2020, Volume 36, Number 3, Page(s) 227-236
Diagnostic Utility of Immunohistochemical Expressions of IMP3 Versus DOG1 and p63 in Salivary Gland Tumors
Taiseer R. IBRAHIM1, Mona Mostafa AHMED1, Abdelmonem Awad HEGAZY2
1Department of Pathology, Zagazig University, Faculty of Medicine, ZAGAZIG, EGYPT
2Department of Anatomy and Embryology, Zagazig University, Faculty of Medicine, ZAGAZIG, EGYPT
Keywords: IMP3, DOG1, p63, Salivary gland tumors, Immunohistochemistry
The diverse site of origin and classification complexity of salivary glands tumors increase difficulties in their diagnosis. This study
aimed to evaluate the specificity and diagnostic ability of immunohistochemical expressions of IMP3 versus DOG1 and p63 in cases of such
Material and Method: Thirty paraffin-embedded salivary gland tumors were obtained from the Pathology Department Archive. Their diagnosis
was confirmed. The specimens were then re-classified and evaluated using the IMP3, DOG1 and p63 immunohistochemical markers.
Results: There were 8 pleomorphic adenoma (PA), 12 mucoepidermoid carcinoma (MEC) and 10 adenoid cystic carcinoma (ADC) cases. All
12 MECs (100%) were IMP3 positive, while 30% of ADCs and only 25% of PAs were positive for IMP3. There was a statistically significant
relationship between salivary gland tumors and IMP3 immunostaining (P =0.03). As regards to DOG1 results, 12.5% of PAs showed variable
luminal positive immunostaining and 40% of ADCs showed weak luminal and abluminal immunostaining while 16.7% of MEC showed
cytoplasmic staining. On the other hand, all ADCs (100%) showed moderate p63 reactivity in the nuclei of abluminal cells. All MEC cases
(100%) were also p63-positive, showing a strong diffuse nuclear reactivity. A statistically significant relationship was noticed between salivary
gland tumors and p63 immunostaining (P <0.05).
Conclusion: IMP3 is more sensitive for diagnosis of MEC than ADC. p63 is statistically significant in diagnosing salivary gland tumors (MEC
and ADC). On the other hand, DOG1 staining is not sensitive in diagnosis of studied malignant salivary gland tumors, limiting its diagnostic
The salivary glands are exocrine organs consisting of ductoacinar
units. Their main function is the formation and
secretion of saliva. There are major and minor glands. The
major glands include three pairs: parotid, submandibular,
and sublingual glands. The minor salivary glands are found
in the oral cavity 1
. The salivary glands have two basic
types of cells: luminal that includes acinar and ductal cells,
and abluminal in the form of myoepithelial and basal cells.
The secretory acini and intercalated ducts are enveloped
with myoepithelial cells, while the striated ducts and
conducting portions are based on basal cells. Salivary gland
tumors usually originate and differentiate along the same
cell lines, i.e., epithelial (acinar and ductal), myoepithelial
and basal. This could lead to a considerable overlap in
diagnosis at all levels because all these cells can show
various metaplastic changes such as oncocytic, sebaceous,
squamous, and chondroid 2
Salivary glands tumors represent about 1% of all neoplasms
and 0.3% of human malignancies. Among head and neck
cancers they represent 3% to 6% of cases. According to
recent data, about 75% of salivary glands tumors develop
in the parotid gland and only 20% of these are malignant.
These tumors have extremely diverse morphology and
heterogeneity with an unpredictable prognosis that
complicate the therapeutic decision 3.
There are 34 different salivary gland epithelial tumors,
including 10 benign and 24 malignant types, according to
the 2005 third histologic classification of the World Health
Organization. Common types of salivary gland tumors
are mucoepidermoid carcinoma (MEC), pleomorphic
adenoma (PA), adenoid cystic carcinoma (ADC) and
Warthin tumor. Although the diagnosis of most salivary
gland tumors can be made on the basis of hematoxylin
and eosin-stained sections, immunohistochemistry can
provide a powerful adjunct tool for pathologists to identify
the cellular differentiation and assign correct classifications
in difficult tumor cases 4.
