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NR 4-6/2008
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Malignant Uveitis
Masquerade Syndromes
Zespoły maskujące złośliwe
zapalenia błony naczyniowej
Agnieszka Kubicka-Trząska, Bożena
Romanowska-Dixon
Department of Ophthalmology, Clinic of Ophthalmology and Ocular
Oncology,
Jagiellonian University, Medical College, Kraków, Poland
Head: Ass. Prof. Bożena Romanowska-Dixon, MD, PhD |
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| Summary: |
The term “Masquerade
Syndrome” was first used in ophthalmology in 1967 by
Theodore, to describe a case of conjunctival carcinoma
that manifested as chronic conjunctivitis. The Uveitis
Masquerade Syndromes (UMS) are a group of various ocular
diseases that may mimic chronic intraocular inflammation.
Many malignant pathologies may result in an appearance
masquerading as uveitis. The article reviews most common
malignant conditions which may be considered masquerades
such as primary intraocular lymphoma, leukemias, uveal
melanoma, retinoblastoma, metastatic lesions, and
paraneoplastic syndromes, among others. Diagnostic
strategies, therapies, and prognosis are also reviewed. |
| Słowa kluczowe: |
zespół maskujący zapaleń
błony naczyniowej, przewlekłe zapalenia wewnątrzgałkowe. |
| Key words: |
uveitis masquerade
syndrome, chronic intraocular inflammation. |
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Mimesis is the Greek word for
imitation or mimicry that represents the ability of simulation
or resemblance of one organism to another or to an object in its
surroundings for concealment and protection from predators. In
medicine mimesis refers to the hysterical simulation of an
organic disease or the imitation of one organic disease by
another. In 1967 Theodore for the first time in medicine and in
ophthalmology used the term “Masquerade Syndrome” to describe a
case of conjunctival carcinoma that manifested as chronic
conjunctivitis (1). Today, it is used to describe disorders that
simulate chronic non-infectious uveitis. The diagnosis of
uveitis masquerade syndromes (UMS) is difficult. Rothova et al.
found a mean interval of nine months between the first
ophthalmologic examination and establishing the definitive
diagnosis of a masquerade syndrome. Malignant diseases took 11
months to diagnose, vs. seven months for nonmalignant conditions.
The authors also reported that only 40 (5%) of 828 patients with
uveitis had a masquerading condition, indicating that the UMS is
relatively rare (2).
The most common malignant disorders masquerading as uveitis are
presented in Table I.
Lymphomas
a. Primary intraocular lymphoma
Primary intraocular lymphoma (PIOL) is the most common
neoplastic UMS involving the eye (3). PIOL is a rare extranodal
non-Hodgkin B-cell lymphoma involving the retina, the subretinal
space, vitreous body and the optic nerve. It is a subset of
primary central nervous system lymphoma (PCNSL), which can occur
either together with or independently of PCNSL (4). The
diagnosis of intraocular lymphoma requires a thorough history
and neurologic examination, magnetic resonance imaging (MRI) and
lumbar puncture. However cytological examination of vitreal
aspirates remains the gold standard for exclusion of neoplastic
disease in this group of patients. The prompt, appropriate
handling of specimens and review by an experienced
cytopathologist are critical to the diagnosis of intraocular
lymphoma (5). Malignant cells often are present in the cerebral
spinal fluid at the time that ocular lymphoma is diagnosed (6).
Nevertheless, multiple vitrectomies and lumbar punctures may be
necessary before the correct diagnosis is made (5,7).
Measurements of various interleukins (IL) levels in the vitreous
can also be helpful in making the diagnosis of PIOL. Often, the
ratio of IL-10 to IL-12 is elevated, in the context of atypia on
vitreal biopsy (8). However Akpek et all. reported that
elevation of vitreous IL-10 level is not diagnostic of PIOL (9).
