Paraneoplastic Granulomatous Vitritis

Elaboration of 8 Cases
Lindsay A. McGrath, FRANZCO,1,* Hardeep S. Mudhar, FRCPath,2,* Richard Sheard, FRCOphth,3,4
Kurt Spiteri-Cornish, FRCOphth,3 Stephen Winder, FRCOphth,3 Paul Rundle, FRCOphth,1
Ian G. Rennie, FRCOphth1

Purpose: To describe the clinical features in a series of 8 patients with cytologically proven granulomatous
vitritis in the context of systemic malignancy.
Design: Retrospective case review series from 2004 through 2018 to identify all cases of cytologically proven
granulomatous vitritis and to analyze its disease associations and causes.
Participants: Twenty-three patients with a cytologic diagnosis of granulomatous vitritis were identified, 8 of
whom demonstrated systemic malignancy.
Main Outcome Measures: To identify a clinical profile of the 8 cases of granulomatous vitritis occurring in
the setting of systemic malignancy, focusing on the timing of the eye presentation compared with the timing of
the systemic malignancy.
Methods: Patients with a cytologic diagnosis of granulomatous vitritis seeking treatment from 2004 through
2018 were included in this retrospective case series. Case notes were recalled and reviewed for demographic
features, medical history, presenting symptoms, investigations, surgical procedures, and follow-up.
Results: Twenty-three patients were diagnosed cytologically with granulomatous vitritis. Ten of 23 patients
(43%) showed autoimmune and infectious causes, 5 of 23 patients (22%) showed were idiopathic causes, and 8
of 23 patients’ (35%) disease was associated with systemic malignancy. In the latter group, the median age at
presentation was 70 years (range, 55e89 years). Six patients showed bilateral disease, and the remaining 3
showed unilateral disease. Three of 8 patients showed primary systemic malignancy diagnosed after eye
symptoms and 5 of 8 showed malignancy before the eye symptoms. These latter 5 patients all demonstrated a
major relapse, metastasis, or both at the time of eye symptoms.
Conclusions: Paraneoplastic vitritis is primarily a disease of older age, with 67% of those affected older than
65 years. Ophthalmologists should maintain a high index of suspicion of paraneoplastic cause in bilateral pos-
terior segment inflammation of uncertain origin, presenting for the first time, or heralding malignancy recurrence or
metastasis in known cases of malignancy. Ophthalmology Retina 2019;3:589-596 ª 2019 by the American
Academy of Ophthalmology

Ocular manifestations of systemic malignancy are important
for the ophthalmologist to recognize because they may pre-
cede the diagnosis of cancer. There are several well-described
ophthalmic paraneoplastic syndromes including carcinoma-
associated retinopathy,1 melanoma-associated retinopathy,2
bilateral diffuse uveal melanocytic proliferation,3 and
paraneoplastic vitelliform retinopathy.4,5 Uveitis has been
noted to occur in the presence of systemic malignancy and has
been termed pseudouveitis.6,7 Nonnecrotizing granulomas
have been reported in association with a variety of solid and
hematologic malignancies. These are reported commonly in
lymph nodes draining the malignancy but also have been
encountered in distant organs.8
We previously reported the first case of paraneoplastic
granulomatous vitritis in the context of recurrent Hodgkin
lymphoma.9 A further series was published in 2015 that
presented 5 patients with sarcoid-like reactions in the eye,
4 of whom had histologically confirmed intraocular granu-
lomas, occurring in the setting of systemic malignancy.10
Herein, we present an additional 8 cases of cytologically
proven granulomatous vitritis heralding systemic
malignancy in 3 patients and indicating relapse or
metastasis of pre-existing malignancy in 5 patients.
Methods
A review of the records from the Ocular Oncology and Uveitis
Services at the Royal Hallamshire Hospital for the diagnosis of
granulomatous vitritis was performed. Patients with a cytologic
diagnosis of granulomatous vitritis seeking treatment from 2004
through 2018 were included in this retrospective case series. Case
notes were recalled and reviewed for demographic features, med-
ical history, presenting symptoms, drug history, investigations,
surgical procedures, and follow-up. The patients gave routine

 2019 by the American Academy of Ophthalmology https://doi.org/10.1016/j.oret.2019.03.003 589

