Idiopathic sclerosing orbital inflammation mimicking a malignant spindle cell tumor in a dog

Abstract

Key Clinical Message
A dog presented with a retrobulbar mass, diagnosed histopathologically as malignant spindle cell neoplasia. Emergence of analogous findings in the contralateral orbit prompted extended immunohistochemistry of the original mass and reassignment to idiopathic sclerosing orbital inflammation. Early incisional biopsy with extended immunohistochemical analysis should be considered for canine orbital tumors.

Full text

CASE REPORT
Idiopathic sclerosing orbital inflammation mimicking a
malignant spindle cell tumor in a dog
Nina Marie Rzechorzek
1,2
, Colin Smith
2
, Tobias Schwarz
1
, Tiziana Liuti
1
, Richard Elders
1
,
Samantha Woods
1
, Jessica Lawrence
1
& Katia Marioni-Henry
1
1
Hospital for Small Animals, Royal (Dick) School of Veterinary Studies and Roslin Institute, University of Edinburgh, Roslin, Midlothian, UK
2
Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, Midlothian, UK
Correspondence
Nina Rzechorzek, Neurology/Neurosurgery
Service, Hospital for Small Animals, Royal
(Dick) School of Veterinary Studies and Roslin
Institute, University of Edinburgh, Easter Bush
Campus, Roslin, Midlothian EH25 9RG, UK.
Tel: +44131 650 7650; Fax: +44131 650
7652;
E-mail: nina.rzechorzek@ed.ac.uk
Funding Information
Nina Rzechorzek is funded by a Wellcome
Trust Integrated Training Fellowship for
Veterinarians (096409/Z/11/Z). Funding
sources did not have any involvement in the
study design; the collection, analysis, and
interpretation of data; writing of the report;
or the decision to submit the article for
publication.
Received: 7 February 2016; Revised: 15 May
2016; Accepted: 6 July 2016
doi: 10.1002/ccr3.639
Key Clinical Message
A dog presented with a retrobulbar mass, diagnosed histopathologically as
malignant spindle cell neoplasia. Emergence of analogous findings in the con-
tralateral orbit prompted extended immunohistochemistry of the original mass
and reassignment to idiopathic sclerosing orbital inflammation. Early incisional
biopsy with extended immunohistochemical analysis should be considered for
canine orbital tumors.
Keywords
Case report, exophthalmos, idiopathic orbital inflammation, IgG4, lymphoplas-
macytic infiltration, magnetic resonance imaging, radiation therapy, retrobulbar.
Case History, Examination, and
Differential Diagnosis
A 7-year-old, entire male crossbreed dog presented with an
11-month history of diffuse, left episcleritis. This was ini-
tially mild and had been managed by the primary veterinar-
ian with 1% prednisolone acetate ophthalmic suspension.
Despite a good therapeutic response, the inflammation
repeatedly recurred after each course of treatment. Over
the course of 7 months, the condition progressed to unilat-
eral exophthalmos alongside clinical signs consistent with
pain including blepharospasm and self-trauma. The dog
was referred to a veterinary ophthalmologist at which point
intraocular pressures (OS 16 mmHg; OD 18 mmHg),
Schirmer Tear Tests, and visual assessments were within
normal limits. Oral prednisolone (0.39 mg/kg PO, q12 h)
treatment induced transient clinical improvement, but
lateral deviation of the left globe ensued over the subse-
quent 4 months. Periorbital ultrasonography revealed a
soft tissue lesion in the left medial retrobulbar space and on
suspicion of an abscess or neoplasm, the dog was referred
to the University of Edinburgh Hospital for Small Animals.
On presentation, left exophthalmos, lateral strabismus,
brown-tinged epiphora, and diffuse scleral congestion
were evident. The globe was soft on palpation but resis-
tant to retropulsion. An acute pain response was not eli-
cited during globe manipulation or upon mouth opening,
inconsistent with the typical presentation of a retrobulbar
abscess in the dog. Direct and consensual pupillary light
reflexes and menace responses were normal OU. Other
ª2016 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.
