Sarcomas of the Female Genital Tract
Moderator: Dr. Marisa Nucci
Case 3 -
"Peripheral-type" Primitive Neuroectodermal Tumor (PNET) of the
Yoshiki Mikami M.D.
Kyoto University Hospital
A 48-year-old G1P1 female presented with constipation and
abdominal fullness, and was referred to the hospital because of an intrapelvic mass and ascites.
Computed tomography revealed massive ascites and a solid and cystic mass measuring 12x19 cm anteriorly in
the pelvic cavity. Laparotomy disclosed a left ovarian mass invading the retroperitoneum and small
intestine. Disseminated tumors were identified in the omentum and on the peritoneum. Grossly, the tumor
was necrotic and was widely spread.
Case 3 - Slide 1
"Peripheral-type" Primitive Neuroectodermal Tumor (PNET) of the
The tumor measured 14x10x3cm, and was whitish in color.
Microscopically, it was composed of uniform small round cells having vesicular nuclei and scant
cvtoplasm, arranged in solid sheets with occasional abortive or Hormer-Wright rosettes. Marked nuclear
pleomorphism was not identified, but extensive coagulative necrosis was observed in some areas. Mitotic
figures were clearly evident. The neoplastic cells harbored diastase-sensitive PAS-positive glycogen
granules in the cytoplasm. Immunohistochemically, the tumor cells were positive for CD99 (MIC2) with
membranous staining, as well as positive for NCAM (CD56), vimentin, and synaptophysin. Chromogranin A,
alpha-inhibin, cytokeratin (AE1/AE3), EMA, GFAP and desmin were negative.
RT-PCR assay, using RNA extracted from formalin-fixed and paraffin-embedded
tissue blocks and reverse-transcribed into cDNA, demonstrated EWS/FLI-1 chimeric gene transcripts. These
products were sequenced and proven to be made up of EWS exon 7 and FII-1 exon 6.
Ovarian primitive neuroectodermal tumor (PNET), showing morphologic features and
cytogenetic alterations similar to Ewing's sarcoma/PNET family tumors arising in bone and soft tissues,
is a rare neoplasm, and only several cases have hitherto been reported. The "peripheral-type" PNET can
be confused with "central-type" neuroectodermal tumor, in particular its poorly differentiated form such
as primitive neuroectodermal tumor (PNET) of the cerebrum and medulloblastoma of the cerebellum. These
tumors are commonly associated with neuroglial tissue in mature or immature teratoma, and are a
genetically distinct group of tumors.
"Central-type" neuroectodermal tumor of the ovary is defined as a tumor closely resembling neoplasms
of the central nervous system with a similar spectrum of differentiation, ranging from "primitive" and
"anaplastic" tumors to differentiated gliomas . The largest series included 25 cases studied and
reported by Kleinman et al. in 1993, who subdivided ovarian neuroectodermal tumors into three categories:
differentiated, primitive, and anaplastic . The primitive subtype resembled primitive neuroectodermal
tumors of the cerebrum and medulloblastoma arising in the cerebellum. They were typically highly
cellular and composed of small cells with hyperchromatic and round to oval nuclei, and scant cytoplasm in
a background of a varying amount of fine fibrillary matrix. The patients were 24.5 years old on average
About half of the tumors were associated with teratomatous components . They were therefore
thought to arise from neuroglial tissue in mature or immature teratomas, explaining the histogenesis of
neuroectodermal tumor in the ovary. The prognosis was poor in the presence of extraovarian spread, and
approximately 50% of the patients died of the disease within seven months .
In 1998, Kawauchi in Japan reported a case of an ovarian tumor showing features of PNET/Ewing's
sarcoma arising in bone or soft tissues with EWS/FLI-1 chimeric mRNA demonstrated by RT-PCR .
Thereafter, additional two cases of tumors of PNET/Ewing's sarcoma family were reported in the English
The age of the patients in these three single but well-examined cases was 29, 18, and
13 years. Interestingly, Chow demonstrated multiple chromosomal aberrations including deletions of Rb,
ARHI, and FAT, as well as amplification of N-myc, FASL, GITRL, and EGFR . On the other hand,
medulloblastoma and supratentorial PNET show distinct genetic alterations. EWS/FLI-1 fusion gene has
been considered to be essential in tumorigenesis of pPNET. Therefore, pPNET appears to be a rather minor
but distinct entity in the category of ovarian PNET
In other words, primitive or poorly
differentiated forms of neuroectodermal tumor in the ovary include at least two distinct groups of
neoplasms, i.e., "central-type" (cPNET) and "peripheral-type" (pPNET). In the current WHO scheme (2003),
however, these two categories are lumped together under the term neuroectodermal tumor and the
distinction between them is not clear . Since information on the management of ovarian
neuroectodermal tumors is very limited, differences in therapeutic strategies and outcome between
patients with central and peripheral types of tumors remain to be elucidated, although both tumors are
considered to be aggressive. Importantly, recent studies suggest that EWS/FLI1 antagonists have been
found to inhibit cell growth of the tumor of Ewing's sarcoma /PNET family in vitro
the correct diagnosis of pPNET with EWS/FLI1 chimeric gene may become crucial for individualized and
optimal therapeutic strategies.
