Thymic Epithelial Tumors

Transcription

1 Thymic Epithelial Tumors What are the Challenges & What is New? Anja C. Roden, M.D. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

2 No disclosures Disclosure

3 Thymic Epithelial Tumors Outline Clinical characteristics WHO classification & updates Molecular findings Staging Thymic carcinoma Differential diagnosis

4 41 yo male Case History Progressive bilateral ptosis and diplopia since 1 yr

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6 3.0 cm

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10 Diagnosis? A. Embryonal carcinoma B. Large B cell lymphoma C.NUT carcinoma D.Thymic carcinoma E. Type B3 thymoma

11 Invasive WHO type B3 Thymoma

12 Additional Case History Weakness in shoulders and arms Serology: + acetylcholine receptor antibodies Tensilon test + Myasthenia gravis

13 Thymoma 21% of patients with MG have thymoma 40% have paraneoplastic syndrome Derived from epithelial cells Incidence, 1-5/million population/year Most common mediastinal & prevascular (anterior) mediastinal neoplasm (adults) No sex predilection Most common age, years Romi F Autoimm dis.; Mao ZF J Clin Neurol.8:161-9 Morgenthaler TI Mayo Clin Proc. 68:

14 50% asymptomatic Substernal pain Compression / obstruction Cough, dyspnea, wheezing SVC syndrome Symptoms Systemic: Fever, weight loss Pulmonary Anatomy (Thorax) flashcards/quizlet

15 Thymic Epithelial Tumors Pathology Evaluation 1. Morphologic features 2. Invasion, implants, LN, distant metastases Staging 3. Evaluation of margins

16 Thymoma Lobulated Architecture Cellular Lobules Fibrous Bands

17 Thymoma WHO Classification Letters shape of tumor cells A - Spindle/oval B - Dendritic or plump ( epithelioid ) Numbers (types B1 B3) Increase in tumor cells : lymphocyte ratio Atypia of tumor cells Presence / absence medullary elements

18 A B1 AB B2 AB B3

19 Uncommon Thymomas

20 Micronodular Thymoma with Lymphoid Stroma

21 Metaplastic Thymoma

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23 Microscopic Thymoma

24 Thymoma on Biopsy

25 Thymoma on Biopsy

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27 Thymoma on Bx Keratin! Keratin AE1/AE3 Potential heterogeneity of thymomas Thymomas are not typed on bx

28 WHO What s New? Thymomas are malignant! Atypical type A thymoma Refinement of histological and IHC criteria Reproducibility obligatory/indispensable vs optional criteria If > 1 subtype in resection recommend to list all types (10% increments) (except AB) Marx A et al J Thorac Oncol; 10:

29 WHO What s New? Combined thymic carcinoma Thymic carcinoma + thymoma/carcinoid tumor (reporting starts with carcinoma) Multiple subtypes of thymic Ca IHC for difficult to classify thymoma and thymic Ca Marx A et al J Thorac Oncol; 10:

30 Atypical Type A Thymoma

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33 Refinement of Types B1 & B2 Type B1= Thymus-like architecture and cytology, abundance of immature T cells, areas of medullary differentiation (medullary islands), paucity of polygonal or dendritic epithelial cells without clustering (i.e., < 3 contiguous epithelial cells) Optional: Hassall corpuscles, perivascular spaces Marx A et al J Thorac Oncol; 10:

34 Type B1 Thymoma

35 Type B2 Thymoma

36 WHO Classification Overall Survival Probability N=456 P= Time (Years) A AB B1 B2 B3 Carcinoma Modified from Roden AC et al. AJSP :

37 Thymoma Prognostic Parameters WHO not prognostic for OS if adjusted for modified Masaoka staging Modified Masaoka staging - independent of histologic classification Complete resection Assess margins Roden AC et al. JTO (4):

38 Why Classify TET by Histology? Follow up of patients Comparison with metastases and recurrences Differences in tumor biology and genetic findings

39 Thymic Epithelial Tumors Molecular Findings Limited overlap of genetic alterations of TET with other cancers LOH in 6q = most common chromosomal deletion FOXC1 potential target (tumor suppressor gene) FOXC1 copy# loss more aggressive tumors, protein expression GTF2I (oncogene) missense mutations = most common alteration overall

40 Molecular Findings by WHO WHO Type LOH in 6q GTF2I Missense mutation (% cases) A + 82 AB + 74 B1-32 B B SQCC + 8 Travis WD et al. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyon, France: IARC Press; 2015.

