Download Ocular manifestations of the phakomatoses

USCAP
Margaret McLaughlin, M.D.
American Association of Ophthalmic Pathologists
Novartis
San Antonio, TX
Oncology Translational Research
February 26, 2011
Cambridge, MA
Ocular manifestations of the phakomatoses
I. Definition of phakomatoses
A. Greek word phakos means “spot, lens”
B. Ophthalmologist Jan van der Hoeve coined term phakomatosis in 1920 for three disorders
(neurofibromatosis, tuberous sclerosis, von Hippel-Lindau syndrome), which affect the nervous system,
eye and skin
C. Conditions commonly included as phakomatoses today
i. Neurofibromatosis 1
ii. Neurofibromatosis 2
iii. Tuberous sclerosis
iv. von Hippel-Lindau syndrome
v. Ataxia telangiectasia
vi. Sturge-Weber syndrome
vii. Incontinentia pigmenti
viii. Gorlin syndrome (Nevoid basal cell carcinoma syndrome)
II. Neurofibromatosis 1
A. Inheritance: Autosomal dominant
i. Mutations in the NF1 gene that encodes the protein neurofibromin, a GTPase activating protein
B. Prevalence: 1:4,000
C. Systemic manifestations
i. Tumors
a. Neurofibroma, MPNST, glioma, leukemia
ii. Other features
a. Café-au-lait macules, skin-fold freckling, skeletal dysplasia, vascular disorder, learning
disability
D. Ocular manifestations
i. Lisch nodules (iris hamartomas)
a. In ~90% of NF1 patients
b. Multiple, bilateral, lightly pigmented, raised nodules on the anterior surface of iris
c. Comprised of pigmented cells and fibroblast-like cells
ii. Glaucoma
a. In ~50% of NF1 patients
b. Multiple mechanisms may contribute: infiltration of anterior chamber angle by
neurofibroma, malformation or immature development of the anterior chamber angle,
secondary angle closure due to infiltration of the ciliary body/choroid
c. Almost always associated with globe enlargement (buphthalmos)
d. Frequently associated with iris ectropion
iii. Neurofibromas (eyelid, orbit, uvea)
a. Choroidal abnormalities detected in 100% of NF1 patients by scanning laser
ophthalmoscopy
b. Ovoid bodies – hyperplasia of Schwann cells around axons, found in choroidal
neurofibromatosis
iv. Optic nerve glioma
v. Orbital bony malformations
a. Absence of the greater and lesser wings of sphenoid
III. Neurofibromatosis 2
A. Inheritance: Autosomal dominant
i. Mutations in the NF2 gene that encodes the protein merlin, which has pleiotropic effects
B. Prevalence: 1:40,000
C. Systemic manifestations
i. Tumors
a. Schwannoma, meningioma, ependymoma, glioma
D. Ocular manifestations
i. Cataract
a. Juvenile posterior subcapsular cataracts are found in 80% of NF2 patients
b. Displaced lens and Wedl/bladder cells are found just anterior to the posterior lens
capsule
ii. Epiretinal membrane
a. In majority of NF2 patients, likely congenital
b. Immunophenotype and ultrastructural features are most consistent with Muller cell
origin
iii. Retinal hamartoma
iv. Optic nerve meningioma
v. Intraocular schwannoma
a. Arise from the long ciliary nerves
vi. Neurotrophic keratopathy
a. Vestibular schwannoma → CN VII dysfunction → poor lid closure → corneal damage
from exposure
IV. Tuberous sclerosis
A. Inheritance: Autosomal dominant
i. Mutations in TSC1 and TSC2 genes that encode the proteins hamartin and tuberin, which inhibit
mTOR signaling
B. Prevalence: 1:6,000
C. Systemic manifestations
i. Tumors
a. Facial angiofibroma, ungual fibroma, cardiac rhabdomyoma, renal angiomyolipoma,
subependymal giant cell astrocytoma
ii. Other features
a. Cortical tubers, subependymal nodule, hypomelanotic macule, shagreen patch,
pulmonary lymphangiomyomatosis, renal nodular hamartomas
D. Ocular manifestations
i. Retinal hamartomas
a. In ~50% of TS patients
b. Cells comprising the lesion may have mixed neuronal and glial features
V. von Hippel-Lindau syndrome
A. Inheritance: Autosomal dominant
i. Mutations in the VHL gene that encode an E3 ubiquitin ligase, which regulates the cellular
response to hypoxia
B. Prevalence: 1:50,000
C. Systemic manifestations
i. Tumors
a. CNS hemangioblastoma, renal cell carcinoma, pheochromocytoma, pancreatic islet
cell tumor, endolyphatic sac tumor, broad-ligament cystadenomas
ii. Other features
a. Renal cysts
D. Ocular manifestations
i. Retinal hemangiomas
a. Multifocal and bilateral
VI. Ataxia Telangiectasia
A. Inheritance: Autosomal recessive
i. Mutations in the ATM gene that encodes a protein involved in DNA repair
B. Prevalence: 1:30,000
C. Systemic manifestations
i. Tumors
a. Lymphoid malignancy
ii. Other features
a. Early onset progressive cerebellar ataxia, immunodeficiency, recurrent infections,
oculocutaneous telangiectasias, absent/rudimentary thymus, insulin-resistant diabetes,
radiosensitivity
D. Ocular manifestations
i. Conjunctival telangiectasias
ii. Oculomotor abnormalities
a. Nystagmus, pursuit and saccade abnormalities, strabismus, poor convergence
VII. Sturge-Weber syndrome
A. Inheritance: Sporadic
B. Prevalence: 1:50,000
C. Systemic manifestations
i. Port-wine stains/nevus flammeus
ii. Seizures, intellectual impairment, migraine headache, hemiparesis, hemianopsia
D. Ocular manifestations
i. Glaucoma
a. In ~30% of SWS patients
b. Usually ipsilateral to the port-wine stain
ii. Diffuse choroidal hemangioma
a. In ~70% of SWS patients
b. Ipsilateral to the port-wine stain
c. “Tomato ketchup” appearance of fundus exam
iii. Episcleral/conjunctival hemangioma
iv. Iris heterochromia
v. Buphthalmos
vi. Retinal pigment degeneration
vii. Retinal detachment
viii. Optic disc coloboma
ix. Cataract
x. Nevus of Ota
VIII. Incontinentia pigmenti
A. Inheritance: X-linked dominant
i. Mutations in the NEMO gene that encodes a protein critical for NF-κB activation
B. Prevalence: 1:390,000
C. Systemic manifestations
i. Disturbance of skin pigmentation, leading to a “marble cake” appearance
ii. Seizures, spastic paralysis, microcephaly, mental retardation
a. Secondary to compromised vascularization of the developing brain
iii. Alopecia, anodentia, nail dystrophy
D. Ocular manifestations
i. Retinal ischemia, leading to reactive neovascularization and fibrovascular scarring
a. In ~30-40% of IP patients
b. May be complicated by retinal detachment
IX. Gorlin syndrome (Nevoid basal cell carcinoma syndrome)
A. Inheritance: Autosomal dominant
i. Mutations in PTCH1 gene that encodes a transmembrane protein, which inhibits hedehog
signaling
B. Prevalence: 1:60,000-1:260,000
C. Systemic manifestations
i. Tumors
a. Multiple basal cell carcinomas, medulloblastoma, fibroma, rhabdomyosarcoma
ii. Other features
a. Odontogenic keratocysts of the jaws, hyperkeratosis of palms and soles, epidermoid
cysts, multiple nevi, skeletal abnormalities, intracranial ectopic calcifications, facial
dysmorphism
D. Ocular manifestations
i. Hypertelorism
ii. Exophthalmos
iii. Rotary nystagmus
iv. Internal strabismus
v. Congenital cataracts
vi. Orbital cysts
vii. Coloboma of iris, choroid and optic nerve
viii. Microphthalmia
ix. Chalazions
x. Transient milia on the palpebral conjunctiva
Definition of phakomatoses
Greek word ϕακóς, phakos,
means “spot, lens”
Ocular manifestations of the
phakomatoses
Café-au-lait spot
Ophthalmologist Jan van der
Hoeve coined the term
phakomatosis in 1920 for
three disorders
(neurofibromatosis, tuberous
sclerosis and von HippelLindau syndrome), which
affect the nervous system,
eye and skin
Margaret McLaughlin, M.D.
