MINI-SYMPOSIUM: NEPHROUROLOGY

Sex cord-stromal tumors female examples. Pure stromal tumors of the testis are much less
common than similar tumors in the ovary and the well-known thecoma

of the testis is remarkably rare in the testis. Fibromas of stromal derivation in the
testis should be distinguished from fibromas that originate from the
tunica albuginea and from examples of the non-neoplastic process
Kristine M Cornejo nodular pseudotumor.
Robert H Young Keywords adult granulosa cell tumor; fibroma; juvenile granulosa
cell tumor; Leydig cell tumor; myoid gonadal stromal tumor; Peutz-
Jeghers syndrome; Sertoli cell tumor; sex cord-stromal tumor; testis
Abstract
Testicular tumors apart from those in the germ cell family are uncom-
mon and are mostly sex cord-stromal tumors and may pose a major Introduction
diagnostic challenge. This review focuses on the clinicopathologic fea- Non-germ cell tumors of the testis are much less common than
tures of these uncommon neoplasms, pertinent differential diagnoses, germ cell tumors, and may pose a major diagnostic challenge,
relevant immunohistochemical and molecular findings as well as the particularly for general pathologists. However, even patholo-
recent updates proposed by the World Health Organization (WHO). gists with special interest in urologic pathology may be chal-
Contrast between these neoplasms as seen in the male and female lenged by these cases because of their relative rarity. Our
gonad will also be made when warranted. The commonest sex cord- current knowledge of sex cord-stromal tumors of the testis is
stromal tumor of the testis is the Leydig cell tumor which, when based on work of many prior investigators but it should be
seen in children, is often associated with sexual precocity. The histo- noted that two of the giants of gonadal pathology Dr. Gunnar
logic features are generally those of an easily recognized oxyphilic Teilum1 and Dr. Robert E. Scully2 have probably contributed
neoplasm but various peculiarities such as microcysts and spindling more than most.3 The former was likely the first to focus on the
of the tumor cells may case diagnostic difficulty on occasion. In the interesting similarities and yet differences between these tu-
male, in contrast to the female, the most common sex cord-stromal mors in the male and female. The latter, based on his own
tumor of epithelial nature is the Sertoli cell tumor. Most of these fall writings and availability of cases sent to him in consultation for
in the not otherwise specified category and are usually characterized study by others, contributed greatly to our knowledge of these
by a diagnostically helpful at least focal hollow or solid tubular pattern. tumors and our debt to these great prior investigators is
Occasional malignant Sertoli cell tumors have a predominantly diffuse acknowledged here. The contributions of British investigators,
pattern sometimes interrupted by septa with a lymphocytic infiltrate particularly those on the British testicular panel of several de-
that can cause seminoma to be mimicked. Rare Sertoli cell tumors cades ago, culminating in an outstanding work published in
are associated with marked sclerosis. The so-called large cell calci- 1964, and also in the meritorious book edited by Dr. R.C.B.
fying Sertoli cell tumor, may be sporadic or associated with manifes- Pugh, published 12 years later, should also not be forgotten.3e5
tations of the Carney syndrome. A distinctive entity referred to as Amongst other things Drs D.H. Collins and T. Symington of that
intratubular hyalinizing Sertoli cell neoplasia occurs in the testis of group were the first to comment on the differential between
young boys with Peutz-Jeghers syndrome. It is often bilateral, micro- Sertoli cell tumor and seminoma.3
scopic and associated with gynecomastia. Testicular granulosa cell Sex cord-stromal tumors are overall infrequent, but are the
tumors are much rarer than their ovarian counterparts but can be simi- second most common testicular tumor after germ cell tumors and
larly subdivided into adult and juvenile forms. In the male, the juvenile are relatively more commonly identified in children (in whom
granulosa cell tumor has a particularly striking tendency to occur in the germ cell tumors are rare), comprising approximately 25% of all
first 6 months of life. The primitive appearance of the nuclei and brisk testicular neoplasms, in contrast to only 2e5% of testicular tu-
mitotic activity of the juvenile granulosa cell tumor may result in a mors in adults.6 Most of the tumors are clinically benign, with
misdiagnosis of a more malignant neoplasm. The histologic spectrum only a small subset (5%) being malignant. Many are non-
of the adult granulosa cell tumor is as seen in the more common functional, but a minority may be associated with isosexual
pseudoprecocity or feminization and/or a genetic or clinical
syndrome.6 We begin by considering by far the most common,
the Leydig cell tumor.

