Moderators: Dr. Gregor Mikuz and Dr. Victor E. Reuter
Section 2 -
Nonseminomatous Germ Cell Tumors of the Adult Testis and Nongerm Cell Tumors Arising in Testicular Germ Cell Tumors
Indiana University School of Medicine
Clarian North Medical Center
Nonseminomatous Germ Cell Testicular Tumors in Adult Patients
Examination Of Testicular Tumor Specimens
Specimens should be received fresh and examined as soon as possible . Difficulties in differential
diagnosis between germ cell tumor types, especially between seminomas and nonseminomatous germ cell
tumors, are enhanced by poor fixation. If the specimen cannot be examined promptly by a pathologist, the
surgeon should bisect the testis before placing it in formalin. This procedure will enhance formalin
penetration and fixation. The tunica should be examined for abnormalities. The proximal margin of the
spermatic cord should be submitted separately from other sections. Any abnormal areas of the spermatic
cord should be submitted, as well as sections from the middle and distal cord. These sections should be
taken before sectioning the testis in order to prevent artifactual displacement of tumor into
lymphovascular spaces. All areas of the neoplasm should be very thoroughly sampled, including
hemorrhagic and necrotic foci and each area that appears different on gross examination. The pathology
report should state the type of tumor (percent of different types in mixed germ cell tumors), presence or
absence of lymphovascular space and tunica invasion, and whether the spermatic cord margin is involved by
95% of primary malignant germ cell tumors of the testis are germ cell tumors. Testicular cancer
accounts for less than 1% of malignant tumors in men, but it is the most common malignant tumor in men
between 15 and 45 years of age . The incidence rises at puberty and peaks between age 25 and 35.
Nonseminomatous germ cell tumors generally occur in a younger age group than patients with pure seminomas
For reasons that are not clear, the incidence of testicular germ cell tumors has increased in
many countries during the last half of the past century. Screening and earlier detection are apparently
not responsible for the increased incidence of these neoplasms. While many agents have been hypothesized
to increase the incidence of testicular cancer, the only well established associations are with
cryptorchidism, a prior testicular germ cell tumor, a family history of testicular germ cell tumor, some
intersex syndromes and infertility . Cryptorchidism has a strong association with germ cell tumors
. Orchidopexy does not affect the elevated incidence of germ cell tumors, suggesting an abnormality
in embryologic development that predisposes to germ cell abnormalities and may also explain familial
Testicular germ cell tumors associated with cryptorchidism are more often seminomas
than other germ cell tumor types .
While pure testicular embryonal carcinomas are rare , embryonal carcinoma is a component of about
40% of all testicular germ cell tumors
and almost 90% of nonseminomatous germ cell tumors . It
occurs at a mean age of 32 years . The vast majority of patients with this tumor present with
testicular masses, but some come to attention because of metastatic disease or hormonal symptoms. Only
40 % of patients with nonseminomatous germ cell tumors have disease limited to the testis at
presentation. Another 40% have retroperitoneal tumor and 20% have more advanced disease . As many
as 2/3 of patients whose testicular tumor is predominantly embryonal carcinoma have had metastatic
disease upon pathological staging .
Embryonal carcinomas are not as well circumscribed as seminomas. They are also generally smaller,
with a mean diameter of 2.5 cm . They are soft, reddish tan tumors, commonly with areas of
hemorrhage and necrosis.
Microscopically, embryonal carcinomas are cohesive tumors which most commonly display solid, glandular
and/or papillary architecture. Necrosis is common. Tumor cells do not have distinguishable cell
borders, in contrast to seminoma. Cytoplasm is amphophilic and nuclei are large and irregular, often
with large, prominent nucleoli. The tumor cells are so crowded that nuclei appear to overlap in paraffin
sections, and the mitotic rate is very high. Intratubular germ cell neoplasia of the unclassified type
(IGCNU) is commonly associated with embryonal carcinoma; it displays PLAP, c-kit and OCT-4 staining.
Intratubular embryonal carcinoma (IEC) may also be present, usually at the periphery of the tumor. IEC
stains with CD30 and OCT-4, but not with c-kit. Staining for CD30 may help identify this lesion .
