Literature Review
Orbitofrontal Cholesterol Granuloma: Four Case Reports and
a Systematic Review of the English Literature
Joshua D. Hughes1, Jeffery T. Jacob1, James A. Garrity2, Diva R. Salomao3, Michael J. Link1
Key words
- Cholesterol granuloma
- Chronic hematic cyst
- Orbital cholesterol granuloma
- Orbitofrontal cholesterol granuloma
Abbreviations and Acronyms
CG: Cholesterol granuloma
OFCG: Orbitofrontal cholesterol granuloma
MRI: Magnetic resonance imaging
From the Departments of 1Neurologic Surgery,
2
Ophthalmology, and 3Pathology, Mayo Clinic School of
Medicine, Rochester, Minnesota, USA
To whom correspondence should be addressed:
Michael J. Link, M.D.
[E-mail: link.michael@mayo.edu]
Citation: World Neurosurg. (2016) 87:355-361.
http://dx.doi.org/10.1016/j.wneu.2015.11.095
Journal homepage: www.WORLDNEUROSURGERY.org
Available online: www.sciencedirect.com
1878-8750/$ - see front matter ª 2016 Elsevier Inc.
All rights reserved.
INTRODUCTION
Cholesterol granuloma (CG) occurs sec-
ondary to an inflammatory response to the
breakdown of blood products.1e5 The
most prominent features of CG are
cholesterol clefts with granulomatous
inflammation without epithelial elements
(which distinguishes CG from choles-
teatoma).6 CG occurs most commonly in
the petrous apex but has rarely been
reported to occur in other regions of the
head, including the orbit. Historically,
orbitofrontal CG (OFCG) occurs most
commonly in the lacrimal fossa and has
been labeled cholesteatoma, lipid
granuloma of the frontal bone,
xanthomatosis of the orbit, and chronic
hematic cyst.4,7e10 Although there are
case reports and small case series on
OFCG, no systematic literature review
has been done to examine patient
characteristics, presentation, treatment,
and outcomes. We present 4 cases that
occurred at our institution and a
systematic review of the English language
literature.
WORLD NEUROSURGERY 87: 355-361, MARCH 2016
- INTRODUCTION: Primary orbitofrontal cholesterol granuloma (OFCG) is rare.
We present 4 cases of OFCG and a systematic literature review to examine
patient characteristics, presentation, treatment, and outcome.
- METHODOLOGY: Our institutional records were reviewed for OFCG cases. A
systematic literature review was performed using PubMed. Inclusion criteria
were English-language studies with pathology-proven OFCG. Exclusion criteria
were OFCG in a craniofacial sinus. The search-string yielded 172 results. Fifty
studies met inclusion criteria (39 primary and 11 secondary), and relevant data
were reviewed.
- RESULTS: Four patients underwent surgery for OFCG at our institution (ages
53, 43, 34, and 43; 3 females, 1 male). All patients were treated with surgery using
a tailored frontal-orbital craniotomy with complete resection. There was no
recurrence at 12-month, 4-year, 10-year, and 22-year follow-up for each patient,
respectively. Systematic review of the literature identified 172 patients. Follow-
up was available in 93 patients (54.1%) with a mean follow-up of 43.3 months.
Seven patients demonstrated recurrence at a median of 36 months following
surgery. Combining our 4 cases with the 93 patients with reported follow-up
gives a recurrence rate of 7% (7/97). Recurrence was associated with incom-
plete resection and an orbital approach.
- CONCLUSION: Thorough removal of the lesion with curettage of the boney
cavity is recommended for OFCG. Recurrence following complete removal of
OFCG is rare.
METHODS secondary). See Figure 1, a flow diagram, for
After institutional IRB approval, the medical systematic literature review. All patients
records at our tertiary medical center were (both institutional and from the literature
reviewed for cases of OFCG and 4 cases were review) were reviewed for patient
discovered. A PubMed search was per- demographics, signs and symptoms,
formed on January 11, 2015 using the history of trauma, imaging, intracranial
following string: “cholesterol granuloma” OR extension, surgery, recurrence, and length
“lipid granuloma” OR “hematic cysts” OR “hematic of follow-up. Various surgical approaches
cyst” OR “chronic hematic cyst” OR “xanthoma- were categorized as a limited orbital or scalp
tosis” AND (frontal OR orbit OR orbital OR orbi- flap approach and were analyzed for recur-
tofrontal) NOT sinus [title]. The PubMed search rence with a chi-square test. A P value < 0.05
yielded 172 results, and 49 potential primary was considered statistically significant.
studies were found and screened for further
sources not found in the PubMed search RESULTS
(secondary sources). Exclusion criteria were
non-English reports, animal studies, and Case 1
undocumented pathology or imaging con- A 53-year-old female presented recently
firming OFCG. Using these criteria, 80 po- with 5 months of left ocular displacement
tential sources (49 primary and 31 secondary) and 3 months of uncomfortable periorbital
were identified, 30 were excluded, and 50 pressure sensation. On examination, she
met inclusion criteria (39 primary and 11 had intact extraocular movements and
www.WORLDNEUROSURGERY.org 355

