The 3rd Surgical UnitJanuary, 2009

THYMOMAS

All thymomas originate from epithelial thymic cells

4% of them consist of a pure population of epithelial cells

Most have mixed populations of lymphoid cells to a varying extent

THYMOMAS

20% of all mediastinal neoplasms

50% of all primary tumors in the anterior compartment

90% of thymic tumors are thymomas

THYMOMASSlow-growing tumors

Exhibit malignant potential: Local invasionSystemic metastasiswithout overt cytological features of

malignancy

More common between ages 40 to 60

Clinical presentation asymptomatic, discovered incidentally on CXR

or at autopsylocal symptoms related with pressure or local

invasion: SVC sdr., cough, chest pain, dysphonia, dysphagia

~20%- 70% associated with an autoimmiune disease:Myasthenia gravisHemolytic anemiaPolymyosistisHypogammaglobulnemia

Classifications Morphologic heterogeneity has caused much confusionregarding their classification.

Several classifications have been proposed to correlate histology and clinical course.

Previous studies have shown that the mediastinal invasion as reflected by the staging system of Masaoka negatively affects survival

Prognostic factors

Stage II tumors can recur after complete resection,

indicating that the Masaoka classification might not be sufficient to classify the role of combined treatment modalities in patients with thymoma

Classifications

Tumor extent but also grading the tumor could be required to predict prognosis and recurrence pattern

which might help to define more precisely the role of adjuvant and neoadjuvant treatments.

Histologic classifications1961- Bernatz et al. –Mayo ClinicAccording to the lymphocyte-epithelial cell

ratio:LymphocyticEpithelialMixedSpindle subtypesAt that time thymic carcinomas were not

segregated but grouped with thymomas

1978 Levine and Rosai

New classification of high clinical relevance

Benign thymoma- circumscribed

Malignant thymomas-invasive:Type I- invasive with minimal atypiaType II- moderate to marked atypia (thymic

carcinoma)

Wick 1982Lewis 1987

ThymomasThymic carcinoma

Mixed thymomas with islets of thymic carcinoma behave clinically like typical thymoma more than like thymic carcinoma

Thymomas carry the potential for malignant transformation into malignant thymic carcinoma

Marino & Muller Hermelink 1985The origin of the cells, according to their

resemblance to the normal epithelial cells in other parts of the thymic lobule

Cortical thymoma - epi. cells are large, round, poligonal

Medullary thymoma - epi. cells are smaller, spindle-shaped

Cortical thymoma more agressive than medullary thymoma

Muller-HermelinkThis classification was suggested to have

independent prognostic implications1990- Pescarmona- 80-patient cases found

that M-H classif. reliably predicted prognosisMedullary thymoma

More encapsulatedClinically act benign

Cortical thymomaMore invasiveMalignant in nature

Muller-HermelinkWilkins-1995 reported:

Few recurrences in patients with medullary and mixed thymoma

Higher recurrences in pts. with cortical thymomas

WHO classificationRosai, 1999Reflects the consensus of the pathologists

The cellular origins are emphasized

Resemble more the M-H classification

Currently –the preferred classification

WHO classificationType A- atrophic adult-life cells, spindle or oval in

shape

Type B- bioactive thymic cells of fetus or infant with dentritic or epitheloid appearanceFurther divided into B1, B2, B3 on the basis of

increasing epithelial to lymfoid ratio and the emergence of atypia of the cells

Type AB- display the common features of type A and B

Type C – franckly malignant cells;low-to-high grade

CLASSIFICATIONS

ROSAI-LEVINE Type WHO MULLER-HERMELINK

BENIGN THYMOMA A MEDULLARY THYMOMA

BENIGN THYMOMA AB MIXED THYMOMA  MALIGNANT TYPE I B1 PREDOMINANT

CORTICAL MALIGNANT TYPE I B2 CORTICAL THYMOMA

MALIGNANT TYPE I B3 WELL-DIFFERENTIATED CARCINOMA

MALIGNANT TYPE II C THYMIC CARCINOMA

Prognosis after histologic type

WHO Histologic Description Free Survival at 10 years, %

• A Medullary thymoma 100

• AB Mixed thymoma 100• B1 Predominantly cortical thymoma 83• B2 Cortical thymoma 83• B3 Well-differentiated carcinoma

35• C Thymic carcinoma 28Series of 100 thymomas resected in Japan between 1973

and 2001 using the WHO classification.