The cells in IEC differ morphologically from those in IGCNU. Syncytiotrophoblast cells are often present
in embryonal carcinoma.
Vascular invasion is very common in embryonal carcinoma, and embryonal carcinoma is the most common
tumor to invade vessels in mixed germ cell tumors .
Immunohistochemical stains may be helpful in distinguishing embryonal carcinoma from other neoplasms
Embryonal carcinomas do not stain for EMA or CEA. They stain positively for PLAP,
pancytokeratin (AE1/AE3 and CAM 5.2) and CD30. They also stain positively for OCT- 4 (POU5F1), a nuclear
transcription factor expressed in human embryonic and stem cells
and the staining is reliable
with either a monoclonal or a polyclonal antibody. NANOG is a regulator of embryonic stem cell
pluripotency that is downregulated earlier in embryogenesis than OCT-4. Like OCT-4, NANOG is also
expressed in embryonal carcinoma but not in more differentiated germ cell tumors . Some embryonal
carcinomas may display focal AFP positivity which may represent partial transformation to yolk sac tumor.
Syncytiotrophoblast cells stain display hCG staining.
Most embryonal carcinomas contain the [i(12p)]. There is a correlation between the number of copies
of the isochromosome and the aggressiveness of the tumor . The number of copies of this
isochromosome is greater in nonseminomatous germ cell tumors than in seminomas .
Recent studies 
indicate that 12p gain is a functionally significant change that leads to activation of proliferation and
reestablishment/maintenance of stem cell function through activation of key stem cell genes. Some
authors  have shown that deregulated apoptosis may be a factor in the histogenesis of embryonal
carcinoma. Survivin (an inhibitor of apoptosis) is expressed at high levels in undifferentiated
testicular germ cell tumors and in normal testis but not in mature teratomas. Its expression correlates
with the amount of differentiation in testicular germ cell tumors.
Seminomas may be misdiagnosed as embryonal carcinoma, especially if fixation is poor. In contrast to
seminoma, embryonal carcinomas contain cells without clearly defined cell borders and more crowded,
pleomorphic nuclei that tend to overlap in paraffin sections. Embryonal carcinoma lacks the fibrous
septae seen in seminomas. True glandular structures are characteristic of embryonal carcinoma and are
not seen in seminomas. Stains for AE1/AE3 and CD 30
are usually positive in embryonal carcinoma
and negative in seminomas. Both seminoma and embryonal carcinoma stain positively for OCT-4.
Placenta-like alkaline phosphatase is more focal and cytoplasmic in nonseminomatous germ cell tumors than
in seminoma . Some patterns of embryonal carcinoma may simulate yolk sac tumor. Association with
other recognized patterns of yolk sac tumor favors that diagnosis. Embryonal carcinoma has larger, more
pleomorphic cells than yolk sac tumor, and it lacks hyaline globules. AFP staining is only focal in
embryonal carcinoma and more diffuse in yolk sac tumor. On the other hand, CD30 and OCT-4 stain
embryonal carcinoma but not yolk sac tumor. While syncytiotrophoblast cells may occur in embryonal
carcinoma, they are not admixed with the cytotrophoblast cells that are seen in choriocarcinoma. Large
cell lymphomas may be mistaken for embryonal carcinomas. Both may stain with CD30, but positive
pancytokeratin and PLAP stains support the diagnosis of embryonal carcinoma
anaplastic large cell lymphoma of the testis consistently statins with EMA , in contrast to embryonal
Recent data suggest that there is a subgroup of patients with embryonal carcinoma that have a high
proliferation index (Ki67), low apoptosis and low p53 expression associated with a better survival than
patients without this tumor profile , The infrequent identification of embryonal carcinoma in late
recurrences of testicular cancer is most likely reflective of its sensitivity to chemotherapy.
Yolk Sac Tumor
This germ cell tumor, which is though to derive from either seminoma or embryonal carcinoma, displays
patterns reminiscent of the embryonal yolk sac, allantois and extraembryonic mesenchyme. The tumor and
its resemblance to portions of the rat placenta were described initially by Teilum
sac tumors of the testis occur in children, but after puberty yolk sac tumor in the testis is usually a
component of a mixed germ cell tumor. While yolk sac tumor has been reported to occur in 44% of
nonseminomatous germ cell tumors , it is the most frequently overlooked component of these tumors
Careful and thorough sectioning of the testis is necessary to detect small foci of yolk sac
tumor. Some are misdiagnosed as embryonal carcinoma.
