleman’s diseaseMononuclueosis infectiosaGranuloma

(Non) Hodgkin’s diseaseMetastatic carcinoma

GERM CELL RESTS

Teratoma SeminomaNon Seminoma

OVERALL INCIDENCE OF MEDIASTINAL TUMORS/MASSES

Ref. : Shields TW. Mediastinal surgery 1991, pp. 11 1-117.Combining 9 series (± 600 children and 2200 adults).

Adults Children

Neurogenic 23% 39%

Thymic 19% 3%

Cysts 18%

Lymphoproliferative 12%

Germ cell 12%

Mesenchymal 8%

Miscellaneous 8%

INCIDENCE OF ANTERIOR MEDIASTINAL TUMORS

ADULTS CHILDREN

ThymicLymphoproliferativeMesenchymalGerm cell

47 %22 %16 %15 %

16%45 %15 %24 %

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

MEDIASTINAL MASS : DIAGNOSTIC APPROACH

•History & 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

THYMUS

The 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

AABB1B2B3C

MedullaryMixed typePredominant corticalCorticalWell diff. thymic ca.SCC, undiff. ca., lymphoepith.-like ca.

The WHO Classification System:indolentaggressive

Lymfo

Epithelial component

CD3 CK5/6

Lymphocytic component Epithelial component

Thymoma WHO B1

Epithelial component

Thymoma WHO B3

CD 56 staining

Mediastinal Carcinoid

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

Mediastinal Large B-cell lymphoma with sclerosis.

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

Mediastinal Rhabdomyosarcoma arising in thymus

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

Survival according to the WHO classification.

Marchevsky et al. Cancer 112,2780,2008.

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

DISTINCTION BETWEEN BENIGN & MALIGNANT THYMOMA

•Cell 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%)

Okumura et al. Cancer 94,624-632,2002

Survival according to the Masaoka staging system

N=282

Typical 10 - 20 yr. survival according to Masaoka stage

Stage I 90 - 100 %Stage II 90 - 100 %Stage III 50 - 90 %Stage IVa 0 - 30 %Stage IVb 0 %

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

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

PROGNOSIS

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

Thymomas - treatment

• Surgery• Chemotherapy• Radiotherapy

• A combination of all three

THYMOMA: THERAPYResectable 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

Okumura et al. Cancer 94,624-629,2002

Survival according to type of resection.

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

Blumberg, Ann. Thor. Surg,1995.

Thymoma: treatment of recurrences

years

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.

Complete surgicalexcision Stage I Never

Stage II Only in high-risk cases (50 Gy)

Stage III Routinely (50 Gy)

Stage IV In stage IVa, where feasiblePost-surgicalrecurrences Re-excision (if possible), followed by radiotherapy (when feasible)Inoperable disease Chemotherapy, followed by one (or more) local treatments

Current Indications Radiotherapy (VUMc)

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

Surgery vs surgery plus radiotherapy in completely resected Masaoka stage II

Stage II Thymoma: Subgroups at high risk for recurrence

• Local recurrence in 20%.

• Local relapses increased in WHO subtypes B2-3.

• Micro scopic invasion into fatty tissue or mediastinal pleura (Masaoka stage IIb): 40% 10-year DFS

• Macro scopic 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 30–50%• 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 Complete Partial Duration of

patients remission remission response Survival Refere nce(%) (%) (mos) (mos)

Steroids 1 — 1 (100) — — Sofer et al., 1952 Cisplatin 1 — 1 (100) 13 — Talley et al., 1973Maytansine 1 — 1 (100) — — Jaffrey et al., 1980Cisplatin 1 1 (100) — 101 — Needles et al., 1981 Cisplatin 1 — 1 (100) 4 13 Hetty and Arora, 1981 Cisplatin 1 — 1 (100) 1 — Baum et al., 1981 Maytansine 4 — 2 (50) 1.5, 4.5 — Chahinian et al., 19 81 Cisplatin 1 1 (100) — 201 — Cocconi et al., 1982 Cisplatin 1 1 (100)a — 2424 1 Levin et al., 1982 Cisplatin 1 — 1 (100) 1 — Giaccone et al., 1985 Steroids b 12 2 (17) 8 (67) — — Hu and Levine, 1986 Doxorubicin 3 — 2 — — Hu and Levine, 1986 Vincristine 2 — — — — Hu and Levine, 1986 Chlorambucil 2 — — — — Hu and Levine, 1986 Nitrogen mustard 1 — — — — Hu and Levine, 1986 Ifosfamide 5 2 (40) 2 (40) — — Harper and Addis, 1988 Steroids 1 — 1 (100) — — Tandan et al., 1990 Cisplatin 24 — 2 (8) — — Bonomi et al., 1993 Cisplatin c 17 6 (35) 5 (29) — — Park et al., 1994

a With radiotherapy.b Corticotropic hormone or corticosteroids.c With or without prednisone.

Hejna M et al, Cancer 85(9):1871, 1999

Combinations in Thymoma (> 10 patients)Agents No. of Complete Partial Duration of

patients remission remission response Survival Refere nce(%) (%) (mos) (mos)

ADOC 37 16 (43) 18 (49) 12 15 Fornasiero et al., 1991

AOCP+/-B 13 5 (38) — — — Goldel et al., 1989

DAC 30 3 (10) 12(40) 12 38 Loehrer et al., 1994

ADOC 16 7(43) 9 (57) — 66 Rea et al., 1993

DAC 74* — — — — Cowen et al., 1995

DAC 15** 8 (62) — — 17+ Milstein et al., 1996

DACP& 12 3 (25) 8 (67) — — Shin et al., 1997

DAC& 23 5 (22) 11 (48) 93.2 93 Loehrer et al., 1997

*all patients received radiotherapy; ** 7 thymic ca rcinomas&=neoadjuvant

A=doxorubicin; D=cisplatin; O=vincristine; C=cyclop hosphamide; P=prednisone; B=bleopmycin

