Primitive neuroectodermal tumors of the spine: a comprehensive review with illustrative clinical cases

Full access

Primary spinal primitive neuroectodermal tumors (PNETs) are uncommon malignancies that are increasingly reported in the literature. Spinal PNETs, like their cranial counterparts, are aggressive tumors and patients with these tumors typically have short survival times despite maximal surgery, chemotherapy, and radiation. Because no standard management guidelines exist for treating these tumors, a multitude of therapeutic strategies have been employed with varying success. In this study the authors perform a comprehensive review of the literature on primary spinal PNETs and provide 2 new cases that highlight the salient features of their clinical management.

Abbreviations used in this paper: GTR = gross-total resection; PNET = primitive neuroectodermal tumor; STR = subtotal resection.

Primary spinal primitive neuroectodermal tumors (PNETs) are uncommon malignancies that are increasingly reported in the literature. Spinal PNETs, like their cranial counterparts, are aggressive tumors and patients with these tumors typically have short survival times despite maximal surgery, chemotherapy, and radiation. Because no standard management guidelines exist for treating these tumors, a multitude of therapeutic strategies have been employed with varying success. In this study the authors perform a comprehensive review of the literature on primary spinal PNETs and provide 2 new cases that highlight the salient features of their clinical management.

Primitive neuroectodermal tumors are a heterogeneous group of malignant neoplasms that occur mostly in childhood and early adulthood. Histologically the PNET cells exhibit a primitive, poorly differentiated morphology with varying degrees of pleomorphism and occasional evidence of neuroectodermal differentiation. Primary spinal PNETs represent a small percentage of these tumors. Like all PNETs, they can fall into 1 of 2 categories: CNS PNETs or central PNETs, and Ewing sarcoma/PNETs or peripheral PNETs. Due to the low incidence of these tumors, the available epidemiology is likely unreliable, and there are currently no standard clinical guidelines outlining their management. In addition, the existing literature on primary spinal PNETs consists mostly of case reports with a variety of clinical presentations, management recommendations, and outcomes data indicating a need for further study.

In this paper we present 2 illustrative cases demonstrating the clinical management of patients with primary spinal PNETs followed by a comprehensive review of the literature on these tumors. To our knowledge, our report contains the first account of an acutely presenting hemorrhagic cervical intramedullary PNET. While most authors describe spinal PNETs as “very rare,” we identified 82 cases (including ours) in the literature, 41 more than the highest reported number to date.3,40,43

Case Illustrations

Case 1

Presentation

T his 27-year-old man with no significant medical history presented to the emergency department of a different hospital complaining of rapidly progressive ascending weakness and sensory changes involving the lower extremities, chest, and upper extremities over a period of hours. The patient described new-onset, bilateral, lower extremity numbness starting 9 days prior to his emergency department arrival and mild bilateral lowerextremity weakness and gait instability for 2 days prior to his emergency department arrival. The patient's condition continued to progress and he became quadriplegic with complete sensory and motor loss below the shoulders (C-5) without evidence of cardiopulmonary compromise. An MR image of the spine demonstrated a 1 × 4 cm expansile intramedullary lesion partially obliterating the spinal canal from the C-5 to the C-7 vertebrae (Fig. 1A). The lesion was hypointense on T1-weighted imaging and hyperintense on T2-weighted imaging sequences with minimal contrast enhancement (Fig. 1A–C). Gradient echo MR imaging suggested the presence of blood products within the lesion (Fig. 1D). Ependymoma, astrocytoma, and hemangioblastoma were considered in the differential diagnosis. The patient was urgently transferred to our institution at the request of his family. Upon arrival in our neurological intensive care unit 24 hours after the onset of complete quadriplegia, his physical examination was significant for 0/5 strength in both upper and lower extremities, complete sensory loss below the C-5 dermatome, and absence of all reflexes. He began receiving dexamethasone and underwent preparation for emergency spinal decompression and possible lesion biopsy.

Fig. 1.
Fig. 1.

Preoperative MR imaging in Case 1. A and C: Sagittal (A) and axial (C) T2-weighted images demonstrating a hyperintense cervical intramedullary lesion. B: Sagittal T1-weighted postcontrast image demonstrating a hypointense lesion with a small inferior region of enhancement. D: Axial T2*-weighted gradient echo image demonstrating central cord hypointensity consistent with blood products.

Surgery

Laminectomies of the C-4 to T-1 vertebrae were performed with preservation of the facet joints. The dura was opened in the midline and tented laterally, revealing a grossly expanded cord, particularly marked at the C5–6 levels. Using microsurgical techniques the arachnoid was opened and a midline myelotomy was made extending just rostral and caudal to the expanded cord. The underlying tissue was diffusely hemorrhagic and discolored. The hematoma was allowed to express itself and tissue was sent for pathological analysis. Resection of grossly abnormal tissue was performed while taking care not to disrupt what appeared to be a ventral plane between the hemorrhagic tissue and more normalappearing cord. The patient was successfully extubated and transferred to the neurological intensive care unit.

Pathology

The pathology specimens consisted of sheets and vague groups of the tumor cells in a hemorrhagic background (Fig. 2A). The tumor cells were mainly grouped around vessels without a distinct histoarchitecture (Fig. 2B). Individual cells had a primitive appearance with large, pleomorphic nuclei and scant cytoplasm. Nuclear molding was prominent in several areas. Abundant karyorrhectic debris was present together with the tumor cell aggregates (Fig. 2B). Immunohistochemical stains revealed that a small subset of tumor cells stained positively for glial fibrillary acidic protein and synaptophysin (not shown), suggesting some degree of glial and neuronal differentiation. The tumor cells did not express CD99, a relatively specific marker for Ewing sarcoma/PNET (Fig. 2C). The MIB-1 (Ki 67) proliferation index was approximately 30% to 40% (Fig. 2D). Fluorescence in situ hybridization analysis using the EWSR1 break apart probe did not reveal a chromosome 22q12 rearrangement. These findings are most consistent with a diagnosis of a CNS PNET.

Fig. 2.
Fig. 2.

Photomicrographs obtained in Case 1. A and B: Tissue sections demonstrating primitive cells with scant cytoplasm in a hemorrhagic background. H & E, original magnification × 10 (A), × 40 (B). C and D: Immunoperoxidase stains show that tumor cells are CD99 negative (C) and have a high Ki 67 proliferation index (D). Original magnification × 40.

Postoperative Course

Within hours of being transferred from the operating room to the neurological intensive care unit the patient required reintubation due to respiratory difficulty believed to be secondary to postsurgical cord edema. Further imaging workup did not reveal metastases or other possible primary lesions. A tracheostomy was performed and the patient was subsequently discharged to a skilled nursing facility with quadriplegia (American Spinal Injury Association Grade A) and was ventilator-dependent but otherwise stable. He was treated with 6 cycles of vincristine, cyclophosphamide, carboplatin, and etoposide (COPE). At a follow-up visit 28 months after surgery, the patient remained progression free and stable.

Case 2

Presentation

This 35-year-old man with no significant medical history was first examined in an office consultation for progressive back and leg pain of 6 months duration. The leg pain was radicular in nature and particularly notable around the knees. His back pain was reported to awaken him at night. On physical examination his motor function, sensory function, gait, and reflexes were intact. Magnetic resonance imaging was obtained, which showed a 1.4 × 4.7 cm intradural mass that extended from the level of the T12–L1 intervertebral space to the L1–2 intervertebral space, with the rostral aspect of the mass abutting the conus medullaris. The mass appeared isointense on T1-weighted sequences and moderately hyperintense on T2-weighted sequences (Fig. 3). Contrastenhanced images were not available. Myxopapillary ependymoma and nerve sheath tumor were considered in the differential diagnosis. Elective surgical intervention was recommended with the goal of GTR.

Fig. 3.
Fig. 3.

Preoperative MR imaging in Case 2. A and C: Sagittal (A) and axial (C) T1-weighted images demonstrating a subtle isointense lumbar intraspinal lesion. B and D: Sagittal (B) and axial (D) T2-weighted images demonstrating a slightly hyperintense intradural lesion abutting the conus.

Surgery

Bilateral laminectomies from T-12 to L-2 with preservation of the facet joints were performed. The dura was opened in the midline and tented laterally, exposing the nerve roots of the cauda equina. Using microsurgical techniques, the arachnoid was incised and a dissection plane was identified between the roots of the cauda equina and the tumor. The highly vascular and friable tumor was well circumscribed without a true capsule, but there was intricate association with, and attachment to, the rootlets of the cauda equina. The tumor was internally debulked and the margins carefully delivered into the surgical field. Intricate tumor attachments to the surrounding rootlets were removed piecemeal. A radical resection (but not GTR) was achieved as there remained small tumor remnants inferiorly that could not be safely resected. The patient was extubated and transferred to the recovery unit uneventfully.

Pathology

On microscopic examination the specimen was highly cellular and predominantly arranged in patternless sheets of cells (Fig. 4A and B). Primitive-appearing, medium-sized cells with indistinct cell borders were present. The nuclei of the neoplastic cells were round-to-oval with stippled or compact chromatin and occasional nucleoli. Nuclear molding was evident. Occasional ill-defined rosettelike structures were noted (not shown), resembling Homer-Wright rosettes. Many mitotic figures and karyorrhectic bodies were noted (Fig. 4B). Vast areas of tumor necrosis were observed (not shown). In immunohistochemical preparations the neoplastic cells diffusely and strongly expressed CD99 (Fig. 4C). The neoplastic cells did not express synaptophysin or glial fibrillary acidic protein (not shown). The MIB-1 (Ki 67) proliferation index was 20%–30% (Fig. 4D). Fluorescence in situ hybridization analysis revealed a chromosome 22q12 rearrangement. These findings are consistent with a diagnosis of Ewing sarcoma/PNET.

