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CASE REPORTS
Oral Maxillofac Surg3:1216-1221, 2005
Peripheral Primitive NeuroectodermalTumor of the Mandible With Cytogenetic
and Molecular Biology AberrationsSadir J. Alrawi, MD, FRCS,* Dongfeng Tan, MD,†
Maureen Sullivan, DDS,‡ Janet Winston, MD,§
Thom Loree, MD,� Wesley Hicks, MD, DDS,¶ and
Nestor Rigual, MD#
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he Ewing’s sarcoma (ES) family of tumors (ESFTs)onstitutes a group of small round-cell tumors of pre-umed neuroectodermal origin. These lesions mostften present as intraosseous or soft tissue masses inhe trunk or axial skeleton in children and youngdults.1 ESFTs comprise osseous and extraosseous ES,eripheral primitive neuroectodermal tumor (pP-ET), and Askin tumor of the thorax. In 1973, Hart
nd Earle2 coined the term “primitive neuroectoder-al tumor” (PNET), which draws attention to therimitive nature of the tumor rather than to its histo-enesis. PNET is primarily a disease of childhood3; inare cases, pPNETs of the head and neck region (man-ible, cerebellopontine area, and skull base) haveeen reported.3
The diagnosis of ES and pPNET is based in a com-ination of light microscopic, immunohistochemical,nd, if necessary, electron microscopic features.ther valuable diagnostic methods include cytoge-etic and molecular biologic analysis. ESs are wellharacterized by unique chromosomal aberrations. Inore than 95% of cases of ESFT, the gene fusion is
eceived from Roswell Park Cancer Institute, Buffalo, NY.
*Fellow, Department of Head and Neck Surgery.
†Associate Professor, Department of Pathology.
‡Assistant Professor, Department of Head and Neck Surgery.
§Associate Professor, Department of Pathology.
�Associate Professor, Department of Head and Neck Surgery.
¶Professor, Department of Head and Neck Surgery.
#Assistant Professor, Department of Head and Neck Surgery.
Address correspondence and reprint requests to Dr Alrawi:
epartment of Head and Neck Surgery, Roswell Park Cancer Insti-
ute, Elm and Carlton Streets, Buffalo, NY 14263; e-mail:
2005 American Association of Oral and Maxillofacial Surgeons
278-2391/05/6308-0026$30.00/0
boi:10.1016/j.joms.2005.04.014
1216
WS-FLI-1 (90% to 95%). Three other translocationsave been found in rare cases of ES and pPNET.4,5
The identification of specific translocations is help-ul in distinguishing ES from other small round-cellumors. Correct diagnosis is critical for selecting ofherapeutic protocols and significantly influences out-ome therapy.6,7
In this article, we describe a rare case of PNET ofhe mandible and review the pertinent literature.
eport of a Case
An 18-year-old black woman initially consulted her physi-ian when she noticed a small painless mass in the lower labialestibule during her first trimester of pregnancy. She wasubsequently referred to her dentist, whose diagnostic impres-ion was “gingivitis.” She was then treated with multipleourses of antibiotics, but the problem failed to respond to thispproach. A few months later she presented to a local emer-ency department complaining of right otalgia and facial pain.here was hypesthesia in the area of the chin and rapidrowth of the mass both intraorally and in the chin region.hortly before this, she had delivered her first child.
Subsequently, she was referred to our institution. Physi-al examination was remarkable for a central mandibularass with erythema of the overlying skin and anesthesia in
he distribution of both mental nerves (Fig 1).Panoramic radiograph revealed lytic ill-defined changes in
he symphyseal and parasymphyseal region with oblitera-ion of the right mental foramen and inferior alveolar canalFig 2). Computed tomography (CT) demonstrated a softissue tumor infiltrating subcutaneous tissue with concom-tant mandibular bone erosion (Fig 3).
An incisional biopsy was performed, with microscopicxamination of the specimen revealing a finding suggestivef PNET. Subsequent CT scan of the chest, abdomen, andelvis revealed no evidence of metastasis. The patient wasreated, as an outpatient, with neoadjuvant chemotherapyonsisting of 2 cycles of Adriamycin (Novaplus, Bedford,H), vincristine, and cytoxan and received inpatient treat-ent with ifosfamide, mesna, and etoposide (VP-16). After
hemotherapy, clinical examination and CT scan revealedartial response.Definitive surgical treatment included segmental mandi-
ulectomy with negative margins, selective neck dissection,
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ALRAWI ET AL 1217
nd immediate mandibular reconstruction with a free fibu-ar microvascular flap, with osteointegrated implants placednto the free flap (Fig 4A, B).
