Therapy and outcome of orbital primitive neuroectodermal tumor

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    Therapy and Outcome of Orbital Primitive Neuroectodermal Tumor

    Sameer Bakhshi, MD,1,2,3* Rachna Meel, MD,3,4,5 Syed Ghaffar Hasan Naqvi, MBBS,1,2,3 B.K. Mohanti, MD,2,3,6

    Seema Kashyap, MD,3,5,7 Neelam Pushker, MS,3,4,5 and Seema Sen, MD3,5,7


    Peripheral primitive neuroectodermal tumor (PNET) along with

    Ewing sarcoma is clubbed under the Ewing sarcoma family of

    tumors [1]. Peripheral PNET is a group of soft tissue malignancies

    that usually affects children and adolescents and represents 4% of

    all childhood and adolescent soft tissue tumors [24]. It is most

    commonly seen in the thoracopulmonary region followed by

    head and neck region [5]. Primary PNET in the orbit are rare with

    only 10 cases reported in English literature to the best of our

    knowledge [614].


    Retrospective data analysis of primary orbital PNET treated at a

    tertiary care cancer center ofAll India Institute ofMedical Sciences,

    between June 2003 and June 2008, was undertaken. Patients

    Primary orbital primitive neuroectodermal tumor (PNET) is rarewith no reported series. We report six cases of orbital PNET treated ata tertiary care oncology center in northern India from 2003 to2008. None of them had distant metastases. All were treated withneoadjuvant chemotherapy followed by exenteration in two, radio-therapy and adjuvant chemotherapy in ve cases. Three out of six

    achieved complete remission at end of therapy with globe salvage inthree and vision in two cases. Chemoradiotherapy may help usto avoid mutilating surgery in large or locally advanced tumors,allowing preservation of vision or the globe. Pediatr Blood Cancer2009;52:544547. 2008 Wiley-Liss, Inc.

    Key words: Ewing sarcoma; orbit; primitive neuroectodermal tumor; therapy

    2008 Wiley-Liss, Inc.DOI 10.1002/pbc.21902Published online 17 December 2008 in Wiley InterScience(

    Additional Supporting Information may be found in the online version

    of this article.

    1Department of Medical Oncology, New Delhi, India; 2Dr B.R.A.

    Institute Rotary Cancer Hospital, New Delhi, India; 3All India Institute

    of Medical Sciences, New Delhi, India; 4Oculoplastics & Ocular

    Oncology Service, New Delhi, India; 5Dr. Rajendra Prasad Centre for

    Ophthalmic Sciences, New Delhi, India; 6Department of Radiotherapy,

    New Delhi, India; 7Ocular Pathology Services, New Delhi, India

    *Correspondence to: Sameer Bakhshi, Associate Professor of Pediatric

    Oncology, Department of Medical Oncology, Dr B.R.A. Institute

    Rotary Cancer Hospital, All India Institute of Medical Sciences, New

    Delhi, India. E-mail:

    Received 9 September 2008; Accepted 12 November 2008

    544 Brief Reports

  • demographic prole, clinical data including ophthalmic ndings,

    imaging, metastatic workup, treatment, globe salvage, and survival

    were studied. Complete remission, partial remission, and progres-

    sive disease were dened as per RECIST criteria [15].


    Clinical Prole

    Six cases of primary orbital PNETwere treated during the study

    period. Three out of these had a large tumor involvingorbit aswell as

    neighboring structures at presentation thatmade it difcult to decide

    the primary site of tumor origin. However, these patients primarily

    presented with ophthalmic signs and symptoms, imaging showed

    predominantly orbital involvement and thus considered as primary

    orbital PNET.

    There were three males and three females with a median age of

    10.5 years (range: 1.5 months to 20 years; Table I). The youngest

    patient who had symptoms from birth was a case of congenital

    primary orbital PNET (case 1; Fig. 1a). Vision on the affected side

    ranged from no perception of light to 6/12. Four out of six cases had

    deterioration of vision secondary to refractive error induced by the

    orbital tumor. One case had severe exposure keratitis (case 1).

    Fundus examination revealed optic atrophy in one (case 3) and disc

    edema with choroidal folds in two patients (cases 2 and 4).