Kristine M. Cornejo MD, Assistant Professor of Pathology, Harvard

Medical School and Assistant in Pathology, Massachusetts General Leydig cell tumors
Hospital, James Homer Wright Pathology Laboratories, Leydig cell tumors (LCTs) account for 1e3% of all testicular
Massachusetts General Hospital and Department of Pathology,
neoplasms and may occur at any age but are most common at 5
Harvard Medical School, Boston, MA, USA. Conflicts of interest:
none declared. e10 years of age in children and 20e50 years of age in adults.
They usually present with a testicular mass or swelling and
Robert H. Young MD, Robert E. Scully Professor of Pathology,
typically present with isosexual pseudoprecocity in children.6e8
Harvard Medical School and Pathologist, Massachusetts General
Feminization such as gynecomastia may be seen at any age.6,8
Hospital, James Homer Wright Pathology Laboratories,
Massachusetts General Hospital and Department of Pathology, Rarely they are associated with hereditary leiomyomatosis and
Harvard Medical School, Boston, MA, USA. Conflicts of interest: renal cell carcinoma syndrome caused by germline fumarate
none declared. hydratase (FH) gene mutations and Klinefelter syndrome.6 Most

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 MINI-SYMPOSIUM: NEPHROUROLOGY

cases are benign, especially in children, but up to 10% are ma-

lignant in adults.6e9
Grossly, the tumors are well-circumscribed, typically with a
homogenous yellow-tan cut surface.6 A golden brown color may
occur depending upon the amount of lipofuscin pigment.9 Ma-
lignant LCTs often display an infiltrative border, sometimes
extending outside of the testis, and also often have areas of
hemorrhage and necrosis.6e9 Microscopically, a diffuse growth of
uniform polygonal cells with abundant eosinophilic, slightly
granular cytoplasm with round nuclei and prominent nucleoli is
typical (Figure 1).6,7 Mitoses are usually rare and nuclear atypia
is generally absent or minimal, but exceptions occur (see
below).9 A nodular pattern separated by collagenous stroma may
also be seen and trabecular, insular, pseudotubular, ribbon-like,
sarcomatoid/spindle and microcystic patterns are less commonly Figure 2 Leydig cell tumor. Typical Leydig cells intermixed with more
identified.6e8,10,11 A pseudopapillary appearance has also been prominent lipid/foamy areas.
described due to areas of necrosis.7 Tumor cells may be vacuo-
lated or foamy and areas of adipocytic differentiation, ossifica-
tion and/or calcification may be seen (Figure 2).6,11 The stroma adrenal hyperplasia and are characteristically functional and
may be hyalinized, myxoid or edematous and crystals of Reinke secrete androgens.13,14 They are typically multifocal and bilateral
are found in a third of cases and lipofuscin pigment in a smaller in comparison to LCTs which are solitary and unilateral; they are
subset.6,7 bilateral in no more than 3% of cases.9,14,15 Identification of
Tumors with malignant features often display two or more of Reinke crystals helps to clench the diagnosis of LCT, which can
the following: size >5 cm, marked cytological atypia, infiltrative be highlighted by a PAS, Giemsa or trichrome stain, as they are
borders, lymphovascular invasion, increased mitotic activity (>3 not seen in TTAGS.9 The latter tend to display bands of fibrosis
mitoses/10 high-power field [HPF]), including elevated MIB-1 with prominent lipofuscin pigment, lymphocytic infiltration,
activity or atypical mitotic features and necrosis.6,9,12 Immuno- adipose metaplasia and scattered nuclear atypia or pleomor-
histochemically, LCTs are typically positive for inhibin, calretinin phism without associated mitotic activity.6,7,14,15 Notably,
and Melan-A.9 fibrous bands and adipocytic metaplasia have been identified in
The histologic differential diagnosis includes Leydig cell hy- occasional LCTs and are not as helpful as once thought in dis-
perplasia, testicular nodules of the adrenogenital syndrome tinguishing the two entities.11 An immunoprofile comprised of
(TTAGS), malakoplakia and less frequently, yolk sac tumor CD56, synaptophysin and androgen receptors have been reported
(YST), Sertoli cell tumor (SCT) (when the latter has eosinophilic to have some utility, in which there is expression for androgen
cells) and sarcoma or malignant mesothelioma (in the case of receptor in LCTs, while it is negative in TTAGS.13 CD56 and
LCTs with a sarcomatoid morphology).9 Leydig cell hyperplasia synaptophysin tend to be positive in TTAGS and negative or
(LCH) is typically multifocal rather than solitary and less than 0.5 focally positive in LCTs.13,14 Typical sex cord markers such as
cm in diameter.9 TTAGS are seen in patients with congenital inhibin, calretinin and Melan-A do not help distinguish these two
entities.9
Malakoplakia may resemble a LCT as it can also present as a
tan-brown solitary nodule and is comprised of histiocytes with
abundant eosinophilic cytoplasm, potentially mimicking Leydig
cells. Features in support of malakoplakia include Michaelis-
Gutmann bodies, a background of inflammation, even with
focal microabscesses and involvement of both the interstitium
and seminiferous tubules.9 SCTs, particularly large cell calcifying
SCTs may enter the differential. SCTs typically display some
tubular differentiation and may show nuclear staining for b-cat-
enin, which is absent in LCTs. Calcifications are rare in LCTs and
often striking in the large cell calcifying neoplasm. When LCTs
display significant spindled or sarcomatoid morphology, a sar-
coma may be considered. Typical components of LCTs are often
intermixed and adequate sampling will help to resolve this
issue.9 YST may enter the differential, particularly when LCTs
form cystic spaces, which are often small but can also be large.10
A helpful clue is intermixed areas of more conventional Leydig
cells, which will assist in making the correct diagnosis and of
Figure 1 Leydig cell tumor. Diffuse growth comprised of typical
polygonal cells with abundant eosinophilic cytoplasm and round nuclei course adequate sampling of the tumor is important.10 LCTs are
with prominent nucleoli. Inset with a Reinke crystal highlighted with a typically negative for AFP and positive for inhibin, in contrast to
trichrome stain. YST.10 A final and rare differential consideration, malignant