Most adult patients present with a painless testicular mass. High levels of AFP correlate with the
presence of yolk sac tumor and are useful in following response to therapy as well as the development of
recurrent disease. However, some yolk sac tumors do not produce AFP, and some embryonal carcinomas can
produce low levels of AFP.
Foci of yolk sac tumor present in mixed germ cell tumor may be characterized on gross examination by
cystic, myxoid and hemorrhagic areas. Several microscopic patterns of yolk sac tumor exist: reticular
(microcystic), festoon (endodermal sinus), papillary, solid, glandular, myxoid, spindle cell,
polyvesicular vitelline, hepatoid and parietal
Some patterns are more common than others, and
some are more commonly seen after chemotherapy. Most primary yolk sac tumors contain more than one
The most common pattern of yolk sac tumor seen in pre-chemotherapy patients is the reticular or
microcystic type. It displays a mesh-like pattern of spaces lined by cells which are smaller than those
seen in embryonal carcinoma. Coalescence of the microcysts results in a macrocystic pattern. Sometimes,
cords of cells are surrounded by myxoid tissue. The endodermal sinus (festoon) pattern is that which was
originally described by Teilum as showing glomeruloid structures resembling the endodermal sinus of the
This tumor variant contains Schiller-Duvall bodies, which consist of papillary
processes containing connective tissue with a blood vessel. These structures, which are covered by a
layer of cuboidal cells, protrude into a cavity that is also lined by typical cells of yolk sac tumor.
Small papillae without the typical glomeruloid pattern may also occur in cystic spaces in papillary yolk
sac tumor. The solid pattern of yolk sac tumor may be seen focally in primary tumors, but it is more
common in postchemotherapy recurrences. It is characterized by solid nests of cells with eosinophilic
cytoplasm and distinct cell borders. It lacks the overlapping, markedly pleomorphic nuclei seen in
embryonal carcinoma and the fibrous septae seen in seminoma. Glandular yolk sac tumor is almost always
seen in conjunction with other histologic patterns of yolk sac tumor. Both enteric and endometrioid
Sometimes, reticular and myxoid patterns of yolk sac tumor give rise to
spindle cell foci that are cytokeratin positive and are thought to resemble the extraembryonic mesenchyme
(so-called "magma reticulare)
of the rat placenta
Cytokeratin positivity supports derivation of
these spindle cell areas from yolk sac tumor. The spindle cell mesenchyme also has the capacity to
differentiate into skeletal muscle and cartilage, indicating a pluripotential nature of this tumor in
some cases . Rarely, cellular and mitotically active spindle cell areas with a sarcomatoid
appearance are seen; these foci also display cytokeratin positivity. The polyvesicular vitteline pattern
of yolk sac tumor is rare in testicular tumors. It displays epithelial-lined cysts with central
constrictions surrounded by spindle or myxoid stroma. Teilum made the analogy with the subdivision of
the primary yolk sac into the secondary yolk sac . Small foci of hepatoid yolk sac tumor contain
polygonal cells with eosinophilic cytoplasm and a central nucleus containing a prominent nucleolus; these
cells resemble hepatocytes and stain positively for AFP. The parietal pattern of yolk sac tumor displays
eosinophilic basement membrane material between tumor cells. The basement membrane material has been
considered analogous to Reichert's membrane in the parietal yolk sac of the rodent
of parietal yolk sac tumor are often seen in nonseminomatous testicular germ cell tumors, but a
predominance of this type of tumor may follow germ cell chemotherapy. Parietal yolk sac tumor may not
produce AFT. Various patterns of yolk sac tumor may contain eosinophilic hyaline globules.
Yolk sac tumors usually stain positively for AFP and cytokeratin. Enteric glands may be CEA positive.
