Diagnostic value of progesterone receptor and
p53 expression in uterine smooth muscle tumors
Iman H Hewedi*, Nehal A Radwan and Lobna S Shash
Background: The diagnosis of uterine smooth muscle tumors depends on a combination of microscopic features.
However, a small number of these tumors still pose difficult diagnostic challenges.
Aim: To investigate progesterone receptor (PR) and p53 expression in leiomyomas (LMs), atypical leiomyomas
(ALMs), smooth muscle tumors of uncertain malignant potential (STUMP), and leiomyosarcomas (LMSs) and to
evaluate the potential utility of the selected immunohistochemical markers in differentiating these tumors.
Materials and methods: Immunohistochemical expression of PR and p53 was investigated in 41 uterine smooth
muscle tumors comprising: 15 LMS, 4 STUMP, 6 ALM and 16 LM. Quantitative evaluation of PR and p53 expression
was graded on a scale from 0 to 3+.
Results: Leiomyosarcomas showed reduced PR expression. All LMs as well as ALMs and STUMP were stained
intensely for PR. Conversely, LMS was strongly stained with p53, while the three non-sarcomatous groups (STUMP,
ALM, LM) were either entirely negative or weakly stained for p53. Regarding both PR and p53 expression, the
difference between the LMS group and the three non-sarcomatous groups was highly significant (p < 0.001).
Combined high PR - low p53 expression was seen in all the 26 examined cases of the non-sarcomatous group
including the STUMP cases and none of the LMS cases. Therefore, it represents a “benign” profile with 100%
specificity in diagnosis of a non-sarcomatous tumor.
Conclusion: Immunohistochemistry for PR and p53 is valuable as an adjunct tool to morphological assessment of
problematic uterine smooth muscle tumors.
Keywords: PR, p53, uterine smooth muscle tumor, Leiomyosarcoma, STUMP
Uterine smooth muscle tumors are the most common
female genital tract neoplasms. They are classified into:
leiomyomas (LMs), smooth muscle tumors of uncertain
malignant potential (STUMP) and leiomyosarcomas
(LMS) . LM is the most common type which occurs
in nearly 40% of women older than 35 years. Uterine
LMSs are relatively rare smooth muscle tumors,
accounting to approximately one third of uterine sarco-
mas and 1.3% of all uterine malignancies .
Most of the uterine smooth muscle tumors are readily
classified into benign or malignant, using a combination
of microscopic features including the presence and type
of necrosis, the degree of cytologic atypia, the mitotic
activity, and the relationship of the tumor to surround-
ing normal structures. However, a small number of uter-
ine smooth muscle tumors constitute difficult diagnostic
challenges. Morphologically, some variants of LM, such
as cellular leiomyoma, atypical leiomyoma (leiomyoma
with bizarre nuclei) (ALM) and mitotically active leio-
myoma can mimic malignancy in one or more aspects.
Also, some smooth muscle tumors that cannot be classi-
fied as benign or malignant based on histopathological
criteria are diagnosed as the smooth muscle tumor of
uncertain malignant potential (STUMP). This term is
used when there is some significant doubt about the
failure probability associated with a particular combina-
tion of microscopic features. The ultimate biological
behavior of tumors classified as STUMP remains uncer-
tain. Thus, it would be clinically valuable to decrease
* Correspondence: firstname.lastname@example.org
Pathology Department, Faculty of Medicine, Ain Shams University, Cairo,
Hewedi et al. Diagnostic Pathology 2012, 7:1
© 2012 Hewedi et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
the percentage of these cases for the optimal manage-
ment of the patients [2,3].
Variations in interpretation and subjective identifica-
tions of some microscopic features (mitotic figures, type
of necrosis) have resulted in introducing potential
diverse diagnostic criteria for uterine smooth muscle
tumors. Few reports investigated steroid receptor
expression in uterine smooth muscle tumors. Significant
differences of PR expression between uterine LM,
STUMP and LMS were observed [4-8]. Therefore, We
explored the PR expression in LMs, ALMs, STUMP,
and LMSs to determine whether PR might be of diag-
nostic value in the assessment of problematic uterine
smooth muscle tumors or not. We also stained the
cases with p53 to investigate whether it might be of
complementary value to PR.
