Tumors of the Testis
Section 4 -
Sex Cord-Stromal Tumors of Testis
Sex cord-stromal tumors constitute about 4% of all testicular neoplasms, but account for approximately
8% of neoplasms in prepubertal males. These tumors are classified based on their resemblance to Sertoli,
Leydig or non-specified stromal cells in the testis (table 1). Leydig cell tumors are the most common
among the pure sex cord-stromal tumors, followed by Sertoli cell tumors, granulosa cell tumors and pure
Sertoli-stromal cell tumors|
Sertoli cell tumor
large cell calcifying
Sertoli-Leydig cell tumor
Leydig cell tumor
Granulosa-stromal cell tumors
Granulosa cell tumor
Tumors in the fibroma-thecoma group
Sertoli-Stromal Cell Tumors
Sertoli Cell Tumor
Sertoli cell tumors (SCT) account for about 1% of all testicular neoplasms. Historically, about one
third of Sertoli cell tumors have been reported in children, although there is some controversy regarding
these neoplasms. The majority of tumors reported as SCTs likely represent juvenile granulosa cell
tumors. On rare occasion, SCTs develop in patients with androgen insensitivity syndrome and even more
rarely arise in association with the Peutz-Jeghers syndrome. In those cases, patients may present with
SCTs have a wide size range with a mean diameter of 3.5 cm, but SCTs associated with the Peutz-Jeghers
syndrome are usually smaller. SCTs are typically unilateral with the exception of tumors in patients
with the Peutz-Jeghers syndrome and some large calcifying SCTs. The tumors are typically well
circumscribed, frequently with a lobulated, yellow tan or white cut surface. Cysts may be present and
At low-power magnification, the tumor shows nodular or diffuse patterns. Most SCTs, not otherwise
specified, show sufficient tubular differentiation to allow the correct diagnosis. The tubules are
hollow and round or solid and elongated but sometimes they may be quite irregular in size and shape and
have a retiform pattern. A cord-like or solid growth may predominate in tumors with only focal tubular
differentiation. The tubules are lined by a single layer of columnar or sometimes cuboidal cells with
moderate to abundant eosinophilic cytoplasm, but the cytoplasm may be pale secondary to lipid
accumulation. Sometimes, large vacuoles are present. The stroma may be scanty or abundant with
prominent edema or hyalinization. Some tumors display marked sclerosis of the stroma encasing and
distorting the tubular architecture (so-called sclerosing Sertoli cell tumor). These tumors are
usually small. Most SCTs show minimal cytologic atypia and scant mitotic activity, but marked
pleomorphism and brisk mitotic activity may be seen in malignant tumors.
Large Cell Calcifying Variant:
Occurs in patients from 2 to 51 years of age and is associated with Carney's syndrome and occasionally
Peutz-Jeghers or androgen insensitivity syndromes. In syndromic cases, associated clinical findings
include acromegaly, pituitary gigantism, hypercortisolemia, sexual precocity, spotty cutaneous
pigmentation and sudden death. The pathologic findings consist of pituitary adenomas, bilateral primary
adrenocortical hyperplasia, testicular Leydig cell tumors, cardiac myxomas and lentigines. Patients with
Peutz-Jeghers syndrome have also elevated levels of estrogens and advanced bone age.
Tumors are usually 4 cm or less (mean 2 cm), frequently multifocal and in 20% of cases bilateral.
They have a firm, yellow to tan to white cut-surface with granular areas.
The tumor cells grow in sheets, nests, trabeculae, cords and solid tubules. Intratubular tumor is
found in approximately one half of the cases. The stroma may be loose and myxoid or extensively
hyalinized. Many tumors have a neutrophilic infiltrate which may be useful in the differential diagnosis
with other sex cord-stromal tumors. The calcification is usually conspicuous and sometimes very large,
laminated calcific nodules are noted. Small psammoma bodies or areas of ossification may be seen. The
tumor cells are large, rounded or polygonal with abundant eosinophilic, granular cytoplasm. The nuclei
are round to oval with one or two small nucleoli. Ultrastructural studies support the origin from
Sertoli cells with identification of Charcot-Böttcher filament bundles in some cases. Tumors occurring
in males with the Peutz-Jeghers syndrome often have some features of large cell calcifying Sertoli cell
tumor, but frequently lack calcification; in other cases they resemble the sex cord-stromal tumor with
annular tubules of the ovary.
Most SCTs behave in a benign fashion. The percentage of malignant SCTs ranges between 10 to 22%.
Malignant SCTs are rare in children. The most common site for metastases is the retroperitoneal lymph
nodes, followed by mediastinal lymph nodes, lung, liver, bones and brain. In a recent study of 60 SCTs,
not otherwise specified, conducted by Young and colleagues (1998), 7/60 SCTs (12%) were clinically
malignant. Four patients had tumor spreading beyond the testis at the time of the diagnosis. Lymph node
involvement was present in all of them with additional lung and bone metastases in one patient. Three
additional patients developed metastases between 1.3 and 12 years after the diagnosis. In that study,
features that correlated with a malignant clinical outcome included: (1) tumors > 5 cm in size, (2)
necrosis, (3) moderate to severe nuclear atypia, (4) vascular invasion and (5) > 5 mitosis/10 high
power fields. Five of the 7 malignant SCTs had at least three of those features.