EMA is negative in yolk sac tumors; in metastatic sites this antibody may be useful in distinguishing
glandular yolk sac tumor from adenocarcinoma. In contrast to embryonal carcinoma, yolk sac tumor is CD30
and OCT-4 negative. Adult yolk sac tumors contain the [i(12p)] seen in other germ cell tumors of the
The solid variant of yolk sac tumor may also resemble seminoma. However, it is usually associated in
the testis with other, more recognizable yolk sac tumor variants. It also contains smaller cells that
those seen in seminomas. Edema in seminomas may simulate the reticular variant of yolk sac tumors, but
the resultant cystic areas are irregular and contain desquamated seminoma cells
Yolk sac tumor
does not contain the fibrous septae with lymphocytes that are characteristic of seminoma. Stains for AFP
and AE1/AE3 are positive in yolk sac tumor and negative in seminoma, and OCT-4 is expressed in seminoma
but not in yolk sac tumor .
Solid yolk sac tumor needs to be distinguished from seminoma ; stains
for cytokeratin, AFP and OCT-4 are helpful in this regard. The hyaline globules and basement membrane
material seen in yolk sac tumors are not observed in seminomas. Several yolk sac patterns may be
confused with embryonal carcinoma. Yolk sac tumor does not display the marked nuclear crowding and
extreme nuclear abnormalities seen in embryonal carcinoma. While both may display cytokeratin and APF
staining, CD 30 and OCT-4 decorate embryonal carcinoma but not yolk sac tumor. Glandular variants of
yolk sac tumor are distinguished from teratoma by the absence of other teratomatous elements such as
muscle  and by positive AFP staining in the former.
The presence of yolk sac tumor in a nonseminomatous germ cell tumor limited to the testis may be
associated with a decreased incidence of relapse
whereas significant areas of embryonal
carcinoma indicate more aggressive disease. On the other hand, yolk sac tumor in patients with advanced
stage testicular cancer is associated with a poor prognosis . It appears that yolk sac tumor has
less metastatic potential than embryonal carcinoma, but yolk sac tumor is also less sensitive to germ
cell tumor chemotherapy.
Next to teratoma, yolk sac tumor is the most common type of tumor seen in late recurrences (46% of
patients). Yolk sac tumor also may occur along with other tumor types in late recurrences. The
frequency of yolk sac tumor in late recurrences of testicular GCT may be due to its relative
chemoresistance compared to other types of germ cell neoplasms. Long-term disease-free survival of
patients treated with cisplatin-based chemotherapy for advanced stage testicular cancer containing yolk
sac tumor (33%) is significantly poorer than that for patients whose advanced disease does not contain
yolk sac tumor (65%)
. It is also noteworthy that the frequency of yolk sac tumor at autopsy in
patients who die with testicular germ cell tumors increased significantly after introduction of
cisplatin-based chemotherapy . Since effective chemotherapy eradicates other types of GCTs, the
relatively more chemoresistant yolk sac tumor has a poorer prognosis and may persist after destruction of
more chemosensitive GCT elements. There are genetic differences between early- and late-relapsing yolk
sac tumor, and these differences may be the basis for the more aggressive, chemotherapy-refractile
behavior of the late recurrences of this tumor .
Yolk sac tumor in late recurrences often displays unusual patterns, including glandular, clear cell
and parietal types . In contrast, the microcystic pattern, which is the most common type of yolk sac
tumor in primary testicular tumors, is infrequent in late recurrences. Damjanov et al  described
transformation of microcystic and pseudopapillary yolk sac tumor of the ovary into disseminated,
chemoresistant, parietal yolk sac tumor after cisplatin-based chemotherapy. The change in morphology was
attributed to selective outgrowth of a chemoresistant clone of yolk sac tumor, a hypothesis that is
consistent with the appearance of unusual forms of yolk sac tumor in late recurrences of testicular GCTs.
Familiarity with these variants of yolk sac tumor is important in order to avoid misdiagnosis in patients
with a remote history of testicular GCTs.
Glandular, clear cell, parietal and hepatoid patterns are especially common in late recurrences.
Glandular yolk sac tumor is characterized by glands lined by columnar epithelium with clear cytoplasmic
vacuoles, similar to endometrioid-like yolk sac tumor . Many late recurrences display substantial
solid areas, which may contain numerous clear cells. Hepatoid yolk sac tumor seen in late recurrences
displays polygonal cells with densely eosinophilic cytoplasm and occasional intercellular sinusoids.