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1

clinical examination findings were unremarkable. Differ-
ential diagnoses included neoplasia, cyst, infection (cel-
lulitis or abscess), noninfectious inflammatory disease, or
foreign body draining tract. The insidious onset of signs
with absence of fever and painless palpation decreased the
likelihood of an infectious etiology. Although globe
retraction (a clinical sign of ocular pain in the dog) could
not be assessed because of the retrobulbar mass, there was
also no behavioral expression of photophobia. Some level
of discomfort was however presumed on the basis of
inflammatory signs.
Investigations, Treatment, and
Outcome
Written informed consent was obtained from the owner
for all procedures performed. A complete blood count
with biochemistry and coagulation profile revealed only
an increase in alkaline phosphatase at 237 U/L (20–60 U/
L; anticipated in respect of recent prednisolone therapy)
and a mild increase in creatine kinase at 259 U/L (50–
200 U/L). Cultures of ultrasound-guided aspirates of the
mass (for aerobic and anaerobic bacteria, mycoplasma,
and fungi) produced no growth; May–Gr€
unwald–Giemsa
(MGG) cytology of the same aspirates yielded only
keratin bars and keratinaceous debris and was considered
nondiagnostic. Magnetic resonance imaging (MRI) of the
head was performed under general anesthesia at 1.5T,
acquiring multi-sequence images in transverse (T2-
weighted [T2w], T1-weighted [T1w], T1w postgadolin-
ium, T1w fast field echo) and dorsal (T1w postgadolin-
ium and short tau inversion recovery) planes. Findings
(Fig. 1) included marked contrast-enhancing swelling of
the left retrobulbar and periorbital space with lack of fat
definition and rostral displacement of the globe. The mass
appeared to breach through the ethmoid bone, compress-
ing the ventrolateral aspect of the left olfactory bulb (with
focal meningeal contrast enhancement); there was also
involvement of the left nasal cavity which was partially
filled with noncontrast-enhancing material. The left zygo-
matic salivary gland and left mandibular and medial
retropharyngeal lymph nodes were enlarged. A mildly
hyperintense signal was noted on T2w and postcontrast
images of the most caudoventromedial aspect of the left
(A) (B)
(C) (D)
Figure 1. MRI of the head highlighting the mass in the left retrobulbar and periorbital region. (A) Mildly hyperintense signal on transverse T2w
sequence (yellow arrow). (B) Moderate to marked contrast-enhancing signal on transverse T1w postgadolinium sequence (yellow arrow). The
medial aspect of the left nasal cavity is partially filled with noncontrast-enhancing material. (C) Moderate to marked contrast-enhancing signal on
dorsal T1w postgadolinium sequence (yellow arrow). A poorly circumscribed, extra-axial contrast-enhancing mass appears to breach through the
ethmoid bone, compressing the ventrolateral aspect of the left olfactory bulb (red arrow); this mass appeared to be contiguous with the
retrobulbar mass and the nasal hyperintensity. (D) Marked meningeal enhancement surrounding the lateral aspect of the left olfactory bulb
(yellow arrow) on a more caudal slice of transverse T1w postgadolinium sequence.
2ª2016 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.
Canine idiopathic orbital inflammation N. Rzechorzek et al.

temporalis muscle. Analysis of cerebrospinal fluid
(obtained from the cisterna magna) revealed an increased
protein concentration (0.79 g/L [<0.45 g/L]) with normal
cytology and total cell count, consistent with central ner-
vous system neoplasia, injury, degeneration, or ischemia.
Specifically, no etiological agents or exfoliating neoplastic
cells were observed, and there was no evidence of menin-
geal inflammation. Fine needle aspiration and MGG
cytology of the left mandibular lymph node indicated
reactive lymphoid hyperplasia, neutrophilia, and sus-
pected histiocytosis; aspirates of the right mandibular
lymph node were nondiagnostic. Together with the avail-
able literature on orbital disorders in canines, the findings
were most consistent with a retrobulbar meningioma or
soft tissue neoplasm with intranasal and intracranial
extension, rhinitis, reactive sialadenitis, and reactive or
metastatic local lymphadenopathy and myositis. However,
lymphatic drainage from an area of primary chronic
inflammation could not be completely excluded.