The MEC represents the commonest primary malignant
neoplasm in the salivary glands and accounts for 29 to 34%
of these malignancies. This tumor has a unique cellular
differentiation, being composed of a mixture of mucous,
intermediate and squamoid cells, making the differential
diagnosis of MEC broad 5. In addition, ADC is a malignant
biphasic tumor composed of modified myoepithelial and
ductal cells that commonly occur in the salivary glands, but
may also be present in other organs like the lung, prostate,
skin, and breast. ADCs are found in various patterns
including cribriform, tubular and solid. Polymorphous
low-grade adenocarcinoma may show a significant
architectural and cytological overlap with ADC. In contrast
to breast ADCs that have a favorable prognosis, the salivary
gland counterpart shows poor long-term outcome 6.
On the other hand, PA might be difficult to distinguish
from several benign and malignant salivary gland tumors.
Histologic findings that may represent diagnostic pitfalls
include the presence of areas of squamous and mucinous
metaplasia. This could mimic the appearance of MEC, or
the presence of areas with cribriform architecture that may
mimic the appearance of ADC 7.
The heterogeneity of cellular differentiation and the
histological patterns makes the diagnosis of salivary gland
tumors a challenging matter. The similarity in histological
patterns among many different tumors further complicates
the diagnosis with subsequent propensity for recurrence
and metastasis. The histologic diversity of these tumors
is due to the presence of myoepithelial cells; tumors
containing myoepithelial cells exhibit slow progression
and a low metastatic capacity. This requires investigating
various biomarkers to support the histological diagnosis
and to distinguish the different varieties of these tumors
Insulin-like growth factor II m-RNA-binding protein 3
(IMP3) is an oncofetal protein. It belongs to the family
of insulin-like growth factor II that is important in cell
migration during early embryogenesis. It represents a
component of RNA-binding protein required for early
cleavage during pre-18s ribosomal RNA processing. IMP3
has been considered as a cancer-associated protein and its
overexpression represents a prognostic marker in a variety
of human types of malignancy 9.
The gene that encodes IMP3 is present on chromosome
7p15 and plays an important role in the migration and
adhesion of cells in various malignant neoplasms. The
3 members of this family are known as IMP1, IMP2 and
IMP3. IMP3 is strongly expressed in malignant tumors but
rarely in normal adult tissues 8.
The gene known as anoctamin-1 (ANO-1), also known as
discovered on GIST-1 (DOG1), was originally distinguished
in gastrointestinal stromal tumors (GIST-1). Its function in
secretory cell types such as those of the salivary gland is
explained by its role in controlling the calcium-activated
chloride channel; this explains its expression in salivary
gland tumors indicating an acinic and intercalated duct cell
p63 protein (p63) is a nuclear P53 homolog; it plays an
essential role in the morphogenesis of the epidermis and
limbs, in addition to acting as a transcription factor in the
growth and development of many epithelial organs. It has
been detected in basal stem cells of squamous epithelia
as well as the basal cells/myoepithelial cells in the breast,
sweat glands, prostate, and salivary glands 11.
The aim of this work was to evaluate the role and sensitivity
of immunohistochemical expressions of IMP3 versus
DOG1 and p63 (myoepithelial marker) in the diagnosis of
salivary gland tumors.
Thirty formalin-fixed and paraffin-embedded salivary
gland tumors were randomly collected from the archive
of Pathology Department, Faculty of Medicine, Zagazig
University in the 2014 - 2017 period. We obtained the
clinical and pathological information from the medical
records of the patients. None of the patients had received
chemotherapy or radiation therapy before surgery.
Histopathological diagnosis and grading were done
according to the World Health Organization classification
. All paraffin blocks were cut at a thickness of 4 microns
and the specimens were stained with the hematoxylin and
eosin (H&E) stain to confirm the diagnosis.
The study was approved by the local ethics committee and
patients’ consent were obtained.
