Elsevier

Human Pathology

Volume 37, Issue 7, July 2006, Pages 845-853
Human Pathology

Original contribution
Peripheral primitive neuroectodermal tumor/Ewing's sarcoma of the craniospinal vault: case reports and review

https://doi.org/10.1016/j.humpath.2006.02.011Get rights and content

Summary

The peripheral primitive neuroectodermal tumor/Ewing's sarcoma family tumor (pPNET/ESFT) group includes small round cell tumors of the bone, soft tissue, and nerve with morphological attributes of the germinal neuroepithelium. Peripheral PNETs/ESFTs also occur within the craniospinal vault, a region including the central nervous system, the meninges, and the cranial and spinal nerve roots. Gene rearrangements between the EWS gene on chromosome 22q12 and members of the ETS gene family are common in and specific to pPNETs/ESFTs. Another defining characteristic of pPNETs/ESFTs is their membranous expression of the MIC2 gene product. We describe 2 cases of pPNETs within the craniospinal vault. An intradural tumor arising from the nerve roots of the cauda equina was discovered in a 32-year-old man presenting with radiculopathic back pain and lower-extremity weakness. An intracranial pPNET that mimicked a meningioma was found in a 21-year-old man presenting with headache and visual disturbances. MIC2 gene product expression and EWS/ETS gene rearrangement were detected in both case patients. The literature with regard to pPNETs/ESFTs arising within the craniospinal vault is reviewed.

Introduction

The term primitive neuroectodermal tumor (PNET) was first used to describe tumors composed of small, round, and undifferentiated cells resembling germinal or matrix cells of the embryonic neural tube and arising in the central nervous systems (CNSs) of children and young adults [1]. The term central PNET (cPNET) has been used to describe such tumors that arise in the brain or spinal cord [2], [3], [4]. Cerebellar medulloblastoma is the most common and best characterized cPNET. The PNET concept has also been applied to non-CNS tumors of soft tissue, bone, and nerve with morphological attributes of the germinal neuroepithelium. These small round cell tumors have been termed peripheral PNET/Ewing's sarcoma family tumors (pPNETs/ESFTs) and include Ewing's sarcoma of the bone, extraosseous Ewing's sarcoma, pPNET (peripheral neuroepithelioma), and Askin's tumor [5], [6].

Peripheral PNETs/ESFTs most commonly develop in the second decade of life and show a slight male predominance. Typical presenting signs and symptoms of pPNETs include a mass and/or pain at the primary site. Bone pPNETs most often arise in the long bones of the extremities as metaphyseal or diaphyseal lesions. Soft tissue pPNETs are found most commonly in chest wall and paravertebral extradural locations but may also be found in the extremities, the retroperitoneum, and sometimes in association with large peripheral nerves such as the brachial plexus or sciatic nerve. These tumors are highly aggressive and progress rapidly with metastases most commonly to the lung, bone, and bone marrow.

The pPNETs/ESFTs differ in pathogenesis from other small round cell tumors. Gene rearrangements between the EWS gene on chromosome 22q12 and members of the ETS gene family are common in and specific to these tumors [4], [5]. Breakpoints at chromosomes 22q12 and 11q24 consistently occur in these tumors, with a reciprocal translocation t(11;22)(q24;q12) occurring in approximately 80% of cases [7], [8], [9], [10]. This translocation fuses the amino terminal–encoding portion of the EWS gene to the carboxyl-terminal DNA-binding domain encoded by the FLI1 gene, a member of the ETS oncogene family of DNA-binding proteins [11]. A chimeric fusion transcript EWS/FLI1 is produced by this translocation and has been shown to possess increased downstream transcriptional activity compared with that of normal FLI1, with the chimeric protein product capable of transforming NIH 3T3 cells in vitro [12]. Furthermore, antagonism of fusion protein translation by antisense RNA expression results in reduced tumor growth in Ewing tumor cell lines and in nude mice [13], [14], [15]. It is likely that EWS/ETS gene rearrangements are important for the production of the ESFT malignant phenotype.

Another defining characteristic of pPNETs/ESFTs is their expression of the MIC2 gene product. The cell surface glycoprotein CD99 (p30/32), the product of the MIC2 gene, is detected in most pPNET cases, and its expression is highly reliable as a positive marker for this tumor group [16], [17], [18], [19]. CD99 immunopositivity has been detected in other small round cell tumors, but staining patterns in these cases are often cytoplasmic, rather than the distinct membranous staining typical of pPNETs/ESFTs [20]. The presence of the product of the MIC2 gene is thus regarded as a highly sensitive, albeit not entirely specific, immunohistochemical marker for this tumor family [20], [21], [22].

Although traditionally thought to arise in bone, soft tissue, or peripheral nerve, pPNETs/ESFTs also occur within the craniospinal vault, a region including the CNS, the meninges, and the cranial and spinal nerve roots. With our presentation of 2 craniospinal vault pPNET cases and review of the associated literature, we hope to alert pathologists, radiologists, oncologists, and surgeons to the fact that this entity is in the differential diagnosis for tumors arising within this location. Case patient 1 is the fourth report of a translocation-confirmed pPNET arising in an intradural extramedullary location. Case patient 2 is the seventh report of a pPNET arising from the intracranial dura mater with confirmation of tumor identity by demonstration of 11;22 chromosomal translocation.

Section snippets

Case patient 1

A 32-year-old man was referred to the University of Michigan Hospital with a 7-month history of low-back pain with radiation to the hips and posterior thighs. Physical examination revealed mild weakness in plantar flexion, dorsiflexion, and hamstring function in the left leg. Magnetic resonance imaging (MRI) of the spine with gadolinium enhancement revealed an enhancing intradural mass filling the dural sac from levels L2 through L4. An ependymoma was thought to be the most likely diagnosis

Histology and immunophenotypic characterization

Surgical specimens were fixed in 10% formaldehyde, embedded in paraffin, sectioned, and stained with hematoxylin and eosin. Immunostaining was done on a Ventana automated immunostainer using Ventana immunohistochemistry kits (Ventana Medical Systems, Tucson, Ariz). An extensive panel of immunohistochemical stains was performed, including the following antibodies: CD99 (p30/32mic2, 1:10, Dako, North America, Carpinteria, Calif), glial fibrillary acidic protein (1:6400, Dako), synaptophysin

Pathology

Gross visualization of the cauda equina tumor of case patient 1 revealed soft tan-to-brown tissue that measured 2.6 cm × 1.5 cm at its largest diameter. On light microscopy, the tumor showed closely packed uniform small round cells with high nuclear/cytoplasmic ratios and finely dispersed chromatin. Mitotic figures were numerous. Homer-Wright rosettes were uncommon. Areas of necrosis were present. On immunohistochemical analysis, cell surface staining for CD99 was strong and greater than

Discussion

Although pPNETs/ESFTs most commonly arise in the bone or in soft tissues of the trunk or retroperitoneum, they also occur in the craniospinal vault. Craniospinal vault pPNETs originate in the spinal epidural space, in the spinal intradural extramedullary region, and from the intracranial dura mater. The treatment and prognosis of these tumors differ from those of other tumors of the craniospinal vault.

Thirty cases of spinal epidural pPNETs have been described; of these, 22 have been reviewed

Acknowledgments

We wish to thank Ricardo V. Lloyd, MD, PhD, Department of Pathology, Mayo Clinic, Rochester, Minn, for providing the chromogranin A primary antibody.

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