Novartis – Oncology Translational Research
Cambridge, MA
USCAP
Karahan E et al. (2007) Internet J Ophthalmol Vis Sci
February 26, 2011
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Conditions included as phakomatoses
Neurofibromatosis 1
Neurofibromatosis 1
Inheritance: Autosomal dominant
Neurofibromatosis 2
Prevalence: 1:4,000
Tuberous sclerosis
Systemic manifestations:
Multiple neurofibromas
• Tumors:
von Hippel-Lindau syndrome
- Neurofibroma
- MPNST
Ataxia telangiectasia
- Glioma
- Leukemia
Sturge-Weber syndrome
• Other features:
Incontinentia pigmenti
- Café-au-lait macules
- Skin-fold freckling
- Skeletal dysplasia
Gorlin syndrome (Nevoid basal cell carcinoma syndrome)
- Vascular disorder
- Learning disability
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NF1 gene encodes the protein neurofibromin, a
GTPase activating protein
Neurofibromatosis 1: Ocular manifestations
Meded.ucsd.edu
Lisch nodules (iris hamartomas)
Glaucoma
Neurofibromas (eyelid, orbit, uvea)
Optic nerve glioma
Oribital bony malformations
• Absence of greater and lesser wings of sphenoid
Le LQ and Parada LF (2007) Oncogene
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‹#›
Lisch nodules
Lisch nodules
In ~90% of NF1 patients
Iris hamartomas comprised of pigmented cells and fibroblast-like
cells
Multiple, bilateral, lightly pigmented, raised nodules on the anterior
surface of the iris
Perlman JI et al. (2005) EOPS
Atlasgeneticsoncology.org
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Glaucoma
Glaucoma
Normal size
In ~50% of NF1 patients
• Some cases are congenital
Normal retina
Multiple mechanisms may
Ganglion cell loss
contribute:
Ganglion cell layer
• Infiltration of anterior chamber angle by
neurofibroma
• Malformation or immature development
of the anterior chamber angle
Globe enlargement in NF1
• Secondary angle closure due to
infiltration of ciliary body/choroid
Almost always associated with
ganglion cell
globe enlargement
(buphthalmos)
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Glaucoma
Choroidal neurofibromatosis
Frequently associated with iris ectropion
Choroidal abnormalities detected in 100% of NF1 patients by
scanning laser ophthalmoscopy
Diffuse thickening of the choroid
Normal
choroid
RPE
Choroid
Sclera
Ovoid body
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‹#›
NF2 gene encodes the protein merlin, which has
pleiotropic effects
Neurofibromatosis 2
Inheritance: Autosomal dominant
Vestibular schwannoma
Prevalence: 1:40,000
Systemic manifestations:
• Tumors:
- Schwannoma
- Meningioma
- Ependymoma
- Glioma
Commons.wikimedia.org
Asthagiri AR et al. (2009) Lancet
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Neurofibromatosis 2: Ocular manifestations
Cataract
Epiretinal membrane
Retinal hamartoma
Optic nerve meningioma
Intraocular schwannoma
Neurotrophic keratopathy (vestibular schwannoma → CN VII
dysfunction → poor lid closure → corneal damage from exposure)
15 |
‹#›
Cataract
Epiretinal membrane
Junvenile posterior subcapsular cataracts are found in 80% of NF2
In majority of NF2 patients, likely congenital
patients
OD
OS
Wedl/bladder cells
displaced lens cells
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Epiretinal membrane (OS)
Epiretinal membrane
Epiretinal membrane
Intraocular schwannoma
Immunophenotype and ultrastructural features are most consistent
with Muller cell origin
long posterior
ciliary nerve
‹#›
Intraocular schwannoma
S100
S100
‹#›
TSC1 and TSC2 encode the proteins hamartin and
tuberin, which inhibit mTOR signaling
Tuberous sclerosis
Inheritance: Autosomal dominant
Prevalence: 1:6,000
Systemic manifestations:
Two tubers thicken the cortex and
obscure the grey-white junction
• Tumors:
- Facial angiofibroma
- Ungual fibroma
- Cardiac rhabdomyoma
- Renal angiomyolipoma
- Subependymal giant cell astrocytoma
• Other features:
- Cortical tubers
- Subependymal nodule
Commons.wikimedia.org
- Hypomelanotic macule
- Shagreen patch
- Pulmonary lymphangiomyomatosis
Orlova KA and Crino PB (2010) Ann NY Acad Sci
- Renal nodular hamartomas
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Tuberous sclerosis: Ocular manifestations
Retinal hamartoma
Retinal hamartomas occur in ~50% of TS patients
Syed NA et al. (2004) EOPS
Syed NA et al. (2004) EOPS
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Ataxia telangiectasia
ATM encodes a protein involved in DNA repair
Inheritance: Autosomal recessive
Cutaneous telangiectasias
Prevalence: 1:30,000
Systemic manifestations:
• Tumors:
- Lymphoid malignancy
• Other features:
- Early onset progressive cerebellar ataxia
- Immunodeficiency and recurrent infections
- Oculocutaneous telangiectasias
- Absent/rudimentary thymus
- Insulin-resistant diabetes
- Radiosensitivity
Emedicine.medscape.com
Fredrick A et al. (2010) FEBS
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‹#›
Ataxia telangiectasia: Ocular manifestations
Conjunctival telangectasias
Conjunctival telangiectasias
Normal conjunctiva
Conjunctival telangiectasias
Conjunctival telangiectasia
Oculomotor abnormalities
• Nystagmus
• Pursuit and saccade
abnormalities
• Strabismus
• Poor convergence
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Amphicytes
Is the term phakomatoses still useful?
Bizarre enlargement of cell nuclei to 2-5 times normal size is found
Lack of consensus as to which conditions are phakomatoses
in many organs in AT
Conditions are due to mutations in distinct genes
Amphicytes in conjunctival epithelium
For the most part, clinical features are nonoverlapping
Commonalities raise similar genetic testing and patient care issues
• Inherited as autosomal dominant, autosomal recessive or X-linked dominant traits
(with the exception of Sturge-Weber syndrome, which is sporadic)
• Chronic
• Progressive
• Pleiotropic
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‹#›
Companion Meeting – American Association of Ophthalmic Pathologists
San Antonio TX, March 2010
Ocular Manifestations of Inflammatory Diseases
Diva Regina Salomão, MD
Department of Laboratory Medicine and Pathology
Mayo Clinic, Rochester, MN
Introduction
A number of inflammatory, non infectious diseases may involve the eye and the
periocular tissues. Often, the systemic disease is already known to the patient and his/her
clinician and the ocular manifestations come at a later stage of the disease. However, on
some occasions, the ocular manifestations may precede the systemic symptoms and
recognition by the ophthalmology and ophthalmic pathologist will allow for an early
treatment.
Herein, we will focus on four diseases that might be seen in tissue biopsies by the
surgical pathologist. Their clinical and pathological features as well as pertinent
differential diagnosis will be discussed.
Sarcoidosis
Sarcoidosis is a multisystem disease of unknown etiology characterized by noncaseating granulomas in various organs. Granulomas most often appear in the lungs
(85%) and lymph nodes (34%), but virtually any organ may be involved including the
eye (27%) and less commonly the central nervous system (1%). It affects most commonly
young adults of both sexes. Incidence is highest for individuals younger than 40 and
peaks in the age-group from 20-29 years; a second peak is observed for women over 50.
The disease is most prevalent in Northern European countries. In USA, sarcoidosis is
more common in African descendent than Caucasians, with annual incidence reported as
35.5 and 10.9/100,000, respectively.
The pathogenesis of this disease is not yet known. The most accepted hypothesis
is that in genetically susceptible individuals, sarcoidosis is caused through alteration in
immune response after exposure to an environmental, occupational or infectious agent.
Studies have shown an increase in B-cell activity with hypergammaglobulinemia in about
50% of the patients. Reduced delayed hypersensitivity is also found in many patients.
Immune dysregulation due to persistent low virulence antigen that is poorly cleared by
the immune system, leading to a chronic T-cell of the Th1 subtype response, with
granulomatous response, has been hypothesized. Medications that increase Th1 response,
such as interferon, have been reported to trigger or exacerbate sarcoidosis. Gli-1
oncogene has been found to be highly expressed in patients with sarcoidosis.
The course of the disease is variable, ranging from self-limited acute disease to a
chronic debilitating disease that might result in death. Spontaneous remissions occur in
2/3 of the patients, but 10-30% of the patients have more chronic or progressive course.
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The mortality rate is 1-6%. Death can be due to pulmonary fibrosis leading to respiratory
failure, myocardial involvement leading to cardiac arrhythmias and cardiac failure, CNS
involvement, renal insufficiency and liver disease.
The eye may be affected by sarcoidosis in a variety of ways, with the most
frequent site being the uveal tract. Obenauf and associates observed anterior
granulomatous uveitis in 52% of the 202 patients with ocular involvement; while James
and colleagues observed iridocyclitis is 72% of 123 patients with ocular sarcoidosis.
Anterior segment involvement is often accompanied by keratic precipitates and posterior
synechia. Posterior segment involvement usually accompanies anterior involvement, but
it may also occur alone, manifesting as retinitis, choroiditis, chorioretinitis, papillitis or
retinal perivasculitis. Posterior involvement may be diffuse. Choroiditis may be localized
or multifocal.
Optic nerve and optic nerve head involvement have been reported in about 5% of
patients with sarcoidosis. Evidence suggests that patients with retinal and optic nerve
involvement are at increased risk to have or to develop CNS involvement. CNS
involvement is rare, observed in 2% of all patients, but CNS complications account for
25% of death caused by sarcoid.
Sarcoid may involve the lacrimal gland, giving rise to keratoconjunctivitis sicca.
