Evaluation of MUC1, MUC2, MUC5AC, and MUC6 Expression Differences in Lung Adenocarcinoma Subtypes by Using a Final Immunoreactivity Score (FIRS)
Melek BUYUK1, Yasemin OZLUK1, Dogu VURALLI BAKKALOGLU1, Berker OZKAN2, Pinar FIRAT3, Dilek YILMAZBAYHAN1
1Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, ISTANBUL, TURKEY
2Department of Thoracic Surgery, Istanbul Faculty of Medicine, Istanbul University, ISTANBUL, TURKEY
3Department of Pathology, Koc University School of Medicine, ISTANBUL, TURKEY
Keywords: Lung adenocarcinoma, Mucin expression, Immunohistochemistry, MUC1, Immune reactivity score
Lung adenocarcinomas are divided into acinar, lepidic, papillary, micropapillary, and solid predominant subtypes according to the
current World Health Organization (WHO) classification. We designed this retrospective study to demonstrate profiles of MUC expression
(MUC1, MUC2, MUC5AC, and MUC6) of different histologic patterns within the same tumor among pulmonary adenocarcinomas and
investigate correlations of MUC expression with clinicopathologic features.
Material and Method: We analyzed the expression of mucins (MUC1, MUC2, MUC5AC, and MUC6) in a series of 99 resected lung
adenocarcinomas, which included a total of 193 patterns (71 acinar, 30 lepidic, 25 papillary, 20 micropapillary, 34 solid and 13 mucinous) and
calculated a final immune reactivity score (FIRS) per tumor.
Results: MUC1 IRS scores were significantly higher in lepidic and solid patterns compared with mucinous patterns (p=0.013). MUC2 expression
was seen only in three cases (1 acinar, 2 mucinous). MUC5AC and MUC2 expression was more common in mucinous patterns (p<0.001 and
p=0.028, respectively). MUC6 expression was only detected in seven patterns and the expression was weak. No significant difference was seen
among histologic patterns for the staining scores of MUC6. Mucinous adenocarcinoma differed from other histologic subtypes regarding MUC1
and MUC5AC expression. Mucinous adenocarcinoma showed less MUC1 expression with lower IRS scores and higher MUC5AC expression.
Tumor size (p=0.006), lymphatic invasion (p=0.018), vascular invasion (p=0.025), perineural invasion (p=0.019), MUC1 IRS scores (p=0.018),
and MUC1 IRS scores >8.5 (p=0.018) were significant predictors for lymph node metastasis.
Conclusion: An alternative scoring for MUC1 can be used as a predictor for lymph node metastasis regardless of the histologic subtype.
In the respiratory system, mucus acts as a protective
barrier against external factors such as pathogens, chemical
agents, and dust particles in the air. In the tracheobronchial
epithelium, mucins are synthesized by goblet cells in the
surface epithelium and mucous cells in the submucosal
. Mucins are categorized into two groups,
membrane-dependent and secretory (gel-forming mucins)
. MUC1 is a membrane-dependent mucin, whereas
others (MUC2, MUC5AC, and MUC6) are gel-forming.
Cancer cells, especially in adenocarcinomas, express
aberrant forms or amounts of mucins. Cancer cells may use
mucins for protection from adverse growth conditions and
to control the local molecular microenvironment during
invasion and metastasis 3
MUC1 is normally expressed on the apical borders of
epithelial cells, which is called polarized expression, in
many tissues including the lung 4-7. MUC1 expression
in cancer cells has been shown on the apical border and
the lateral cell membrane and in cytoplasm (depolarized
staining). MUC1 overexpression enhances the invasion
capacity of cancer cells by inhibiting E-cadherinmediated
cell-cell adhesion and integrin-mediated cell
adhesion to extracellular matrix components 8,9.
