Moderators: Dr. Gregor Mikuz and Dr. Victor E. Reuter
Section 4 -
Sex Cord / Gonadal Stromal Tumors of the Testis
Isabell A. Sesterhenn
Sex-cord/ gonadal stromal tumors account for 3-6% of
testicular tumors in adults and 20-30% in prepubertal children
Unlike germ cell tumors
they are equally common in patients of different race. The histology of these tumors recapitulates the
appearance of Leydig, Sertoli and granulosa cells, and nonspecific stromal cells of the immature and
mature testis. The classification is listed in Table 1: .
Table 1: Classification of Stromal tumors
The most helpful immunohistochemical markers are inhibin and calretinin although the absence of these
markers does not exclude the diagnosis of a stromal tumor
A whole host of markers e.g.
keratins, desmin has been observed.
|Sex Cord/Gonadal Stromal Tumours|
Leydig cell tumor |
Malignant Leydig cell tumor
Sertoli cell tumour
Sertoli cell tumor lipid rich variant
Sclerosing Sertoli cell tumor
Large cell calcifying Sertoli cell tumou
Malignant Sertoli cell tumour
Granulosa cell tumour
Adult type granulosa cell tumour
Juvenile type granulosa cell tumour
Tumours of the thecoma/fibroma group
Sex cord/gonadal stromal tumors, incompletely differentiated
Sex cord/gonadal stromal tumors, mixed forms
Malignant sex cord/gonadal stromal tumors
Tumors containing both germ cell and sex cord/gonadal stromal elements
Germ cell-sex cord/gonadal stromal tumor, unclassified
The behavior of sex cord/ stromal tumors may be unpredictable since tumors with bland histological
features can metastasize. However, tumors exhibiting necrosis, nuclear anaplasia, frequent and abnormal
mitoses, irregular borders and large size (greater than 5 cm), extension into paratesticular tissue and
vascular invasion are more likely to progress
Included in this category are Leydig cell tumors, Sertoli cell tumors, granulosa
cell tumors and tumors of the thecoma/fibroma group.
A. Leydig Cell Tumor
Macroscopically, the tumor appears circumscribed, even encapsulated, homogeneous,
bulging and yellowish or mahogany brown. Histologically, it is composed of elements recapitulating
normal development and evolution of Leydig cells
The most common appearance is that of
medium-sized cells with distinct cell borders, eosinophilic cytoplasm and a round or oval vesicular and
rarely grooved nucleus, frequently containing a prominent nucleolus. The cells may be larger with finely
or coarsely vacuolated cytoplasm containing lipids, while others consist of elongated, spindle-shaped
cells with granular eosinophilic cytoplasm. The nuclei may vary from small to large, round to oval, or
vesicular to pyknotic. Occasional cells may be binucleated. The Reinke crystals are helpful in the
identification of Leydig cell tumor, but they are detectable in only about 40% of cases. Lipofuscin
pigment is often present. The cells occur in sheets, columns, cords and trabeculae. Rare tumors are
microcystic . About 10% of Leydig cell tumors are malignant. Criteria for the diagnosis of
malignancy are anaplasia of the cells, individual cell necrosis, large areas of tumor necrosis, extension
to the tunica or epididymis, frequent mitoses, vascular invasion and tumor size of 5 or more cm
However, rarely the tumor may show none of these features but metastasize. In such cases, the
metastases are usually delayed five or more years.
Leydig cell tumors have to be distinguished from nodules of Leydig cell hyperplasia
found in the testes of persons with atrophy, cryptorchid, the Klinefelter syndrome and Klinefelter-like
syndrome. In such cases, the testes are small and the seminiferous tubules are small and often
sclerotic. Hyperplasia differs from neoplasia in that the tubules are entrapped in the former but not in
the latter; although a few entrapped tubules may be seen in the periphery of a tumor. Leydig cell tumors
and hyperplasia can be distinguished from similar changes in the androgen insensitivity and the
adreno-genital syndromes by the absence of clinical symptoms or laboratory evidence of those syndromes.
B. Sertoli Cell Tumors
Macroscopically, the tumors are rather firm, grayish-white or yellow and appear
encapsulated. The cells range in shape from oval to columnar. They have a small or medium-sized, round
or oval vesicular nucleus containing a fine chromatin network and a solitary, small basophilic
nucleolus. The cytoplasm may be scanty or abundant with a single large or multiple small lipid vacuoles.
The cells form tubules with a more or less distinct lumen which may contain basement membrane-like
material, or the tubules appear solid as in the prepubertal testis
The tumor may occur in
sheets with only occasional tubule formation. The stroma can be scanty or composed of abundant,
sometimes hyalinized, fibrous tissue. The tumors with extensive hyalinization are known as the
"sclerosing Sertoli cell tumor". . Sertoli cell tumors constitute about 3% of testicular tumors -
occur in all ages, but mostly in infants and children . In adults, 40% show gynecomastia. In a few
instances estrogens and pregnanediol are elevated. The tumors are usually benign, but 10% are malignant,
and those patients who are going to die usually do within one year
Sertoli cell tumors must be
distinguished from the small nodules of coiled tubules lined by immature Sertoli cells found in over 20%
of cryptorchids and occasionally in descended testes. Such nodules are sometimes mislabeled Sertoli cell
or tubular adenoma, but represent residual nodules of immature tubules. Occasionally, scattered
spermatogonia are found within the tubules of the Sertoli cell nodules.
