Case 4 -
Cheryl M. Coffin
Primary Children's Medical Center
University of Utah
Salt Lake City
Click on each slide thumbnail image for an enlarged view
A 13-month old boy developed a left testicular mass over a period of a few weeks. An ultrasound
showed irregularity and vascularity within the mass. Serum alpha-fetoprotein and human chorionic
gonadotropin levels were normal. A CT scan of the chest, abdomen, and retroperitoneum showed no evidence
of malignancy. A left radical orchiectomy was performed, and subsequently the patient underwent inguinal
lymph node biopsy and staging bone marrow biopsies.
Case 4 - Slide 1
Case 4 - Figure 1
The paratesticular ectomesenchymoma shows a proliferation of spindle and polygonal cells in sheets and fascicles.
Case 4 - Figure 2
The spindle cells are embedded in a myxoid and collagenized background and have elongated eosinophilic cytoplasmic extensions.
Case 4 - Figure 3
Mature ganglion cells with eosinophilic cytoplasm are intermingled with spindle cells.
Case 4 - Figure 4
The spindle cells have oval to elongated nuclei with granular chromatin, occasional prominent nucleoli and variable amounts of eosinophilic cytoplasm, with a focal strap-like configuration.
Case 4 - Figure 5
The mature ganglion cells are intermingled with spindle cells and in some areas the background resembles neuropil.
Case 4 - Figure 6 - MYOGENIN
Diffuse nuclear reactivity for myogenin is present in areas of rhabdomyoblastic differentiation.
Case 4 - Figure 7 - DESMIN
Diffuse cytoplasmic reactivity for desmin is present in areas of rhabdomyoblastic differentiation.
Case 4 - Figure 8 - SYNAPTOPHYSIN
Cytoplasmic reactivity for synaptophysin is present in ganglion cells N
The radical orchiectomy specimen weighed 11 g and contained a testicle measuring 3.7 x 2.7 x 2.5 cm
with an attached spermatic cord measuring 3.5 cm in length and 0.5 cm in diameter. Sectioning revealed a
firm, fibrous, white-tan paratesticular mass that compressed the adjacent testis and did not involve the
epididymis or spermatic cord.
The paratesticular mass was composed predominantly of spindle cells intermingled with numerous large
ganglion cells. The spindle cells were arranged in sheets and bundles and contained variable amounts of
eosinophilic cytoplasm. The vesicular nuclei had fine chromatin and occasional prominent nucleoli, with
some variability in nuclear size and staining. Mitoses were present, with a mitotic rate of
approximately 18 per 10 high power fields. No zonal areas of necrosis were identified. In some areas
the spindle cell proliferation was accompanied by an inflammatory infiltrate of lymphocytes, plasma
cells, and occasional eosinophils. Occasional spindle cells had brightly eosinophilic cytoplasm with a
strap-like configuration. Mature ganglion cells were irregularly dispersed throughout the lesion and had
vesicular nuclei with a prominent nucleolus and amphophilic cytoplasm with variable amounts of Nissl
substance. Occasional multinucleated ganglion cells were seen, and in some areas the ganglion cells were
accompanied by spindle cells with delicate eosinophilic cytoplasm and buckled wavy nuclei with a neural
or schwannian appearance. No immature neuroblasts or areas with an alveolar architecture were
identified. In some areas the mesenchymal cells appeared less spindled and more plump and round to
polygonal with more hyperchromatic nuclei. The epididymis, vas deferens, pampiniform plexus, and
spermatic cord margin showed no evidence of malignancy. Testicular development was appropriate for age.
The inguinal lymph node and bone marrow showed no evidence of malignancy.
The spindle cells showed strong nuclear reactivity with myogenin and myo-D1 and strong cytoplasmic
reactivity for muscle-specific actin and desmin. The ganglion cells displayed cytoplasmic reactivity for
synaptophysin. An S100 protein stain revealed focal reactivity in areas with a schwannian stromatous
appearance and weak cytoplasmic reactivity in ganglion cells.
Chromosome analysis of tumor tissue with G-banding revealed a karyotype of 46, XY, inv(9)(p11q13).