The large calcifying variant of SCT may have a malignant course. Patients with malignant tumors are
older (mean 30 years) than those with benign tumors (mean 17 years). Malignant tumors are typically
unilateral and unifocal in contrast to the benign tumors that are multifocal and bilateral. Morphologic
features that suggest a malignant course in the large cell variant of SCT are similar to those used for
the conventional SCTs. The initial treatment for SCTs is orchidectomy. Retroperitoneal lymph node
dissection is indicated in cases with radiographically evident retroperitoneal involvement.
The broad differential diagnosis includes non-neoplastic lesions such as Pick's adenoma as well as
testicular neoplasms (granulosa cell tumor, Leydig cell tumor, seminoma, endometrioid adenocarcinoma),
paratesticular tumors (adenomatoid tumor, sertoliform rete cystadenoma) and metastases. The most
relevant are discussed below.
Sertoli Cell Nodule (so-called Pick's adenoma): These typically are
microscopic non-neoplastic lesions, although they may be seen grossly as tiny white nodules. On
microscopic examination, aggregates of closely clustered tubules with interspersed Leydig cells are seen.
The tubules are lined by immature Sertoli cells and rarely contain spermatogonia. Intratubular laminated
calcified bodies are occasionally present. This type of proliferation is typically seen in cryptorchid
or undescended testes.
Granulosa Cell Tumor: Juvenile granulosa cell tumor has typically been
confused with SCT. In contrast to SCT, juvenile granulosa cell tumor exhibits prominent follicles that
are irregular in size and shape. If no follicular differentiation is present, the diagnosis of juvenile
granulosa cell tumor can still be made with the finding of intercellular basophilic matrix imparting a
chondroid appearance on the tumor. In contrast, SCTs usually display tubular differentiation. Juvenile
granulosa cell tumor typically has more immature nuclei with conspicuous mitotic activity and importantly
occurs in the first few months of life.
Leydig Cell Tumor (LCT): On gross examination, these tumors
characteristically have a yellow to brown cut surface. At the histologic level, SCT may be confused with
LCT, especially if it is associated with a diffuse growth of cells with abundant eosinophilic cytoplasm.
The most helpful difference is the presence of tubular differentiation in SCTs.
Furthermore, almost half of LCTs contain crystals of Reinke. Immunohistochemical stains may be of
relative help as cytokeratin shows much stronger and diffuse positivity in SCTs than in LCTs and in
contrast, inhibin is much more intense and diffuse in LCTs. The large calcifying variant of SCT can be
confused with a LCT, but the former shows tubular growth and they are commonly multifocal and bilateral.
Calcification is not a feature of LCTs, however, extremely rare ossifying LCTs have been noted.
Seminoma: SCTs may have a diffuse growth pattern of cells with clear
cytoplasm (secondary to lipid content) and have a non-specific chronic inflammatory infiltrate including
lymphocytes resulting in a superficial resemblance to seminoma. Rarely seminomas may grow in a solid
tubular pattern that at low-power suggests SCT. The presence of granulomas, rounded nuclei with
"flattened" edges, one to four prominent nucleoli and glycogen content in the cytoplasm of the neoplastic
cells will favor the diagnosis of seminoma. The finding of intratubular germ cell neoplasia and positive
staining for glycogen, placental-like alkaline phosphatase and CD117 in seminoma and cytokeratin, inhibin
and calretinin staining in SCTs are helpful in this differential diagnosis.
Unclassified Mixed Germ Cell Tumor: Sometimes sex cord-stromal tumors,
more commonly SCTs or unclassified sex cord-stromal tumors, may incorporate germ cells but typically this
occurs at the periphery and they are arranged in clusters, but occasionally they are in the center or
have a diffuse distribution in the tumor. In most cases, these cells resemble spermatogonia and they do
not stain for a variety of germ cell markers.
Sertoli-Leydig Cell Tumor
These tumors are rare and their histologic appearance is similar to that seen in their ovarian
They typically have a solid, yellow and often lobulated cut surface.
Most tumors have tubules, cords and trabeculae in a haphazard arrangement in a background stroma that
frequently contains Leydig cells. The majority of these tumors are of intermediate differentiation but
rarely well differentiated, poorly differentiated tumors and tumors with retiform differentiation have
been described. One of these tumors has been reported to contain osteosarcoma. The typical heterologous
elements as seen in the ovary have not yet been reported.
The main differential diagnosis is with SCTs if the tumor shows prominent tubular differentiation.
The presence of a cellular neoplastic stroma, sometimes with a Leydig cell component, is helpful in the
diagnosis of Sertoli-Leydig cell tumor.
Leydig Cell Tumor
Leydig cell tumors (LCTs) account for 2-3% of all testicular neoplasms. They are the most common sex
cord-stromal tumors. Approximately 20% are diagnosed during the first decade of life, 25% between 10 and
30 years, 30% between 30 and 50 years and 25% beyond 50 years. Clinically, patients typically present
with a testicular mass but 15-30% of patients also develop gynecomastia. Other symptoms include decrease
in libido or potency and children almost always present with isosexual pseudoprecocity owing to
elaboration of androgens. Almost 10% of patients are asymptomatic and another 10% have undescended
testis. Rare examples have occurred in patients with Klinefelter's or Turner's syndromes. The tumors
typically produce testosterone, but secretion of other hormones has been reported. They can have high
levels of estrogens and in those cases the levels of testosterone and follicle-stimulating hormone have
been shown to be low. About 3% of these tumors are bilateral and 10-17% are malignant, the latter
occurring only in adults.