Recently, Whitcup and al. have reported elevated vitreous levels
of IL-10 relative to levels of IL-6 in PCNSL (6). Chorioretinal
biopsy increases the chance of diagnosing or excluding a PIOL
involving the retina and choroid (5). PIOL usually develops in
patients between the fifth and sixth life decade. The
presentation of the disease is with blurred vision and floaters,
but the vision is often better than the clinical symptoms.
Anterior segment examination shows mild chronic anterior uveitis
with hypopyon unresponsive to steroid therapy. In the vitreous,
there are cells occuring in sheets, with subretinal yellow
infiltrates through a hazy vitreous (Fig. 1). Occasionally,
there is haemorrhagic retinal vasculitis and intermediate
uveitis. The optic disc infiltration may be also seen. Bilateral
but asymmetrical involvement is observed in about 80% of cases
(4,6,10).
The optional therapy for PIOL has not been yet determined. It is
generally believed that PIOL should be treated with a
combination of systemic chemotherapy with high-dose methotrexate
and radiotherapy (11). Recently intraocular methotrexate has
been introduced as a therapeutic method for isolated ocular
recurrences (4). Several new strategies for PIOL with CNS
involvement have been reported: inrathecal therapy with
methotrexate or anti CD 20 antibodies and autologous stem-cell
transplantation (12). PIOL remains one of the most difficult
diagnoses to establish, particularly due to its ability to mimic
other diseases in the eye. The differential diagnosis of
intraocular lymphoma include: sarcoidosis, syphilis,
tuberculosis, acute retinal necrosis, CMV retinitis, white dot
syndrome, Behςet disease, serpiginous choroidopathy
(2,3,7,10,13). Thus, diagnostic tests for these entities should
be performed prior or in conjunction with those for intraocular
lymphoma. The prognosis is poor. The five-year survival rate is
less than 5% (10).
b. Systemic non-Hodgkin lymphoma metastatic to eye
Both cutaneous or visceral T-cell lymphomas may metastize to the
eye. Such metastasis can present as anterior uveitis with
hypopyon or hyphema, posterior uveitis, retinal vasculitis and
choroidal mass. Choroid is the primary site of ocular
involvement. Ocular symptoms may be the initial presentation of
the disease however most patients with ocular metastasis
manifest the systemic symptoms of the disease (10).
c. Hodgkin lymphoma
Hodgkin lymphoma very rare metastases to the eye. Only a few
sporadic cases of intraocular metastases in Hodgkin disease have
been reported. The most common clinical presentation of the
disease is uveitis and periphlebitis (10,13,14).
Leukemias
Various forms of leukemia may infiltrate the ocular tissues,
causing morphologic changes masquerading as uveitis. The eye is
involved most often in acute than in chronic leukemia and all
ocular structures may be infiltrated by leukemic cells. Ocular
involvement in leukemia can be caused by direct leukemic
infiltration or indirectly due to the effects of low hematocrit,
anemia, thrombocytopenia, hyperviscosity, or compromised immune
status (15). The UMS in a course of leukemia is due to direct
infiltration of ocular tissues by leukemic cells.
UMS associated with leukemia may precede the diagnosis or occur
during the course of the disease. The choroid is the most
commonly affected part of the eye (16). Pigment epitheliopathy
develops secondary to choroidal infiltration and is
characterized by a “leopard spot patterns”. In children and
young adults, acute lymphoblastic leukemia may manifest as acute
unilateral anterior uveitis with massive anterior chamber
cellular infiltrates which form pseudohypopyon characterized by
shaggy, irregular, free-floating material that fails to settle
inferiorly. Acute unilateral hypopyon may be a first sign of
extramedullary relapse of leukemia (17,18). Acute papillitis
with papilloedema, retinal vasculitis, vitritis, intravitreal
haemorrhage, retinal infiltrates mimicking white dots, orbital
and eye-lid involvemet have been also observed in leukemic
patients (15,16).