On the basis of our most likely differential, the dog
was referred internally to the Oncology Service 7 days
later, by which point there was marked left ocular conges-
tion, corneal ulceration, and constant blepharospasm.
Three-view thoracic radiographs were taken to complete
staging and no gross metastatic disease was observed. Left
enucleation was elected as a diagnostic and therapeutic
measure and required a complex transpalpebral approach
with frontal craniectomy. The retrobulbar mass was
observed extending deep into the orbit and appeared to
be invading the skull in the region of the ethmoidal
foramina. The lesion was successfully debulked prior to
gentle dissection of the abnormal tissue just lateral to the
olfactory bulb –this was removed with part of the cribri-
form plate and olfactory nerves, followed by lavage of the
site and routine closure. Standard intra- and peri-opera-
tive analgesia and antibiosis were provided.
Histopathologically, the retrobulbar mass contained
skeletal muscle and adipose tissue diffusely infiltrated by
a nonencapsulated spindle cell tumor with a fascicular
(bundled) architecture lacking storiform structure (a mat-
ted, irregularly whorled appearance typical of fibrous his-
tiocytoma) (Fig. 2). The spindle cells showed moderate
nuclear pleomorphism, although mitotic figures were rel-
atively sparse (<1 per 10 high-powered fields at 40X) and
there was no intrinsic tumor necrosis. Myofiber loss and
regenerative changes were evident. There was a promi-
nent inflammatory infiltrate, consisting of diffuse inflam-
mation interspersed with inflammatory nodules
(lymphoplasmacytic aggregates). The tumor also extended
into mature cancellous and cortical bone of the skull.
The spindle cell proliferation expanded and effaced the
retrobulbar soft tissue and skeletal muscle. Together with
lymphoplasmacytic infiltration and a prominent reactive
fibroblastic profile, the aggressive nature of this mass was
consistent with a malignant spindle cell tumor, a scleros-
ing form of idiopathic orbital inflammation (ISOI) or an
inflammatory myofibroblastic tumor (IMT) [1–3]. Given
the sparcity of literature describing IMT in the dog, the
absence of any reports describing ISOI in this species,
and the distribution of the lesion, the most likely histo-
logical diagnosis was malignant peripheral nerve sheath
tumor.
(A) (B)
Figure 2. Photomicrographs capturing key histological features of the left retrobulbar mass (hematoxylin and eosin stain). Spindle cell
proliferation with lymphoplasmacytic inflammatory nodules (yellow arrows; lacking germinal follicular architecture) and diffuse inflammation
infiltrating muscle and adipose tissue. (A) Scale bar =200 lm (B) scale bar =50 lm.
ª2016 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd. 3
N. Rzechorzek et al.Canine idiopathic orbital inflammation

Due to incomplete excision of the suspected retrobul-
bar sarcoma, definitive-intent radiation therapy was rec-
ommended to decrease the likelihood of tumor
recurrence. Radiation therapy consisted of 19 fractions of
2.8 Gy prescribed to the planning target volume (PTV) to
a total dose of 53.2 Gy, normalized to 100% in isocenter.
The clinical target volume (CTV) included all residual
tumor tissue, postsurgical swelling, and 3–5 mm radially
to account for microscopic disease. The PTV was created
following an expansion of the CTV by 3 mm in all
dimensions. Tissue equivalent material (5 mm) was uti-
lized to ensure adequate dose to the superficial subcuta-
neous tissues. The minimum dose and heterogeneity
within the PTV and CTV were 49.3 Gy and 14% and
50.1 Gy and 12%, respectively; the maximum dose was
contained within the PTV. The dog tolerated radiation
therapy well, although he developed acute grade 2 skin
toxicity with erythema and dry desquamation and grade 3
oral mucositis [4]. These signs were effectively managed
with a standard combination of antiinflammatories, anal-
gesics, antipruritics, antibiotics, and topical treatments,
and resolved within 3 weeks.