Fig. 4.
Fig. 4.

Photomicrographs obtained in Case 2. A and B: Tissue sections shows densely packed sheets of primitive appearing cells. H & E. Original magnification × 10 (A), × 40 (B). C and D: Immunoperoxidase stains show strong membranous CD99 immunoreactivity highlighting cell borders (C) and an elevated Ki 67 proliferation index (D). Original magnification × 40.

Postoperative Course

The patient awoke from surgery neurologically intact. His preoperative back pain resolved but his leg pain remained, and he subsequently began receiving gabapentin. Postoperative MR imaging of the spine demonstrated a 9-mm residual nodule at the inferior portion of the resection. Further imaging workup did not reveal metastases or other possible primary lesions. A protocol of focal external beam radiation therapy and chemotherapy was recommended, but the patient returned to his home country and was lost to follow-up approximately 2 months following surgery.

Discussion

History and Classification

Primary spinal PNETs are histologically indistinguishable from other neural axis PNETs. The earliest recognized case report of a spinal PNET is from a paper by Smith et al. published in 1969.87 Their use of the term PNET is problematic, however, because the nomenclature and criteria for diagnosing PNET were not formally introduced until 1973 by Hart and Earle,35 and therefore it is unclear whether or not the tumor they reported actually met the criteria for a PNET. The original classification scheme for PNETs arose from the hypothesis that all tumors of this category share a common progenitor cell. However, in 1993 the WHO determined that this claim could not be substantiated.53,83 The WHO description of PNETs has evolved such that several tumors once included under this nomenclature are now understood as distinct diagnoses, including such notable examples as medulloblastoma, atypical teratoid/rhabdoid tumors, and pineoblastomas.54,55,64 In addition, tumors that exhibit more extensive differentiation are considered to be distinct diagnoses, including neuroblastomas, ganglioneuroblastomas, medulloepitheliomas, and ependymoblastomas.55,64 Similarly, it has been argued that embryonal tumor with abundant neuropil and true rosettes represents a distinct entity as well.21,30,64

Those tumors currently understood as PNETs are further divided into 2 categories: CNS PNETs and Ewing sarcoma/PNETs. They can both be found anywhere along the neural axis. Genetic and immunohistopathological analyses are used to distinguish these 2 subtypes, but the clinical significance of this segregation continues to remain unclear.

Epidemiology

Little reliable information is available on the incidence of primary spinal PNETs.64,85 A recent large series of patients indicates that PNETs represent less than 1% of primary spinal tumors.22 However, whereas primary spinal PNETs are rare, they are perhaps more common than has been previously recognized. Our review of the literature yielded 82 cases (including ours) reported since 1969 (Table 1). Interestingly, the majority of these cases were reported within the last decade, possibly indicating an increased awareness of the diagnosis (Fig. 5). The assertion that primary spinal PNETs are most prevalent in the pediatric and young-adult populations and are observed more commonly in males than in females is supported by our analysis of reported cases.40,45,48 The median age at the time of diagnosis was 24 years (range 0.25–70 years) and there was a nearly 2:1 male sex preponderance (Table 1).

TABLE 1:

Clinical characteristics of reported spinal PNET cases*

Case No.Authors & YearAge (yrs), SexDuration of Symptoms (wks)Survival (mos)PNET Location
1Smith et al., 196924, MNA10intradural-extramedullary
2Kosnik et al., 1978NANA<12NA
3NANA<12NA
4NANA<12intramedullary
5Kepes et al., 198524, MNA18intradural-extramedullary
656, MNAalive at 36intradural-extramedullary
739, MNA42intradural-extramedullary
8Liu et al., 198726, FNAalive at 6extradural
9Sevick et al., 198726, MNA36intradural-extramedullary
10Jaksche et al., 198815, FNA18intramedullary
1126, MNA36intramedullary
12Freyer et al., 19897, MNA20intramedullary
13Ogasawara et al., 199216, F829intramedullary
14McDermott et al., 199447, M7216intradural w/ extradural extension
15Kwon et al., 19960.25, F10.5intramedullary
16Deme et al., 199722, F2.5alive at 15intramedullary
17Hisaoka et al., 199714, M12alive at 3intradural-extramedullary
18Mottl & Koutecky, 1997NA, FNAalive at time of studyNA
19Miller et al., 1997NANANAintramedullary
20NANANAintramedullary
21Meltzer et al., 199825, MNA60intramedullary
22Papadatos et al., 199823, F52alive at 12intradural-extramedullary
23Koot et al., 19982, F3several daysintradural w/ extradural extension
24Dorfmüller et al., 199917, M3alive at 23extradural
2532, M1629intradural w/ extradural extension
26Isotalo et al., 200052, M24alive at 12intradural-extramedullary
27Weil et al., 200121, M24alive at 30intramedullary
28Izycka-Swieszewska et al., 200113, F4alive at 31extradural
29Mawrin et al., 200269, M203intramedullary
30Virani & Jain, 20025, M4alive at 8intramedullary
31Yavuz et al., 200218, F8alive at 25intradural-extramedullary
32Reihani-Kermani & Amizadeh, 200222, F4alive at 9intradural-extramedullary
33Mawrin et al., 200238, MNA18intramedullary
34Albrecht et al., 200329, FNA17intramedullary
35Albrecht et al., 200349, FNA23intradural-extramedullary
36Izycka-Swieszewska et al., 200326, M523intradural-extramedullary
37Harimaya et al., 200312, F0.5732extradural
3810, M1.2822extradural
3930, F614intradural-extramedullary
4014, M12alive at 67intradural-extramedullary
41Aydin et al., 200416, M24alive at 7extradural
42Akyüz et al., 200431, F122intradural-extramedullary
43Kim et al., 200417, M4alive at 4intramedullary
44Weber et al., 200426, M3alive at 16extradural
45Bohn Sarmiento et al., 200537, MNA6intradural-extramedullary
46Kampman et al., 20063, M20.25intramedullary
47Jain et al., 200654, F4NAintramedullary
48De Tommasi et al., 200638, M818intramedullary
49Fabre et al., 200670, M16alive at 12intradural-extramedullary
50Koudelová et al., 200628, FNAalive at 24extradural
51Nutman et al., 200719, F8alive at 24intradural-extramedullary
52Kumar et al., 20079, F8alive at 18possibly intramedullary
538, M20alive at 8intradural w/ extradural extension
5418, M16alive at 6intramedullary
55Perry et al., 200727, M32alive at 72intradural w/ extradural extension
5616, F12alive at 5intradural-extramedullary
57He et al., 20078, F810extradural
58Sahu et al., 200711, MNANAintradural-extramedullary
59Feng et al., 200824, M4alive at 14extradural
60Han et al., 200817, M224intramedullary
6140, F38alive at 8intramedullary
62Musahl et al., 200827, M4alive at 24extradural
63Cai et al., 20083, M46extradural
64Hrabálek et al., 200929, M124intradural-extramedullary
65Theeler et al., 200928, F52alive at 2extradural
66Kiatsoontorn et al., 200925, M2–3alive at 6extradural
67Otero-Rodríguez et al., 20091.58, M24alive at 6intramedullary
68Jingyu et al., 200919, F6.5alive at 10intradural-extramedullary
6946, M0.6alive at 14intradural-extramedullary
7058, M2.1alive at 25extradural
7114, M16alive at 6intradural-extramedullary
72Chang et al., 201015, F4alive at 12extradural
73Alexander et al., 201045, M16alive at 13intradural-extramedullary
74Duan et al., 201024, M1630extradural
7514, MNANAextradural
7626, FNANAextradural
777, MNANAextradural
788, MNANAintradural-extramedullary
7925, MNANAintradural-extramedullary
8034, MNANAextradural
81present study, Case 127, M1.28alive at 28.4intramedullary
82present study, Case 235, M24alive at 2intradural-extramedullary

* NA = not available.

Fig. 5.
Fig. 5.

Distribution of spinal PNET case reports by decade. Since the original description of a spinal PNET in 1969 there has been a steady increase in the number of reports, and since the year 2000 there have been at least 57 reports, the most in any decade.

Genetics

Much of the revision of the classification schema for PNETs has resulted from advances in their genetic characterization. It is important to note that there is currently no known genetic distinction between cranial/supratentorial PNETs and spinal PNETs; thus genetic analyses from intracranial PNETs may also inform our understanding of spinal PNETs.64 This idea is supported by the fact that both CNS PNETs and Ewing sarcoma/PNETs can each be found either intracranially or intraspinally. Thus, anatomical location cannot be used to distinguish PNETs.