They are usually well circumscribed and range in size from 3 to 5 cm. They show a uniform solid,
yellow to tan, although occasionally brown to brown-green cut surface. Lobulation is sometimes seen and
areas of hemorrhage, necrosis or both are present in approximately 30% of the cases.
LCTs commonly show diffuse or nodular growth patterns. In the latter, the stroma may be prominent and
extensively hyalinized forming broad bands that subdivide the tumor in nodules. Occasionally, the stroma
has a myxoid or edematous quality and the cells form regular nests, irregular clusters, trabeculae or
cords. Adipose and osseous metaplasia has been described including the presence of psammomatous
calcification. The cells are typically large and polygonal with abundant, slightly granular,
eosinophilic cytoplasm. Cytoplasmic clearing is sometimes seen correlating with abundant lipids. Rare
cases show spindle shaped cells forming ill defined fascicles as described by Ulbright and colleagues.
Crystals of Reinke are identified in one third of cases and lipochrome pigment in 10-15% of cases. The
nuclei are typically round and contain a single prominent nucleolus. Nuclear atypia is marked in 30% of
tumors. Mitotic activity is low, but may be brisk in cases with marked atypia. Most cells containing
fat in LCTs probably arise from lipid accumulation within the neoplastic Leydig cells and they stain for
the same markers (inhibin, melan A) as typical Leydig cells but they also stain for S-100 indicating a
hybrid phenotype. In the series reported by Ulbright and colleagues only 4/12 LCTs with adipose
differentiation had fat of stromal derivation, either adipocytes or lipoblasts and the cells were
negative for inhibin and melan-A and positive for S-100. Spindled areas when present do not seem to
stain for Leydig cell markers.
In the largest series of LCTs of the testis conducted by Kim and colleagues, 5 of 30 patients with
follow-up develop metastases (17%). Helpful features in predicting the behavior of these tumors include:
Malignant LCTs typically spread to regional lymph nodes. Distant sites include lung, liver and bone.
About 20% of patients with clinically malignant tumors have metastases at the time of initial diagnosis.
The treatment requires orchidectomy and retroperitoneal lymph node dissection due to the high likelihood
of lymph node involvement.
- Older age. Patients with malignant tumors had a
average age of 63 years compared to 40 years for patients with LCTs in general.
- Larger size. In the series reported by Kim and
colleagues, tumors larger than 6.9 cm were most likely to metastasize. Benign tumors average 2.7 cm.
- Infiltrative margins and extension outside the
- Increased mitotic activity (> 3 mitosis/10 high
power fields) and nuclear atypia.
- Aneuploidy and high proliferative index. Cheville
and colleagues found that all LCTs that metastasized were aneuploid. In contrast, only 38% of the
non-metastasizing tumors were aneuploid by static image analysis. Furthermore, in the same study,
malignant LCTs had a mean MIB-1 activity of 18.6% compared with 1.2% in non-metastasizing tumors.
Leydig cell tumors may be confused with non-neoplastic and neoplastic lesions, the latter including
SCT, yolk sac tumor, placental site trophoblastic tumor, lymphoma and metastases. The most relevant
lesions are discussed here.
Leydig Cell Hyperplasia: This entity may represent a problem especially
when it is florid as occurs in cryptorchid testes. Features that favor the diagnosis of Leydig cell
hyperplasia include the lack of a discrete mass on gross examination and the presence of atrophic tubules
intermixed with the lesion. Sometimes, Leydig cell hyperplasia is nodular and the presence of multiple
nodules favors a hyperplasia over neoplasia.
Malakoplakia: It may form a single, homogeneous, yellow or brown mass
grossly indistinguishable from a Leydig cell tumor. However, the presence of an abscess is a clue to the
diagnosis of malakoplakia. Histiocytes with abundant eosinophilic cytoplasm may be confused with Leydig
cells, however, the histiocytes are present in the interstitium as well as in the tubules and they are
admixed with other inflammatory cells. The presence of Michaelis-Gutmann bodies is diagnostic of
Testicular Tumor of the Adrenogenital System (TTAGS): TTAGS closely
resembles LCT but is typically multifocal and bilateral. TTAGS have a darker brown color and
seminiferous tubules are present within the lesion. The constituent cells tend to be larger than cells
of LCT and have more abundant cytoplasm. They contain more abundant lipochrome pigment and lack crystals
of Reinke. Thick fibrous bands separating cellular sheets is typical of TTAGS.
Similar nodules may be seen in patients with the Nelson's syndrome. Fat may be present in both TTAGS
and LCT and for that reason is not helpful in the differential diagnosis.
Yolk Sac Tumor: When a LCT has abundant myxoid background and the cells
contain cytoplasmic vacuoles, the tumor may be confused with a yolk sac tumor, more specifically with the
microcystic pattern. The absence of other patterns typical of yolk sac tumor, the presence of typical
areas of LCT, absence of a primitive appearance of the cells and low mitotic activity are helpful to make
the diagnosis of LCT. Inhibin positivity, and AFP and cytokeratin negativity also help in the diagnosis
of LCT versus yolk sac tumor.
Metastatic Carcinoma: Metastatic carcinoma , especially prostate cancer
when there is a diffuse growth pattern may be confused with LCT. In such cases the clinical history is
useful and at least focally one can usually identify characteristic prostatic glandular patterns.
