Clinicopathological and Prognostic Significance of the EML4-ALK Translocation and IGFR1, TTF1, Napsin A Expression in Patients with Lung Adenocarcinoma
Pýnar BULUTAY1, Nalan AKYÜREK2, Leyla MEMIÞ2
1Department of Pathology, Koç University Hospital, ISTANBUL, TURKEY
2Gazi University Hospital, ANKARA, TURKEY
Keywords: Lung adenocarcinoma, EML4-ALK, IGFR1, TTF1, Napsin A
Patients with lung adenocarcinoma who harbor ALK gene rearrangements can demonstrate significant clinical benefit with ALK
tyrosine kinase inhibitors. Insulin-like growth factor receptor 1 (IGFR1) is a cellular membrane receptor that is overexpressed in many tumors.
It plays an important role in cancer progression and is associated with increased postoperative recurrence and poorer disease-free survival. The
aim of this study was to determine the EML4-ALK mutation and IGFR1 expression in lung adenocarcinoma and analyze their prognostic value.
Material and Method: In this study, we analyzed the EML4-ALK mutation using the FISH and IHC techniques in 251 lung adenocarcinoma
(203 primary resections, 48 metastasectomies) cases. Correlative analyses were performed between the EML4-ALK mutation, the IGFR1, TTF1,
and NapsinA expression, and the clinicopathologic factors in lung adenocarcinomas.
Results: The EML4-ALK mutation was observed in 3.8% of the cases and it was associated with the solid pattern, signet ring cell morphology,
and larger tumor size. IGFR1 expression was identified in 49% of the cases and most of the ALK-mutated cases were also expressing the IGFR1
protein (66%). IGFR1 expression frequency was increased in metastasectomy specimens.
Conclusion: A solid signet-ring cell pattern or mucinous cribriform pattern was present at least focally in all ALK-positive tumors, consistently
with the literature. In addition, IGFR1 expression levels showed an increase in the EML4-ALK-mutated cases in our series, but the clinical
significance of this finding should be supported by larger series and survival analysis. Our findings show that IGFR1 expression may be useful
as a poor prognostic marker in patients with lung adenocarcinoma.
Lung cancer is the most frequent cause of cancer deaths,
accounting for approximately 1.6 million deaths per year
worldwide (1). Primary lung cancer is mainly divided into
two pathological types: small cell lung cancer (SCLC) and
non-small cell lung cancer (NSCLC), of which NSCLC
accounts for approximately 85% and adenocarcinoma is
the most frequent histological subtype of NSCLC (2).
Many studies on lung cancer carcinogenesis have been
conducted over the years. These studies are especially
important for clinical treatment strategies and the
development of targeted therapies. Intratumoral epidermal
growth factor receptor (EGFR) mutation status has
been especially found to be a strong predictive factor in
lung adenocarcinomas (AC) for the efficacy of EGFRtyrosine
kinase inhibitors (TKI) (3). Translocation and inversion of the ‘Anaplastic lymphoma kinase‘ (ALK)
gene with ‘Echinoderm microtubule-associated proteinlike
4’ (EML4) has also been detected in a subset of nonsmall
cell lung cancer (NSCLC) patients in 2007 (4). ALK
mutations are present in approximately 3-6% of NSCLCs
(5). Crizotinib is a first-generation TKI of ALK and it is
the first drug with advanced ALK-positive NSCLC (6),
and the patients can obtain effective results through
treatment with inhibitors of ALK kinase (7). Although
immunohistochemistry (IHC) is a nearly equivalent
alternative to detect ALK mutation, fluorescent in-situ
hybridization (FISH) technique still remains a reliable
method for the diagnosis of ALK-rearranged fusions in
NSCLC (8). Several studies have shown that certain patient
characteristics such as younger age, never or light smoker,
signet ring cell morphology, and adenocarcinoma subtype
increase the probability of finding an ALK mutation (9,10).
