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CLINICAL, HISTOLOGICAL AND PROGNOSTIC ASPECTS IN THYMOMAS

CLINICAL, HISTOLOGICAL AND PROGNOSTIC ASPECTS IN THYMOMAS. The 3 rd 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.

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CLINICAL, HISTOLOGICAL AND PROGNOSTIC ASPECTS IN THYMOMAS

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  1. CLINICAL, HISTOLOGICAL AND PROGNOSTIC ASPECTS IN THYMOMAS The 3rd Surgical Unit January, 2009

  2. 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

  3. THYMOMAS • 20% of all mediastinal neoplasms • 50% of all primary tumors in the anterior compartment • 90% of thymic tumors are thymomas

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

  5. 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

  6. Classifications Morphologic heterogeneity has caused much confusion regarding their classification. • Several classificationshave been proposed to correlate histology and clinicalcourse. • Previous studies have shown that the mediastinal invasion as reflected by the staging systemof Masaoka negatively affects survival

  7. Prognostic factors Stage II tumors canrecur after complete resection, indicating that the Masaokaclassification might not be sufficient to classify the role ofcombined treatment modalities in patients with thymoma

  8. Classifications Tumor extent but also grading the tumor could be requiredto predict prognosis and recurrence pattern which might help to define more preciselythe role of adjuvant and neoadjuvant treatments.

  9. 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

  10. 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)

  11. Wick 1982Lewis 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

  12. 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, spindle-shaped Cortical thymoma more agressive than medullary thymoma

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

  14. Muller-Hermelink • Wilkins-1995 reported: • Few recurrences in patients with medullary and mixed thymoma • Higher recurrences in pts. with cortical thymomas

  15. WHO classificationRosai, 1999 • Reflects the consensus of the pathologists • The cellular origins are emphasized • Resemble more the M-H classification • Currently –the preferred classification

  16. 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

  17. 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

  18. Prognosis after histologic type WHO Histologic DescriptionFree Survival at 10 years, % • A Medullarythymoma 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 thymomasresected in Japan between 1973 and 2001 using the WHO classification.

  19. “Prognostic Relevance of Masaoka and Muller-Hermelink Classification in Patients WithThymicTumors” 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 ofOncology and Clinic of Radio-oncology, University of Berne, Berne, Switzerland

  20. 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.

  21. 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.

  22. Results Medullary, mixed, and well-differentiated organoid tumorswere correlated with stage I and II, Thymic carcinoma and endocrine carcinoma with stage IIIand IV (p < 0.001

  23. Results • Multivariate analysis showed age,gender, myasthenia gravis, and postoperative adjuvanttherapy not to be significant predictors of survival after complete resection, whereas • the Muller-Hermelink and Masaoka classifications wereindependent significant predictors (p < 0.05)

  24. 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

  25. 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

  26. 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

  27. 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

  28. 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

  29. WHO TNM Classification • M factor • Mx- distant metastases can not be assessed • M0- no distant metastases • M1- hematogenous metastases

  30. 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

  31. 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

  32. 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

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

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

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

  36. 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.

  37. 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.

  38. 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)- antifolateantineoplastic 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 thymictumors over-expressing the c-kit and/or PDGF genes.

  39. 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.

  40. 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%

  41. Histologic distribution Clasificarea WHO Muller-HermelinkType A-2 cases medullary- 2 casesType AB-7 cases mixt -7 casesType B1-9 cases predominant cortical-9 casesType B2- 0 cases cortical- 0 casesType B3-3 cases well differentiated -3 casesType C- 1case carcinom anaplazic-1 caseThymiccarcinoid – 1 case

  42. 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

  43. 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

  44. 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

  45. “Asociatiachimioterapie-radioterapie in tratamentultimoamelormaligne” AndaI.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.

  46. Radiochemotherapy in locally advanced malignant thymomas 4 cases oflocallyadvancedmalignantthymomaprovenonbiopsy Case I -invasivemixedthymoma, stage III, female, 31 yearsold, 4 sessionsof ADOC (Adriamicine,Cisplatin,Vincristine,Ciclophosphamide) partial response+ radiotherapy 44GY + 1 session ADOC. At 6 yearsthe tumor sizedecreasedwith 75%, no symptoms. Case 2- female, 27 yearsold, mixedthymomastage III, SVC sdr. 4 sessions ADOC with complete remission+ radiotherapy 44 Gy, At 1 year posttherapy- no detectable tumor on CT, and no symptoms

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

  48. CT aspect after chemo/radiotherapy

  49. CT aspect after chemo/radiotherapy

  50. 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.

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