Immunohistochemical stains for prostate-specific acid phosphatase and prostate-specific antigen are also
helpful. Another tumor in the differential diagnosis is malignant melanoma. Melanomas may have a
diffuse or nodular growth pattern and cells with abundant eosinophilic cytoplasm. In general, the cells
will show more nuclear atypia, mitotic activity and the clinical history will also be helpful.
Immunohistochemical stains for HMB-45, S-100 and inhibin will be the most helpful in this differential
Granulosa-Stromal Cell Tumors
Granulosa cell tumors are subdivided in two major categories, adult and juvenile similar to their
Adult Granulosa Cell Tumor
These are very rare tumors that occur in adult males with an average age of 42 years, the youngest
patient reported to date was 16 years old. Patients may have a testicular mass for several years and/or
The tumors may be as large as 13 cm and typically they have a homogeneous, yellow-gray or white, firm
and lobulated cut surface and cysts may be present.
The appearance is similar to ovarian adult granulosa cell tumors with the more common patterns being
diffuse and microfollicular with Call-Exner bodies. Other patterns may be found. The cells typically
have scant cytoplasm and the nuclei are elongated with frequent grooves. The mitotic rate is generally
low. The tumors may have a prominent fibromatous or fibrothecomatous background similar to that seen in
ovarian counterparts. Immunohistochemical stains have shown that these tumors are positive for vimentin
and negative for keratin.
Gross or microscopic features that have been associated with aggressive behavior are size greater than
7 cm, vascular or lymphatic invasion and hemorrhage or necrosis. Four patients with adult granulosa cell
tumors have developed metastases. Two are alive, at 14 months and 14 years while the other two died of
Unclassified Sex Cord-Stromal Tumor: These tumors may have an appearance
similar to that of an adult granulosa cell tumor but only focally.
Juvenile Granulosa Cell Tumor
Juvenile granulosa cell tumor is the most common neoplasm of the testis during the first 6 months and
almost all tumors are diagnosed during the first year of life. This tumor is occasionally seen in older
children and rarely in adults. Approximately 20% of tumors occur in neonates with sex chromosome
abnormalities affecting the Y chromosome and ambiguous genitalia (Drash syndrome), and nearly 40% occur
in cryptorchid testes. In most cases, the tumors present as an asymptomatic scrotal mass with no
associated endocrine manifestations. No malignant cases have been reported.
The tumors measure up to 6.5 cm in largest dimension. They may be solid, cystic or both. The solid
areas have a yellow-orange or tan-white cut surface and the cysts are thin and smooth.
Solid, nodular or follicular patterns are the most common and sometimes alternate. The follicles vary
from large and round to oval, to small and irregular. They contain basophilic or eosinophilic secretion
that is mucicarmine positive. In the more solid or nodular areas, the cells grow in sheets or irregular
clusters. The cells have moderate to large amounts of pale to eosinophilic cytoplasm, round to oval
hyperchromatic nuclei, some of which contain nucleoli. Mitotic activity is usually brisk in contrast to
the adult granulosa cell tumor. Some cases show extensive hyalinization in the form of nodules and may
have a prominent myxoid background. The juvenile granulosa cells stain for cytokeratin and the
neoplastic spindle cells between the cysts and solid nodules show smooth muscle differentiation with
positivity for muscle-specific actin, smooth muscle actin and desmin.
Most patients undergo orchidectomy as the only treatment. No patients have developed recurrence or
Yolk Sac Tumor: Approximately 60% of testicular tumors occurring in
infancy and childhood are of germ cell derivation, with yolk sac tumor accounting for almost two-thirds
of the cases. However, in contrast to juvenile granulosa cell tumor, yolk sac tumor occurs in infants
and children typically one year of age or older. From the microscopic point of view, the presence of
irregular clusters of cells in a myxoid background showing brisk mitotic activity may cause confusion
with a yolk sac tumor. The latter will have other typical protean microscopic patterns, more primitive
cells that will stain for alpha-fetoprotein and will be negative for inhibin and calretinin.
Adult Granulosa Cell Tumor: These tumors also have a follicular growth
pattern but the follicles tend to be larger, more regular and do not contain basophilic material. The
nuclei are grooved and there is minimal mitotic activity. Finally, the age of the patient is also
helpful as adult granulosa cell tumors occur in adult patients.
Sertoli Cell Tumor: See previous section.
Embryonal Rhabdomyosarcoma: This tumor may enter in the differential
diagnosis because of the presence of relatively primitive nuclei, brisk mitotic activity, eosinophilic
cytoplasm and follicles. However, embryonal rhabdomyosarcoma occurs in older children (mean 7 years), is
typically paratesticular in location and some of the cells will show cross-striations. In difficult
cases, immunohistochemical stains may be helpful (myoD1, myogenin and desmin).
These are uncommon tumors that resemble their ovarian counterpart, with thecomas being truly
exceptional. They may be seen at any age (5 to 52 years) and patients present with a testicular mass.
The tumors are variable in size but they are typically well circumscribed with a firm, white-tan to
yellow cut surface.
Fibroma-thecomas are composed of spindle shaped fibroblasts that grow in a storiform pattern in a
background with variable amounts of collagen or edema. The tumors may be cellular as described in the
ovary and may also have up to 2 mitotic figures/10 high power fields. Immunohistochemical results have
shown that the cells stain for vimentin, actin and sometimes inhibin. They can also be focally positive
for desmin, keratin and S-100.