“Prognostic Relevance of Masaoka and Muller- Hermelink Classification in Patients With Thymic Tumors”

Didier Lardinois, Renate Rechsteiner, R. Hubert Lang et al.

(Ann Thorac Surg 2000;69:1550 –5)

Department of Thoracic and Cardiovascular Surgery, Institute of

Pathology, Division of Pulmonary Medicine, Institute of Oncology and Clinic of Radio-oncology, University of Berne, Berne, Switzerland

Results

Masaoka stage found Stage I - 31 patients (44.9%), stage II - 17 (24.6%), stage III - 19 (27.6%), and stage IV - 2 (2.9%).

The 10-year overall survival rate was;83.5% for stage I, 79 % for stage II, 44% for stage III, 0% for stage IV.

ResultsHistologic classification according to Muller-

Hermelink - medullary tumors in 7 patients (10.1%),

- mixed in 18 (26.1%), - organoid in 14 (20.3%), - cortical in 11 (15.9%), - well-differentiated carcinoma in 14

(20.3%), - endocrine carcinoma in 5 (7.3%),

10- year overall survival rates of 100%, 75%, 92%, 87.5%, 30%, and 0%, respectively.

ResultsMedullary, mixed, and well-

differentiated organoid tumors were correlated with stage I and II,

Thymic carcinoma and endocrine carcinoma with stage III and IV (p < 0.001

ResultsMultivariate analysis showed age,

gender, myasthenia gravis, and postoperative adjuvant therapy not to be significant predictors of survival after complete resection, whereas

the Muller-Hermelink and Masaoka classifications were independent significant predictors (p < 0.05)

Masaoka Classification-1981STAGE IEncapsulated tumor with no gross or microscopic invasion

TREATMENT Complete surgical excisionSTAGE IIMacroscopic invasion into the mediastinal fat or pleura or microscopic invasion into the capsule

TREATMENT Complete surgical excision and postoperative radiotherapy to decrease the incidence of local recurrenceSTAGE IIIMacroscopic invasion of the pericardium, great vessels, or lung

TREATMENT Complete surgical excision and postoperative radiotherapy to decrease the incidence of local recurrenceSTAGE IVAPleural or pericardial metastatic spread

TREATMENT Surgical debulking, radiotherapy, and chemotherapySTAGE IVBLymphogenous or hematogenous metastases

TREATMENT Surgical debulking, radiotherapy, and chemotherapy

Modified Masaoka Clinical Staging as used by Koga 1994 and Nakagawa 2003 More widely adopted Incorporated microscopic incomplete capsular invasion into stage I, leaving transcapsular invasion in stage II

Stage I - fully encapsulated tumor ( a thymoma completely surrounded by a fibrous capsule that is not infiltrated in its full thickness)

Stage II- tumor infiltrates beyond the capsule into the thymus or fatty tissue. Adhesion to the mediastinal pleura may be present

Stage III- macroscopic invasion into neighboring organsStage IVA- pleural or pericardial disseminationStage IVB- lymphogenous or hematogenous metastases

Proposed WHO TNM Classification

So much controversy during the past 4 decades, no authorized TNM system has been adopted

The proposed WHO TNM scheme remains tentative pending validation of its reliability, reproducibility and predictive power

WHO TNM ClassificationT factor

Tx- primary can not be assessedT0- no evidence of primary tumorT1- macroscopically completely encapsulated

and microscopically no capsular invasionT2- macroscopically adhesion or invasion into

surrounding fatty tissue or mediastinal pleura or microscopic invasion into the capsule

T3-invasion into neighboring organs such as pericardium, great vessels, lung

T4- pleural or pericardial dissemination

WHO TNM ClassificationN factorNx- regional lymph nodes can not be

assessedN0- no lymph nodes metastasisN1- metastases to anterior mediastinal lymph

nodesN2- metastases to intrathoracic lymph nodes

except anterior mediastinal lymph nodesN3- metastases to extrathoracic lymph nodes

WHO TNM Classification

M factorMx- distant metastases can not be assessedM0- no distant metastasesM1- hematogenous metastases

Stage grouping as detailed by Haserjion 2005

Stage I- T1, N0,M0

Stage II- T2, N0, M0

Stage III- T1, N1, MO; T2, N1, MO, T3, N0-1, MO

Stage IV- T4, any N, M0; any T, N2-3, M0; any T, any N, M1

DIAGNOSIS• Chest CT scan is the imaging procedure of

choice in patients with MG. – Thymic enlargement should be determined

because most enlarged thymus glands on CT scan represent a thymoma.