The postoperative course was uncomplicated. Fourteenonths after completion of treatment, the patient was free
f disease and tolerated a regular diet. There was no evi-ence of local recurrence or distant metastasis (Figs 5, 6).
PATHOLOGIC EVALUATIONOn gross examination, the biopsy specimen consisted of
an, soft, friable tissue fragments measuring 2.1 � 1.6 � 0.3m in aggregate. The tissue was fixed in 10% neutral buff-red formalin and processed routinely for examination. Mi-roscopic examination revealed fibroconnective tissue, ex-ensively infiltrated by a proliferation of small round cells.he tumor was arranged in sheets and lobules with promi-ent well-defined rosettes of the Homer Wright and Flex-er-Wintersteiner types. The cells exhibited a high nuclear/ytoplasmic ratio, scanty cytoplasm, and ill-definedytoplasmic boundaries. The nuclei were round to oval
IGURE 1. Preoperative view of the patient. Prominence of chin atime of presentation.
lrawi et al. Primitive Neuroectodermal Tumor of the Mandible.Oral Maxillofac Surg 2005.
IGURE 2. Panoramic radiograph reveals “moth-eaten” appearancef the symphyseal and parasymphyseal area.
dlrawi et al. Primitive Neuroectodermal Tumor of the Mandible.Oral Maxillofac Surg 2005.
ith finely stippled chromatin and inconspicuous nucleoli.here was extensive single cell necrosis and mitotic activity
n excess of 20/10 high-power fields (Fig 7A).On immunohistochemical analysis, the tumor cells were
trongly and diffusely positive for neural markers, includingeuron-specific enolase (NSE), synaptophysin, and neuro-lament. In addition, there was focal positivity for MIC2CD99) and nonreacting for leukocyte common antigenLCA), cytokeratin, desmin, and S100. There was no in-reased intracytoplasmic glycogen detected by periodic ac-d-Schiff (PAS) stain with and without diastase. The well-efined rosettes and the immunohistochemical positivityor neural markers (Fig 5A, B) and MIC2 were supportive ofhe diagnosis of primitive neuroectodermal tumor (PNET)Fig 7B).
CYTOGENETICS/MOLECULAR BIOLOGYFluorescence in situ hybridization (FISH) was used in this
tudy to detect the genetic mapping of the specified tumor.SI EWSR 1 dual-color, break-apart Rearrangement ProbeVysis, Inc, Abbott Park, IL) was used. Paraffin-embeddedections of the PNET tumor samples were screened, show-ng minimal and nonrearranged overlapping orange andreen EWSR1 loci signals in several cells (Fig 8) (arrowsndicate 2 representative signals), indicating no major trans-ocations or deletions in the specified loci of that tumor.
iscussion
PNETs are classified within the family of smallound-cell sarcomas; these are closely related to ES. ESas first described by Ewing in 19218 as a diffuse
ndothelioma of bone. Historically, the origin andlassification of ES have been debated widely. In 1972he World Health Organization postulated that ESriginated from the medullary bone cavity. Other in-estigators thought that ES was derived from myelog-nous9 or vascular10 tissue, as well as from undiffer-ntiated mesenchymal and reticuloendothelial cells inhe bone marrow, respectively.11,12 Roessner et al13
IGURE 3. Computed tomography reveals significant soft tissue tu-or infiltrating skin and subcutaneous tissue.
lrawi et al. Primitive Neuroectodermal Tumor of the Mandible.Oral Maxillofac Surg 2005.
emonstrated a close association between ES, meta-
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1218 PRIMITIVE NEUROECTODERMAL TUMOR OF THE MANDIBLE
tatic neuroblastoma, alveolar rhabdomyosarcoma,nd extragonadal non-Hodgkin’s lymphoma. They de-cribed these tumors as being composed of small,last-like round cells typically containing intracyto-lasmic glycogen and therefore classified them into 3ubgroups, namely typical Ewing’s sarcoma (TES),typical Ewing’s sarcoma, and PNET. Among the cellines that might be responsible for the developmentf PNETs, there are 3 likely candidates: the neuralrest, primordial germ cells, and uncommitted mes-nchymal cells. It is now believed that the likelyrogenitor cells of PNETs are mesenchymal stemells.14 Tumors of the ES family are very rare. Theyomprise only 0.5% of all malignancies and affect 6 of0 million people in the general population.15 Thectual incidence of PNET is difficult to ascertain be-ause stringent diagnostic criteria have only recentlyeen delineated.16
PNET was first reported by Stout in 1918.17 InitiallyNETs were believed to arise from major nerves. Latereports described these tumors in other anatomicocations as well, including the chest wall, retroperi-oneum, the extremities, bone, and paraspinal sites.oday, the tumor is considered to be a neoplasm ofonneural soft tissue that primarily affects childrennd adolescents without an apparent gender predilec-ion.17,18
PNET predominantly involves central and axial skel-ton as well as the diaphyses of long bones; in con-rast, ES usually appears in the metaphyses and epiph-ses. PNETs are grouped by site of origin and dividednto central and peripheral tumors. Central PNETssuch as medulloblastoma” originate in the brain orpinal cord, whereas peripheral PNETs include adre-al and extra-adrenal neuroblastomas of soft tissues,erve, and bone.18 Although the head and neck re-
IGURE 6. Intraoral photograph 3 months postoperatively showingsteointegrated implant.