Fibromatous Tumors of the Testicular Tunics: Both tumors may have a
similar microscopic appearance although the tunical fibromas tend to be less cellular and generally lack
Fibrosarcoma: There are no established criteria to differentiate these
tumors, but the criteria used for the ovary can be applied here.
Sex Cord-Stromal Tumor, Unclassified: By definition, these tumors have
at least focal epithelial differentiation, even though the fibromatous component is very prominent. It
is important to separate both categories as all fibromas reported to date have been benign.
Leiomyoma: The cells in leiomyomas have more abundant eosinophilic
cytoplasm and form larger fascicles.
Sex Cord-Stromal Tumors, Mixed and Unclassified
As it occurs in the ovary, sex cord-stromal tumors of the testis may be mixed. All the components
should be recorded although the clinical behavior is most likely to be that of the prominent pattern or
that in which the histologic appearance is most atypical.
Sex cord-stromal tumors unclassified are those that lack specific differentiation or contain patterns
and cells resembling to varying degrees both testicular and ovarian elements. They occur at all ages and
the most common clinical symptom is a painless testicular mass, although approximately 10% of patients
These tumors are typically well circumscribed and they have a white to yellow, often lobulated cut
surface that may be traversed by gray-white septa.
In those tumors, a spectrum of patterns may be seen, ranging from predominantly epithelial to
predominantly stromal. There frequently are solid or hollow tubules or cords with cells resembling
Sertoli cells and islands or nodules of cells resembling granulosa cells in the better differentiated
tumors, although the overall appearance of the tumor is not typical of a Sertoli or granulosa cell tumor.
The stromal component is frequently fibromatous but may be densely cellular and may contain Leydig cells.
If the tumor is less differentiated, it tends to exhibit more degree of nuclear atypia and mitotic
activity. Diffuse and sarcomatoid patterns are commonly seen. Unclassified sex cord-stromal tumors
often show positivity for S-100, muscle-specific actin and smooth muscle actin and some authors suggest a
relationship to granulosa cell tumors.
It is important to note that these tumors are almost never malignant in children but they are
malignant in approximately 25% of adult patients. Features that are associated with a malignant behavior
include large size, extratesticular spread, necrosis, vascular invasion, marked nuclear atypia and brisk
mitotic activity. If metastases are present, these are more frequently seen in lymph nodes but visceral
dissemination is not rare.
The most problematic differential diagnosis is the distinction from all the pure sex cord-stromal
tumors discussed earlier.
Sex cord-stromal tumors are positive for vimentin but this immunostain is not specific and for that
reason not helpful in the diagnosis of these tumors. Keratin is frequently positive in Sertoli cell
tumors, while the staining is focal or absent in Leydig cell and granulosa cell tumors and it is
typically negative in fibromas. Epithelial membrane antigen (EMA) is typically negative in all these
tumors but rare LCTs and SCTs have been reported positive. Commonly used immunohistochemical markers for
sex cord-stromal tumors are as follows:
Inhibin: This is a 32-kDA heterodimeric glycoprotein hormone composed of
a and b subunits. Inhibin is best known for its ability to suppress follicle-stimulating hormone. In
men, the testis is the main source of inhibin, where it is secreted by Sertoli cells. Within the testis,
inhibin is involved in the regulation of spermatogenesis as well as of steroidogenesis. In normal
testis, inhibin stains Sertoli and Leydig cells as well as epididymis. In testicular sex cord-stromal
tumors, inhibin positivity has been shown systematically in juvenile granulosa cell tumors, a very
helpful finding to differentiate these tumors from yolk sac tumor. Leydig cell tumors also are
consistently positive for inhibin even at metastatic sites. Sertoli cell tumors are not so uniformly
positive for inhibin. In the series reported by Kommoss and colleagues only 30% of cases (6/20) were
inhibin positive. McCluggage reported 28% positivity (2/7), in contrast to 91% positivity reported by
Iczkowski (10/11). Occasionally, it may be morphologically difficult to distinguish between a SCT and a
LCT. Because SCTs are inhibin negative in some cases, whereas LCTs are consistently positive, a lack of
staining may be helpful in the differential diagnosis. As pointed out by McCluggage and colleagues,
inhibin may be useful to distinguish LCTs from yolk sac tumor, as the former may have on occasion a
Calretinin: This is a 29-kilodalton calcium-binding protein of the
calmodulin superfamily, acting as a buffer to prevent an abnormal intracellular calcium increase. It was
originally discovered in neuronal tissue but subsequently found in mesothelial cells and in ovarian theca
cells. In postpubertal testis, this antibody is expressed in Leydig cells but not in most Sertoli cells.
In a very recent study using tissue microarray, Lugli and colleagues found consistent expression of
calretinin in Leydig cells of the testis and strong and diffuse positivity in 5/5 Leydig cell tumors.
Calretinin may be used if positive in the rare case of differential diagnosis of a Sertoli cell tumor
from an adenomatoid tumor.
Melan A: This is an antigen recognized by cytotoxic T cells, mainly
expressed in melanocytes. However, melan A has been found to be positive in 4 Leydig cell tumors of the
testis in the study conducted by Busam and colleagues. This must be taken into account, especially in
cases where the differential diagnosis may include melanoma metastatic to the testis. In those cases,
S-100 and HMB-45 as well as a previous history of melanoma will be helpful in establishing the diagnosis.