Immunostaining was done using the standard avidin-biotin
peroxidase method. Paraffin sections were de-paraffinized
in xylene, and then rehydrated using descending grades
of ethanol. Afterwards, antigen retrieval was done by
treating the sections with 0.01 M citrate buffer (pH 6.0)
for 30 minutes. After rapid rinsing in phosphate buffered
saline (PBS), the sections were incubated in 0.3% hydrogen
peroxide for 30 minutes to stop endogenous peroxidase
enzyme (Dako ko411 kit). The sections were then treated
with 5% horse serum for 2 hours at room temperature to
inhibit the non-specific immunoreactions.
Primary monoclonal antibodies were incubated overnight
in a humidity chamber (Table I). After washing the
sections in PBS, they were then incubated with biotinylated
secondary antibodies for 30 minutes, and then treated with
avidin-biotin peroxidase complex for another 30 minutes,
according to the manufacturer’s instructions (Universal
Detection Kit, Dako, Denmark). Finally, after visualization
of the immune reaction using 3,3 - diaminobenzidine tetra
hydrochloride (DAB, Dako K0114 Kit) for 5 minutes, the
slides were counterstained with Mayer’s hematoxylin and
All the steps were performed at room temperature. Negative
controls for all markers by omission of the primary antibody
were performed. The surrounding normal salivary tissue
was used as internal control.
Interpretation of Immunohistochemical Markers
The immunostaining was semiquantitatively evaluated by
2 pathologists (TI &MM).
Interpretation of IMP3 immunostaining: scoring was
performed by counting the percentage of the positive cells:
0 if <10%; 1 if 10%-25%; 2 if 26%-50%; and 3 if >50%.
Staining was seen in the nucleus or the cytoplasm or both.
The reaction was considered positive if more than 10%;
focal or heterogenous if more than 10% and less than 50%;
and diffuse when more than 50% stained cells were present
Interpretation of DOG1 immunostaining: The staining
intensity was graded as negative, weak (focal cytoplasmic
staining), or strong (diffuse cytoplasmic staining). The
reactions were considered positive if > 5% stained cells,
further divided into focal if more than 5 and less than 10%,
moderate between 10 and 50%, and diffuse if more than
50% of cells showed positivity 11.
Interpretation of p63 immunostaining: Nuclear staining
was scored as follows: Negative when <10% of nuclear
stained cells; weakly positive from 10% to 25%; moderately
positive from 26% to 75%; and strongly positive when
>75% of nuclear stained cells 10.
The data were collected and analyzed using Microsoft Excel
software, and then imported to the SPSS (Statistical Package
for the Social Sciences) version 20.0 software for analysis.
According to the type of data, qualitative variables were
represented as numbers and percentages; and quantitative
data represented by mean ± SD. The McNemar test and
Kappa Agreement were used to investigate differences
in variables for significance. The P value was considered
significant if it was <0.05 and highly significant when
<0.001. The validity of the immunohistochemical
markers were measured by sensitivity, specificity, positive
predictive value (PPV), negative predictive value (NPV)
and diagnostic accuracy.
The diagnosis of the thirty salivary gland tumors was PA in
8 and malignant tumors (12 MEC and 10 ADC) in 22.
IMP3 Immunohistochemical Expression (Tables II,III)
Click Here to Zoom
|Table II: Comparison between pleomorphic adenoma and malignant tumors as regard expression of immunohistochemical markers
using the McNemar test.
Click Here to Zoom
|Table III: Comparison between malignant tumors as regard immunohistochemical markers using the McNemar test.
The surrounding normal salivary tissue beside the tumors
was used as internal positive control. The ductal segment
showed positive cytoplasmic IMP3 staining in luminal
and extraluminal cells, while the intercalated duct showed
cytoplasmic staining in the luminal cells only.
Only 2 cases of pleomorphic adenoma (25%) showed
positive cytoplasmic immunostaining for IMP3 while 6
cases (75%) were negative. Staining was mainly observed in
areas of squamous metaplasia (Figure 1A).
Click Here to Zoom
|Figure 1: Representative samples of IMP3 expression in studied
cases. A) Pleomorphic adenoma, score 3. (IHC; x200)
B) Mucoepidermoid carcinoma with more than 90% of cells
showing positive cytoplasmic expression, score 2. (IHC; x200)
C) Adenoid cystic carcinoma with moderate positive cytoplasmic
expression, score 2. (IHC; x200).