JOSHUA D. HUGHES ET AL.
Figure 1. Flow diagram of systematic literature review.
normal visual acuity and visual fields to
confrontation in both eyes. Her left globe
was depressed. Magnetic resonance imag-
ing (MRI, Figure 2) showed an abnormality
in the left frontal bone expanding into the
superior left orbit displacing the globe
inferiorly. It had an expansile appearance
and was T1 and T2 hyperintense with
patchy mild enhancement and no
restricted diffusion (Figure 2B and C). She
underwent a left orbitofrontal craniectomy
with complete evacuation of the cyst
contents and drilling of the boney cavity.
Pathology was consistent with CG
(Figure 3). She had no recurrence at 12-
month follow-up (see Figure 2D).
Case 2
A 43-year-old female presented with
headaches and 1.5-year history of
increasing left eye swelling. On further
history, she reported that people had
noticed her left eye appeared different
than her right for 20 years, which was
confirmed by pictures. She endorsed oc-
casional double vision. On examination,
she had downward displacement of the
356 www.SCIENCEDIRECT.com
ORBITOFRONTAL CHOLESTEROL GRANULOMA
globe with proptosis of 2
3 mm and
restricted left upper gaze. Computed to-
mography (CT) of her head showed a 2.5-
cm expansile cystic mass in the left
lacrimal fossa. No MRI was done. She
underwent a left frontotemporal crani-
otomy with left superior orbitotomy. The
defect had eroded into the anterior fossa
but did not invade the dura. The defect
was curettaged until no membranes
remained. There was no recurrence at 120
months.
Case 3
A 34-year-old male presented with 8
months of blurred vision and a sensation
of pressure in his right eye. He had a
remote history of trauma to the temporal
area 4
5 years prior. On examination he
had 1 mm of proptosis and 2 mm of globe
displacement. CT of his head showed a
mass in the right lacrimal fossa with
erosion into the right frontal sinus. MRI
showed a 1.5-cm mass that was bright on
T1- and T2-weighted images. There was
no enhancement. He underwent a right
frontal craniotomy through a bicoronal
WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2015.11.095
LITERATURE REVIEW
flap. A small frontal craniotomy was per-
formed around the lesion and was
removed en bloc. The frontal sinus was
breeched, and the pericranium was used
to exclude the sinus. He has had no
recurrence at 264 months.
Case 4
A 43-year-old female presented with a
sensation of pressure behind the right eye
that had been increasing for a few years.
She had no history of trauma. Her exam-
ination was significant for 3 mm of right
eye proptosis and 2 mm of displacement.
CT showed a uniform soft tissue mass in
the right lacrimal fossa that measured 2.5
cm with boney destruction of the lateral
orbit and middle fossa. There was no
enhancement on MRI. She underwent a
right frontotemporal craniotomy. There
was no erosion of the lesion into the
periorbital or dura, and it was removed
with curettes. There was no recurrence at
48 months.
Systematic Literature Review
In 50 studies, 172 patients were found with
pathologically confirmed OFCG.1-50 The
studies were published between 1934 and
2015 (median 1994). The median number
of patients in each study was 1 (range,
1
31). See Table 1 for a list of included
studies and patient demographics.
The mean patient age was 42 (range,
14
83) years, and 154 (89.5%) patients
were male. There was no history of trauma
in 117 (68.0%) patients, and 37 (21.5%)
patients had either a remote or recent
trauma history. The most common pre-
senting symptom and physical examination
finding was proptosis (61.6% and 84.9%,
respectively). See Table 2 for a complete
listing of patient signs and symptoms and
physical examination findings. The most
common location was either the right
(n ¼ 77, 44.8%) or left (n ¼ 60, 34.9%)
superolateral portion of the orbit. The
location was unspecified in 31 (18.0%)
patients.
Regarding symptoms, patients com-
plained of the following: 106 (61.6%) eye
protrusion, 62 (36.0%) eye swelling, 53
(30.8%) diplopia, 35 (20.3%) pain, 21
(12.2%) vision changes, and 8 (4.7%) eye
displacement. The mean duration of symp-
toms before diagnosis was 20.5 (0.25
312)
months. On physical examination findings,
patients suffered from the following: 146
 LITERATURE REVIEW
JOSHUA D. HUGHES ET AL. ORBITOFRONTAL CHOLESTEROL GRANULOMA