Cytogenetic analysis of CNS PNETs has revealed several notable alterations. These include RASSF1A promoter methylation, expression of the Neuro D family of basic helix-loop-helix transcription factors (bHLH), and expression of achaete scute, a transcription factor with homology to Neuro D.64 Using fluorescence in situ hybridization analysis of 30 patients with PNETs, Behdad and Perry7 identified several MYC gene amplifications, including MYCN and MYCC, and found that polysomies of chromosomes 2 and 8 are significant prognostic indicators of poor survival in adult patients with PNET. In addition, the NOTCH1 gene, neuroglial differentiation gene SOX2, and the bHLH suppressor gene ID1 have been shown to be upregulated in supratentorial PNETs.80 Several studies have demonstrated that chromosomal deletions at 16p and 19p are common in CNS PNETs.12,41 Interestingly, CNS PNETs generally lack the i(17)q abnormality present in 30%–50% of medulloblastoma specimens, a feature greatly responsible for their reclassification into distinct entities.29,55,64

Ewing sarcoma/PNETs demonstrate the characteristic translocation (11;22) (q24;q12) in more than 90% of cases.6,15,67 Most commonly, this involves a rearrangement of the EWS and FL1 genes (85%) or EWS and ERG genes (10%).6,16,88,98 The presence of an (11;22) (q24;q12) translocation is therefore the strongest diagnostic tool in identifying Ewing sarcoma/PNET. The presence of this translocation may be confirmed by either fluorescence in situ hybridization or reverse transcription polymerase chain reaction. Upregulation of the MIC2 gene, which encodes the surface protein CD99, is also usually present in Ewing sarcoma/PNETs and is another useful diagnostic indicator. The membrane proteins HNK1 and CAV1 have been implicated in Ewing sarcoma/PNET as well.62

Histopathology and Immunohistochemistry

Central nervous system PNETs are generally characterized by poorly differentiated, often densely packed cells with high nuclear-to-cytoplasmic ratios.64 Both nuclear pleomorphism and molding are often observed, as demonstrated in Case 1. Individual cells may exhibit differentiation along neuronal, astrocytic, or ependymal lineages with corresponding nuclear and cytoplasmic features. Tumor cells can be arranged in a number of patterns, including parallel streams, palisades, and/or single file. Homer-Wright rosettes are often present, but not definitive. Degenerate regions usually show calcification and many tumors demonstrate vascular-endothelial proliferation.

Electron microscopy of CNS PNETs often reveals scant cytoplasmic organelles and reflects individual lineage differentiation. Compact arrays of cytoplasmic glial filaments suggest glial differentiation, while the presence of growth cones would support ganglionic differentiation.

The immunohistochemical profile of CNS PNETs is variable. Cells exhibiting neuronal differentiation express synaptophysin, Class III β-tubulin, and neurofilament protein and have recently been shown to overexpress the oncogenic transcription factor Y-box-binding protein-1.31,93 These cells may also express S100, neuron-specific enolase, and Leu-7 (CD-57).82 Glial fibrillary acidic protein is expressed in tumors with astrocytic differentiation. Mitotic activity is highly variable. In general, intertumor variability is too high to base diagnosis on a single antigen expression pattern.64

Ewing sarcoma/PNETs are histologically characterized by sheets of primitive-appearing cells with thin rims of periodic acid-Schiff positive, diastase-sensitive, glycogen-rich cytoplasm.25 Some degree of cytoplasmic clearing may also be evident. Homer-Wright rosettes are sometimes present. Most tumors stain at least focally with neuronal markers such as synaptophysin and neuron-specific enolase. Cytokeratin stains are usually negative.64

The membrane proteins FLI1, HNK1, and CAV1 are commonly expressed in Ewing sarcoma/PNETs.18,26,27,63,69–71,91 In addition, upregulation of the MIC2 gene in Ewing sarcoma/PNET results in a high degree of expression of the transmembrane glycoprotein CD99. Conversely, CD99 is generally not expressed in CNS PNETs.4,95 In a study of 402 confirmed cases of Ewing sarcoma/PNET, Llombart-Bosch et al.62 found that 99% expressed CD99 either focally or globally. However, MIC2/CD99 is also highly expressed in a number of other tumors including ependymomas, low-grade astrocytomas, glioblastomas, choroid plexus carcinomas, and rarely, in CNS PNETs.14,32,36,64,89,95 Thus, while CD99 immunopositivity can be useful in differentiating CNS PNETs and Ewing sarcoma/PNET, it is not specific. The presence of an (11;22) (q24;q12) translocation is necessary for definitive diagnosis.

Clinical Presentation

As demonstrated by our 2 case illustrations, the clinical presentation of spinal PNETs is variable. The development of pain, paresthesias, weakness, or incontinence over several weeks to months is nonspecific but commonly observed (Table 1). Conversely, intratumoral hemorrhage resulting in acute neurological decline, such as that observed in our first case, has not been previously reported. Our second case represents a more typical subacute presentation.

Radiographic Findings

The radiographic findings of spinal PNETs vary from patient to patient and are generally not helpful in differentiating them from other primary spinal lesions such as ependymoma or astrocytoma. Magnetic resonance imaging with and without Gd contrast is the imaging modality of choice in detecting spinal PNETs. As demonstrated by our reported cases, spinal PNETs are typically hypo-to isointense on T1-weighted MR imaging and iso-to hyperintense on T2-weighted imaging. There is often minimal contrast enhancement and, less frequently, the appearance of cystic regions. Fluorine-18–labeled fluorodeoxyglucose PET-CT is another useful adjunct in guiding the management of patients with these tumors; in particular, it can be helpful in detecting metastatic disease and tumor progression.20,68,94 Determining that the tumor is restricted to the spine is important because spinal PNETs can be metastatic from extraspinal primary lesions at presentation. Conversely, primary spinal PNETs may metastasize extraspinally (Table 2).

TABLE 2:

Disease extent, intervention, and pathological markers*

Case No.Authors & YearExtraspinal MetastasesOpChemotherapy AgentsRadiationCD99t(11;22)
1Smith et al., 1969lungyesnoneyesNANA
2Kosnik et al., 1978NAresectionmethotrexate, vincristine, lomustine4000–6000 radsNANA
3NAresectionmethotrexate, vincristine, lomustine4000–6000 radsNANA
4lung, bone marrow, lymph node, brainresectionmethotrexate, vincristine, lomustine4000–6000 radsNANA
5Kepes et al., 1985NAyesnoneyesNANA
6NAyesnoneyesNANA
7NAyesnoneyesNANA
8Liu et al., 1987NAyesnoneyesNANA
9Sevick et al., 1987NAyesnoneyesNANA
10Jaksche et al., 1988noneyesmethotrexate, vincristine, lomustine, cisplatincraniospinalNANA
11brainSTRyescraniospinalNANA
12Freyer et al., 1989noneyesyesyesNANA
13Ogasawara et al., 1992brainSTRranimustine, cisplatin, etoposide36 Gy to spine, 20 Gy to brain metastasisNANA
14McDermott et al., 1994nonemin resectionyesyesNANA
15Kwon et al., 1996brainbiopsyvincristine, cisplatin, procarbazine, hydroxyurea, lomustine, cytosine arabinoside, cyclophosphamidenoneNANA
16Deme et al., 1997noneGTRetoposide, carboplatin, iphosphamidecraniospinalNANA
17Hisaoka et al., 1997NAresectionNANA++
18Mottl & Koutecky, 1997nonebiopsyvincristine, carboplatin, cyclophosphamide, etoposide30 GyNANA
19Miller et al., 1997NANANANANANA
20NANANANANANA
21Meltzer et al., 1998brainresectionvincristine, lomustinecraniospinalNANA
22Papadatos et al., 1998noneSTRcyclophosphamide, cisplatinum, etoposide36 Gy w/ 9 Gy boostNANA
23Koot et al., 1998NAyesnoneyesNANA
24Dorfmüller et al., 1999noneGTRvincristine, doxorubicin, ifosfamide, actinomycin D49 Gy hyperfractionated++
25brainGTRcisplatin, vincristine, actinomycin D, ifosfamide, doxorubicincraniospinal++
26Isotalo et al., 2000noneSTRnone38.5 Gy craniospinal, 17.5 Gy to tumor+NA
27Weil et al., 2001noneNANANA++
28Izycka-Swieszewska et al., 2001lungbiopsycarboplatin, epirubicin, etoposide, vincristine, ifosfamide, actinomycin, trofosfamid, idarubicin33 Gy++
29Mawrin et al., 2002noneSTRnone50.4 GyNANA
30Virani & Jain, 2002mediastinalGTRnoneyesNANA
31Yavuz et al., 2002noneSTRvincristine, doxorubicin, cyclophosphamide, ifosfamide, etoposide34 Gy craniospinal, 20 Gy to tumorNANA
32Reihani-Kermani & Amizadeh, 2002noneGTRnonecraniospinalNANA
33Mawrin et al., 2002noneyesyesyesNANA
34Albrecht et al., 2003nonebiopsydoxorubicin, etoposide, cyclophosphamide53.2 Gy total w/ 35.2 Gy boostNA
35Albrecht et al., 2003noneGTRvincristine, cisplatinum50.4 Gy initially, 32.4 Gy to recurrence+NA
36Izycka-Swieszews-ka et al., 2003NASTRnonecraniospinal
37Harimaya et al., 2003mediastinalSTRvincristine, doxorubicin, cyclophospha-mide, actinomycin D, carboplatin, etoposide (w/ autologous stem cell rescue)30 GyNANA
38lungSTRvincristine, doxorubicin, ifosfamide, actinomycin D30 GyNANA
39noneSTRvincristine, doxorubicin, ifosfamide, actinomycin D50 GyNANA
40noneGTRvincristine, doxorubicin, ifosfamide, actinomycin D, carboplatin, etoposide, ifosfamide (w/ autologous stem cell rescue)noneNANA
41Aydin et al., 2004noneGTRvincristine, cyclophosphamide, doxo-rubicinyesNANA
42Akyüz et al., 2004brainSTRvincristine, lomustine, cisplatin, vincristine52.8 Gy hyperfraction-ated+NA
43Kim et al., 2004noneSTRnone50.4 Gy craniospinal+NA
44Weber et al., 2004noneGTRvincristine, ifosfamide, doxorubicin, etoposide, actinomycin, cyclophos-phamide63 CGE fractionated protons to tumor, 36 Gy craniospinal+NA
45Bohn Sarmiento et al., 2005rib cage, liver, lung, spleen, testicles, bone marrowSTRnone30 Gy+NA
46Kampman et al., 2006noneSTRnonenoneNA
47Jain et al., 2006noneSTRnonecraniospinal w/ boost to tumorNA
48De Tommasi et al., 2006nonebiopsyvincristine, chloroethylnitrosourea, cis-platinumnoneNANA
49Fabre et al., 2006noneSTRdoxorubicin, ifosfamide, cisplatin, vin-cristine30 Gy++
50Koudelová et al., 2006NAyesyesyesNANA
51Nutman et al., 2007noneGTRvincristine, cyclophosphamide, carboplatin, thiotepa, etoposide (w/ auto-logous stem cell rescue)craniospinal w/ 9 Gy boost+NA
52Kumar et al., 2007noneSTRyesyesNANA
53noneGTRnonenoneNANA
54nonebiopsyyesyes+NA
55Perry et al., 2007noneGTRcyclophosphamide, doxorubicin, vin-cristine, ifosfamide, etoposide, topo-tecan, temozolomide, thiotepa, car-boplatin (w/ autologous stem cell rescue)45 Gy hyperfractionated+
56noneSTRcyclophosphamide, doxorubicin, vin-cristine, etoposide, ifosfamide45 Gy++
57He et al., 2007lungSTRcyclophosphamide, doxorubicin, vin-cristine50 Gy+NA
58Sahu et al., 2007noneSTRifosfamide, etoposide, cyclophospha-mide, doxorubicin, vincristine, actinomycin D55 Gy fractionated+NA
59Feng et al., 2008noneGTRnone45 Gy hyperfractionated+
60Han et al., 2008NASTRyesyesNANA
61NAGTRyesyesNANA
62Musahl et al., 2008lung, lymph nodeGTRvincristine, doxorubicin, cyclophospha-mideyesNANA
63Cai et al., 2008lungGTRnonenone+NA
64Hrabálek et al., 2009noneSTRvincristine, ifosfamide, doxorubicin, etoposidenone++
65Theeler et al., 2009nonestereotactic biopsyvincristine, cyclophosphamide, doxoru-bicin, ifosfamide, etoposideyes++
66Kiatsoontorn et al., 2009noneGTRifosfamide, cisplatin, etoposide45 Gy fractionated+NA
67Otero-Rodríguez et al., 2009noneSTRcisplatin, carboplatin, etoposide, cyclo-phosphamide, methotrexatenoneNANA
68Jingyu et al., 2009noneSTRcyclophosphamide, temozolomidecraniospinalNANA
69noneGTRvincristine, cyclophosphamide, doxoru-bicinyesNANA
70noneGTRnonenoneNANA
71noneGTRcyclophosphamide, temozolomidecraniospinalNANA
72Chang et al., 2010noneSTRnonenone+NA
73Alexander et al., 2010noneSTRnone54 Gy++
74Duan et al., 2010lungbiopsy (w/ some hemorrhage)vincristine, doxorubicin, cyclophospha-mide50 Gy fractionated+NA
75noneresectionyes35 Gy+NA
76lungresectionyes50 Gy+NA
77noneresectionnone30 Gy+NA
78noneresectionyes30 Gy+NA
79noneresectionyes50 Gy+NA
80noneresectionnonenone+NA
81present study, Case 1noneSTRcyclophosphamide, vincristine, carboplatin, etoposidenone
82present study, Case 2noneSTRnonenone++

* CGE = cobalt gray equivalent; min = minimal; + = positive; − = negative.

Diagnosis

A definitive diagnosis of PNET can only be made after tumor tissue is obtained from a limited biopsy or a radical resection specimen. The specific diagnostic criteria used are as described in the clinical cases and in the section on histopathology. In terms of subtyping, in our first case the diagnosis of CNS PNET was based on characteristic histology, supportive immunohistochemistry revealing a lack of tumor cell CD99 expression, and cytogenetics demonstrating normal chromosomal arrangement. Conversely, in our second case, a Ewing sarcoma/PNET was diagnosed based on characteristic histology, robust tumor cell expression of CD99, and cytogenetic analysis revealing a chromosome 22q12 translocation.

The segregation of primary intraspinal PNETs into their respective subtypes has not been systematic throughout the literature. Of the 82 total cases in our review of the literature, only 16 (19.5%) included chromosome 22 rearrangement analysis while 37 (45.1%) reported on tumor cell expression of CD99 (Table 2). Although it has been suggested that there are differences with regard to the clinical evolution and the optimal medical management of PNET subtypes, there is a paucity of data available in the literature to confirm that this is indeed the case.48,49,75,96 We therefore advocate that all spinal PNET specimens undergo standard subtyping analyses to facilitate advancements in our understanding of these tumors.

Management

From a clinical perspective, there are no standard protocols employed in the management of spinal PNETs. Instead, most treating physicians use empirical and often kitchen-sink type approaches. Furthermore, as the literature on these tumors consists mainly of case reports with short follow-up times, it is difficult to draw conclusions regarding the appropriateness of any single strategy. In general most centers employ surgical biopsy or resection, chemotherapy, and radiation therapy in their treatment protocols.

Surgery

The surgical treatment of spinal PNETs, as with most spinal tumors, is guided by the principles that one should: 1) decompress neural elements to prevent further neurological decline, 2) obtain an adequate tissue sample for pathological examination, and 3) resect as much tumor as can be safely removed. Exposure over the entire rostrocaudal extent of the tumor is generally necessary to accomplish these goals. While a standard laminectomy with preservation of the facet joints is usually performed in adults, laminoplasty may be considered in pediatric patients.

In our review of 82 reported cases, 81 underwent some form of open surgical procedure and 1 underwent stereotactic biopsy (Table 2). Of those cases from which the information could be extracted, GTR was achieved in 35% (20 of 57), STR was achieved in 51% (29 of 57), and biopsy only was achieved in 14% (8 of 57).

Adjuvant Therapy

Evidence of benefit from adjuvant therapy in treating spinal PNETs is anecdotal at best. Nevertheless, both radiation and chemotherapy are commonly used. The optimal radiation strategy, the necessity of full neural axis radiation in the setting of localized disease, and dosing are all controversial topics in the treatment of primary spinal PNETs.94 In the cases we reviewed, 65 (83%) of 78 patients received radiation therapy (Table 2). Total doses ranged from 30 Gy to 60 Gy. Some authors advocate for hyperfractionated radiotherapy, but there is currently no data to suggest any benefit to this strategy.2

Much like the variety of radiation strategies employed, a multitude of chemotherapeutic agents have been advocated for use in patients with spinal PNETs (Table 2). Regimens that combine high-dose chemotherapy and autologous stem cell rescue in addition to surgery and radiation have shown promising results in several reports.75,96

Follow-Up and Prognosis

The prognosis in most cases of spinal PNETs appears to be poor with a median patient survival of 1 to 2 years.48,59 Approximately one-third of patients will exhibit cerebrospinal dissemination of their tumor.39 Extraneural metastases to bone, liver, and cervical lymph nodes have also been reported, thus follow-up with MR imaging and possibly FDG PET scanning are important.8,64

Conclusions

Primary spinal PNETs are devastating malignancies that appear to be more common than has previously been reported. The clinician should give consideration to the possibility of this diagnosis, especially in the setting of a young adult or child with an intraspinal mass. While there are no widely accepted standards for the management of spinal PNETs, we advocate complete resection when possible with the goals of neurological stabilization and obtaining sufficient tissue for accurate diagnosis. This should then be followed by an individualized combination of chemotherapy and/or radiation. As much remains to be learned about these tumors, especially regarding the prognostic implication of PNET subtyping, pathological samples should be analyzed for CD99 immunoreactivity and the (11;22) (q24;q12) translocation. Only by carefully delineating primary intraspinal PNET subtypes, as was completed in the 2 case illustrations we presented, will the clinical differences and optimal management strategies become apparent for these aggressive tumors.

Disclosure

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author contributions to the study and manuscript preparation include the following. Conception and design: Ellis, Moise, Kaiser, McCormick. Acquisition of data: Ellis, Rothrock, McCormick II. Analysis and interpretation of data: Ellis. Drafting the article: Ellis, Rothrock. Critically revising the article: Moise, Tanji, Canoll, Kaiser, McCormick. Reviewed final version of the manuscript and approved it for submission: Kaiser, McCormick.

