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Non Small Cell Lung Cancer New Pathological Staging System Oscar Nappi Anatomia Patologica AORN A. Cardarelli - Napoli Highlights in the Management of.

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Presentation on theme: "Non Small Cell Lung Cancer New Pathological Staging System Oscar Nappi Anatomia Patologica AORN A. Cardarelli - Napoli Highlights in the Management of."— Presentation transcript:

1 Non Small Cell Lung Cancer New Pathological Staging System Oscar Nappi Anatomia Patologica AORN A. Cardarelli - Napoli Highlights in the Management of lung cancer Domus Sessoriana, Rome May 15 – 16, 2009

2 Nella nuova classificazione TNM dei tumori polmonari,la presenza di noduli separati nello stesso lobo si indica con la sigla 1.M1 2.M0+ 3.T4 4.T2c 5.T3 0 / 30 Cross-tab label

3 Nella nuova classificazione TNM dei tumori polmonari la sigla T1a configura 0 / 5 Cross-tab label 1.Tumore inferiore o uguale a 3 cm 2.Tumore inferiore o uguale a 2 cm 3.Tumore compreso tra due e tre cm 4.Tumore superiore a 3 cm 5.Tumore compreso tra 1 e 3 cm

4 Nella nuova classificazione TNM dei tumori polmonari, un tumore che presenta anche noduli pleurici omolaterali o versamento pleurico maligno si indica con la sigla 1.M1b 2.M1 3.T4 4.M1a 5.T4a 0 / 5 Cross-tab label

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7 TNM Clinical cTNM or TNM Pathologic pTNM Retreatment rTNM Autopsy aTNM

8 Italy Dr Antonino Carbone (chair) Dr Emilio Bajetta Dr Franca Fossati Bellani Dr Generoso Bevilacqua Dr Emilio Bombardieri Dr Paolo Crosignani Dr Francesco Facciolo Dr Vincenzo Mazzaferro Dr Renato Musumeci Dr Giovanni Muto Dr Oscar Nappi Dr Donato Nitti Dr Roberto Orecchia Dr Ugo Pastorino Dr Marco Piemonte Dr Aldo Scarpa Dr Rosella Silvestrini Dr Giuseppe Spriano Dr Mauro Trovo Dr Mauro Truini National commites UICC

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10 Proposed Revisions for the 7 th Edition AJCC Cancer Staging Manual Disease Site Major ChangesFinal TNM Stage Groups New Site-Specific Factors Notes / Comments Head and Neck Introduction Resectable Moderately advanced Unresectable Very advanced T4a – Moderately advanced local disease T4b – Very advanced local disease Stage IVa, Moderately advanced, Local/regional disease Stage IVb, Very advanced, Local/regional disease Stage IVc, Distant, Metastatic disease Nodes No major changes Two descriptors added Upper (U) or Lower (L) neck Extracapsular spread, ECS +, ECS - Lip and Oral Cavity T4a – Moderately advanced T4b – Very advanced Stage IVa, Moderately advanced, Local/regional disease Stage IVb, Very advanced, Local/regional disease Stage IVc, Distant, Metastatic disease No change Pending Task Force submission CONFIDENTIAL: NOT FOR DISTRIBUTION 1 of 19

11 Lung Pending Task Force submission International Association for the Study of Lung Cancer IASLC

12 Proposed changes for lung cancer staging 7th edition of TNM T component Tumour size Multiple tumours Pleural invasion N component No changes in N component M component Minimal but significant change

13 Proposed changes for lung cancer staging 7th edition of TNM

14 TNM T1

15 T1 ( 6th ed ) Tumour < 3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus ( i.e. not in the main bronchus )

16 T1 6th Edition Tumour < 3 cm 7th Edition T1a Tumour < 2 cm T1b Tumour > 2 but < 3 cm

17 T2 6th edition Tumor with any of the following features of size or extent : more than 3 cm in greatest dimension involves main bronchus, 2 cm or more distal to the carina invades the visceral pleura associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung

18 T2 7th edition Tumor >3 cm but < 7 cm T2a - Tumor >3 cm but < 5 cm T2b - Tumor >5 cm but < 7 cm Tumor with any of the following features: * Involves main bronchus, 2 cm distal to carina * Invades visceral pleura * Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung

19 T2 6th Edition Tumor > 3 cm 7th Edition T2a Tumor > 3 cm but <5 cm Tumour between 3 and 7cm T2b Tumor > 5 cm but <7cm

20 T3 6th edition Tumor of any size that directly invades any of the following: chest wall (including superior sulcus tumors),diaphragm,mediastinal pleura,parietal pericardium Tumor of any size in the main bronchus less than 2 cm distal to the carina but without involvement of the carina Tumor of any size associated atelectasis or obstructive pneumonitis of the entire lung