All 12 MEC cases (100%) were IMP3 positive (Figure
1B). Cytoplasmic granular staining was observed in areas
corresponding to squamous and intermediate cells while
mucosal cells were negative.
Three out of ten (30%) ADC cases showed positive IMP3
staining (Figure 1C). In these tumors, cytoplasmic and
membranous staining was detected in the cribriform and
There was a statistically significant relationship between all
cases of salivary gland tumors and IMP3 immunostaining
DOG1 Immunohistochemical Expression (Tables ttable2>II, III)
The normal salivary tissue adherent to tumors showed
both membranous and cytoplasmic staining in serous acini
at an apical/luminal side, while the intercalated ducts were focally positive and more proximal larger ducts showed
Only one case of PA showed variable luminal positive
DOG1 (12.5%) (Figure 2A).
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|Figure 2: Immunohistochemical expression of DOG1 in studied
cases. A) Mild expression in pleomorphic adenoma (IHC; x200).
B) Negative expression in mucoepidermoid carcinoma (IHC;
x400). C) Mild cytoplasmic immunostaining in adenoid cystic
carcinoma (IHC; x200).
Ten out of twelve MEC (83.3%) were DOG1 negative,
while the remaining two cases (16.7%) showed weak
positive cytoplasmic staining in the mucous and some of
the intermediate cell components (Figure 2B).
Six out of ten (60%) adenoid cystic carcinomas showed
negative DOG1 staining while the remaining four cases
(40%) showed weak luminal and abluminal immunostaining
p63 Immunohistochemical Expression (Tables II, III)
p63 nuclear expression was found in the normal salivary
tissue adjacent to tumors in the basal and myoepithelial
Two out of eight cases of pleomorphic adenoma showed
p63 staining in abluminal and myoepithelial cells (Figure
Click Here to Zoom
|Figure 3: p63 expression in studied cases. A) Positive nuclear
expression in myoepithelial cells in pleomorphic adenoma (IHC;
x200). B) Mucoepidermoid carcinoma showing nuclear staining
in squamous and intermediate cells only (IHC; x200). C) Nuclear
immunostaining in abluminal cells while the luminal cells are
negative in adenoid cystic carcinoma (IHC; x200).
All 12 (100%) MEC were p63 positive showing a strong
diffuse nuclear reactivity in intermediate, squamous, and
clear cells while the mucous cells were negative (Figure 3B).
Moderate p63 nuclear reactivity was seen in all adenoid
cystic carcinomas (100%) in the abluminal cells while it was
absent in the luminal cells (Figure 3C).
A statistically significant relationship was found obtained
between salivary gland tumors and p63 immunostaining (P
<0.05) (Table II).
Validity of Immunohistochemical Markers in the
Diagnosis of the Studied Cases
In this study, we tested the validity of the markers in
diagnosing studied cases. The sensitivity of IMP3 in
diagnosing studied salivary gland tumors was 68.2%, the
specificity 75%, the positive predictive value (PPV) 88.2%, negative predictive value (NPV) 46.1 % and diagnostic
accuracy 70%. The sensitivity of DOG1 was 27.3 %,
the specificity 87.5%, the PPV 85.7%, NPV 30.4%, and
diagnostic accuracy 30.4%. Meanwhile, the sensitivity of
p63 was 100%, the specificity 75%, PPV 91.6 %, NPV 100%
and diagnostic accuracy 93.3% (Table IV).
Click Here to Zoom
|Table IV: Diagnostic performance of immunohistochemical markers in diagnosis of studied cases.
Validity of IMP3 in the Diagnosis of the Studied MEC
In this study, the sensitivity of IMP3 in diagnosing the
studied MEC cases was 100%, the specificity 70%, the PPV
80%, NPV 100%, and diagnostic accuracy 86.3% For DOG1, the sensitivity was 40%, specificity 83.3%, PPV 66.7%, NPV
62.5%, and diagnostic accuracy 63.6% (Table V).