– CT scan with intravenous contrast dye is preferred – to show the relationship between the thymoma and

surrounding vascular structures, – to define the degree of its vascularity, – to guide the surgeon in removal of a large tumor,

possibly involving other mediastinal structures 

MV, male, 46 years old, 6w. history of MG- Oss. III, CT suspicious for thymoma, Op. 2004, histology- thymic lymphoid hyperplasia + mediastinal ectopies, post.op.- complete remission

GE, 19 years old man, Hashimoto thyroiditis, hemolytic anemia, (Hb-2,6g/dl), CT- thymoma, op.dec 2005, histology- thymic lymphoid hypertrophy

PF, female, 21 years old, MG- OSS III, CT- thymic hyperplasia, op. 1997- histology- lymphocitic thymoma

SURGERY

The preferred approach is a median sternotomy:

- providing adequate exposure of the mediastinal structures

- allowing complete removal of the thymus,

Radiotherapy

• Adjuvant radiation therapy in completely or incompletely resected stage III or IV thymomas is considered a standard of care.

• The use of postoperative radiation therapy in stage II thymomas has been more questionable.

Chemotherapy• The most common chemotherapy drugs in the

treatment of thymoma are:• doxorubicin (Adriamycin, Rubex), • cisplatin (Platinol), • cyclophosphamide (Cytoxan, Neosar), • etoposide (VePesid, Etopophos, Toposar), and • ifosfamide (Ifex, Holoxan).

• The common combinations used for the treatment of thymoma include:• cyclophosphamide, doxorubicin, and cisplatin, • or etoposide and cisplatin.

Chemotherapy

Drug combinations. • The combination of carboplatin (Paraplatin) and

paclitaxel (Taxol) is being studied for the treatment of advanced thymoma.

New agents. Therapies explored in clinical trials:• Premetrexed (Alimta)- antifolate antineoplastic agent

for treating advanced thymic cancers.• Imatinib (Gleevec) is a drug that turns off an enzyme

that causes cells to become cancerous and multiply. It is being studied to treat patients with thymic tumors

over-expressing the c-kit and/or PDGF genes.  

Recurrence

Relapse after primary therapy for a thymoma may occur after 10-20 years.

Therefore, long-term follow-up probably should continue to be performed throughout the patient's life.

Thymomas operated in the IIIrd. Surgical Unit

82 thymic lesions operated over a period 1982-2008

23 thymomas- 28%

Out of 23 thymomas- 19 cases were associated with MG- 82,6%

Histologic distribution

Clasificarea WHO Muller-HermelinkType A-2 cases medullary- 2 casesType AB-7 casesmixt -7 casesType B1-9 cases predominant cortical-9 casesType B2- 0 cases cortical- 0 casesType B3-3 caseswell differentiated -3 casesType C- 1case carcinom anaplazic-1 caseThymic carcinoid – 1 case

TREATMENTStage Masaoka I- 9 cases:

4 no adjuvant therapy,2 radiochemotherapy, death at 4 months and 6

years due to acute respiratory failure, 1 radiotherapy only 2 chemotherapy onlyWHO classification of thymomas stage Masaoka IType A -2 casesType B1-5 cases,- 2 deathsType B3-1 case

TreatmentMasaoka II- 5 cases 1 case radiotherapy only 1 case chemotherapy only 3 cases radio+chemotherapyAfter Who classification:Type AB-2Type B1-2Type B3-1

TreatmentMasaoka III- 8cases: radiochemotherapy in all 3 deaths:

2 deaths at 2(C) and 6(AB) postop. years due to acute resp. failure

1 death at 17(AB) postop. years due to miocardial infarction

Who classification: Type AB-5 cases, Type B1-1, Type B3-1, Type C-1Ovaral mortality 5 out of 28 cases:1 medical cause1 unresectable malignant II thymomas- Bx

“Asociatia chimioterapie-radioterapie in tratamentul timoamelor maligne” Anda I.Buiuc, Lidia Andriescu, Elena AlbulescuRev. Romana de Oncologie, 36(2),171-175, 1999

11 invasive thymoma patients, treated over a period of 10 years: 1989-1999

• Multimodal treatment: surgery, chemotherapy, radiotherapy.