lrawi et al. Primitive Neuroectodermal Tumor of the Mandible.Oral Maxillofac Surg 2005.
IGURE 4. A, Intraoperative photograph of the patient showing theeconstructed mandible with fibular osseous microvascular free flapith osteointegrated implants into the mandibular graft. B, Intraopera-
ive picture of the resected specimen of the tumor and the mandible.
lrawi et al. Primitive Neuroectodermal Tumor of the Mandible.
IGURE 5. Postoperative panoramic radiograph demonstrates freebular flap in position plus osteointegrated implant.
ion is a rare site of origin for these malignant neo-
Table 1. CHARACTERISTICS OF PATIENTS WITH MANDIBULAR TUMOR
PatientAge(yr) Gender
Location inMandible
ChromosomalStudy Immunohistochemistry Treatment Modalities
Follow-up(mo)
Recurrence/Metastasis Status
1 38 Female Mental andparasymphyseal
Not performed Positive for neuron-specificenolase (NSE)immunoreactiveneurofilaments, CD57,synaptophysin, negativefor AE1/AE3, desmin,CD99, and chromogranin
Mandibulectomy, neckdissection, postoperativechemotherapy of 6 courses,followed by palliative external-beam irradiation
18 Lung metastasis Dead
2 6 Female Mental andparasymphyseal
Not performed Positive for NSE,synaptophysin,chromogranin, negativefor cytokeratin, desmin,vimentin, and leukocytecommon antigen (LCA)
Marginal mandibulectomyfollowed by chemotherapy,reoperated withmandibulectomy
10 Localrecurrence,reoperated,free of tumor
Alive
Presentpatient
18 Female Mental andparasymphyseal
Performed Strongly and diffuselypositive for neuralmarkers: NSE,synaptophysin, andneurofilament, focallypositive for MIC2(CD99), and negative forLCA, cytokeratin,desmin, and S100
Preoperative chemotherapyfollowed by mandibulectomyand neck dissection
14 No localrecurrence ordistantmetastasis
Alive
Alrawi et al. Primitive Neuroectodermal Tumor of the Mandible. J Oral Maxillofac Surg 2005.
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1220 PRIMITIVE NEUROECTODERMAL TUMOR OF THE MANDIBLE
lasms, they have been reported in skull, orbit, mas-eter muscle, and maxilla. To the best of ournowledge, only 2 other reports of PNET in the man-ible have been previously published.19
The likelihood of metastatic disease at the time ofiagnosis of ES and PNET ranges from 14% to 50%.20
he lung is the most common metastatic site.Diagnosis of PNET is based on clinical parameters
nd histopathologic and immunohistochemical exam-nation. Light microscopy generally reveals sheets ofmall, round to oval cells with scant cytoplasm andoarse chromatin material. Rosette formation is nec-ssary to confirm the diagnosis by light microscopy,hereas the finding of cytoplasmic process, fila-ents, microtubules, and neurosecretory granules is
haracteristic at the ultrastructural level.21 Immuno-istochemically, PNETs are generally positive forD99, NSE, neurofilament, HNK-1 (Leu-7), FLI-1,
IGURE 7. A, Primitive neuroectodermal tumor (PNET) with well-efined rosettes and single cell necrosis (hematoxylin and eosin,200). B, PNET with strong and diffuse immunoreactivity for synap-
ophysin (�400).
lrawi et al. Primitive Neuroectodermal Tumor of the Mandible.Oral Maxillofac Surg 2005.