Rarely, it extends beyond the lacrimal gland into orbital soft tissue. This was seen in only
2 of 202 cases (1%) studied by Obenauf et al. Although conjunctival involvement is also
infrequent, because of the easy access, it is often biopsied in the search of granulomas to
support the diagnosis of sarcoidosis. The yield is approximately 30% positivity in
patients with well established diagnosis, 17% positivity in patients with strong clinical
suspicion and 0% positivity when sarcoid is only entertained in the diagnosis.
The diagnosis of sarcoidosis is often a matter of exclusion of other diseases
including neoplasm. It is made on the basis of signs and symptoms, patient’s age and race
and laboratory findings. A definitive diagnosis requires that a biopsy be performed. The
typical lesion in the biopsy is characterized by circumscribed epithelioid granulomas with
little or no necrosis, and few Langhans giant cells. Giant cells may contain asteroid or
Schaumann bodies. A sparse lymphocytic infiltrate might be seen in the periphery of
these granulomas, the reason these are referred as naked granulomas.
The differential diagnosis of sarcoidosis includes mainly granulomatous
infectious processes such as tuberculosis and fungus infection. Therefore, special stains
and tissue cultures for microorganisms must be obtained on routine basis.
Oral corticosteroids are usually the treatment of choice for symptomatic patients.
Systemic cytotoxic agents like methrotexate, azathioprine and Chlorambucil may be used
in refractory cases. Infliximab, a tumor necrosis factor inhibitor, that neutralizes cytokine
TNF-alpha and inhibits it from binding to TNF-alpha receptor, is a promising option for
patients with recurrent disease. The visual prognosis of sarcoidosis is usually good.
Wegener’s granulomatosis
In 1931, Heinz Klinger, a medical student of the University of Berlin, first
reported two patients who died of inflammation of the blood vessels scattered throughout
the body. Five years later, Friederic Wegener, a German pathologist described three
additional patients with necrotizing granulomas involving both the upper and lower
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respiratory tract. He was the first one to recognize this disorder as a distinct form of
vasculitis.
Wegener's granulomatosis (WG) is an uncommon disease defined by vasculitis and
necrotizing granulomatous inflammation involving the kidneys (glomerulonephritis) and the
upper and lower respiratory tract (sinuses, nose, trachea, and lungs). Wegener's
granulomatosis most commonly affects individuals in the 4th or 5th decade of life. The disease
can, however, affect people at any age (age range: 5-91 years), with approximately 15% of
cases beginning before 20 years of age. Wegener's granulomatosis strikes both men and
women. It is most common in Caucasians (97%) and is rare in African Americans (2%).
Ocular symptoms may be the first manifestation in 16% of patients with Wegener's
granulomatosis, while overall approximately half of patients will eventually develop ocular
involvement. A common problem in patients with Wegener's granulomatosis is tearing due to
nasolacrimal duct obstruction. The orbital inflammation can cause loss of vision, pain,
diplopia, proptosis, or orbital bone erosion. Orbital involvement has been reported in 45-70%
of patients, and in rare occasions it may precede the detection of the systemic disease. Other
ocular manifestations of WG are peripheral ulcerative keratitis and scleritis as well as less
commonly uveitis, retinal vasculitis and optic neuropathy.
The histological diagnosis is characterized by the presence of necrobiotic coagulative
necrosis, a large number of neutrophils and eosinophils, forming small clusters and
intermixed with the necrosis; associated with histiocytic granulomatous reaction around the
large areas of necrosis and small vessel vasculitis. Early lesions might not show the fullblown picture (vasculitis, geographic necrosis and granulomatous inflammation). The
differential diagnosis is mainly with idiopathic orbital inflammation, in which one should not
observe the presence of vasculitis or necrosis.
Wegener’s granulomatosis is considered part of a group of autoimmune disorders
known as antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, which also
includes microscopic polyangiitis, Churg-Strauss syndrome and renal-limited vasculitis.
These disorders are characterized by the presence of necrotizing small-vessel vasculitis with
the presence of serum autoantibodies directed against neutrophil cytoplasmic constituents, in
particular protein 3 (PR3) and myeloperoxidase (MPO). ANCA tests can be performed by
both indirect immunofluorescence assay and antigen-specific enzyme-linked
immunoabsorbent assay (ELISA). ANCA are believed to play a role a role in the
pathogenesis of the vasculitis via activation of neutrophils, but mostly important, they are
useful in diagnosis and the management of these disorders. The specificity of c-ANCA in
biopsy proven WG has been shown to be 90%. The sensitivity depends on the extent and the
activity of the disease. C-ANCA is not detected in most patients at complete remission and
rising levels might be indicative of relapse.
The most commonly postulated scenario for ANCA-mediated vasculitis is the
interaction of neutrophils and the endothelial cells via cell adhesion molecules, which results
in releasing cytokines with damage to the vascular walls. Although many advances have
occurred in the understanding of the pathogenesis of WG, so far, it is still not known how
tolerance to the autoantigen PR3 is broken and how is the immune response sustained. PR3
induces dendritic cell maturation via the protease activated receptor (PAR)-2 and evokes a
strong Th1-type T-cell response in WG. Clusters of PR3 positive cells (neutrophils and
monocytes) surrounded by antigen presenting cells, Th1-type CD4+CD28- effector memory
T-cells, maturing B- and plasma cells are found in the granulomatous responses of WG
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lesions. Several important studies have characterized the role of PR3 and PAR-2 in the
initiation of this process. These might provide evidences for a more target-specific antiinflammatory therapy for these patients.
Necrobiotic Xanthogranuloma
Necrobiotic xanthogranuloma (NXG), a distinctive dermal and subcutaneous
xanthogranulomatous reaction, is a rare form of paraneoplastic syndrome often associated
with paraproteinemia. It is a potentially disfiguring disease that can involve the face,
trunk or extremities with a particular predilection for the periorbital region.
It was first recognized in 1980 (Kossard and Wilkeman1980). In their report, the
authors described 8 patients with multiple xanthomatous plaques and subcutaneous
nodules involving the periorbital area, flexures and trunk with a tendency to ulcerate. Six
of these patients had IgG monoclonal gammopathy. The ophthalmic features of this
disease were later described by Robertson and Wilkelman (1984). Of the16 patients
reported, which included the 8 patients previously described by Wilkeman, 13 had eyelid
lesions, 2 had orbital masses, 3 had conjunctival involvement, 2 had keratitis, 3 had
scleritis or episcleritis and 3 had anterior uveitis. Eleven of sixteen patients had IgG
monoclonal gammopathy, 3 patients had multiple myeloma and one patient had nonHodgkin’s lymphoma. Since then, several single cases have been reported in the
literature.
Clinically, NXG is characterized by large often yellow, indurated plaques
sometimes associated with telangiectasia. The lesions often become inflamed leading to
superficial ulceration. The most common locations are the periorbital region and thorax.
Extensive lesions involving the eyelids may extend into the orbital soft tissues. The
clinical differential diagnosis includes mainly xanthelasma and xanthoma, lesions that are
not usually indurated. The association of NXG with monoclonal gammopathy is
characteristic. Although IgG monoclonal gammopathy represents the most common
association, a rare form of IgA gammopathy has also been reported (Fortson and
Schroeder 1990), as well as the association with other hematologic disorders such as
multiple myeloma, chronic lymphocytic leukemia, lymphoma and other less common
diseases such as cryoglobulinemia.
The histopathology is characterized by infiltrates containing mostly macrophages,
foamy cells associated with extensive necrobiosis (degeneration of collagen) surrounded
by palisading granulomatous reaction. Numerous giant cells, Touton and foreign-body
types are usually seen. Cholesterol clefts which have been reported previously do not
appear to be as common as initially thought (Finnan 1987). Other findings are lymphoid
follicles and a mixture of other inflammatory cells. This particular case was unusual in
the finding of small lymphocytic lymphoma, this patient systemic disease, in association
with NXG in the same tissue biopsy.
The differential diagnosis includes other necrobiotic disorders, especially
necrobiosis lipoidica, subcutaneous granuloma annulare, and rheumatoid nodule. In
NXG, the necrobiosis is more extensive than in other diseases and often occurs in broad
bands. More important, the clinical presentation differs in each of these lesions.
Necrobiosis lipoidica tends to affect mainly pretibial areas in diabetic patients.
Granuloma annulare is characterized by papules often in young adults and rheumatoid
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nodules are seen in patients with clinically apparent rheumatoid arthritis. Other lesions
considered in the differential because of the presence of foamy histiocytes and Touton
type giant cells are xanthogranuloma and Erdheim-Chester disease. These entities do not
show the necrobiosis that characterizes NXG.
Necrobiotic xanthogranuloma can cause impairing sequela. The cutaneous lesions
tend to progress and the course is unpredictable with periods of stabilization, reduction
and more aggressive periods with extensive ulceration (Mehregan et al 1992, Ugurlu et al
2000). The treatment is difficult and should include management of the underlying
systemic disease and control of the skin lesions. Surgical removal of the lesions is
generally not recommended because of the risk of recurrence which was around 42% in a
large series (Ugurlu 2000). However, surgery might be necessary to correct scarring and
eyelid malfunction. Systemic prednisone and steroid injections have been proposed as
alternative forms of treatment, as well as low dose radiation therapy and alkylating
regimens.
