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Pediatr Blood Cancer 2009;53:669–671
BRIEF REPORTLocalised Peripheral Primitive Neuroectodermal Tumour (PNET) of the Conjunctiva
Andrew S. Moore, MBBS,1*,{ Peter G. Wilson, MBBS, FRACP,2{ Penny McKelvie, MBBS, FRCPA,3#
Jamie La Nauze, FRANZCO, MMedSci(ClinEpi),4,§ and Lawrence W. Hirst, MD, MPH, FRANZCO5,§
INTRODUCTION
The Ewing sarcoma family of tumours (ESFT) are a group of
aggressive, small blue round cell tumours including classic Ewing
sarcoma of bone, extra-skeletal Ewing sarcoma, peripheral neuro-
ectodermal tumours (PNET, also known as peripheral neuro-
epithelioma) and the small cell tumour of the thoracopulmonary
region (Askin tumour). Usually occurring during adolescence,
ESFT have a slight predominance in males and an unusual
predilection for Caucasians. The prognosis for ESFT varies
depending on the size, location and resectability of the primary
lesion, presence or absence of metastases, type of genetic
rearrangement and age [1,2].
The cytogenetic hallmark of ESFT is the reciprocal translocation
t(11;22)(q24;q12), with breakpoints at the EWSR1 region of
chromosome 22 and EWSR2 region of chromosome 11, resulting
in an EWS-FLI1 fusion transcript in 85% of ESFT [3,4]. In
approximately 10% of cases the EWS fusion partner is the ERG
gene on chromosome 21q22. The remaining cases (<1% each)
usually involve pairings of EWS-ETV1, EWS-E1AF or EWS-FEV
[1,2]. The detection of one of these fusion transcripts by RT-PCR or
a breakpoint at EWSR1 or EWSR2 by fluorescence in-situ
hybridisation (FISH) is diagnostic [1–4].
The most common sites for ESFT are the pelvis (26%), femur
(20%), tibia/fibula (18%), chest wall (16%), upper limbs (9%) and
spine (6%). Approximately 25% of patients have metastatic disease
at diagnosis, usually lung (10%) or bone/bone marrow (10%).
Primary skull lesions, including those arising from the orbit account
for only 2% of cases [1,2]. There are limited case reports in the
literature describing metastatic ocular involvement of ESFT, but no
cases of primary conjunctival involvement [5,6].
CASE REPORT
A 16-year-old Caucasian male presented with a 3-month history
of an asymptomatic enlarging conjunctival lesion. The patient was
otherwise well and had no significant past medical history. There
was a family history of optic atrophy in the patient’s father and
paternal grandfather, but no history of malignancy.
The lesion was located just medial to the insertion of the medial
rectus muscle, approximately 5 mm from the limbus and extending
5 mm nasally. Clinically, the differential diagnoses included a
benign naevus and melanoma. The lesion was completely excised
with the closest lateral margin measuring 0.15 mm. Histologically,
the biopsy showed conjunctiva with a multinodular tumour in the
stroma adjacent to a benign compound naevus. The tumour was
composed of lobules and focal sheets of medium to large atypical
epithelioid cells with high nuclear/cytoplasmic ratio, a number of
apoptotic figures, scattered foci of necrosis and a number of mitotic
figures. There was eccentric eosinophilic cytoplasm in some cells
and prominent nucleoli. There was no peripheral palisading, no
squamous nor definite sebaceous differentiation and no perineural
nor vascular invasion (Fig. 1).
Immunohistochemistry showed diffuse strong membranous stain-
ing with CD99, strong filamentous reactivity for vimentin, strong
reactivity for CD56, focal reactivity with a membranous pattern for
cytokeratin 20 and MNF116 (a cytokeratin marker), focal reactivity for
BCL-2 but negative staining for desmin and WT-1. There was also
focal dot-like reactivity with cytokeratin 20. Chromogranin and
synaptophysin were negative. Three melanoma markers (repeat S100,
melan A and HMB-45) were negative in the tumour but reactive in the
adjacent naevus. FISH with the Ewing break-apart probe (22q12
EWSR1) demonstrated a split signal at 22q12, confirming the diagnosis
of a primitive neuroectodermal tumour (Fig. 2). PCR analysis of the
remaining paraffin-embedded tissue was attempted retrospectively but
failed due to RNA degeneration.
The patient underwent wide re-excision 3 weeks after the
initial resection, with no histological evidence of residual tumour.
A 16-year-old male presented with a 3-month history of anasymptomatic, enlarging conjunctival lesion. An excisional biopsywas performed and histologic and immunohistochemical examina-tion showed characteristic features of a peripheral primitive neuro-ectodermal tumour (PNET) adjacent to a benign compound naevus.FISH analysis, demonstrating a split-signal at 22q12, confirmed the
diagnosis. Staging investigations were negative confirming theprimary nature of the lesion. The patient was treated withlocal wide re-excision and chemotherapy. He remains alive andwell 29 months after initial resection. Pediatr Blood Cancer 2009;53:669–671. � 2009 Wiley-Liss, Inc.