Hejna M et al, Cancer 85(9):1871, 1999

Prospective chemotherapy trials in advanced thymoma (1)

Author Regimen N RR(%) Duration Medianof response survival

Bonomi, et al Cisplatin 21 10 NA 1 yearHighley, et al Ifosfamide 13 46 66+ months NALoehrer, et al Cisplatin 30* 50 11.8 months 37.7 months

Cyclophosph.Doxorubicin

Oshita, et al Cisplatin 14** 43** NA 14.7 monthsCyclophosph.Doxorubicin Etoposide

Notes: * 1 had thymic carcinoma ** 7 thymomas, 7 thymic carcinomas;3/6 responders had thymoma

Lara PN jr. Canc Tr Rev 26:127, 2000

Prospective chemotherapy trials in advanced thymoma (2)

Author Regimen N RR(%) Duration Medianof response survival

Giaccone et al Cisplatin 16 56 3.4 years 4.3 yearsEtoposide

Loehrer et al Cisplatin, 14 43 NA NAEtoposideIfosfamide

Berruti et al* Doxorubicin 16 81 NA 47.5 mo.CisplatinVincristineCyclophosph.

*probably not based on prospective protocol treatment

Loehrer et al. J. Clin. Oncol. 15,3093,1997

Neoadjuvant chemotherapy in locally advanced thymoma

• 1983 – 1995 Intergroup• 23 eligible patients (2 thymic carcinomas)• Cisplatin 50 mg/m 2, doxorubicin 50 mg/m 2,

cyclophosphamide 500 mg/m 2, every 3 weeks

• Radiotherapy 54 Gy to responders• Evaluation after 2 and 4 cycles

Neoadjuvant chemotherapy in locally advanced thymoma

• After chemotherapy:• 5 CRs, 11 PRs, 7 NC, 1 PD• Response rate 69.6% (95% CI: 47.1 –

86.8%)• After radiotherapy:

• 1 PR CR• 1 NC CR• 3 NC PR

Neoadjuvant chemotherapy in locally advanced thymoma

• None of the 5 CRs relapsed• 8/11 PRs relapsed <2 years• Median time to progression : 93.2

months ( 1 – 110 months)• 5-year failure-free survival : 54%• Median survival : 93 months• 5-year survival : 52%

Loehrer PJ et al, JCO 15: 3093, 1997

New targets for thymic malignancies

Palmieri et al. New Eng. J. Med. 336,236,1997

A case of thymoma responding to octreotide

• Uptake of Indium-labeled octreotide in some thymomas

• 56 yr old patient with thymoma and pure red cell aplasia

• Received 6 courses of cisplatin, cyclophosphamide and prednisone with large residual mass

• Octreotide scan intenstely positive• Treated with octreotide 0.5 mg tid sc. + prednisone• Rapid improvement of anemia and tumor shrinkage;

complete remission after 15 months

Mechanisms of somatostatin antitumor activity

• Inhibition of growth factors: EGFR, TGFß, GH, ILGF-1

• Modulation of immune activity• Inhibition of angiogenesis

Somatostatin scan in thymoma

Loehrer et al. J. Clin. Oncol. 22,293,2004

Octreotide +/- prednisone

• Positive octreotide scan• Octreotide t.i.d. s.c. – 2 months• Stable patients: prednisone 0.6 mg/kg/day• Progressive patients: off-study

Loehrer et al. J. Clin. Oncol. 22,293,2004

Octreotide +/- prednisone

• 38 eligible patients• 32 thymomas• 5 thymic carcinomas and 1 carcinoid• Octreotide: 4 PRs / 38 (10.5%)• Octreotide + prednisone: 2 CR+6 PRs / 21

(31.6%)• Overall: 2 CR + 10 PR / 38 (31.6%)• No responses in non-thymomas

VUMC experience with somatostatin

Hist, gender, age, stage

Prior therapy Somatostatin

response

Somatostatin+pred resp

TC, F, 47, IV RT, VIP, CT, Gefitinib (PD)*

PD PD

T, M, 46, IV PE, CAP PD PR

T, M, 58, IV CE PD

T, M,57, IV BEP, VIP* PRT=thymoma, TC=thymus carcinoma; C=carboplatin; T=taxol*SU....= 2 MR

Image.jpg8 Dec 033 Feb 04

Somatostatin + prednisone in a patient with metastatic thymoma

Henley et al. J. Cancer Res. Clin. Oncol. 130,222,2004

EGFR and c-Kit expression in thymic tumors

EGFR -C-Kit -

EGFR -C-Kit +

EGFR +C-Kit -

EGFR +C-Kit +

Total cases

Thymomas (WHO type B)

2 0 9 1 12

Thymic carcinoma (WHO type C)

1 1 0 2 4

Courtesy J. Schellens.

Thymus carcinoma

• ♂ 53 yrs• Thymus carcinoma since 2004• Multiple metastases: lungs, liver• 2006: novel c-kit mutation (exon 9)• Start imatinib 1x400 mg

7x4 cm5x2.5 cm

Targeted Agents and Thymoma

• Anecdotal Responses to– Imatinib– Dasatenib– Cetuximab

• Phase II trial Imatinib (n=9, all c-Kit+): ORR 0%(Giaccone et al. Proc ASCO 2008)

CONCLUSIONS

• Rare disease• Diagnosis made clinically• Resectional therapy whenever possible• 3D conformational high dose radiotherapy

incompletely resected disease• Chemotherapy ill defined• Combined modality treatments preferably

in designated centres.• Targeted agents deserve further study