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 MINI-SYMPOSIUM: NEPHROUROLOGY

mesothelioma, exemplifies the importance of being aware where which encodes the b-catenin protein, in a significant proportion
an intrascrotal neoplasm is predominantly located when exam- of NOS and sclerosing SCTs.6,18,19 The lipid-rich variant is no
ining testicular and paratesticular neoplasms. Malignant LCTs longer considered a separate entity as many SCTs contain lipid
may be spindled and extend beyond the testis and conversely and vacuolization, and it is rare to find a purely lipid-rich SCT.
malignant mesotheliomas may be spindled and involve the testis. Uncommonly, metastases develop, usually involving lymph
Careful gross evaluation should suggest the likely correct diag- nodes, with occasional instances of hematogenous spread to lung
nosis in such cases but if needed immunohistochemistry with and bone.20
inhibin and other markers will be helpful. Grossly, the neoplasms usually measure 2e5 cm and are well-
circumscribed, firm, tan-white to gray or rarely yellow, with a
minor cystic component occurring in a third of cases.6,20 Areas of
hemorrhage and necrosis are uncommon. Tumors with promi-
nent stromal sclerosis are typically smaller (<2 cm) and lack cyst
Practice points formation.6,21,22 Microscopically, they display some tubular dif-
ferentiation, at least focally, often in a nodular pattern separated
C Leydig cell tumors are the most common sex cord-stromal tumor.
by fibrovascular and occasionally myxoid stroma (Figure 3).16
C May be associated with HLRCC and Klinefelter syndrome.
The tubules can be hollow/round to elongated and solid,
C Diffuse growth composed of round/polygonal cells with eosino-
showing various amounts of cystic dilation (Figure 4).6,16 A
philic cytoplasm and small nucleoli.
diffuse growth of cells may rarely be seen, often traversed by
C Subset contain Reinke crystals and lipofuscin pigment.
fibrous stroma and sometimes associated with an inflammatory
C Differential diagnosis includes Leydig cell hyperplasia (<0.5 cm;
cell infiltrate. Rarely a retiform pattern is seen.6,16 The cells often
multifocal), testicular tumors of the adrenogenital syndrome
contain clear or pale to eosinophilic cytoplasm and may display
(bilateral; multifocal; androgen receptor negative; CD56/syn-
lipid or vacuoles, but usually only focally (Figure 5).6,16 Mitotic
aptophysin positive), malakoplakia (Michaelis-Gutmann bodies,
activity and cytological atypia is typically absent to minimal, but
involvement of interstitium and seminiferous tubules), yolk sac
may occur in a small subset, especially those displaying diffuse
tumor (AFP positive; inhibin negative), Sertoli cell tumors (tubular
growth.6,16 A subset of tumors contain prominent hypocellular
differentiation; nuclear b-catenin) and mesothelioma (gross ex-
hyalinized stroma and when it constitutes 50% of the tumor, is
amination/dominantly paratesticular; inhibin negative).
designated the sclerosing variant of SCT, NOS (Figure 6).6,22
Identifying this variant is important as it correlates with better
outcome and a lower risk of metastasis.21,22
Sertoli cell tumors Metastasis occurs in 5% of tumors and features of malignancy
Sertoli cell tumors, not otherwise specified (NOS) include size >5 cm, extratesticular spread, moderate to severe
Sertoli cell tumors (SCTs) occur at all ages, but most commonly cytological atypia, >5 mitoses/10 HPFs, lymphovascular inva-
in adults and comprise <1% of testicular neoplasms.6,7 Most sion and necrosis.6,20 Immunohistochemically, the tumor ex-
present after 30 years of age (mean age 45 years), but they presses nuclear b-catenin in 60e70% of cases.18,19,23
nonetheless account for a higher percentage of testicular tumors Additionally, they are often positive for inhibin (50% of cases),
in children due to the rarity of germ cell neoplasms before 15 Melan-A, WT-1, calretinin, synaptophysin, chromogranin, SOX9,
years of age. They present with a slow-growing, unilateral SF1, PAX2/PAX8, epithelial membrane antigen (EMA) and
testicular mass, usually without hormonal manifestations.6,16 pancytokeratin.6,20,24
Lipid-rich and sclerosing variants are now classified as SCT, The histologic differential includes Sertoli cell nodules, LCT,
not otherwise specified (NOS) (Table 1).6,17 The latest WHO seminoma, adenomatoid tumor and rete cystadenoma. Sertoli
classification of urologic tumors (2016) reflects this new classi- cell nodules occur in cryptorchid or undescended testis and are
fication based upon identification of CTNNB1 gene mutations, usually microscopic (<1 cm), although rarely mass-forming
nodules have been reported, comprised of aggregates of non-
neoplastic immature Sertoli cells within seminiferous tu-
bules.20,25 Helpful clues include an association with scattered
Classification of sertoli cell tumors
spermatogonia, lack of stromal invasion and rounded aggregates
Tumor type Genetic characteristic/ of hyaline material, while SCTs are often mass-forming (>1 cm)
syndrome with stromal invasion.16,20 SCTs may display diffuse growth with
abundant eosinophilic cytoplasm and resemble LCTs. However,
Sertoli cell tumor, not otherwise CTNNB1 gene mutation identifying Reinke crystals in LCTs and tubular differentiation in
specified (NOS) SCTs helps to separate the two entities, although a pseudotubular
- Sclerosing variant pattern may rarely be seen in LCTs.16,20 Immunohistochemistry
Large cell calcifying PRKAR1A gene mutation/ will also help as LCTs are often strongly positive for inhibin,
sertoli cell tumor deletion while SCTs are positive for b-catenin, pancytokeratin and var-
Carney complex iably for inhibin.19,20 Therefore, a negative inhibin stain would
Intratubular large cell STK11 gene mutation support an SCT.
hyalinizing sertoli cell neoplasia Peutz-Jeghers syndrome SCTs may occasionally display a diffuse pattern with inflam-
mation and a seminoma may be considered.16 Additionally,
Table 1
seminomas may show tubular morphology, mimicking SCTs.

