1. Non Small Cell Lung Cancer New Pathological Staging System
Highlights in the Management of lung cancer
Domus Sessoriana, Rome
Non Small Cell Lung Cancer New Pathological Staging System
Oscar Nappi
Anatomia Patologica
AORN A. Cardarelli - Napoli
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 M1
M0+ T4
T2c T3
Cross-tab label
0 / 30

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

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

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

8. Dr Antonino Carbone (chair) Dr Emilio Bajetta
National commites
UICC
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

10. New Site-Specific Factors
Proposed Revisions for the 7th Edition
AJCC Cancer Staging Manual
Disease Site
Major Changes
Final 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
No change
Pending Task Force submission
CONFIDENTIAL: NOT FOR DISTRIBUTION 1 of 19

11. International Association for the Study of Lung Cancer IASLC
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
T component
Tumour size
Multiple tumours
Pleural invasion

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. T1b Tumour > 2 but < 3 cm
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. T2a Tumor > 3 cm but <5 cm
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 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 T th 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

25. Tumour size Summary Size cut off 3 cm ( T1 ) 6th ed
New size cut off cm ( T1a )
7th ed 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

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

38. Main changes in stage groupings
T2b N0M from IB to IIA
T2a N1M from IIB to IIA
T4 N0 ( N1) M from IIIB to IIIA

39. 5 years survival
IA %
IB %
IIA %
IIB %
IIIA %
IIIB %
IV %

40. SCLC
NSCLC

41. NSCLC 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

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. 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

49. IHC in distinguish SCC and AC in poorly differentiated tumours
Type
TTF-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 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
CD56/NCAM
Bcl-2
ChrA
TTF-1

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

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) ?
YES NO
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

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
Rossi, G. et al. J Clin Oncol; 23:

59. 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

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.
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
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

62. 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
Lymphoepitelioma-like
True entity but very rare
Cases EBV – probably are Adenocarcinomas

63. 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

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. 60% ADC 22% SqC 9% LCNEC 8 % ADSq 1 % Pleo
Am J Clin Pathol 2004; 122:
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 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

67. 67

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

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

70. EPITHELIAL-MESENCHYMAL TRANSITION (EMT)
EMT 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) 70

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 M1
M0+ T4
T2c T3
Cross-tab label
0 / 5

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

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