2017, Volume 33, Number 1, Page(s) 001-008
The Diagnostic and Prognostic Utility of DOG1 Expression on Gastrointestinal Stromal Tumors
Sevinç ŞAHİN1, Özgür EKİNCİ2, Selda SEÇKİN1, Ayşe DURSUN2
1Department of Pathology, Bozok University, Faculty of Medicine, YOZGAT, Turkey
2Gazi University, Faculty of Medicine, ANKARA, Turkey
Keywords: DOG1, Gastrointestinal stromal tumor, Immunohistochemistry
We aimed to review our archives in order to evaluate both the diagnostic and prognostic significance of DOG1 on gastrointestinal
stromal tumors (GISTs), and add further insight about those issues to the current literature including some conflicting results.
Material and Method: DOG1 was evaluated in 100 cases of GISTs, immunohistochemically. Immunostaining index was counted for each
antibody by using both the intensity and extent of staining. The association between immunostaining index of DOG1 and CD117, CD34, SMA
desmin, S-100, and Ki-67 index and clinicopathological features were analyzed.
Results: Ninety cases were positive for DOG1, and 89 were positive for CD117. All CD117-negative tumors were positive for DOG1. High-risk
group was directly correlated with tumor diameter, cellularity, necrosis, nuclear pleomorphism, mitotic count and Ki-67 index, by univariate
analysis. The association between high-risk group and tumor diameter, mitotic count, and Ki-67 index was proved by multivariate analysis.
Immunostaining index of DOG1, Ki-67 index, mitotic count, ulceration and hemorrhage were inversely correlated with overall survival by
univariate analysis. The adverse impact of DOG1 ISI and mitotic count on overall survival were supported by multivariate analysis.
Conclusion: DOG1 positivity was detected in most of GISTs and all in CD117-negative cases as a result underlining its diagnostic utility.
Additionally, DOG1 overexpression was related with adverse prognosis. Thus, we suggest that immunostaining index of DOG1 should routinely
be used while diagnosing GIST, and DOG1 might be considered as a potential prognostic tool and a target for novel therapies.
Gastrointestinal stromal tumor (GIST) is the most
common mesenchymal neoplasm in gastrointestinal tract
. It is considered to be originated from the interstitial
cells of Cajal 2
. Most GISTs have a mutation of c-KIT
(CD117) proto-oncogene that encodes the CD117 protein
a transmembrane tyrosine kinase receptor 2
approximately 4-5% of the GISTs miss this mutation, and
show immunonegativity for CD117 3
. The exact diagnosis
of CD117-negative GISTs is crucial because more than
two-thirds of them are still sensitive for imatinib-a smallmolecule
of tyrosine-kinase inhibitor-an effective targeted
therapy for GIST 3
. Thus, some molecules alternative
for CD117 such as DOG1 (discovered on GIST-1) have
been reported recently to be positive in especially CD117-
negative GISTs 3
DOG1 is a calcium-dependent chloride channel protein
that is encoded by a gene called TMEM16A (TMEM16
FLJ10261, ANO1, ORAOV2, and AOS2) located on
chromosome 11q13 3. DOG1 has many significant
functions such as regulation of the cholinergic activity of
gastrointestinal smooth muscle 4-6, and regulation of
both the survival and proliferation of cells 7. In addition
DOG1 activates alternative signals downstream of the
RAS/RAF/MEK/ERK and the insulin-like growth factor
(IGF)- dependent pathways 4, 8-9. These findings suggest
that DOG1 may play a role in GIST development and
progression, regardless of KIT and platelet-derived growth
factor receptor alpha (PDGFRA) activation. DOG1 has
been demonstrated to be positive in 89% of GISTs that have
not CD117 or PDGFRA mutations 3. In addition, DOG1
is claimed to be more sensitive and specific than CD117
in many studies, with some contradictory results in the
literature 10-12. About one third to one half of CD117-
negative GISTs are reported to be positive for DOG1 3.
Although the diagnostic utility of DOG1 for accurate GIST
diagnosis is being widely investigated, its prognostic role
is little evaluated in the literature. A few recent studies
suggest that DOG1 expression affect the prognosis with
some conflicting results 4, 10-15.