References

  • 1

    Akyüz MDemiral ANGürer IEUçar TTuncer R: Primary primitive neuro-ectodermal tumor of cauda equina with intracranial seeding. Acta Neurochir (Wien) 146:5255282004

    • Search Google Scholar
    • Export Citation
  • 2

    Albrecht CFWeiss ESchulz-Schaeffer WJAlbrecht TFauser SWickboldt J: Primary intraspinal primitive neuroectodermal tumor: report of two cases and review of the literature. J Neurooncol 61:1131202003

    • Search Google Scholar
    • Export Citation
  • 3

    Alexander HSKoleda CHunn MK: Peripheral Primitive Neuroectodermal Tumour (pPNET) in the cervical spine. J Clin Neurosci 17:2592612010

    • Search Google Scholar
    • Export Citation
  • 4

    Ambros IMAmbros PFStrehl SKovar HGadner HSalzer-Kuntschik M: MIC2 is a specific marker for Ewing's sarcoma and peripheral primitive neuroectodermal tumors. Evidence for a common histogenesis of Ewing's sarcoma and peripheral primitive neuroectodermal tumors from MIC2 expression and specific chromosome aberration. Cancer 67:188618931991

    • Search Google Scholar
    • Export Citation
  • 5

    Aydin MVSen OOzel SKayaselcuk FCaner HAltinors N: Primary primitive neuroectodermal tumor within the spinal epidural space: report of a case and review of the literature. Neurol Res 26:7747772004

    • Search Google Scholar
    • Export Citation
  • 6

    Bailly RABosselut RZucman JCormier FDelattre ORoussel M: DNA-binding and transcriptional activation properties of the EWS-FLI-1 fusion protein resulting from the t(11;22) translocation in Ewing sarcoma. Mol Cell Biol 14:323032411994

    • Search Google Scholar
    • Export Citation
  • 7

    Behdad APerry A: Central nervous system primitive neuroectodermal tumors: a clinicopathologic and genetic study of 33 cases. Brain Pathol 20:4414502010

    • Search Google Scholar
    • Export Citation
  • 8

    Bennett JP JrRubinstein LJ: The biological behavior of primary cerebral neuroblastoma: a reappraisal of the clinical course in a series of 70 cases. Ann Neurol 16:21271984

    • Search Google Scholar
    • Export Citation
  • 9

    Bohn Sarmiento UAguiar Bujanda DCamacho Galán RRivero Vera JCAguiar Morales J: Lumbar region intra-spinal primitive neuroectodermal tumour (PNET) combined with neurofibromatosis type 1. Clin Transl Oncol 7:4644672005

    • Search Google Scholar
    • Export Citation
  • 10

    Cai CZhang QShen CHu X: Primary intraspinal primitive neuroectodermal tumor: a case report and review of literature. J Pediatr Neurosci 3:1541562008

    • Search Google Scholar
    • Export Citation
  • 11

    Chang SITsai MCTsai MD: An unusual primitive neuroectodermal tumor in the thoracic epidural space. J Clin Neurosci 17:2612632010

    • Search Google Scholar
    • Export Citation
  • 12

    Dallas PBTerry PAKees UR: Genomic deletions in cell lines derived from primitive neuroectodermal tumors of the central nervous system. Cancer Genet Cytogenet 159:1051132005

    • Search Google Scholar
    • Export Citation
  • 13

    De Tommasi ADe Tommasi COcchiogrosso GCimmino AParisi MSanguedolce F: Primary intramedullary primitive neuroectodermal tumor (PNET)—case report and review of the literature. Eur J Neurol 13:2402432006

    • Search Google Scholar
    • Export Citation
  • 14

    Dedeurwaerdere FGiannini CSciot RRubin BPPerilongo GBorghi L: Primary peripheral PNET/Ewing's sarcoma of the dura: a clinicopathologic entity distinct from central PNET. Mod Pathol 15:6736782002

    • Search Google Scholar
    • Export Citation
  • 15

    Delattre OZucman JMelot TGarau XSZucker JMLenoir GM: The Ewing family of tumors—a subgroup of smallround-cell tumors defined by specific chimeric transcripts. N Engl J Med 331:2942991994

    • Search Google Scholar
    • Export Citation
  • 16

    Delattre OZucman JPlougastel BDesmaze CMelot TPeter M: Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature 359:1621651992

    • Search Google Scholar
    • Export Citation
  • 17

    Deme SAng LCSkaf GRowed DW: Primary intramedullary primitive neuroectodermal tumor of the spinal cord: case report and review of the literature. Neurosurgery 41:141714201997

    • Search Google Scholar
    • Export Citation
  • 18

    Dierick AMRoels HLanglois M: The immunophenotype of Ewing's sarcoma. An immunohistochemical analysis. Pathol Res Pract 189:26321993

    • Search Google Scholar
    • Export Citation
  • 19

    Dorfmüller GWürtz FGUmschaden HWKleinert RAmbros PF: Intraspinal primitive neuroectodermal tumour: report of two cases and review of the literature. Acta Neurochir (Wien) 141:116911751999

    • Search Google Scholar
    • Export Citation
  • 20

    Duan XHBan XHLiu BZhong XMGuo RMZhang F: Intraspinal primitive neuroectodermal tumor: imaging findings in six cases. Eur J Radiol [epub ahead of print]2010

    • Search Google Scholar
    • Export Citation
  • 21

    Eberhart CGBrat DJCohen KJBurger PC: Pediatric neuroblastic brain tumors containing abundant neuropil and true rosettes. Pediatr Dev Pathol 3:3463522000

    • Search Google Scholar
    • Export Citation
  • 22

    Engelhard HHVillano JLPorter KRStewart AKBarua MBarker FG II: Clinical presentation, histology, and treatment in 430 patients with primary tumors of the spinal cord, spinal meninges, or cauda equina. Clinical article. J Neurosurg Spine 13:67772010

    • Search Google Scholar
    • Export Citation
  • 23

    Fabre EGuillevin RChretien FLe Guerinel CDuffau H: Peripheral primitive neuroectodermal tumor of the cauda equina in an elderly patient. Case report. J Neurosurg Spine 5:68712006

    • Search Google Scholar
    • Export Citation
  • 24

    Feng JFLiang YMBao YHPan YHJiang JY: Multiple primary primitive neuroectodermal tumours within the spinal epidural space with non-concurrent onset. J Int Med Res 36:3663702008

    • Search Google Scholar
    • Export Citation
  • 25

    Fletcher CDMUnni KKMertens F: World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Soft Tissue and Bone LyonIARC Press2002

    • Search Google Scholar
    • Export Citation
  • 26

    Folpe ALGoldblum JRRubin BPShehata BMLiu WDei Tos AP: Morphologic and immunophenotypic diversity in Ewing family tumors: a study of 66 genetically confirmed cases. Am J Surg Pathol 29:102510332005

    • Search Google Scholar
    • Export Citation
  • 27

    Folpe ALHill CEParham DMO'Shea PAWeiss SW: Immunohistochemical detection of FLI-1 protein expression: a study of 132 round cell tumors with emphasis on CD99-positive mimics of Ewing's sarcoma/primitive neuroectodermal tumor. Am J Surg Pathol 24:165716622000

    • Search Google Scholar
    • Export Citation
  • 28

    Freyer DRHutchinson RJMcKeever PE: Primary primitive neuroectodermal tumor of the spinal cord associated with neural tube defect. Pediatr Neurosci 15:1811871989

    • Search Google Scholar
    • Export Citation
  • 29

    Frühwald MCO'Dorisio MSDai ZRush LJKrahe RSmiraglia DJ: Aberrant hypermethylation of the major breakpoint cluster region in 17p11.2 in medulloblastomas but not supratentorial PNETs. Genes Chromosomes Cancer 30:38472001

    • Search Google Scholar
    • Export Citation
  • 30

    Gessi MGiangaspero FLauriola LGardiman MScheithauer BWHalliday W: Embryonal tumors with abundant neuropil and true rosettes: a distinctive CNS primitive neuroectodermal tumor. Am J Surg Pathol 33:2112172009

    • Search Google Scholar
    • Export Citation
  • 31

    Gould VERorke LBJansson DSMolenaar WMTrojanowski JQLee VM: Primitive neuroectodermal tumors of the central nervous system express neuroendocrine markers and may express all classes of intermediate filaments. Hum Pathol 21:2452521990

    • Search Google Scholar
    • Export Citation
  • 32

    Gyure KAPrayson RAEstes ML: Extracerebellar primitive neuroectodermal tumors: a clinicopathologic study with bcl-2 and CD99 immunohistochemistry. Ann Diagn Pathol 3:2762801999

    • Search Google Scholar
    • Export Citation
  • 33

    Han IHKuh SUChin DKKim KSJin BHCho YE: Surgical treatment of primary spinal tumors in the conus medullaris. J Korean Neurosurg Soc 44:72772008

    • Search Google Scholar
    • Export Citation
  • 34

    Harimaya KOda YMatsuda STanaka KChuman HIwamoto Y: Primitive neuroectodermal tumor and extraskeletal Ewing sarcoma arising primarily around the spinal column: report of four cases and a review of the literature. Spine 28:E408E4122003

    • Search Google Scholar
    • Export Citation
  • 35

    Hart MNEarle KM: Primitive neuroectodermal tumors of the brain in children. Cancer 32:8908971973