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 MINI-SYMPOSIUM: NEPHROUROLOGY

Figure 3 Sertoli cell tumor, NOS. Small to medium sized hollow tu- Figure 6 Sertoli cell tumor, sclerosing variant. Abundant collagen be-
bules separated by myxoid stroma. tween compressed cords and tubules.

adenomatoid tumor which are most often paratesticular, which is

a helpful clue, but may involve the testicular parenchyma.
Adenomatoid tumors typically display a variety of morphologies,
including, helpfully, typical vacuoles and lymphoid aggregates,
while SCTs tend to have a more uniform pattern and although
there may be lipid vacuoles, the typical formations of the ade-
nomatoid tumor are absent.20,27 Thread-like bridging strands
which cross the pseudotubular spaces have been reported as a
helpful identifying histologic feature in adenomatoid tumors.28
Immunohistochemically, both are positive for WT-1 and calreti-
nin as well as various keratins, but inhibin may be helpful as it
can be positive in SCT. Recently, TRAF7 mutations have been
identified in adenomatoid tumors which results in the expression
of L1CAM.29 Lastly, rete cystadenomas may display a Sertoliform
Figure 4 Sertoli cell tumor, NOS. Elongated and variably cystically pattern, but the distinct rete location helps to distinguish these
dilated tubules in a hyalinized background. two entities.30,31

Practice points

C Sertoli cell tumor, not otherwise specified is the second most

common sex cord-stromal tumor.
C Associated with CTNNB1 gene mutations and nuclear b-catenin
expression.
C Nodular pattern of cells with pale to eosinophilic cytoplasm
showing at least focally tubular differentiation, with vacuoles and/
or lipid.
C Sclerosing variant requires hypocellular fibrotic stroma >50% of
the tumor and is associated with a better prognosis.
C Differential diagnosis includes Sertoli cell nodules (<1 cm;
intratubular immature Sertoli cells; no stromal invasion), Leydig
Figure 5 Sertoli cell tumor, NOS. Interanastomosing growth of more cell tumor (Reinke crystals; inhibin positive; b-catenin negative),
solid tubules with abundant lipid vacuoles. seminoma (GCNIS; OCT3/4 and SALL4 positive), adenomatoid
tumor (paratesticular, typical vacuoles, thread-like bridging
strands) and rete cystadenomas (rete location).
The presence of germ cell neoplasia in situ (GCNIS) and granu-
lomatous inflammation with staining for OCT3/4 and/or SALL4
aid in identifying seminoma, while SCTs are often positive for sex
cord-stromal tumor markers such as inhibin and calretinin.26 Large cell calcifying sertoli cell tumor
When an inflammatory infiltrate is present in SCTs, it is often Large cell calcifying Sertoli cell tumor (LCCSCT) are rare. Most
plasma cell rich, in comparison to that of seminoma.16 The are sporadic, but one-third present in patients with Carney
tubular architecture of SCTs may also be misidentified for an complex.6,32,33 A germline mutation in the PRKAR1A gene has

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 MINI-SYMPOSIUM: NEPHROUROLOGY