The goals of the present study were to review our archives
in order to evaluate both the diagnostic and prognostic
significance of DOG1 on GISTs, and achieve further data
to clarify those issues in the current literature containing
some contradictory results.
After obtaining Bozok University Ethic Committee
approval, 100 cases of GIST diagnosed between 2008
and 2014 were included in the study. Ninety-six cases
were from the archives of Department of Pathology, Gazi
University School of Medicine, and 4 cases were retrieved
from the archives of Department of Pathology, Bozok
University School of Medicine. The clinicopathological
features [age, gender, risk group, mitotic count in 50 high
power fields (HPFs), tumor size, tumor location, growth
pattern, cellularity, nuclear pleomorphism, ulceration
hemorrhage, necrosis, cell type, surgical/biopsy procedure
type, and Ki-67 proliferation index] were achieved from
the original pathology reports. Risk-groups had been
established and adopted according to the criteria of
Fletcher et al. 16
based on tumor size and mitotic count in
50 HPFs. In the present study, the cases were divided into
two groups as the “lower-risk group” and “high-risk group”
to predict the prognosis of GISTs. Very low-risk, low-risk
and intermediate-risk groups according to Fletcher et al.
were considered as “lower-risk group”, and high-risk
group according to Fletcher et al. was considered as “highrisk
group” in the study. Paraffin blocks were cut into
4-μm sections, deparaffinized and dehydrated according
to standard protocols. Then, immunohistochemistry
was performed using the streptavidin-biotin-peroxidase
method for DOG1 (ready to use, mouse anti-human
monoclonal antibody, clone K9, Leica Biosystems, United
Kingdom) in an automated stainer (Leica Bond-Max
Leica Biosystems, United Kingdom). Cytoplasmic staining
was considered as positive for DOG1. Besides DOG1, the
slides of CD117, CD34, SMA, desmin, S-100 performed
at the time of initial diagnosis were re-evaluated for both
extent and intensity of staining. Five random HPFs were
examined to count immunoreactive cells under light
microscope. Extent of staining was scored as: score 0=no
staining, score 1=<10%, score 2=10-60%, score 3=61-100%.
Lower than 10% staining was considered as negative, ≥10%
was considered as positive regardless from the intensity.
Intensity of staining was scored as follows: score 0=no
staining, score 1=mild, score 2=moderate, score 3=strong.
Then, an immunostaining index (ISI) for each stain was
calculated by multiplying the scores of extent of staining
and intensity similar to the study of Wang et al. (ISI=extent
X intensity scores) 17
. The ISI of the antibodies ranged
from 0 to 9. The ISI was considered as a feature indicating
the expression of each stain in the study. The cases were
divided into two groups according to Ki-67 proliferation
index as <10% and ≥10%. ISI’s of DOG1, CD117, CD34
SMA, desmin, and S-100 were correlated with each other
and the clinicopathological parameters (age, gender, risk
group, tumor location, tumor size, mitotic count, cell type
cellularity, nuclear pleomorphism, necrosis, hemorrhage
ulceration, and growth pattern), and Ki-67 proliferation
index statistically. Follow-up and survival data were
retrieved from the hospital records. Patients with severe
diseases during follow-up were excluded from the survival
All data were analyzed using PASW Statistics version 18.0
(SPSS Inc. Chicago. IL. USA). The demographic variables
were detected using descriptive statistics. The compliance
of data with normal distribution was evaluated with the
Kolmogorov - Smirnov and Shapiro-Wilk tests. Independent
Samples t-test (t test for independent groups) and One-
Way ANOVA tests were used in order to investigate the
quantitative data with normal distribution. Mann-Whitney
U and Kruskal-Wallis H tests were used in the evaluation of
the data that did not show normal distribution. The Tukey
HSD test was applied in order to determine from which
group the difference was originated. The Chi-squared test
Fisher’s exact tests, Pearson and Spearman’s Rho correlation
analysis were used for investigating the association between
ISI’s of antibodies and the clinicopathological parameters.
