Mixed Epithelial and Stromal Tumor Family of Kidney (Adult Cystic Nephroma, Mixed Epithelial and Stromal Tumor): Retrospective Clinicopathological Evaluation
Hale DEMIR1, Zehra SAHIN2, Oktay OZMAN3, Muhammed DEMIRBILEK4, Sami Berk OZDEN4, Iclal GURSES5, Haydar DURAK6, Nesrin UYGUN5, Bulent ONAL41
1Department of Pathology, Amasya University, Faculty of Medicine, AMASYA, TURKEY
2Gaziosmanpaþa Training and Research Hospital, ISTANBUL, TURKEY
3Department of Urology, Netherlands Cancer Institute, Antoni Van Leeuwenhoek Hospital, AMSTERDAM, NETHERLANDS
4Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, ISTANBUL, TURKEY
5Department of Pathology, Istanbul University-Cerrahpasa, Cerrahpasa Faculty of Medicine, ISTANBUL, TURKEY
6Acibadem Hospital, ISTANBUL, TURKEY
Keywords: Mixed epithelial stromal tumor, Adult cystic nephroma, Kidney, Renal cyst
Tumors belonging to the mixed epithelial stromal tumor family (MESTF) are rare; thus clinicopathological experience about them are
limited. Each epithelial and stromal component shows different patterns in these tumors.
Material and Method: Clinicopathological features of 11 MESTF cases that were diagnosed between 2000 and 2021 at a single center were
Results: Ten of the 11 patients were female (F:M = 10:1). The mean age of the females was 47 (31-63) years; the male patient was 45 years old.
The mean tumor diameter was 6.7 (3.5-19) cm. All tumors had varying proportions of cystic and solid components. Eight cases were well
circumscribed, and the others had distinct but irregular borders. Two of the tumors with irregular borders were bulging into the renal sinus.
The epithelial component was dominant in most cases. In the epithelial component, macrocyst, microcyst, and tubules were the most common
patterns and the most common types of lining epithelium were flat, cuboidal and hobnail. The stromal component was variable in most cases
and included hypocellular (mostly collagenous) and cellular areas. In most cases, the cellular stroma had an ovarian-like appearance. Among the
other features observed, hyalinization and dystrophic calcification were common. The positivity for estrogen and progesterone receptor in the
stromal component was observed in almost all female cases.
Conclusion: MESTF, which has distinctive features, should be considered in the differential diagnosis of cystic kidney tumors.
Cystic nephroma (CN) and mixed epithelial and stromal
tumor (MEST) are rare complex kidney tumors consisting of
epithelial and stromal elements 1-3
. Adult CN (ACN) and
MEST have clinic, morphologic and immunophenotypic
. It was also shown that ACN and MEST
exhibited similar mRNA expression profiles that were
distinct from the other renal tumors 5
. In the 2016 World
Health Organization (WHO) classification, these two
entities were accepted as same type of tumors that could
be more cystic (ACN) and more solid (MEST), and were
grouped under the title of “mixed epithelial and stromal
tumor family” (MESTF) 6,7
. In contrast, pediatric CN
(PCN) is accepted as a different entity. Although the role of
DICER 1 mutation was well established in PCN, there is no evidence revealing the presence/absence of this mutation
in ACN and MEST yet 8
MESTF cases were reported mostly among perimenopausal
women 1-3. Clinically, they most commonly present with
palpable abdominal mass, flank pain, and hematuria 2,9. Radiologically, these are mostly well-circumscribed,
multicystic masses with solid components 9,10. They can
be localized in the medulla or cortico-medullar region or
can be centered in the renal pelvis. Medullar tumors may
bulge into the renal pelvis 7.
