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