    Diagnostic work up including bone marrow biopsy, bone scan, and

    CT scan chest did not reveal metastasis or primaries elsewhere in

    any case.

    Local Imaging

    Computed Tomography (CT) scan of brain and orbit showed a

    variably enhancing mass lesion with heterogenous attenuation in

    all cases, and average size being 4.25 cm (range: 2.56 cm).

    Hypodense areas suggestive of necrosis and hemorrhage were

    present in one case (case 1); small calcic densities in two cases

    (Fig. 1b) and osseous-cartilaginous calcied matrix with admixed

    radiating spicules in another (Fig. 1c). There was bone erosion in

    ve out of six cases with tumor extension beyond the orbit in four

    cases (Table I).


    Histopathology revealed a small round malignant tumor with

    cells arranged in nests and sheets; rosettes were not seen. The cells

    had a high nucleocytoplasmic ratio with frequent mitotic gures.

    Periodic acid Schiff stain was negative in all cases. The tumor cells

    were positive forMIC 2 antigen and S100 protein in all cases; either

    neuron specic enolase and/or synaptophysin were also positive.

    They were negative for desmin, actin, cytokeratin, and leukocyte

    common antigen. One case was initially misdiagnosed as brosar-

    coma on incisional biopsy, probably because of a small specimen

    that was not representative of thewhole tumor. However, we did not

    have the facility to study the reciprocal chromosomal translocation

    t(11;22)(q24;q12), which is considered pathognomic for this


    Pediatr Blood Cancer DOI 10.1002/pbc

    TABLE I. Details of Present Case Series

    Case#1 Case#2 Case#3 Case#4 Case#5 Case#6

    Age/sex 1.5 months/M 4 years/M 9 years/F 12 years/M 13 years/F 20 years/F

    Chief complaint Proptosis Proptosis Proptosis Proptosis Lower eyelid and

    cheek swelling

    Upper eyelid


    Duration of symptoms 1.5 months 2 months 6 months 1.5 months 2 months 10 months


    Size (maximum dimension) 3 cm 4.5 cm 2.5 cm 3 cm 6 cm 6 cm

    Bone erosion Yes Yes Yes Yes Yes No

    Calcication Yes (Calcic


    No Yes (Calcic


    No Yes (Osseous


    matrix with




    Extraorbital extension Yes (Anterior

    cranial fossa)

    Yes (Sino


    Yes (Sino nasal,

    Anterior cranial


    No Yes (Sino nasal) No

    Evaluation after 45 cycles Died after 4 cycles

    due to progressive



    Radiotherapy None 55 Gy/30 Fr

    6 weeks

    550 Gy/30 Fr,

    7 weeks

    50 Gy/25 Fr,

    5 weeks

    45 Gy/25 Fr ,

    5 weeks

    55 Gy/30 Fr,

    6 weeks

    Surgery None None None Debulking Exenteration and



    Globe salvage NA Yes Yes Yes No No

    Final outcome NA CR Died of

    chemotoxicity at

    24 weeks of


    CR Lost to follow up

    after 27 weeks

    of chemotherapy


    Follow up since diagnosis NA 40 months NA 20 months NA 17 months

    M, male; F, female; PR, partial remission; CR, complete remission; Gy, grays; Fr, fractions; NA, not available.

    Brief Reports 545

  • Therapy and Outcome

    Incisional biopsy was done in ve cases and tumor debulking in

    onewhere the tumor appeared small and non-inltrative on imaging

    (case 4). Chemotherapy was given using vincristine, doxorubicin,

    actinomycin-D, and cyclophosphamide alternating with ifosfamide

    and etoposide [16]. The patient initially diagnosed as brosarcoma

    received four cycles of ifosfamide and doxorubicin as neoadjuvant

    chemotherapy. Repeat evaluation of the tumor after 45 cycles of

    neoadjuvant chemotherapy revealed complete remission in one and

    partial remission in four cases. One case progressed after four

    cycles and died (case 1). Of the four cases in partial remission, one

    with a large residual tumor mass underwent exenteration and

    maxillectomy with tumor free margins on histopathology (case 5).