Parietal yolk sac tumor is frequently seen in late recurrences; it has eosinophilic basement-membrane
material between nests of cells.
Some late recurrences contain yolk sac tumor with an unusual degree of nuclear pleomorphism. No
festoon or polyvesicular vitteline patterns of yolk sac tumor were identified in a large study of these
All patients reported in the literature
with late recurrences containing tumor besides
teratoma have fared poorly and very few have responded to chemotherapy. A recent study has shown that
alpha-Fetoprotein levels greater than 100 U/l indicate a poor prognosis in late recurrence of germ cell
tumors ; this finding is consistent with the poor prognosis seen in histologically verified yolk sac
tumor late recurrences. Late recurrences should be treated surgically if at all possible.
Choriocarcinoma is characterized by an admixture of malignant syncytiotrophoblast and cytotrophoblast.
Pure testicular choriocarcinoma is very rare . Focal choriocarcinoma is seen in some mixed germ cell
tumors, but it is less common that previously discussed germ cell tumor types. It is associated with hCG
Choriocarcinoma is usually hemorrhagic and necrotic on both gross and microscopic examination. Blood
vessel invasion by tumor is common.
Choriocarcinomas may display patchy PLAP positivity and CEA staining
In contrast to other
germ cell tumors, choriocarcinoma may stain positively for EMA, which is located in the
syncytiotrophoblast cells .
Choriocarcinoma needs to be distinguished from seminoma or embryonal carcinoma containing
synctiotrophoblast cells. The biphasic pattern characteristic of choriocarcinoma is the key to the
correct diagnosis. Syncytiotrophoblast cells in all types of testicular germ cell tumors stain with HCG
and also with epidermal growth factor receptor (EGFR)
Choriocarcinomas disseminate by hematogenous routes and therefore are associated with a poorer
prognosis than that of other germ cell types. Increased amounts of choriocarcinoma in mixed germ cell
tumors correlate with adverse outcome
Teratomas display differentiation toward either mature or immature somatic tissues. They most often
occur as components of mixed germ cell tumors. Even patients with pure testicular teratomas often
develop metastatic disease containing nonteratomatous germ cell tumor elements
the testicular teratoma arises from embryonal carcinoma that metastasizes before differentiating to
teratoma in the testis.
The more primitive precursor may differentiate into teratoma at metastatic sites also, or the teratoma
itself may metastasize. Invasion of vascular spaces by teratoma has been documented . All teratomas
of the adult testis have metastatic potential and represent malignant tumors, regardless of whether they
contain mature or embryonal tissue components . Patients typically present with testicular
enlargement or symptoms related to metastatic disease.
On gross examination, teratomas are usually solid but may have cystic areas. They may contain
keratinous material, mucin and cartilage. Mature teratomas may display any adult type of somatic tissue.
Squamous and glandular mucosa are common. There may be a partial layer of muscle beneath glands so that
structures resembling intestine or bronchi are present. Cartilage and neuroglia are also frequently
identified. Immature teratomas display components of embryonal type tissue, most frequently immature
neuroepithelium. Tubular structures and rosettes may be seen in the immature neural tissue, which is
highly cellular with numerous mitoses. Foci resembling Wilms' tumor and tissue resembling embryonal
rhabdomyoblastic tissue may also be seen. Some testicular teratomas contain somatic malignancies.
Testicular teratomas in adults all have metastatic potential, regardless of whether histologic
components appear mature or immature. They derive from malignant germ cells and represent an end-stage
of differentiation of a malignant tumor .
They contain the [i(12p)] and are associated with
intratubular germ cell neoplasia of the unclassified type. They have shown the same allelic losses as
non-teratomatous components of the same mixed germ cell tumor . They must be distinguished from
dermoid and epidermoid cysts of the testis, which are not associated with intratubular germ cell
neoplasia and represent benign lesions. Metastatic teratoma is treated surgically, with excellent
A recent, large study of the histology of late recurrences  showed that teratoma is the most
common type of tumor in late recurrences (60% of patients), although other types of recurrent tumor are
often present in addition to the teratoma. Patients whose late recurrences contain only teratoma have a
good prognosis, with 79% free of disease at last followup . Cystic trophoblastic tumor, a
postchemotherapy lesion in which cystic spaces are lined by mononucleated trophoblast cells with smudged
nuclei and only rare mitotic figures, behaves like residual teratoma 
Mixed Germ Cell Tumors
Mixed germ cell tumors contain more than one of the tumor types listed above. They represent the
majority of nonseminomatous germ cell tumors
The diagnosis of malignant mixed germ cell tumors
should include a list of its components with the approximate percentage of each germ cell tumor type.