Key words: conjunctiva; Ewing/PNET; Ewing sarcoma; ocular tumours; rare tumours; soft tissue sarcoma
� 2009 Wiley-Liss, Inc.DOI 10.1002/pbc.22062Published online 2 June 2009 in Wiley InterScience(www.interscience.wiley.com)
——————1Section of Paediatric Oncology, The Institute of Cancer Research &
Royal Marsden Hospital, Sutton, Surrey, UK; 2Queensland Children’s
Cancer Centre, Royal Children’s Hospital, Brisbane, QLD, Australia;3St Vincent’s Pathology, St Vincent’s Hospital, Melbourne, VIC,
Australia; 4Ballina Eye Centre, Ballina, NSW, Australia; 5Queensland
Eye Institute, University of Queensland, Brisbane, QLD, Australia
{Clinical Research Fellow.
{Paediatric Oncologist.
§Ophthalmologist.
#Pathologist.
*Correspondence to: Andrew S. Moore, Section of Paediatric
Oncology, The Institute of Cancer Research & Royal Marsden
Hospital, 15 Cotswold Rd, Sutton, Surrey, SM2 5NG, UK.
E-mail: andrew.moore@icr.ac.uk
Received 2 February 2009; Accepted 20 March 2009
The conjunctival wound healed well and vision was preserved. Staging
investigations including MRI of the brain and orbits, CT scans of chest,
abdomen and pelvis, technetium bone scan and bone marrow biopsies,
showed no evidence of disease elsewhere. A number of skin lesions
were subsequently removed but all were benign.
The patient was treated with 14 cycles of chemotherapy given
approximately every 21 days according to the standard arm of the
Children’s Oncology Group AEWS0031 protocol: vincristine 2 mg/
m2 on day 1, doxorubicin 37.5 mg/m2 on days 1 and 2 (omitted in
cycles 11 and 13) and cyclophosphamide 1,200 mg/m2 on day 1;
alternating with ifosfamide 1,800 mg/m2 on days 1–5 and
etopophos 114 mg/m2 on days 1–5. Pegylated granulocyte colony
stimulating factor (G-CSF) was given after each cycle. Chemo-
therapy was well tolerated and only complicated by a central venous
line infection requiring line replacement following cycle 11.
In view of the location of the lesion and wide re-excision failing
to show any sign of residual disease, it was decided not to administer
local radiation therapy. Re-evaluation after cycle 14 with MRI of
brain and orbits and CT scan of chest, abdomen and pelvis showed
the patient to be in complete remission. The patient remains in
complete remission both clinically and radiologically 29 months
after the initial resection. His vision is normal.
DISCUSSION
Whilst the histogenesis of ESFT has traditionally been
considered neuroectodermal in origin, the ability of ESFT to
display epithelial and mesenchymal characteristics and arise in
tissues not related to the neural crest means that other histogenic
mechanisms are possible [7]. Conjunctival epithelium, the primary
site of PNET in our patient, is derived embryologically from surface
ectoderm rather than neuroectoderm [8]. Ocular components
derived from neuroectoderm include the neural retina, retinal
pigment epithelium, pigmented and nonpigmented ciliary epithe-
lium, pigmented iris epithelium, sphincter and dilator muscles of the
iris, optic nerve, axons and glia and vitreous [8].
Although our patient’s lesion arose in the conjunctiva, its natural
history may be somewhat similar to cutaneous ESFT. Chow et al. [9]
reviewed 14 cases of cutaneous and subcutaneous ESFT treated at
St. Jude Children’s Research Hospital, plus 23 similar cases
reported previously in the literature. Similar to our patient, all the
reported cases were Caucasians in the second decade of life (median
age 15–16 years) with localised disease, and brief duration of
symptoms with a lump or mass (median 2 months). Those in whom
complete surgical resection was achieved had excellent local control
without the need for radiation [9].
Therapy cannot be evidence-based in such rare situations and
one must return to general principles. Given the high propensity for
micrometastatic spread in ESFT, chemotherapy was deemed
necessary for our patient. Radiation therapy was also carefully
considered but withheld in view of the complete absence of tumour
at primary re-excision and potential toxicity, including the risk of
radiation-induced cataract.
This case highlights the need for early and appropriate referral of
patients with unexpected and unusual tumours for further opinion with
respect to both diagnosis and management. The cooperation of both
adult and paediatric specialists involved in this case ultimately lead to
the correct diagnosis and appropriate treatment being undertaken in
a timely manner, with an excellent outcome for the patient.
Pediatr Blood Cancer DOI 10.1002/pbc
Fig. 2. Fluorescent in-situ hybridisation with the Ewing break-apart probe (22q12 EWSR1) demonstrating a normal (A) and split signal at 22q12
(B, green arrows). [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]
Fig. 1. High power magnification (400�) showing a highly cellular
small round blue cell tumour with little cytoplasm arranged in cords and
lobules. [Color figure can be viewed in the online issue, which is
available at www.interscience.wiley.com.]
670 Moore et al.
ACKNOWLEDGMENT
The histological and FISH images were kindly provided by
Dr John Lukin and Dr Kevin Whitehead from Sullivan Nicolaides
Pathology.
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8. Azar NF, Davis EA. Embryology of the eye. In: Yanoff M, Duker JS,
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Pediatr Blood Cancer DOI 10.1002/pbc
Conjunctival PNET 671
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