flap with or without craniotomy (n ¼ 23,

12.9%). The surgical approach was un-
known in 71 patients (39.9%). At surgery, 37
(21.5%) patients were found to have intra-
cranial extension. Mean follow-up was 43.3
(2
204) months in the 93 (54.1%) patients
who had documented follow-up.
Seven patients exhibited recurrence with a
median time to recurrence of 36 (range,
1
240) months.1,25,26,28,36,38,47 Combining
our 4 cases with the 93 patients with reported
follow-up gives a recurrence rate of 7% (7/
97). One case1 recurred after 7 months, and
the cause was thought to be known
residual. Another case recurred 20 years
after a prior surgery and then again 1
month after needle aspiration and
drainage.38 The other cases had surgery at
other institutions, and although the
surgical approach was known, the extent of
the first surgery was unknown. Out of 93
patients with known surgical approaches
and follow-up, 64 of them (73%) were
orbital and 22 of them (27%) were scalp
approaches (including our 4 cases). All 7
patients with recurrence underwent an
orbital approach (P ¼ 0.04 comparing
orbital and scalp approaches for recurrence).

Figure 2. A 53-year-old female underwent a left orbitofrontal craniectomy for a left lacrimal fossa DISCUSSION
lesion. Pathology returned as orbitofrontal cholesterol granuloma. Preoperative computed
tomography (A) showed an osteolytic lesion. Preoperative magnetic resonance imaging (MRI)
showed a primarily hyperintense lesion on both T1 and T2 sequences (B and C) with some contrast
History and Nomenclature
enhancement (B). She had no recurrence at 3-month follow-up, and MRI (D) showed no residual In a review by McNab et al.,4 the first
cholesterol granuloma. reported OFCG was credited to Denig,
who called his findings a subperiosteal
blood cyst. However, on review of this
source, no cholesterol granules were
(84.9%) proptosis, 90 (52.3%) eye displace- the right or left lacrimal fossa (n ¼ 137,
reported on microscopic examination. In
ment, 73 (42.4%) extraocular motility prob- 79.7%). The most common surgical
a review by Hanbery and Rayport,20 they
lems, and 24 (14.0%) vision examination approach was an orbitotomy through a brow
state that Pincus was the first to report
changes. The most common location was incision (n ¼ 79, 44%), followed by a scalp
OFCG in 1933, labeling the pathology
“pseudo-cholesteatoma”; as Pincus’s
article is in German, it was excluded in
our analysis. However, other English
literature papers support that Pincus’s
microscopic pathology was consistent
with CG.9,20,34 Knapp is the first to clearly
report a pathology consistent with OFCG
in the English literature,20,34 which he
called “xanthomatosis.” Ramsey et al.40
were the next to report on OFCG, which
they labeled “post-traumatic granuloma.”
Interestingly, one of these cases was
operated on by Wilder Penfield. Hanbery
and Rayport20 were the first to offer
Figure 3. Hematoxylin-eosin pathology slides for Case 1 at 100 (A) and 400 (B) magnification
showing cholesterol crystals in an inflammatory background with hemosiderin deposits.
the label “orbitofrontal cholesterol
granuloma.” Despite this early suggestion

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 LITERATURE REVIEW
JOSHUA D. HUGHES ET AL. ORBITOFRONTAL CHOLESTEROL GRANULOMA