Also, MUC1 inhibits cytotoxic T lymphocyte-tumor cell
interaction 10. Several studies have been performed on
adenocarcinomas and expression abnormalities of mucin
glycoproteins because mucins are known to be present in
glandular epithelial cells 11-14. Among the mucins, high
levels of MUC1 expression in particular are significantly
associated with poor prognosis. High expression of MUC1 was associated with the presence of axillary lymph node
metastases in breast carcinoma 11 and similarly, high
expression of MUC1 was related to a significantly shorter
overall survival (OS) in sinonasal adenocarcinomas 12. In
gastric and pancreatic carcinomas, MUC1 overexpression
and its association with poor prognosis have been well
Lung adenocarcinomas are heterogeneous groups of
tumors and have different histologic patterns (lepidic,
acinar, papillary, micropapillary, solid, fetal, and
enteric). Invasive mucinous adenocarcinoma and colloid
adenocarcinoma also are additional distinctive patterns
15. MUC1 overexpression or depolarized expression also
acts as a poor prognostic parameter in lung cancer (16-
20). MUC1 is overexpressed in lung cancer, making it an
excellent target for immunotherapy. Several clinical trials
of MUC1 vaccines in non-small cell lung cancer (NSCLC)
have also been reported 21,22.
Previous studies have shown specific mucin expression
profiles (overexpression MUC5AC and MUC6) for invasive
mucinous carcinoma (formerly known as mucinous
bronchioloalveolar adenocarcinoma) 23-27.
However, to the best of our knowledge, differences in
the expression profiles of MUCs among different histologic
patterns of lung adenocarcinomas have not yet been
published. With this aim, we designed this retrospective
study to demonstrate profiles of MUC expression (MUC1,
MUC2, MUC5AC, and MUC6) of different histologic patterns
within the same tumor among pulmonary adenocarcinomas
and investigate correlations of MUC expression
with clinicopathologic features. In this retrospective study,
we tried to answer the following questions:
1- Are there any differences between histologic subtypes
of pulmonary adenocarcinomas regarding MUC
2- Is the profile of MUC expression related to any
3- Since adenocarcinomas are heterogeneous, how should
we evaluate MUC1 staining within different patterns of
the same tumor?
4- Which parameters are predictors for lymph node
This study was approved by the Clinical Research Ethics
Committee of the Istanbul University Faculty of Medicine
(file number: 2012/1729-1289).
We retrospectively evaluated 99 resection materials of
preoperatively untreated lung adenocarcinomas with
available paraffin blocks between January 2007 and
December 2013. Patients with distant metastasis were not
included. Histopathologic and clinical data were retrieved
from the pathology reports and clinical records.
All archived hematoxylin-eosin–stained tumor slides were
re-examined by two pathologists (DY, an experienced
pulmonary pathologist, and MB) who were blinded to all
clinical data. Based on the 2021 WHO classification 15,
the diagnoses were revised according to the predominant
pattern. All histologic patterns and their percentages, in 5%
increments, were recorded.
Some histopathological features known to have prognostic
significance, such as angiolymphatic invasion, vascular invasion,
tumor diameter, pleural invasion, and lymph node
metastasis were also documented.
Paraffin blocks that were representative of all
histologic patterns present together were selected for
immunohistochemical analysis. For this purpose, one to
two blocks per case were used. Immunostaining for MUC1,
MUC2, MUC5AC, and MUC6 proteins was performed
on 4-μm tissue sections, using an automated staining
module (Ventana Medical System-Benchmark XT/ISH
Staining Module, Roche, Switzerland). Tissue sections
were incubated with the primary antibodies with different
incubation periods and different dilutions. Anti-MUC1
antibody (Ma695, 1:100, Leica/Novocastra), anti-MUC2
antibody (Ccp58, 1:50, Leica/Novocastra), anti-MUC5AC
antibody (CLH2, 1:50, Leica/Novocastra) and anti-MUC6
antibody (CLH5, 1:50, Leica/Novocastra) were used.
Evaluation of Immunohistochemistry Results
We evaluated the percentages and the intensity of staining
for each antibody (MUC1, MUC2, MUC5AC, and MUC6).
Cytoplasmic staining was observed for antibodies MUC2,
MUC5AC, and MUC6. MUC1 expression was subclassified
depending on the expression pattern into ‘polarized’ or
‘depolarized’ expression as follows: (1) polarized expression
if MUC1 was localized into the cellular membrane of the
apical portion of tumor cells (Figure 1b2, c2, d2), (2)
depolarized if MUC1 was observed over the entire cell
surface or whole cytoplasm (Figure 1a2, e2). In tumors
showing both polarized and depolarized expression, if the areas with depolarized expression comprised more than
20% of the tumor, the staining was accepted as depolarized.
The pattern of MUC1 staining was further divided into
two subgroups for statistical comparisons, one containing
negative and polarized stained cases and the other
containing depolarized stained cases.