Materials and methods
• Tissue collection
This retrospective study included 41 uterine smooth
muscle tumors. Cases were retrieved from the archives of
the Early Cancer Detection Unit, Ain Shams Obstetrics
and Gynaecology Hospital, Cairo, Egypt. All the speci-
mens had been routinely fixed in formalin and processed
in paraffin wax. The cases were reviewed and the histolo-
gical diagnosis was assigned according to the recently
published criteria . After ruling out infarcted and
mitotically active leiomyomas, the histopathologic diag-
nostic criteria applied in this study are summarized in
Table 1. All atypical leiomyoma, STUMP and leiomyosar-
coma cases received between 2005 and 2010 were
included, while a comparable number of LMs received
during the same period, were randomly sampled. Accord-
ingly, cases included 16 leiomyomas, 6 atypical leiomyo-
mas, 4 STUMP and 15 leiomyosarcomas. The study was
carried out with full local ethics approval.
Immunohistochemical analysis for PR and p53 with a
technique was performed on formalin-fixed and paraf-
fin-embedded tumor sections. Commercially available
ready to use rabbit monoclonal antibody against PR
(Cell Marque- CA- USA- Cat. #323R-18) and mouse
monoclonal antibody against p53 (Lab vision- CA-
USA- Cat. # MS-104-R7) were used in this study. Anti-
gens were retrieved by microwaving in citrate buffer for
20 minutes for PR and p53. The final reaction product
was developed with diaminobenzidine. Proper positive
and negative controls were performed.
• Immunohistochemical Analysis
The immunohistochemical preparations were assessed
by the three authors using a multi-headed microscope.
Only nuclear staining was considered as a positive
reaction for PR and p53. Due to different staining
properties, the assessment of the degree of immunohis-
tochemical staining was made according to two scoring
scales based on the percentage of the stained cells as
described by Gökaslan et al. . The quantitative eva-
luation of PR was made as follows: 3+ for > 50% of the
cells immunostained, 2+ between 10 and 50%, 1+ for <
10% and 0 (none) for no staining. At the same time,
p53 was evaluated as: 3+ for > 20% of the cells immu-
nostained, 2+ between 5 and 20%, 1+ for < 5% and 0
(none) for no staining. For both immunostains, 0 and
1+ are regarded as low expression, while 2+ and 3+
are regarded as high expression.
• Statistical analysis
Chi-square tests were used to compare the frequency
distributions of PR and p53 expression between the ana-
lyzed tumor groups. P values of less than 0.05 were con-
sidered statistically significant and those less than 0.01
were highly significant. IBM SPSS statistics (V. 19.0,
IBM Corp., USA, 2010) was used for data analysis.
Results are shown in Tables 2 and 3 in addition to Fig-
ures 1, 2, 3, 4, and 5.
Table 1 Histologic criteria employed in this study for the diagnosis of uterine smooth muscle tumors
DiagnosisTumor cell necrosis Atypia MF/10 HPF*
LeiomyosarcomaPresentDiffuse moderate to severeAny level
PresentNone to mild
AbsentDiffuse moderate to severe
STUMPPresentNone to mild< 10
AbsentDiffuse moderate to severe5-9 or atypical mitotic figures
Absent Focal moderate to severe
Atypical leiomyomaAbsentFocal or diffuse moderate to severe < 5
LeiomyomaAbsentNone to mild< 5
*Mitotic figures per 10 High power field
Hewedi et al. Diagnostic Pathology 2012, 7:1
Page 2 of 6
Leiomyosarcoma showed reduced PR expression.
Negative PR expression was noted in 13 out of 15
LMSs. None of the LMSs studied exhibited 3 + PR posi-
tivity. However, all LMs showed intense staining for PR
(all samples, 3+). The ALMs and STUMP were also
intensely stained for PR (all samples 2+ or 3+). The dif-
ference between the LMS group on one hand and the
combined three non-sarcomatous groups (LM, ALM,
and STUMP) on the other hand, regarding PR expres-
sion this difference proved to be highly significant (x2=
38.126, p < 0.001). The difference of PR expression
among LMSs in comparison to each individual, non-
sarcomatous group was also highly significant with p <
0.001 (LMS vs. STUPM; x2= 15.99, LMS vs. ALM; x2=
18.55, LMS vs. LM; x2= 31.00).
On the contrary, the malignant side of the spectrum
(LMS) was strongly stained with p53 (all samples 2+ or
3+), while the three non-sarcomatous groups were
either entirely negative or weakly stained for p53.