    The patient with initial diagnosis of brosarcoma underwent

    exenteration because of an incorrect diagnosis (case 6). Radio-

    therapy was given after ve cycles of neoadjuvant chemotherapy in

    ve patients at a dose of 4555 Gy in 2530 fractions, 5 days

    a week, over 56 weeks (Table I). Further chemotherapy was given

    in all ve cases following radiotherapy and/or surgery as per

    protocol [16].

    Three of the ve cases who responded to neoadjuvant chemo-

    therapy achieved complete remission at end of therapy and continue

    to be so at a median follow up of 20 months (range: 1740 months)

    since diagnosis (Table I). Among these ve responders following

    neoadjuvant chemotherapy, globe salvage was achieved in three

    with preservation of vision in two (cases 2 and 4) at end of therapy.


    Orbital PNET is a rare tumor that was postulated to arise

    from cell rests of neural crest origin in orbit that may occur

    when peripheral nerves of the orbit are developing, ectopic

    brain rests that may occur in orbit due to defects in bony

    orbit or cell rests in the optic nerve that develop directly from

    the cerebral tissue [6]. The clinical, imaging and treatment

    details of previously reported cases showed the median age to be

    10 years with no sex predilection (Supplemental Table I). Six of

    the eight reported cases with follow-up were alive at minimum

    6 months.

    There have been 21 cases of congenital PNETreported so far and

    this entity has a 5% chance of survival owing to low cure rates and

    high morbidity [1]. One of these cases of congenital PNET involved

    the eyelid region [17]; our case of congenital PNET is probably

    the second case of congenital orbital PNET and happened to be the

    only one who died of progressive disease.

    Imaging ndings in PNET suggest presence of large, inltrative,

    poorly circumscribed masses with heterogenous attenuation and

    variable contrast enhancement [18]. Calcication is unusual with

    only three cases of pulmonary PNET previously reported with

    amorphous calcication [19,20]. No calcication was seen in any of

    the reported cases of orbital PNETwhile in our series small calcic

    densities were observed in two cases. One of our cases had osseous

    cartilaginous matrix with spicules, which has not been previously

    reported in peripheral PNET.

    The reported rate of metastasis in PNET is approximately 20

    25% [16]. At our institute, almost half of our cases of PNET are

    metastatic at presentation, possibly because of a referral bias and

    delayed presentation. Four of six cases in our series had extra orbital

    involvement with large locally advanced tumors. In contrast most of

    the reported cases had small orbital tumors with extra orbital

    extension seen in only 2/10 cases. Interestingly, none of our cases or

    the previously reported cases of primary orbital PNET had systemic

    metastasis. It appears that the rate of metastasis is lesser in orbital

    PNETas compared to PNETat other sites. This could be attributed to

    the absence of lymphatics in the orbit [12].

    Six of the ten previously reported cases were surgically excised

    in toto or debulked before a diagnosis of PNET was made on

    histopathology. The small number of cases reported, short periods of

    follow up and the variability of therapy make the evaluation of

    different therapeutic modalities difcult in the previously reported


    We have used the same treatment protocol in all our cases,

    wherein local therapy in the form of radiotherapy with or without

    surgery was given after neoadjuvant chemotherapy and then

    followed by adjuvant chemotherapy.With this therapeutic protocol,

    Pediatr Blood Cancer DOI 10.1002/pbc

    Fig. 1. Clinical photograph of child with congenital primary orbitalPNET (case 1) (a). CT scan (coronal cut) showing large heterogenousmass lling the orbit and extending into the anterior cranial fossa with

    small calcic densities (case 1) (b) and CT scan (coronal cut) showinglarge mass with osseous-cartilaginous calcied matrix and radiating

    spicules (case 5) (c).

    546 Brief Reports

  • three out of six cases achieved sustained remission and globe

    preservation with useful vision in two cases. The eye that was

    exenterated because of a misdiagnosis of brosarcoma could

    probably have been saved after neoadjuvant chemotherapy. In

    geographical regions where patients may present in advanced

    stages, we feel that globe salvage is possible even in large tumors

    and chemoradiation may be used as the only modality of treatment

    as in orbital rhabdomyosarcoma. For smaller tumors, surgery may

    be done initially; however,...


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