  • 36

    Hasegawa SLDavison JMRutten AFletcher JAFletcher CD: Primary cutaneous Ewing's sarcoma: immunophenotypic and molecular cytogenetic evaluation of five cases. Am J Surg Pathol 22:3103181998

    • Search Google Scholar
    • Export Citation
  • 37

    He SSZhao JHan KWHou TSHussain NZhang SM: Primitive neuroectodermal tumor of lumbar spine: case report. Chin Med J (Engl) 120:8448462007

    • Search Google Scholar
    • Export Citation
  • 38

    Hisaoka MHashimoto HMurao T: Peripheral primitive neuroectodermal tumour with ganglioneuroma-like areas arising in the cauda equina. Virchows Arch 431:3653691997

    • Search Google Scholar
    • Export Citation
  • 39

    Horten BCRubinstein LJ: Primary cerebral neuroblastoma. A clinicopathological study of 35 cases. Brain 99:7357561976

  • 40

    Hrabálek LKalita OSvebisova HEhrmann J JrHajduch MTrojanec R: Dumbbell-shaped peripheral primitive neuroectodermal tumor of the spine—case report and review of the literature. J Neurooncol 92:2112172009

    • Search Google Scholar
    • Export Citation
  • 41

    Inda MMPerot CGuillaud-Bataille MDanglot GRey JABello MJ: Genetic heterogeneity in supratentorial and infratentorial primitive neuroectodermal tumours of the central nervous system. Histopathology 47:6316372005

    • Search Google Scholar
    • Export Citation
  • 42

    Isotalo PAAgbi CDavidson BGirard AVerma SRobertson SJ: Primary primitive neuroectodermal tumor of the cauda equina. Hum Pathol 31:99910012000

    • Search Google Scholar
    • Export Citation
  • 43

    Izycka-Swieszewska EDebiec-Rychter MWasag BWozniak AGasecki DPlata-Nazar K: A unique occurrence of a cerebral atypical teratoid/rhabdoid tumor in an infant and a spinal canal primitive neuroectodermal tumor in her father. J Neurooncol 61:2192252003

    • Search Google Scholar
    • Export Citation
  • 44

    Izycka-Swieszewska EStefanowicz JDebiec-Rychter MRzepko RBorowska-Lehman J: Peripheral primitive neuroectodermal tumor within the spinal epidural space. Neuropathology 21:2182212001

    • Search Google Scholar
    • Export Citation
  • 45

    Jain AJalali RNadkarni TDSharma S: Primary intramedullary primitive neuroectodermal tumor of the cervical spinal cord. Case report. J Neurosurg Spine 4:4975022006

    • Search Google Scholar
    • Export Citation
  • 46

    Jaksche HWöckel WWernert N: Primary spinal medulloblastomas?. Neurosurg Rev 11:2592651988

  • 47

    Jingyu CJinning SHui MHua F: Intraspinal primitive neuroectodermal tumors: report of four cases and review of the literature. Neurol India 57:6616682009

    • Search Google Scholar
    • Export Citation
  • 48

    Kampman WAKros JMDe Jong THLequin MH: Primitive neuroectodermal tumours (PNETs) located in the spinal canal; the relevance of classification as central or peripheral PNET: case report of a primary spinal PNET occurrence with a critical literature review. J Neurooncol 77:65722006

    • Search Google Scholar
    • Export Citation
  • 49

    Kazmi SAPerry APressey JGWellons JCHammers YPalmer CA: Primary Ewing sarcoma of the brain: a case report and literature review. Diagn Mol Pathol 16:1081112007

    • Search Google Scholar
    • Export Citation
  • 50

    Kepes JJBelton KRoessmann UKetcherside WJ: Primitive neuroectodermal tumors of the cauda equina in adults with no detectable primary intracranial neoplasm—three case studies. Clin Neuropathol 4:1111985

    • Search Google Scholar
    • Export Citation
  • 51

    Kiatsoontorn KTakami TIchinose TChokyu ITsuyuguchi NOhsawa M: Primary epidural peripheral primitive neuroectodermal tumor of the thoracic spine. Neurol Med Chir (Tokyo) 49:5425452009

    • Search Google Scholar
    • Export Citation
  • 52

    Kim YWJin BHKim TSCho YE: Primary intraspinal primitive neuroectodermal tumor at conus medullaris. Yonsei Med J 45:5335382004

    • Search Google Scholar
    • Export Citation
  • 53

    Kleihues PBurger PCScheithauer BW: The new WHO classification of brain tumours. Brain Pathol 3:2552681993

  • 54

    Kleihues PCavenee WK: World Health Organization Classification of Tumours: Pathology & Genetics: Tumours of the Nervous System LyonIARC Press1997

    • Search Google Scholar
    • Export Citation
  • 55

    Kleihues PCavenee WK: World Health Organization Classification of Tumours: Pathology & Genetics: Tumours of the Nervous System ed 2LyonIARC Press2000

    • Search Google Scholar
    • Export Citation
  • 56

    Koot RWHenneveld HTAlbrecht KW: [Two children with unusual causes of torticollis: primitive neuroectodermal tumor and Grisel's syndrome.]. Ned Tijdschr Geneeskd 142:103010331998. (Dutch)

    • Search Google Scholar
    • Export Citation
  • 57

    Kosnik EJBoesel CPBay JSayers MP: Primitive neuroectodermal tumors of the central nervous system in children. J Neurosurg 48:7417461978

    • Search Google Scholar
    • Export Citation
  • 58

    Koudelová JKunesová MKoudela K JrMatejka JNovák PPrausová J: [Peripheral primitive neuroectodermal tumor—PNET.]. Acta Chir Orthop Traumatol Cech 73:39442006. (Czech)

    • Search Google Scholar
    • Export Citation
  • 59

    Kumar RReddy SJWani AAPal L: Primary spinal primitive neuroectodermal tumor: case series and review of the literature. Pediatr Neurosurg 43:162007

    • Search Google Scholar
    • Export Citation
  • 60

    Kwon OKWang KCKim CJKim IOChi JGCho BK: Primary intramedullary spinal cord primitive neuroectodermal tumor with intracranial seeding in an infant. Childs Nerv Syst 12:6336361996

    • Search Google Scholar
    • Export Citation
  • 61

    Liu HMYang WCGarcia RLNoh JMMalhotra VLeeds NE: Intraspinal primitive neuroectodermal tumor arising from the sacral spinal nerve root. J Comput Tomogr 11:3503541987

    • Search Google Scholar
    • Export Citation
  • 62

    Llombart-Bosch AMachado INavarro SBertoni FBacchini PAlberghini M: Histological heterogeneity of Ewing's sarcoma/PNET: an immunohistochemical analysis of 415 genetically confirmed cases with clinical support. Virchows Arch 455:3974112009

    • Search Google Scholar
    • Export Citation
  • 63

    Llombart-Bosch ANavarro S: Immunohistochemical detection of EWS and FLI-1 proteins in Ewing sarcoma and primitive neuroectodermal tumors: comparative analysis with CD99 (MIC-2) expression. Appl Immunohistochem Mol Morphol 9:2552602001

    • Search Google Scholar
    • Export Citation
  • 64

    Louis DNOhgaki HWiestler ODCavenee WK: WHO Classification of Tumours of the Central Nervous System ed 4LyonIARC2007. 1:

  • 65

    Mawrin CSynowitz HJKirches EKutz EDietzmann KWeis S: Primary primitive neuroectodermal tumor of the spinal cord: case report and review of the literature. Clin Neurol Neurosurg 104:36402002

    • Search Google Scholar
    • Export Citation
  • 66

    McDermott VGel-Jabbour JNSellar RJBell J: Primitive neuroectodermal tumour of the cauda equina. Neuroradiology 36:2282301994

  • 67

    Meier VSKühne TJundt GGudat F: Molecular diagnosis of Ewing tumors: improved detection of EWS-FLI-1 and EWSERG chimeric transcripts and rapid determination of exon combinations. Diagn Mol Pathol 7:29351998

    • Search Google Scholar
    • Export Citation
  • 68

    Meltzer CCTownsend DWKottapally SJadali F: FDG imaging of spinal cord primitive neuroectodermal tumor. J Nucl Med 39:120712091998

    • Search Google Scholar
    • Export Citation
  • 69

    Mhawech-Fauceglia PHerrmann FPenetrante RBeck ASait SBlock AM: Diagnostic utility of FLI-1 monoclonal antibody and dual-colour, break-apart probe fluorescence in situ (FISH) analysis in Ewing's sarcoma/primitive neuroectodermal tumour (EWS/PNET). A comparative study with CD99 and FLI-1 polyclonal antibodies. Histopathology 49:5695752006

    • Search Google Scholar
    • Export Citation
  • 70

    Michels SSwanson PERobb JAWick MR: Leu-7 in small cell neoplasms. An immunohistochemical study with ultrastructural correlations. Cancer 60:295829641987

    • Search Google Scholar
    • Export Citation
  • 71

    Miettinen MChatten JPaetau AStevenson A: Monoclonal antibody NB84 in the differential diagnosis of neuroblastoma and other small round cell tumors. Am J Surg Pathol 22:3273321998

    • Search Google Scholar
    • Export Citation
  • 72

    Miller DCRorke LBWeinberg JAllen JCEpstein FJ: Histopathologic diagnoses of intramedullary spinal cord tumors in children. J Neuropathol Exp Neurol 56:6071997. (Abstract)