Published by Elsevier Inc. ISSN 2468-6530/19
 Ophthalmology Retina Volume 3, Number 7, July 2019
Table 1. Patients Whose Systemic Malignancy Was Diagnosed after Vitrectomy
Time to
Patient Age Ocular Vitrectomy
No. (yrs) Gender Findings (mos)
1 66 F Right eye, 6/9; left eye, 6/ T þ 12
5; bilateral vitritis, 1þ;
mild periphlebitis
2 71 F Right eye, 6/36; left eye, Tþ8
6/6; right eye, mutton
fat KP, 2þ AC, and
vitreous cells
3 55 F Right eye, 6/24; left eye, Tþ1
6/18; bilateral vitritis
2þ, bilateral retinal
vasculitis
AC ¼ anterior chamber; F ¼ female; T ¼ time of ophthalmology presentation, timing of clinical events is shown as months before (minus) or after (plus).
consent for surgery and for use of their photographs. The work was
carried out in accordance with the tenets of the 1964 Declaration of
Helsinki and its subsequent modifications. The Research and
Development Office (equivalent of an institutional research board)
at our institution confirmed this study was a clinical retrospective
case review and not research.
All patients underwent systemic screening before surgery to
determine a cause of their symptoms. This included blood testsd
complete blood count, serum liver enzymes, renal function,
electrolytes, inflammatory markers (erythrocyte sedimentation rate,
C-reactive protein), angiotensin-converting enzyme, rheumatologic
markers (antinuclear antibody, antineutrophil cytoplasmic anti-
body, and rheumatoid factor)dinfective screen (syphilis and
tuberculosis), and chest radiography. All patients underwent 23- or
25-gauge pars plana vitrectomy performed by 1 of 3 authors (RS,
SW, or KS-C). Our vitrectomy technique has been described
elsewhere.11,12 The indications for diagnostic vitrectomy were to
exclude intraocular lymphoma, infection, or atypical clinical fea-
tures or progression where systemic investigations revealed no
cause.
The vitreous cassette washings were fixed rapidly in theatre
with an equal volume of methanol-based fixative to preserve cell
morphologic features for cytologic examination. Two thirds of the
vitreous cassette washings were centrifuged at 3000 rpm for 40
minutes to create a pellet, which then was processed without
formalin fixation to paraffin wax. Twenty to 40 serial sections
were cut with every tenth stained with a standard
hematoxylineeosin stain for light microscopic examination. The
intervening spare sections were stained with the following: gram
stain for bacteria, periodic acideSchiff for fungi and intracellular
organisms (e.g., Whipple’s disease), Grocott’s stain for fungi, and
ZiehleNeelsen for mycobacteria. Every patient underwent
immunohistochemical staining with a panel that comprised the
following antibodies: CD3, CD20, CD68 (PGM1), CD30, and
Ki67. Additional lymphoid immunohistochemical panels were
used according to the clinical context. One third of the remaining
vitreous washings were saved for B- and T-cell clonality analysis
and for MYD88 mutational analysis if required. The patients were
followed up at regular intervals according to the postoperative
protocols in place at the time. Continuous variables such as age,
time to diagnosis, and duration of follow-up were described using
mean, standard deviation, and median values in the studied
patients.
590
Survival after
Date of Malignancy Diagnosis
Malignancy Type of and Cause of Death
Diagnosis (mos) Malignancy (mos)
T þ 84 Breast adenocarcinoma Died T þ 132 of
metastatic breast
carcinoma
T þ 84 Gallbladder carcinoma Died T þ 84 of metastatic
with multiple gallbladder carcinoma
peritoneal metastases
Tþ3 CD30-positive cerebral T- Died T þ 3 of CD30-
cell lymphoma positive aggressive
cerebral T-cell
lymphoma
Results
A total of 23 patients underwent diagnostic vitrectomy according to
the indications described above. All 23 patients were diagnosed
cytologically with granulomatous vitritis. Ten of 23 cases of
granulomatous vitritis (43%) were attributable to autoimmune or
infectious causes (autoimmune causes included 1 case each of
Crohn’s uveitis, sarcoid, and multiple sclerosis; infectious causes
included 2 cases each of Candida and Toxoplasmosis infection and
1 case each of cytomegalovirus, cytomegalovirus and Aspergillus
species infection, and coagulase-negative Staphylococcus species
infection), and 5 of 23 cases of granulomatous vitritis (22%) were
idiopathic. An infectious cause was confirmed with sampling of
blood and vitreous samples.12 The remaining 8 of 23 cases of
granulomatous vitritis (35%) were associated with systemic
malignancy, and these cases are discussed in detail as follows.
The average age at presentation was 70 years (median, 70 years;
range, 51e89 years). Six of 8 patients demonstrated bilateral
disease, and the remaining 2 patients demonstrated unilateral
disease.
None of this group of patients were using any medications
associated with uveitis such as antibiotics, checkpoint inhibitors, or
tumor necrosis factor a antagonists. Three of 8 patients demon-
strated primary systemic malignancy diagnosed after eye symp-
toms at a mean of 57 months later (median, 84 months later; range,
3e84 months later; see Table 1). Two of these malignancies were
carcinomas, and the third was a primary central nervous system
T-cell lymphoma. In 5 of 8 patients, systemic malignancy was
diagnosed before vitritis; clinically, all were in remission. In
these patients, the development of vitritis heralded a relapse of a
previous malignancy or a newly diagnosed metastasis from the
original malignancy, at the time of the eye symptoms (see
Table 2). One patient’s disease was associated with Hodgkin’s
lymphoma, 2 patients’ disease was associated with chronic
lymphocytic lymphoma or leukemia, 1 patient’s disease was
associated with malignant adrenal pheochromocytoma, and 1
patient’s disease was associated with endometrial adenocarcinoma.
The mean ophthalmology follow-up was 55 months (median,
36 months; range, 3e132 months). Only 3 patients survived during
 Table 2. Patients with Pre-existing Malignancy in Whom the Vitritis Heralded a Recurrence or Metastasis

