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[page 10] [Eye Reports 2012; 2:e3]

Orbital metastatic primary
mediastinal neuroendocrine
tumor: a histopathological case
report
Hind Alkatan,1 Ayman Ayoubi2
1Pathology and Laboratory Medicine
Department; 2Oculoplastic and Orbit
Division, King Khaled Eye specialist
Hospital, Riyadh, Saudi Arabia

Abstract 

Neuroendocrine tumors most frequently
involve the gastrointestinal tract and bron-
chopulmonary system. Few cases of presumed
primary neuroendocrine tumors in the orbit
have been reported so far and most of the
orbital cases are actually metastatic.

We describe the unusual occurrence of this
tumor in the orbit of a 16-year-old boy. The
lesion was initially thought to be primary; how-
ever, the diagnosis of a metastatic orbital
lesion was later supported by the histopatho-
logical appearance of his orbital biopsy, char-
acteristic immunohistochemical profile and
the presence of a primary mediastinal tumor.
The patient did not have any symptoms sug-
gestive of a carcinoid syndrome during the
course of his disease. Unfortunately, tests
showed lymph node involvement and distant
metastatic lesions and he died from these a
few months later while on palliative therapy.

Introduction

Carcinoid tumors are neoplasms that are
believed to arise from neuroendocrine cells of
the gastrointestinal mucosa and in other
anatomical locations such as lungs, ovaries,
thyroid and breasts.1 Neuroendocrine tumors
(NET) are often referred to using the term car-
cinoid, but the newer WHO classification uses
the term NET. The classification of lesions is
based on size, localization, proliferation rate,
differentiation and hormone production.
Metastatic spread to the eye and ocular adnex-
ae is relatively uncommon and primary orbital
cases are also rare.2

We report a patient who presented with an
orbital neuroendocrine tumor that was finally
concluded to be metastatic. His systemic
workup before his death revealed a primary
chest lesion.

Case Report

A 16-year-old male presented with rapidly
progressing right side painless proptosis and
diplopia over the previous month. The patient
was healthy prior to his presentation. There
was no history of preceding trauma and no
other symptoms such as fever, night sweats,
loss of weight or appetite; there was no history
of skin lesions.

Visual acuity was 20/30 (uncorrected) on
the affected side. External examination
showed 8 mm of proptosis on the right side
using Hertel exophthalmometer at base 102.
There was limitation of right eye abduction,
dilated conjunctival blood vessels temporally,
mild superficial exposure keratopathy and
optic disc swelling on the same side (Figure
1a). Initial systemic examination revealed cer-
vical lympadenopathy on the right side. Lymph
nodes were soft, rubbery and non-tender with
no overlying skin changes. Initial clinical diag-
nosis was rhabdomyosarcoma in view of his
age and the rapidly progressing tumor or lym-
phoma, also taking into consideration his lym-
phadenopathy and the painless proptosis.  

Magnetic resonance imaging of the orbits
showed a large right temporally located extra-
conal orbital mass (3¥2.5 cm) abutting the lat-
eral rectus muscle and extending to the orbital
apex. The mass was isodense to the adjacent
muscles with faint marginal contrast enhance-
ment (Figure 1b). The radiology report sug-
gested the possibility of a neurogenic tumor or
rhabdomyosarcoma. Orbital incisional biopsy
through right lateral orbitotomy showed tumor
lobules separated by fibrous stroma in the
hematoxylin and eosin stained histopathology
slides. The lobules consist of poorly differenti-
ated cells with small round to cuboidal nuclei
and abundant cytoplasm (Figure 2a). Mitotic
figures were frequent (Figure 2b). The tumor
cells expressed cytokeratin CK8/18, chromo-
granin (Figure 3a) and synaptophysin (Figure
3b). Negative markers included desmin, myo-
genin, CD99, S-100, smooth muscle actin
(SMA) and epithelial membrane antigen
(EMA). Proliferation rate was 20% by Ki67.
The final diagnosis was neuroendocrine tumor
with histological grading grade 2. The patient
was referred to a general tertiary care center
for tests and management. His further sys-
temic workup did not reveal any gastrointesti-
nal primary tumor, but a computerized tomog-
raphy (CT) scan of his chest showed a het-
erogenous lobulated mediastinal mass meas-
uring 11.6¥9¥6 cm compressing the bronchial
branches in addition to multiple nodules
involving the lung parenchyma bilaterally. His
total body CT scan also showed metastatic
bone lesions involving lumbar vertebrae, left
side of the sacrum and right iliac bone.
Bilateral multiple enlarged supraclavicular

lymph nodes were also evident by magnetic
resonance imaging in addition to pararenal
soft tissue lesions adjacent to the left kidney
and dorsolateral to the right iliopsoas muscle. 