The majority of the tumors are well circumscribed, with
capsules of variable thickness, containing smooth muscle
11. Each of the epithelial and stromal components may
show different patterns. The epithelial component, which
rarely contains complex structures, shows a tubular and cystic pattern lined with flat, cuboidal, and hobnail type
epithelium 4,5. Heterologous epithelial differentiations
(müllerian, urothelial, etc.) can be also seen 7. The
stroma can be hypocellular or hypercellular and is often
variable. The hypocellular stroma is mostly collagenous
while the hypercellular stroma is mostly ovarian-type. It
may contain different mesenchymal metaplasias (smooth
muscle, lipomatous, ect.) 1-4. Minimal atypia can be
seen in both of the components, but mitosis and necrosis
are rare pathological findings 7. Immunohistochemical
positivity for estrogen and progesterone receptors in the
stromal component were reported in most cases 1,4.
Most cases are benign and radical/partial nephrectomy is
the curative treatment option 1,12. However, recurrence
and malignant transformation were reported in a limited
number of cases 12-15.
The aim of this retrospective study was to evaluate the
clinicopathological features of 11 MESTF cases.
The study protocol was approved by the Clinical Research
Ethics Committee of a local university (No: 57, Date:
This study included 11 cases that were diagnosed with ACN
and MEST in the pathology department of an university
hospital, between 2000 and 2021. For each case, clinical
data including age, gender, symptoms, hormonotherapy
history, radiological features, surgery type, and followup
were recorded. In addition, by using the pathological
reports, macroscopic features of the tumor such as size,
borders, cystic or solid appearance, and extension beyond
the parenchyma were recorded.
Hematoxylin & Eosin stained slides of each case were
reevaluated. At low magnification, border characteristics of
the tumors and ratio of epithelial and stromal components
of each tumor were evaluated. Cysts, which are an element
of the epithelial component, were classified according to
their size; microcyst <5 mm, macrocyst >5 mm. Afterwards,
the histopathological features of the components were
examined in details and recorded. Cytological atypia,
mitosis and necrosis were also noted.
Immunohistochemical studies were performed for ER and
PR expression in all cases. The only tumor resected from a
male patient was also examined for androgen receptor (AR)
expression. The findings related to these were recorded
from pathology reports.
Ten of 11 patients were female (F:M = 10:1). The mean age
of the female cases was 47 (31-63) years; the male patient
was 45 years old.
The complaints reported were flank pain, abdominal
pain, abdominal mass, hematuria and polyuria in order
of frequency. A 61-year-old female patient had hormone
replacement therapy for 2 years in the postmenopausal
period. There was no hormonotherapy history of other 8
cases including the male patient. This data could not be
reached in 2 cases. Six (54.5%) of the tumors were localized
in the left kidney and 5 (45.5%) were in the right. The
tumors were localized in the middle portion of the kidney
in 8 cases (72.7%) and in the polar region in the other 3
cases (27.3%). Radiologically, the tumors were defined as
a complicated cystic lesion in 4 cases, a cystic-solid lesion
in 2 cases including the male patient, and a solid mass
in 2 cases; these data could not be reached for 3 cases.
Partial nephrectomy was performed in 2 cases and radical
nephrectomy in 9. The follow-up periods of 10 cases were
known and ranged from 4 to 258 (mean 81) months. There
was no recurrence or metastasis in any of the cases. Clinical
findings were summarized in Table I.
The mean tumor diameter was 6.7 (3.5-19) cm. The tumors
were localized in the cortico-medullary, cortical and
medullary regions in 7 (63.6%), 3 (27.3%) and 1 (9.1%)
cases, respectively. In 7 (63.6%) cases, tumors appeared
as a multicystic mass consisting of multiple simple cysts
of varying size, uniloculated, containing serous fluid;
solid component between them was very scarce. In one
case (9.1%), both components were almost equal to each
other. In 3 (27.3) cases including the male patient, tumors
were usually cream-white in color, hard consistency,
lobulated and solid in appearance, and contained few cystic
structures up to 1.5 cm in diameter. The tumors were well
circumscribed in 8 (72.7%) cases. Tumor borders were
distinct but irregular in 3 (27.3%) cases and 2 of the tumors
were bulging into renal sinus (Table II) (Figure 1).
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|Table II: Macroscopic and general histopathological features of the MESTF cases.
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|Figure 1: Macroscopic image of a MESTF case, which has solid
component predominance. The tumor border is distinct and
partly irregular, the tumor is bulging into renal sinus (arrow).