been identified in up to 70% of Carney complex-associated tu-

mors, but have also been reported in a subset of sporadic
cases.6,34 Most syndrome related LCCSCTs are benign and occur
in teenage boys or young adults (mean age 17 years; range 2e38
years) with bilateral and multifocal involvement, in comparison
to the malignant tumors which are more often sporadic, occur in
an older population (mean age 39 years; range 28e51 years) and
are unifocal and unilateral.32,33,35 LCCSCTs arising in the setting
of a syndrome, often are indolent in behavior and may not
require surgical intervention, as treatment with aromatase in-
hibitors are often effective.35
Grossly, the tumors are tan-yellow or gray and vary in size,
where most benign tumors are smaller (mean 1.4 cm; range 0.8
e2.3 cm) in comparison to those that are malignant (mean 5.4
cm; range 2e15 cm). Calcifications are grossly evident in most Figure 8 Large cell calcifying Sertoli cell tumor. Cords and solid tu-
cases. Hemorrhage and necrosis may be seen in malignant tu- bules comprised of cells with abundant eosinophilic cytoplasm and
focal calcification within a myxoid stroma (left).
mors, but are typically not found in those that are benign. His-
tologically, LCCSCTs are characterized by sheets, nests, cords
and solid tubules of large Sertoli cells containing abundant
eosinophilic cytoplasm associated with variable amounts of tubular differentiation, intratubular involvement and neutro-
calcification which may be intra or extratubular (Figures 7 and philic infiltrate help to distinguish LCT from LCCSCT, while the
8).32,33,36 A neutrophil-rich infiltrate is also typically seen and latter will lack lipofuscin pigment and Reinke crystals.33 On the
they may have a myxoid stroma and an intratubular rare occasion when immunohistochemistry is needed, S100 may
component.16,33 be helpful as it is positive in LCCSCT and negative in most
Features of malignancy include at least two of the following LCTs.37
features: tumor size 4 cm, extratesticular involvement, high-
grade cytological atypia, >3 mitoses/10 HPFs, lymphovascular
invasion and necrosis.33 Hematogenous spread may also occur to
liver, bone and lungs.33 Immunohistochemically, the tumor dis- Practice points
plays variable S100, inhibin, calretinin and cytokeratin expres-
sion and are often negative for CD99.33,36 Electron microscopy C Large cell calcifying Sertoli cell tumors are associated with Carney
may reveal Charcot-Bӧttcher filaments which supports Sertoli complex and mutations in the PRKAR1A gene.
cell differentiation.33 C Syndrome related neoplasms are benign, multifocal, bilateral and
The main differential is LCT as both may display sheets, nests occur in young patients compared to those that are non-
and cords of cells with abundant eosinophilic cytoplasm and syndromic.
calcification. However, the rarity of calcifications, and lack of C Malignant tumors are more often sporadic, unifocal, unilateral
and occur in older patients than benign examples.
C Comprised of large cells with abundant eosinophilic cytoplasm,
prominent calcifications and associated with a neutrophilic
infiltrate.
C Differential diagnosis includes Leydig cell tumor (fewer calcifica-
tions; lack tubular differentiation, intratubular involvement or
neutrophilic infiltrate; S100 negative).

Intratubular large cell hyalinizing sertoli cell neoplasia

Intratubular large cell hyalinizing Sertoli cell neoplasia
(ILCHSCN), occurs in boys (mean 6.5 years; range 4e13 years)
with Peutz-Jeghers syndrome caused by germline mutations in
the STK11 gene.6,38 Most present with bilateral testicular
enlargement, often in the absence of a distinct mass or with
multifocal nodularity, and endocrine abnormalities such as
Figure 7 Large cell calcifying Sertoli cell tumor. Low-power view gynecomastia.38
showing a nodule on the right with prominent stromal edema with focal
Histologically, ILCHSCN is characterized by an intratubular
myxoid quality, while on the left is a more diffuse growth pattern with
lymphoid aggregates and fibrous septae which on intraoperative proliferation of large Sertoli cells with pale to eosinophilic cyto-
consultation may be confused with seminoma. This section did not plasm, which is often vacuolated, and prominent globoid extra-
show calcifications, which can be quite focal, requiring thorough cellular basement membrane deposits which protrude from
sampling.

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 MINI-SYMPOSIUM: NEPHROUROLOGY

Practice points

C Intratubular large cell hyalinizing Sertoli cell neoplasia is associ-

ated with Peutz-Jeghers syndrome and STK11 gene mutations.
C Expanded seminiferous tubules with large cells with abundant
eosinophilic and often vacuolated cytoplasm and globules of
basement membrane deposits protruding from thickened peri-
tubular basement membrane.
C Differential diagnosis includes large cell calcifying Sertoli cell
tumor (stromal invasion; conspicuous calcification; PRKAR1A
gene mutation) and Sertoli cell nodule (associated with cryptor-
chid/undescended testis and spermatogonia).

Figure 9 Intratubular large cell hyalinizing Sertoli cell neoplasia. Low

power view showing scattered clusters of expanded seminiferous
tubules. Granulosa cell tumors
Granulosa cell tumors are subclassified into adult and juvenile
types to signify the age group in which they typically occur. The
juvenile seems to be more common than the adult type in the
testis, which is the opposite situation to that in the ovary.16

