Brambilla, Elisabeth

Eymin, Béatrice

Gazzeri, Sylvie

Lantuejoul, Sylvie

Merdzhanova, Galia

Salon, Caroline

Elsevier - Publisher Connector 

Journal of Thoracic Oncology • Volume 2, Number 8, Supplement 4, August 2007  12th World Conference on Lung Cancer
Copyright © 2007 by the International Association for the Study of Lung CancerS400
2. collapse with bronchioalveolarcell carcinoma (CwB), 3. adenocar-
cinoma cells (Cells), 4. ﬁbroblasts (F), and 5. mucus (M). Areas of 
air-type adenocarcinomas (in 49 cases) demonstrated predominantly 
C and/or CwB (C/CwB type: in 46 cases). Areas of solid-type adeno-
carcinomas (in 69 cases), in comparison, demonstrated predominantly 
Cells and/or Cells/F (Cells/F type: in 66 cases). We noted a statistically 
signiﬁcant difference between the histopathological ﬁndings of the 
areas of tumor opacity on mediastinal window images of air-type and 
solid-type tumors. In 34 cases, Cells/F type adenocarcinomas revealed 
microscopic evidence of metastasis (pleural involvement, vascular 
invasion, lymphatic permeation, or lymphnode metastsis). Whereas, no 
C/CwB type adenocarcinomas cases revealed any microscopic metasta-
sis. The prognosis of C/CwB after resection is better than for Cells/F.
Conclusion: We found that ‘Air-type’ adenocarcinomas demonstrated 
C/CwB type, and that ‘Solid-type’ adenocarcinomas demonastrated 
Cells/F type. We concluded that the histopathological ﬁndings of small 
pulmonary adenocarcinomas could be classiﬁed into two groups: 
C/CwB type and Cells/F type. The prognosis of C/CwB is better than 
for Cells/F.
D4-02 Pathology, Thu, 12:30 - 14:15
Aneusomy by FISH analysis and histology as predictors of invasive 
lung cancer in bronchial biopsies from high risk subjects
Jonsson, Steinn1 Varella-Garcia, Marileila2 Miller, York E.3 Wolf, Holly 
J.2 Byers, Tim2 Kiatsimkul, Porntip2 Bjornsson, Johannes O.1 Lam, 
Stephen C.4 Hirsch, Fred R.2 Franklin, Wilbur A.2 
1 University of Iceland, Reykjavik, Iceland 2 University of Colorado, Au-
rora, CO, USA 3 University of Colorado, Denver, CO, USA 4 University 
of British Columbia, Vancouver, BC, Canada 
Background: The development of Lung Carcinoma (LC) is accompa-
nied by ﬁeld changes of histological and chromosomal abnormalities in 
the airway mucosa. Neither histological grade nor markers of chro-
mosomal abnormalities in preneoplastic epithelial lesions have been 
adequately validated as predictors of invasive LC. 
Methods: Histological dysplasia score and chromosomal aneusomy 
measured by FISH analysis were compared as correlates of invasive 
LC in a case-control study of 44 individuals with LC (cases) and 90 
individuals without LC (controls). We used bronchial biopsy samples 
from subjects found by LIFE or white light bronchoscopy to have had 
moderate dysplasia (MD), severe dysplasia (SD) or carcinoma in situ 
(CIS). Tissue samples were reviewed by the study pathologist, the 
grades of preneoplastic change were veriﬁed and the appropriate areas 
in each histological slide were selected for FISH analysis. A 4-color 
FISH probe was used for aneusomy detection targeting centromere 6, 
5p15.2, 7p12 (EGFR) and 8q24 (CMYC). Three or more copies for two 
or more of these DNA targets indicated an aneusomic cell. Premalig-
nant lesions were classiﬁed as aneusomic when displaying aneusomic 
cells above the threshold deﬁned in normal bronchial epithelium (mean 
+ 3 SD). 
Results: The population included 104 males and 30 females with a 
mean age of 64 years and a mean smoking history of 62 pack-years. 
There was no difference in mean age, sex distribution or pack-years 
of smoking between LC cases and controls, but cases had a higher 
frequency of current smokers (p=0.05). Thirty two had CIS as the 
highest histological grade of mucosal abnormality, 48 had SD and 54 