Although genetic analysis may contribute to establishing the diagnosis, morphologic features of pPNET
are characteristic and triage for genetic study can be achieved by careful morphologic observation with
the aid of immunohistochemistry. cPNET typically shows, as mentioned above, features of medulloblastoma
or supratentorial PNET characterized by primitive cells with scant cytoplasm and hyperchromatic nuclei
with elongated or so-called carrot-shaped morphology and hyperchromasia. On the other hand, pPNET is
composed of a proliferation of cells with rather uniform morphology characterized by small round and
vesicular nuclei with occasional rosette formation. MIC2 (CD99), a transmembrane glycoprotein product of
the MIC2 gene, is commonly expressed in pPNET, whereas negative in cPNET .
The list of differential diagnoses for ovarian pPNET (PNET/Ewing's sarcoma group tumor) is long, and a
variety of small round cell tumors need to be considered before establishing the diagnosis, including
other ovarian neuroectodermal tumors of central-type, anaplastic carcinoma, small cell carcinomas,
intra-abdominal desmoplastic small round cell tumor, endometrial stromal sarcoma, granulosa cell tumor,
malignant lymphoma, and leukemia.
Among the other central type ovarian neuroectodermal tumors, ependymoma, diffuse astrocytoma,
oliogodendroglioma, and neuroblastoma may be considered. Ependymoma, in particular its "cellular" form,
is characterized by perivascular "nuclear-free zones" formed by radiating processes of neoplastic cells
with small round nuclei (perivascular pseudorosette). A "true" ependymal rosette can be seen, and its
surface is lineally delineated by antibodies to epithelial membrane antigen (EMA). Diffuse astrocytoma
can be distinguished by the presence of neoplastic cells with eosinophilic cytoplasm and cell processes
and GFAP-positivity. Oligodendroglioma is characterized by perinuclear halos, delicate arcuate arteries,
calcospherites, and microcysts. Neuroblastoma shows a varying amount of fibrillary matrix and immature
looking cells forming nests encircled by fine fibrovascular septae.
Small cell carcinoma of the ovary is divided into two distinct groups including pulmonary and
hypercalcemic types. The former shows features similar to pulmonary small cell endocrine carcinoma
characterized by cells with hyperchromatic nuclei with molding and DNA streaming resulting in the
so-called Azzopardi effect. This tumor should be distinguished from metastatic small cell carcinoma of
the lung or other organs. The coexistence of other components, such as endometrioid adenocarcinoma or
squamous or mucinous differentiation, indicates the ovarian origin of the tumor. On the other hand,
small cell carcinoma of hypercalcemic type is characterized by younger aged patients, and shows a variety
of features including cystic spaces lined by stratified squamous epithelium and/or mucus cells, and
rhabdoid features. It is notable that hypercalcemia can be absent in the case of morphologically typical
hypercalcemic-type. Immunohistochemically, small cell carcinoma is distinguished from PNET by positivity
for cytokeratin and negative staining for vimentin.
Intra-abdominal desmoplastic small cell tumor rarely affects the ovary of children, and few cases have
been reported. This tumor is characterized by dense fibrous stroma traversing between sheets of small
round cells with scant cytoplasm and hyperchromatic nuclei, and divergent differentiation such as
evidenced by immunoreactivity for epithelial markers (cytokeratin, EMA), WT1, or desmin. The detection
of EWS/WT1 chimeric gene transcripts, resulting from translocation t(11;22)(p13;q12), is diagnostic of
Low-grade endometrial stromal sarcoma (ESS) is a cellular neoplasm composed of a proliferation of
short spindle cells with ovoid nuclei, with arterioles resembling spiral arteries of the endometrium,
imparting a resemblance to endometrial stroma of the proliferative phase. Cellular portions can look
like PNET, but finding the classical features resolves the problem. In addition, CD10
immunohistochemistry is useful.
Granulosa cell tumor (GCT) can be a serious diagnostic concern. From the view of routine practice, it
is a practical approach for the diagnostic pathologist to think first of rather common diagnoses.
Adult-type GCT is a representative blue cell tumor of the ovary, characterized by proliferation of cells
with nuclear grooves, arranged in a microfollicular, macrofollicular, trabecular, insular, or glandular
pattern. Occasionally tumors show diffuse patterns, and in such cases, the characteristic nuclear
morphology is crucial and may resolve the problem. Although commonly the nuclear morphology is uniform,
GCT may show marked nuclear pleomorphism focally. Call-Exner bodies are fluid-filled spaces between
neoplastic cells, and may form a rosette-like structure, which should be distinguished from the true
rosette as seen in PNET. Juvenile-type GCT is composed of cells with rather hyperchromatic nuclei and
abundant cytoplasm, arranged in sheets with or without variably-sized follicles. The nuclei are larger
than those of adult-type GCT and may be very bizarre in appearance. Inhibin immunohistochemistry is an
adjunctive tool for the diagnosis of GCT.
A variety of malignant lymphomas rarely involve the ovary primarily or secondarily. The types of
lymphoma involving the ovary include diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, and
Burkitt lymphoma. Granulocytic sarcoma may be manifested by an ovarian mass, showing proliferation of
immature looking myeloid precursor cells mixed with a varying amount of cells with eosinophilic and
somewhat granular cytoplasm. Immunostaining for CD13, CD33, and myeloperoxidase, is diagnostic.
Finally the diagnosis of small round cell tumor of the ovary is challenging and needs a constellation
of findings including clinical features, gross and microscopic findings, immunophenotype, and/or genetic
abnormalities, combined together. MIC2 (CD99) immunohistochemistry may be contributory in the diagnosis
of PNET, but it should be kept in mind that this marker can be positive in cases of T-lymphoblastic
lymphoma, rhabdomyosarcoma, desmoplastic small round cell tumor, and sex cord-stromal tumors. Therefore,
a use of panel of antibodies is recommended to resolve the problems.
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