McGrath et al
Malignancy Date of
Date of Date of Status Recurrence Features of
Age Malignancy Malignancy Ocular Vitrectomy at Time of Eye or Metastasis Recurrence or
Patient No. (yrs) Gender (mos) Type Findings (mos) Presentation Diagnosis (mos) Metastasis Outcome
4 51 M T e 108 Adrenal Right eye, 6/5; left eye, T þ 13 Remission; no T þ 36 Multiple systemic Alive T þ 58
phaeochromocytoma 6/4; right eye, 1þ AC treatment metastases


cells, 2þ vitritis
Tþ1 Tþ6 Died T þ 96

Paraneoplastic Granulomatous Vitritis

5 70 F T e 24 Nodular sclerosing Right eye, 6/9; left eye, 6/ Remission; no Hilar and
Hodgkin lymphoma 4; right eye, 1þ vitritis treatment mediastinal lymph
node recurrence
6 75 F T e 36 Chronic lymphocytic Right eye, 1/60; left eye, Tþ1 Remission; no Tþ0 Recurrence in both optic Died T þ 18
leukemia 6/18; right eye, optic treatment nerves
disc swelling; left eye, (under
vitritis 2þ observation)
7 89 F T e 120 Chronic lymphocytic Right eye, 6/12; left eye, Tþ1 Remission; no Tþ0 Increased Alive T þ 8
leukemia 6/18; bilateral 2þ AC treatment abdominal, mesenteric,
cells; bilateral vitritis and retroperitoneal LN;
1þ new head of pancreatic
mass; increased
hepatosplenomegaly
8 84 F T  24 Endometrial Right eye, 6/12; left eye, Tþ1 Remission; No Tþ0 Multiple pulmonary Alive T þ 12
adenocarcinoma 6/18; bilateral 1þ AC treatment metastases (palliative care)
cells; bilateral vitritis
1e2þ

AC ¼ anterior chamber; F ¼ female; LN ¼ lymph node; M ¼ male; T ¼ time of ophthalmology presentation, timing of clinical events is shown as months before (minus) or after (plus).
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 Ophthalmology Retina Volume 3, Number 7, July 2019

Table 3. Summary of Cytologic and Additional Investigation Findings in the Vitreous Samples