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|Figure 1: Expressions of MUC1, MUC2, MUC5AC, and MUC6 in various histologic patterns of invasive adenocarcinoma (a-f). The
acinar pattern shows MUC1 (depolarized staining), MUC5AC, and MUC6 positivity (a2, a4, a5). MUC2 is negative in this pattern
(a3). The lepidic pattern shows polarized staining for MUC1 (b2). MUC5AC and MUC6 are focally positive and MUC2 is negative
(b3-5). Papillary and micropapillary patterns show polarized staining for MUC1 (c2, d2). MUC2, MUC5AC, and MUC6 are negative
in papillary (c3-5) and micropapillary (d3-5) patterns. The solid pattern shows MUC1 (depolarized staining), MUC5AC and MUC6
positivity (e2, e4, e5). MUC2 is negative (e3). Mucinous adenocarcinoma shows both polarized and depolarized MUC1 expression (f2).
MUC2, MUC5AC, and focal MUC6 positivity in mucinous adenocarcinoma (f3-5). (a1, a3, b3, c3, d1, d5, f2, f3 x100; c2, e1, e5 x400;
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|Figure 2: Kaplan-Meier survival analysis for predominant histologic patterns (n=85).
The percentage of positive cells and the staining intensity
were recorded for each pattern and scored using a widely
used combined scoring system (immunoreactive score,
IRS) (28). IRS gives a score between 0 and 12 as a product
of multiplication of positive cells proportion score (0-
4) and staining intensity score (0-3). According to the IRS,
scores of 0-1 are considered negative, scores 2-3 as mild, scores 4-8 as moderate, and scores 9-12 as strongly positive
After calculating IRS scores for each histologic pattern, we
calculated a final IRS score (FIRS) per tumor due to the
histologic variety of lung adenocarcinomas. Because lung
adenocarcinomas contain more than one pattern and the
percentage and intensity of staining in each pattern vary,
we calculated the FIRS with a formula as follows: (IRS score
of i pattern x % of i pattern) + (IRS score of ii pattern x % of
ii pattern) + (IRS score of iii pattern x % of iii pattern) + .....
the same formula for any other pattern(s) if present. The
final IRS score (FIRS) was further categorized as negative,
mild, moderate, and strong, similar to IRS.
For statistical analysis, the cases were divided into two groups
depending on the MUC1 staining intensity. Negative (FIRS
0-1) and mild-staining (FIRS 2-3) groups were accepted
as group 1, and moderate (FIRS 4-8) and strong-staining
(FIRS 9-12) groups were accepted as group 2.
All statistical analyses were performed using the Statistical
Package for Social Sciences (SPSS) software for Windows
version 21.0 (IBM Corp, Armonk, NY, USA). The
normality of continuous data was checked using both
numerical tests (Kolmogorov-Smirnov and Shapiro-Wilk
tests) and graphical methods (histogram, Q-Q, and box
plots). Data are given as mean and standard deviation
(mean ± SD) or median (interquartile range, [IQR]).
Categorical variables were compared using Chi-square
and Fisher’s exact tests where appropriate. Proportions
are given as percentages. Mann-Whitney U and Kruskal-
Wallis tests were used for quantitative variables with nonparametric
distribution. The Bonferroni correction was
used for pairwise comparisons for Kruskal-Wallis test.
Significant factors found in univariate tests were included
in multivariate analysis. Logistic regression analysis was
used for multivariate analysis to identify predictors for
lymph node metastasis and the associated risk in terms of
odds ratio (OR) and 95% confidence intervals (CI). The
Kaplan-Meier test was performed using both SPSS 21.0
and MedCalc statistical software version 20.113 (Ostend,
Belgium) for OS comparing survival with the log-rank test
and the inclusion of the number at risk table. P-values of less
than 0.05 were considered significant in all comparisons.
The study included 75 males (75.8%) and 24 females
(24.2%). The mean age was 64 (range, 36-84) years. The
median tumor size was 3.5 [IQR: 2.5-5] cm. Patients
underwent lobectomy (n=83, 83.8%), pneumonectomy
(n=5, 5.1%) or wedge resection (n=11, 11.1%). Thirty-nine
patients had lymph node metastasis [stage N1: 19 (19.2%), stage N2: 18 (18.2%), stage N3: 2 (2%)]. The median followup
time was 123 [IQR: 94-141.5] months.