Adult granulosa cell tumor

Adult granulosa cell tumors (AGCT) occur over a broad age
range (mean 40 years; range 14e87 years), and typically present
with a unilateral testicular mass or swelling and no endocrine-
related symptoms, although the latter has been reported in up
to a fourth of cases.16,39 A subset contain somatic FOXL2 gene
mutations, which is identified less commonly than in the ovary.40
Grossly, the tumors are tan-yellow to white and predomi-
nantly solid and measure up to 6.0 cm (mean 2.8 cm; range 0.5
e6.0 cm).39 Histologically, they are often well-circumscribed
Figure 10 Intratubular large cell hyalinizing Sertoli cell neoplasia. High with a nodular low-power appearance and a diffuse and less
power view showing expanded seminiferous tubules with prolifera- commonly spindled, micro/macrofollicular, insular and corded
tions of large Sertoli cells containing abundant pale to eosinophilic pattern (Figure 11).39 The cells contain round to elongated ovoid
cytoplasm associated with thickened peritubular basement membrane nuclei, indistinct cell borders, longitudinal nuclear grooves and
which project and form intratubular globular eosinophilic deposits. pale to eosinophilic cytoplasm.39 Call-Exner bodies were only
identified in 22% of cases in our series.39 Immunohistochemi-
cally, AGCTs are highlighted by inhibin, calretinin and FOXL2,
thickened peritubular basement membrane (Figures 9 and 10).38 with more variable staining for S100 and cytokeratin.24,39
Superimposed calcifications on the intratubular basement mem-
brane deposits may also be seen. Spermatogonia are not associ-
ated with the affected tubules. Immunohistochemically, the
lesional cells are positive for inhibin, cytokeratin and aroma-
tase.38 These tumors are clinically indolent and conservative
treatment with aromatase inhibitors is recommended.38
The main differential is with LCCSCT as they contain some-
what overlapping histological features. However, ILCHSCN has a
predominant intratubular growth pattern with prominent base-
ment membrane deposits, less conspicuous calcifications, as well
as a different clinical presentation, as it presents in prepubertal
males with gynecomastia, while endocrine manifestations are
not a typical finding in LCCSCT, and is associated with different
genetic alterations.6,38 Sertoli cell nodules may also be consid-
ered as it also displays a patchy, intratubular growth pattern and
may contain deposits of globular basement membrane. Helpful
features are that Sertoli cell nodules are typically identified in
cryptorchid or undescended testes and associated with sper- Figure 11 Adult granulosa cell tumor. Corded and trabecular pattern
matogonia, unlike ILCHSCN.38 with cells containing typical longitudinal nuclear grooves.

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 MINI-SYMPOSIUM: NEPHROUROLOGY

Features of malignancy include size >4 cm, infiltrative bor-

ders and lymphovascular invasion.39 Mitotic activity did not
appear to have prognostic significance in our series.39 Most tu-
mors are cured by surgical resection with an overall good prog-
nosis. Those with risk for more aggressive behavior seem to
benefit from retroperitoneal lymph node dissection.39 Rarely,
hematogenous spread has been reported such as to lung and
bone.39 Since metastases can occur years after diagnosis, long-
term follow-up is recommended.
The histologic differential includes Leydig and Sertoli cell tu-
mors. LCTs contain sheets of round cells with abundant eosin-
ophilic cytoplasm and may contain Reinke crystals and lipofuscin
pigment.8 SCTs may display a variety of patterns such as corded,
diffuse and trabecular, which overlap those of AGCTs and LCTs
Figure 12 Juvenile granulosa cell tumor. Low power view showing
may contain cells with nuclear grooves. SCTs display tubular numerous macrofollicles that vary in size and shape containing
differentiation and lack the typical microfollicular pattern of basophilic material with a fibrotic stroma.
AGCTs. Grooved nuclei are also much more conspicuous in
AGCTs than in SCTs.20 It is important to note that FOXL2 staining
is not specific for AGCTs and has been identified in other
testicular sex cord-stromal tumors such as fibrothecomas, SCTs
and myoid gonadal stromal tumors.24,41

Practice points

C Adult granulosa cell tumors are associated with FOX2L gene

mutations and positive for FOX2L immunostaining.
C Less common than the juvenile form in the testis.
C Comprised of round to ovoid cells with nuclear grooves with
follicular differentiation forming Call-Exner bodies.
C Differential diagnosis includes Leydig cell tumors (Reinke crystals;
lipofuscin pigment) and Sertoli cell tumors (tubular differentia- Figure 13 Juvenile granulosa cell tumor. High power view showing
tion; lack microfollicular pattern). macrofollicles with follicular stratification imparting a vague sertoliform
appearance.

