Transcript CLINICAL, HISTOLOGICAL AND PROGNOSTIC ASPECTS IN …

The 3rd Surgical Unit
January, 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
THYMOMAS
 Slow-growing tumors
 Exhibit malignant potential:
 Local invasion
 Systemic metastasis
without overt cytological features of malignancy
 More common between ages 40 to 60
Clinical presentation
 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
Classifications
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
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 classifications
 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
1978 Levine and Rosai
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)
Wick 1982
Lewis 1987
 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
Marino & Muller Hermelink 1985
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
Muller-Hermelink
 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
Muller-Hermelink
 Wilkins-1995 reported:
 Few recurrences in patients with medullary and mixed
thymoma
 Higher recurrences in pts. with cortical thymomas
WHO classification
Rosai, 1999
 Reflects the consensus of the pathologists
 The cellular origins are emphasized
 Resemble more the M-H classification
 Currently –the preferred classification
WHO 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
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
28
Series of 100 thymomas resected in Japan between 1973 and
2001 using the WHO classification.
“Prognostic Relevance of Masaoka and MullerHermelink 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.
Results
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.
Results
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
Results
 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)
Masaoka Classification-1981
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 invasion 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
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 Classification
 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
WHO TNM Classification
 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
WHO TNM Classification
 M factor
 Mx- distant metastases can not be assessed
 M0- no distant metastases
 M1- 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, histologythymic 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 overexpressing 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-Hermelink
Type A-2 cases
medullary- 2 cases
Type AB-7 cases
mixt
-7 cases
Type B1-9 cases
predominant cortical-9 cases
Type B2- 0 cases
cortical0 cases
Type B3-3 cases
well differentiated -3 cases
Type C- 1case
carcinom anaplazic-1 case
Thymic carcinoid – 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
Treatment
 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
Treatment
 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
retrosternal mass
Well-encapsulated mass
TYPE AB THYMOMA, HE,
Transcapsular microscopic invasion
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
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.