41 *Roden, AC. Unpublished data. Travis WD et al. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyon, France: IARC Press; WHO AB B2 B3 Molecular Findings More frequent and complex than A A areas genetically different from A thym. More alterations than A, less than B3 Copy# gain of BCL2, loss of CDKN2A TCa SQCC KIT mutation (up to 11%); Copy# gain of BCL2, loss of CDKN2A Loss of p16 associated with RFS & OS*

42 Thymic Epithelial Tumors Staging No AJCC Thymoma: Modified Masaoka (Koga) staging Thymic carcinoma: TNM Modified Masaoka

43 Masaoka A Cancer.48: Koga K et al. Pathol Int : Stage I II III IV Modified Masaoka (Koga) Staging Macroscopically completely encapsulated, microscopically no capsular invasion A. Microscopic transcapsular invasion B. Macroscopic invasion into extracapsular soft tissue, or tumor grossly adherent to mediastinal pleura or pericardium Macroscopic invasion into neighboring organs A. Pleural or pericardial dissemination B. Lymphogenous or hematogenous mets

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46 What is the stage of this TET? A. I B. II C.III D.IVA E. IVB

47 Modified Masaoka Stage Overall Survival Probability I II III IV Time (Years) N=456 p< Modified from Roden AC et al. AJSP :

48 Challenges of Current Staging Should be applicable to thymoma, thymic carcinoma and NET Occasional lack of complete capsule Difference between macroscopic invasion and adherence to the mediastinal pleura or pericardium? Difference between invasion of and breaking through mediastinal pleura / pericardium Detterbeck FC et al J Thorac Oncol. 9:S

49 Proposed IASLC/ITMIG Staging Stage T N M Definition I Up to extension into mediastinal fat/pleura II Pericardium Lung, BCV, SVC, chest wall, IIIa phrenic nerve, hilar (extrapericardial) pulmonary vessels Staging requires microscopic confirmation Detterbeck FC et al J Thorac Oncol. 9:S

50 Proposed IASLC/ITMIG Staging Stage T N M IIIb IVa any IVb any 1 0,1 2 any 0 1a 0,1a 1b Definition Aorta, arch vessels, main PA, myocardium, trachea, esophagus Anterior (perithymic) nodes Pleural / pericardial nodule(s) Deep intrathoracic / cervical nodes Pulm intraparenchymal nodule, distant organ met

51 Type B3 Thymoma

52 Differential Diagnosis Thymoma, type A Thymic carcinoma Lymphoma Neuroendocrine tumor (esp. carcinoid) Germ cell tumors

53 Thymic carcinoma Architecture distorted Desmoplasia

54 Aggressive Thymic carcinoma Frequently metastasize and recur 10-yr survival 0-34% (67%, single study) Median time to death, yrs Often diagnosed at high stage unresectable and/or require neoadjuvant therapy.

55 Thymic Carcinoma Distorted Architecture

56 Squamous cell carcinoma

57 Thymic Carcinoma on Biopsy 48 yo man, prevascular med. mass

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61 p40 TdT Squamous cell carcinoma Ki-67

62 Ki-67 Labelling Index in Type A & B3 Thymoma and Thymic Ca Ki-67 LI (%) < < Prediction A Inconclusive TCa Observed, n (%) A 4 (100) 25 (58) 0 B (35) 0 TCa 0 3 (7) 9 (100) Roden AC et al. Hum Pathol :17-25

63 22 yo, cough, hemoptysis, night sweats Prevascular. med. mass compressing trachea

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66 CK5/6

67 EBV ISH Lymphoepithelioma- Like Carcinoma

68 17 yo, large right mainstem / subxiphoid process mass, metastases

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72 Keratin AE1/AE3 CK7 p40 TTF-1 CK5/6+, CD5-, CD117-

73 NUT NUT Carcinoma

74 Rare but aggressive NUT Carcinoma Midline predominance (90%) Most common: Thorax (57%), head & neck Pleuritic chest pain, non-productive cough, SOB, weight loss (thoracic tumor) No sex predominance Age, median 16-50yrs (range, ) Kubonishi I et al. Cancer Res : Suzuki S et al Pathol Res Pract.

75 Dey A et al. PNAS : French CA et al. Cancer Res : French CA et al. J Clin Oncol : French CA et al : NUT Ca-Pathogenesis Aggressive subset of SQCC Karyotype - simple ( most solid malignancies) Rearrangement and translocation of NUT (NUTM1) gene - BRD4-NUT - t(15;19)(q14;p13.1) (70%) - BRD3-NUT 2,3 - NUT-variant fusions

76 Diagnosis of NUT Carcinoma

77 Histopathology Undifferentiated morphology - Small-to-medium sized neoplastic cells - Monotonous round-to-oval nuclei - Clear/vesicular cytoplasm - Prominent nucleoli - Might mimic small cell carcinoma +/- Abrupt squamous differentiation French CA. Annu Rev Pathol :

78 Undifferentiated morphology

79 Abrupt squamous differentiation

80 NUT Carcinoma - IHC NUT immunostain - Nuclear staining, speckled pattern - Specificity 100%, sensitivity 87% (non-germ cell carcinoma) Markers of squamous differentiation TTF-1, CD34 focally in some cases Haack H et al. AJSP :

81 CK 7 CK 5/6 TTF-1 multifocal NUT

82 NUT Ca Cytogenetics/Molecular FISH RT-PCR Karyotype Because of PPV of IHC confirmatory FISH, PCR, cytogenetics are not necessary

