- Germ Cell Tumors
After completing this section you will:
- know the classification of testicular germ cell tumors
and how they originate
- know the commonest type
- be able to describe clinical and histologic features
- know which tumor produces which marker
- predict possible clinical outcomes and response to
- Sex Cord-Stromal Tumors
After completing this section you will:
- know the sex cord-stromal tumors of the testis
- know their hormonal effects
- describe clinical features
- describe their biologic behavior
- Germ cell tumors
Germ cell tumors (GCTs) are more common in whites than blacks, both African
and North American, and Asians. The peak incidence is between 20 and 34 years
when it is the most common malignancy in males. Germ cell tumors are uncommon
after 50 years of age. The mean age of seminoma is about 40 years and that
for teratoma is about 30 years.
Question: What is the commonest malignant testicular tumor after 50
years of age?
The cause of germ cell tumors is unknown. Cryptorchidism significantly increases
the risk, 4 to 10 fold, of subsequent development of germ cell tumors. Development
of a germ cell tumor in one testis increases the risk of developing a tumor
in the contralateral testis.
Histogenesis and Classification
There are several classification systems of testicular germ cell tumors.
All of these derive from the concept that testicular GCTs originate from germ
cells, which may develop along two unrelated pathways. Seminomas (germinomas)
recapitulate some aspects of spermatogenesis and are distinct from other tumors,
called non-seminomatous germ cell tumors (NSGCTs). Non-seminomatous
germ cell tumors represent progeny of pluripotent embryonic cells formed from
germ cells through the process of parthenogenesis.
All testicular GCTs originate from intratubular germ cells that pass through
a pre-invasive carcinoma-in-situ stage. There are many GCTs that contain both
seminoma and NSGTs and whether these tumors derive clonally from a single
transformed cell or from multifocal carinogenesis is not known. The transition
from carcinoma-in-situ to invasive carcinoma is marked by a long latency period.
It is not known whether the intratubular cells have the potential to grow
invasively from the beginning or additional steps are required for acquisition
Question: Germ cell tumors may also arise in extra-gonadal sites.
What are these sites?
This is the commonest single type of primary testicular tumor. It occurs
in two forms: Classic (or conventional) and spermatocytic seminomas. Seminoma
accounts for 35 to 70% of testicular neoplasms and does not develop before
Classic seminoma usually forms a mass situated anywhere in the testis and
produces a moderate smooth or bosselated enlargement of the organ. Typically
the cut surface is uniform yellow or tan. Hemorrhage and necrosis are uncommon.
Classic seminoma. The cut surface is tan and bosselated.
seminoma. A nodular tumor completely replaces the testis.
Microscopically, the tumor is composed of sheets of uniform undifferentiated
germ cells with clear or fine granular cytoplasm, well-defined cell border
and round nuclei, frequently with prominent nucleoli. The sheets of tumor
cells are separated by slender fibrous septa. Diffuse or focal intense lymphoid
infiltrate is seen in most tumors. Glycogen may be demonstrated in the cytoplasm
of the tumor cells.
Classic seminoma. Sheets of tumor cells separated by thin fibrous septa heavily
infiltrated by lymphocytes.
High magnification showing uniform tumor cells.
Mitotic figures are usually infrequent. In about a third of cases, noncaseating
granulomatous areas containing small giant cells are found. Tumor giant cells
that mimic syncytiotrophoblasts in appearance and which may contain intracytoplasmic
ß-hCG are present in some tumors. This may lead to a mild increase in
serum ß-hCG. In some seminomas, the neoplastic cells are more pleomorphic
and have more mitotic figures than in typical seminoma. These tumors have
been called anaplastic seminomas. Although these tumors tend to occur at higher
stages than classical seminoma, stage for stage this subgroup has the same
prognosis as the classical type.
seminoma. Left panel shows multinucleate giant cells of foreign body type.
Right panel shows syncytiotrophoblast-like tumor giant cell.
When metastases occur, they tend to involve regional lymph nodes initially,
followed by systemic spread. Classic seminoma is highly sensitive to radiation
therapy, and the overall 5-year survival is in the order of 90-95%. Seminomas
containing syncytiotrophoblastic giant cells should not be considered as mixed
germ cell tumors.
This is a rare but distinct clinicopathologic variant of seminoma that occurs
only in the descended testes of elderly men and forming about 5% of seminomas.