Rosai Dorfmann Disease
Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive
lymphadenopathy was first reported in 1969, as a distinct histiocytic disorder in young
black men, presenting with bilateral, painless, massive cervical lymphadenopathy with a
protracted clinical course, in most cases associated with fever, anemia, neutrophilia,
elevated erythrocyte sediment rate and polyclonal gammopathy.
This disorder is most common in the first and second decade of life, but it can
occur at any age. Painless lymphadenopathy is the most frequent systemic symptom,
involving lymph nodes in the neck (90%), inguinal (26%) and axillary (24%) regions, or
mediastinum (15%) in the majority of the cases. Extranodal disease is reported in 43% of
patients, some without associated lymphadenopathy. The most common sites of
extranodal involvement are skin, nasal cavity and paranasal sinus, eyelid, orbit, bone,
salivary gland and CNS.
RDD can involve any part of the eye or orbit, but infiltration of the intraconal
space orbital soft tissue is the most common ocular manifestation. Proptosis is the most
common symptom; blurred vision, diplopia, dry eye and epiphora can also be seen. On a
series by Vemuganti and collaborators, RDD involving the orbit represented 2.3% of all
orbital lesions diagnosed in a large tertiary center. Other ophthalmic manifestations
include epibulbar masses, compressive optic nerve neuropathy, marginal corneal
infiltrates and uveitis. Eyelid thickening is an uncommon manifestation of RDD and in
most cases of eyelid involvement it occurs in conjunction with orbital disease. Eyelid
involvement as part of generalized cutaneous RDD is very uncommon and it seems affect
older patients.
RDD is one of the non-Langerhans cell benign histiocytosis, where predominantly
the sinuses or interfollicular area are infiltrated with distinctive histiocytes with round or
oval vesicular nuclei, well-defined, delicate nuclear membranes and a single prominent
nucleolus. The hallmark of RDD is the presence of lymphophagocytosis or
emperipolesis, where viable lymphocytes are located in vacuoles of intact histiocytes.
Plasma cells, neutrophils and red blood cells may also be seen within the cytoplasmic
vacuoles. The involved histiocytes are activated macrophages that express S100 protein,
5
HAM 56, α 1 antitrypsin, α 1 chymotrypsin, lysozyme and CD30, but are negative for
CD1a. The histopathologic features of RDD in extranodal sites are similar to the nodal
disease except for that fibrosis tends to be more prominent and emperipolesis less
evident. The differential includes non-specific sinus histiocytosis (lacks emperipolesis
and histiocytes are S100 negative), Langerhans’ cell histiocytosis (positive for S100 and
CD1a), hemophagocytic syndromes, storage disorder, necrobiotic granuloma,
lymphoproliferative disorder, leprosy and metastatic melanoma.
Despite its well-recognized clinical presentation, the precise etiology of RDD
remains unknown. The current thinking is that Fas/FasL signaling leading to altered
apoptosis may be an important mechanism in the abnormal histiocytic proliferation. A
possible viral etiology, related to parvovirus B19 has also been suggested by a recent
study.
RDD is relatively unaffected by therapy and it shows a variable presentation. In
some cases, the disease has a fast course with complete resolution. In others, it follows a
chronic course with episodes of exacerbation and periods of remission. Recurrence might
occur later at a different site. Rare cases of death-related to RDD have been reported.
Management options include observation, surgical excision or debulking, systemic
corticosteroids, chemotherapy or radiotherapy. The treatment of the orbital RDD aims to
control functional and cosmetic abnormalities, usually through surgical resections.
Recurrent orbital disease or significant residual lesion following surgery may be treated
with systemic corticosteroids, radiation or chemotherapy. Chemotherapy has also been
used to relieve sight threatening optic nerve compression.
Selected references
Sarcoidosis
1. Bonfioli AA, Orefice F. Sarcoidosis. Semin Ophthalmol 2005; 20 (3):177-82
2. Caça I, Unlu K, Buyukbayram H, Ari S. Conjunctival deposits as the first sign of
systemic sarcoidosis in a pediatric patient. Eur J Ophthalmol 2006; 16 (1):168170
3. Dios E, Saomil MA, Herreras JM. Conjunctival biopsy in the diagnosis of ocular
sarcoidosis. Ocul Immunol Inflamm 2001; 9 (1):59-64
4. Hellingenhaus A, Wefelmeyer E, Rosel M, Schrenk M. the eye as a common site
for the early clinical manifestation of sarcoidosis. Ophthalmic Res 2010; 46 (1):
9-12
5. Herbort CP, Rao NA, Mochizuki M. International criteria for the diagnosis of
ocular sarcoidosis: results of the first international workshop in ocular sarcoidosis
(IWOS). Ocul Immunol Inflamm 2009; 17(3): 160-9
6. Leavitt JA, Campbell RJ. Cost-effectiveness in the diagnosis of sarcoidosis: the
conjunctival biopsy. Eye 1998; 12 (6):959-62
7. Obenauf CD, Shaw HE, Snyder CF, Klintworth GK. Sarcoidosis and its
ophthalmic manifestations. Am J Ophthalmol 1978; 86 (5): 648-55
8. Macaron NC, Cohen C, Chen SC, Arbiser JL. Gli-1 Oncogene is highly expressed
in granulomatous skin disorders, including sarcoidosis, granuloma annulare, and
necrobiosis lipoidic diabeticorum. Arch Dermatol 2005; 141(2): 259-62
6
9. Rybicki BA, Major M, Popovich J Jr, Maliarik MJ, Iannuzzi MC. Racial
differences in sarcoidosis incidence: a 5-year study in a health maintenance
organization. Am J Epidemiol 1997; 145(3): 234-41
Wegener’s Granulomatosis
1. Brouwer E, Stegmena CA, Huitema MG, Limburg PC, and Kallenbert CG. T cell
reactivity to proteinase 3 and myeloperoxidase in patients with Wegener’s
granulomatosis (WG). Clin Exp Immunol 1994; 98(3):448-453
2. Bullen CL, Liesegang TJ, McDonald TJ and De Remee RA. Ocular
complications of Wegener’s granulomatosis. Ophthalmology, March 1983;
90(3):279-290
3. Chen M, Feng Y, Zhang Y and Zhao MH. Antineutrophil Cytoplasmic
Autoantibody-Associated Vasculitis in older Patients. Medicine 2008; 87(4):203209
4. Coppeto JR, Yamase H, Monteiro MLR: Chronic ophthalmic Wegener’s
granulomatosis. J Clin Neuro Ophthalmolol 1985; 5:17-25
5. Coutu RE, Klein M, Lessell S, et al: Limited form of Wegener’s granulomatosis:
Eye involvement as a major sign. JAMA 1975; 233:868-871
6. Cross CE, Lillington GA: Serodiagnosis of Wegener’s granulomatosis:
Pathologic and clinical implications (editorial). Mayo Clin Proc 1989; 64:119-122
7. Csernok E, MaiXing A, Wolfgang GL, Wicklein D, Petersen A, Linder B,
Lamprecht P, Holle JU, and Hellmich B. Wegener autoantigen induces
maturation of dendritic cells and licenses them for TH1 priming via the proteaseactivated receptor-2 pathway. Blood 2006; 107(11): 4440-4448
8. Gupta D, Hemment B, Marsha. T. A complex orbit. Orbit 2008; 27(4): 297-9.
9. Haynes BF¸ Fishman ML, Fauci AS, Wolff SM: The ocular manifestations of
Wegener’s granulomatosis. Fifteen years experience and review of the literature.
Am J Med 1977; 63:131-141
10. Holland M, Hewins P, Goodall M, Adu D, Jefferies R, Savage COS. Antineutrophil cytoplasm antibody IgG subclasses in Wegener’s granulomatosis: a
possible pathogenic role for the IgG4 subclass. Clin Exp Immunol 2004;
138:183-192
11. Jannette JC, Falk RJ: Small-vessel vasculitis. NEJM 1997; 1512-1523
12. Koyama T. Matsuo N, Wantanabe Y, et al: Wegener’s granulomatosis with
destructive ocular manifestations. Am J Ophthalmol 1984; 98:736-740
13. Kyndt X, Reumaux D, Bridoux F, Tribout B, Bataille P, Hachulla E, Hatron PY,
Duthilleul P, Vanhille, P. Serial measurements of antineutrophil cytoplasmic
autoantibodies in patients with systemic vasculitis. Amer J Med 1999; 106:527-33
14. Lamprecht P, Gross WL. Current knowledge on cellular interactions in the WGgranuloma. Clin Exp Rheumatol. 2007 Jan-Feb; 25(1 Suppl 44):S49-51