IMP3 plays a vital role in cell migration in early
embryogenesis; it is also required for ribosomal RNA
processing. Expression of IMP3 is low or absent in adult
tissues. The high and strong expression has been suggested
to be a prognostic marker in a large variety of human types
of cancers 8,9,12
. In the present study, IMP3 expression
was detected in the cytoplasm of normal salivary duct cells
of adjacent normal tissues that was used as internal control. On the other hand, these findings were not detected in
human breast and normal pancreatic tissue that did not
show positivity for IMP3 but they are important in the
differentiation between benign and malignant pancreatic
IMP3 expression was detected in 25% (2/8) of studied
pleomorphic adenoma cases. These results differ from
that of Isomerism et al. who reported that all cases of
pleomorphic adenoma were positive for IMP3 8. On the
other hand, Elshafey et al. demonstrated that all cases of
pleomorphic adenoma involved in their study and normal
salivary gland tissues were negative for IMP3 staining 5.
In studied cases of ADC, IMP3 expression was observed in 30% (3/10). Isomerism et al. found that IMP3 expression
was present in 57% of cases of ADC 8.
In this study, all cases of MEC were positive for IMP3
expression. These findings are similar to that of Isomerism
et al. 8. Elshafey et al. reported in their study that 51.4%
of MEC cases were positive for IMP3 5. In this study, the
sensitivity of IMP3 in diagnosing studied MEC was 100%,
the specificity 70%, PPV 80%, NPV 100%, and diagnostic
accuracy 86.3%. Elshafey et al. reported that IMP3
expression is highly important in evaluating the outcome of
MEC, and IMP3 can be used to differentiate MEC from PA
(pleomorphic adenoma) of salivary glands 5. Isomerism
et al. concluded that MEC seems to be more sensitive to
IMP3 than ADC 8.
The difference was statistically significant between all
studied tumors and between malignant ones (MEC and
ADC) (P =0.03 and 0.0004 respectively). These findings
seem to suggest that IMP3 staining differs between these
tumors, allowing us to assume that this protein is an
important biomarker of salivary tumors with squamous
differentiation. Several studies have revealed the expression
of IMP3 in squamous cell carcinoma which supports this
DOG1 is plasma membrane protein acting as a calciumdependent
chloride-channel and a marker of GIST (gastrointestinal
stromal tumor) by gene expression profiling.
It is considered as a marker for differentiated acinic cells
and intercalated duct cells as it is detected in secretory
acini and diminished at the level of intercalated ducts and
was completely absent more proximally in the normal
salivary gland. This pattern of staining is in keeping with
the secretory function of DOG1 18-20. In the present
study, only one case of pleomorphic adenoma (12.5%)
showed DOG1 expression. These findings are similar to
those of Khurram and Speight who reported that 28% of
pleomorphic adenomas express DOG1 staining in the ductal
component only 18. Andrade et al. demonstrated that
DOG1 expression in benign salivary gland tumors like PA
was similar to normal salivary gland tissues and concluded
that it might be utilized as good marker for neoplastic cells
derived from intercalated ducts or its progenitor cells 21.
In this work, 83.3% (10/12) of MEC were negative for DOG1
and 16.7% (2/12) were positive. These results are similar to
that of Abd Rabbah and Hakim who reported that 90.9% of
MEC were negative for DOG1; and the positive cases (9.1%)
stained both the mucous and some of the intermediate cell
components 10. Also, Chenevert et al. found negative
DOG1 staining in most mucoepidermoid carcinomas
but the positive cases showed only focal weak staining in
the mucous cell component 19. Khurram and Speight
reported that MEC showed focal staining for DOG1 in 8
of 11 cases. In 3 of them, there was weak luminal staining
and the remaining 5 showed weak or faint membranous
expression in mucosal cells 18. In our study, four cases
(40%) of ADC showed weak focal reactivity for DOG1.
These results are similar to that of Khurram and Speight
who reported that only two cases of ADC were positive
for DOG1 expression 18. However, these are somewhat
different to previous findings of Abd Rabbah and Hakim
and Chenevert et al. who demonstrated DOG1 positivity
in both ductal and myoepithelial components in 70-80% of
cases and reported consistent luminal staining within the
cribriform areas 10,19.