Seven cases had a partial or complete capsule of variable
thickness (Figure 2A,B). Five of them contained smooth
muscle. The epithelial component was dominant in 7 cases
(63.6%), the stromal component was dominant in 3 cases
(27.3%); both components were almost equal in one case
(9.1%). Mild epithelial atypia in the form of scattered foci
was observed in all cases and most of them (72.7%) also had
similarly stromal atypia (Table II). Necrosis and notable
mitotic activity were not observed in any case.
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|Figure 2: Tumor borders.
A) Capsule with variable thickness,
containing smooth muscle and
dystrophic calcification around the
cellular stromal tumor component
(HE x100), B) Cystic tumor
component separated from the
kidney parenchyma by an irregular
border (HE x40).
In the epithelial component, the macrocyst was the
dominant pattern in all cases. Varying proportions of
microcysts and glandular structures accompanied. Rare
tubulopapillary pattern and short cell cords (collapsed
tubules) were seen in 4 and 3 cases, respectively. Flat and cuboidal type lining epithelium was observed in all cases;
hobnail type epithelium was also observed in 10 of them.
Columnar epithelium was only seen in 2 cases. The cell
cytoplasm was usually amphophilic and eosinophilic.
In some cases, a small amount of foamy and/or clear
cytoplasm was also seen. Focal urothelial metaplasia of
the lining epithelium was observed in 3 cases. In one case,
several glandular structures lined with epithelium that had
müllerian features (in tubal appearance) were observed.
Epithelial component features were summarized in Table
III and demonstrated in Figure 3A-H.
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|Figure 3: Features of epithelial
component A) Flat type epithelium
lining the collapsed macrocysts
(HE x40), B) Microcysts surrounded by
ovarian-type stroma (HE x100),
C) Tubular structures lined by cuboidal
epithelium (HE x400), D) Complex
glandular structure with cystic papillary
appearance (HE x100), E) Hobnail type
epithelium lining the cyst (HE x400),
F) Epithelium with foamy cytoplasm
lining part of the cyst lumen (HE x400),
G) Urothelial metaplasia of the lining
epithelium (HE x100), H) Glandular
structure lined with epithelium that has
müllerian features (in tubal appearance)
In 7 cases, the stromal component was variable and
included hypocellular and cellular areas. In all of them,
hypocellular areas were predominant and in the form of
fibrous stroma with extensive collagenization, and 3 of
them had also myxoid change. The cellular areas were
mostly concentrated around the epithelial component
and usually had an appearance of ovarian-type stroma.
In 2 cases, the stromal component was almost entirely
hypocellular and consisted mostly of collagenous and
minimally ovarian-type stroma. In the other 2 cases, the
stromal component was uniform and cellular; it consisted
mostly of ovarian-type stroma in one case and spindle cells
arranged in fascicles in the other, like spindle cell tumor.
Pericystic, and/or corpus albicans-like nodular or patchy
hyalinization was observed in 8 cases. Focal phyllodestype
architecture, smooth muscle metaplasia, dystrophic calcification, lipomatous and osseous metaplasia were
other features observed. In addition, accompanying thickwalled
vessels and various inflammatory reactions were
seen in most of the cases. Stromal component features were
summarized in Table IV and demonstrated in Figure 4A-H.
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|Figure 4: Features of stromal component
A) Ovarian-type cellular stroma
(HE x200), B) Collagenous stroma with
septal characteristics (HE x200),
C) Variable stroma with collagenous and
cellular areas (HE x100), D) Hypocellular
stroma with myxoid change (HE x200),
E) Phyllodes-type architecture observed
focally (HE x40), F) Smooth muscle
metaplasia in nodular form (HE x200),
G) Lipomatous metaplasia (HE x200),
H) Corpus albicans-like nodular
hyalinization (HE x200).
The stromal component was positive for both ER and PR
in 9 of the female cases, and the staining was diffuse in all
but one case that had focal positivity. In the other female
patient, PR was focal positive, but ER was negative.