that clearly defined the pathology,

Table 1. Systematic Literature Review of Orbital Cholesterol Granuloma nomenclature continued to vary, including
Author Year Term Number Age* Male the terms cholesteatoma, chronic hematic
cyst, chocolate cyst, xanthomatosis,
1 Aferzon 2002 Cholesterol granuloma 1 42 0 post-traumatic granuloma, and lipid-
2 Alport 1954 Cholesteatoma 1 45 1 containing granuloma, but most reports
have used “cholesterol granuloma” (n ¼ 34,
3 Alsuhaibani 2011 Cholesterol granuloma 2 49.5 1
68%).
4 Arat 2003 Cholesterol granuloma 8 45 6
5 Bergin 1988 Chronic hematic cysts 3 41.3 3 Pathophysiology
The exact pathophysiology and mechanism
6 Chow 2005 Cholesterol granuloma 6 44.7 6
of OFCG formation remain largely un-
7 Dickey 1992 Cholesterol granuloma 1 36 1 known. In petrous apex CG, the prevailing
8 Dobben 1998 Cholesterol granuloma 3 50.3 3 theory regarding development is the
“obstruction-vacuum theory,”51 which states
9 Eijpe 1990 Cholesterol granuloma 11 41.2 11
that CG develops after blockage of normal
10 Eugenidis 1980 Cholesterol granuloma 1 31 1 airflow in mastoid air cells that causes
11 Fukuta 1990 Cholesterol granuloma 1 41 1 negative pressure and subsequent
hemorrhage. This theory developed mainly
12 Garcia-Gonzalez 2010 Cholesterol granuloma 2 41 2
from experimental animal models.52-60
13 Gillissen 1984 Chocolate cyst 3 31 2 However, as OFCG does not occur in
14 Hanbery 1955 Cholesterol granuloma 3 32 3 pneumatized bone, this theory has fallen
15 Heaton 1993 Cholesterol granuloma 1 31 1
out of favor. Furthermore, CG has been
reported in other areas of the body such as
16 Hill 1992 Cholesterol granuloma 31 43 28 the breast, lung, and abdomen.61-63
17 Imre 2015 Cholesterol granuloma 1 44 1 One of the more common theories
18 Jordan 2007 Cholesterol granuloma 1 29 1 regarding OFCG is that it is associated
with an anomaly that develops in the
19 Karim 2000 Cholesterol granuloma 1 51 1 frontal bone after trauma.4,40 Evidence for
20 Kersten 1988 Chronic hematic cyst 2 37.5 1 this is cited in that the vast majority of
21 Khalatbari 2012 Cholesterol granuloma 1 14 0 OFCG occurs in males (89.5% in our re-
view). However, in our review, the major-
22 Kim 2014 Cholesterol granuloma 1 32 0
ity of patients (68.0%) had no history of
23 Knapp 1934 Xanthomatosis 2 35.5 2 significant trauma. This is assuming that
24 Lloyd 1986 Cholesterol granuloma 15 44.2 14 the degree of trauma it might take to cause
an abnormality in the bone to cause OFCG
25 Loeffler 1997 Cholesterol granuloma 6 43 6
is enough to be noted by the patient if it
26 Luxenberg 1990 Hematic cyst 1 46 0 occurred in the remote past. It could still
27 Madaree 1997 Chronic hematic cyst 1 50 0 be true that OFCG is induced by minimal
trauma.
28 Mani 2001 Cholesterol granuloma 1 40 1
Parke et al. theorized that OFCG may
29 McNab 1990 Cholesterol granuloma 27 43.7 24 arise from a nontraumatic irregularity in
30 Miller 1999 Cholesterol granuloma 1 53 1 the diploe. Selva et al.5 presented evidence
in support of this theory in that there is
31 Milne 1987 Chronic hematic cysts 3 38 3
“woven bone arranged in a dysplastic
32 Nicholls 1956 Cholesterol-containing granuloma 3 47.7 3 fashion at the periphery” of 2 OFCGs in
33 Okay 2010 Cholesterol granuloma 1 50 1 which they subject bone specimens for
analysis. There is one case of Paget
34 Ong 2008 Cholesterol granuloma 1 43 1
disease causing OFCG.32
35 Parke 1982 Cholesterol granuloma 2 32.5 2
36 Pfeiffer 1948 Cholesteatoma 1 43 1 Presentation, Physical Examination, and
37 Polito 1994 Cholesterol granuloma 1 32 1
Natural History
The most common presenting symptom
38 Ramsey 1948 Post-traumatic granuloma 2 50.5 2 was proptosis (61.6%), which was docu-
39 Rizvi 2014 Cholesterol granuloma 1 42 1 mented on clinical examination in 84.9%
40 Roman-Romero 2011 Cholesterol granuloma 2 41 2 of patients. Diplopia was present in 30.8%
of patients, and extraocular motility ab-
Continues normalities were noted in 42.4%, most