The effects of associated variables were studied by multiple
linear regression analysis using backward method. P-value
<0.05 was considered as significant.
| Clinicopathological Findings
We examined specimens from 100 patients (53 women and
47 men) with a mean age of 58.3}12.4 years (range 21 to
84). The tumors ranged from 0.4 to 25 cm (mean=6.06}4.24
cm) in diameter. Mitotic count varied from 0 to 80
(mean=7.4}15.3) per 50 high-power fields (HPFs). Four
tumors were from esophagus, 60 tumors were from
stomach, 7 were from duodenum, 11 were from jejunum
3 were from ileum, 3 were from colon, and 12 were from
mesentery/omentum. According to the criteria of Fletcher
et al., 70 (70%) cases were classified as lower-risk group
(15 were very low-, 37 were low-, 18 were intermediate-risk
group), and 30 (30%) cases as high-risk group. The followup
time ranged from 1 to 94 months (mean=45.2}23.9
months). Thirteen of the 100 cases were deceased, and
87 cases were alive when the follow-up was finished. It
was detected during follow-up that 2 cases died due to
renal cell carcinomas, and the other 2 died due to colon
adenocarcinomas, so those 4 cases were excluded from the
survival analysis. Overall survival (OS) ranged from 1 to 94
months (mean=82.2}2.9 months). The clinicopathological
features and their correlation with DOG1 expression of 100
GIST’s are summarized in Table I.
Ninety of 100 cases were positive for DOG1, 89 were
positive for CD117, 77 were positive for CD34, 22 were
positive for SMA, 10 were positive for desmin, and one
was positive for S-100 .The detailed immunohistochemical
findings underlining the correlation of DOG1 with other
markers are given in Table II and Table III.
Click Here to Zoom
|Table II: The correlations of DOG1 and other immunohistochemical markers (n: 100)
All CD117-negative GISTs (11 cases) were positive for
DOG1 (Figure 1A-C). Eight of them were positive for
CD34, while 3 of them were negative for CD34. One of
them was positive for SMA, while 10 of them were negative
for SMA. All CD117-negative GISTs were negative for both
desmin and S-100 . Male/female ratio in CD117-negative
GISTs were 3/8. The mean age was 62.9}1.8 (range: 50-
83). Nine cases were in lower-risk group, 2 cases were in
high-risk group. Nine tumors were from stomach, one was
from sigmoid colon, and one was from mesentery. They
were ranged from 0.4 to 11 cm in diameter. All of them had
expansive growth pattern. Seven of them were composed of
spindle cells, 3 were of epithelioid cells, and remaining one
was of mixed (spindle+epithelioid) cells. Six showed mild
cellularity, 3 showed moderate cellularity, and 2 showed
high cellularity. Mild cellular atypia was present in 6 cases
moderate cellular atypia was found in 2 cases, high cellular
atypia was found in 2 cases, and no significant atypia
was found in one case. Only one case showed ulceration.
Hemorrhage was not present in any case. The mean mitotic
count was 1.81}2.08 in 50 HPFs. Ki-67 proliferation index
varied from 0% to 20% (mean=3.09}5.75%).
Click Here to Zoom
|Figure 1: Photomicrographs of a case of CD117-negative GIST. A) The tumor was composed of both epithelioid and spindle cells (H&E; x200). B) CD117 immunonegativity of the tumor cells (CD117; x200). C)Diffuse and strong immunopositivity of the tumor cells for DOG1 (DOG1; x200).
During follow-up, we detected that 3 of 10 DOG1 negative
cases were deceased, while remaining 7 were alive. Ten of
90 DOG1 positive cases were found to be deceased. Six of
those cases were deceased due to GISTs, 2 of those cases
were deceased due to RCCs, and 2 of those were deceased
due to colon carcinomas. Remaining 80 of DOG1 positive
cases were found to be alive. There was no statistically
significant correlation with DOG1 expression and current
status of the patients (p=0.092). Mean OS was 52.4}33.2
months in DOG1 negative cases, while it was 44.5}22.8 in
DOG1 positive cases. There was no statistically significant
correlation between DOG1 positivity and OS (p=0.1).
However, we detected that when ISI of DOG1 increased
OS decreased, and that was statistically significant both by
univariate (p=0.023) and multivariate analysis (p=0.006
β=-0.269, t=-2.819). The data about the mean OS of the
cases according to the ISI of DOG1 is given in Table IV.