MD. The strongest correlate with invasive LC was CIS by histological 
examination (OR=12.5, 95% CI 4.1 to 38.1). Chromosomal aneusomy 
was seen in 64% of the LC cases but in only 31% of the controls. (OR 
= 4.6, 95% CI 2.0 to 10.9). The proportion of subjects with chromo-
somal aneusomy increased from moderate dysplasia (22.2%) to severe 
dysplasia (41.7%) and CIS lesions (71.9%) and showed a similar trend 
for cases and controls. Presence of aneusomy slightly increased the risk 
for LC in MD (OR=1.91, 95% CI 0.26 to 13.8) but was a substantial 
impacting factor in subjects with SD (OR=7.06, 95% CI 0.82 to 60.1) 
and CIS (OR=5.93, 95% CI 0.5 to 69.7).
Conclusions: CIS on histological examination and abnormal FISH 
analysis are both associated with lung cancer cross-sectionally. Future 
studies need to examine these biomarkers prospectively, and to assess 
their interaction in predicting lung cancer risk. 
D4-03 Pathology, Thu, 12:30 - 14:15
SCF protein (Skp2, CUL1) regulate the E2F1 dependent 
transcriptional activity and cyclin E in human lung tumors
Brambilla, Elisabeth1 Salon, Caroline1 Merdzhanova, Galia1 
Lantuejoul, Sylvie1 Gazzeri, Sylvie1 Eymin, Béatrice2 
1 Lung Tumor Research Group INSERM U823, University Joseph 
Fourier, Grenoble, France 2 INSERM U823, University Joseph Fourier, 
Grenoble, France 
Background: The E2F1 transcription factor is a cell cycle and onco-
genic protein which plays ambiguous role in promoting proliferation 
or apoptosis depending on histological cell type of lung cancer (Salon 
et al. Cell Death and Differ. 2006). Accordingly, its activity is tightly 
controlled by transcriptional and post-transcriptional events in which 
the ubiquitin-proteasome pathway mediated by SCF complexes such 
as Skp2 and Cullin 1 (CUL1) proteins play a role in its degradation. 
We have previously identiﬁed differential pattern of E2F1 protein 
expression in human lung cancer with high expression in high grade 
neuroendocrine tumors, in contrast with low or no expression in non 
small cell carcinoma and in carcinoids (small cell lung carcinoma and 
large cell neuroendocrine carcinoma) (Eymin et al. Oncogene 2001). 
In order to investigate the role of proteasome degradation in E2F1 
expression and activity we analyzed the components of SCF complex 
(Skp2 and CUL1) to understand their role on expression of E2F1 and 
its transcriptional targets cyclin E, important regulators of cell cycle at 
G1-S transition.
Methods: Using immunohistochemistry and immunoblotting we ana-
lyzed 128 lung tumors of all histological types for the relationship link-
ing E2F1 and two components CUL1 and Skp2 of the ubiquitin-protein 
ligase SCFSkp2 <involved in E2F1 proteolysis and the consequence on 
cyclin E level expression.
Results: Skp2 protein was more often overexpressed in high grade neu-
roendocrine (HGNE) carcinoma (46/54; 86 %) than in NSCLC (16/50; 
32 %) (p<0.0001), and undetectable in 25/25 carcinoids. Overexpres-
sion of E2F1 and Skp2 proteins were directly correlated in HGNE 
tumors where Skp2 overexpression was correlated with advanced stage 
(p<0.0001) and nodal metastasis (p<0.0001). There was a signiﬁcant 
correlation between Skp2 and Ki67 across histological types (p=0.01). 
No correlation was found between E2F1 and CUL1. In in vitro cellular 
models we provided evidence that Skp2 is a novel transcriptional target 
of E2F1. Skp2 interacts with E2F1 and stimulates its transcriptional 
activity toward the cyclin E promoter. Consistently, we found a cor-
relation between Skp2 and cyclin E (p<0.0001) and between E2F1 and 
cyclin E in neuroendocrine lung tumors (p=0.0001). In contrast, CUL1 
Copyright © 2007 by the International Association for the Study of Lung Cancer S401