CD99: The MIC-2 gene product is a reliable marker for Ewing's sarcoma
and primitive neuroectodermal tumors. It is also expressed in normal Sertoli and granulosa cells and sex
cord-stromal tumors of the ovary and testis. In the series reported by Kommoss and colleagues, CD99 was
not as reliable a marker for sex cord-stromal tumors as inhibin. In that series, all but one CD99
positive tumors were also inhibin positive. Conversely, a number of inhibin positive tumors were CD99
S-100: In a recent study, Tanaka and co-workers have shown that normal
Sertoli and Leydig cells and rete testis may stain for this antibody. In that study, all 8 SCTs of the
large cell variant, conventional SCTs and LCTs were also positive.
Chromogranin: This antibody has been shown to be focally positive in
non-neoplastic Sertoli and Leydig cells and in 82% of SCTs, 92% of benign LCTs and 43% of malignant LCTs
in the series reported by Iczkowski and colleagues. However, in the series reported by Kommoss and
colleagues, all sex cord-stromal tumors were negative for chromogranin.
- Cheville JC. Classification and pathology of testicular germ cell and sex cord-stromal tumors. Urol
Clin North Am. 1999;26:595-609.
- Goswitz JJ, Pettinato G, Manivel JC. Testicular sex cord-stromal tumors in children:
clinicopathologic study of sixteen children with review of the literature. Pediatr Pathol Lab Med.
- Mosharafa AA, Foster RS, Bihrle R, Koch MO, et al. Does retroperitoneal lymph node dissection have a
curative role for patients with sex cord-stromal testicular tumors? Cancer 2003;98:753-7.
- Sugita Y, Clarnette TD, Cooke-Yarborough C, Chow CW, et al. Testicular and paratesticular tumors in
children: 30 years' experience. Aust N Z J Surg. 1999;69:505-8.
- Young RH, Talerman A. Testicular tumors other than germ cell tumors. Semin Diagn Pathol.
Sertoli Cell Tumor
- Alikasifoglu A, Gonc EN, Akcoren Z, et al. Feminizing Sertoli cell tumor associated with
Peutz-Jeghers syndrome. J Pediatr Endocrinol Metab. 2002;15:449-52.
- Amin MB, Young RH, Scully RE. Large cell hyalinizing Sertoli cell tumor of the testis: A distinctive
estrogenic tumor of boys with Peutz-Jeghers syndrome (PJS): A report of six cases. (abstract). Mod
- Anderson GA. Sclerosing Sertoli cell tumor of the testis: a distinct histological subtype. J Urol.
- Borer JG, Tan PE, Diamond DA. The spectrum of Sertoli cell tumors in children. Urol Clin North Am.
- Cano-Valdez AM, Chanona-Vilchis J, Dominguez-Malagon H. Large cell calcifying Sertoli cell tumor of
the testis: a clinicopathological, immunohistochemical and ultrastructural study of two cases.
Ultrastruct Pathol. 1999;23:259-65.
- Chang B, Borer JG, Tan PE, Diamond DA. Large cell calcifying Sertoli cell tumor of the testis: case
report and review of the literature. Urology. 1998;52:5a20-3.
- De Diego Rodriguez E, Pascual Soria C, Portillo Martin JA, Martin Garcia B, Villanueva Pena A.
Sclerosing Sertoli cell tumor of the testis in an HIV patient. Arch Esp Urol. 2001;54:1129-32.
- Giglio M, Medica M, De Rose AF, Germinale F, Ravetti JL, Carmignani G. Testicular Sertoli cell tumors
and relative subtypes. Analysis of clinical and prognostic features. Urol Int. 2003;70:205-10.
- Gilcrease MZ, Delgado R, Albores-Saavedra J. Testicular Sertoli cell tumor with a heterologous
sarcomatous component: immunohistochemical assessment of Sertoli cell differentiation. Arch Pathol Lab
- Henley JD, Young RH, Ulbright TM. Malignant Sertoli cell tumors of the testis: a study of 13
examples of a neoplasm frequently misinterpreted as seminoma. Am J Surg Pathol. 2002;26:541-50.
- Jacobsen GK. Malignant Sertoli cell tumors of the testis. J Urol Pthol. 1993:233-255.
- Kratzer SS, Ulbright TM, Talerman A, Srigley JR, et al. Large cell calcifying Sertoli cell tumor of
the testis: contrasting features of six malignant and six benign tumors and a review of the literature.
Am J Surg Pathol. 1997;21:1271-80.
- Perez-Atayde AR, Nuñez AE, Carroll WL, Murthy AS, et al. Large cell calcifying Sertoli cell tumor of
the testis. An ultrastructural, immunocytohchemical and biochemical study. Cancer. 1983;51:2287-92.
- Plata C, Algaba F, Andujar M, Nistal M, et al. Large cell calcifying Sertoli cell tumor of the
testis. Histopathology. 1995;26:255-9.
- Proppe KH, Scully RE. Large cell calcifying Sertoli cell tumor of the testis. Am J Clin Pathol.
- Reale D, Pascale M, Vitullo G, Di Virgilio M, Pizzicannella J. Piccolitti G. Sclerosing Sertoli cell
tumor of the testis. Report of a case and review of the literature. Minerva Urol Nefrol.
- Sharma S, Seam RK, Kapoor HL. Malignant Sertoli cell tumor of the testis in a child. J Surg Oncol.
- Sysocka B, Serkies K, Debniak J, Jassem J, et al. Sertoli cell tumor in androgen insensitivity
syndrome – a case report. Gynecol Oncol. 1999;75:480-3.