Click Here to Zoom
|Table IV: The overall survival of cases according to ISI (immunostaining index) of DOG1
Sixty-seven cases showed <5 mitoses/50 HPFs with a
mean OS of 48.1}24.3 months, while remaining 33 cases
showed ≥5 mitoses/50 HPFs with a mean OS of 39.5}22.4
months. According to those data, OS was detected to be
inversely correlated with mitotic count by both univariate
(p=0.012) and multivariate analysis (p=0.003, β=-0.289
t=-3.032). Additionally, OS was found to be negatively
correlated with Ki-67 proliferation index, ulceration and
hemorrhage by univariate analysis (p=0.039, p=0.043
p=0.043, respectively), but those findings were not
supported by univariate analysis. The results of univariate
and multivariate analysis of clinicopathological and
immunohistochemical features are summarized in Table V.
Click Here to Zoom
|Table V: Statistically significant associations between immunohistochemical and clinicopathologic characteristics (p<0.05)
High-risk group was directly correlated with tumor
diameter, cellularity, necrosis, cellular pleomorphism
mitotic count and Ki-67 proliferation index (p=0.000
p=0.004, p=0.019, p=0.000, p=0.005, p=0.000, respectively)
by univariate analysis. The association between highrisk
group and tumor diameter, mitotic count and Ki-67
proliferation index was supported by multivariate analysis
No statistically significant association was detected between
expression of DOG1 and CD117, CD34, desmin, S-100
Ki-67 proliferation index, mitotic count, age, gender, risk
group, tumor size, growth pattern, cellularity, nuclear
pleomorphism, ulceration, hemorrhage, and necrosis
The diagnosis of CD117-negative GISTs is still problematic
in the literature 3
. Recently, DOG1 has been suggested
to be an alternative fruitful molecule for establishing GIST
diagnosis, particularly for CD117-negative GISTs 11
a result of wide review of the literature, CD117 and DOG1
positivity rate were found to be 91% and 93%, respectively
in about 3000 GIST cases 18
. In parallel to the literature
we have documented CD117 and DOG1 positivity rate as
89% and 90%, respectively. In addition, the rate of DOG1
positivity in CD117-negative GISTs range from 20% to
100%, in the literature 18
. This discrepancy might be
attributed to the clinicopathological differences between the
study groups. One of those differences may be the clone of
DOG1 used in the study. In the literature, the sensitivity of
clone K9 of DOG1 is suggested to be superior to other clones
. In our study, we have used clone K9 and found that all
CD117-negative cases (100%) were positive for DOG1 by
immunohistochemistry. However, it should be noted that
DOG1 is not pathognomonic for GIST 19-20
. The data
about the specificity of DOG1 is controversial in the literature
. DOG1 may also be positive in some nonneoplastic
tissues such as gastric epithelium, breast, testis, salivary
gland, gallbladder, liver, lung, prostate, stomach, pancreas
urinary bladder, sweat glands, endometrium, and renal
. In addition, germ cell tumors, melanomas
some mesenchymal tumors and carcinomas are described
to be positive for DOG1 3, 20
. In order to make differential
diagnosis and establish accurate GIST diagnosis, a panel
composed of CD117, CD34, SMA, desmin, and S-100 is
routinely used in many laboratories to differ its mimickers
similar to ours. We suggest that DOG1 might be added this
panel, since 90% of GISTs showed positivity for DOG1 in
our study. In addition, some researchers recommend using
a first step immunohistochemical panel composed of only
CD117 and DOG1 may be more useful and reliable for
the diagnosis of GISTs, especially for the CD117-negative
. Additional immunohistochemical antibodies
including CD34, SMA, desmin, and S-100 are suggested to
be performed in the cases that are negative for either CD117
or DOG1 3
. The rate of CD34, SMA, desmin, and S-100
are reported to be as 72-78%, 19-57%, 4.1-5%, and 6-28%
in various studies 12
. In the present study the rate of
positivity for CD34, SMA, desmin, and S-100 were as 77%
22%, 10%, and 1%.