    • Search Google Scholar
    • Export Citation
  • 73

    Mottl HKoutecky J: Treatment of spinal cord tumors in children. Med Pediatr Oncol 29:2932951997

  • 74

    Musahl VRihn JAFumich FEKang JD: Sacral intraspinal extradural primitive neuroectodermal tumor. Spine J 8:102410292008

  • 75

    Nutman APostovsky SZaidman IElhasid RVlodavsky EKreiss Y: Primary intraspinal primitive neuroectodermal tumor treated with autologous stem cell transplantation: case report and review of the literature. Pediatr Hematol Oncol 24:53612007

    • Search Google Scholar
    • Export Citation
  • 76

    Ogasawara HKiya KKurisu KMuttaqin ZUozumi TSugiyama K: Intracranial metastasis from a spinal cord primitive neuroectodermal tumor: case report. Surg Neurol 37:3073121992

    • Search Google Scholar
    • Export Citation
  • 77

    Otero-Rodríguez AHinojosa JEsparza JMunoz MJIglesias SRodríguez-Gil Y: Purely intramedullary spinal cord primitive neuroectodermal tumor: case report and review of the literature. Neurocirugia (Astur) 20:3813872009

    • Search Google Scholar
    • Export Citation
  • 78

    Papadatos DAlbrecht SMohr Gdel Carpio-O'Donovan R: Exophytic primitive neuroectodermal tumor of the spinal cord. AJNR Am J Neuroradiol 19:7877891998

    • Search Google Scholar
    • Export Citation
  • 79

    Perry RGonzales IFinlay JZacharoulis S: Primary peripheral primitive neuroectodermal tumors of the spinal cord: report of two cases and review of the literature. J Neurooncol 81:2592642007

    • Search Google Scholar
    • Export Citation
  • 80

    Phi JHKim JHEun KMWang KCPark KHChoi SA: Upregulation of SOX2, NOTCH1, and ID1 in supratentorial primitive neuroectodermal tumors: a distinct differentiation pattern from that of medulloblastomas. Clinical article. J Neurosurg Pediatr 5:6086142010

    • Search Google Scholar
    • Export Citation
  • 81

    Reihani-Kermani HAmizadeh B: Primary intraspinal primitive neuroectodermal tumors: report of a case. Arch Iranian Med 5:2622662002

    • Search Google Scholar
    • Export Citation
  • 82

    Rhodes RHCole MTakaoka YRoessmann UCotes EESimon J: Intraventricular cerebral neuroblastoma. Analysis of subtypes and comparison with hemispheric neuroblastoma. Arch Pathol Lab Med 118:8979111994

    • Search Google Scholar
    • Export Citation
  • 83

    Rorke LB: The cerebellar medulloblastoma and its relationship to primitive neuroectodermal tumors. J Neuropathol Exp Neurol 42:1151983

    • Search Google Scholar
    • Export Citation
  • 84

    Sahu JKSeth RKarak AThavaraj VKabra SK: Primitive neuroectodermal tumour presenting as cauda equina syndrome. Indian J Med Paediatr Oncol 28:34372007

    • Search Google Scholar
    • Export Citation
  • 85

    Schellinger KAPropp JMVillano JLMcCarthy BJ: Descriptive epidemiology of primary spinal cord tumors. J Neurooncol 87:1731792008

    • Search Google Scholar
    • Export Citation
  • 86

    Sevick RJJohns RDCurry BJ: Primary spinal primitive neuroectodermal tumor with extraneural metastases. AJNR Am J Neuroradiol 8:115111521987

    • Search Google Scholar
    • Export Citation
  • 87

    Smith DRHardman JMEarle KM: Metastasizing neuroectodermal tumors of the central nervous system. J Neurosurg 31:50581969

  • 88

    Sorensen PHLessnick SLLopez-Terrada DLiu XFTriche TJDenny CT: A second Ewing's sarcoma translocation, t(21;22), fuses the EWS gene to another ETS-family transcription factor, ERG. Nat Genet 6:1461511994

    • Search Google Scholar
    • Export Citation
  • 89

    Stevenson AJChatten JBertoni FMiettinen M: CD99 (p30/32MIC-2) neuroectodermal/Ewing's sarcoma antigen as an immunohistochemical marker: review of more than 600 tumors and the literature experience. Appl Immunohistochem 2:2312401994

    • Search Google Scholar
    • Export Citation
  • 90

    Theeler BJKeylock JYoest SForouhar M: Ewing's sarcoma family tumors mimicking primary central nervous system neoplasms. J Neurol Sci 284:1861892009

    • Search Google Scholar
    • Export Citation
  • 91

    Tirado OMMateo-Lozano SVillar JDettin LELlort AGallego S: Caveolin-1 (CAV1) is a target of EWS/FLI-1 and a key determinant of the oncogenic phenotype and tumorigenicity of Ewing's sarcoma cells. Cancer Res 66:993799472006

    • Search Google Scholar
    • Export Citation
  • 92

    Virani MJJain S: Primary intraspinal primitive neuroectodermal tumor (PNET): a rare occurrence. Neurol India 50:75802002

  • 93

    Wachowiak RThieltges SRawnaq TKaifi JTFiegel HMetzger R: Y-box-binding protein-1 is a potential novel tumour marker for neuroblastoma. Anticancer Res 30:123912422010

    • Search Google Scholar
    • Export Citation
  • 94

    Weber DCRutz HPLomax AJSchneider ULombriser NZenhausern R: First spinal axis segment irradiation with spot-scanning proton beam delivered in the treatment of a lumbar primitive neuroectodermal tumour. Case report and review of the literature. Clin Oncol (R Coll Radiol) 16:3263312004

    • Search Google Scholar
    • Export Citation
  • 95

    Weidner NTjoe J: Immunohistochemical profile of monoclonal antibody O13: antibody that recognizes glycoprotein p30/32MIC2 and is useful in diagnosing Ewing's sarcoma and peripheral neuroepithelioma. Am J Surg Pathol 18:4864941994

    • Search Google Scholar
    • Export Citation
  • 96

    Weil RJZhuang ZPack SKumar SHelman LFuller BG: Intramedullary Ewing sarcoma of the spinal cord: consequences of molecular diagnostics. Case report. J Neurosurg 95:2 Suppl2702752001

    • Search Google Scholar
    • Export Citation
  • 97

    Yavuz AAYaris NYavuz MNSari AReis AKAydin F: Primary intraspinal primitive neuroectodermal tumor: case report of a tumor arising from the sacral spinal nerve root and review of the literature. Am J Clin Oncol 25:1351392002

    • Search Google Scholar
    • Export Citation
  • 98

    Zucman JMelot TDesmaze CGhysdael JPlougastel BPeter M: Combinatorial generation of variable fusion proteins in the Ewing family of tumours. EMBO J 12:448144871993

    • Search Google Scholar
    • Export Citation

If the inline PDF is not rendering correctly, you can download the PDF file here.

Article Information

Address correspondence to: Jason A. Ellis, M.D., Department of Neurological Surgery, Neurological Institute, 710 West 168th Street, New York, New York 10032. email: jae2109@columbia.edu.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Preoperative MR imaging in Case 1. A and C: Sagittal (A) and axial (C) T2-weighted images demonstrating a hyperintense cervical intramedullary lesion. B: Sagittal T1-weighted postcontrast image demonstrating a hypointense lesion with a small inferior region of enhancement. D: Axial T2*-weighted gradient echo image demonstrating central cord hypointensity consistent with blood products.

  • View in gallery

    Photomicrographs obtained in Case 1. A and B: Tissue sections demonstrating primitive cells with scant cytoplasm in a hemorrhagic background. H & E, original magnification × 10 (A), × 40 (B). C and D: Immunoperoxidase stains show that tumor cells are CD99 negative (C) and have a high Ki 67 proliferation index (D). Original magnification × 40.

  • View in gallery

    Preoperative MR imaging in Case 2. A and C: Sagittal (A) and axial (C) T1-weighted images demonstrating a subtle isointense lumbar intraspinal lesion. B and D: Sagittal (B) and axial (D) T2-weighted images demonstrating a slightly hyperintense intradural lesion abutting the conus.

  • View in gallery

    Photomicrographs obtained in Case 2. A and B: Tissue sections shows densely packed sheets of primitive appearing cells. H & E. Original magnification × 10 (A), × 40 (B). C and D: Immunoperoxidase stains show strong membranous CD99 immunoreactivity highlighting cell borders (C) and an elevated Ki 67 proliferation index (D). Original magnification × 40.

  • View in gallery

    Distribution of spinal PNET case reports by decade. Since the original description of a spinal PNET in 1969 there has been a steady increase in the number of reports, and since the year 2000 there have been at least 57 reports, the most in any decade.