Twenty weeks postsurgery, the dog was clinically well
and restaging with computed tomography (CT) provided
no evidence of local tumor recurrence (Fig. 3). The
regional lymph nodes, left eye socket, left orbital bone
lysis, seroma, and soft tissue lesion within the left nasal
cavity were static compared to images acquired immedi-
ately postsurgery. There was, however, mild contrast
uptake in the right orbital rim and 26 weeks postsurgery,
the dog represented to the referring veterinarian with
right ocular discomfort, right-sided head tilt, and vacant
episodes. Meloxicam (0.1 mg/kg PO, q24 h) and 1%
prednisolone acetate ophthalmic suspension (one drop in
the affected eye, q6–8 h) failed to resolve all of the signs
(although the head tilt and vacancy disappeared, suggest-
ing that these signs were related to pain rather than to
lesions of the vestibular system or forebrain, respectively).
The dog returned to the hospital with right exophthal-
mos, conjunctival hyperemia, mild episcleral congestion,
and ulcerative keratitis. Pupillary light reflex, menace
response, lacrimation, and intraocular pressure
(19 mmHg) were normal, digital retropulsion was
reduced, and ultrasonography revealed a heterogenous
mass ventromedial to the orbital rim. Advanced imaging
demonstrated similar findings to those observed in the
left retrobulbar space at initial referral. A right retrobul-
bar soft tissue mass (lacking fat intensity), with right
temporal and pterygoid myositis was observed with both
MRI and CT, but no evidence of the original tumor was
seen (Fig. 4). Immunosuppressive therapy (prednisolone
at 2 mg/kg PO, q24 h for 7 days, then switching to dex-
amethasone at 0.3 mg/kg PO, q24 h) temporarily relieved
the clinical signs, but the dog died 9 days later due to
clinical signs unrelated to the ocular mass and further
investigations including necropsy were declined. Retro-
spective immunohistochemical labeling (Table 1) of the
left retrobulbar mass was negative for S100, CD34, bcl2,
desmin, MyoD, and smooth muscle actin, ruling out
IMT [2, 5] and most spindle cell sarcomas including a
peripheral nerve sheath tumor. The inflammatory infil-
trate was composed predominantly of T lymphocytes
(CD3), with small numbers of plasma cells (CD138), a
subset of which expressed IgG4 (Fig. 5). However, the
lesion did not fulfill suggested histological criteria for
IgG4-related disease (including an IgG4+/IgG+plasma
(A) (B)
Figure 3. Computed tomography images of the head, postresection of left retrobulbar mass; soft tissue window postcontrast (iohexol). (A)
Immediately postsurgery for radiation therapy planning, showing local inflammation around the surgical site. (B) 20 weeks postsurgery. Thickened
subcutaneous tissue can be seen within the irradiated field with mild contrast enhancement (yellow arrows) but no gross tumor recurrence. The
regional lymph nodes, left eye socket, left orbital bone lysis, seroma, and soft tissue lesion within the left nasal cavity are static compared to (A).
There is evidence of reduced local inflammatory reaction (lack of contrast enhancement) in the left retro-orbital region. Note, however, mild
contrast uptake in the right orbital rim –potentially a sign of early inflammation developing on this side (red arrows).
4ª2016 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.
Canine idiopathic orbital inflammation N. Rzechorzek et al.

cell ratio of >40%) and the final diagnosis was most con-
sistent with ISOI [6, 7].