Examination of the aqueous humor aspirate with the presence of
malignant cells is useful in establishing the diagnosis in a
case of atypical anterior uveitis with hypopyon unresponsive to
steroids therapy (17). The treatment options include
chemotherapy and radiotherapy to the CNS (17,19).
Ocular metastases
The uveal tract is a preferential site of ocular spread for most
solid tumors. The incidence of uveal metastases among various
groups of cancer patients varies from 5 to 27%. Renal, lung,
breast carcinomas are most likely to manifest with ocular
metastases (20). The most frequent site of intraocular
metastasis is the posterior choroid, which appears the “site of
choice”, then the orbit, the iris and the ciliary body.
Metastases within the eye may masquerade as a non-infectious
anterior and posterior uveitis, choroidal effusion, retinitis or
papillitis (20). About fifty percent of ocular metastases are
recognized before the diagnosis of underlying malignant process.
The therapy of intraocular metastases include: external beam
radiotherapy (EBR), brachytherapy, transpupillary thermotherapy
(TTT) and enucleation (21).
Lymphoid Hyperplasia of the Uvea
Lymphoid hyperplasia of the uvea, also known as inflammatory
pseudotumors of the uveal tract or intraocular pseudotumors, is
characterized by infiltration of the uveal tract by
well-differentiated small lymphocytes. Clinical features include:
anterior uveitis, vitritis, choroidal infiltrates, and iris
heterochromia. Extraocular extension may present as conjunctival
salmon-colored lesions, or orbital masses which may cause
proptosis and diplopia (22). The results of biopsy are essential
for diagnosis. Lymphoid hyperplasia of the uvea often responds
to corticosteroids and moderate dose of radiotherapy. The
prognosis is favorable (22).
Uveal Melanoma
Choroidal melanoma can present as focal choroidal mass, which
may mimic sarcoid or tuberculous granuloma, endophthalmitis and
posterior scleritis. In these cases ultrasonography, computed
tomography (CT), magnetic resonance imaging (MRI) may be
sufficient for correct diagnosis, however where the diagnosis
cannot be established the fine needle aspiration biopsy may be
indicated (23). Ciliary body melanoma with the presence of
sentinel vessels may mimic the clinical manifestation of
episcleritis or scleritis (Fig. 2).
Secondary glaucoma as a result of pigment dispersion and tumor
invasion of the anterior chamber angle may also be present. The
uveitis is rarely associated with ciliary body melanoma.
Slit-lamp biomicroscopy with a triple-mirror contact lens
through a dilated pupil is essential for diagnosis but in the
presence of opaque media high-frequency ultrasonography is
useful. Fine needle-aspiration biopsy may be helpful in selected
cases (23). There are three patterns of iris melanoma: ring,
tapioca and diffuse. All of them may mimic anterior uveitis and
can cause secondary glaucoma. Diffusely growing melanoma may
give rise to ipsilateral heterochromia and may masquerade as
Fuchs heterochromic uveitis (10). The documented growth of the
lesion is essential for diagnosis (23).
Childhood Malignancies
Retinoblastoma is the most common malignant intraocular tumor in
childhood. The initial presentation of retinoblastoma can be
quite diverse, from tumor cells in the anterior chamber,
masquerading as iritis, leucokoria, strabismus, secondary
glaucoma and orbital inflammation mimicking orbital cellulitis.
In some cases retinoblastoma may manifest as endophthalmitis
(10,24). In these cases the differential diagnosis from
intraocular inflammation associated with Toxocarosis may be
difficult. The diagnostic methods of retinoblastoma include:
ultrasonography, CT which detect the presence of calcifications
and MRI. In some cases the measurement of aqueous humor lactate
dehydrogenase (LDH) levels may be useful for diagnosis (25).
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Medulloepithelioma is a
rare, locally invasive tumor which arises from the non-pigmented
ciliary epithelium. It can mimic mild anterior uveitis and for
the correct diagnosis the histopathological examination is
needed.