Juvenile granulosa cell tumor 1, WT1 and calretinin with more variable staining for cytokeratin
The majority of juvenile granulosa cell tumors (JGCT) occur in and SOX9, and with negative staining for SALL4.41
the first 6 months of life, with only 10% occurring after that age JGCTs are benign with indolent behavior and are typically
in our case series (range: 30 weeks gestational age to 10 years), treated with surgical resection.41 Despite a subset containing a
with a report of a case occurring in a 27 year old.41,42 Most high proliferative index (>40 mitoses/10 HPFs), none had evi-
present with a unilateral testicular mass or enlargement and dence of disease with follow-up.41
rarely with endocrine manifestations.41 Occasionally, tumors The histologic differential includes YST as both may occur in
arise in boys with cryptorchid testes or gonadal dysgenesis and the young. The age of the patient is helpful as JGCT occur in
karyotypic abnormalities.41,43 A FOX2L gene mutation has not those <6 months of age, whereas most children with YST are
been identified in JGCT, but only a rare case has been tested.40 older (mean 20.7 months; range 5e71 months).41,44 JGCTs
Grossly, the tumors measure up to 5 cm (mean 1.7 cm; range display follicular differentiation, which is not a feature of YSTs,
0.5e5.0 cm), and are tan-yellow to gray and contain a cystic albeit the polyvesicular vitelline variant with cysts may mimic
component, often with a mucoid or watery fluid-like sub- follicles, and both may contain solid growth.16,41,44,45 Immuno-
stance.36,41 Histologically, JGCTs usually display a lobular ar- histochemistry is also helpful as YSTs are positive for SALL4,
chitecture containing follicles of varying size and shape with glypican-3 and AFP, while JGCTs are highlighted by sex cord
basophilic and/or eosinophilic material (Figure 12).41 The -tromal tumor markers such as inhibin, calretinin and WT-
stroma is often fibromyxoid or fibrous and the cells which often 1.41,44,46
line the follicles in single or multiple layers, contain round to Other entities to consider in the differential include SCTs,
ovoid nuclei with pale to eosinophilic cytoplasm and inconspic- sarcoma and AGCTs. SCTs show tubular differentiation rather
uous nucleoli (Figure 13).41,43 Longitudinal grooves are infre- than follicular differentiation, and age is helpful in separating
quent and abundant mitoses defined as 10 mitoses/10 HPFs are these two entities. The follicles of JGCTs are typically larger than
identified in approximately 40% of cases.41 Immunohis- the tubules of SCTs, often with multilayering of cells which may
tochemically, the tumors are highlighted by inhibin, FOXL2, SF- be mitotically active and nodular in appearance with a myxoid or

DIAGNOSTIC HISTOPATHOLOGY 25:10 404 Ó 2019 Elsevier Ltd. All rights reserved.
 MINI-SYMPOSIUM: NEPHROUROLOGY

fibromyxoid stroma.41 Occasionally, JGCTs display a significant cord component, a reticulin stain may be helpful.48 Fibrous
spindled component and a sarcoma, such as embryonal rhab- pseudotumors may also be considered as it similarly presents as
domyosarcoma may be considered. However, other typical a well-circumscribed white-tan or yellow mass with a whorled or
components of JGCTs are present such as follicle formation and bulging cut surface.49,50 Histologically, it is composed of uniform
the location may be a helpful clue as sarcomas are typically spindled cells arranged in whorls with a myxoid or collagenous
paratesticular.7,36,41 AGCTs may also enter the differential, but stroma and small vessels, often with inflammation.49e51 The
JGCTs occur in a much younger age group and typically lack the helpful clue is the predominant paratesticular location, typically
conspicuous longitudinal grooves.41 Although both granulosa with attachment to the tunica.49 Immunostains for S100 and
cell tumors express FOX2L, as mentioned previously, immuno- inhibin may be helpful as they are usually negative in fibrous
reactivity has been identified in other sex cord-stromal tumors pseudotumor, while variably positive in fibroma.49,50 Lastly,
and it is not specific. myoid gonadal stromal tumors (MGSTs) may also be considered
as it is also comprised purely of spindled cells forming fascicles.
Immunohistochemistry may be helpful as MGSTs are typically
Practice points negative for inhibin, SOX9 and calretinin, while often positive in
fibroma.52
C Juvenile granulosa cell tumors are not associated with FOX2L
gene mutations.
C More common than adult granulosa cell tumors in the testis and Practice points
occur in the first 6 months of life.
C Solid and cystic neoplasm comprised of varying sized follicles, C Fibromas are composed of spindled cells in a storiform or
with round to ovoid cells, inconspicuous nucleoli and uncom- fascicular pattern with variable amounts of collagen.
monly display nuclear grooves. C Differential diagnosis includes unclassified sex cord-stromal
C Differential diagnosis includes yolk sac tumor (SALL4/glypican-3/ tumor (reticulin stain highlights nests of cells), fibrous pseudo-
AFP positive), Sertoli cell tumors (tubular differentiation; no tumor (paratesticular; S100/inhibin negative) and myoid gonadal
multilayering of cells) and sarcoma (paratesticular; lack follicle stromal tumor (inhibin/SOX9/calretinin negative).
formation). C Thecoma of the testis using ovarian criteria is exceptionally rare.

