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
Mar 26, 2015
Non Small Cell Lung Cancer
New Pathological Staging System
Oscar NappiAnatomia Patologica
AORN A. Cardarelli - Napoli
Highlights in the Management of lung cancerDomus Sessoriana, Rome
May 15 – 16, 2009
Nella nuova classificazione TNM dei tumori polmonari,la presenza di noduli separati nello
stesso lobo si indica con la sigla
1. M12. M0+3. T44. T2c5. T3
0 / 30 Cross-tab label
120%
220%
320%
420%
520%
20%
20%
20%
20%
20%
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
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. M1b2. M13. T44. M1a5. T4a
0 / 5 Cross-tab label
20% 20% 20% 20% 20%
1 2 3 4 5
TNM
• Clinical cTNM or TNM
• Pathologic pTNM
• Retreatment rTNM
• Autopsy aTNM
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 commitesUICC
Proposed Revisions for the 7th EditionAJCC Cancer Staging Manual
Disease Site
Major Changes Final TNM Stage GroupsNew Site-Specific
FactorsNotes /
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 diseaseNodes•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
Lung Pending Task Force submission
Pending Task Force submission Pending Task Force submission
International Association for the Study of Lung CancerIASLC
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
Proposed changes for lung cancer staging 7th edition of TNM
T component
Tumour size
Multiple tumoursMultiple tumours
Pleural invasionPleural invasion
TNM
T1
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 )
T1
6th Edition
Tumour < 3 cm
7th Edition
T1a Tumour < 2 cm
T1b Tumour > 2 but < 3 cm
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
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
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
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
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
6th ed T4 7th ed
Tumor of any size thatinvades any of the following
• mediastinum • heart • great vessels • trachea • esophagus • vertebral body
* carina
Tumor of any size thatinvades any of the following • mediastinum• heart• great vessels• trachea• esophagus,• vertebral body • carina • Recurrent laryngeal nerve
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
Tumour sizeSummary
• Size cut off 3 cm ( T1 )
6th ed
• New size cut off 2 cm ( T1a )
7th ed 5 cm ( T2a )
7 cm ( T2b )
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
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 )
Small cell carcinoma
Shepherd FA, Crowley J, Van HP et al
The International Association for the Studyof lung cancer staging project : proposalregarding the clinical staging of small celllung cancer in the fothcoming ( seventh )edition of the tumor, node, metastasisclassification for lung cancer
J Thoracic Oncol 2 : 1067 – 1077, 2007
Carcinoid tumours
The IASLC Staging Committee hasreccomended that in the 7th
editionthat the TNM be applied to
pulmonarycarcinoid tumours
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
5 years survival
• IA 50%
• IB 47%
• IIA 36%
• IIB 26%
• IIIA 19%
• IIIB 7%
• IV 2%
SCLC
NSCLC
NSCLC
• Squamous cell carc.• Adenocarcinoma• Large cell carcinoma• Adenosquamous carc.• Sarcomatoid carc.
Renewed interest in lung cancer histotype
The advent of effective targeted therapies !
• Anti EGFR ( Erlotinib, Gefinitib )
• Anti VEGF ( Bevacizumab )
• New chemotherapic agents
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… )
Diagnostic IHC in confirming and subtyping primary lung cancer
• TTF 1
• P 63
Diagnostic IHC in confirming and subtyping primary lung cancer
Napsin A
Pathologist’s 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
IHC in distinguish SCC and AC in poorly differentiated tumours
Type TTF-1
Napsina A
p63
34betaH11
CK8
SCC _ _ _ +++ _ _ _
ADENO +++ _ _ _ +++
Large Cell CarcinomaLarge Cell CarcinomaWHO 2004WHO 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
Large Cell Carcinoma sec WHO 2004Large Cell Carcinoma sec WHO 2004Does 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
LCNECLCNEC
LCNEC - LCNEC - immunohistochemistryimmunohistochemistry
c-kitc-kit
TTF-1TTF-1
CD56/NCAMCD56/NCAM
ChrAChrA
Bcl-2Bcl-2
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
SCLC
LCNEC
NSCLC
Molecular findings
&Prognosis
Clinical presentation&
Pathologic features
Tumours with NE morpholohyWHO 2004
• Typical carcinoid
• Atypical carcinoid
• Small cell carcinoma ( SCLC )
• Large cell NEC ( LCNEC )
Should SCLC and LCNEC be included in the Should SCLC and LCNEC be included in the same category (as high-grade NE same category (as high-grade NE
carcinomas) ?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
YESYES NONO
Copyright © American Society of Clinical Oncology
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 mosNSCLC-based: 15 patients; median survival: 11 mos
Large Cell CarcinomaLarge Cell CarcinomaWHO 2004WHO 2004
• poorly differentiated NSCLC that lacks cytologic and architectural features of SCLC and glandular or squamous differentiation
• 5 variants:– LCNEC LCNEC Large Cell Neuroendocrine Large Cell Neuroendocrine
CarcinomaCarcinoma– Basaloid– Lymphoepithelioma-like– Clear cell– Large cell with rhabdoid phenotype
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.