The patient was considered to have stage 4
disease because of his distant metastasis with
the primary lesion being in the chest. No tis-
sue diagnosis was considered. Because of the
wide-spread disease, exenteration was not
performed and he was started on chemothera-
py consisting of cisplatin and etoposide.
Response to the 1st cycle of treatment was poor,
as documented in his medical records. He also
received palliative radiotherapy to the supra-
clavicular lymph nodes and his enlarging right
orbital lesion. He was given a total dose of 20-
30 Gy in 5-10 fractions. He was then trans-
ferred to another local health care facility in
his family’s home town for supportive care. His
condition deteriorated over the next few
months and he died from his metastatic dis-
ease.  

Discussion 

NET originates from the chromaffin cells of

Eye Reports 2012; volume 2:e3

Correspondence: Hind Alkatan, King Khaled Eye
Specialist Hospital, Riyadh, Saudi Arabia. 
Tel: +966.1.4821234 Ext 3131; Mobile: +966-
504492399. E-mail: hkatan@kkesh.med.sa

Key words: neuroendocrine, carcinoid, orbit.

Acknowledgements: this paper was presented at
the Eastern Ophthalmic Pathology Society
(EOPS) Meeting, Cleveland, Ohio, USA,
September 2010. IRB/EC: this case study was not
registered with the IRB but followed the guide-
lines stipulated by the ethics committee of the
institution.

Contributions: HA is fully responsible for the
accuracy of the information and for preparation
of the manuscript; AA has provided clinical data
and is the treating physician responsible for the
case. 

Conflict of interests: the authors declare no
potential conflict of interests.

Received for publication: 31 May 2011.
Revision received: 6 February 2012.
Accepted for publication: 13 February 2012.

This work is licensed under a Creative Commons
Attribution NonCommercial 3.0 License (CC BY-
NC 3.0).

©Copyright H. Alkatan and A. Ayoubi, 2012
Licensee PAGEPress, Italy
Eye Reports 2012; 2:e3
doi:10.4081/eye.2012.e3

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[Eye Reports 2012; 2:e3] [page 11]

the gastrointestinal and bronchial tract.1,3

Carcinoid syndrome may develop in a small
number of patients, usually in association with
metastatic disease, and it manifests as cuta-
neous flushing, cyanosis, diarrhea, asthma
and endocardial fibrosis.4 Ophthalmic mani-
festations of this syndrome include conjuncti-
val injection, intravascular sludging, perivas-
cular pigment clumping and a decrease in the
ophthalmic artery pressure that are believed to
be attributed to serotonin and vasoactive pep-
tides secreted by a functioning NET.5

Several cases of non-ocular NET in various
anatomic locations have been reported; howev-
er, primary orbital NET is rare.1,2 Orbital
involvement by NET accounts for only 4-5% of
all orbital metastatic disease and it is usually
from a gastrointestinal primary tumor, while
ocular uveal involvement is often from primary
bronchopulmonary NETs.2,6 Bilateral orbital
metastasis has been also reported.7,8

An overall high proportion of NET cases
(15%) metastasize to the orbit, although it is
considered a relatively rare site for metastatic
disease.9 Of these cases of orbital involvement
by NET, the majority of the metastases are
from primary gastrointestinal tumors or
tumors of unknown primary origin. Mititelu et
al. reported a presumed primary left orbital
NET progressing to neoplastic meningitis
while the original tumor site was never identi-
fied.10 Riddle et al. reported 15 cases of eye and

orbit NET metastases. Of the 12 cases in whom
the primary site was known: 7 cases were
bronchial, 4 from the ileum and one case only
was from trachea. However, if we isolate these
7 orbital cases, the primary site was unknown
in 3, was ileum in 3 and trachea in one case
only.11 In a review by Shetlar et al. of 18 cases
of orbital metastases, including 3 cases report-
ed by the authors and an additional 15 cases
reported by others, 11 were of gastrointestinal
origin, the primary site was unknown in 5,
mediastinal in one and trachea in one.4

Mehta et al. reported their 13 cases of
orbital metastatic NET among whom 11 were
of gastrointestinal origin (ileal in 7 and colonic
in 4), and only one each from breast and
bronchus. Mehta et al. also reviewed the liter-
ature of NET metastasis to the orbit and out of
23 cases reported by others (in which the pri-
mary tumor was known), 16 were of gastroin-
testinal origin, 5 of bronchopulmonary origin,
one was of renal origin and one was of medi-
astinal origin.12