a. Large Cell Calcifying Sertoli Cell Tumor
On gross examination the tumors are tan to yellow, often multifocal and firm. 20%
are bilateral and most of these are associated with Carney syndrome. The cells are large with cuboidal,
hexagonal, columnar, or spindle shapes. The cytoplasm is abundant, finely granular, and eosinophilic,
but may be amphophilic and slightly vacuolated, and contain abundant lipid in fine droplets or large
vacuoles. The nuclei are round, oval, or elongated with one or two small nucleoli. Mitoses are
generally absent or rare. The neoplastic cells often form tubules or cords, clusters, trabeculae, or
solid sheets. The stroma may be loose, myxoid or densely collagenous with varying degrees of
calcification. Calcification appears as large, wavy, laminated nodules or massive deposits; sometimes it
is sparse. In the absence of prominent tubule formation and minimal calcification, the tumor may
simulate a Leydig cell tumor, especially in a child with precocious puberty
The large cell
calcifying Sertoli cell tumor is most common in children and is often associated with Carney syndrome:
hyperplasia and neoplasia of other endocrine organs, bilateral primary adrenocortical hyperplasia and
pituitary adenomas, spotty mucocutaneous pigmentation, and cardiac myxomas . Clinical associations
have included sexual precocity, acromegaly, pituitary gigantism, hypercortisolemia, and sudden death.
b. Testicular Tumors in Peutz-Jeghers Syndrome
Stromal tumors in the Peutz-Jeghers syndrome resemble the sex-cord stromal tumors
with annular tubules or the large cell calcifying Sertoli cell tumor. They have a prominent intratubular
component and lack the calcifications
C. Granulosa Cell Tumors
Two types are recognized: the adult and the juvenile. Both display the same
histologic patterns as their ovarian counterparts.
a. Granulosa Cell Tumor, Adult Type
The gross appearance is grayish-white or yellow, homogeneous lobulated. The nuclei
are vesicular and grooved, but they may be large, round, and hyperchromatic. The cells are small, round,
or hexagonal; the cytoplasm is generally scant. The tumor may have a diffuse or microfollicular pattern
with Call-Exner bodies. About half of the patients have gynecomastia
b. Granulosa Cell Tumor, Juvenile Type
Macroscopically, they are lobulated often with a cystic component. The cells are
polyhedral or round and contain abundant pale to eosinophilic cytoplasm. The nuclei are round or oval
and hyperchromatic with occasional nucleoli. There may be many mitoses. Histologically, the tumor is
usually cystic but may be follicular or have solid areas. The follicles are usually large and round.
The tumor is almost always encountered before the age of two years. It is the most common testicular
tumor of the newborn. A few have been reported in cryptorchid testes with intersex disorders
D. Tumors of the Thecoma/Fibroma Group
These tumors are known under a number of synonyms and today are considered to be
fibromas with the histologic features of their ovarian counter parts
Tumors showing both germ cell and gonadal stromal elements
Macroscopically, the tumor is multinodular with yellowish gritty cut surface. The
nodules are composed of two principal cell types: large germ cells and small cells resembling immature
Sertoli and granulosa cells; elements resembling Leydig and lutein cells may also be present. The two
cells (germ cell and sex cord/gonadal stromal elements) are usually in irregular or rounded discrete
nests presenting one or more of three patterns. Most often the sex cord cells surround rounded hyaline
nodules of basement membrane substance which merges with the surrounding basement membrane. The second
pattern consists of nests composed of large germ cells surrounded by many smaller Sertoli cells. In the
third growth pattern, the Sertoli cells form a ring of single cells at the periphery of a central nest of
germ cells. Focal calcification may begin in hyaline bodies, sometimes forming large, wavy, laminated
masses separated by dense fibrous tissue. Large polyhedral cells resembling Leydig cells but without
Reinke crystals may be present after puberty . By immunohistochemistry, the germ cells are positive
for VASA, p53 and other germ cell markers. They also can be positive for PLAP and c-kit. The stromal
cells are positive for inhibin and WT-1 .
Sometimes the germ cells of a gonadoblastoma transgress the margins of the nests and
grow as a seminoma or embryonal carcinoma with only small foci of gonadoblastoma within them or at their
margins. The type of germ cell tumor should be specified. Gonadoblastomas arise almost exclusively in
patients with rudimentary or streak gonads, most of whom are phenotypic females and almost all of whom
are X-chromatin-negative and have a Y-chromosome.
B. Mixed Germ Cell Sex Cord/Gonadal Stromal Tumors, Unclassified
A tumor consisting of closely admixed germ cells and sex/cord gonadal stromal
cells. The germ cells resemble spermatogonia with ample cytoplasm and varying amounts of glycogen. The
nuclei are round and may have nucleoli. The germ cells are seen either as single cells or small groups
and grow in association with cells resembling Sertoli, granulosa and/or Leydig cells. The proportions of
the constituent cells vary. Mitotic activity can occur, but the tumor appears to be benign. The germ
cells are probably entrapped and not neoplastic . In contrast to gonadoblastoma, these tumors occur
in testes of normal
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