Clinical presentation is the same as that seen for other germ cell tumors.
The gross appearance of these tumors is variable, depending on the germ cell tumor components present.
Microscopic examination may reveal any number and combination of germ cell tumor types. The most common
association of tumor types in mixed germ cell tumors is teratoma with yolk sac tumor . A very rare
component of some mixed germ cell tumors is polyembryoma, which is considered by some authorities to
represent an admixture of yolk sac tumor and embryonal carcinoma
sometimes with associated
Thorough sectioning of these tumors is very important in order to identify all cell types present.
The type of germ cell tumor elements present has some prognostic significance. The presence of
teratoma with embryonal carcinoma is associated with a lower metastatic rate than that seen with
embryonal carcinoma alone . The coexistence of teratoma may indicate a tendency of embryonal
carcinoma to differentiate and therefore be less aggressive in this situation. There is a lower rate of
occult metastases in patients with mixed germ cell tumors that contain a teratomatous component
The presence of yolk sac tumor also is associated with a decreased tendency for these tumors to
metastasize, possibly due to a tendency toward differentiation .
Nongerm Cell Tumors Arising in Patients with Testicular Germ Cell Tumors
Nongerm cell malignant tumors, including various sarcomas, carcinomas, neuroectodermal tumors,
carcinoid tumors and other neoplasms usually seen outside the gonads, may arise from germ cell tumors.
Nongerm cell malignant tumors arise in 3-6 %  of patients with metastatic germ cell tumors, and may
strongly affect disease course in these patients. They are associated with an increased number of
recurrences, decreased relapse-free survival and decreased overall survival . The criterion for
identifying somatic malignancies in germ cell tumors is stromal invasion, which is straightforward in
many epithelial malignancies that invade as irregular, haphazardly arranged nests of cells identical to
invasive patterns in epithelial malignancies elsewhere in the body. However, identification of invasion
in mesenchymal malignancies in germ cell tumors is more difficult because they may be well circumscribed.
A pure nodule of hightly atypical somatic-type cells that overgrows surrounding germ cell tumor elements
and exceeds the size of one-half to one microscopic field seen with a X4 objective is now considered to
represent a nongerm cell tumor
Nongerm cell tumors may be seen in either the primary germ cell tumor or in metastatic sites, but most
have been metastatic at the time of diagnosis . The type and anatomic location of the nongerm cell
tumor are prognostically significant. A primary site in the mediastinum is an adverse prognostic factor
Nongerm cell tumors that are localized to the testis do not affect prognosis beyond that of the
associated germ cell tumor, but somatic malignancies in extratesticular sites are associated with a poor
prognosis . Rhabdomyosarcoma and primitive neuroectodermal tumor arising in germ cell tumors
correlate with adverse outcomes
whereas nephroblastoma-like tumors behave like teratomas
. High cure rates have been demonstrated in patients whose nongerm cell tumors were carcinoma or
nonrhabdomyosarcomatous, nonneural sarcomas .
Most of these tumors arise from teratomas ,
but some may be derived from yolk sac tumor .
Teratoma is the germ cell tumor most commonly associated with nongerm cell tumors
Chemotherapy is not a prerequisite for the development of these tumors because they may be seen in
primary testicular tumors, but destruction of chemotherapy-sensitive germ cell tumor elements may unmask
the nongerm cell tumors and allow them to then dictate the course of disease. Chromosome abnormalities
typical of germ cell tumors [i(12p)] have been identified in these neoplasms, including adenocarcinoma,
primitive neuroectodermal tumor and sarcoma . In addition, chromosomal abnormalities associated with
the somatic malignancies have been seen in cases of rhabdomyosarcoma and primitive neuroectodermal tumor
Kernek et al  studied diverse types of nongerm cell tumors arising in patients with testicular
germ cell malignancies. The nongerm cell tumors included carcinomas and sarcomas. A gain in 12p was
seen in the nongerm cell tumors arising in the setting of testicular germ cell neoplasia, whereas it did
not occur in other somatic malignancies.