The tumor is bilateral in about 6% of cases compared to about 2% in classic
The tumor tends to be poorly demarcated, usually soft with a gelatinous or
mucoid appearance. Cystic areas, especially in the center, are common but
hemorrhage or necrosis is almost always absent.
Spermatocytic seminomas form solid sheets of cells without the nesting pattern
of classical seminoma. The overall pattern has some superficial resemblance
to the early stage germ cells of the testis. Three populations of tumor cells,
separated according to size, are seen: 1) small cells that superficially resemble
lymphocytes, 2) intermediate or medium-sized cells, the commonest cell type,
have round nuclei and finely granular chromatic pattern, and 3) large or giant
cells. Mitotic figures are usually abundant and the lymphocytic infiltrate
and granulomas seen in classic seminoma are absent.
Spermatocytic seminoma is an extremely indolent tumor with rather limited
malignant potential and rarely if ever metastasizes.
This subtype of GCTs represents the most primitive form of the NSGCTs. It
accounts for about 15 to 35% of testicular GCTs.
Grossly, the tumors are large, often hemorrhagic and necrotic producing a
variegated cut surface.
carcinoma. Tumor replaces the whole testis.
Histologically, they are extremely pleomorphic and show a variety of patterns
forming glands, tubules, and even primitive embryo-like structures. Many mitotic
figures are present.
Anaplastic and solid undifferentiated areas may present as sheets of cells
with large, hyperchromatic nuclei, prominent nucleoli and poorly-defines cell
differentiated area in embryonal carcinoma.
When large numbers of the embryo-like structures are present the tumor is
referred to as a polyembryoma. These structures contain a disc and two cavities
surrounded by loose mesenchyme simulating a 2 week embryo.
Left panel shows an embryo; right panel shows embryo-like structure in polyembryoma.
Embryonal carcinoma metastasizes early and widely via both lymphatic and
hematogenous routes. Radiation is not as effective as with seminoma, but newer
chemotherapeutic agents have greatly improved prognosis. Tumors confined to
the testis now have a prognosis essentially identical to that of seminoma
(95% 5-year survival). Unlike seminoma, however, many embryonal carcinomas
are high stage tumors at the time of presentation. These more widely disseminated
tumors still have "a cure rate greater than 50%".
Yolk Sac Tumor (Endodermal Sinus Tumor)
Yolk sac tumor (YST), also known as endodermal sinus tumor, is a distinct
entity from embryonal carcinoma of which it was considered a variant in the
past. It is noted for its resemblance to rat fetal yolk sac and the presence
of microscopically distinctive structures known as Schiller-Duval bodies.
Testicular yolk sac tumors occur in two forms: either as a pure form in young
children or as a focal differentiation within other NSGCTs, mainly embryonal
carcinoma, in adults. Pure YST of the adult testis is rare. In this form,
it presents as a fairly rapid testicular enlargement. The cut surface is gray-white
and may be cystic.
Microscopically, the tumor shows a variety of patterns, the commonest of
which is a loose meshwork of small spaces and cysts (producing a sieve-like
appearance) lined by either flattened cells or vacuolated cells with nuclei
that protrude in a "hobnail" fashion.
Yolk sac tumor showing tubules and cysts lined by flattened cells producing
a sieve-like appearance.
A solid pattern that resembles embryonal carcinoma is also seen. In some
tumors, Schiller-Duval bodies (endodermal sinus) are seen. These are glomerulus-like
structures with a central core of blood vessel surrounded by an inner layer
of epithelial-like cells, a space and an outer layer of similar cells. Varying
numbers of eosinophilic globules may be seen.
YST is almost invariably associated with production of large amounts of alpha-fetoprotein
(AFP) and also alpha-1 antitrypsin (a -1AT).
AFP may be followed as a marker of disease progression in the patient's serum.
Antibodies directed against AFP may also be used to stain the tumors and aid
in their diagnosis.
sac tumor stained with antibodies against AFP. Note the brown staining of
the epithelium indicating the presence of AFP.
The biologic behavior of YST is similar to that of embryonal carcinoma.
It is in this group that confusion over terminology and subgrouping exist
between the various classification schemes. In the British Testicular Tumor
Panel classification (used widely in Europe), all testicular GCTs excluding
classic seminoma, spermatocytic seminoma, and YST in children are called teratomas.
In the WHO classification (used in the US) the term is restricted to a tumor
typically composed of several tissues representing two or more germinal layers.
In the latter classification, teratomas are further subdivided into mature,
immature and teratoma with malignant transformation. However,
all three are included under teratoma differentiated in the BTTP scheme
while teratoma undifferentiated refers to embryonal carcinoma.