15. Spalton DJ, Graham EM, Page NGR, Sanders M.D: Ocular changes in limited
forms of Wegener’s granulomatosis. Br J Ophthalmol 1981; 553-563
Necrobiotic Xanthogranuloma
1. Kossard S, Winkelmann RK. Necrobiotic xanthogranuloma with paraproteinemia.
J Am Acad Dermatol 1986; 3: 257
7
2. Finan MC, Winkelmann RK. Necrobiotic xanthogranuloma with paraproteinemia.
Review of 22 cases. Medicine 1986; 65: 376
3. Finan MC, Winkelmann RK. Histopathology of necrobiotic xanthogranuloma
with paraproteinemia. J Cutan Pathol 1987; 14:92
4. Mehregan DA, Winkelmann RK. Necrobiotic xanthogranuloma. Arch Dermatol
1992; 128:94
5. Ugurlu S, Bartley GB, Gibson LE. Necrobiotic xanthogranuloma: long-term
outcome of ocular and systemic involvement. Am J Ophthalmol 2000; 129:651
6. Schaudig U, Al-Samir K. Upper and lower eyelid reconstruction for severe
disfiguring necrobiotic xanthogranuloma. Orbit 2004; 23:65
7. Jakobiec FA, Mills MD, Hiadayat AA, Dallow RL, Townsend DJ, Brinker EA,
Charles NC. Periocular xanthogranulomas associated with severe adult-onset
asthma. Trans Am Ophthalmol Soc 1993; 91:99
8. Robertson DM, Wilkelmann RK. Ophthalmic features of necrobiotic
xanthogranuloma with paraproteinimia. Am J Ophthalmol 1984; 97: 173
9. Hammond MD, Niemi EW, Ward TP, Eiseman AS. Adult orbital
xanthogranuloma with associated adult-onset asthma. Ophthal Plast Reconstr
Surg 2004; 20:329
10. Rose GE, Patel BC, Garner A, Wright JE. Orbital xanthogranuloma in adults. Br J
Ophthalmol 1991; 75 (11): 680
11. Valentine EA, Friedman HD, Zamkoff KW, Streeten BW. Necrobiotic
xanthogranuloma with IgA multiple myeloma: a case report and literature review.
Am J Hematol 1990; 35 (4): 283
12. Scupham RK, Fretzin DF. Necrobiotic xanthogranuloma with paraproteinemia.
Arch Pathol Lab Med 1989; 113 (12): 1389
13. Johnston KA, Grimwood RE, Meffert JJ, Deering KC. Necrobiotic
xanthogranuloma with paraproteinemia: an evolving presentation. Cutis 1997; 59
(6): 333
14. Burdick AE, Sanchez J, Elgart GW. Necrobiotic xanthogranuloma associated with
a benign monoclonal gammopathy. Cutis 2003; 72(1): 47
Rosai-Dorfmann Disease
1. Eisen RN, Buckley PJ, Rosai J. Immunophenotypic characterization of sinus
histiocytosis with massive lymphadenopathy (Rosai Dorfman Disease). Semin
Diagn Pathol 1990; 7: 74-82
2. Foucar E, Rosai J, Dorfman RF. The ophthalmic manifestations of sinus
histiocytosis with massive lymphadenopathy. Am J Ophthalmol 1979; 87: 354-67
3. Friendly DS, Font RL, Rao N. Orbital involvement by sinus histiocytosis – a
report of four cases. Arch Ophthalmol 1977; 95: 2006-2011
4. Goldberg S, Mahadevia P, Lipton M, Rosenbaum PS. Sinus histiocytosis with
massive lymphadenopathy involving the orbit: reversal of compressive optic
neuropathy after chemotherapy. J Neuropathol 1998; 18: 270-275
5. Khan R, Moriarty P, Kennedy S. Rosai Dorfman disease or sinus histiocytosis
with massive lymphadenopathy of the orbit. B J Ophthalmol 2002; 9: 1054
6. Lee-Wing M, Oryschak A, Attariwala G, Ashenhurst M. Rosai Dorfman disease
presenting as bilateral lacrimal gland enlargement
8
7. Lu D, Estallila OC, Manning JT, Medeiros LJ. Sinus histiocytosis with massive
lymphadenopathy and malignant lymphoma involving the same lymph node: a
report of 4 cases and review of the literature. Mod Pathol 2000; 13: 414-419
8. Mehraein Y, Wagner M, Remberger K, Fuzesi L, Middel P, Kaptur S, Schmitt K,
Meese E. Parvovirus B19 detected in Rosai Dorfman disease in nodal and
extranodal manifestations. J Clin Pathol 2006; 59: 1230-1236
9. Meyer CH, Sel S, Horle S et al. Rosai Dorfman disease with bilateral serous
retinal detachment. Arch Ophthalmol 2003; 12 (5): 733-735
10. Mohadjer Y, Holds JB, Rootmann J, Wilson MW, Gigantelli JW, Custer PL. the
spectrum of orbital Rosai-Dorfman disease. Ophthalmic Plast Reconstr Surg
2006; 22: 163-168
11. Prabhakaran VC, Bhatnagar A, Sandilla J, Olver J, Leibovitch I, Ghabrial R,
Goldenberg RA, Selva D. Orbital and adnexal Rosai Dorfman Disease. Orbit
2008; 27: 356-362
12. Reddy A, Beiji B, Linardos E. Rosai-Dorfman syndrome affecting the lacrimal
gland. Orbit 2001; 20: 239-242.
13. Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy. A
newly recognized benign clinicopathological entity. Arch Pathol 1969; 87:63-70
14. Rumelt S, Cohen I, Rehany U. Marginal corneal infiltrates a possible new
manifestation of sinus histiocytosis with massive lymphadenopathy. Cornea 2000;
19:857-858.
15. Sennes L, Koishi H, Chali R, Sperandino F, Butugan O. Rosai Dorfman Disease
with extranodal manifestation in the head. Ear, Nose and throat journal 2004; 12:
844-847
16. Vemuganti GK, Naik MN, Honavar SG. Rosai Dorfman disease of the orbit.
Journal of Hematology and Oncology 2008; June: 1-7
9
2011 USCAP COMPANION MEETING
American Association of Ophthalmic Pathologists
“Ocular Manifestations of Systemic Diseases”
OCULAR MANIFESTATIONS OF INFECTIOUS DISEASES
Patricia Chévez-Barrios, MD, FCAP
Professor of Pathology & Laboratory Medicine and Ophthalmology
Weill Medical College of Cornell University
Professor of Ophthalmology (adjunct)
Baylor College of Medicine
Director, Ophthalmic Pathology Program
Department of Pathology
The Methodist Hospital
Co-Director, Retinoblastoma Center of Houston
Director, TMHRI Summer Student Program
The Methodist Hospital Research Institute
6565 Fannin ST, MS205
Houston, TX, 77030
email [email protected]
HANDOUT
Take Home Points:
•
•
•
•
•
Bacterial, fungal, viral, and parasitic systemic infections may
spread to the eye
Dissemination of these pathogens to the eye is via the
bloodstream
Visual loss is more common in bacterial or fungal
endophthalmitis
Toxoplasmosis is a major cause of ocular morbidity and poor
vision after congenital or acquired infection
Toxocariasis is an important differential diagnosis in children
1
•
•
•
Acute retinal necrosis syndrome is associated to viral etiology
with confirmation of diagnosis by PCR in aqueous humor or
vitreous samples
Indirect mechanisms (eg, HIV-mediated immunosuppression) of
some pathogens may lead to opportunistic infections or other
ocular manifestations
Successful outcome for patients with ocular infection depends on
close collaboration between clinicians, timely identification and
treatment of underlying disease, and ophthalmic evaluation and
intervention if needed
•
Introduction:
Systemic infections can affect any part of the eye, and the resultant
inflammation and scarring can permanently damage vision. Although
many different organisms disseminate via the bloodstream and can
directly affect the eye, the most frequent organisms are metastatic
bacterial and fungal sepsis. Alternatively, organisms might have
secondary effects that could give rise to ocular complications. For
example, HIV immunosuppression might lead to opportunistic eye
infections or immune recovery uveitis associated with CMV in these
patients. In addition, the eye provides a unique window and might be
the first opportunity to diagnose underlying systemic infection. More
unusual infections and their eye complications are seen in specialized
settings, such as critical-care units or in immunocompromised patients
(eg, in transplantation or HIV medicine). Knowledge of the
complications—eg, endophthalmitis in candidaemia—is mandatory for
physicians working in relevant disciplines, including pathologist to
assertively and timely make the diagnosis. The eye has several
properties that make it very sensitive to infection and further sequela.
The intraocular tissues are enclosed by the thick sclera and the
vascular uveal tissue, thus, the immune response incited by infection
(mostly neutrophilic and macrophagic with enzymatic release) can
damage the retina in addition to the direct damage caused by the
infectious pathogens. As a result, steroids are often used with
antimicrobial drugs to reduce the inflammatory response and thereby
limit the damage caused. The healthy eye is protected by tight bloodaqueous and blood-retinal barriers, which limit access to the retina but
it is damaged during infection and inflammation. Thus, these barriers
become leaky and this becomes critical to the pharmacokinetics of
various antiinfection drugs. Prompt and accurate histopathologic,
cytologic and/or microbiologic diagnosis of these diseases then turns
out to be essential in the treatment of these patients to avoid long
2
term and unrecoverable damage to the retina and other vital tissue for
vision and for life.