Discussion
We have reported the progressive clinical course and key
diagnostic features of a novel, noninfectious inflammatory
orbital disease in a dog. Such disorders occur infrequently
in animals and include immune-mediated conditions and
idiopathic orbital inflammation (IOI; otherwise known as
orbital pseudotumor) [1, 2, 8]. We consider that the term
“pseudotumor” is less than ideal for these orbital inflam-
matory growths –we have thus adopted the most recent
nomenclature from the human literature to promote
cohesive cross-translational understanding of the pathol-
ogy while awaiting a more refined classification in
companion species. Most orbital tumors are considered
to be malignant with a poor to guarded prognosis [9,
10]; by contrast, IOI is defined as benign, orbital inflam-
mation without evidence of a specific local or systemic
etiology [8, 11–14]. A common disorder in humans, IOI
occurs most often between the third and fifth decades of
life [8, 11, 13, 15]. These lesions may be bilateral or alter-
nating (ipsilateral remission followed by contralateral
emergence) but typically present unilaterally, thus mim-
icking neoplasms [8, 15–17]. Although nonmetastatic, IOI
is locally aggressive, often leading to severe visual and
oculomotor dysfunction, requiring surgical intervention
[12, 13]. Having excluded a specific cause for the dog’s
presenting signs, and noting the late mimicry of these
signs in the right orbit, we considered IOI as a differential
diagnosis.
Other differentials for progressive inflammatory lesions
leading to exophthalmos in the dog include nodular gran-
ulomatous episcleritis (NGE), nodular fasciitis, and
fibrous histiocytoma [9]. Nodular granulomatous episcle-
ritis typically affects the cornea or adnexal structures such
as the temporal limbus and nictitating membrane and is
often bilateral, although the single published report of
orbital NGE in the dog had a unilateral presentation [9].
Likewise, canine ophthalmic nodular fasciitis appears to
affect the conjunctiva and eyelids rather than the orbit
[18] and we are not aware of any bilateral presentations
of this disorder in humans or animals. Unlike the lesion
described above, the orbital NGE lesion reported by Bar-
nes et al. [9] appeared to communicate with the nictitat-
ing membrane without any bony involvement or
extension beyond the orbit. In addition, regional lym-
phadenopathy was not detected [9]. While the retrobulbar
mass in this report had a nodular component histologi-
cally, it lacked the true lymphoid follicular architecture
(A) (B)
Figure 4. Contralateral emergence of identical retrobulbar lesion 26 weeks postsurgery, identified with advanced imaging. (A) CT (soft tissue
window postcontrast) shows right retrobulbar soft tissue mass (yellow arrow), lacking fat intensity, with right temporal and pterygoid myositis. (B)
Concordant findings on MRI (dorsal T1w postgadolinium sequence; yellow arrow). The following additional sequences were also performed in
transverse (T1w, T2w, T1w postgadolinium, T2w*, fluid-attenuated inversion recovery), sagittal (T2w), and dorsal (T2w) planes (data not shown).
Table 1. Details of immunohistochemical methods.
Antibody
mAb*/
pAb
†
Dilution Blocking Pretreatment Supplier
S100 pAb 1:1500 Peroxide Enzyme Dako
CD34 mAb 1:50 Peroxide EDTA
‡
Dako
Bcl2 mAb 1:50 Peroxide EDTA Dako
Desmin mAb 1:100 Peroxide EDTA Dako
MyoD mAb 1:50 Peroxide Citrate Dako
SMA
§
mAb 1:1000 Peroxide EDTA Dako
CD3 mAb 1:200 Peroxide EDTA Leica
CD138 mAb 1:100 Peroxide EDTA Dako
IgG4 mAb 1:8000 Peroxide EDTA TBS
–
*Monoclonal antibody.
†
Polyclonal antibody.
‡
Ethylenediaminetetraacetic acid.
§
Smooth muscle actin.
–
The Binding Site.