Histopathologic subtypes were as follows: acinar predominant
(34.3%, n=34), solid predominant (23.3%, n=23), lepidic
predominant (14.1%, n=14), papillary predominant
(10.1%, n=10), micropapillary predominant (7.1%, n=7),
and invasive mucinous adenocarcinoma (11.1%, n=11). A
total of 193 patterns including tumors with more than one
pattern (71 acinar, 30 lepidic, 25 papillary, 20 micropapillary,
34 solid, and 13 mucinous) were evaluated. Lymphovascular
invasion, venous invasion, and perineural invasion
were seen in 62%, 35%, and 15% of 99 adenocarcinoma
Expressions of MUC1, MUC2, MUC5AC, and MUC6
in various histologic patterns are shown in Figure 1. The
MUC1, MUC2, MUC5AC, and MUC 6 expression and
IRS scores calculated for all histologic patterns are shown
in Table II. Although there were no significant differences
regarding MUC1 expression (positive vs. negative)
among the histologic patterns, MUC1 IRS scores were
significantly higher in lepidic and solid patterns compared
to the mucinous pattern (p=0.006 and 0.0222, respectively).
MUC2 expression was only seen in three cases (1 acinar,
2 mucinous). MUC5AC and MUC2 expression were
more commonly seen in mucinous patterns (p<0.001
and p=0.028, respectively), and IRS scores for MUC5AC
and MUC2 were higher in the mucinous pattern when
compared with the other patterns (p<0.001 and p=0.003,
respectively). MUC6 expression was only seen in seven
patterns with weak expression. No significant difference
was seen among histologic patterns for the staining scores
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|Table II: MUC1, MUC2, MUC5AC, and MUC6 expressions and average IRS scores by pattern.
The clinicopathologic features for both group 1 and
group 2 of MUC1 expression are summarized in Table
III. No significant difference was detected between the
two groups for parameters such as sex, age, tumor stage, tumor size, angiolymphatic invasion, vascular invasion, or
stage. There was no difference in MUC1 staining intensity
among predominant histologic patterns except mucinous
adenocarcinoma, in which MUC1 showed low expression
more frequently than in other histologic subtypes (p=0.01).
High MUC1 expression was also more frequently observed
in lymph node-positive cases and cases with perineural
invasion (p=0.003 and p=0.036, respectively).
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|Table III: Relationships between clinicopathologic features and expression of MUC1 in patients with lung adenocarcinoma
The differences between polarized and depolarized MUC1
expression among histologic subtypes are summarized in
Table IV. Depolarized MUC1 expression was higher in
acinar and solid patterns, whereas polarized expression was
seen very frequently in lepidic, papillary, micropapillary,
and mucinous patterns (p<0.001). We found that
depolarized expression was significantly more frequent in
acinar and solid patterns when compared with the others
(p<0.001 and p<0.001, respectively).
Depolarized MUC1 expression was related to the presence
of lymphatic invasion, tumor diameter, and stage.
Depolarized expression was detected more common in
tumors with lymphatic invasion when compared with
tumors without (73% vs. 27%, respectively; p=0.015).
Tumors with depolarized staining were larger tumors
(4.8±3 cm vs. 3.3±1.9 cm, p=0.013) and of more advanced
stage (p=0.035). However, no significant correlation was
observed between depolarized MUC1 expression and
the presence of vascular invasion (p=0.724), perineural
invasion (p=0.313), or lymph node metastasis (p=0.135).
Univariate tests and Multivariate Analyses for Lymph
We found that tumor size (p=0.006), lymphatic invasion
(p=0.018), vascular invasion (p=0.025), perineural invasion (p=0.019), mean MUC1 IRS score (p=0.018), and MUC1
IRS scores >8.5 (p=0.018) were significant predictors for
lymph node metastasis (Table V).
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|Table V: Univariate tests and multivariate logistic regression analysis of lymph node metastasis.
Tumor size, lymphatic invasion, vascular invasion,
perineural invasion, and MUC1 IRS scores indicated
that larger tumor size (OR: 1.197, 95% CI: [1.009-1.419];
p=0.039) and higher MUC1 IRS scores (OR: 1.814, 95% CI:
[1.092-3.013]; p=0.021) were independent predictors for an
increased risk of lymph node metastasis (Table V).