The inversion of chromosome 9 around the centromere in each metaphase cell was interpreted as a normal
variant in the population, with no clinical significance.
Ectomesenchymoma (biphenotypic sarcoma with spindle cell rhabdomyosarcoma and neural differentiation
with ganglion cells).
This represents an ectomesenchymoma of the paratesticular region. This tumor has also been called
gangliorhabdomyosarcoma in the past. The current case essentially represents a spindle cell embryonal
rhabdomyosarcoma that contains ganglion cells and some schwannian elements. This case was selected to
review the clinicopathologic features of ectomesenchymoma with emphasis on differential diagnosis,
especially with rhabdomyosarcoma, and to discuss the pathologic evaluation of a paratesticular mass in a
Paratesticular masses in pre-pubertal males are uncommon, and clinically a solid scrotal mass in a
child is malignant until proven otherwise and warrants evaluation for both testicular and paratesticular
malignancies. The clinical evaluation prior to surgery includes obtaining serum tumor markers such as
beta human chorionic gonadotropin and alpha-fetoprotein levels and performing imaging studies of the
scrotum. The surgical procedure is usually a radical inguinal orchiectomy, although testis-sparing
surgery can be done for benign lesions. The most frequent paratesticular masses in prepubertal males are
rhabdomyosarcoma and neuroblastoma, but a wide spectrum of benign, intermediate, and malignant tumors can
occur in this region (Table 1).
The pathologic evaluation of a prepubertal paratesticular mass begins with a careful gross examination
of the fresh specimen to gather information that will allow staging according to both TNM and
rhabdomyosarcoma clinical group staging systems. The gross specimen should be weighed and measured and
the type of specimen designated. The length of the spermatic cord, if present, should be measured.
Specific information for documentation of the mass includes its location, size in three dimensions,
appearance of external and cut surfaces, distance from soft tissue margins, and whether it appears solid
or cystic and circumscribed or infiltrative. For radical inguinal orchiectomy specimens, histologic
sampling includes sections of the mass, testis, epididymis, spermatic cord at approximately 1 cm from the
testis and at the proximal cord margin (if any), and soft tissue margins if the tumor appears to be
present at or close to the margin. In prepubertal patients it is important to obtain tissue for
cytogenetic and potential molecular genetic studies, and in some cases material for flow cytometry may be
Ectomesenchymoma has been defined as a malignant neoplasm that usually consists of rhabdomyosarcoma
with a neural component. The name ectomesenchymoma has been used to designate a possible origin from
ectomesenchyme, which is migratory neural clefts tissue that shows mesenchymal differentiation during
embryogenesis. The neural component of most ectomesenchymomas consist of ganglion cells, but schwannian
and neuroblastic elements may also be admixed.
Ectomesenchymoma is a rare tumor that was initially designated as "gangliorhabdomyosarcoma" in a case
report by Holimon and colleagues in 1971. The term ectomesenchymoma was coined in the mid-1970s
following description of additional cases. From then until the early 1990s a variety of case reports and
small series of ectomesenchymoma were published that emphasized the mixed mesenchymal and neuroepithelial
components. In these early reports, a wide spectrum of mesenchymal components were described in addition
to rhabdomyosarcoma, including malignant peripheral nerve sheath tumor, liposarcoma, chondrosarcoma, and
malignant fibrous histiocytoma, and neuroepithelial components included primitive neuroectodermal tumor,
ganglioneuroblastoma, neuroblastoma, and melanocytic proliferations. From the mid-1990s to the present,
the concept of ectomesenchymoma in children has changed because of its clinical and pathologic overlap
with rhabdomyosarcoma and the clinicopathologic differences between ectomesenchymoma in children versus
adults. In 2000, Boue and colleagues published a series of 15 ectomesenchymomas in children from the
Intergroup Rhabdomyosarcoma Study Groups III and IV and reviewed 21 previously published cases. In this
series and in a previous report in 1996 by Mouton and colleagues, the clinical and pathologic overlap
with rhabdomyosarcoma was emphasized, with similarities in age at diagnosis, sex incidence, anatomic
sites, and prognosis. Recently several cases of rhabdomyosarcoma have been reported that show
ganglioneuromatous differentiation following treatment, a phenomenon that further emphasizes the
potentially close relationship between rhabdomyosarcoma and ectomesenchymoma.