Insulin-like growth factor receptor-1 (IGFR1) is a
transmembrane protein implicated in promoting
oncogenic transformation, growth, and survival of cancer
cells (11) The overexpression of IGFR1 has been shown to
correlate with postoperative recurrence and is associated
with a poorer DFS in NSCLC patients (12). CT-707 is a
mutant-selective inhibitor of ALK/focal adhesion kinase
(FAK) and IGFR1 and it is designed to be a targeted
therapeutic agent for NSCLC patients harboring ALK
active and crizotinib-resistant mutations (13,14). However,
to the best of our knowledge, there is no study in the
literature showing whether there is a relationship between
intratumoral IGFR1 expression and ALK mutation status
in lung adenocarcinomas.
In this study, we investigated the histopathological
features and clinical characteristics of patients with
lung adenocarcinomas who harbored the EML4-ALK
translocation in 251 lung resection (203 cases) and
metastasectomy (48 cases) specimens. We used both
the FISH and immunohistochemistry techniques for
detection of ALK rearrangement. In addition, we analyzed
the clinical and pathological role of IGFR1 expression
and its association with the EML4-ALK mutation. Also,
we examined the relationship between IGFR1, TTF-1
and Napsin-A expression, the ALK mutation, and the
clinicopathological features. (15,16).
From 2006 to 2013, a total of 251 lung adenocarcinoma
cases were included in our study. Two hundred three
were pulmonary resection and 48 were lung cancer
metastasectomy specimens. Clinical and pathological data
were recorded using electronic medical files and pathology
reports. The hematoxylin and eosin (H&E) stained slides
were retrieved from the pathology archives and reviewed
by two experienced pulmonary pathologists (PB, NA). The
subtypes of adenocarcinoma were determined according to
the International Association for the Study of Lung Cancer
(IASLC) / American Thoracic Society (ATS) / European
Respiratory Society (ERS) International Multidisciplinary
Classification of Lung Adenocarcinoma (17). All samples
were reclassified and updated according to the 2015 WHO
classification and TNM staging (8th edition) for lung
carcinomas (18). Tumor areas were selected and marked
on hematoxylin & eosin stained sections. The slide was
then overlaid on the original paraffin block to determine
the corresponding area to be used. TMAs were constructed
by using a 3 mm punch biopsy tool and, 2 representative cylindrical cores were taken from each tissue block and
then arranged sequentially into a recipient paraffin block.
This study was supported by the ‘Gazi University Scientific
Research Projects Unit’ in Turkey with the number of
01/2012-79. Ethics committee approval had been obtained
on 23.05.2012 with decision number 213 at Gazi University,
EML4-ALK Analysis by FISH
(Fluorescent In-Situ Hybridization) Technique
To detect EML4-ALK rearrangement, the ‘Vysis Abbott
Molecular ALK Break Apart FISH probe kit’ and
‘Paraffin Pretreatment Kit IV’ were used. The evaluation
was performed with the BX51 Olympus fluorescence
microscopy. The cell was regarded as positive when a
nucleus had at least one set of broken apart signals, or
had a single red signal (deleted green signal) in addition
to fused and/or broken apart signals. The distance between
two separate red and green signals was estimated using two
times the biggest signal size. The samples were considered
positive if more than 25 out of 50 tumor cells were positive,
and negative if less than 5 tumor cells were positive. The
sample with 5-25 positive tumor cells was considered
equivocal, and was then evaluated by a second pathologist.
If the average percent of the positive cells was 15% or more,
the sample was considered positive. Otherwise, it was
considered negative for ALK rearrangement (Figure 1A,B).
Click Here to Zoom
|Figure 1: A) EML4-ALK gene rearrangement by FISH technique (FISH; x100). B) EML4-ALK positive tumor sample with solid pattern
and signed ring cell morphology (H&E; x40).
The IHC staining of TMA sections was performed using
the Ventana automated IHC staining system (Leica, Bond-
Max). All the antibody labeling was detected using the
3,3´-diaminobenzidine (DAB) detection kit. Anti IGFR1
mouse monoclonal antibody was used against human
IGFR1 (ab4065; Abcam, Cambridge, MA, USA), diluted
1:10 in PBS, and unstained slides were kept at room
temperature for 45 minutes after boiling with EDTA for
20 minutes. IHC was considered positive when a distinct
cell membrane staining was evident (Figure 2A-F). Nontumoral
prostate tissue used for positive control. A cutoff
value of 5% was used for the positivity rate and the positive
cases were subclassified according to weak (1+) or strong
(2+) staining rates.