In the male patient, the stromal component was negative
for ER and PR. Although both receptors were also negative
in the epithelial component, in the examined preparation,
focal positive staining for AR was observed in the lining
epithelium that has mostly müllerian features (in tubal
appearance). Immunohistochemical features were
demonstrated in Figure 5A-D.
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|Figure 5: Immunohistochemical panel. A,B) The positivity for estrogen and progesterone receptor in the stromal component. A: ER
x400, B: PR x400. C,D) Positivity for androgen receptor in the lining epithelium that has müllerian features. C: H&E x200, D: AR x200.
The clinicopathological experience about MESTF cases is
limited, due to their rare nature. These tumors were mostly
reported in middle-aged perimenopausal women 1-3
However, it can be seen in men 14-16
. The female:male
ratio has been reported as 2:1 for ACN 9
. In a series of 53
MEST cases, this ratio was found to be 6.6:1, and the median
age in males was shown to be higher than in females (49 in
females and 71 in males) 1
. Including this study, in small
series and the case reports, the age range has been reported
as 19-82 in men 2,3,14-16
. Unlike the literature, 4 of our
female cases (40%) were in the reproductive period, and
the remaining cases were in the peri- or postmenopausal
period. One of our cases was a 45-year-old man.
Although the histogenesis is not clearly known, it is thought
that neoplastic transformation could have developed
from müllerian remnants 4. The fact that it is common
in women who have hormonal imbalance or received
hormone therapy and in men with long-term sex-steroid
exposure suggests that there may be a relationship between
steroid hormones and MESTF cases 2,3,12. However,
there are also studies in which this relationship cannot
be demonstrated 17. A history of 2 years of hormone
replacement therapy was determined in only one of our
cases where clinical information was available.
While some of the cases occurred with nonspecific
symptoms, some of them were detected incidentally 2,3,9. All of our cases presented with findings such as flank
pain, abdominal pain, abdominal mass, hematuria and
polyuria as reported in the literature.
MESTF cases are described as solitary, unilateral, well
circumscribed, fluid-density masses with multiple
septations on contrast-enhanced CT 9. Bilateral and
multiple cases are rare 18. All of our cases were unilateral
and interestingly most of them (72.7%) were located in
the middle part of the kidney. Most of them (72.7%) were
localized in the cortico-medullary or medullar region rather
than the cortex, similar to previous reports 7. Our cases with known radiological features were mostly described as
complicated cysts with regular borders.
Macroscopically, the tumor had an expansive border in
72.7% of our MESTF cases, while the others’ borders were
irregular. All of them exhibited a combination of solid and
cystic areas in variable proportions, as in the literature 1,3. It has been reported that some tumors may compress the pelvicalyceal system but true sinus fat infiltration is
rare 9. Two of our tumors that had irregular borders
were bulging into the renal sinus but did not have true fat
Both components show diversity in these tumors with
biphasic characteristics. In this study, the epithelial
component was dominant in 63.6% and the stromal
component was dominant in 27.3% of the cases including
the male case. The components were almost equal in one
case. All histopathological features we found in our cases,
which were reevaluated in detail, were in parallel with the
For the epithelial component, macrocysts, microcysts and
tubular pattern were frequent patterns. Tubulopapillary
structures and short cell cords were rare patterns. Flat,
cuboidal and hobnail epithelium were the most frequent
but columnar epithelium was also observed in 2 (18.2%) of
the cases. The epithelium-dominant areas with tubular and
tubulopapillary pattern had more cuboidal-columnar cells,
while the epithelium that lined the cysts was more flattened,
as described in the literature 3. Hobnail cells that lined
the cysts were also seen in varying proportions in almost all
cases. Urothelial metaplasia was seen in 3 (27.3%) cases and
müllerian metaplasia was seen in only one (9.1%) case. The
cell cytoplasm was usually amphophilic and eosinophilic;
however, a small number of clear or foamy cells were also
observed in some cases.