Ectomesenchymoma mainly affects infants and young children, with one-third of cases occurring in
infancy and two-thirds in the first five years of life. Some series have suggested a slight male
predominance. The most common sites are the paratesticular region and external genitalia, pelvis and
abdomen, and head and neck. Syndromic associations have not been observed except for one case that
occurred in a patient with linear epidermal nevi. Currently, ectomesenchymomas are treated according to
Intergroup Rhabdomyosarcoma Study Protocols regardless of the neural component. In the past, 50% were
fatal, but with current treatment, the outcome is similar rhabdomyosarcoma, based on the subtype of
rhabdomyosarcoma, anatomic site, and patient age. Among paratesticular ectomesenchymomas, all cases with
followup have been disease free at four years or longer, following diagnosis. Additional potential
favorable prognostic features for ectomesenchymoma includes size less than 10 cm, absence of metastases,
superficial location, and absence of a histologic component of alveolar rhabdomyosarcoma.
Pathologically, ectomesenchymomas range in size from 3 to 18 cm and most are greater than 5 cm in
diameter. The multilobular, thinly encapsulated mass is tan and fleshy, with variable areas of necrosis
and hemorrhage. Some may appear locally infiltrative. Histologically, the rhabdomyosarcomatous
component is usually embryonal, with admixed ganglion cells, ganglioneuroma, or neuroblastoma.
Occasionally areas resembling malignant peripheral nerve sheath tumor are seen. The ganglion cells are
found individually scattered or clustered within the rhabdomyosarcomatous components. Histologic
variants include areas of alveolar rhabdomyosarcoma, foci resembling peripheral primitive neuroectodermal
tumor, and focal anaplasia. Necrosis is variable. The mitotic rate often exceeds 5 per 10 high power
fields. Immunohistochemical analysis reveals muscle markers including myogenin, Myo-D1, desmin, and
muscle-specific actin in the rhabdomyosarcomatous component and synaptophysin, chromogranin, and
neuron-specific enolase in the ganglion cells. When schwannian foci are present, staining for S100
protein may be seen, although rhabdomyosarcomas may also show focal staining with this marker.
Ectomesenchymomas are not reactive for CD99, neurofilament, or cytokeratin. Electron microscopy shows a
combination of skeletal muscle differentiation and variable neural differentiation, including cytoplasmic
processes with microtubules and dense core granules. No specific cytogenetic abnormalities have been
reported for ectomesenchymoma. However, one case of intracranial ectomesenchymoma had a complex
karyotypic abnormality, but without gene fusions associated with alveolar rhabdomyosarcoma or Ewing
sarcoma, and similarities to malignant peripheral nerve sheath tumor was noted with gene expression
microarray analyses. The MYCN amplification status for ectomesenchymoma is unknown.
The differential diagnosis includes rhabdomyosarcoma, Ewing sarcoma/PNET, neuroblastoma, other tumors
with rhabdomyoblastic foci and other tumors that can contain ganglion cells (Table 2). Rare biphenotypic
sarcomas with EWS/Fli-1 gene fusions with or without accompanying PAX 3/FKHR gene fusions have been
reported, and these cases seem to differ histologically from most ectomesenchymomas.
Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. The histologic-prognostic
subtypes have been defined in the International Classification of Rhabdomyosarcoma (Table 3). In
addition to the botryoid, spindle cell, embryonal, and alveolar variants of rhabdomyosarcoma in the
International Classification of Rhabdomyosarcoma, the World Health Organization Classification also
includes pleomorphic rhabdomyosarcoma, which is principally a neoplasm of adulthood. Embryonal
rhabdomyosarcoma most often occurs in the head and neck and genitourinary tract and has a predilection
for the first decade, while alveolar rhabdomyosarcoma has a predilection for the extremities and occurs
most often in the second decade of life. Embryonal rhabdomyosarcoma, not otherwise specified, accounts
for nearly half of rhabdomyosarcomas and displays a range of morphology from primitive mesenchymal cells
to highly differentiated neoplastic muscle cells with rhabdomyoblastic, strap-cell, and myotube
configurations. At the less differentiated end of the spectrum, the cells are fusiform or stellate with
scant cytoplasm and minimal nuclear or cytoplasmic maturation. Botryoid embryonal rhabdomyosarcoma
accounts for 5% of rhabdomyosarcomas and is distinguished by a cambial layer of condensed tumor cells
beneath an epithelial surface, with variable differentiation, cellularity, and degree of myogenesis.