Yang et al. demonstrated in a recent study that DOG1(C
kit) and p63 were expressed at rates of 61% and 64%,
respectively, in salivary adenoid cystic carcinoma. They
added that no significant differences in the expression of
these markers among breast, salivary and metastatic ADC
were noticed 6. The discrepancy between these studies
might be due to the difference in antibody clones used in
the different studies 18.
p63 is a marker for basal cells of the stratified epithelium
and myoepithelial cells that occur to variable degrees in
pleomorphic adenoma, adenoid cystic carcinoma and
intermediate cells of mucoepidermoid carcinoma 22.
In the present study, only 25% (2/8) of pleomorphic
adenoma showed positive p63 staining in abluminal
and myoepithelial cells. On the other hand, Ladeji et al.
demonstrated that all PA used in their study were positive
for p63 antibody; and p63 staining was observed in the
myoepithelial-like (abluminal) cells where they were seen
to express a range of weak to moderate positivity 22.
Among all MEC cases, 12 (100%) were p63 positive
with strong diffuse nuclear reactivity in intermediate,
squamous and clear cells while mucous cells were negative.
These findings are in line with Sams and Gnepp who
demonstrated that salivary gland MEC showed positive
staining for p63 in 100% of tumors in their study and added
that p63 immunohistochemical staining can be useful in
the differential diagnosis of acinic cell and MEC of the
salivary, especially in mucin rich MEC, the mucous cells
frequently will not stain with p63 while the adjacent basal
and intermediate cells are always positive 23.
On the other hand, all adenoid cystic carcinomas (100%)
showed moderate p63 reactivity in the nuclei of abluminal
cells while the luminal cells were negative. These findings
are consistent with other studies that reported that all
adenoid cystic carcinomas showed positive moderate
staining for p63 in abluminal cells only and strong positive
nuclear staining for p63 in 100% of evaluated MEC 10,23-25. However, Khurram and Speight demonstrated that
75% of ADC showed positive p63 staining in abluminal
and myoepithelial cells 18. In this study, a statistically
significant relationship was found between salivary gland
tumors and p63 immunostaining (P <0.05).
In this work, the diagnostic performance of the
immunohistochemical markers was as follows: Sensitivity
of IMP3 in diagnosing studied salivary gland tumors was
68.2%, the specificity 75%, the PPV 88.2%, NPV 46.1%,
and diagnostic accuracy 70%. The sensitivity of DOG1 was
27.3%, the specificity 87.5%, the PPV 85.7%, NPV 30.4%, and diagnostic accuracy 30.4%. The sensitivity of p63 was
100%, the specificity 75%, the PPV 91.6%, NPV 100%,
and diagnostic accuracy 93.3%. According to the current
results, we suggest that p63 represents a reliable and
statistically significant immunohistochemical marker in
the diagnosis of salivary gland tumor. Butler et al. reported
that the sensitivity, specificity, positive predictive value,
and negative predictive value for p63 to detect MEC were
95.4, 87.2, 91.2 and 93.2%, respectively 26.
The limitations of this study include the low number of
existing cases for each tumor type and absence of some
tumor types due to their low incidence in our locality.
Therefore, we recommend further studies for these markers
on larger numbers of cases that involve all types of salivary
In conclusion, IMP3 has higher efficacy in diagnosis of
mucoepidermoid carcinoma than adenoid cystic carcinoma,
especially in problematic conflicts like suspicious cases or
poor tissue sampling, and demonstrated the role of this
protein in diagnosing salivary gland tumors. We think that
IMP3 is a valuable marker of salivary tumors with squamous
differentiation. DOG1 staining in myoepithelial cells is
not reliable in diagnosis of mucoepidermoid carcinoma
and adenoid cystic carcinoma, restricting its diagnostic
utility. On the other hand, p63 is statistically significant
in diagnosing salivary gland tumors (mucoepidermoid
carcinomas and adenoid cystic carcinoma). Therefore, we
suggest this panel of immunohistochemical markers in the
diagnosis of challenging cases of salivary gland tumors.
We acknowledge Dr. Abd EL Azem W, lecturer of
Community and Occupational Medicine, Faculty of
Medicine, Zagazig University, for his assistance in the
statistical analysis of the collected data of the study.
CONFLICT of INTEREST
The authors declare no conflict of interest.
The authors declared that this study has received no
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