21 T3 7th edition Tumour >7 cm Direct invasion of any of the following: chest wall, diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium, Tumour in the main bronchus <2 cm from carina (without involvement of carina) Atelectasis or obstructive pneumonitis of the entire lung Separate tumor nodules in the same lobe

22 6th ed T4 7th ed Tumor of any size that invades any of the following mediastinum heart great vessels trachea esophagus vertebral body * carina Tumor of any size that invades any of the following mediastinum heart great vessels trachea esophagus, vertebral body carina Recurrent laryngeal nerve

23 6th ed T4 7th ed * Tumor of any size with satellite tumor nodule(s) within the primary tumor lobe * Tumor of any size with a malignant pleural effusion * Separate tumor nodules in a different ipsilateral lobe

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25 Tumour size Summary Size cut off 3 cm ( T1 ) 6th ed New size cut off 2 cm ( T1a ) 7th ed 5 cm ( T2a ) 7 cm ( T2b )

26 Hsu PK, Huang HC, Hsich CC et al Effect of formalin fixation on tumor size determination in stage I non-small cell lung cancer Ann Thorac Surg 84 : 1825 – 1829, 2007 After formalin fixation 20% of tumours > 3 cm shrank by an average of 1cm ! Downstaged ! Size should be recorded from the unfixed specimen

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33 Multiple tumours It is important the communication between Surgeon and Pathologist ! Some tumours are more difficult to find for the Pathologist than the Radiologist ( i.e. Broncho-Alveolar Carcinoma )

34 Small cell carcinoma Shepherd FA, Crowley J, Van HP et al The International Association for the Study of lung cancer staging project : proposal regarding the clinical staging of small cell lung cancer in the fothcoming ( seventh ) edition of the tumor, node, metastasis classification for lung cancer J Thoracic Oncol 2 : 1067 – 1077, 2007

35 Carcinoid tumours The IASLC Staging Committee has reccomended that in the 7th edition that the TNM be applied to pulmonary carcinoid tumours

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38 Main changes in stage groupings T2b N0M0 from IB to IIA T2a N1M0 from IIB to IIA T4 N0 ( N1) M0 from IIIB to IIIA

39 5 years survival IA 50% IB 47% IIA 36% IIB 26% IIIA 19% IIIB 7% IV 2%

40 SCLC NSCLC

41 Squamous cell carc. Adenocarcinoma Large cell carcinoma Adenosquamous carc. Sarcomatoid carc.

42 Renewed interest in lung cancer histotype The advent of effective targeted therapies ! Anti EGFR ( Erlotinib, Gefinitib ) Anti VEGF ( Bevacizumab ) New chemotherapic agents

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44 Pathologists and Lung cancer 2/3 of lung cancer are unresectable/advanced Diagnosis of lung cancer is achieved on cytology ( even effusion ) or small biopsies Goal : To optimize the tumour tissue 1. Diagnosis 2. Possible biological markers ( EGFR,k-ras,ERCC1 etc… )

45 Diagnostic IHC in confirming and subtyping primary lung cancer TTF 1 P 63

46 Diagnostic IHC in confirming and subtyping primary lung cancer Napsin A

47 Pathologists Role At present Any effort has to be made in order to typizing Squamous Cell Carcinoma and Adenocarcinoma. A diagnosis of NSCLC - NOS should be avoided

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49 IHC in distinguish SCC and AC in poorly differentiated tumours TypeTTF-1 Napsina A p63 34betaH11 CK8 SCC_ _ _ +++ _ _ _ ADENO +++ _ _ _ +++

50 Large Cell Carcinoma WHO 2004 poorly differentiated NSCLC that lacks cytologic and architectural features of SCLC and glandular or squamous differentiation 5 variants: –LCNEC Large Cell Neuroendocrine Carcinoma –Basaloid –Lymphoepithelioma-like –Clear cell –Large cell with rhabdoid phenotype

51 Large Cell Carcinoma sec WHO 2004 Large Cell Carcinoma sec WHO 2004 Does it exist ? It should be considered a container of tumor patterns with different immuno- ( and geno ) typing profiles Today, in order to planning a correct therapy, it should be necessary to identify the clone of origin

52 LCNEC

53 LCNEC - immunohistochemistry c-kit TTF-1 CD56/NCAM ChrA Bcl-2

54 LCNEC – molecular biology LCNEC and SCLC seem to share common molecular alterations: p53 cell-cycle proteins (Rb, Cyclin D1, p16) apoptosis regulation- bax/bcl2 assessment of LOH by microsatellite markers

55 SCLC LCNEC NSCLC Molecular findings & Prognosis Clinical presentation & Pathologic features

56 Tumours with NE morpholohy WHO 2004 Typical carcinoid Atypical carcinoid Small cell carcinoma ( SCLC ) Large cell NEC ( LCNEC )