Spindle cell embryonal rhabdomyosarcoma accounts for 3% of rhabdomyosarcomas and consists of elongated
spindle cells with a fascicular, storiform or whorled pattern, and variable collagen between tumor
cells. Alveolar rhabdomyosarcoma accounts for 31% of rhabdomyosarcomas and classically displays
anastomosing fibrovascular septa lined by round tumor cells with fine nuclear chromatin and variable
amounts of myogenic cytoplasm. The solid and microalveolar variants of alveolar rhabdomyosarcoma create
challenges in recognition. Anaplastic features characterized by nuclear cytomegaly, hyperchromasia, and
atypical mitotic figures may be seen in all histologic subtypes of rhabdomyosarcoma and appear to confer
unfavorable prognostic features. Several cases of rhabdomyosarcoma have been reported that have
displayed differentiation to ganglion cells or ganglioneuroma following treatment. These observations
further suggest that ectomesenchymoma may represent a histologic variant of rhabdomyosarcoma with
divergent differentiation, similar to other neoplasms that may display divergent differentiation. The
immunohistochemical profile of rhabdomyosarcoma includes reactivity for myogenin, myo-D1, muscle-specific
actin, and desmin. The most specific and sensitive markers are myogenin and myo-D1, and alveolar
rhabdomyosarcoma tends to display more extensive nuclear staining for these two markers, while embryonal
rhabdomyosarcoma and its variants generally display more focal reactivity. Recently, comparative
expression of specific protein subsets has been reported for rhabdomyosarcoma, with AP-2 beta and
p-cadherin in alveolar rhabdomyosarcoma and EGFR and fibrillin 2 in embryonal rhabdomyosarcoma.
Cytogenetic and molecular genetic abnormalities in rhabdomyosarcomas have been studied extensively (Table
5). Although it was initially thought that nearly all alveolar rhabdomyosarcomas harbored translocations
involving PAX and FKHR genes, it is now recognized that at least 20% of alveolar rhabdomyosarcomas lack
the PAX-FKHR gene fusion. Although a variety of genetic abnormalities have been described for embryonal
rhabdomyosarcoma, a consistent and diagnostically useful genetic abnormality has yet to be identified.
Ewing sarcoma is the second most common childhood soft tissue sarcoma after rhabdomyosarcoma. Ewing
sarcoma/PNET is a member of a family of tumors with EWS gene rearrangements. Pathologically, the round
to ovoid tumor cells with minimal cytoplasm are arranged in sheets, nests, festoons, filigree, or a
trabeculae with or without pseudorosette formation. Histologic variants include spindled, hyalinizing,
sclerosing, clear cell, anaplastic, and adamantinoma-like Ewing sarcoma. Rare cases have been reported
that contain ganglion cells before or after treatment, and in such cases with genetic analysis, the
translocation between chromosomes 11 and 22 has been present. Immunohistochemically Ewing sarcomas are
typically reactive for CD99, Fli-1 (approximately 70% of cases), vimentin, and neuron-specific enolase,
with variable reactivity for synaptophysin, leu-7, and cytokeratin. Occasional cases display desmin
reactivity. The most common translocations in Ewing sarcoma involve t(11;22) with EWS/Fli-1 or t(21;22)
with EWS/ERG. Other rare translocations involving EWS and ETS family genes have been reported. Recently
several cases of childhood sarcomas with morphologic features of Ewing sarcoma, but lacking an EWS gene
rearrangement and containing a t(4;19) with a CIC/DUX4 gene fusion have been reported. The gene fusion
product in these cases includes ETS family genes that might result in the development of Ewing sarcoma
via a different mechanism than the EWS/ETS chimeric tumors.