Juvenile xanthogranuloma is a self-limited skin disorder in
childhood. Ocular involvement is one of the most common
manifestation of the disease. Involvement of the uvea leads to
uveitis or spontaneous hyphema. The presence of the iris mass
which may cause an acquired heterochromia may masquerade as
Fuchs heterochromic uveitis. The diagnosis is based on biopsy of
an iris lesion which disclose the presence of specific Touton
cells (26).
Histiocytosis X and Rosari – Dorfman disease may masquerade as
anterior and intermediate uveitis. The presence of periorbital
infiltrations may mimic orbital cellulitis (10).
Paraneoplastic syndromes
a. Cancer-associated retinopathy
Cancer-associated retinopathy (CAR) was first described by
Sawyer in 1976 in three patients with oat cell carcinomas of the
lung (27). CAR may be a first clinical sign of an underlying
systemic malignancy. Presentation is with subacute loss of
vision, shimmering and flickering lights. The fundus can appear
normal early in the course of the disease. However, there may be
eventual vascular sheathing, disturbances of the RPE, optic disc
pallor and mild vitritis. Retinal autoantibodies have been
identified in patients with CAR reacting against the 23kD
antigen (recoverin) a component of photoreceptors (28). ERG is
severely attenuated under photopic and scotopic condition, dark
adaptation is abnormal. The prognosis for both vision and life
is poor (28).
b. Melanoma-associated retinopathy
Melanoma-associated retinopathy (MAR) develops months to years
after diagnosis of metastatic cutaneous melanoma (29).
Presentation is with acute onset of night blindness with
shimmering and flickering lights. Visual acuity and color vision
are normal or mildly impaired. In longstanding cases RPE
irregularity, arteriolar attenuation, optic disc pallor are seen.
Vitritis and retinal periphlebitis may be present. Retinal
autoantibodies against the bipolar cells are present in
patients’ serum with MAR. ERG shows marked reduction of scotopic
and photopic b-wave and preservation of a-wave. The amplitude
and implicit time of the b-wave are abnormal. The visual
prognosis is good and most patients maintain stable vision (29).
c. Bilateral Diffuse Uveal Melanocytic Proliferation
Bilateral diffuse uveal melanocytic proliferation (BDUMP)
syndrome is a rare paraneoplastic disorder characterized by
bilateral diffuse infiltration of the uvea by melanocytic tumors
in the presence of an associated systemic malignant neoplasm
arising from ovaries, uterus or lungs (30). In half of the cases,
the ocular symptoms manifest before the diagnosis of an
underlying malignancy. Ocular findings in BDUMP include:
multiple subtle round and oval subretinal yellow-orange lesions,
multiple, slightly elevated, pigmented, and non-pigmented uveal
melanocytic tumors with evidence of diffuse thickening of the
uveal tract. Episcleral injection, cataract, vitritis, and
exudative retinal detachment can also be seen (30).
There are many malignant conditions that can present as a
masquerading syndrome, mimicking a chronic intraocular
inflammation. The ophthalmologist may be the first to recognize
this malignant, life-threatening disease. Malignancy and other
diseases should be considered in cases of chronic uveitis that
do not respond to aggressive steroid therapy. Any patient over
50 or 60 years of age who has a first episode of uveitis
deserves a closer look for malignancy. Incorrect diagnosis and
therapy of the malignant UMS may have severe consequences not
only for vision but also for the life of the patient.
Praca została przedstawiona w formie wykładu
na I Międzynarodowym Sympozjum i Kursie: „Postępy w diagnostyce
i leczeniu zapaleń błony naczyniowej”, które odbyły się w
Krakowie w dniach 24-26.05.2007 r.
References:
1. Theodore FH: Conjunctival carcinoma masquerading as chronic
conjunctivitis. Eye Ear Nose Throat Mon 1967, 46(11), 1419-1420.