Stain Results
Periodic
Patient Vitreous Cytologic Analysis Acide Ziehle Immunohistochemical Additional Histologic
No. Light Microscopic Findings Gram Schiff Grocott Neelsen Findings Investigation Results
1 DM, G, SL, and some MNG; no Negative Negative Negative Negative G, CD68þ; SL, CD3þ; None
atypical lymphoid population CD20e, CD30e, Ki67,
<1%
2 DM, G, and SL; no atypical Negative Negative Negative Negative G, CD68þ; SL, CD3þ; PCR on paraffin section; no
lymphoid population CD20e, CD30e, Ki67, mycobacteria DNA detected
<1%
3 DM, G, and SL; no atypical Negative Negative Negative Negative G, CD68þ; SL, CD3þ; PCR for T- and B-cell clonality on
lymphoid population CD20e, CD30e, Ki67, vitreous showed no clones;
10% (T-cells and MYD88, no mutation identified
macrophages)
4 DM, G, and SL; no atypical Negative Negative Negative Negative G, CD68þ; SL, CD3þ; None
lymphoid population CD20e, CD30e, Ki67,
<1%
5 DM, G, and SL; no atypical Negative Negative Negative Negative G, CD68þ; SL, CD3þ; CD15 negative; EBV negative (no
lymphoid population; small CD20e, CD30e, Ki67, evidence of Hodgkin’s cells in
retina fragment showing <1% vitreous or retina)
granulomas and giant cells
6 DM, G, and SL; No atypical Negative Negative Negative Negative G, CD68þ; SL, CD3þ; No B cells were present in the
lymphoid population CD20e, CD30e, Ki67, vitreous (CD20 negative); CD5
<1% stained reactive T cells and no
CD23-positive cells present;
therefore, no evidence of
vitreous CLL
7 DM, G, and SL; no atypical Negative Negative Negative Negative G-CD68þ, SL-CD3þ, No B cells were present in the
lymphoid population CD20e, CD30-Ki67 5% vitreous (CD20 negative); CD5
(T cells and stained reactive T cells and no
macrophages) CD23-positive cells present;
therefore, no evidence of
vitreous CLL
8 DM, G, and SL; no atypical Negative Negative Negative Negative G-CD68þ, SL-CD3þ, Cytokeratin (AE1, AE3, MNF116)
lymphoid population CD20e, CD30-Ki67-5% negative and therefore showed
(T cells and no metastatic carcinoma in the
macrophages) vitreous

CLL ¼ chronic lymphocytic leukemia; DM ¼ dispersed macrophages; EBV ¼ Epstein-Barr virus; G ¼ granulomas; MNG ¼ multinucleate giant cells;
PCR ¼ polymerase chain reaction; SL ¼ small reactive lymphocytes.

the follow-up period. Of the patients who died, they did so at a
mean of 57 months (median, 51 months; range, 3e132 months)
after presentation to the ophthalmology department. All 8 patients
showed very similar cytologic findings, and these are summarized
in Table 3. All the patients showed dispersed populations of
epithelioid histiocytes accompanied by small lymphocytes, with
well-formed granulomas made up of congregating epithelioid his-
tiocytes (Fig 1A, B). The dispersed epithelioid histiocytes and
granulomas showed positive results for CD68 (a marker of
macrophages), and the small lymphocytes showed positive
results for CD3, indicating they were reactive T cells (Fig 1C,
D). In 1 patient, multinucleate giant cells were seen (patient 1).
None of the patients showed a B-cell lymphoid population (no
CD20-positive cells seen). None of the patients showed infec-
tious agents when the samples were stained with a panel of gram,
periodic acideSchiff, Grocott, or ZiehleNeelsen stains. We
describe 3 illustrative cases in detail to highlight the range of
clinicopathologic presentations.
Case Reports
Patient 3: Vitritis before the Diagnosis of a Hematologic
Malignancy. A 55-year-old woman sought treatment for a
2-month history of debilitating floaters in both eyes but worse in the
right eye. She had a history of cutaneous lymphocytic vasculitis
diagnosed 6 months before presentation. At presentation, visual
acuity was 6/24 in the right eye and 6/18 in the left eye. Exami-
nation revealed moderate vitritis in both eyes, and fluorescein
angiography showed evidence of vascular permeability
(Fig 2AeD). The patient underwent systemic screening to rule out
inflammatory and infective causes of intraocular inflammation. All
serologic testing and chest imaging results were within normal
limits. The patient underwent diagnostic vitrectomy that showed
CD68-positive granulomas and dispersed epithelioid histiocytes,
accompanied by some CD3-positive reactive T cells. T- and B-cell
clonality testing revealed no clonal lymphoid populations. The
patient was treated with a 6-week course of oral prednisolone. Four
months later, the patient experienced headaches and confusion, with
brain imaging showing a large cerebral tumor. Biopsy revealed an
aggressive, CD30-positive T-cell lymphoma (Fig 2E, F). The
patient died soon after the cerebral biopsy.
Patient 6: Vitritis Heralding Recurrent Hematologic
Malignancy. A 72-year-old woman with a 3-year history of
chronic lymphocytic leukemia and immunoglobulin M k para-
proteinemia sought treatment for reduced vision in both eyes with a
visual acuity of hand movements in the right eye and 6/18 in the left
eye. Examination revealed right-sided optic disc swelling and
bilateral vitritis with moderate (2þ) vitreous cells (Fig 3A, B). She

