THYMOMAS

1. THYMOMAS Clinical, pathological and prognostic aspects

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 • ~50% - asymptomatic, discovered incidentally on CXR or at autopsy • ~30% local symptoms related with pressure or local invasion: SVC sdr., cough, chest pain, dysphonia, dysphagia • ~20%- 70% associated with an autoimmiune disease: • Myasthenia gravis • Pure red cell aplasia • Polymyosistis • hypogammaglobulnemia

6. Prognostic factors Theirmorphologic 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. Prognostic factors 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. Therefore, not only staging, the several histologic classifications have been assessed, butthey did not help to predict the evolution of thymictumors after resection

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 • Is a successful synthesis of the most widely used classification • 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 Tip 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. WHO Classification Type A thymoma. • This type accounts for approximately 4% to 7% of all cases of thymoma, and is also referred to as spindle cell thymoma or medullarythymoma. • The prognosis for people with type A thymoma is good, with a 15-year relative survival rate near 100%.

19. WHO Classification Type AB thymoma. • Type AB thymoma, or mixed thymoma, accounts for approximately 28% to 34% of thymoma cases. • Type AB thymoma is similar to type A; however, there are lymphocytes that are mixed in the tumor, and approximately 16% of cases are thought to be associated with myasthenia gravis. • The prognosis for people with type AB thymoma is also good, with a 15-year relative survival rate of approximately 90%.

20. WHO Classification Type B1 thymoma. • Type B1 thymoma accounts for approximately 9% to 20% of thymoma cases, and is also known as lymphocyte-rich thymoma, lymphocytic thymoma, predominantly cortical thymoma, and organoidthymoma. • This type of thymoma has a high concentration of lymphocytes in the tumor, but the cells of the thymus appear normal. Approximately 57% of type B1 thymoma cases are thought to be associated with myasthenia gravis. • The prognosis for people with type B1 thymoma is also good, with a 20-year relative survival rate of approximately 90%.

21. WHO Classification Type B2 thymoma. • Type B2 thymoma has a high concentration of lymphocytes, like type B1 thymoma; however, the thymus cells do not appear normal. • Type B2 thymoma is also known as cortical thymoma and polygonal cell thymoma, and accounts for approximately 20% to 36% of all thymoma cases. • About 71% of cases of type B2 thymoma are thought to be associated with myasthenia gravis. • The 20-year relative survival rate for people with type B2 thymoma is approximately 60%.

22. WHO Classification Type B3 thymoma. • Type B3 thymoma is also known as epithelial thymoma, atypical thymoma, squamoidthymoma, and well-differentiated thymoma. • It accounts for approximately 10% to 14% of thymoma cases. • This type of thymoma has few lymphocytes, and the thymus cells look close to normal. • About 46% of type B3 thymoma cases are thought to be associated with myasthenia gravis, and the 20-year relative survival rate is approximately 40%.

23. WHO Classification Type C thymoma (or Thymic carcinoma). • Type C thymoma is very aggressive. The cells in thymic carcinoma do not look like normal thymus cells, but like cancers in other organs of the body. • Thymic carcinoma may start from a pre-existing thymoma that has transformed into a more aggressive tumor. • This type of thymoma is often advanced when diagnosed, • Can be divided into two categories: low grade (better prognosis) and high grade (more likely to grow and spread quickly).

24. WHO Classification Low-grade thymic carcinoma includes: - basaloid, - mucoepidermoid, - well-differentiated squamous cell types. High-grade thymic carcinoma includes: - anaplastic/undifferentiated, - clear cell, - poorly differentiated squamous cell, - sarcomatoid, - small cell/neuroendocrine types.

25. Thymic carcinoma • People with thymic carcinoma do not have associated myasthenia gravis. • The five-year relative survival rate of people with thymic carcinoma is 38%. • The 10-year relative survival rate of people with thymic carcinoma is 28%.

26. 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 thymic carcinoma 35 • C Thymic carcinoma 28 Series of 100 thymomasresected in Japan between 1973 and 2001 using the WHO classification.

27. “Prognostic Relevance of Masaoka and Muller-Hermelink Classification in Patients WithThymic Tumors” Didier Lardinois, MD, Renate Rechsteiner, MD, R. Hubert La¨ ng, MD, Matthias Gugger, MD, Daniel Betticher, MD, Christian von Briel, MD, Thorsten Krueger, MD, and Hans-Beat Ris, MD (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

28. 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, 100% for stage IIa, 58% for stage IIb, 44% for stage III, 0% for stage IV.