There was no statistically significant relationship between
sex, T stage, N stage, lymphovascular invasion, venous
invasion, perineural invasion, predominant histologic
pattern, MUC1, MUC2, MUC5AC, MUC6 expression,
depolarized MUC1 staining, and OS according to Kaplan-
Meier survival estimates (p >0.05). However, solid and
micropapillary predominant adenocarcinomas had poor
survival compared to acinar predominant tumors (p=0.003
and p=0.019, respectively) (Figure 2).
We assessed the expression profiles of MUC1, MUC2,
MUC5AC, and MUC6 in pulmonary adenocarcinomas
in terms of their differences between histologic patterns
and their relations with clinicopathologic parameters.
We further tested a unique calculation model for
immunoreactivity score for MUC1, in which the differences
between each histologic pattern were also taken into
account (FIRS score). To our knowledge, this is the first
report on expression patterns of various MUCs in different
histologic subtypes of lung adenocarcinomas. MUC1
FIRS scores may be used as a predictor for lymph node metastasis in addition to conventional parameters such as
lymphovascular and perineural invasion.
Previous studies showed controversial results for MUC2,
MUC5AC, and MUC6 expression in lung adenocarcinomas
23-26. In a study comparing 7 mucinous adenocarcinomas (previously known as mucinous bronchioloalveolar
carcinoma (mBAC)) and 27 non-mucinous BAC,
higher levels of MUC2, MUC5AC, and MUC6 expression
were found in mucinous BAC 26. In another study, the
expression percentages of MUC2, MUC5AC, and MUC6 were
higher in mBAC than in solid adenocarcinoma (17%
vs. 10%, 97% vs. 21%, and 75% vs. 10%, respectively) 24.
Similar results were found for MUC5AC in 10 mucinous
adenocarcinomas (mBAC) (100%), but not for MUC2
(0%) in another study 25. Low frequency of MUC2 expression
was also demonstrated in another study (only in
one of 25 invasive mucinous adenocarcinomas) 23. Our
data on MUC2 and MUC5AC expression in mucinous tumors
were similar to the literature with low expression for MUC2 (2/13) and high expression (11/13) for MUC5AC.
Conflictingly, MUC6 was also low (2/13) in our series.
MUC6 expression has been thought to be based on either
a metaplastic or a heterotopic presence of gastric mucosa
24. We could not demonstrate any significant MUC6
expression either in mucinous or non-mucinous patterns
(acinar, lepidic, papillary, micropapillary, or solid).
MUC6 expression was present only in two mucinous and
five non-mucinous cases with very low IRS scores. In summary, based on our data, expression of MUC2 and MUC6
was present in a limited number of cases and did not differ
among histologic patterns. We think that these two types
of MUCs are not useful for histologic subtyping and do not
play a role in pulmonary carcinogenesis.
In our study, mucinous adenocarcinoma differed from
other histologic subtypes regarding MUC1 and MUC5AC
expression. Mucinous adenocarcinoma showed less MUC1
expression with lower IRS scores and higher MUC5AC
expression. MUC1 IRS scores were moderate to high in
acinar, lepidic, papillary, micropapillary, and solid patterns of non-mucinous adenocarcinomas. The highest MUC1
expression levels were observed in lepidic and solid patterns.
Similar to our results, mucinous adenocarcinomas showed
apical MUC1 expression in less than 50% of tumors and
was more commonly expressed in lepidic predominant
adenocarcinomas compared with invasive mucinous
adenocarcinomas in the literature 23,26.
MUC1 expression in cancer cells has been shown on both
the apical border and the lateral cell membrane and in the
cytoplasm (depolarized staining). Both the overexpression
of MUC1 and the depolarized pattern of its expression act as a poor prognostic parameter in lung cancer 16-20. Decreased polarized and increased depolarized
MUC1 expression was significantly associated with the
progression from atypical adenomatous hyperplasia
through bronchioloalveolar carcinoma to mixed types
26. Depolarized MUC1 expression and its relationship
with poor prognostic parameters such as lymph node
metastasis and stage have been well documented among
lung adenocarcinomas 19. However, there are conflicting
results on the prognostic significance of the depolarized
pattern of expression for MUC1 18,29. Although some
researchers demonstrated a relation between depolarized
MUC1 expression and early postoperative death 18, no
relation between depolarized MUC1 expression and poor
survival was found by others 29. In our study, tumors
with depolarized MUC1 expression showed lymphatic
invasion more frequently and were larger in diameter
with advanced stage. However, we found no correlation
between depolarized staining and lymph node metastasis
or OS. Polarized MUC1 expression was more common in
micropapillary and papillary patterns, which are known
to have a poor prognosis. Therefore, the presence of
depolarized MUC1 expression may be a poor prognostic
parameter, but expression levels and interpretation criteria
may also be important.