Selected cases of ocular infections in systemic disease and the
prefer mode of diagnosis
METASTATIC ENDOGENOUS ENDOPHTHALMITIS- DIAGNOSTIC CYTOLOGY/CULTURES
Metastatic (endogenous) endophthalmitis occurs when pathogens
(mainly bacteria and fungi that cause bloodstream infection and
systemic sepsis) disseminate to the eye, leading to intraocular
infection. It might arise at the same time as infection at other body
sites, which include bone, heart valves, liver, lung, and brain.
Alternatively, endophthalmitis could be the only clinically apparent site
of infection where initial bacteremia or fungemia has not been
recognized or detected. Further investigation of affected patients can
identify infection at other sites. Failure to recognize ocular involvement
in the treatment of focal infection at other sites can lead to insufficient
treatment or eradication of eye infection. Patients might then present
with endophthalmitis some time after their initial systemic illness.
Although metastatic spread to the eye is a rare complication of sepsis,
it can lead to catastrophic visual loss. Early recognition of ocular
involvement is essential, because many systemically administered
antibiotics penetrate poorly into the eye and a change or addition of
other antimicrobial drugs might be needed to control both systemic
and eye infections. Aqueous humor or vitreous samples should be
treated as STAT specimens to procure the fastest and accurate
diagnosis possible. It is suggested that both cytology and cultures with
possible PCRs are processed to obtain best results. Two thirds of the
bacteria found in these cases are gram-positive-Streptococcus spp and
Staphylococcus spp organisms, but many others such as Neisseria
meningitidis can also disseminate to the eye. The most frequent
underlying problems are endocarditis, gastrointestinal tract infection,
and pneumonia. Other less common primary sites of infection include
skin abscess, infected joints, and the urinary tract. Patients at high
risk of fungemia are those with indwelling central venous catheters,
long-term stay in intensive care units, use of broad-spectrum
antibiotics, intravenous drug abuse, and neutropenia. The most
frequent fungal pathogens found in endogenous endophthalmitis
include: Candida albicans, C glabrata, C tropicalis, C parapsilosis, C
krusei, Aspergillus niger, and others. Systemic fusarium infections
3
might also cause endophthalmitis and this organism has been in the
rise as causative pathogen of exogenous and endogenous
endophthalmitis.
ACUTE RETINAL NECROSIS AND CMV,HZV , EBV, HSV AND TOXOPLASMA –
DIAGNOSTIC PCR-CYTOLOGY
Acute retinal necrosis (ARN) is an uncommon intraocular inflammatory
syndrome characterized by severe and diffuse uveitis, retinal
vasculitis, and retinal necrosis. It is typically described to occur in
immunocompetent patients, but can also be found in
immunocompromised subjects. Varicella-zoster virus (VZV), herpes
simplex virus (HSV 1 and 2), cytomegalovirus (CMV), and Epstein-Barr
virus (EBV) have been implicated in the etiology of ARN. The diagnosis
of ARN is usually suspected based on clinical features but may be
included in the differential diagnosis of the masquerade syndrome
(lymphoma, Toxoplasma, vs. other). Cytology of the vitreous sample is
helpful in differentiating other causes of the masquerade syndrome.
The use of polymerase chain reaction (PCR) in aqueous humor samples
or better in vitreous samples, is the most useful to identify the etiology
of the disease.
Toxoplasmosis, infection with Toxoplasma gondii, is the most common
cause of infectious uveitis worldwide. Although most eye infections
were thought to be acquired in utero, at least a third of patients
presenting with active eye disease are now estimated to have been
infected postnatally. Although cats are the definitive hosts in which
sexual reproduction can only occur, humans can be infected directly by
cysts in cat feces and from eating meat from intermediate hosts
(chickens, lambs, and pigs) that contain cysts with larval forms of the
parasite. Primary toxoplasmosis is generally asymptomatic in
immunocompetent individuals, although patients might occasionally
experience systemic illnesses, including lymphadenopathy or hepatitis.
Symptomatic ocular involvement in primary infection is rare but local
ocular reactivation of disease without systemic reactivation is frequent.
In primary infection, typical lesions are related to retinitis, have no
evidence of previous chorioretinal scarring, and have a mild intraocular
inflammatory response. Many lesions are self-limiting and heal,
forming characteristic pigmented scars in the retina where toxoplasma
cysts are found. Scars can be seen anywhere in the retina, are often
unilateral, but can be bilateral.107 Reactivation of infection from
quiescent scars is rare in childhood (whenever infection was acquired)
and the mean age of first symptomatic recurrence is 20–25 years.
4
Active, white lesions form on the edge of scars, with a striking
intraocular inflammatory response. The immune response stimulated
by active T gondii infections is substantial enough to contribute to
retinal damage. Although these lesions are usually self-limiting,
combined treatment with corticosteroids and antitoxoplasma drugs is
often given if active lesions are close to the optic nerve or macula or if
there is a severe intraocular inflammatory response. In
immunocompetent hosts, there is no evidence that any of the
presently used antitoxoplasmosis drugs have any effect on the natural
history of the disease, but drug regimens in general use do vary in
their side-effect profiles. Typical symptoms and signs of
toxoplasmosis, such as ocular scars, can appear at birth or later in life.
Patients with severe immune compromise either because of
immunosuppressive drugs or HIV infection might acquire primary
toxoplasma infection, but disease is more commonly due to
reactivation. For example, in patients with HIV-related disease, 90% of
CNS toxoplasmosis is due to reactivation. Patients with active eye
lesions present with sore red eyes, or floaters due to the vitritis or
visual loss. Additionally, they could also have coexistent cerebral
lesions, which can appear as contrast enhancing on CT or MRI scans,
causing sixth cranial nerve palsies and papilloedema. Drug treatment
for ocular and cerebral toxoplasmosis is the same and lesions will
continue to grow without therapy. In immunecompromised individuals
these presentation may have a broader differential diagnosis and
vitreous cytology with PCR may be necessary for definitive diagnosis
and treatment.
IMMUNE RECOVERY UVEITIS – DIFFERENTIAL DIAGNOSIS IN CYTOLOGY
SPECIMENS/PCR(CMV)
Immune recovery uveitis occurs only in patients who are receiving
potent antiretroviral therapy and whose CD4 T-lymphocyte count has
increased (a marker for improved immune function), thus, it is a
response against cytomegalovirus within the eye. A simple model to
explain some of the features of immune recovery uveitis includes that
as immune function improves, a threshold is reached at which the
body can mount an intraocular inflammatory response to
cytomegalovirus antigens present in the eye. It is known that
continued production of viral proteins can occur in cytomegalovirus
retinitis lesions that appear clinically inactive. With continued recovery
of immune function, a
higher threshold is reached at which the immune system inactivates
cytomegalovirus, production of antigen then stops, and inflammatory
5
reactions subside. This simple model does not, however, explain why
some patients are reported to develop immune recovery uveitis long
after initiation of potent antiretroviral therapy, or why it persists in
others. An intriguing theory is that control of cytomegalovirus retinitis
is incomplete in some individuals, with subclinical production of virus
or viral proteins that continue to stimulate the immune system.
Researchers have found persistence of detectable cytomegalovirus in
the blood of individuals after the start of potent antiretroviral therapy,
despite the apparent inactivity of cytomegalovirus retinitis on clinical
examination. This observation suggests the possibility that continuing
maintenance anticytomegalovirus therapy during a prolonged period
after initiation of potent antiretroviral therapy might reduce the
frequency and severity of immune recovery uveitis. Immune recovery
uveitis can, however, develop even in patients receiving specific
anticytomegalovirus therapy.
HERPES SIMPLEX VEGETANS IN EYELIDS. BIOPSY AND IMMUNOHISTOCHEMISTRY
Cutaneous infection with HSV can occur in immunocompetent or
immunocompromised hosts, however the clinical manifestions vary
greatly based on the immune status of the patient. The most common
cutaneous manifestations of HSV in immunocompromised patients
such as solid organ transplant recipients are oral and genital mucosal
ulcerations and vesicular lesions; however, they also may present with
ulcers that can become confluent, chronic, and granulating. In rare
cases, disseminated skin lesions resembling erythema multiforme can
develop. Herpes simplex vegetans is a rare variant that can occur in
immunocompromised patients. The five published case reports of
herpes simplex vegetans describe exophytic, sometimes exudative or
ulcerated growths that may mimic malignancy. These have been
reported to occur on digits, genitalia and oral mucosa and we have
reported the first case in the eyelids. To our knowledge, this is the first
report in a patient with a congenital immunodeficiency, occurring as an
eyelid lesion. The clinical differential diagnosis for a solid, ulcerating
mass in an immunodeficient patient is fairly broad, including
mycobacterial and fungal infections as well as malignancies such as
squamous cell carcinoma and cutaneous t-cell lymphoma. It is
important to biopsy the lesion to make the diagnosis. The pathologic
features of herpes simplex vegetans include an intense inflammatory
response with granulation tissue, many plasma cells and sometimes
eosinophils. The typical viral inclusions are usually seen on the
periphery of the lesions, although in our case these cells were seen in
the subepithelial tissue and along the hair follicles.i Given the intense
6
lymphoplasmacytic reaction seen with this type of lesion it is important
to rule out Epstein-barr virus associated lymphoproliferative disease
that can occur not uncommonly in immunocompromised patients. This
is easily done by immunohistochemistry. Treatment failure with
acyclovir is almost a definining feature of herpes simplex vegetans.