On the other hand, only a few cases of
metastatic ocular uveal NET have been report-
ed.11 Metastatic spread to the eye itself is more
likely to arise from bronchial tumors, and it
involves primarily the uveal tract where it can
be misdiagnosed as uveal melanoma.4,13 The
primary tumor in almost all uveal metastasis
has been shown to arise from the bronchus.
The reasons behind this predilection are not

understood. Riddle et al. reported that out of 8
cases of metastasis to the ocular uveal tissue
from NET, 7 were of bronchial origin and the
remaining single case was of ileal origin.11 Out
of 12 uveal metastatic NET reviewed by Shetlar
et al., in contrast to the orbital cases in the
same review discussed above, the primary site
was bronchial in 11 cases and the ileum in one
case only.4 In their review, Mehta et al. com-
mented that this might be due to intrinsic
properties of the tumors affecting their ability
to develop a metastasis.12

Metastases are uncommon in typical bron-
chopulmonary NET, but regional lymph node
secondary tumors occur more commonly in
atypical settings; although distant metastasis
occurs less frequently. Usual metastases are to
lymph nodes, contralateral lung, liver, bone,
ovaries, brain and skin.14 Metastatic intraocu-
lar or orbital NET usually presents after the
primary neoplasm is diagnosed.2,11

Symptoms of the carcinoid syndrome are
commonly observed in cases of metastatic dis-
ease in general, as functioning NET metas-
tases (usually hepatic) may secrete vasoactive
substances, detected as raised urinary 5-HIAA,
and manifest clinically as symptoms of carci-
noid syndrome, such as facial flushing, diar-
rhea, abdominal cramps, asthma and tachycar-
dia.11,12 However, Carcinoid syndrome is rare in
bronchpulmonary NET without metastasis;
therefore, symptoms are usually absent.15

Case Report

Figure 1. (a) Clinical appearance of the
proptotic right globe in our 16-year-old
patient. (b) Axial T1-magnetic resonance
imaging showing the right isodense mass
pushing the optic nerve, with ring of con-
trast enhancement.

Figure 2. (a) Histopathology picture of the
tumor lobules (Hematoxylin and Eosin,
original magnification x 200). (b) Mitotic
figure (white arrow) (Hematoxylin and
Eosin, original magnification x 1000).

Figure 3. (a) Positivity of the tumor cells as
indicated by dark brown staining to chro-
mogranin A (original magnification x
400). (b) Positive islands of tumor cells to
synaptophysin stained brown within light
colored stroma (original magnification x
200). 

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[page 12] [Eye Reports 2012; 2:e3]

Zimmerman and his co-authors reviewed 15
cases of orbital/ocular metastatic NET and only
4 of these patients had elevated 5-HIAA and/or
symptoms of the carcinoid syndrome.2 Even
with metastasis to the orbit, symptoms of car-
cinoid syndrome are often absent. Only 2
patients out of the 13 cases of orbital metasta-
tic NET reported by Mehta et al. had elevated
urinary 5-HIAA without hepatic metastasis,
thus suggesting a significant production of the
vasoactive substances by the orbital metastatic
tumor itself.12

The location of his ocular metastatic lesion
makes our patient unique. His primary medi-
astinal NET was asymptomatic and he present-
ed first with the orbital metastatic lesion
before the primary lesion was discovered. This
is considered unusual since the metastatic dis-
ease was orbital instead of being intraocular
(uveal). Sira and co-authors similarly reported
the first case of NET metastasizing from the
larynx to the orbit; however, in their case the
involvement was bilateral.8 Our patient also
did not have symptoms suggestive of a carci-
noid syndrome to attract attention to his pri-
mary disease. The absence of carcinoid syn-
drome manifestations delayed his diagnosis. 

Another interesting but rare finding in
metastatic NET is their presentation as orbital
inflammation that must be carefully distin-
guished from the systemic carcinoid syn-
drome. This presentation is thought to be
related to spontaneous release of intrinsic
inflammatory mediators.8,16