Fibroma Myoid gonadal stromal tumor

Tumors in the fibroma-thecoma category are rare and we believe, Myoid gonadal stromal tumor (MGST) is an emerging entity in
despite the WHO nomenclature, true thecomas have not been the 2016 WHO classification. It is an extremely rare neoplasm
described in the testis (according to our criteria) and neoplasms thought to arise from peritubular myoid cells, and occurs in
in this group are all fibromas, unlike the ovary where bona-fide younger men (mean 37 years; range 4e59 years) with a unilat-
thecomas are seen.47 See paper just cited for thorough presen- eral testicular mass without endocrine manifestations.52,53
tation of the morphology of thecomas. Fibromas occur in a wide Although only a handful of cases have been reported, they
age range (mean 44 years; range 16e69 years) and present as a appear to behave indolently.
unilateral testicular mass.48 Grossly, the tumors are tan-yellow and well-circumscribed,
Grossly, the tumors measure up to 7.6 cm (mean 1.8 cm; with a whorled cut appearance, measuring up to 3.5 cm in size
range 0.5e7.6 cm) and are well-circumscribed, tan-white or (mean 2.3 cm; range 1.2e3.5 cm).52 Histologically, the tumor is
uncommonly yellow, often without hemorrhage or necrosis.48 comprised of spindled cells forming fascicles with various
Histologically, fibromas are comprised of spindled cells ar- amounts of intervening collagen. The cells contain elongated
ranged in a storiform or fascicular pattern with variable amounts nuclei with small nucleoli, occasional nuclear grooves and pale
of collagen deposition. Uncommonly, an elevated mitotic index to eosinophilic cytoplasm. No lymphovascular invasion or ne-
>5 mitoses/10 HPFs, infiltrative border and hypercellularity can crosis has been identified and there is typically a low proliferative
be identified.48 Despite these features, they have an indolent index (up to 5 mitoses/10 HPFs).52 Immunohistochemically, the
behavior and are benign.48,49 Immunohistochemically, the cells cells are positive for inhibin, SF-1, FOXL2, S100 and SMA, with
are highlighted by inhibin, Melan-A and SMA, with more vari- more variable staining for desmin, calponin and WT1, and
able staining for calretinin, desmin, S100, pancytokeratin, BCL2 negative for h-caldesmon, CD34, calretinin and SOX9.52
and CD34.48 The histologic differential includes fibroma and leiomyoma.
The diagnosis of fibroma is usually straightforward, but other As mentioned previously, fibromas are highlighted by inhibin,
more common sex cord-stromal tumors may enter the differential SOX9 and calretinin, which is negative in MGSTs; both can be
which can display spindled morphology such as SCTs, LCTs and positive for SMA and desmin and will not be useful. Leiomyomas
granulosa cell tumors. However, these latter tumors will show are characteristically paratesticular and contain broad fascicles
variable growth patterns, which should be apparent with with cigar-shaped nuclei, perinuclear vacuoles and abundant
adequate sampling and often contain more round to ovoid cells eosinophilic cytoplasm, which is not typical of MGSTs. Immu-
rather than spindled, while the opposite is seen in fibroma.48 In nostaining may also be useful as MGSTs are positive for S100,
rare instances in which an unclassified sex cord-stromal tumor FOX2L and SF-1 and negative for h-caldesmon, while the oppo-
contains a prominent stromal element and a less conspicuous sex site pattern occurs in leiomyoma.52

DIAGNOSTIC HISTOPATHOLOGY 25:10 405 Ó 2019 Elsevier Ltd. All rights reserved.
 MINI-SYMPOSIUM: NEPHROUROLOGY

13 Wang Z, Yang S, Shi H, et al. Histopathological and immuno-

Practice points phenotypic features of testicular tumour of the adrenogenital
syndrome. Histopathology 2011; 58: 1013e8.
C Myoid gonadal stromal tumor is considered as an emerging but 14 Ashley RA, McGee SM, Isotaolo PA, Kramer SA, Cheville JC.
distinct entity, arising from peritubular myoid cells. Clinical and pathological features associated with the testicular
C Composed of spindled cells forming fascicles with various tumor of the adrenogenital syndrome. J Urol 2007; 177: 546e9.
amounts of collagen. discussion 9.
C Differential diagnosis includes fibroma (inhibin/SOX9/calretinin 15 Rutgers JL, Young RH, Scully RE. The testicular “tumor” of the
positive) and leiomyoma (paratesticular; contain perinuclear adrenogenital syndrome. A report of six cases and review of the
vacuoles; S100/FOX2L/SF-1 negative). literature on testicular masses in patients with adrenocortical
disorders. Am J Surg Pathol 1988; 12: 503e13.
16 Young RH. Sex cord-stromal tumors of the ovary and testis: their
Conclusion similarities and differences with consideration of selected prob-
lems. Mod Pathol 2005; 18(suppl 2): S81e98.
In summary, we have attempted to provide a brief review
17 Idrees MT, Ulbright TM, Oliva E, et al. The World Health Organi-
regarding the largest group of non-germ cell tumors, those of sex
zation 2016 classification of testicular non-germ cell tumours: a
cord-stromal type. Among this category of neoplasms, LCTs
review and update from the international society of urological
predominate, followed by SCTs. We have touched upon the
pathology testis consultation panel. Histopathology 2017; 70:
recent updates proposed by the World Health Organization
513e21.
(WHO), such as the new classification of SCT and its variants, as
18 Perrone F, Bertolotti A, Montemurro G, Paolini B, Pierotti MA,
well as the emerging entity of MGST, in hopes to provide a better
Colecchia M. Frequent mutation and nuclear localization of beta-
understanding of these uncommon neoplasms. A
catenin in sertoli cell tumors of the testis. Am J Surg Pathol 2014;
38: 66e71.
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DIAGNOSTIC HISTOPATHOLOGY 25:10 407 Ó 2019 Elsevier Ltd. All rights reserved.