Radiochemotherapy in locally advanced malignant thymomas

4 cases of locally advanced malignant thymoma proven on biopsy

Case I -invasive mixed thymoma, stage III, female, 31 years old, 4 sessions of ADOC

(Adriamicine,Cisplatin,Vincristine,Ciclophosphamide) partial response+ radiotherapy 44GY + 1 session ADOC. At 6 years the tumor size decreased with 75%, no symptoms.

Case 2- female, 27 years old, mixed thymoma stage III, SVC sdr.4 sessions ADOC with complete remission+ radiotherapy 44 Gy,

At 1 year posttherapy- no detectable tumor on CT, and no symptoms

 

AS, female, 27 years old, CT-1998- TUMOR MASS WITH NECROTIC AREAS IN THE ANTERO-SUPERIOR MEDIASTINUM

CT aspect after chemo/radiotherapy

CT aspect after chemo/radiotherapy

Radiochemotherapy in locally advanced thymomas

Case 3- male, 27 years old, thymic carcinoma stage III- SVC sdr.

Chemotherapy- cisplatin, vinblastin, bleomicina, adriamicina- 5 sessions with partial remission after the first 2 cycles, radiotherapy-44Gy ,

CHTX.- ADOC+CISPLATIN/ETOPOSID, partial response, death at 2 years from diagnosis

Case 4.- male, 38 years old, anaplasic thymic carcinoma invading the ribs, left lung, compressing trachea, SVC.

Chemotherapy + RXT: 2 cycles ADOC, 40GY- reduction 50%, 3 cycles ADOC+ bleomicina- complete remission for 4 months, Bilateral adrenal MTS, cisplatin/etoposid partial response after 3 cycles. Liver MTS death at 15 months from diagnosis.

CT, 60 years old, thymoma+MG, Oss.IV, op. 2002, Lymphocitic thymoma (type I malignant thymoma)-Masaoka II ( well encapsulated but microscopic capsular invasion), adhesions to left M. pleura which was resected

Radiotherapy 44 Gy, chemotherapy, 1 year CP+PDNPericarditis and mixedema at 1 year postRxTRemission of MG for 5 years, 2008- AChE

AM, 46 years old, multinodular goitre with hyperthyroidy and myasthenia gravisCompressive goitre Retrosternal goitre

Normal thymus on CT scan ?, Total thyroidectomy for MNG, myasthenia gravis persisted

Normal Chest Normal thymus

Thymic scintigraphy- hypercaptation of 99m-Tc-tetrofosmin consistent with a thymomaThymectomy 6 months after total thyroidectomy

Antero- inferior mediastinal massParamedian low retrosternal mass

Well-encapsulated mass

TYPE AB THYMOMA, HE, Transcapsular microscopic invasionDr. D. Ferariu

GM, 32 years old, Cushing sdr. , ACTH -292pg/ml.(n<46). CT- anterior mediastinal mass, pericardial adhesion,Op. sept. 2008-thymectomy+pericardectomy+mediastinal pleurectomy. Histology: well-differentiated thymic neuroendocrine carcinoma, transcapsular invasion, pT2NxMx, Post.op. ACTH-37pg/ml. Cushingoid clinical aspect dissapeared

GV, female, 59 years old, MG-Oss.III, CT- anterior mediastinal mass invading left mediastinal pleura, Op. -2004, Histology- predominant cortical thymoma, B1, Masaoka II, Adjuvant RxT

GV, B1 type thymoma, R0 extended thymectomy, good recovery after radiochemotherapy

A.Gh. 65 years old, 3 w. of severe myasthenia, Oss.III-preop.IOTCT-calcified thymoma adherent to the left mediastinal pleura, op. 2003, histology- type A, medullary thymoma without capsular invasion, Masaoka-I, chemotherapy CP+PDN, obvious improvement

Conclusions

No clear histologic distinction between benign and malignant thymomas exists.

The propensity of a thymoma to be malignant is determined by the invasiveness of the thymoma.

Future treatment• Studies have investigated the molecular changes in

thymomas. In one study, 10 out of 12 thymomas exhibited epidermal growth factor receptor (EGFR) expression.

This information would be useful in selecting patients that may benefit from EGFR inhibitors as part of their treatment regimen.

• Other areas of investigation include apoptosis-related markers, such as p63, a member of the p53 family. p63 was found to be expressed in virtually all thymomas.

• Further research pertaining to the biology of thymomas will allow more adequate approaches to treatment.