2. Rothova A, Ooijman F, Kerkhoff F, Van Der Lelij A, Lokhorst
HM: Uveitis masquerade syndrome. Ophthalmology 2001, 108(2),
386-399.
3. Choi JY, Kafkala C, Foster CS: Primary intraocular lymphoma:
A review. Semin Ophthalmol 2006, 21(3), 125-133.
4. Coupland SE, Heimann H, Bechrakis NE: Primary intraocular
lymphoma: a review of the clinical and molecular biological
features. Graefes Arch Clin Exp Ophthalmol 2004, 242(11),
901-913.
5. Coupland SE, Bechrakis NE, Anastassiou G, Foerster AM,
Heiligenhaus AA, Pleyer U, Hummel M, Stein H: Evaluation of
vitrectomy specimens and chorioretinal biopsies in the diagnosis
of primary intraocular lymphoma in patients with Masquerade
syndrome. Graefes Arch Clin Exp Ophthalmol 2003, 241(10),
860-870.
6. Whitcup SM, Stark-Vancs V, Wittes RE, Solomon D, Podgor MJ,
Nussenblatt RB, Chen CC: Association of interleukin-10 in the
vitreous and cerebrospinal fluid and primary central nervous
system lymphoma. Arch Ophthalmol 1997, 115(9), 1157-1160.
7. Whitcup SM, de Smet MD, Rubin BI, Palestine AG, Martin DF,
Burnier M Jr, Chan CC, Nussenblatt RB: Intraocular lymphoma.
Clinical and histopathological diagnosis. Ophthalmology 1993,
100(9), 1399-1406.
8. Chan CC, Whitcup SM, Solomon D, Nussenblatt RB:
Interleukin-10 in the vitreous of patients with primary
intraocular lymphoma. Am J Ophthalmol 1995, 120(5), 671-673.
9. Akpek EK, Maca SM, Christen WG, Foster CS: Elevated vitreous
interleukin-10 level is not diagnostic of intraocular-central
nervous system lymphoma. Ophthalmology 1999, 106(12), 2291-2295.
10. BenEzra D: Masquerade syndrome in: Ocular inflammation.
Basic and Clinical Concepts. pp 463-480, chapter 29, ed. Martin
Dunitz Ltd, 1999, London.
11. Kim SK, Chan CC, Wallace DJ: Management of primary
intraocular lymphoma. Curr Oncol Rep 2005, 7(1), 74-79.
12. Antonini G, Cox MC, Montefusco E, Ferrari A, Conte E, Morino
S, Latino P, Trasimeni G, Monarca B: Intrathecal anti-CD20
antibody: an effective and safe treatment for leptomeningeal
lymphoma. J Neuro-Oncol 2007, 81(2), 197-199.
13. Read RW, Zamir E, Rao NA: Neoplastic masquerade syndromes.
Surv Ophthalmol 2002, 47(2), 81-124.
14. Barr CC, Joondepth HC: Retinal periphlebitis as the initial
clinical finding in a patient with Hodgkin’s disease. Retina
1983, 3, 253-257.
15. Schachat AP, Markowitz JA, Guyer DR, Burke J, Karp JE,
Graham ML: Ophthalmic manifestations of leukemia. Arch
Ophthalmol 1989, 107, 697-700.
16. Reddy SC, Jackson N, Menon BS: Ocular involvement in
leukemia: A study of 288 cases. Ophthalmologica 2003, 217(6),
441-445.
17. Yi DH, Rashid S, Cibas ES, Arriqq PG, Dana MR: Acute
unilateral leukemic hypopyon in an adult with relapsing acute
lymphoblastic leukemia. Am J Ophthalmol 2005, 139(4), 719-721.
18. Decker EB, Burnstine RA: Leukemic relapse presenting as
acute unilateral hypopyon in acute lymphocytic leukemia. Ann
Ophthalmol 1993, 25(9), 346-349.