592
 McGrath et al 
Paraneoplastic Granulomatous Vitritis

Figure 1. A, Photomicrograph showing cytologic preparation of the vitreous washings from one of the 8 cases. This shows a granuloma (black arrow)
composed of a collection of epithelioid histiocytes (stain, hematoxylineeosin; original magnification, 400). B, Photomicrograph from the same case
showing dispersed epithelioid histiocytes (broad arrow) and numerous small lymphocytes (slender arrows; stain, hematoxylineeosin; original
magnification, 400). C, Photomicrograph showing positive brown staining of the central granuloma and the dispersed epithelioid histiocytes (immu-
nohistochemical agent, CD68; original magnification, 400). D, Photomicrograph showing positive brown staining of the small lymphocytes, indicating
reactive T cells (immunohistochemical agent, CD3; original magnification, 400).

underwent a right-sided core vitreous tap that was acellular and then
was referred to the Sheffield Ocular Oncology Service for further
management. On further examination, the right disc swelling was
confirmed and thought to be an infiltrative optic neuropathy caused
by chronic lymphocytic leukemia. She underwent a left diagnostic
pars plana vitrectomy that showed CD68-positive granulomas and
dispersed epithelioid histiocytes, accompanied by some CD3-
positive reactive T cells. There was no evidence of a B-cell popu-
lation in the vitreous (no CD20-positive cells) and no evidence of
atypical lymphoid infiltrate. After a 2-week period of watching and
waiting (because of no adverse systemic symptoms), the patient
demonstrated left optic disc swelling, with new left-sided parotid
lymphadenopathy and computed tomography scans showing new
abdominal lymphadenopathy. High-dose steroids were commenced
followed by Rituximab (Roche Products Ltd, Hertfordshire, UK)
administration. This resulted in a dramatic resolution of the optic disc
swelling, reduction in the vitritis, improvement in vision, and
reduction in the lymphadenopathy over a period of 3 weeks after
commencing treatment.
Patient 9: Vitritis Heralding Metastatic Adenocarci-
noma. An 84-year-old woman sought treatment for floaters and
blurred vision in both eyes. The patient had an unremarkable past
ocular history. Ophthalmic examination revealed corrected visual
acuity of 6/12 in the right eye and 6/18 in the left eye. Bio-
microscopic examination showed mild (1þ) inflammation and
bilateral vitreous syneresis with moderate (2þ) clumped cells
(Fig 4AeC). Specific blood tests ruled out concurrent
rheumatologic disease. Two months after presentation, the patient
underwent a right diagnostic vitrectomy to determine the cause
of her inflammation. Cytologic analysis showed CD68-positive
granulomas and dispersed epithelioid histiocytes, accompanied
by some CD3-positive reactive T cells. Further immunohisto-
chemistry analysis with broad-spectrum cytokeratins (AE1AE3
and MNF116) showed no evidence of metastatic carcinoma. The
patient had a history of high-grade endometrial adenocarcinoma
treated with surgical resection 2 years previously. Nine months
after surgery, she showed recurrence that was treated successfully
with brachytherapy. At presentation with vitritis, the patient