ª2016 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd. 5
N. Rzechorzek et al.Canine idiopathic orbital inflammation

noted in NGE and was predominated by T lymphocytes
rather than B lymphocytes [9]. The lack of a moderate
eosinophilic component and the aggressive fibrotic prolif-
eration further distinguish this lesion from NGE, and
fibrous histiocytoma is ruled out by the absence of histio-
cytic cells. Nodular fasciitis (also described as pseudosar-
comatous fasciitis and nodular fibrositis) rarely affects the
orbit and tends to have a more rapid clinical course
[19–22]. Like ISOI, its histological features mimic sar-
coma and involvement of adipose tissue and skeletal mus-
cle may be observed along with nerve entrapment and
some mitotic figures [20]. However, most reported cases
of nodular fasciitis affecting the eye and adnexa in
humans have demonstrated a variable amount of intercel-
lular myxoid ground substance, multinucleated giant cells,
and only scant infiltration of lymphocyte and mononu-
clear cells rather than lymphocytic aggregates [20, 22] –
histopathological features distinct from ISOI. In addition,
although bony erosion has been reported in a few cases
[23, 24], the prognosis for nodular fasciitis is generally
excellent after local excision [20–22].
The left retrobulbar mass described herein penetrated
the bony walls of the orbit, and compressed the left olfac-
tory bulb. Likewise, bony destruction occasionally results
from severe chronic IOI in humans, which classically
involve orbital fibrosis, optic nerve compression, and
impaired ocular rotation [15]. As noted in the dog, subse-
quent intracranial infiltration produces local meningeal
contrast enhancement on MRI [25]. However, in contrast
to humans, the canine orbital margin is incomplete, with
contributions from the zygomatic salivary gland and
medial surface of the temporalis muscle [13]. Changes in
these structures on MRI may thus represent a manifesta-
tion of IOI peculiar to the dog. Although many human
IOI lesions appear hypointense on T2w images, the
hyperintensity of the canine retrobulbar mass is typical of
sclerosing subtypes of human IOI (ISOI) in which active
inflammation and edema can mask the effects noted in
other types [11, 16]. In essence, the canine imaging data
effectively mirror that described for human ISOI, except-
ing minor differences explained by species-specific anat-
omy.
Histologically, the canine mass was dominated by pat-
chy aggregates of lymphocytes and fibrous proliferation –
akin to late-stage human IOI lesions in which increased
connective tissue is consistently present [15]. Descriptions
of orbital pseudotumor in the veterinary literature, how-
ever, include only one prosimian primate and a lacrimal
pseudotumor in a bull terrier [26, 27]. Feline lesions orig-
inally recorded as orbital pseudotumor have since been
reclassified as feline restrictive orbital myofibroblastic sar-
coma (FROMS) owing to their highly aggressive nature,
resulting in bilateral exenteration and/or euthanasia in all
reported cases [1, 3, 28, 29]. However, a few early reports
in this species did describe a relatively extended survival
time alongside immunosuppressive treatment [13], sug-
gesting one or more of the following: (1) that a less
aggressive subtype exists, (2) that patient-derived factors
modify disease progression and/or therapeutic response,
or (3) that FROMS and feline IOI are two separate dis-
ease entities. The course of FROMS resembles the clinical
history of the dog, with insidious exophthalmos and
(A) (B)
Figure 5. Photomicrographs capturing key immunohistochemical features of the left retrobulbar mass. (A) The inflammatory infiltrate (brown-
stained cells) was predominantly composed of T lymphocytes (CD3 immunolabel; scale bar =50 lm). (B) Small numbers of IgG4-expressing
plasma cells were noted (brown-stained cells highlighted by yellow arrows; IgG4 immunolabel; scale bar =50 lm).
6ª2016 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.
Canine idiopathic orbital inflammation N. Rzechorzek et al.