- Tetu B, Ro JY, Ayala AG. Large cell calcifying Sertoli cell tumor of the testis. A
clinicopathologic, immunohistochemical and ultrastructural study of two cases. Am J Clin Pathol.
- Venara M, Rey R, Bergada I, Mendilaharzu H, et al. Sertoli cell proliferations of the infantile
testis: an intratubular form of Sertoli cell tumor? Am J Surg Pathol. 2001;25:1237-44.
- White MD, Loughlin MW, Kallakury BV, Ross JS, et al. Bilateral large cell calcifying Sertoli cell
tumor of the testis in a 7 year old boy. J Urol. 1997;158:1547-8.
- Young RH, Koelliker DD, Scully RE. Sertoli cell tumors of the testis, not otherwise specified: a
clinicopathologic analysis of 60 cases. Am J Surg Pathol. 1998;22:709-21.
- Zukerberg LR, Young RH, Scully RE. Sclerosing Sertoli cell tumor of the testis. A report of 10
cases. Am J Surg Pathol. 1991;15:829-34.
Leydig Cell Tumor
- Billings SD, Roth LM, Ulbright TM. Microcystic Leydig cell tumors mimicking yolk sac tumor: a report
of four cases. Am J Surg Pathol. 1999;23:546-51.
- Cheville JC, Sebo TJ, Lager DJ, Bostwick DG, Farrow GM. Leydig cell tumor of the testis: a
clinicopathologic, DNA content and MIB-1 comparison of non-metastasizing and metastasizing tumors. Am J
Surg Pathol. 1998;22:1361-7.
- Datta MW, Young RH. Malignant melanoma metastatic to the testis: a report of three cases with
clinically significant manifestations. Int J Surg Pathol. 2000;8:49-57.
- Freeman A, Morris LS, Laskey R, Coleman N, Parkinson MC. Testicular Leydig cell tumors: prognostic
value of proliferation markers. (abstract). Mod Pathol. 2003;14:108A.
- Gulbahce HE, Lindeland AT, Engel W, Lillemore TJ. Metastatic Leydig cell tumor with sarcomatoid
differentiation. Arch Pathol Lab Med. 1999;123:1104-7.
- Hekimgil M, Altay B, Yakut BD, Soydan S, Ozyurt C, Killi R. Leydig cell tumor of the testis:
comparison of histopathological and immunohistochemical features of three azoospermic cases and one
malignant case. Pathol Int. 2001;51:792-6.
- Kim I, Young RH, Scully RE. Leydig cell tumors of the testis. A clinicopathological analysis of 40
cases and review of the literature. Am J Surg Pathol. 1985;9:177-92.
- McCluggage WG, Shanks JH, Arthur K, Banerjee SS. Cellular proliferation and nuclear ploidy
assessments augment established prognostic factors in predicting malignancy in testicular Leydig cell
tumors. Histopathology. 1998;33:361-8.
- Richmond I, Banerjee SS, Eyden BP, Sissons MC. Sarcomatoid Leydig cell tumor of testis.
- Rutgers JL, Young RH, Scully RE. The testicular "tumor" of the adrenogenital syndrome. A report of
six cases and review of the literature on testicular masses in patients with adrenocortical disorders.
Am J Surg Pathol. 1988;12:503-13.
- Ulbright TM, Srigley JR, Hatzianastassiou DK, Young RH. Leydig cell tumors of the testis with unusual
features: adipose differentiation, calcification with ossification and spindle shaped tumor cells. Am J
Surg Pathol. 2002;26:1424-33.
Granulosa Cell Tumor
- Al-Bozom IA, El-Faqih SR, Hassan SH, El0-Tiraifi AE, et al. Granulosa cell tumor of the adult type:
a case report and review of the literature of a very rare testicular tumor. Arch Pathol Lab Med.
- Chan JK, Chan VS, Mak KL. Congenital juvenile granulosa cell tumor of the testis: report of a case
showing extensive degenerative changes. Histopathology. 1990;17:75-80.
- Chan YF, Restall P, Kimble R. Juvenile granulosa cell tumor of the testis: report of two cases in
newborns. J Pediatr Surg. 1997;32:752-3.
- Fagin R, Berbescu E, Landis S, Strumpf K, et al. Juvenile granulosa cell tumor of the testis.
- Jimenez-Quintero LP, Ro JY, Zavala-Pompa A, Amin MB, et al. Granulosa cell tumor of the adult testis:
a clinicopathologic study of seven cases and a review of the literature. Hum Pathol. 1993;24:1120-5.
- Lawrence WD, Young RH, Scully RE. Juvenile granulosa cell tumor of the infantile testis. A report of
14 cases. Am J Surg Pathol. 1985;9:87-94.
- Matoska J, Ondrus D, Talerman A. Malignant granulosa cell tumor of the testis associated with
gynecomastia and long survival. Cancer. 1992;69:1769-72.
- Nistal M, Redondo E, Paniagua R. Juvenile granulosa cell tumor of the testis. Arch Pathol Lab Med.
- Perez-Atayde AR, Joste N, Mulhern H. Juvenile granulosa cell tumor of the infantile testis. Evidence
of a dual epithelial-smooth muscle differentiation. Am J Surg Pathol. 1996;20:72-9.
- Pinto MM. Juvenile granulosa cell tumor of the infant testis: case report with ultrastructural
observations. Pediatar Pathol. 1985;4(3-4):277-89.