Sarcomas in Testicular Germ Cell Tumors
Sarcomas represent the most common type of somatic malignancy associated with testicular germ cell
Most patients have had testicular mixed germ cell tumors, but several cases of
sarcoma associated with spermatocytic seminoma have also been described
Sarcomas in patients with germ cell tumors are generally not apparent on gross examination of
specimens. With the exception of those sarcomas associated with spermatocytic seminoma, most sarcomas
are associated with teratomas, although origin of spindle cell sarcomas from yolk sac tumor has been
proposed in two men with testicular germ cell tumors . A few of these tumors have been localized to
the testis, but most are seen in metastatic sites (either with or without testicular involvement).
About half of these sarcomas are undifferentiated sarcomas. Most of the remainder show striated or
smooth muscle differentiation. Rhabdomyosarcomas contain scattered rhabdomyoblasts with abundant
eosinophilic cytoplasm scattered among small round blue cells with numerous mitoses. Actin and desmin
stains are positive in these tumors. Leiomyosarcomas have spindle-shaped cells with oval nuclei.
Isolated examples of chondrosarcoma, malignant giant cell tumor, malignant fibrous histiocytoma,
malignant peripheral nerve sheath tumor and fibrosarcoma have been reported . While these tumors may
occur in primary testicular neoplasms, most patients (except those with spermatocytic seminoma) have been
treated with cisplatin-based germ cell tumor chemotherapy before the diagnosis of sarcoma. Sarcomas
arising in GCT patients do not respond to germ cell chemotherapy; treatment is predominantly surgical
Carcinomas Arising in Germ Cell Tumors
Carcinomas are among the least common somatic neoplasms to arise from testicular germ cell tumors
Almost all patients have received germ cell tumor chemotherapy before developing carcinoma.
These lesions are not distinguishable on gross examination from metastatic germ cell tumor in
retroperitoneal lymph node dissection specimens. Thorough sectioning is necessary in order to identify
these neoplasms. Adenocarcinomas, squamous carcinomas and neuroendocrine carcinomas have all been
These tumors display the same histologic features that are seen in similar
carcinomas elsewhere in the body. They stain for cytokeratins, EMA and sometimes CEA. Stains for PLAP,
AFP and hCG are negative.
Surgical excision is necessary. The prognosis for these patients is better than that for patients
with rhabdomyosarcoma or primitive neuroectodermal tumor in metastatic germ cell tumors.
Primitive Neuroectodermal Tumors in Patients with Testicular Germ Cell Tumors
In the previous decade, the occurrence of primitive neuroectodermal tumors (PNETs) in a number of
patients with testicular germ cell tumors became evident
PNETs may occur in primary
testicular neoplasms, in metastatic sites, or in both primary and metastatic sites. Almost all reported
cases of PNET in the testis have been associated with intratubular or invasive germ cell tumor elements.
Teratoma has been present in the testis in most, but not all cases. Histologically, these tumors may
resemble neuroblastoma, medulloepithelioma, peripheral neuroectodermal tumor or ependymoblastoma. They
are composed of sheets of small round blue cells with enlarged, hyperchromatic nuclei and numerous
mitoses. They may contain rosettes, Homer Wright rosettes and tubules. Immunohistochemical evidence of
neuroendocrine differentiation is helpful in distinguishing these neoplasms from other small round blue
cell tumors. The specific histologic type of the testicular PNET does not correlate with biologic
behavior; about half of the patients in the largest series  developed PNET in extratesticular
locations regardless of the histologic features of the testicular PNET. The most common germ cell tumor
to accompany PNET in metastatic sites is teratoma. PNETs in the setting of a germ cell tumor most likely
arise from teratoma. However, they often grow and metastasize independently of germ cell tumor elements.
