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 Gravis
THYMOMA (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 MASS

THYMUS 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 MASS

Benign 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/MASSES

Adults 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 TUMORS

ADULTS 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 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

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 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%)

Survival according to the Masaoka staging system

N=282

Okumura et al. Cancer 94,624632,2002

Typical 10 - 20 yr. survival according to Masaoka stage

Stage 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 Thymoma

Agent 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 Cisplatinc
a 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, 1981 Baum et al., 1981 Chahinian et al., 1981 Cocconi et al., 1982 Levin et al., 1982 Giaccone et al., 1985 Hu and Levine, 1986 Hu and Levine, 1986 Hu and Levine, 1986 Hu and Levine, 1986 Hu and Levine, 1986 Harper and Addis, 1988 Tandan et al., 1990 Bonomi et al., 1993 Park et al., 1994

With radiotherapy. 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 patients Complete remission (%) 16 (43) 5 (38) 3 (10) 7(43) 8 (62) 3 (25) 5 (22) Partial remission (%) 18 (49) 12(40) 9 (57) 8 (67) 11 (48) Duration of response (mos) 12 12 93.2 Survival (mos) 15 38 66 17+ 93 Reference

ADOC AOCP+/-B DAC ADOC DAC DAC DACP& DAC&

37 13 30 16 74* 15** 12 23

Fornasiero et al., 1991 Goldel et al., 1989 Loehrer et al., 1994 Rea et al., 1993 Cowen et al., 1995 Milstein et al., 1996 Shin et al., 1997 Loehrer et al., 1997

*all patients received radiotherapy; ** 7 thymic carcinomas &=neoadjuvant A=doxorubicin; D=cisplatin; O=vincristine; C=cyclophosphamide; 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 of response 10 46 50 NA 66+ months 11.8 months Median survival 1 year NA 37.7 months

Bonomi, et al Highley, et al Loehrer, et al

Oshita, et al

Cisplatin Ifosfamide Cisplatin Cyclophosph. Doxorubicin Cisplatin Cyclophosph. Doxorubicin Etoposide

21 13 30*

14** 43**

NA

14.7 months

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 of response 3.4 years Median survival 4.3 years

Giaccone et al

Cisplatin Etoposide Cisplatin, Etoposide Ifosfamide Doxorubicin Cisplatin Vincristine Cyclophosph.

16

56

Loehrer et al

14

43

NA

NA

Berruti et al*

16

81

NA

47.5 mo.

*probably not based on prospective protocol treatment

Neoadjuvant chemotherapy in locally advanced thymoma

1983 1995 Intergroup 23 eligible patients (2 thymic carcinomas) Cisplatin 50 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2, every 3 weeks Radiotherapy 54 Gy to responders Evaluation after 2 and 4 cycles

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

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

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

Mechanisms of somatostatin antitumor activity

Inhibition of growth factors: EGFR, TGF, GH, ILGF-1 Modulation of immune activity Inhibition of angiogenesis

Somatostatin scan in thymoma

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

VUMC experience with somatostatin

Hist, gender, age, stage TC, F, 47, IV T, M, 46, IV T, M, 58, IV T, M,57, IV Prior therapy RT, VIP, CT, Gefitinib (PD)* PE, CAP CE BEP, VIP* Somatostatin response PD PD PD PR Somatostatin+pred resp PD PR

loxat=T ;nitalpobrac=C
*SU....= 2 MR

;amonicrac sumyht=CT ,amomyht=T

40 beF 3
gpj.egamI

30 ceD 8

amomyht citatsatem htiw tneitap a ni enosinderp + nitatsotamoS

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)

12

Thymic carcinoma (WHO type C)

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

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

Courtesy J. Schellens.

7x4 cm

5x2.5 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