29. 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. Medullary, mixed, and well-differentiated organoid tumorswere correlated with stage I and II, Well-differentiatedthymic carcinoma and endocrine carcinoma with stage IIIand IV (p < 0.001)

30. 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 for overall (p < 0.05)

31. Masaoka anatomic classification 1981 • Based on the presence or abscence of gross or microscopic invasion of the tumor capsule as well as the metastatic status • Medullary and mixed thymomas are usually not invasive and correspond to stages I and II • Cortical thymomas are more commonly invasive and more likely to be in stages III and IV

32. 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

33. 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

34. “Observer variation in the histopathological classification of thymoma: correlation with prognosis.”A Dawson, N B Ibrahim, and A R Gibbs Department of Histopathology, Llandough Hospital, Cardiff. AIMS -To assess the ability of three histopathologists, experienced in thoracic surgical reporting, consistently to classify thymomas as cortical, medullary, or mixed pattern tumours METHODS--Three histopathologists classified 74 thymomas (none frank carcinomas) as of either cortical, medullary, or mixed pattern, on two separate occasions. Kappa statistics were used to assess inter- and intra-observer agreement. Tumour type was compared with surgical stage as a predictor of biological behaviour.

35. RESULTS Inter- and intra-observer agreement were only moderate (kappa 0.48 and 0.52, respectively). For only 26 of 74 tumours could a categorisation be consistently agreed on. . The prognoses for those 26 of 74 cases appeared to be at variance from previously reported studies, and showed internal inconsistency, with the mixed pattern category showing a worse survival than the cortical category. For the group as a whole, however, stage at presentation was related to survival, with an overall five year survival of 78% 100% for stage I, 84% for stage II, 27% for stage III and 0% for stage IV

36. CONCLUSIONS The classification of thymomas into cortical, medullary, or mixed pattern tumours is difficult to apply. Surgical stage remains a better guide to prognosis.

37. 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

38. 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

39. 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

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

41. 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

42. DIAGNOSIS Biopsy: • If a patient presents with atypical features or is found to have an invasive tumor and is under consideration for induction therapy, obtaining preoperative biopsy is indicated. • The limited anterior mediastinotomy (Chamberlain approach) is the standard approach that typically is performed over the projection of the tumor. • A thoracoscopic approach for biopsy also can be used

43. 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, and • to guide the surgeon in removal of a large tumor, possibly involving other mediastinal structures

44. 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

45. GE, 19 years old man, Hashimoto thyroiditis, hemolytic anemia, (Hb-4g/dl), CT- thymoma, op.dec 2005, histology- thymic lymphoid hypertrophy

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

47. DIAGNOSIS • Magnetic resonance imaging (MRI). An MRI uses magnetic fields, not x-rays, to produce detailed images of the body. • Positron emission tomography (PET) scan. In a PET scan, radioactive sugar molecules are injected into the body. Cancer cells absorb sugar more quickly than normal cells, so they light up on the PET scan. PET scans are often used to complement information gathered from CT scan, MRI, and physical examination. CT scanning reveals evidence of an anterior mediastinal mass, the PET scan shows a hypermetabolic mass consistent with this location, thereby raising suspicion of malignancy. PET scanning should be added to the armamentarium as an available diagnostic modality to aid in staging and excluding extramediastinal involvement

48. PROGNOSIS • The prognosis of a person with a thymoma is based on the tumor's gross characteristics at operation, not the histological appearance. • Benign tumors are noninvasive and encapsulated. • Conversely, malignant tumors are defined by local invasion into the thymic capsule or surrounding tissue. • The Masaoka staging system of thymomas is the most commonly accepted system. • Preponderance of evidence indicates that all thymomas, except completely encapsulated stage 1 tumors, benefit from adjuvant radiation therapy

49. SURGERY • The preferred approach is a median sternotomy providing adequate exposure of the mediastinal structures and allowing complete removal of the thymus, • If the tumor is small and appears readily accessible, perform a total thymectomy with contiguous removal of mediastinal fat. • If the tumor is invasive, perform a total thymectomy in addition to en bloc removal of involved pericardium, pleura, lung, phrenic nerve, innominate vein, or superior vena cava. Resect one phrenic nerve; however, if both phrenics are involved, do not resect either nerve, and debulk the area. • Clip areas of close margins or residual disease to assist the radiation oncologist in treatment planning

50. 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. • Thymomas are indolent tumors that may take at least 10 years to recur; therefore, short-term follow-up will not depict relapses accurately. • Furthermore, the gross appearance of tumor invasiveness is subjective, depending on the opinion of the surgeon. In one report at Massachusetts General Hospital, 22% of patients (5 out of 23) with stage II disease developed recurrence, leading to a proposed recommendation that postoperative radiation be instituted in all patients with stage II thymoma