The few case reports report various treatment strategies, but all of
them describe resistance or treatment failure with acyclovir. Treatment
with valcyclovir, foscarnet, famicyclovir and even imiquimod, in one
case report, seemed to have better responses. It is unclear how long
these patients need to be treated or if recurrence is common on
chronic suppressive therapy. One report suggested that herpessimplex impaired production of interferon-alpha, implied by successful
treatment with topical imiquimod.
TOXOCARIASIS. ELISA IN SERUM AND VITREOUS/CYTOLOGY
Toxocara is widely distributed and is acquired mainly by children ages
4 to teens, secondary to contact with puppy dogs and cats or their
excreta. Ocular symptoms of infection with toxocara are rarely
associated with systemic infection of visceral larval migrans. Current
detection of antitoxocara antibodies by ELISA has poor sensitivity, and
the titre can be very low or absent in active ocular disease. Thus,
ELISA on vitreous fluid samples improves detection especially
combined with the results of the ELISA in serum. Ocular involvement
is unilateral, the eyes appear quite without conjunctival or ciliary
involvement, and the diagnostic feature is a peripheral white mass
(snow bank) is often visible. Other ocular features depend on the
location of the worm within the eye and the inflammatory response it
generates. These include a tractional vitreous band from the optic
nerve to the peripheral white mass. In young children, the disease
might present as endophthalmitis and can resemble retinoblastoma,
but calcification is rare. Treatment is rarely needed because
inflammation is often occult and subsides spontaneously. However, in
extreme cases the anterior chamber is involved by inflammation or its
complications and secondary glaucoma or even ocular atrophy as
consequence of the inflammation may occur.
ORBITAL MUCORMYCOSIS. BIOPSY WITH HISTOPATHOLOGIC TYPICAL FINGINGS
Rhino-cerebral-orbital mucormycosis (zygomycosis)infection is an
aggressive fungal infections with a high mortality rate. It has a higher
incidence in patients with untreated diabetes, kidney diseases or with
7
hematological malignancies. Following aspergillosis, mucormycosis is
the second most frequent mycosis caused by filamentous fungi. The
family of the Mucoraceae is divided into the subspecies absidia,
rhizopus and mucor. The most typical clinical manifestations are rhinocerebral, maxillo-facial and pulmonary mucormycosis. Rhino-cerebral
mucormycosis starts in the nose or oral cavity infiltrating the
paranasal sinuses, the orbit or the brain over the orbital apex or the
cribriform plate. The first symptoms are non-specific with headache,
fever or rhinorrhea. Frequently, intranasal black necrotic crusts can be
found. At the time of presentation, the symptoms often are advanced
and patients already show complications like orbital involvement of the
disease with proptosis, ophthalmoplegia or worse with intracerebral
spread with meningitis or brain abscess. Three clinical stages for
mucormycosis infection have been identified: patients with limited
sino-nasal disease (clinical stage I), patients with limited
rhino-orbital disease (clinical stage II) and patients with rhino-orbitalcerebral disease (clinical stage III). A CT scan is crucial for
identification of the bony destruction. MRI provides early detection of
meningeal or intraparenchymatous spread and intracranial vascular
occlusion. The definite diagnosis can only be verified by histological
examination. Hyphae are typical and specific for each fungus. Mucor
presents large, broad non-septate hyphae with rightangle branching..
The best way to detect is looking at the vessel walls as they are
usually either forming a thrombus or invading the wall itself. Many
times they can be visible with routing H&E stains and PAS and GMS
are confirmatory. Mucormycosis requires early aggressive and
extensive surgery of all infected devitalized tissue. If the underlying
immune deficiency is not successfully treated, the prognosis is very
poor. Especially the orbital apex appears to be an area particularly in
danger of further intracranial spread because of
numerous potential pathways, like the superior orbital fissure and the
optic canal. The addition of exenteration to sino-nasal debridement did
not improve patients’ outcome when the state of the underlying
disease was poor or not corrected. Nevertheless, aggressive surgical
treatment is still recommended, including exenteration of the orbit.
Once the endocranium is reached by fungal disease, a craniotomy with
debridement should be considered immediately, as well as hyperbaric
oxygen therapy combined with antifungal drug treatment.
8
References:
Khan A, Okhravi N, Lightman S. The eye in systemic sepsis. Clin Med.
2002 Sep-Oct;2(5):444-8. Review. PubMed PMID: 12448593.
Bonfioli AA, Eller AW. Acute retinal necrosis. Semin Ophthalmol. 2005
Jul-Sep;20(3):155-60. Review. PubMed PMID: 16282149.
Schrier RD, Song MK, Smith IL, Karavellas MP, Bartsch DU, Torriani FJ,
Garcia CR, Freeman WR. Intraocular viral and immune pathogenesis
of immune recovery uveitis in patients with healed cytomegalovirus
retinitis. Retina. 2006 Feb;26(2):165-9. PubMed PMID: 16467672.
Kuppermann BD, Holland GN. Immune recovery uveitis. Am J
Ophthalmol. 2000 Jul;130(1):103-6. Review. PubMed PMID:
11004267.
Siqueira RC, Cunha A, Oréfice F, Campos WR, Figueiredo LT. PCR with
the aqueous humor, blood leukocytes and vitreous of patients affected
by cytomegalovirus retinitis and immune recovery uveitis.
Ophthalmologica. 2004 Jan-Feb;218(1):43-8. PubMed PMID:
14688435.
Sabrosa NA, de Souza EC. Nematode infections of the eye:
toxocariasis and diffuse unilateral subacute neuroretinitis. Curr Opin
Ophthalmol 2001; 12: 450–54.
Guevara N, Roy D, Dutruc-Rosset C, Santini J, Hofmann P, Castillo L.
Mucormycosis—early diagnosis and treatment. Rev Laryngol Otol
Rhinol (Bord) 2004; 125:127–131
Blieden LS, Chévez-Barrios P, Yen MT. Herpes Simplex Vegetans
Presenting as an Eyelid Mass. Ophthal Plast Reconstr Surg. 2010 Sep
8. [Epub ahead of print] PubMed PMID: 20829726.
9
OCULAR METASTATIC MALIGNANCIES
Nora V. Laver, MD
Ocular Pathology Laboratory
New England Eye Center
Tufts Medical Center
Boston, Massachusetts
Learning objectives
1. To discuss the most common malignancies that metastasizes to the eye.
2. To familiarize the audience with the most prevalent clinical presentations
and findings.
3.
To compare and contrast the different histopathological findings of the
most common tumor types.
I. INTRODUCTION
Long-term survival from systemic malignancies continues to increase; therefore
pathologists will be confronted with a growing incidence of intraocular and orbital
metastatic disease requiring appropriate prompt recognition and diagnosis for patient
management. The increased incidence of metastasis to the eye is due to the increase
incidence of tumors that metastasize to the eye (lung, breast), a prolonged survival of
patients with certain cancers (breast cancer) and increasing awareness among medical
oncologists and ophthalmologists of the pattern of metastatic disease.
The mechanism of intraocular metastasis is secondary to hematogenous
dissemination of tumor cells. The anatomical ocular arterial supply dictates the
predilection of metastatic disease. The posterior choroid, with its rich vascular supply, is
the most favored site of intraocular metastases, and it is affected 10-20 times more
frequently than the iris or ciliary body. The retina and optic disc, supplied by the single
central retinal artery, is rarely the sole site of involvement. Bilateral ocular involvement
has been reported in 20-25% of cases, and multifocal deposits are frequently seen
within the involved eye. Many patients with ocular metastases also have concurrent
CNS metastasis.
Primary tumor sites
The majority to metastatic solid tumors to the eye are carcinomas from various
organs. Cutaneous melanoma rarely metastasizes to the eye. Table 1 shows the most
common primary tumors that metastasize to the choroid. Breast and lung carcinomas
for women and lung and gastrointestinal carcinomas for men most commonly
metastasize to the eye and orbit.
1
Table 1. Primary Sites of Choroidal Metastasis
Males
Females
Lung (40%)
Breast (68%)
Unknown (29%)
Lung (12%)
Gastrointestinal (9%)
Unknown (12%)
Kidney (6%)
Others (4%)
Prostate (6%)
Gastrointestinal (2%)
Skin (4%)
Skin (1%)
Others (4%)
Kidney (<1%)
Breast (1%)
Shields CL, Shields JA, Gross NE, et al. Survey of 520 eyes with uveal
metastases. Ophthalmology 1997; 103:1265-1276.
Clinical Findings
The clinical features of intraocular metastasis depend on the site of involvement.