Click Here to Zoom
|Figure 2: A) TTF1 nuclear positive staining; 1+ positive (IHC; x40). B) TTF1 nuclear positive staining; 2+ positive (IHC; x40).
C) TTF1 nuclear positive staining; 3+ positive (IHC; x40). D) Napsin A cytoplasmic granular staining (IHC; x40). E) IGFR-1 membranous
staining; 1+ positive (IHC; x40). F) IGFR-1 membranous staining; 2+ positive (IHC; x20).
TTF1 (Cell Marque, mouse monoclonal, clone 8G7G3/1;
Ventana), and NapsinA (Cell Marque, NapsinA rabbit
polyclonal; Ventana) were investigated on an automated
immunostainer. The positive controls for TTF-1 labeling
were non-tumoral lung parenchyma and alveolar
macrophages were used for NapsinA. TTF1 expression was subclassified according to the staining intensity as
high (3+), moderate (2+), and low (1+). NapsinA staining
was considered positive when tumor cells had cytoplasmic
granular staining at any intensity.
IHC for ALK expression was performed wýth the D5F3
rabbit monoclonal antibody and ultrasensitive OptiView
DAB IHC Detection Kit with amplification (Ventana anti-
ALK (D5F3) IHC Assay). Strong granular cytoplasmic
staining in tumor cells was defined as positive, and no
staining was considered as negative (Figure 3A,B).
Statistical Analysis: Student’s-t test was used for tumor
size and age. Variables were analyzed, as appropriate, with
the χ2 test, or the Mann-Whitney U test, to compare the
differences in categorical variables. P value of less than
0.05 was considered statistically significant. The statistical
analyses were carried out by using the SPSS for Windows
17.0 program (SPSS Inc., Chicago, IL).
The baseline characteristics of resected lung adenocarcinoma
cases are shown in Table I
. There were 203 patients in total;
150 (73.9 %) were women and 53 (26.1 %) were men. The
female to male ratio was 2.8:1. The age ranged from 38
to 85 years. The mean age was 63 years, and the median
age was 62 years. A hundred-sixty (78.8%) had a smoking
history, and 43 cases (21.2 %) did not. According to the
eighth edition of the TNM Classification of Lung Cancer (2015), the majority of the cases were stage I (49.8%), and
24 cases (11.8%) were stage IV.
Click Here to Zoom
|Table I: Characteristics of the ‘203 primary resection lung adenocarcinoma specimens’ and correlations between the patients harboring
Clinical and Histological Correlations Between the
Patients Harboring EML4-ALK Mutation
We identified 9 patients who harbored the EML4-ALK
fusion gene (3.9% (9/229) (Figure 1A,B). Five (2.6%) of
these positive cases, were lung resection specimens, and 4
(8.3%) were at metastasectomy specimens. Overall 13 cases
were left out from the study as no fluorescent signal could
be received. The mean tumor size of EML4-ALK positive
cases was significantly larger than in EML4-ALK negative
cases (mean±SD, 5.54±3.34 vs 3.61±2.02, 0.037) (Table I).
Of the FISH positive cases, the male-to-female ratio was 5:4,
and the mean age was 58.2 (ranging from 48 to 81 years).
A predominant solid/cribriform pattern was observed in 6
(66.6%) of the 9 cases, and a predominant acinar pattern in
3 cases (33.4%) (Table II). A solid predominant pattern was
also significantly found to be related with the EML-ALK
mutation (0.008). More than half of the cases (5/9) showed
signet ring cells (Figure 4A,B). No significant differences
were found in age, gender, smoking history, pathological
N-stage, tumor location, and visceral pleural invasion with
the EML-ALK translocation (>0.05) (Table I).
Click Here to Zoom
|Table II: Detailed clinicopathological features of EML4-ALK-positive cases (Case 1 to 5 are from the primary resection, and Case 6 to
9 are from the metastasectomy specimens).
Six of the 9 FISH-positive cases were also positive with IHC
whereas 3 cases were negative with ALK IHC (Figure 3A,B).