Conflicting results may be due to the lack of standardized
immunohistochemical evaluation for MUC1. In previous
studies, several criteria for MUC1 immunohistochemical
evaluation were introduced 16-18,23,24,26,29. These
methods have been used as follows: (a) a four-tiered system
depending on the percentage of positive tumor cells (score
0, 0%; score 1, 1-25%; score 2, 26-50%; score 3, 51-75%;
score 4, >76%) 24, (b) a four-tiered system depending
on the percentage of the polarized or depolarized staining
(low-grade polarized, fewer than 50%; high-grade
polarized, more than 50%; low-grade depolarized, fewer
than 10%; high-grade depolarized, more than 10%) 18,26, (c) a binary system (positive or negative) using the
multiplying the percentages of positive-stained cells by the
staining intensity and considered positive when the score
was ≥10 17,23, (d) a binary system using a cut-off level
(5%) for positivity 16, and (e) a binary system depending
on the depolarized expression percentage (positive, >25%;
negative, 0-25%) 29. The dominant pattern was used
for scoring in another study because tumors showed
heterogeneous staining 17. We think that the different
criteria for MUC1 immunohistochemical staining are the
reasons for such conflicting results. Due to the heterogeneity
of pulmonary adenocarcinomas, immunohistochemical stains may show different degrees of staining in each
pattern. Therefore, a standard evaluation system is needed
for immunohistochemical results to obtain objective
data. We tested a final IRS score, in which the differences
between each histologic pattern were taken into account.
We showed that MUC1 FIRS scores were higher in patients
with lymph node metastasis, and tumors with a FIRS score
of >8.5 were 2.75 times more likely to metastasize.
MUC1 is overexpressed in lung cancer, making it an
excellent target for immunotherapy. Several clinical trials
of MUC1 vaccines (L-BLP25) in lung cancer have been
reported 21,22. A randomized phase IIb study of L-BLP25
(MUC1) vaccine in stage IIIB and IV NSCLC was conducted
looking at survival and toxicity in patients 22. The study
showed that the median survival time of patients receiving
immunotherapy (88 patients) was 4.4 months longer than
that of patients in the control group (83 patients). A phase
I trial of the BLP25 (MUC1 peptide) liposomal vaccine
in patients with advanced-stage lung cancer established
its safety profile and immunogenicity 21. Although the
vaccine did not induce a specific humoral response, it did
induce cytotoxic T-cell activity in five of 12 patients. There
were no objective clinical responses among the 12 patients.
In these studies, the intensity of MUC1 expression in the
tumor was not taken into account. More promising results
can be obtained with new studies in which the degree of
MUC1 expression is also considered.
As a limitation, we did not consider the molecular basis of
our retrospective study cohort and oncologic approaches
affecting prognosis. Nevertheless, our study is one of the
few studies examining the differences in mucin expression
in lung adenocarcinoma. In addition, we investigated
detailed immunohistochemical evaluation according to the
patterns and compared them with the prognostic data.
In summary, the present study introduces an alternative
scoring for MUC1 that may serve as a predictor for lymph
node metastasis regardless of the histologic subtype.
Furthermore, MUC1 may be a useful biologic marker
for lung adenocarcinoma treatment. MUC1-targeted
immunotherapy may be more appropriate for tumors
showing high scores of MUC1 expression. Further clinical
studies are needed to confirm the role of MUC1 in clinical
practice and develop novel therapeutic approaches. We
think that our method can also be used to evaluate other
immunohistochemical stains used for other heterogeneous
tumors to provide objective data collection.
Conflict of Interest
There are no conflicts of interest.
Funding received from the Scientific Research Projects Unit of
Istanbul University for this study.
Concept: DY, MB, YO, Design: MB, DY, YO, PF, Data collection
or processing: MB, DY, YO, Analysis or Interpretation: MB, DY,
YO, PF, DVB, BO, Literature search: MB, YO, DY, DVB, BO, PF,
Writing: MB, YO, DY, Approval: MB, YO, DVB, BO, PF, DVB.
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