References

  • 1

    Akyüz MDemiral ANGürer IEUçar TTuncer R: Primary primitive neuro-ectodermal tumor of cauda equina with intracranial seeding. Acta Neurochir (Wien) 146:5255282004

    • Search Google Scholar
    • Export Citation
  • 2

    Albrecht CFWeiss ESchulz-Schaeffer WJAlbrecht TFauser SWickboldt J: Primary intraspinal primitive neuroectodermal tumor: report of two cases and review of the literature. J Neurooncol 61:1131202003

    • Search Google Scholar
    • Export Citation
  • 3

    Alexander HSKoleda CHunn MK: Peripheral Primitive Neuroectodermal Tumour (pPNET) in the cervical spine. J Clin Neurosci 17:2592612010

    • Search Google Scholar
    • Export Citation
  • 4

    Ambros IMAmbros PFStrehl SKovar HGadner HSalzer-Kuntschik M: MIC2 is a specific marker for Ewing's sarcoma and peripheral primitive neuroectodermal tumors. Evidence for a common histogenesis of Ewing's sarcoma and peripheral primitive neuroectodermal tumors from MIC2 expression and specific chromosome aberration. Cancer 67:188618931991

    • Search Google Scholar
    • Export Citation
  • 5

    Aydin MVSen OOzel SKayaselcuk FCaner HAltinors N: Primary primitive neuroectodermal tumor within the spinal epidural space: report of a case and review of the literature. Neurol Res 26:7747772004

    • Search Google Scholar
    • Export Citation
  • 6

    Bailly RABosselut RZucman JCormier FDelattre ORoussel M: DNA-binding and transcriptional activation properties of the EWS-FLI-1 fusion protein resulting from the t(11;22) translocation in Ewing sarcoma. Mol Cell Biol 14:323032411994

    • Search Google Scholar
    • Export Citation
  • 7

    Behdad APerry A: Central nervous system primitive neuroectodermal tumors: a clinicopathologic and genetic study of 33 cases. Brain Pathol 20:4414502010

    • Search Google Scholar
    • Export Citation
  • 8

    Bennett JP JrRubinstein LJ: The biological behavior of primary cerebral neuroblastoma: a reappraisal of the clinical course in a series of 70 cases. Ann Neurol 16:21271984

    • Search Google Scholar
    • Export Citation
  • 9

    Bohn Sarmiento UAguiar Bujanda DCamacho Galán RRivero Vera JCAguiar Morales J: Lumbar region intra-spinal primitive neuroectodermal tumour (PNET) combined with neurofibromatosis type 1. Clin Transl Oncol 7:4644672005

    • Search Google Scholar
    • Export Citation
  • 10

    Cai CZhang QShen CHu X: Primary intraspinal primitive neuroectodermal tumor: a case report and review of literature. J Pediatr Neurosci 3:1541562008

    • Search Google Scholar
    • Export Citation
  • 11

    Chang SITsai MCTsai MD: An unusual primitive neuroectodermal tumor in the thoracic epidural space. J Clin Neurosci 17:2612632010

    • Search Google Scholar
    • Export Citation
  • 12

    Dallas PBTerry PAKees UR: Genomic deletions in cell lines derived from primitive neuroectodermal tumors of the central nervous system. Cancer Genet Cytogenet 159:1051132005

    • Search Google Scholar
    • Export Citation
  • 13

    De Tommasi ADe Tommasi COcchiogrosso GCimmino AParisi MSanguedolce F: Primary intramedullary primitive neuroectodermal tumor (PNET)—case report and review of the literature. Eur J Neurol 13:2402432006

    • Search Google Scholar
    • Export Citation
  • 14

    Dedeurwaerdere FGiannini CSciot RRubin BPPerilongo GBorghi L: Primary peripheral PNET/Ewing's sarcoma of the dura: a clinicopathologic entity distinct from central PNET. Mod Pathol 15:6736782002

    • Search Google Scholar
    • Export Citation
  • 15

    Delattre OZucman JMelot TGarau XSZucker JMLenoir GM: The Ewing family of tumors—a subgroup of smallround-cell tumors defined by specific chimeric transcripts. N Engl J Med 331:2942991994

    • Search Google Scholar
    • Export Citation
  • 16

    Delattre OZucman JPlougastel BDesmaze CMelot TPeter M: Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours. Nature 359:1621651992

    • Search Google Scholar
    • Export Citation
  • 17

    Deme SAng LCSkaf GRowed DW: Primary intramedullary primitive neuroectodermal tumor of the spinal cord: case report and review of the literature. Neurosurgery 41:141714201997

    • Search Google Scholar
    • Export Citation
  • 18

    Dierick AMRoels HLanglois M: The immunophenotype of Ewing's sarcoma. An immunohistochemical analysis. Pathol Res Pract 189:26321993

    • Search Google Scholar
    • Export Citation
  • 19

    Dorfmüller GWürtz FGUmschaden HWKleinert RAmbros PF: Intraspinal primitive neuroectodermal tumour: report of two cases and review of the literature. Acta Neurochir (Wien) 141:116911751999

    • Search Google Scholar
    • Export Citation
  • 20

    Duan XHBan XHLiu BZhong XMGuo RMZhang F: Intraspinal primitive neuroectodermal tumor: imaging findings in six cases. Eur J Radiol [epub ahead of print]2010

    • Search Google Scholar
    • Export Citation
  • 21

    Eberhart CGBrat DJCohen KJBurger PC: Pediatric neuroblastic brain tumors containing abundant neuropil and true rosettes. Pediatr Dev Pathol 3:3463522000

    • Search Google Scholar
    • Export Citation
  • 22

    Engelhard HHVillano JLPorter KRStewart AKBarua MBarker FG II: Clinical presentation, histology, and treatment in 430 patients with primary tumors of the spinal cord, spinal meninges, or cauda equina. Clinical article. J Neurosurg Spine 13:67772010

    • Search Google Scholar
    • Export Citation
  • 23

    Fabre EGuillevin RChretien FLe Guerinel CDuffau H: Peripheral primitive neuroectodermal tumor of the cauda equina in an elderly patient. Case report. J Neurosurg Spine 5:68712006

    • Search Google Scholar
    • Export Citation
  • 24

    Feng JFLiang YMBao YHPan YHJiang JY: Multiple primary primitive neuroectodermal tumours within the spinal epidural space with non-concurrent onset. J Int Med Res 36:3663702008

    • Search Google Scholar
    • Export Citation
  • 25

    Fletcher CDMUnni KKMertens F: World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Soft Tissue and Bone LyonIARC Press2002

    • Search Google Scholar
    • Export Citation
  • 26

    Folpe ALGoldblum JRRubin BPShehata BMLiu WDei Tos AP: Morphologic and immunophenotypic diversity in Ewing family tumors: a study of 66 genetically confirmed cases. Am J Surg Pathol 29:102510332005

    • Search Google Scholar
    • Export Citation
  • 27

    Folpe ALHill CEParham DMO'Shea PAWeiss SW: Immunohistochemical detection of FLI-1 protein expression: a study of 132 round cell tumors with emphasis on CD99-positive mimics of Ewing's sarcoma/primitive neuroectodermal tumor. Am J Surg Pathol 24:165716622000

    • Search Google Scholar
    • Export Citation
  • 28

    Freyer DRHutchinson RJMcKeever PE: Primary primitive neuroectodermal tumor of the spinal cord associated with neural tube defect. Pediatr Neurosci 15:1811871989

    • Search Google Scholar
    • Export Citation
  • 29

    Frühwald MCO'Dorisio MSDai ZRush LJKrahe RSmiraglia DJ: Aberrant hypermethylation of the major breakpoint cluster region in 17p11.2 in medulloblastomas but not supratentorial PNETs. Genes Chromosomes Cancer 30:38472001

    • Search Google Scholar
    • Export Citation
  • 30

    Gessi MGiangaspero FLauriola LGardiman MScheithauer BWHalliday W: Embryonal tumors with abundant neuropil and true rosettes: a distinctive CNS primitive neuroectodermal tumor. Am J Surg Pathol 33:2112172009

    • Search Google Scholar
    • Export Citation
  • 31

    Gould VERorke LBJansson DSMolenaar WMTrojanowski JQLee VM: Primitive neuroectodermal tumors of the central nervous system express neuroendocrine markers and may express all classes of intermediate filaments. Hum Pathol 21:2452521990

    • Search Google Scholar
    • Export Citation
  • 32

    Gyure KAPrayson RAEstes ML: Extracerebellar primitive neuroectodermal tumors: a clinicopathologic study with bcl-2 and CD99 immunohistochemistry. Ann Diagn Pathol 3:2762801999

    • Search Google Scholar
    • Export Citation
  • 33

    Han IHKuh SUChin DKKim KSJin BHCho YE: Surgical treatment of primary spinal tumors in the conus medullaris. J Korean Neurosurg Soc 44:72772008

    • Search Google Scholar
    • Export Citation
  • 34

    Harimaya KOda YMatsuda STanaka KChuman HIwamoto Y: Primitive neuroectodermal tumor and extraskeletal Ewing sarcoma arising primarily around the spinal column: report of four cases and a review of the literature. Spine 28:E408E4122003

    • Search Google Scholar
    • Export Citation
  • 35

    Hart MNEarle KM: Primitive neuroectodermal tumors of the brain in children. Cancer 32:8908971973

  • 36

    Hasegawa SLDavison JMRutten AFletcher JAFletcher CD: Primary cutaneous Ewing's sarcoma: immunophenotypic and molecular cytogenetic evaluation of five cases. Am J Surg Pathol 22:3103181998

    • Search Google Scholar
    • Export Citation
  • 37

    He SSZhao JHan KWHou TSHussain NZhang SM: Primitive neuroectodermal tumor of lumbar spine: case report. Chin Med J (Engl) 120:8448462007