Beside those immunohistochemical markers, performing
Ki-67 is strongly recommended while diagnosing a GIST
since high Ki-67 proliferation index is widely considered
as an indicator of poor outcome in the literature 12,]
18. Recently, some studies have suggested that Ki-67
proliferation index over than 10% indicates poor outcome
12, 21-24. Similar to the literature, Ki-67 proliferation
index more than 10% was found to be associated with low
OS by univariate analysis in our study. We have also found
a direct association with higher mitotic count and low OS
and high-risk group by univariate analysis, similar to Ki-
67 labeling index. Nevertheless, we have demonstrated an
inverse correlation between OS and higher mitotic count
but not with Ki-67 proliferation index by multivariate
analysis. This result might be contributed to the fact that
mitotic count reflects the M phase of mitotic cycle, while
Ki-67 indicates the proliferative cells in G1, S, and G2
phases 21. Therefore, we think that higher mitotic count
is still more reliable prognostic indicator than Ki-67 for
GIST, and future studies should be conducted to clarify
Some recent studies have indicated that DOG1 might have
potential prognostic affect in GIST 10, 12, 13, while some
others have reported that it has only a diagnostic utility
but not a prognostic value 25. Sozutek et al. claimed that
DOG1 negativity in GISTs may indicate poor prognosis
however their result was not statistically significant
12. Jung et al. have proposed that DOG1 negativity is
significantly correlated with recurrence and/or metastasis
13. However, Rizzo et al. have recently suggested that
DOG1 overexpression might be used to predict poor
prognosis of GISTs, since they have found low relapse-free
survival in the cases with DOG1 overexpression than the
cases with lower expression 4. Similar to Rizzo et al., we
have demonstrated an inverse correlation between OS and
ISI of DOG1 by both univariate and multivariate analysis.
In parallel to our and Rizzo et al.’s study 4, Li et al. 15
have documented that higher levels of DOG1 expression
in peripheral blood mononuclear cells of GIST patients
indicate poor prognosis and might be used for monitoring
recurrence and investigating efficacy of imatinib therapy
for GIST patients. In addition, DOG1 is known to intervene
the receptor-activated chloride current and modulate the
cell proliferation by influencing the retinoblastoma (Rb)
tumor activating the MEK/ERK pathway 8. Additionally
xenograft DOG1-/- models of GISTs exhibit an impaired
cell proliferation as a result of the reduced IGF binding
protein-5 levels that inhibit IGF-mediated downstream
signals by trapping both IGF1 and IGF2 9, 26. Thus, these
data are likely that DOG1 overexpression might supply a
proliferative advantage to malignant stromal cells, and
elevated levels of DOG1 might adversely affect prognosis.
However, we have not shown any association between ISI
of DOG1 and Ki-67 proliferation index and mitotic count.
That contradictory result might have been obtained due to
other unknown signaling mechanisms related with DOG1
that should be clarified.
In the literature, there are some risk group classifications
established for predicting the prognosis and malignant
potential of GISTs 27-28. In this study, we have used the
risk assessment of Fletcher et al., due to its simplicity and
widely use. Mitotic count, tumor size, anatomic location
tumor necrosis, and nuclear pleomorphism have also
been shown to be the prognostic parameters for GIST
27-29. Similar to the literature, necrosis, high mitotic
count, high cellularity, greater tumor size and high nuclear
pleomorphism were also detected to be associated with
high-risk group in the present study. Thus, we suggest that
these features should be noted in the pathology reports as
indicators of poor prognosis.
In summary, this study has showed that DOG1 is a
reproducible and reliable marker for GIST diagnosis
particularly for CD117-negative GISTs. We also
strongly recommend that adding DOG1 in the routine
immunohistochemical panel of GIST differential
diagnosis (CD117, CD34, SMA, desmin, S-100) would
aid establishment of accurate diagnosis of GIST. In
addition, we have documented that DOG1 overexpression
is related with poor outcome by both univariate and
multivariate analysis. Thus, DOG1 ISI, referring the score
of multiplication of staining intensity and extent, seems to
be a useful prognostic tool as well as an ancillary diagnostic
method. We claim that more comprehensive future studies
including higher number of patients and longer follow-up
might clarify the potential role of DOG1 on pathogenesis
and prognosis of GISTs.
CONFLICT of INTEREST
The authors declare no conflict of interest.
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