The clinical features of ocular metastasis may include:
- eyelid or conjunctival mass
- iridocyclitis
- secondary glaucoma
- hyphema (blood in the anterior chamber)
- irregular pupil
- proptosis
- orbital mass
- poor vision
- pain and photopsia
Most patients have a history of systemic malignancy. Some patients however,
have no previous history of malignancy. This is especially true of patients with ocular
metastasis from the lung. The diagnosis of tumor metastatic to the uvea implies a poor
prognosis, because widespread dissemination of the primary tumor has usually
occurred. It has been reported that the survival time following diagnosis of metastasis to
the uvea ranged from 1 to 67 months, depending on the primary cancer type.
Treatment
The goal in ophthalmic management of ocular metastases is preservation or
restoration of vision and palliation of pain. The short-term prognosis for vision is usually
good after an individualized therapeutic approach (chemotherapy, hormonal therapy,
external beam radiotherapy, or plaque radiotherapy), but the systemic prognosis is poor.
The visual paraneoplastic syndromes encompass several distinct clinical and
pathological entities including carcinoma-associated retinopathy (CAR), melanomaassociated retinopathy (MAR), and bilateral diffuse melanocytic uveal proliferation
(BDUMP). The CAR syndrome affects photoreceptors, MAR is thought to affect bipolar
2
cell function, and BDUMP targets the uveal tract. Identification of circulating antibodies
against retinal proteins (recovering, 23-kDa retinal protein; 46-kDa and 60-kDa retinal
proteins) serves to recognize the paraneoplastic nature of the patient's symptoms, which
frequently develop before the cancer is diagnosed. Anecdotal therapeutic responses are
described after systemic steroids, immunoglobulin injection, and plasmapheresis.
Recognition of the visual symptoms and ocular findings should alert to the possibility of
cancer and systemic evaluation should be pursued.
II. CASE PRESENTATIONS
CASE NUMBER 1
Chief Complaint: A 70-year-old Asian male patient presented to the New England Eye
Clinic with a 3-week onset of rapidly growing lesion of his left upper eyelid with bleeding
(picture 1). He denied fever, chills, night sweats, weight or appetite loss, chest pain,
back pain, diarrhea, constipation or headache. Warm compresses and erythromycin
ointment were applied to the lesion, without any obvious improvement.
Past Medical History: myocardial infarct in 1986, cardiomyopathy, emphysema, COPD,
hypertension, and chronic renal disease secondary to hypertension. He had no previous
ocular history.
Social History: He had a 40-pack-year history of smoking, quit in 1986. He had no
history of alcohol abuse, and had worked in a laboratory with unknown chemicals. He
was married, retired, and lived alone.
Medications: Isosorbide and lisinopril.
Radiology Data: A head CT scan showed a 9 mm x 6 mm left eyelid lesion. No
intracranial brain lesion, intracranial hemorrhage or edema was found.
General Impression and Differential Diagnosis: A tissue biopsy was performed of the
eyelid lesion. The differential diagnosis included among others basal cell carcinoma,
squamous cell carcinoma, sebaceous carcinoma, lymphoma, Merkel cell carcinoma,
Kaposi’s sarcoma, metastatic tumor, neurofibroma, sarcoid nodule, SLE nodule,
hemangioma, and chalazion.
Histopathological Evaluation: A predominantly subconjunctival epithelial tumor mass
with focal surface erosion is present. A tumor showing solid growth patten with round to
oval or fusiform population of cells, scantly cytoplasm, hyperchromatic finely granular
nuclei and inconspicuous nucleoli was present. Numerous mitotic figures, apoptotic cells
and focal necrosis was also found. Immunohistochemistry staining showed the tumor
cells immunoreactive to CK7, pancytokeratin, EMA, synaptophysin, and TTF-1 (thyroid
transcription factor 1). They were negative for CEA, CK20, S100, Melan A, HMB45,
CD45 and chromogranin. The histopathological features coupled with the
immunohistochemical profile favored a metastatic carcinoma, highly suggestive of lung
origin.
Staging and Treatment: A CT scan of the chest showed a right upper lobe nodule
anteriorly, soft tissue fullness in the superior mediastinum and below the left upper lobe
bronchus. The changes were consistent with lung tumor with possible malignant
lymphadenopathy. There were also bilateral lung apices scarring, and radiolucencies
consistent with bullous disease and emphysema. Multiple calcified tiny nodules were
present, probably representing old TB. A PET scan confirmed a lung lesion and
mediastinal adenopathy, adrenal, distant lymphadenopathy and retropharyngeal
involvement.
3
The patient was treated with six cycles of chemotherapy (etoposide, vincristine) for 5
months. He developed a superior vena cava syndrome, a residual lung nodule and
mediastinal adenopathy as well as a large adrenal mass. He died nine months after the
initial diagnosis.
Figure 1. Clinical Presentation
CASE NUMBER 2
Chief Complaint: A 74-year-old man presented with episodic blurred vision in the right
eye of two months duration. In addition, he noted a supero-nasal visual field defect when
closing his left eye. The patient had no monocular complaints.
Clinical Examination: On ophthalmological examination his visual acuity was 20/400 in
the right eye and 20/25 in the left eye. Funduscopic examination disclosed an inferotemporal amelanotic choroidal tumor with associated sub-retinal fluid. A B-scan showed
a vascular dome-shaped lesion of medium to high internal reflectivity measuring 7.6 x
8.4. x 3 mm (Figure 1). A fluorescein angiogram showed early fluorescein uptake by the
tumor with a mottled hyperfluorescent pattern.
Past Medical History: no significant past medical history was present.
Radiology Data: The patient was referred for an oncologic work-up including CTs of the
chest and abdomen as well as routine blood work up. These studies were negative for
systemic malignancy. A fine needle aspiration of the lesion was attempted but was nondiagnostic.
General Impression and Differential Diagnosis: The tumor continued to grow after six
weeks of follow up and studies and developed cystic cavities. Based on the
funduscopic, fluorescein angiography and B-scan findings, a metastasis was suspected
rather than a primary amelanotic choroidal melanoma. Due to continued growth of the
neoplasm and negative systemic work-up, the eye was enucleated.
Histopathological Evaluation: The globe contained an infero-temporal amelanotic
choroidal mass with an overlying and peripheral retinal detachment. Microscopic
examination showed a metastatic adenocarcinoma. Immunohistochemistry staining for
PSA and PSAP were positive in the tumor cells. The findings were consistent with a
prostatic primary.
Staging and Treatment: A serum PSA (which had not be evaluated prior to the
enucleation) was markedly elevated at 640 ng/ml (normal <5 ng/ml). A bone scan
revealed metastatic disease of the entire axial skeleton. Prostatic biopsies confirmed the
diagnosis of adenocarcinoma. The patient underwent radiation therapy and
chemotherapy.
4
Figure 1. Choroidal metastatic disease, ultrasonography
.
Selected References
Shields CL, Shields JA, Gross NE, Schwartz GP, Lally SE. Survey of 520 eyes with
uveal metastasis. Ophthalmology 1997; 104(8): 1265-76.
Levy J, Monos T, Cagnano E, Lifshitz T. Adenocarcinoma of the eyelid as the
presenting sign of breast carcinoma. Can J Ophthalmol. 2004 Oct;39(6):679-81.
Bachmeyer C, Henni AM, Cazier A, Putterman M, Morel X. Eyelid metastases
indicating neuroendocrine carcinoma of unknown origin. Eye. 2004 Jan;18(1):94-5.
Van der Zee J, Koper PC, Jansen RF, de W inter KA, van Rhoon GC. Re-irradiation and
hyperthermia for recurrent breast cancer in the orbital region: a case report. Int J
Hyperthermia. 2004 Feb;20(1):1-6.
Claessens N, Pierard GE. The eyelids and metastatic breast carcinoma. Dermatology.
2003;206(2):181-2.
Kramer TR, Grossniklaus HE, McLean IW , Orcutt J, Green W R, Iliff NT, Tressera F.
Histiocytoid variant of eccrine sweat gland carcinoma of the eyelid and orbit: report of
five cases. Ophthalmology. 2002 Mar;109(3):553-9.
Kreusel KM, Bornfeld N, Hosten N, Wiegel T, Foerster MH: Solitary choroidal
metastasis as the first sign of metastatic lung carcinoid. Arch Ophthalmol
1998, 116:1396-1.
Simsek T, Ozdamar Y, Berker N: Choroidal mass as an initial presentation
of lung cancer. Med Oncol 2008, 25:400-2.
5
George B, Wirostko WJ, Connor TB, Choong NW: Complete and durable
response of choroid metastasis from non-small cell lung cancer with
systemic bevacizumab and chemotherapy. J Thorac Oncol 2009, 4(5):6612.
Fernandes BF, Fernandes LH, Burnier MNJr: Choroidal mass as the
presenting sign of small cell lung. Can J Ophthalmol 2006, 41:605-8.
Kreusel KM, Wiegel T, Stange M, Bornfeld N, Hinkelbein W, Foerster MH:
Choroidal metastasis in disseminated lung cancer: frequency and risks
factors. Am J Ophthalmol 2002, 134:445-7.
6