The difference between the LMS group on one hand
and the combined three non -sarcomatous groups (LM,
ALM, and STUMP) on the other hand, regarding p53
expression was also highly significant (x2= 41.00, p <
0.001). This highly significant difference, regarding p 53
expression (p < 0.001) was also extended on comparing
LMS to each of the non-sarcomatous groups (STUMP,
ALM, and LM) individually with x2= 19.00, 21.00 and
On exploring the combined results of the used mar-
kers, it was evident that the profile of high PR expres-
sion (2+ or 3+) and low p53 expression (0 or 1+) is
100% specific for the non-sarcomatous diagnosis. This
“benign” profile of high PR- low p53 expression is seen
in all the 26 examined non sarcomatous cases including
the STUMP and in none of the LMS cases. The single
LMS case that showed high PR expression (2+) also
exhibited intense p53 staining (3+).
Previous studies have shown that the distinction
between LMS, STUMP and ALM may sometimes be
problematic because of inaccurate and inconsistent defi-
nitions in diagnostic criteria [9,10]. Earlier reports have
investigated PR and p53 expression in uterine smooth
muscle tumors [5-7,11,12]. Yet, the current study is the
leading one to study these two markers among diverse
uterine smooth muscle tumors subsequent to applica-
tion of the recent diagnostic criteria published in 2011
by Zaloudek et al . Additionally, we chose to apply a
simple, yet efficient method to assess the immunostain-
ing results that can be used not only in academic set-
tings, but also in clinical practice.
PR is routinely determined in patients with breast and
endometrial cancer . Previous reports had shown that
LMs are hormone- dependent tumors and for the last
few years investigators focused on LMS, STUMP and
specific subtypes of LMs [6-8,13-16]. Little is still
known about the progesterone receptor expression pat-
tern of ALMs, and STUMP . Gökaslan et al. stated
that all their nine ALMs were immunopositive for PR
with a moderate-to-strong staining intensity . Zhai
and colleagues observed a strong positive staining for
PR in all of the eight STUMP cases included in their
study . Likewise, Mittal and Demopoulos detected
immunopositivity for PR in all of their seven STUMP
cases . Bodner et al. detected PR expression in 17 of
Table 2 Expression of PR and p53 in uterine smooth muscle tumors
Tumor typePR expression P53 expression
High -expression Low-expressionHigh-expressionLow-expression
+3+2 +10 +3+2 +10
• Atypical leiomyoma
*STUMP = smooth muscle tumor of unknown malignant potential
Table 3 combined PR-p53 expression profile in uterine smooth muscle tumors
Tumor typeCombined PR- p53 expression profile
High PR- Low p53Low PR- High p53High PR- High p53
Non-sarcomatous tumors (LM+ALM+STUMP)26/260/260/26
*Abbreviations: LM = leiomyoma, ALM = atypical leiomyoma, STUMP = smooth muscle tumor of unknown malignant potential, LMS = Leiomyosarcoma
X2= 41.00, p < 0.001
Hewedi et al. Diagnostic Pathology 2012, 7:1
Page 3 of 6
their 24 STUMP cases . We found PR expression in
all of our 16 LM cases, and in our series ALMs and
STUMP showed a markedly similar PR staining pattern
to that of LMs.
Most researchers detected low immunostaining rates
of PR in LMSs [6,11,17]. We have detected a promi-
nent reduction in PR expression in LMS cases where
only a couple of cases showed progesterone receptor
expression with slight-to-moderate intensity. Bodner et
al.  reported that progesterone receptors were
expressed in 43% of the leiomyosarcoma cases; a per-
centage which is much higher than the one detected in
this study. However, they also reported that such
expression did not influence the prognosis of LMS.
The use of earlier diagnostic criteria in Bodner et al.
study might allow inclusion of few STUMP cases
among their leiomyosarcomas. This could be explained
in view of the fact that previous diagnostic criteria for
smooth muscle tumors  did not allow the presence
of tumor cell necrosis into the STUMP category and
pushed them into leiomyosarcomas which has been
modified into the recent criteria applied in the current
The present study found a prominent difference in PR
expression between LMS and STUMP. Meanwhile, the
staining pattern of the STUMP group was strikingly
similar to that of LM. These results were in concor-
dance with the results of Mittal & Demopolous  and
Petrovic et al. . In addition, our study also demon-
strated that ALMs had a similar intensive and strong
staining pattern of progesterone receptors to that of
LM. We suggest that progesterone receptor expression
analysis can aid us in effectively distinguishing both
ALMs and STUMP from LMSs.
Figure 1 High PR expression (3+) in a leiomyoma,(PR × 400).