- Talerman A. Pure granulosa cell tumor of the testis. Report of a case and review of the literature.
Appl Pathol. 1985;3:117-22.
- Young RH, Lawrence WD, Scully RE. Juvenile granulosa cell tumor-another neoplasm associated with
abnormal chromosomes and ambiguous genitalia. A report of three cases. Am J Surg Pathol. 1985;9:737-43.
- Allen PR, King AR, Sage MD, Sorrel VF. A benign gonadal stromal tumor of the testis of spindle
fibroblastic type. Pathology 1990;22:227-9.
- Deveci MS, Deveci G, Onguru O, Kilciler M, Celasun B. Testicular (gonadal stromal) fibroma: case
report and review of the literature. Pathol Int. 2002;52:326-30.
- Greco MA, Feiner HD, Theil KS, Muffarrij AA. Testicular stromal tumor with myofilaments:
ultrastructural comparison with normal gonadal stroma. Hum Pathol 1984;15:228-43.
- Jones MA, Young RH, Scully RE. Benign fibromatous tumors of the testis and paratesticular region: a
report of 9 cases with a proposed classification of fibromatous tumors and tumor-like lesions. Am J Surg
- Miettinen M, Salo J, Virtanen I. Testicular stromal tumor: ultrastructural, immunohistochemical and
gel electrophoretic evidence of epithelial differentiation. Ultrastruct Pathol 1986;10:515-28.
- Weidner N. Myoid gonadal stromal tumor with epithelial differentiation (?testicular myoepithelioma).
Ultrastruct Pathol 1991;15:409-16.
Sex Cord-Stromal Tumor, Unclassified
- Eble JN, Hull MT, Warfel KA, Donohue, JP. Malignant sex cord-stromal tumor of testis. J Urol
- Renshaw AA, Gordon M, Corless CL. Immunohistochemistry of unclassified sex cord-stromal tumors of the
testis with a predominance of spindle cells. Mod Pathol 1997;10:693-700.
- Ulbright TM, Srigley JR, Reuter VE, Wojno K, et al. Sex cord-stromal tumors of the testis with
entrapped germ cells: a lesion mimicking unclassified mixed germ cell sex cord-stromal tumors. Am J
Surg Pathol. 2000;24:535-42.
- Augusto D, Leteurtre E, De La Taille A, Gosselin B, Leroy X. Calretinin: a valuable marker of normal
and neoplastic Leydig cells of the testis. Appl Immunohistochem Mol Morphol. 2002;10:159-62.
- Bertschy S, Genton CY, Gotzos V. Selective immunocytochemical localization of calretinin in the human
ovary. Histochem Cell Biol. 1998;109:59-66
- Busam KJ, Iversen K, Coplan KA, et al. Immunoreactivity for A103, an antibody to melan-A (Mart-1), in
adrenocortical and other steroid tumors. Am J Surg Pathol. 1998;22:57-63.
- Cao QJ, Jones JG, Li M. Expression of calretinin in human ovary, testis and ovarian sex cord-stromal
tumors. Int J Gynecol Pathol. 2001;20:346-52.
- Deavers M, Malpica A, Liu J, Broaddus R, Silva E. Ovarian sex cord-stromal tumors: An
immunohistochemical study including a comparison of calretinin and inhibin. Mod Pathol. 2003;16:584-90.
- Gordon MD, Corless C, Renshaw AA, Beckstead J. CD99, keratin and vimentin staining of sex cord-stromal
tumors, normal ovary and testis. Mod Pathol. 1998;11:769-73.
- Hekimgil M, Altay B, Yakut BD, Soydan S, Ozyurt C, Killi R. Leydig cell tumor of the testis:
comparison of histopathological and immunohistochemical features of three azoospermic cases and one
malignant case. Pathol Inter 2001;51:792-6.
- Iczkowski KA, Bostwick DG, Roche PC, Cheville JC. Inhibin A is a sensitive and specific marker for
testicular sex cord-stromal tumors. Mod Pathol. 1998;11:774-9.
- Kommoss F, Oliva E, Bittinger F, Kirkpatrick CJ, et al. Inhibin-alpha, CD99, HEA 125, PLAP and
chromogranin immunoreactivity in testicular neoplasms and the androgen insensitivity syndrome. Hum
- Lugli A, Forster Y, Haas P, et al. Calretinin expression in human normal and neoplastic tissues: a
tissue microarray analysis on 5233 tissue samples. Hum Pathol. 2003;34:994-1000.
- McCluggage WG, Shanks JH, Whitesidse C, Maxwell P, et al. Immunohistochemical study of testicular sex
cord-stromal tumors, including staining with anti-inhibin antibody. Am J Surg Pathol. 1998;22:615-9.
- McLaren K, Thomson D. Localization of S-100 protein in a Leydig and Sertoli cell tumor of testis.
- Sasano H, Nakashima N, Matsuzaki O, Kato H, et al. Testicular sex cord-stromal lesions:
immunohistochemical analysis of cytokeratin, vimentin and steroidogenic enzymes. Virchows Arch Pathol
Anat Histopathol. 1992;421:163-9.
- Tanaka Y, Carney JA, Ijiri R, et al. Utility of immunostaining for S-100 protein subunits in gonadal
sex cord-stromal tumors, with emphasis on the large cell calcifying Sertoli cell tumor of the testis.
Hum Pathol. 2002;33:285-9.