Journal of Thoracic Oncology • Volume 2, Number 8, Supplement 4, August 2007  12th World Conference on Lung Cancer
correlated with downregulation and low cyclin E level (p=0.0003), and 
low Ki67 proliferative marker across histological types (p=0.005).
Conclusions: Our data provide the ﬁrst evident of a direct and func-
tional interconnection linking E2F1, the ratio of Skp2 / CUL1, and 
cyclin E oncoproteins in human tumors. Whereas Skp2 cooperate with 
E2F1 to activate its transcriptional function of E2F1 towards cyclin E, 
CUL1 was identiﬁed as a negative regulator of cyclin E suggesting that 
CUL1 could play a role in limiting the progression of neuroendocrine 
lung tumors. This indicates therapeutic target for inhibitors of protea-
some in high grade neuroendocrine lung tumors. 
D4-04 Pathology, Thu, 12:30 - 14:15
Useful prognostic factors in small-sized adenocarcinoma
Anami, Yoichi1 Suzuki, Kenji2 Matsuno, Yoshihiro3 Yokota, Jun4 
Noguchi, Masayuki1 
1 Dept. of Pathology, Graduate School of Comprehensive Human Sci-
ence, University of Tsukuba., Tsukuba, Japan 2 Division of Thoracic 
Surgery, National Cancer Center Hospital, Tokyo, Japan 3 Diagnostic 
Pathology Division, National Cancer Center Hospital, Tokyo, Japan 
4 Biology Division National Cancer Center Research Institute, Tokyo, 
Japan 
Background: With the progression of radiologic methodology such as 
thin section CT and/or high resolution CT, recently we become to diag-
nose many small-sized adenocarcinoma (less than 2 cm in diameter). In 
order to diagnose the degree of their malignancy, we need convenient 
prognostic factors. On the other hand, there are numerous prognostic 
factors reported those are useful to predict the prognosis of lung non-
small cell carcinoma and/or adenocarcinoma. However, the comparison 
among the factors has not been performed sufﬁciently, especially about 
small-sized early adenocarcinoma. This time, we selected 10 immuno-
histochemical prognostic factors reported before, such as CEA, p53, 
MIB1, p27, EGFR, pEGFR, Cox2, Neuromatin, γH2AX, and TTF-1 
and compared their conveniences using same series of small-sized 
adenocarcinomas. Furthermore, we also examined the ratio of bronchi-
oloalveolar cell carcinoma (BAC) component and micropapillary com-
ponent in maximum cut surface of the tumor as histologic factors and 
genome abnormalities of p53, K-ras, and EGFR were also examined. 
Methods: We conducted a retrospective review of 138 consecutive 
patients who underwent complete resection for small-sized adenocar-
cinoma and did not receive any chemotherapy and/or radiotherapy 
prior to surgery in National Cancer Center Hospital (Tokyo, Japan) 
from January 1993 to December 2000. We selected CEA, p53, MIB1, 
p27, EGFR, pEGFR, Cox2, Neuromatin, γH2AX and TTF-1 as im-
munohistochemial prognostic factors. In addition to the factors, we 
examined the ratio of BAC component and micropapillary component 
in maximum cut surface of the tumor using H.E. staining sections. 
Furthermore, p53, EGFR, and K-ras mutation analysis were performed 
on 78 cases. 
Results: Among the 10 immunohistochemical factors, two histological 
factors, and three genomic factors, CEA, MIB1 index, and BAC com-
ponent ratio were signiﬁcantly associated with the prognosis of small-
sized adenocarcinomas. Cases stained strongly with anti-CEA antibody 
showed signiﬁcantly less favorable prognosis than negative cases 
(p=0.02). Cases that revealed more than 10% of MIB1 index showed 
less favorable prognosis than cases less than 10% of the index. And 
cases with more than 50% of BAC component showed more favorable 
prognosis than cases with less than 50% of BAC component (p<0.01). 
However, the other factors were not related with the prognosis. 
Conclusion: Although numerous prognostic factors were reported about 