• 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
Large Cell CarcinomaLarge Cell CarcinomaWHO 2004WHO 2004
• poorly differentiated NSCLC that lacks cytologic and architectural features of SCLC and glandular or squamous differentiation
• 5 variants:– LCNEC LCNEC Large Cell Neuroendocrine Large Cell Neuroendocrine
CarcinomaCarcinoma– BasaloidBasaloid– Lymphoepithelioma-like– Clear cell– Large cell with rhabdoid phenotype
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
Large Cell CarcinomaLarge Cell CarcinomaWHO 2004WHO 2004
• poorly differentiated NSCLC that lacks cytologic and architectural features of SCLC and glandular or squamous differentiation
• 5 variants:– LCNEC LCNEC Large Cell Neuroendocrine Large Cell Neuroendocrine
CarcinomaCarcinoma– BasaloidBasaloid– Lymphoepithelioma-likeLymphoepithelioma-like– Clear cell– Large cell with rhabdoid phenotypeLarge cell with rhabdoid phenotype
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 approachO Nappi, SE Mills, PE Swanson, MR WickSem diagn Pathol 14 :164 – 174, 1997
Am J Clin Pathol 2004; 122: 884-893
ADC-immunophenotype when CK7+, TTF-1+ 60% ADC22% SqC9% LCNEC8 % ADSq1 % Pleo
SqC-immunophenotype when 34E12 +
LCNEC-immunophenotype when CD56+variably CK7+, TTF-1+34E12-
Large Cell Carcinoma sec WHO 2004Large Cell Carcinoma sec WHO 2004Does 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
2004
5. Pulmonary blastoma 8972/3
Sarcomatoidcarcinomas
ICD-O codes
4. Carcinosarcoma 8980/3
3. Giant cell carcinoma 8031/3
2. Spindle cell carcinoma 8032/3
1. Pleomorphic carcinoma 8022/3
AC
LCC
SCC
CKsEMAE-cadherinp27 p21FHIT
VimentinSMAFascinMVD
• EMT refers to the loss of epithelial cell traits and EMT refers to the loss of epithelial cell traits and the acquisition of a mesenchymal phenotype by the acquisition of a mesenchymal phenotype by cells with motile properties cells with motile properties
• EMT is pivotal in a variety of conditions including EMT is pivotal in a variety of conditions including normal ontogenesis, fibrosis, wound healing, normal ontogenesis, fibrosis, wound healing, inflammation and tumor progression (with inflammation and tumor progression (with invasiveness and metastasis formation)invasiveness and metastasis formation)
EPITHELIAL-EPITHELIAL-MESENCHYMALMESENCHYMAL
TRANSITION (EMT)TRANSITION (EMT)
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
Grazie
Nella nuova classificazione TNM dei tumori polmonari,la presenza di noduli separati nello
stesso lobo si indica con la sigla
1. M12. M0+3. T44. T2c5. T3
0 / 5 Cross-tab label
120%
220%
320%
420%
520%
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. M1b2. M13. T44. M1a5. T4a
0 / 5 Cross-tab label
20% 20% 20% 20% 20%
1 2 3 4 5
20%
20%
20%
20%
20%
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