83 NUT Carcinoma - Outcome Metastasis at presentation 51% Usually fatal Overall survival, median 6.7 mos Aggressive initial surgical resection +/- postop. chemoradiation or radiation associated with increased survival Chemotherapy or radiation alone ineffective Bauer DE et al Clin Cancer Res 2012; 18: N=63, Outcome N=54 Chau NG et al. J Clin Oncol. 2014; 32:5s. N=40, head & neck NUT Ca

84 NUT Carcinoma Outcome Treatment N 2-yr PFS (%) P- value 2-yr OS (%) P- value Surgery +/- chemo or RT RT +/- chemo or chemo +/- surgery or RT head & neck NUT Ca, 31 with outcome data Chau NG et al. J Clin Oncol. 2014; 32:5s. N=40, head & neck NUT Ca

85 NUT Ca-Treatment Options Phase I clinical trials with BET inhibitors (bromodomain and extraterminal domain family) - Target BRD4-NUT protein - Induce squamous differentiation International NUT midline carcinoma registry.

86 NUT Ca-Treatment Options In vitro therapy with histone deacetylase inhibitors (restore chromatin acetylation) induced terminal differentiation of NMC cells Phase 2 trial of dual PI3 kinase/ HDAC inhibitor drug Diagnosis of NUT Carcinoma is important (FISH and/or IHC) International NUT midline carcinoma registry.

87 Thymic carcinoma Squamous cell carcinoma (29-67%) Basaloid carcinoma Mucoepidermoid carcinoma Lymphoepithelioma-like carcinoma Clear cell carcinoma Sarcomatoid carcinoma Adenocarcinoma NUT carcinoma Undifferentiated Carcinoma Others

88 Metastases Thymic Ca, Non-Lymphoid % Metastasis, % CD * CD ** CD5 & CD (lung SQCC) CD FoxN * Adeno Ca of GI, breast, lung, GYN, epithelioid sarcoma, mesothelioma, UCC; clone dependent ** SQCC of lung, GIST, Germ cell tumors

89 Thymic Carcinoma vs Met. Clinical & radiologic correlation

90 Thymic Epithelial Tumors Response to Treatment Neoadjuvant therapy resectability No standardized reporting system Can radiologic treatment response predict pathologic treatment response? Unresectable TET (28 thymoma, 21 thymic Ca) neoadjuvant treatment Tumor response grade (TRG) Johnson G et al In Press, JTO.

91 Tumor 1 Response Grade (TRG) 2

92 Tumor 3 Response Grade (TRG) 4 5

93 Thymic Epithelial Tumors Response to Treatment TRG easy, reproducible (Krippendorff α,0.84) Morphologic response: Thymic Ca > thymoma ( % viable tumor, TRG) Imaging reasonable predicts pathologic response: Partial radiologic response / larger reduction in tumor diameter/volume % viable tumor, TRG Johnson G et al. In Press, JTO.

94 66 yo, 6.7cm thymic mass; 2 yrs later retrocrural LN met

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97 Mitoses 3/10 Hpf

98 Keratin AE1/AE3 Synaptophysin Atypical Carcinoid Tumor TTF-1 Ki-67

99 Neuroendocrine Tumors Typical carcinoid Atypical carcinoid - Mitoses 2 10 / 10 Hpf and / or - Necrosis Large cell neuroendocrine carcinoma Small cell carcinoma Combined SCC/LCNEC

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101 TdT Keratin CD3 T-Lymphoblastic Lymphoma in Thymic Gland

102 Lymphoma in Mediastinum T-/ B- lymphoblastic leukemia/lymphoma Classical Hodgkin lymphoma, NS type Diffuse large B-cell lymphoma Primary mediastinal (thymic) large B-cell lymphoma Extranodal and nodal marginal zone B-cell lymphomas

103 20 yo, shoulder pain, fatigue, clavicular mass, bx susp. for lymphoma; w/u revealed prevascular med. mass

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108 Keratin CD117 OCT4 Seminoma

109 Germ Cell Tumors 15% (adults), 24% (children) of prevascular mediastinal tumors? Develop in cell rests that failed complete migration from urogenital ridge to gonads Exclude metastasis Testicular exam Testicular seminoma rarely metastasize to mediastinum if negative retroperitoneal LN Serology: β HCG - embryonal carcinoma AFP - yolk sac tumor or ECa

110 Architecture Other Prevascular Mediastinal Mass Thymoma Thymic Ca. Lobulated Distorted Pre- Fibrous bands Thymic Gland Cortex & Medulla Neuroendocrine Tumor served Neuroendocrine Desmoplasia Neuroendocrine IHC Lymphoma Usually Effaced Follicular Lymphoma IHC/Flow Keratin Diffuse Diffuse Focal Diffuse Negative TdT+ thymocytes Present Absent Present Absent? Immature T cells +/-

111 Take Home Message Thymoma: Staging, resection status Thymoma vs thymic carcinoma: Morphology Thymic carcinoma vs metastasis: Correlation with clinic and radiology Consider differential diagnosis Molecular Findings more to come soon

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