-100 protein, and MB2. i
To identify the specific chromosomal transloca-ions of various members of this tumor family, cyto-enetic, molecular biological assay with FISH, andolymerase chain reaction are considered importantiagnostic tools for the evaluation and management ofS tumor family patients. ESs are well characterizedy unique chromosomal aberrations t(11;22)(q24;12), t(21;22)(q22;q12,), t(7;22)(p22;q12), t(17;2)(q12;q12), and t(2;22)(q33;q12). In more than5% of the cases of ESFT, the gene fusion is EWS-FLI-190% to 95%), because of t(11;22), or EWS-ERG (5% to0%), because of t(21;22). Three other translocationsave been found in rare cases of ES and pPNET. Thesehromosomal aberrations result in a fusion of EWSene on chromosome 22 with the ETS family geneFLI-1 at 11q24, ERG at 21q22, ETV1 at 7p22, E1AF at7q12, and FEV at 2q33).4,5
Deletion of chromosome (5)(p11) and transloca-ion (11;22)(q24;q12) were not found in the cellsnalyzed in our case. The translocation (11;22) is aiagnostically important cytogenetic rearrangementypical of ES/pPNET. Although 95% of ES/pPNET pa-ients exhibit this rearrangement, the case presentedere represents a rare genetic and molecular biologi-al aberration, and probably accounts for initial favor-ble clinical response.
Initial work-up of this biologically aggressive tumorncludes tissue sampling, chest radiography, CT imag-ng of lungs and abdomen, bone scans, and bone
arrow aspiration/biopsy to rule out bony involve-ent prior to treatment planning. Recently, protonR spectroscopy has proved to be invaluable for
umor characterization, especially when tumor arises
IGURE 8. Fluorescence in situ hybridization (FISH) using the LSIWSR 1 dual-color, break-apart Rearrangement Probe on paraffin-mbedded section showing nonrearranged overlapping orange andreen EWSR1 loci signals in several cells. (Arrows indicate 2 repre-entative signals.)
lrawi et al. Primitive Neuroectodermal Tumor of the Mandible.Oral Maxillofac Surg 2005.
n anatomically inaccessible regions.22,23
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ALRAWI ET AL 1221
The prognosis of PNETs is poor, with a 2-yearurvival rate of only 65% after diagnosis, regardless ofreatment modality applied.19 Previously reportedandibular tumor cases demonstrated either local or
istant metastasis within 1 year of follow-up. At 14onths of follow-up, our patient was disease free
Table 1).Due to the relative paucity of PNET cases, no stan-
ardized treatment paradigms have been established.s a result of large multicenter soft tissue sarcomatudies, identification of more effective treatmenttrategies and improved prognoses have beenchieved over the past 30 years. The recommendedreatment is similar to that for ES, with a combinationf chemotherapy, surgery, and, in selected cases, ra-iation therapy.24 Although PNET is considered radi-sensitive, radiation is generally administered as andjuvant therapy in cases of incomplete surgical re-ection or where there are close tumor margins. Fre-uently used chemotherapeutic agents include cyclo-hosphamide, ifosfamide, vincristine, doxorubicin,nd Dactinomycin (Merck, Philadelphia, PA).
Successful treatment requires close cooperationmong the surgeons and medical and radiation oncolo-ists to ensure the most effective management ap-roach. In our case, the patient was given 2 cycles ofhemotherapy as neoadjuvant treatment followed byurgery. No radiation therapy was given due to refusaln the part of both the patient and the family. A fewatients, even with widely metastatic disease, can haven excellent response to therapy, resulting in possibleears of survival.20 The genetic mapping and genomicnstabilities of those tumor samples needed to be evalu-ted to delineate the secret behind their survival.
Poor prognostic factors for PNETs include agereater than 10 years, bony infiltration and bone mar-ow metastasis, radiation therapy at doses greaterhan 55 Gy, and high-dose chemotherapy with hema-opoietic stem cell rescue. Due to the rarity and bio-ogical aggressiveness of PNET, multi-institutionallinical trials are necessary to formulate more effec-ive therapeutic regimen.25
In conclusion, PNET is a rare but highly aggressiveumor of the head and neck region. It is characterized byll-defined presentation and rapid growth. To date, therere no clinical or radiological modalities that ensurearly detection of this rare tumor. However, histopathol-gy, immunohistochemistry, and electron microscopyre the key tools for its diagnosis. Early recognition,horough work-up, and aggressive treatment are essen-ial to improving the outcome of this disease.
There is no standard regimen for managing PNET.owever, multimodality therapy including surgery, che-otherapy, and selective use of radiation therapy are
cceptable modalities of management. Finally, radiationnd chemotherapy have been found to be effective for
alliative treatment in unresponsive cases.26eferences1. Rodrigue-Galindo C, Marina NM, et al: Is a primitive neuroec-
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