the lung adenocarcinoma, this study indicated that only three factors, 
namely, two immunohistochemical factors of CEA and MIB1 index and 
histological factor of the ratio of BAC component in the maximum cut 
surface of the tumor were signiﬁcantly associated with the prognosis of 
small-sized adenocarcinoma of the lung. In order to construct a desirable 
and evidence-based selective diagnosis of the cases for reduction sur-
gery, more extended study for searching convenient prognostic factors 
about small-sized adenocarcinoma should be performed.
D4-05 Pathology, Thu, 12:30 - 14:15
Is survival after surgical resection of lung cancer influenced by the 
presence of atypical adenomatous hyperplasia (AAH)?
Kerr, Keith M.1 Devereux, Graham1 Chapman, Andrea D.2 Fyfe, Nicky2 
Buchan, Keith2 Remmen, Hardy2 
1 Aberdeen University Medical School, Aberdeen, UK 2 Aberdeen Royal 
Infirmary, Aberdeen, UK 
Atypical adenomatous hyperplasia (AAH) is a recognised precur-
sor for peripheral parenchymal-type adenocarcinoma whereby AAH 
transforms into localised non-mucinous bronchioloalveolar carcinoma, 
wherein alveolar collapse, stromal ﬁbrosis and invasion develop. In our 
patient population, AAH has been found in around 12% of lung cancer 
resections and in 23% of resections for adenocarcinoma. About half re-
ported AAH lesions are solitary, some cases yield between 2-5 lesions 
but up to 20% show over 5 lesions.
Little is known about the likelihood or rate of transformation of AAH 
into adenocarcinoma. The few follow-up studies published have involved 
relatively short follow-up and none have shown any relationship between 
AAH and survival. We present the ﬁrst case-control study investigating 
the survival of patients with AAH in lung resection specimens.
Methods: 116 patients with AAH in their resection specimen were 
compared with 232 controls without AAH. Cases and controls were 
matched for tumour histology, T & N stage, age and year of surgery. All 
cases were treated in the Aberdeen Cardio-Thoracic Surgery Unit, the 
tertiary specialist referral centre for the north of Scotland. All cases of 
AAH were detected during routine gross and histological examination 
of lungs resected for primary carcinoma. All lesions identiﬁed on gross 
examination of 1cm thick parasagittal slices of formalin-inﬂated lung 
resections were sampled and/or up to 6 random parenchymal tissue 
blocks were taken. Survival data were derived from our lung cancer 
resection database, Cancer Registry and Hospital patient data sources.
Results: Tumour stage, nodal status and histology (WHO 2004) were 
100% matched between cases and controls. Median ages were 65.4 
(IQR 57.5 - 71.0) and 64.5 (58.3 - 70.2) years respectively for cases 
and controls. More AAH patients were female (50.9% vs 35.3%, 
p=0.005). Of those cases with AAH, 15% had more than 5 lesions 
recorded. As expected, most (69%) of the cases had adenocarcinomas. 
Median follow-up was 32 months for cases and 30 months for controls 
(95th centiles 130 and 147 months respectively). 
No difference was found in the survival of cases with AAH and 
controls (Median survival [95% conﬁdence interval], 35 [12.3 - 57.7] 
months vs 39 [29.0 - 49.0] months respectively, p=0.81). When cases 
were categorised to identify patients with more than 5 AAH lesions 
(n=17), median survivals for cases with 1-5 AAH lesions was 36 
[11.9 - 60] months while for those with over 5 AAHs it was 22 [0 


D4-03: SCF protein (Skp2, CUL1) regulate the E2F1 dependent transcriptional activity and cyclin E in human lung tumors 

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D4-03: SCF protein (Skp2, CUL1) regulate the E2F1 dependent transcriptional activity and cyclin E in human lung tumors

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