Progressive exophthalmos +/– strabismus
Resistance to retropulsion and pain*
+/– pyrexia +/– haematological changes
Resistance to retropulsion and no pain*
or pyrexia +/– biochemical changes
Unilateral retrobulbar or periorbital
mass on ultrasonography
Infecous inflammatory lesion
(abscess, foreign body, cellulis) No evidence of infecous cause
Neoplasm
Non-infecous inflammatory lesion
IgG4+/IgG+ rao > 40%
Consider IgG4-RD
IgG4+/IgG+ rao < 40%
Consider IOI/ISOI
Consider immunosuppressive therapy +/– surgical
debulking and radia on therapy**
Rule out IMT, NGE and
nodular fasciis
Consider IOI, ISOI, IgG4-RD
Oncology/surgery referral for
staging and treatment
Monitor for contralateral
emergence
Monitor for
recurrence/metastasis
Figure 6. Proposed diagnostic approach to progressive exophthalmos in the dog. Early referral to ophthalmology (and/or neurology) is indicated for
progressive exophthalmos. Ultrasonography should include both orbits; upon observation of a retrobulbar mass, ultrasound-guided FNA for cytology
and culture and sensitivity (aerobic/anaerobic bacteria, mycoplasma, and fungi) should be performed. In some geographical locations, a latex
cryptococcal antigen agglutination test might be warranted. For infectious inflammatory lesions, blood culture and targeted antimicrobial therapy
with or without surgical exploration should be considered. Lack of evidence for an infectious cause should prompt advanced imaging including MRI
with contrast and CSF analysis (if MRI indicates intracranial and/or meningeal involvement). At this stage, an incisional biopsy of any soft tissue mass
should be performed followed by histopathology, extensive immunohistochemistry, and culture. Incisional biopsy was not considered prior to
enucleation and debulking in this case because of (a) the rapid progression of clinical signs and pain that were compromising welfare (b) the
consideration that biopsy would also require general anesthesia and (based on our top differential) we anticipated that debulking of the mass would
still be required in due course, and (c) that incisional biopsy would have provided less information than excision with respect to diagnosis and staging.
In the case of a positive culture, the diagnosis should be revised (dotted arrow). For confirmed neoplasms, three-view thoracic radiographs and FNA of
regional lymph nodes are required for staging. Note that a bilateral presentation should rouse suspicion of a noninfectious inflammatory
pathogenesis. For these lesions, the subtype should be determined and IgG4/IgG ratio should be investigated by both serology and
immunohistochemical analysis. Monitoring for pain and ulcerative keratitis is paramount throughout the diagnostic work-up and should be treated
promptly. *Signs of ocular pain in the dog include photophobia, blepharospasm, self-trauma, increased lacrimation, acute aversive response on
palpation of the globe or upon mouth opening and globe retraction (note that globe retraction may be prohibited by a retrobulbar mass).
**Enucleation may be required at later disease stages on welfare grounds. IMT, inflammatory myofibroblastic tumor; NGE, nodular granulomatous
episcleritis; IgG4-RD, IgG4-related disease; IOI, idiopathic orbital inflammation; ISOI, idiopathic sclerosing orbital inflammation.
ª2016 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd. 7
N. Rzechorzek et al.Canine idiopathic orbital inflammation

progressive lack of globe mobility [1, 3]. Neither FROMS
nor IOI are reported to metastasize –however, they exhi-
bit divergent microscopic features. Feline restrictive orbi-
tal myofibroblastic sarcoma displays a mixed
inflammatory response with perivascular cellular infiltrate
and fibrous tissue spreading along fascial planes [1]. Mild
fibroblastic pleomorphism without mitotic figures and
positive immunohistochemistry for S100, smooth muscle
actin and vimentin (with or without glial fibrillary acidic
protein) are additional characteristic features not seen in
the canine mass [1, 28].
Idiopathic sclerosing orbital inflammation accounts for
6–8% of human inflammatory orbital lesions and is
otherwise described as “sclerosing orbital pseudotumor”
[11, 16, 30]. ISOI patients exhibit fewer inflammatory
signs, a more chronic onset, and more aggressive disease
course than other IOI types, reminiscent of that seen in
the dog [30]. Histopathologically, ISOI comprises a dense
fibrosis with a paucicellular infiltrate of lymphocytes, his-
tiocytes, eosinophils, and plasma cells [30, 31]. This dam-
ages orbital structures via cicatricial entrapment with
mass effect and is associated with a poor response to con-
ventional therapy (corticosteroids radiation) [11, 17,
25, 30, 31]. While several of these features may be seen
with aggressive orbital neoplasms, we are not aware of
any neoplastic disorders that would present independently
(and almost identically) in both orbits. Overall therefore,
the clinical, radiological, and immunohistochemical fea-
tures of the lesion in this dog are most consistent with
ISOI.