The stromal component of MESTF cases is characterized
by a spindle cell proliferation ranging from hypocellular
to cellular areas 3. In one study, hypocellular stroma was
found to be significantly more common in larger tumors
and cellular stroma was found to be significantly more
common in smaller tumors. It was thought that there was
active proliferation in the stroma when the lesion was
small, and fibrous stroma was more dominant as the size
increased 1. In our series, the mean tumor size was 6.7
(3.5-19) cm and hypocellular stroma was dominant except
in 2 cases. One of the cellular tumors had the smallest size
in our series, and the other was also below average in size.
Smooth muscle stroma, which is a frequent stromal
feature, was described in smaller tumors, but no statistical
relationship has been demonstrated 1. In our study, 6
(54.5%) of the tumors had smooth muscle metaplasia in the
stroma and these were in variable amounts.
Lipomatous metaplasia has been reported to be significantly
related with larger tumors 1. There were 2 (18.2%) cases
with lipomatous metaplasia and one of them was the largest
tumor (19 cm) in our series.
The 8 (72.7%) cases of ours showed hyalinization as
pericystic and/or corpus albicans-like nodular or rarely
scattered foci. In addition, accompanying dystrophic calcification,
thick-walled vessels, and various inflammatory
reactions were seen in most of the cases. Focal phyllodestype
architecture and osseous metaplasia were other rare
features that we observed.
In MESTs, the ER and PR positivity in the stromal
component was reported as 73% and 85%, respectively 1.
In another study, these rates were 62% and 85% in MESTs,
while 19% and 40% in ACNs 4. In our study, stromal PR
positivity was observed in all female cases. ER positivity
was seen in 9 (90%) of female cases. In the male case, the
stromal component was negative for both receptors.
We observed focal positive staining for AR in the lining
epithelium, with mostly müllerian features, in the male
case. Maclean et al. showed that AR was expressed in the
epithelial cells of the fallopian tube regardless of menopausal
status and cyclic phase in premenopausal women 19. In
another study, Kamal et al. showed that postmenopausal
endometrial epithelial cells had significantly higher AR
expression compared to proliferative endometrium
20. As supported by the literature data, we considered
AR positivity in the epithelium, which showed mostly
müllerian features, as an ordinary finding in our case.
Multilocular cystic renal neoplasia with low malignant
potential, cystic renal cell carcinoma, tubulocystic
carcinoma, and angiomyolipoma with epithelial cysts
should be evaluated in the differential diagnosis of MESTF
cases with a complex cystic mass, and definitive diagnosis
can be made only with pathological evaluation 9. Adult
nephroblastoma, mesoblastic nephroma, sarcomatoid renal
cell carcinoma, and metanephric adenofibroma should
be considered in the differential diagnosis in more solid tumors 3,11. Some infectious etiologies such as renal
abscess, aspergillosis and echinococcus can be excluded
MESTs are generally benign and surgical resection is
sufficient for treatment 1,12. Malignant MEST cases have
been reported rarely, and malignancy may have epithelial
or stromal components. Malignant transformation of
the stromal component consists of synovial sarcoma,
rhabdomyosarcoma, chondrosarcoma, and unclassified
sarcoma 14. Malignancies of the epithelial component
consist of undifferentiated large cell carcinoma, mucinous
borderline tumor and endometrioid adenocarcinoma 11.
Carcinosarcoma arising in MEST has also been reported
21. Although the information on this subject is limited, it
has been reported that aggressive malignant MESTF cases
may respond to chemotherapy 13.
In this study, although mild atypia in the form of scattered
foci in both epithelial and stromal components was
frequently observed, no features indicating malignancy such as necrosis, increased mitotic activity, and diffuse and
severe atypia were found in any of the cases.
After partial or radical nephrectomy, 10 of our 11 patients,
who could be followed up for 4-258 months, were alive and
In conclusion, MESTF, which has distinctive features,
should be in consideration during the differential diagnosis
of cystic kidney tumors.
Conflict of Interest
There is no conflict of interest.
Concept: HD, ZS, NU, Design: HD, ZS, NU, Data collection or
processing: HD, ZS, OO, MD, SBO, IG, HD, NU, BO, Analysis or
Interpretation: HD, IG, NU, Literature search: HD, Writing: HD,
OO, IG, NU, Approval: HD, ZS, OO, MD, SBO, IG, HD, NU, BO.
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