593
 Ophthalmology Retina Volume 3, Number 7, July 2019
Figure 2. Widefield fundus images of (A) the right eye and (B) the left eye
of patient 3 showing vitreous debris blurring view of retinal elements. Late-
phase fluorescein angiograms of (C) the right eye and (D) the left eye of
patient 3 showing vascular permeability. Magnetic resonance imaging (E)
T1-weighted axial and (F) T2-weighted coronal scans from patient 3
showing a mass in the left temporal lobe with associated inflammation that
biopsy demonstrated to be a high-grade T-cell lymphoma.
underwent chest radiography to exclude sarcoidosis or infection.
Chest computed tomography scans showed multiple pulmonary
metastases (Fig 4D), and biopsy confirmed metastatic endometrial
Figure 3. Fundus photographs from patient 6: (A) the right eye showing optic disc swelling resulting from chronic lymphocytic leukemia infiltration and
(B) the left eye showing vitreous haze resulting from the presence of cytologically proven granulomatous vitritis.
594
adenocarcinoma. The patient declined further treatment given her
disseminated disease and advanced age.
Discussion
This report presents the largest series of cases of cytologically
proven granulomatous vitritis in the context of systemic ma-
lignancy. Our series included 2 clinicopathologic groups:
cases of granulomatous vitritis that occurred before a diag-
nosis of malignancy and cases of vitritis that occurred in pa-
tients with known malignancy and that heralded recurrent or
metastatic malignancy. To date, only 6 reported cases
describing this entity have appeared in the literature.9,10 Our
series of 8 cases increases this figure to 14. Collating data from
the 14 cases identifies certain distinguishing features of
granulomatous paraneoplastic vitritis.
In keeping with the known epidemiologic features of
granulomatous conditions, paraneoplastic granulomatous
vitritis seems to be primarily a disease of older age, with all
of those who have been affected being older than 50 years
and 67% being older than 65 years of age in reported cases.
It is predominantly bilateral and presents with granuloma-
tous vitritis, with associated features including optic nerve
swelling and increased vascular permeability. Some patients
showed anterior chamber inflammation, but there were no
cases with pseudohypopyon in our series.
When the host immune system fails to clear antigenic
stimuli completely, granulomatous inflammation can arise.
This pattern of chronic inflammation consists of a micro-
scopic aggregation of macrophages that are transformed into
epithelioid cells, surrounded by a collar of mononuclear
leukocytes, principally lymphocytes. These immune granu-
lomas can be seen in response to infectious agents, in
sarcoidosis (where no etiologic agent has yet been identi-
fied), and more rarely in patients who do not fulfill the
criteria for systemic sarcoidosis.
Herxheimer13 was the first to recognize sarcoid-like re-
actions as a tumor-related tissue response in 1917; however,
most descriptions of this phenomenon are by Brincker8 are
dated almost 70 years later. These sarcoid-like granulomas
 McGrath et al 
Paraneoplastic Granulomatous Vitritis
Figure 4. Images from patient 9: (A) right eye and (B) left eye widefield
fundus images, (C) ultrasound biomicroscopy showing vitritis (arrow), and
(D) computed tomography scan showing a right-side pulmonary metastasis
of endometrial adenocarcinoma (white arrow).
have been seen in the context of a variety of neoplasms and
can occur within tumors themselves, adjacent to tumors, or
in lymph nodes draining the neoplasm. The involved lymph
nodes usually are free of metastases, although occasionally,
granulomas may be seen in relationship to the metastatic
neoplasm.14 The cause of this reaction is postulated to be
secondary to an induced T-cellemediated host response to
soluble antigenic tumor factors.8,15 These factors either
may be shed by tumor cells or may be released during tumor
necrosis. They are then carried to regional lymph nodes or
distant organs where nonnecrotizing granulomatous
inflammation ensues. Some authors also postulate that true
sarcoidosis and sarcoid-like reactions are the clinical ex-
tremes of a common pathologic process.16
A recent study of uveitis in the elderly found that
sarcoidosis accounted for most cases of the disease, with
uveitis being diagnosed more frequently than in younger
populations.17 However in this study, almost one third of the
cases of uveitis were classified as idiopathic. It is possible
that this group may have been harboring systemic
malignancy. Systemic sarcoid-like reactions have been
estimated to occur most commonly in association with
Hodgkin disease (up to 14%) and non-Hodgkin lymphoma