Neuroblastoma is a tumor of the sympathetic nervous system and is the most common extracranial tumor
of childhood. The pathologic spectrum ranges from undifferentiated neuroblastoma to fully differentiated
ganglioneuroblastoma and is summarized in the International Neuroblastoma Pathology Classification.
Classic neuroblastoma contains abundant, small, undifferentiated, poorly differentiated, and
differentiating neuroblastic cells in varying proportions in a scant schwannian stroma with occasional
cells that demonstrate differentiating toward ganglion cells. Mitoses, karyorrhexis, rosette formation,
neuropil, and ganglion cells are variable. Half of patients are less than 2 years old at initial
diagnosis, and more than 95% of cases occur in the first decade of life. Primary sites include the
adrenal gland in 40% of neuroblastic tumors, followed by the abdominal, thoracic, cervical, and pelvic
sympathetic ganglia. Ganglioneuroblastoma has areas resembling classic neuroblastoma or differentiating
neuroblastoma and also displays a schwannian stroma that occupies more than 50% of the tumor. Two
subtypes of ganglioneuroblastoma have different prognostic significance. Intermixed ganglioneuroblastoma
contains microscopic foci of neuroblastic elements in an expanding schwannian stroma without grossly
visible nodule formation and is a favorable histologic-prognostic subtype. Nodular ganglioneuroblastoma
contains one or more visible neuroblastic nodules, coexisting with either intermixed ganglioneuroblastoma
or ganglioneuroma, and is an unfavorable pathologic prognostic subtype. Ganglioneuroma is the benign and
most differentiated member of the neuroblastic tumor family and consists of mature ganglion cells in a
benign schwannian background with only rare differentiating neuroblasts identified in the maturing
subtype of ganglioneuroma. The immunohistochemical profile of neuroblastoma includes reactivity for
neuron-specific enolase, synaptophysin, chromogranin, leu-7, PGP 9.5, NB84, and other neural antigens.
Neuroblastoma lacks expression of CD99 and muscle markers such as myogenin and myo-D1. Amplification of
the MYCN proto-oncogene is present in more than 25% of neuroblastomas and is a poor prognostic indicator
that correlates with higher stage, lower survival, advancing age, and high mitotic-karyorrhectic index.
Abnormalities of ploidy and deletion of chromosomes 1p and 11q have been reported in neuroblastoma and
are additional prognostic indicators. A biologic and clinical classification of neuroblastoma subdivides
the tumor into low, intermediate, and high-risk groups based on a variety of prognostic indicators.
Other tumors that can occur in the paratesticular region in prepubertal males include malignant
rhabdoid tumor, desmoplastic small round cell tumor, Wilms tumor (either arising in a renal heterotopia
or by extension or metastasis), melanotic neuroectodermal tumor of infancy, giant cell fibroblastoma,
fibrous hamartoma of infancy, angiomyofibroblastoma, and calcifying fibrous pseudotumor. For most of
these lesions, the differential diagnosis with rhabdomyosarcoma and ectomesenchymoma is quite
straightforward based on standard histologic features.
Although ectomesenchymoma is a rare tumor and data is limited, the available information suggests that
childhood ectomesenchymoma that are composed of rhabdomyosarcoma with neuroblastic components may better
be regarded as a variant of rhabdomyosarcoma than as a separate entity.
Take Home Messages
- Paratesticular masses in prepubertal males are
malignant until proven otherwise and preoperative evaluation of serum tumor markers, such beta human
chorionic gonadotropin and alpha-fetoprotein levels is important.
- The pathologic
evaluation of a prepubertal paratesticular mass should be approached with the assumption that the lesion
is malignant and staging information should be obtained, with histologic sampling of the mass, testis,
epididymis, spermatic cord at 1 cm from the testis, and the proximal spermatic cord margin and soft
- The most common sarcomas of childhood and adolescents are
rhabdomyosarcoma, Ewing sarcoma/PNET, synovial sarcoma, and malignant peripheral nerve sheath tumor.
These can usually be distinguished with a combination of conventional histopathology,
immunohistochemistry, and cytogenetic or molecular diagnostic tests.
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