Figure 2 Atypical leiomyoma with high PR expression (3+),(PR
Figure 3 Smooth muscle tumor of uncertain malignant
potential (STUMP) with high PR expression (3+),(PR × 400).
Figure 4 A leiomyosarcoma exhibits negative immuno-
reactivity for PR,(PR × 400).
Hewedi et al. Diagnostic Pathology 2012, 7:1
Page 4 of 6
This study also investigated the expression of p53; a
suppressor gene that was very commonly found in leio-
myosarcomas. All our Leiomyosarcoma samples were
almost equally divided into either 2+ or 3+ regarding
p53 immunostaining. Mittal and Demopoulos 
reported 5 out of 12 LMS cases which expressed p53 in
≥ 15% of the cells while 4 LMS cases showed positivity
in ≥ 40% of the cells in their study.
In the female genital tract and breast tumors, Westhof
et al.  assumed that elevated levels of p53 protein
might indicate p53 gene mutations. They concluded that
p53 expression and overexpression were organ-depen-
dent. De Vos et al.  were the first to suggest that
p53 mutations are more frequent in leiomyosarcomas.
They claimed that the acquisition of p53 mutation was
the one distinguishing difference between leiomyomas
and leiomyosarcoma. Hong et al.  stated that even
though p53 expression in leiomyosarcoma was signifi-
cantly higher than leiomyoma, the frequency of p53
positivity was not as high as expected. Jeffers et al. 
claimed that positive immunohistochemistry did not
always correlate positively with the presence of muta-
tion. Nordal et al.  indicated that p53 alterations
might play an important role in the carcinogenesis of
uterine sarcomas. Nonetheless, they also emphasized
that p53 accumulation had no impact on prognosis.
Wang et al.  proposed p53 could be applied as an
accessory criterion in the differential diagnosis of
smooth muscle tumors of the uterus. Kayser et al. 
claimed that benign metastasizing leiomyoma showed
p53 over expression.
We observed intense staining of our leiomyosarcoma
samples and poor staining of all the rest of the smooth
muscle tumors, including STUMP cases. These findings
were primarily in accordance with the study of Mittal
and Demopoulos . According to our study, p53 was
more clearly shown to be an indicator of malignancy
with strong statistical significance.
In keeping with the excellent prognosis in patients
with STUMP previously reported [1,7], the immunopro-
file of STUMP for PR and p53 in this series was much
closer to leiomyomas than leiomyosarcomas. It would
be of interest to know if the immunoprofile of an occa-
sional STUMP behaving in a malignant fashion is closer
to that of leiomyosarcomas than to that of leiomyoma.
The findings of the current and previous studies can
be used to evaluate cases of uterine smooth muscle
tumors in which histologic findings are ambiguous or
borderline. These would include tumors where mitotic
figures are clumped or poorly formed, and thus difficult
to identify. Smooth muscle tumors, in which nuclear
atypia is moderate to severe with 5 to 9 mitoses/10 HPF
can also be further evaluated. Moreover, they can be
used to evaluate cases in which only a small sample of
the tumor is available for study. As to the evaluation of
any lesion, the immunohistochemical findings of com-
bined PR and p53 expression should be used in concert
with clinical, gross, and light microscopic findings to
arrive at a final diagnosis.
Although leiomyosarcomas are usually negative for
PR, occasional cases showed positive staining for these
receptors. Hormonal management in these cases might
be helpful in controlling these tumors.
In conclusion, PR and p53 immunostaining profile is
useful in distinguishing leiomyosarcomas from STUMP
and atypical leiomyomas. So we can improve the objec-
tivity and raise the degree of certainty concerning the
histopathologic decision; allowing for optimal manage-
ment of such tumors.
IHH conceived, designed and coordinated the study, evaluated
immunohistochemistry, performed the statistical analysis and drafted the
manuscript. NAR reviewed the histological diagnosis, evaluated
immunohistochemistry, carried out photographing, participated in the study
design and helped to draft the manuscript. LSS participated in the sequence
alignment, performed data collection, evaluated immunohistochemistry and
critically reviewed the manuscript. All authors read and approved the final
The authors declare that they have no competing interests.
Received: 6 December 2011 Accepted: 5 January 2012
Published: 5 January 2012
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Cite this article as: Hewedi et al.: Diagnostic value of progesterone
receptor and p53 expression in uterine smooth muscle tumors.
Diagnostic Pathology 2012 7:1.
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