19. Kincaid MC, Green WR: Ocular and orbital involvement in
leukemia. Surv Ophthalmol 1983, 27(4), 211-232.
20. Nussenblatt RB, Whitcup SM, Palestine AG: Uveitis.
Fundamentals and Clinical Practice, pp 385-395, chapter 29,
Second Edition, Mosby, 1996, St. Louis.
21. Kubicka-Trząska A, Romanowska-Dixon B: Choroidal metastases
from breast cancer – clinical observation of 18 cases. Klin
Oczna 2006, 108(7-9), 281-283.
22. Henderson HWA, Davidson F, Mitchell SM: Intraocular
inflammation and the diffuse infiltrative lymphocytosis syndrome.
Am J Ophthalmol 1998, 126, 462-464.
23. Kanski JJ: Intraocular tumours. [in]: Clinical Ophthalmology,
chapter 8, pp 320-349, 4th ed., Butterworth-Heinemann, Oxford,
1999.
24. Croxatto JO, Fernandez MR, Malbran ES: Retinoblastoma
masquerading as ocular inflammation. Ophthalmologica 1983, 186,
48-53.
25. Singh R, Kaurya O, Shukla PK, Ramputty R: Lactate
dehydrogenase (LDH) isoenzymes patterns in ocular tumours.
Indian J Ophthalmol 1991, 39, 44-47.
26. De Barge LR, Chan CC, Greenberg SC, McLean IW, Yannuzzi LA,
Nussenblatt RB: Chorioretinal, iris and ciliary body
infiltration by juvenile xanthogranuloma masquerading as uveitis.
Surv Ophthalmol 1994, 39, 65-71.
27. Sawyer RA, Selhorst JB, Zimmerman LE, Hoyt WF: Blindness
caused by photoreceptor degeneration as a remote effect of
cancer. Am J Ophthalmol 1976, 81(5), 606-613.
28. Ohguro H, Maruyama I, Nakazawa M, Oohira A: Antirecoverin
antibody In the aqueous humor of a patent with cancer-associated
retinopathy. Am J Ophthalmol 2002, 134(4), 605-607.
29. Kim RY, Retsas S, Fitzke FW, Arden GB, Bird AC: Cutaneous
melanoma-associated retinopathy. Ophthalmology 1994, 101,
1837-1843.
30. O’Neal KD, Butnor KJ, Perkinson KR, Proia AD: Bilateral
diffuse uveal melanocytic proliferation associated with
pancreatic carcinoma: a case report and literature review of
this paraneoplastic syndrome. Surv Ophthalmol. 2003, 48(6),
613-625.
Praca włynęła do redakcji 12.12.2007 r. (1007)
Zakwalifikowano do druku 26.03.2008 r.
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| Lymphomas |
Primary intraocular lymphoma
Systemic non-Hodgkin lymphoma metastatic to eye
Hodgkin lymphoma metastatic to eye |
| Leukemias |
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| Ocular metastases |
Breast
Lungs
Kidney |
Lymphoid hyperplastic
of the uvea |
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| Uveal melanoma |
Iris
Ciliary body
Choroid |
| Childhood malignancies |
Retinoblastoma
Medulloepithelioma
Juvenile xanthogranuloma
Histiocytosis X |
| Paraneoplastic syndromes |
Carcinoma – associated retinopathy
Melanoma – associated retinopathy
Bilateral diffuse uveal melanocytic proliferation |
Tab. I. Malignant ocular disorders
masquerading as intraocular inflammation.
Tab. I. Oczne zespoły maskujące jako złośliwe zapalenie
wewnątrzgałkowe.
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Fig. 1. Intraocular primary lymphoma
masquerading as uveitis
Ryc. 1. Pierwotny chłoniak z obrazem zapalenia błony
naczyniowej.
Fig. 2. Sentinel vessels in a course of
ciliary body melanoma.
Ryc. 2. Poskręcane naczynia w przebiegu czerniaka ciała
rzęskowego.
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