A small proportion of IgG4-positive plasma cells were
identified within the ISOI which, to the best of our
knowledge, is the first reported observation of this cell
subclass within a pathological lesion affecting the canine
orbit. Recently characterized, human IgG4-related disease
comprises a group of fibro-inflammatory conditions of
unknown origin featuring tumor-like expansions in one
or multiple organs, with sclerosing fibrosis and a dense
lymphoplasmacytic infiltrate rich in IgG4-positive plasma
cells [6, 7]. A significant proportion of human ISOI cases
are now known to be IgG4-related, and importantly, this
trait imparts favorable susceptibility to steroid and radia-
tion therapy [31]. Although the canine lesion exhibited
many characteristics of IgG4-related ISOI, the relative
density of IgG4-positive plasma cells was insufficient to
make this diagnosis based on the proposed human crite-
ria [6, 7]. This is consistent with the steroid resistance
observed initially, however, we cannot exclude the possi-
bility that early treatment with antiinflammatory doses of
prednisolone may have altered the IgG4-positive compo-
nent of our immunohistochemical readout in favor of an
ISOI diagnosis [31]. Many human patients experience
recurrence following acute-phase resolution of IOI with
immunosuppressive corticosteroid treatment [3, 17].
Unfortunately, in this dog, the long-term efficacy of the
immunosuppressive treatment with corticosteroids could
not be evaluated due to his unexpected death. The evi-
dence base is equally unclear for the use of nonsteroidal
antiinflammatories, chemotherapeutic agents, and other
immunomodulatory drugs in the context of ISOI [2, 12,
17]. Although the relative long-term benefit of radiation
therapy cannot be determined in this case, local control
of residual tumor tissue in the left orbit was retained for
at least 26 weeks.
In conclusion, this report represents the first descrip-
tion of ISOI in an animal, with pathological features
distinct from FROMS, IMT, NGE, and nodular fasciitis.
Whilst IOI is rare beyond human medicine, our find-
ings highlight the need to consider this diagnosis in
dogs presenting with recalcitrant ophthalmic signs asso-
ciated with a retrobulbar mass. Given their proximity to
the brain, and propensity for local invasion and con-
tralateral emergence, early referral for these lesions is
warranted, even though a standard-of-care therapy is
not clear [1, 28, 29]. Advanced imaging instituted
promptly may capture early changes in the contralateral
orbit (for bilateral presentations) before clinical signs
emerge, and immunomodulatory therapy (with or with-
out surgery) may improve patient welfare. Most impor-
tantly, however, the diagnostic challenge of this case
argues for incisional biopsy of orbital masses at first
presentation, followed by extended immunohistochemi-
cal analysis to rule out chronic inflammation and other
benign lesions that mimic neoplastic disease (Fig. 6).
Specific stains for inflammatory cell phenotypes and
polyclonality of lymphoplasmacytic populations can
delineate IOI from lymphoproliferative disease and other
neoplasms. Whether ISOI represents a malignant trans-
formation of IOI is worthy of further investigation. On
the basis of this case, we propose that ISOI be consid-
ered as a differential diagnosis for progressive exoph-
thalmos in the dog.
Acknowledgment
The authors gratefully acknowledge Richard McCallum of
Batchelor Davidson and Watson Ltd and the following at
the Royal (Dick) School of Veterinary Studies for their
clinical and technical expertise: Spela Bavcar, Elizabeth
Munro, Victoria Macklin, Sionagh Smith, and all staff
members that supported the diagnostic work-up and
management of this case.
Conflict of Interest
None declared.
8ª2016 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.
Canine idiopathic orbital inflammation N. Rzechorzek et al.

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ª2016 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd. 9
N. Rzechorzek et al.Canine idiopathic orbital inflammation