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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
INTRODUCTION
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 [2–4]. 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 [6–14].
METHODS
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. Patient’s
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 five 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;52:544–547. � 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(www.interscience.wiley.com)
——————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: [email protected]
Received 9 September 2008; Accepted 12 November 2008
544 Brief Reports
demographic profile, clinical data including ophthalmic findings,
imaging, metastatic workup, treatment, globe salvage, and survival
were studied. Complete remission, partial remission, and progres-
sive disease were defined as per RECIST criteria [15].
RESULTS
Clinical Profile
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 difficult 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: 2.5–6 cm).
Hypodense areas suggestive of necrosis and hemorrhage were
present in one case (case 1); small calcific densities in two cases
(Fig. 1b) and osseous-cartilaginous calcified matrix with admixed
radiating spicules in another (Fig. 1c). There was bone erosion in
five out of six cases with tumor extension beyond the orbit in four
cases (Table I).
Histopathology
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 figures.
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 specific enolase and/or synaptophysin were also positive.
They were negative for desmin, actin, cytokeratin, and leukocyte
common antigen. One case was initially misdiagnosed as fibrosar-
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
disease.
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
swelling
Duration of symptoms 1.5 months 2 months 6 months 1.5 months 2 months 10 months
Imaging
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
Calcification Yes (Calcific
densities)
No Yes (Calcific
densities)
No Yes (Osseous
cartilaginous
matrix with
radiating
spicules)
No
Extraorbital extension Yes (Anterior
cranial fossa)
Yes (Sino
nasal)
Yes (Sino nasal,
Anterior cranial
fossa)
No Yes (Sino nasal) No
Evaluation after 4–5 cycles Died after 4 cycles
due to progressive
disease
PR CR PR PR PR
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
maxillectomy
Exenteration
Globe salvage NA Yes Yes Yes No No
Final outcome NA CR Died of
chemotoxicity at
24 weeks of
chemotherapy
CR Lost to follow up
after 27 weeks
of chemotherapy
CR
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 five cases and tumor debulking in
onewhere the tumor appeared small and non-infiltrative 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 fibrosarcoma
received four cycles of ifosfamide and doxorubicin as neoadjuvant
chemotherapy. Repeat evaluation of the tumor after 4–5 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 fibrosarcoma underwent
exenteration because of an incorrect diagnosis (case 6). Radio-
therapy was given after five cycles of neoadjuvant chemotherapy in
five patients at a dose of 45–55 Gy in 25–30 fractions, 5 days
a week, over 5–6 weeks (Table I). Further chemotherapy was given
in all five cases following radiotherapy and/or surgery as per
protocol [16].
Three of the five 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: 17–40 months)
since diagnosis (Table I). Among these five responders following
neoadjuvant chemotherapy, globe salvage was achieved in three
with preservation of vision in two (cases 2 and 4) at end of therapy.
DISCUSSION
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 findings in PNET suggest presence of large, infiltrative,
poorly circumscribed masses with heterogenous attenuation and
variable contrast enhancement [18]. Calcification is unusual with
only three cases of pulmonary PNET previously reported with
amorphous calcification [19,20]. No calcification was seen in any of
the reported cases of orbital PNETwhile in our series small calcific
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 difficult in the previously reported
cases.
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 orbital
PNET (case 1) (a). CT scan (coronal cut) showing large heterogenous
mass filling the orbit and extending into the anterior cranial fossa with
small calcific densities (case 1) (b) and CT scan (coronal cut) showing
large mass with osseous-cartilaginous calcified 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 fibrosarcoma 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, larger or locally advanced tumors,
attempts should be made to salvage the globe by using chemo-
therapy initially rather than going for extensive and mutilating
surgery straightaway. A study of the type of reciprocal translocation
between Ewing sarcoma gene on chromosome 11 and the Friend
leukemia virus integration site 1 (Fli1) gene on chromosome 22 or
fli1 related genes may prove to be useful.
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Pre-Freeze and Post-Thaw Characteristics on Chimerism Patterns inDouble-unit Cord Blood Transplantation
Tang-Her Jaing, MD,1,2* Pei-Kwei Tsay, PhD,3 Tung-Liang Lin, MD,1,4 Chao-Ping Yang, MD,1,2
Iou-Jih Hung, MD,1,2 and Yu-Chuan Wen, RN5
We analyzed the pre-freeze and post-thaw characteristics onchimerism patterns in 20 cases of double-unit cord blood trans-plantation. The cord blood units (CBUs) were a 4/6 HLA match orbetter with recipients and achieved a minimum combined precryo-preservation cell dose of 3.7� 107 total nucleated cell (TNC)/kg. Theunit with a higher cell dose was infused first. All evaluable patients
engrafted at a median of 18 days. By day 42, neutrophil engraftmentwas derived from both donors in 63% of cases and a single donor in37% of patients. By day 100, one unit predominated in 80% of thepatients. Higher pre-freeze TNC and CD34þ cell doses wereassociated with cord predominance in 67% of patients. PediatrBlood Cancer 2009;52:547–550. � 2008 Wiley-Liss, Inc.
Key words: cell dose; double cord blood transplantation; neutrophil engraftment; predominant unit
——————1DivisionofHematology andOncology,ChangGungMemorialHospital,
Chang Gung University, Taoyuan, Taiwan; 2Department of Pediatrics,
Chang Gung Memorial Hospital, Chang Gung University, Taoyuan,
Taiwan; 3Department of Public Health and Center of Biostatistics, Col-
legeofMedicine,ChangGungUniversity,Taoyuan,Taiwan; 4Department
of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung
University, Taoyuan, Taiwan; 5Department of Nursing, Chang Gung
Memorial Hospital, Chang Gung University, Linkou, Taoyuan, Taiwan
——————Tang-Her Jaing and Pei-Kwei Tsay contributed equally to this work.
*Correspondence to: Tang-Her Jaing, Division of Hematology and
Oncology, Department of Pediatrics, Chang Gung Memorial Hospital,
Chang Gung University, Taoyuan, Taiwan, 5 Fu-Shin Street, Kwei-
Shan, Taoyuan, Taiwan. E-mail: [email protected]
Received 9 August 2008; Accepted 30 October 2008
� 2008 Wiley-Liss, Inc.DOI 10.1002/pbc.21882Published online 5 December 2008 in Wiley InterScience(www.interscience.wiley.com)
Brief Reports 547