The histological differential diagnosis sug-
gested by Zimmerman et al. includes amelan-
otic melanoma, paraganglioma and metastasis
from oat cell carcinoma, retinoblastoma, neu-
roblastoma, since they all share the histologi-
cal cellular appearance of small dark cells, but
can otherwise be eliminated according to clin-
ical, immunohistochemical and ultrastructural
criteria. The differential diagnosis also
includes non-orbital NET; this is more prob-
lematic.2 Therefore, immunohistochemical
methods are important for proper diagnosis
with frequent reactivity to chromogranin A and
synaptophysin. Chromogranin A is one of the
acidic proteins present in the secretory gran-
ules of neuroendocrine cells and is seen in
most NET, while synaptophysin is another
broad-spectrum neuroendocrine marker local-
ized in cytoplasmic vesicles in neurons, neu-
roendocrine cells and their neoplasms. Other
useful markers for NET include neuron-specif-
ic enolase that is a highly sensitive, but not
specific, marker for NET, in addition to sero-
tonin and calcitonin for metastatic NET,
depending on the characteristic hormone or
marker related to the primary site. It has been
suggested to use a selective panel of antibod-
ies to obtain the greatest diagnostic accuracy.4

The differential diagnosis in our case, based

on the histopathological appearance of the
tumor and the clinical suspicion, included
desmoplastic round cell tumor. This was ruled
out by the lack of prominent desmoplastic stro-
ma and muscular differentiation (negative
desmin, SMA and myogenin). Our patient had
positive staining to chromogranin A (polyclon-
al rabbit anti-human) and synaptophysin
(monoclonal mouse antibody).

Magnetic resonance imaging is helpful in
localizing the tumor which may demonstrate
the same density as the extraocular muscles in
both T1- and T2-weighted images.3 This was
also seen in our case.  

No exact data is available for long-term sur-
vival of ocular metastatic NET. The overall
median survival of 227 cases of ocular metasta-
tic disease reported by Ferry and Font was 7.4
months and only 2 out of these were NET.17 In
general, a relatively good prospect for long-
term survival in NET cases is expected, thus
excision of small solitary metastatic lesions in
the orbit is recommended to achieve local con-
trol of the disease. Enucleation or exenteration
might also be ultimately required to ensure
total surgical excision and local control of the
disease that is believed to prolong survival
time.3,4 The role of chemotherapy and external
beam irradiation for orbital NET has not been
well defined. However, some have reported an
effective response to chemotherapy with cis-
platin and etoposide.3

Our patient had incisional biopsy aimed at
reaching the proper diagnosis before defini-
tive surgical treatment was planned. However,
he was found to have a late stage disease and
only palliative therapy was offered to him in
the referral hospital.

In conclusion, we report an unexpected
metastatic NET in a patient with absent carci-
noid syndrome manifestations. These factors
helped a proper diagnosis to be made but also
led to an unfavorable outcome. Periodic oph-
thalmological examination of patients with
NET is recommended for early detection of any
ocular involvement and to guide treatment. On
the other hand, ophthalmologists should also
be aware of the rare occurrence of these
tumors in the orbit and eye in order to avoid
any delay in management.

References

1. Godwin JD II.  Carcinoid tumors:  an analy-
sis of 2837 cases. Cancer 1975;36:560-9.

2. Zimmerman LE, Stangl R, Riddle PJ.
Primary carcinoid tumor of the orbit: a
clinicopathologic study with histochemical
and electron microscopic observations.
Arch Ophthalmol 1983;101:1395-8. 

3. Fan JT, Buettner H, Bartley GB, Bolling JP.
Clinical features and treatment of seven
patients with carcinoid tumor metastatic
to the eye and orbit. Am J Opthalmol 1995;
119:211-8.

4. Shetlar DJ, Font RL, Ordonez N, et al. A
clinicopathologic study of three carcinoid
tumors metastatic to the orbit: Immunohi -
stochemical, ultrastructural, and DNA flow
cytometric studies. Ophthalmology 1990;
97:257-64.

5. Wong VG, Melmon KL. Ophthalmic mani-
festations of the carcinoid flush. N Engl J
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6. Goldberg RA, Rootman J, Cline RA. Tumors
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7. Sivagnanavel V, Riodan-Eva P, Jarosz J, et
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8. Sira M, Clauss RP, Maclean C, Rose GE.
Orbital metastases from neuroendocrine
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9. Isidori AM, Kaltsas G, Frajese V, et al.
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10. Mititelu M, Stanton CA, Yeatts RP. Primary
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11. Riddle PJ, Font RI, Zimmerman LE.
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12. Mehta JS, Abou-Rayyah Y, Rose GE. Orbital
carcinoid metastasis. Ophthalmology
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13. Bardenstein DS, Char DH, Jones C, et al.
Metastatic ciliary body carcinoid tumor.
Arch Ophthalmol 1990;108:1590-4.

14. Aburn NS, Whitehead K, Sullivan TJ.
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15. Conley YD, Cafoncelli AR, Khan JH, et al.
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16. Knox RJ, Gigantelli JW, Arthurs BP.
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17. Ferry AP, Font R. Carcinoma metastatic to
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Case Report

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