The tumor is composed exclusively of well-differentiated tissues and by definition,
contains no malignant-looking tissue. Some may consist of nests of mature
cartilage, smooth muscle and squamous or mucous epithelial-lined cysts. In
others, more complex and organoid arrangement is seen and abortive gastrointestinal
tract, brain, eye, pancreas, salivary gland, and other organs can easily be
teratoma showing cysts lined by mucous epithelium (left) and keratinizing
squamous epithelium (right).
Mature teratoma. Mature cartilage (left) and spaces lined by mucus secreting
glandular epithelium (right) are present.
Another example of a mature teratoma.
Although the tumor has a benign histologic appearance, its clinical course
in the adult is unpredictable and it can metastasize. The metastases show
the same well-differentiated picture as the primary tumor. In children, teratomas
whatever their histological appearances behave in a benign fashion.
In this type of teratoma there are incompletely differentiated, fetal-appearing
tissues, often of neural differentiation.
Immature teratoma with primitive brain tissue (upper left corner) and well-differentiated
glands (lower half).
Teratoma with Malignant Transformation
This is a rare type of teratoma in which the malignant component is a typical
malignant tumor seen in other organs and may be epithelial, squamous cell
or adenocarcinoma, or a sarcoma.
AFP may be present in any teratoma that contains gastrointestinal mucosa
or clusters of liver-like cells.
This is a highly malignant neoplasm that is usually widely disseminated and
frequently fatal. In this form of testicular GST the cells differentiate in
the direction of trophoblastic (placental) tissue and both cytotrophoblast
and syncitiotrophoblast must be present for the diagnosis to be made. Pure
choriocarcinoma of the testis is extremely rare, and the tumor is much more
common as a component of mixed GCTs.
The tumor typically presets in adolescent or young adults with widespread
disease, and an often small, painless primary lesion in the testis. It is
extensively hemorrhagic and necrotic and, sometimes, may be reduced to a fibrous
scar, leaving widespread metastases with no apparent testicular mass. On occasion,
the tumor may be large and bulky. Hemoptysis due to pulmonary involvement
large, hemorrhagic, necrotic tumor.
Microscopically, the tumor is composed of two types of cells: syncytiotrophoblasts,
large multinucleate cells with abundant vacuolated cytoplasm containing hCG
and cytotrophoblasts, polygonal cells with distinct cell borders and single
nuclei, which grow in clusters and are surrounded by the syncytiotrophoblasts.
left panel, and placenta, right panel. Note similarity in histologic appearances.
Sheet of cytotrophoblasts surrounded by syncytiotrophoblasts.
Choriocarcinoma often responds well to chemotherapy but the advanced destructive
nature of the tumor still results in a high mortality rate.
Question: Choriocarcinoma is one of the very few carcinomas that metastasize
more frequently via bloodstream than lymphatics. What are the others?
Mixed Germ Cell Tumors
All germ cell tumors presumably arise from primordial germ cells and so it
is not surprising that mixed forms are quite common. Up to half of primary
testicular GSTs contain mixtures of two or more of the pure forms described
above, while apparently pure primary tumors may give rise to metastases containing
mixtures of pure forms or pure metastases of another type. Most of the patients
with seminoma initially who die of the disease have another, more aggressive
form of GST in their metastases.
When mixed germ cell tumors occur, the prognosis is usually that of the worst
component. However, choriocarcinoma is an exception to this rule. Mixed tumors
containing choriocarcinoma tend to be less advanced at diagnosis than pure
choriocarcinoma and their prognoses are correspondingly better.
- Sex Cord/Gonadal Stromal Tumors
Sex cord/gonadal stromal tumors are rare and constitute about 5% of testicular
Leydig/Interstitial Cell Tumor
These tumors are functionally active, secreting androgens, estrogens or both.
They occur at any age but are most common between 20 and 60 years. In pre-pubertal
boys, hormonal effects dominate the clinical picture and manifest primarily
as sexual precocity. In some adults, feminization and gynecomastia are observed.
Most are benign with about 10% in adults giving rise to metaststases. It
is difficult to predict biological behavior on histological grounds.
Sertoli Cell Tumor
These tumors are more rare than Leydig cell tumors. They elaborate androgens
or estrogens. Occasionally, they cause gynecomastia but sexual precocity is
Most are benign but a few, about 10%, behave in a malignant fashion.