The 3 rd Surgical Unit
January, 2009

 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

 20% of all mediastinal neoplasms
 50% of all primary tumors in the anterior compartment
 90% of thymic tumors are thymomas

 Slow-growing tumors
 Exhibit malignant potential:
 Local invasion
 Systemic metastasis without overt cytological features of malignancy
 More common between ages 40 to 60

 asymptomatic, discovered incidentally on CXR or at autopsy
 local symptoms related with pressure or local invasion:
SVC sdr., cough, chest pain, dysphonia, dysphagia
 ~20%- 70% associated with an autoimmiune disease:
 Myasthenia gravis
 Hemolytic anemia
 Polymyosistis
 Hypogammaglobulnemia

Morphologic heterogeneity has caused much confusion regarding 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

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

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.

 1961- Bernatz et al. –Mayo Clinic
 According to the lymphocyte-epithelial cell ratio:
 Lymphocytic
 Epithelial
 Mixed
 Spindle subtypes
At that time thymic carcinomas were not segregated but grouped with thymomas

New classification of high clinical relevance
 Benign thymoma- circumscribed
 Malignant thymomas-invasive:
 Type I- invasive with minimal atypia
 Type II- moderate to marked atypia (thymic carcinoma)

 Thymomas
 Thymic 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

The 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, spindleshaped
Cortical thymoma more agressive than medullary thymoma

 This classification was suggested to have independent prognostic implications
 1990- Pescarmona- 80-patient cases found that M-H classif. reliably predicted prognosis
 Medullary thymoma
 More encapsulated
 Clinically act benign
 Cortical thymoma


More invasive
Malignant in nature

 Wilkins-1995 reported:
 Few recurrences in patients with medullary and mixed thymoma
 Higher recurrences in pts. with cortical thymomas

 Reflects the consensus of the pathologists
 The cellular origins are emphasized
 Resemble more the M-H classification
 Currently –the preferred classification

 Type A- atrophic adult-life cells, spindle or oval in shape
 Type B- bioactive thymic cells of fetus or infant with dentritic or epitheloid appearance
 Further 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

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

•
•
•
•
•
•
WHO Histologic Description
A
AB
B1
B2
B3
C
Medullary thymoma
Mixed thymoma
Predominantly cortical thymoma
Cortical thymoma
Well-differentiated carcinoma
Thymic carcinoma
Free Survival at
10 years, %
100
100
83
83
35
28
Series 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

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.

Histologic 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.

Medullary, 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

 Multivariate 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)

STAGE I
Encapsulated tumor with no gross or microscopic invasion
TREATMENT Complete surgical excision
STAGE II
Macroscopic 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 recurrence
STAGE III
Macroscopic i nvasion of the pericardium, great vessels, or lung
TREATMENT Complete surgical excision and postoperative radiotherapy to decrease the incidence of local recurrence
STAGE IVA
Pleural or pericardial metastatic spread
TREATMENT Surgical debulking, radiotherapy, and chemotherapy
STAGE IVB
Lymphogenous 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 organs
Stage IVA- pleural or pericardial dissemination
Stage IVB- lymphogenous or hematogenous metastases

 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

 T factor
 Tx- primary can not be assessed
 T0- no evidence of primary tumor
 T1- macroscopically completely encapsulated and microscopically no capsular invasion
 T2- 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

 N factor
 Nx- regional lymph nodes can not be assessed
 N0- no lymph nodes metastasis
 N1- metastases to anterior mediastinal lymph nodes
 N2- metastases to intrathoracic lymph nodes except anterior mediastinal lymph nodes
 N3- metastases to extrathoracic lymph nodes

 M factor
 Mx- distant metastases can not be assessed
 M0- no distant metastases
 M1- hematogenous metastases

 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

• 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, histologythymic lymphoid hypertrophy

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

The preferred approach is a median sternotomy:
providing adequate exposure of the mediastinal structures
allowing complete removal of the thymus,

• 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.

•
•
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.

•
Drug combinations.
The combination of carboplatin (Paraplatin) and paclitaxel
(Taxol) is being studied for the treatment of advanced thymoma.
New agents.
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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 overexpressing the c-kit and/or PDGF genes.

 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.

 82 thymic lesions operated over a period 1982-2008
 23 thymomas- 28%
 Out of 23 thymomas- 19 cases were associated with
MG- 82,6%

Clasificarea WHO
Type A-2 cases
Type AB-7 cases
Type B1-9 cases
Type B2- 0 cases
Muller-Hermelink medullary- 2 cases mixt -7 cases predominant cortical-9 cases cortical0 cases
Type B3-3 cases
Type C- 1case
Thymic carcinoid – 1 case well differentiated -3 cases carcinom anaplazic-1 case

TREATMENT
 Stage 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 only
WHO classification of thymomas stage Masaoka I
Type A -2 cases
Type B1-5 cases,- 2 deaths
Type B3-1 case

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

 Masaoka 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-1
Ovaral mortality 5 out of 28 cases:
1 medical cause
1 unresectable malignant II thymomas- Bx

“Asociatia chimioterapie-radioterapie in tratamentul timoamelor maligne”
Anda I.Buiuc, Lidia Andriescu, Elena Albulescu
Rev. 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+PDN
Pericarditis and mixedema at 1 year postRxT
Remission of MG for 5 years, 2008- AChE

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

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

Thymic scintigraphy- hypercaptation of 99m-Tctetrofosmin consistent with a thymoma
Thymectomy 6 months after total thyroidectomy

Antero- inferior mediastinal mass
Paramedian low
Well-encapsulated mass retrosternal mass

Dr. 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.IOT
CT-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

 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.

• 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.
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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.