57 Should SCLC and LCNEC be included in the same category (as high-grade NE carcinomas) ? Differential diagnosis may be difficult Similar prognosis Identical IHC profile Very similar molecular profile, such as cell cycle regulatory proteins alterations (Rb/P16/Ciclina D1), p53, bcl2 Similar prognosis is not definitively proven It is not well-demonstrated that patients with LCNEC have the same clinical benefit from the therapeutical regimens adopted in SCLC YESNO

58 Rossi, G. et al. J Clin Oncol; 23:8774-8785 2005 Kaplan-Meier curves for overall survival stratified according to different chemotherapeutic regimens in the adjuvant setting SCLC-based:13 patients; median survival: 42 mos NSCLC-based:15 patients; median survival: 11 mos

59 Large Cell Carcinoma WHO 2004

60 Lung carcinomas with a basaloid pattern: a study of 90 cases focusing on their poor prognosis. Moro-Sibilot D, Lantuejoul S, Diab S, Moulai N, Aubert A, Timsit JF, Brambilla C, Brichon PY, Brambilla E. Moro-Sibilot DLantuejoul SDiab SMoulai NAubert ATimsit JF Brambilla CBrichon PYBrambilla E Basaloid carcinoma is a unique entity ( Variant of SCC + Variant of LCC ) Compared with NSCLC, in Stage I – II patients, its overall survival is significantly lower ( 29 vs 49 % ) as well as its 5 years survival rate ( 27% vs 44% ) Eur Resp 31 : 854 – 859, 2008

61 Large Cell Carcinoma WHO 2004

62 Lymphoepitelioma-like True entity but very rare Cases EBV – probably are Adenocarcinomas LCC with Rhabdoid phenotype * Rhabdoid pattern is a phenotype, never an entity. * It is very rare in the lung but it is a powerful adverse prognostic factor

63 Large Cell Carcinoma WHO 2004

64 Clear cell carcinoma It is not an Entity It is a pattern of SCC or Adenoca need to defining the origin clone by IHC DD Metastatic from other organs Clear cell tumors of unknown nature and origin : A systematic approach O Nappi, SE Mills, PE Swanson, MR Wick Sem diagn Pathol 14 :164 – 174, 1997

65 Am J Clin Pathol 2004; 122: 884-893 ADC-immunophenotype when CK7+, TTF-1+ 60% ADC 22% SqC 9% LCNEC 8 % ADSq 1 % Pleo SqC-immunophenotype when 34 E12 + LCNEC-immunophenotype when CD56+ variably CK7+, TTF-1+ 34 E12-

66 Large Cell Carcinoma sec WHO 2004 Large Cell Carcinoma sec WHO 2004 Does it exist ? It should be considered a container of tumor patterns with different immuno- ( and geno ) typing profiles Today, in order to planning a correct therapy, it should be necessary to identify the clone of origin : Squamous, Adenoca, Neuroendocrine Immunophenotypes

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68 2004 5. Pulmonary blastoma 8972/3 Sarcomatoid carcinomas ICD-O codes 4. Carcinosarcoma 8980/3 3. Giant cell carcinoma 8031/3 2. Spindle cell carcinoma 8032/3 1. Pleomorphic carcinoma 8022/3

69 AC LCC SCC CKs EMA E-cadherin p27 p21 FHIT Vimentin SMA Fascin MVD

70 EMT refers to the loss of epithelial cell traits and the acquisition of a mesenchymal phenotype by cells with motile propertiesEMT refers to the loss of epithelial cell traits and the acquisition of a mesenchymal phenotype by cells with motile properties EMT is pivotal in a variety of conditions including normal ontogenesis, fibrosis, wound healing, inflammation and tumor progression (with invasiveness and metastasis formation)EMT is pivotal in a variety of conditions including normal ontogenesis, fibrosis, wound healing, inflammation and tumor progression (with invasiveness and metastasis formation) EPITHELIAL- MESENCHYMAL TRANSITION (EMT)

71 Sarcomatoid carcinoma It is not an Entity but a Phenotype secondary to selection of aggressive cellular clones arising in SCC or Adenocarcinoma The EMT ( epithelial- mesenchymal transition ) patway is involved, probably by the upregulation of c-Jun gene Implication in therapy

72 Grazie

73 Nella nuova classificazione TNM dei tumori polmonari,la presenza di noduli separati nello stesso lobo si indica con la sigla 1.M1 2.M0+ 3.T4 4.T2c 5.T3 0 / 5 Cross-tab label

74 Nella nuova classificazione TNM dei tumori polmonari, un tumore che presenta anche noduli pleurici omolaterali o versamento pleurico maligno si indica con la sigla 1.M1b 2.M1 3.T4 4.M1a 5.T4a 0 / 5 Cross-tab label

75 Nella nuova classificazione TNM dei tumori polmonari la sigla T1a configura 0 / 5 Cross-tab label 1.Tumore inferiore o uguale a 3 cm 2.Tumore inferiore o uguale a 2 cm 3.Tumore compreso tra due e tre cm 4.Tumore superiore a 3 cm 5.Tumore compreso tra 1 e 3 cm


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