Detailed clinical, histological and immunohistochemical
findings of the EML4-ALK FISH positive cases are shown
in Table II.
Click Here to Zoom
|Figure 3: ALK IHC and ALK FISH. A) IHC positive FISH positive (IHC; x40) (FISH; x100). B) IHC negative FISH positive (IHC; x40)
Click Here to Zoom
|Figure 4: A) ALK positive tumor sample (IHC; x40) with B) signet ring cell morphology (H&E; x40).
Correlation of the IGFR1 Expression and
IGFR1 expression was identified in 123 (49%) of the 251
patients. There was no significant association between
IGFR1 expression and the clinical parameters (Table III).
Click Here to Zoom
|Table III: Characteristics of staining with TTF-1, Napsin-A and IGFR-1 in lung adenocarcinomas.
Relationship Between IGFR1 Expression and
According to our results, the IGFR1 expression rate
was significantly higher in metastasectomy specimens
(45.2% vs 81.2%) (0.02). At the same time, IGFR1 staining
intensity was stronger (2+) than in the primary resections
(7.9% vs 35.4%) (Table IV). These results explain the
effect of IGFR1 expression on the prognosis. Besides these
results, IGFR1 expression was not associated with any
clinicopathological characteristics in primary tumors as
well as metastasectomies (Table III).
Click Here to Zoom
|Table IV: IGFR1 staining rates between metastasectomy and resection cases.
Relationship Between IGFR1 Expression and
Most of the ALK mutated cases were also expressing
the IGFR1 protein (66%). However, this result was not
statistically significant. This may be due to the small
number of EML4-ALK-positive cases (>0.05).
Correlation Between TTF1 and Napsin A Expression
and Clinicopathological Parameters
TTF-1 Expression and Clinicopathological Parameters
TTF1 expression was seen in 202 (80.5%) (79.3% resection,
85.4% metastasectomy) cases, and 49 (19.5%) cases were negative for TTF1. TTF1 expression had a significant
correlation with the female sex and it was more frequently
seen in the acinar, papillary, and lepidic patterns (81.7%)
rather than solid and mucinous patterns (66.7 %) (0.036).
Likewise, TTF-1 expression was more frequent in smaller
tumors than the larger ones (0.042). Furthermore, there
was no significant association of TTF1 expression with
age, lymph node involvement, visceral pleural invasion,
stage, and smoking status, in both primary cases and
metastasectomies (>0.05) (Table III). We could not find a
relation between expression intensity and the histological
patterns, but most acinar and papillary patterns and all
lepidic, micropapillary, fetal, and enteric patterns had
intense (3+) expression, while others had a lower expression
intensity (1+, 2+) expression with TTF1 (No data shown).
Napsin A Expression and Clinicopathological
Napsin A expression was seen in 74% (74.9% resection,
66.7% metastasectomy) of our cases. Napsin A expression
was associated with the female sex (<0.001), lymph
node metastasis (0.018), and the tumor size (0.013). The
expression rate of Napsin A significantly decreased with
tumor size (Table III). Similar to the TTF1 expression,
Napsin A expression was also more frequent in welldifferentiated
patterns (acinar, papillary, and lepidic)
rather than solid and mucinous patterns in both primary
resection (68.6%) (0.048) and metastasectomy specimens
(92.3%) (0.002). Napsin A expression was not correlated
with age or smoking.
Personalized targeted therapy has emerged as a promising
strategy in lung cancer treatment. Several oncogenic drivers
have been reported in this context. ALK rearrangement
is responsible for about 3-6% of all non-small cell lung
cancers. Although it is seen in only a small percentage of
lung cancers, it is an important predictor of response to anti-
ALK targeted therapies (19). Selection of patients based on
their ALK status is therefore vital, on account of the high
response rates with the ALK targeted agents. In our study,
we used the ALK FISH assay, which is accepted as the gold
standard in the assessment of ALK gene rearrangement
(20). We found the overall frequency of ALK mutation
to be 3.8%, which was almost consistent with previous
reports. The ALK mutation rate decreases with increasing
patient age in most studies (21,22). In our study, we could
not find a statistical correlation with age, but the median
age of our positive cases was younger than the negative
ones as in the literature (59 vs. 63). Shaw et al. (23) noted
that the rate of EML4-ALK fusion gene mutation is higher
in men than in women (22.9% vs. 8.6%). Similarly, the
mutation risk is higher in men than in women, but we did
not find a statistical correlation. Some studies have shown
that ALK-positive adenocarcinomas were more common
in patients at advanced T stages (22,24). Consistently, our
ALK positive cases had a larger tumor size (median 5 cm vs.