Michael et al  reported PNETs that were unaccompanied by GCT elements in at least some anatomic
locations in 12 patients. PNET represented the sole component of all extratesticular disease in 6
patients, supporting the autonomous behaviour of these neoplasms. Fli-1, a marker expressed in Ewing's
sarcoma and primitive neuroectodermal tumors, stained these neoplasms derived from germ cell tumors
relatively weakly and inconsistently in our experience .
The significance of PNET in a testicular germ cell tumor patient is dependent on the location of
disease. PNET limited to the testis does not change prognosis from that of the associated germ cell
tumor. However, PNET in metastatic sites has a very poor prognosis. These tumors do not respond to germ
cell tumor chemotherapy, and treatment is focused on resection. All 19 patients in the largest series
 were either dead of disease, alive with disease, or alive with very short follow-up. Neuroblastoma
chemotherapy along with radiation has been effective in a rare case  with widespread disease.
Additional experience with these rare neoplasms is necessary to determine optimal therapy
Nephroblastoma Associated with Testicular Germ Cell Tumors
It is important to recognize nephroblastoma-like tumors in patients with testicular germ cell tumors
because they have been confused with other neoplasms with different prognostic and therapeutic
implications. We have seen three cases diagnosed as PNET that showed features similar to Wilms' tumor
upon review. Likewise, one case originally thought to represent a nephroblastoma-like tumor was later
reclassified as a PNET, and that patient died shortly after diagnosis.
Nephroblastoma-like tumors are rare in the setting of testicular germ cell tumors. This lesion has
been described in a primary testicular germ cell tumor .
One case  was unassociated with
invasive germ cell tumor elements in the testis, but germ cell origin was established by the concurrence
of intratubular germ cell neoplasia and demonstration of [i(12p)] in the nephroblastoma-like tumor. More
recently, a case of a malignant mixed germ cell tumor of the testis which also contained nephroblastoma
and rhabdomyosarcoma was reported . Loss of heterozygosity was demonstrated at four DNA loci. The
same pattern of allelic loss was demonstrated at all four loci in all of the different components of the
primary tumor and two metastatic teratomas, supporting the germ cell origin of the nephroblastoma
component. Most reported cases of nephroblastoma associated with testicular germ cell tumors have
occurred at metastatic sites .
Nephroblastoma is not evident on gross examination of testicular cancer specimens. Microscopically, a
triphasic pattern similar to that of the classic Wilms' tumor of childhood is apparent, although the
amounts of epithelium, blastema and stroma are variable. Epithelial elements include tubules and
glomeruloid structures. Tubules display clear luminal spaces surrounded by epithelial cells with
parallel nuclei; the nuclear pseudostratification and central fibrillary material seen in PNETs is not
present in nephroblastoma-like tumors. Glomeruloid structures display papillary tufts of epithelial
cells in epithelial lined spaces. Blastema surrounds the epithelial structures and consists of small
round blue cells with scattered mitotic figures. Stroma contains mainly spindle cells resembling
embryonic mesenchyme, but striated muscle may also be a component of the stroma and can be seen in
hematoxylin and eosin-stained slides or with stains for desmin and actin. The absence of staining with
specific neuroendocrine markers (synaptophysin and chromogranin) and HBA.71 is useful in excluding the
possibility of PNET. Immunostains for Fli-1 are negative. Stains for WT-1 may not stain these neoplasms
Most reported cases of nephroblastoma in GCT patients have displayed coexistant teratoma
However, in some cases, the teratoma consisted of only rare glands at the edges of sizeable areas of
nephroblastoma. Teratoma is the most likely source of these tumors, although some may overgrow the
teratoma of origin.
Rare examples of nephroblastoma have occurred in germ cell tumor patients who have not received
chemotherapy, but most have been seen in patients with initial stage II or III disease who received
cisplatin-based chemotherapy before excision of the nephroblastoma. In contrast to the dismal outlook
for patients with PNET, nephroblastoma in germ cell tumor patients has a favorable prognosis. Most
patients reported by Michael et al  were alive without disease with prolonged followup. Surgical
excision appears to be adequate therapy. These tumors appear to have a prognosis similar to that for
Recently, Emerson et al  demonstrated loss of heterozygosity at 11p13, the locus of WT1
inactivation in patients genetically predisposed to nephroblastoma; this loss may be a mechanism for
nephroblastomatous differentiation in germ cell tumors.
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