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 LITERATURE REVIEW
JOSHUA D. HUGHES ET AL. ORBITOFRONTAL CHOLESTEROL GRANULOMA

all the cases reviewed. Although there are

Table 1. Continued not enough data to analyze for factors
Author Year Term Number Age* Male associated with recurrence, our careful
review suggests that residual disease after
41 Rosca 2006 Cholesterol granuloma 4 40 4 incomplete removal is the most likely
42 Selva 2003 Cholesterol granuloma 2 38 2 cause of recurrence. All 7 instances of
43 Selva 2004 Cholesterol granuloma 1 54 1 recurrence were with an orbital approach,
and none with craniotomy. Although we
44 Selva 2003 Cholesterol granuloma 1 50 1 did find a statistically significant differ-
45 Shapiro 1986 Hematic cyst 2 36.5 2 ence (P ¼ 0.04) between the approaches
46 Sia 2012 Cholesterol granuloma 1 66 1 regarding recurrence, the data are not
enough to recommend one approach over
47 Wheeler 1937 Orbital cyst w/o epithelial lining 1 45 1
another. It is logical that better visualiza-
48 Wiot 1989 Chronic hematic cyst 2 37.5 1 tion is achieved with a scalp flap, as
49 Wolter 1966 Blood cyst with foreign body reaction 1 54 1 opposed to a more limited orbital
approach, which likely leads to more
50 Wright 1970 Lipid-containing granuloma 1 33 1
through curettage. Recently, there have
*Average age when >1 patient. been reports of combining endoscopy with
orbital approaches44,45,47 to better allow
for complete curettage, allowing minimal
invasion of an orbital incision with the
often in the superolateral direction. symptomatic and therefor undergo surgery. visualization of a scalp flap. Regardless,
Although severe pain was uncommon, One patient had an incidentally found pre- with any surgical approach the goal should
20.3% of patients had a dull ache in the sumed OFCG4 that was being observed, but be complete removal with thorough
affected orbit. Symptoms were present the outcome is unknown. Two cases had curettage or drilling of the boney cavity.
over a wide time range, from weeks to extensive OFCG. One caused boney
months, before patients came to medical destruction of the lateral orbit and
attention. Visual acuity was affected in 24 extended into the middle and anterior CONCLUSION
patients (14%) either by a mechanically cranial fossa.1 Another led to a phthisical Orbital frontal cholesterol granuloma is a
induced astigmatism or choroidal folds. globe and extensive boney destruction rare pathology that commonly presents
The lacrimal fossa was the most common and required orbital exoneration and with proptosis and diplopia. At least 172
location (79.7%) for OFCG. reconstruction of the orbit with calvarial reported cases of OFCG exist in the En-
The natural history of OFCG is unknown bone graft, temporalis muscle, and a glish literature. We report 4 additional
secondary to its rarity, and almost all pa- fascial flap.30 cases, for a total of 176 cases. Though
tients who come to medical attention are expansion causing extensive boney
Imaging Characteristics destruction is rare, there are a few re-
On skull radiographs, OFCG appears as an ported cases of OFCG becoming large and
osteolytic lesion with clear, regular mar- requiring extensive surgery. Therefore, we
Table 2. Clinical Findings in 172 gins and no sclerotic edges.14,27 CT find- recommend removal of the lesions when
Patients with Orbital Cholesterol ings are similar except the bone appears symptomatic. Asymptomatic lesions can
Granuloma more corrugated, and an isodense, non- be observed, though the need for tissue
enhancing, soft tissue mass can be seen diagnosis may lead to surgical treatment.
Signs and symptoms
extending into the affected orbit.14,15,27 Either primary orbital approaches or
Proptosis 106 (61.6%)
MRI typically shows a nonenhancing frontal flaps with or without craniotomy
Orbital swelling 62 (36.0%) mass with both high T1 and T2 signal are acceptable, though recurrence was
because of the paramagnetic hemoglobin more likely after an orbital approach.
Diplopia 53 (30.8%)
degradation products,1,4,11,13,14,19,25,26 Regardless of approach, complete surgical
Pain 35 (20.3%) extirpation, including curettage and dril-
though at least 1 case of pathology-
Vision changes 21 (12.2%) proven OCG with low T1 signal has been ling of involved bone, should be the goal.
Globe displacement 8 (4.7%) reported.2
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Conflict of interest statement: No part of this draft has been
published or submitted for publication before, and none of
the authors have any conflicts of interest, financial or
ethical, to disclose.
Received 17 October 2015; accepted 26 November 2015
Citation: World Neurosurg. (2016) 87:355-361.
http://dx.doi.org/10.1016/j.wneu.2015.11.095
Journal homepage: www.WORLDNEUROSURGERY.org
Available online: www.sciencedirect.com
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