3 cm) than the negative ones (0.037).
Our results further indicate that the EML4-ALK translocation
occurs mostly in solid predominant and signet
ring cell morphology tumors (0.008), and this finding
is consistent with the results of other published studies.
Rodig SJ. et al. demonstrated the pattern relationship with
EML4-ALK translocation in lung adenocarcinomas (25).
Similarly, the EML4-ALK translocation was observed more
frequently in cases with solid or acinar growth patterns,
cribriform structure, mucous cells (signet-ring cells, or
goblet cells), and abundant extracellular mucus, and also
in those lacking lepidic growth and significant nuclear
pleomorphism in a different study (26).
We could not find any statistically significant correlation
between TTF1, NapsinA, or IGFR1 expression and the
The present study revealed a significant finding regarding
IGFR1 expression. IGFR1 expression was correlated
with increased metastasis risk. These results indicate that
IGFR1 expression can be used to indicate a poor prognosis.
Nakagawa et al. have shown that high IGFR1 expression
is associated with increased postoperative recurrence
and poorer disease-free survival (12). Many studies share the correlation of IGFR1 expression with cell survival,
growth, proliferation and angiogenesis, as well as blocking
of apoptosis, and it is also linked with many cancers in
different organs (27,28). In a recent study blocking ALK
and IGFR1 receptors together with the CT-707 drug,
which is one of the FAK (focal adhesion kinase) inhibitors,
significantly inhibited tumor growth without obvious side
effects (13,29). Overexpression of IGF1R and FAK are
closely associated with metastatic breast tumors (30). Our
results indicate increased levels of IGFR1 expression in
metastasectomy specimens. However, we could not find a
relationship with the other prognostic parameters, maybe
due to the low number of cases in our study.
Few studies have implicated a correlation between TTF1
positivity by IHC and EGFR, KRAS mutation status (31).
However, the role of TTF1 in lung cancer pathogenesis and
its relationship with the ALK translocation status is unclear.
TTF1 and NapsinA are mainly used as diagnostic markers
of lung adenocarcinomas in daily practice. In our cohort,
80% of the cases were positive with TTF1 and/or NapsinA.
In addition, 33 cases (13%) were negative with both TTF1
and NapsinA. These cases were diagnosed as pulmonary
adenocarcinoma based on the morphological features and
the clinical ruling out of other possible primaries with IHC.
Our results showed that TTF1 and NapsinA expression
were associated with the female sex and smaller tumor sizes.
Napsin A expression was also related to a good prognosis
because of its relationship with the N0 cases. These results
are consistent with the literature. (32).
In our study, we investigated the correlation of TTF1 and
NapsinA expression by IHC with EML4-ALK mutations
and also with the clinicopathological characteristics.
According to our results, all EML4-ALK mutated cases
were positive with TTF1 and NapsinA (100%). This result
is consistent with the other similar study in the literature
(33). Inamura et al. explained the TTF1 positivity of EML4-
ALK lung cancers with the ‘terminal respirator unit (TRU)
histogenesis. TRU-type lung cancers with a TTF1 positive
cell lineage often occur in non or light smokers, which
frequently harbor EGFR mutations (61%) and have lessfrequent
TP53 mutations (36%) compared to non-TRUtypes
CONFLICT of INTEREST
The authors declare no confict of interest.
This study was funded by the ‘Gazi University Scientific
research projects unit’ in Turkey with the number of
Concept: NA, LM, Design: NA, Data collection or
processing: PB, NA, Analysis or Interpretation: PB, NA,
Literature search: PB, Writing: PB, Approval: PB.
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