(7%) and less commonly in carcinomas (4%).8 Our series
showed an equal spread of cases of uveitis developing in
the context of lymphoma versus in the context of
carcinoma. Given the paucity of cases with intraocular
involvement, it is difficult to estimate the frequency with
which these reactions may occur in the vitreous; however,
it is likely underdiagnosed because of underrecognition.
The prognostic differences between paraneoplastic
granulomas occurring before the diagnosis of malignancy
or those heralding recurrent or metastatic disease are not
possible to ascertain from this study given the small
number of cases involved.
The ophthalmologist is usually the first clinician from
whom the patient with paraneoplastic vitritis seeks treatment
and thus can play an important role in the early investigation
of this condition. As with other paraneoplastic syndromes,
the importance of early diagnosis and treatment cannot be
overestimated. Ophthalmologists should be alert for mas-
querades in uveitis and should consider diagnostic vitrec-
tomy in suspicious or recalcitrant cases of uveitis with no
known underlying cause. Systemic enquiry should include a
screen for other causes of intermediate and posterior uveitis,
especially sarcoidosis.
In most cases, signs and symptoms resolved with
management of the primary systemic malignancy without
the need for systemic or periocular corticosteroids. Such
treatment should be reserved for cases of recurrent or sight-
threatening intraocular inflammation.
Because pathologists will make the diagnosis of vitreous
granulomas on cytologic analysis, it is critical that they are
aware that vitreous granulomas can be associated with
systemic malignancy and that they suggest further in-
vestigations, preferably in a multidisciplinary team meeting.
Failure to mention this could result in an avoidable delay in
diagnosing systemic malignancy, recurrence, or metastases.
In summary, ophthalmologists should maintain a high
index of suspicion of a paraneoplastic cause in bilateral
posterior segment inflammation of uncertain origin pre-
senting for the first time in an elderly patient or heralding
recurrence or metastasis in known cases of malignancy. We
recommend in such circumstances an investigative pathway
designed to exclude systemic malignancy or recurrence of a
malignancy or metastasis.
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Footnotes and Financial Disclosures
Originally received: December 24, 2018.
Final revision: February 25, 2019.
Accepted: March 7, 2019.
Available online: March 14, 2019. Manuscript no. ORET_2019_71.
1 Analysis and interpretation: McGrath, Mudhar, Sheard, Spiteri-Cornish,
Sheffield Ocular Oncology Service, Royal Hallamshire Hospital, Shef-
field, United Kingdom.
2 Data collection: McGrath, Mudhar, Sheard, Spiteri-Cornish, Winder,
National Specialist Ophthalmic Pathology Service, Department of Histo-
pathology, Royal Hallamshire Hospital, Sheffield, United Kingdom.
3 Obtained funding: N/A
Sheffield Vitreoretinal Service, Department of Ophthalmology, Royal
Hallamshire Hospital, Sheffield, United Kingdom.
4
Tasmanian Eye Clinics, Hobart, Australia.
*Both authors contributed equally as first authors.
Financial Disclosure(s):
The author(s) have no proprietary or commercial interest in any materials
discussed in this article.
No financial support was received for this study.
HUMAN SUBJECTS: Human subjects were included in this study. The
Research and Development Office (equivalent of an institutional research
board) of the Sheffield Teaching Hospitals NHS Trust, Royal Hallamshire
Hospital, Sheffield, UK confirmed this study was a clinical retrospective
case review and not research. All research adhered to the tenets of the
Declaration of Helsinki. All participants provided informed consent.
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No animal subjects were included in this study.
Author Contributions:
Conception and design: McGrath, Mudhar, Sheard, Rennie
Winder, Rundle, Rennie
Rundle
Overall responsibility: McGrath, Mudhar, Sheard
Abbreviations and Acronyms:
CLL ¼ chronic lymphocytic leukaemia; DM ¼ dispersed macrophages;
EBV ¼ Epstein-Barr virus; G ¼ granulomas; MNG ¼ multinucleate giant
cells; PCR ¼ polymerase chain reaction; SL ¼ small reactive lymphocytes;
AC ¼ anterior chamber; F ¼ female; T ¼ time of ophthalmology pre-
sentation, timing of clinical events is shown as months before (minus) or
after (plus); LN ¼ lymph node; M ¼ male.
Correspondence:
Hardeep S. Mudhar, FRCPath, National Specialist Ophthalmic Pathology
Service, Department of Histopathology, Royal Hallamshire Hospital,
Sheffield S10 2JF, United Kingdom. E-mail: hardeep.mudhar@sth.nhs
.uk.