AMELANOTIC CHOROIDAL TUMORS

EFTHYMIA PAVLIDOU

AMELANOTIC CHOROIDAL TUMORS

• Choroidal malanoma

• Osteoma

• Choroidal hemangioma

• Choroidal metastases

• Vitreoretinal Lymphoma

• Choroidal lymphoma

CHOROIDAL MELANOMA

DIFFUSE CMM

CHOROIDAL OSTEOMA

DEFINITION-INCIDENCE

• Choroidal osteoma is a benign tumor of the choroid composed of mature bone

• It is typically found in healthy young females in the second or third decades of life

• However, some males, children and adults over age of 30 years have been diagnosed

• There is no predilection for race

• Is unilateral in approximately 75% of caces

• Appears as yellow-white to orange-red

– Varying degrees of clumping of brown, orange or gray pigment can be detected on the tumor surface

• Tends to be located in the juxtapapillary or peripapillaryarea

• It may extend into the macular region

• May show evidence of slow enlargement in basal diameter over time

• May occur gradual decalcification over several years

• Asymptomatic

• Or, blurred vision due to CNV or decalcification

– Subretinal neovascularization has been found in approximately 47% of eyes

– CNV tends to occur in the portion of the tumor nearest the fovea and appears to progress toward the foveola

• In fact, this the major cause of visual loss in eyes with osteoma

DIAGNOSTIC APPROACH

• Mild patchy early hyperfluorescence of the tumor that evolves to a diffuse intense late staining

• The yellow-white portions of the tumor show early hyperfluorescence of the capillary network on the inner surface of the bony tumor. This fades slightly in the later stages

• Overlying subretinal neovascularization shows a lacy pattern or early hyperfluorescence with early leakage of dye and late staining of the surrounding tissue

INDOCYANINE GREEN ANGIOGRAPHY

• Shows early hypofluorescence of the choroidal mass

• Fine diffuse fluorescence of the mass is seen by 2 min and seems to emanate from ill-defined multifocal points within the area of the mass, perhaps related to the fine perforating vessels of the tumor

• The fluorescence gradually becomes confluent and almost isofluorescent in the late frames

ULTRASOUND

• Is very useful for differentiating choroidal osteomas from other clinically similar lesions

• B-scan demonstrates a slightly elevated, highly reflective choroidal mass

• Acoustic shadowing of the orbit occurs just posterior to the choroidal mass, giving the appearance of a pseudo- optic nerve

OPTICAL COHERENCE TOMOGRAPHY

TREATMENT

• In case of CNV formation there is good response to Anti – VEGF injections

PROGNOSIS

• The visual prognosis is quite varied and unpredictable

• Most patients with an extrafoveal choroidal osteoma have good visual acuity

• Some patients with a subfoveal choroidal osteoma retain good visual acuity for months to years

• Gradual visual loss may occur with progressive degeneration of the overlying retinal pigment epithelium and sensory retina

• More acute visual loss may be secondary to hemorrhagic subretinal fluid from CNV

PROGNOSIS

• Aylward et al

• Arch ophthalmology 1998

• 36 patients

• Mean follow up 10 years

• Loss of VA < 20/200 in 58% at 10 years

• Shields et al

• Arch ophthalmology 2005

• 74 eyes, 61 patients

• Loss of VA <20/200 in 56% at 10 years

• 50% of tumors decalcify

• Particularly bad prognosis

CHOROIDAL HEMANGIOMA

• Choroidal hemangioma is a benign and relatively rare tumor that occurs in two different forms:

– Circumscribed

– Diffuse

• Is associated with the Sturge Weber syndrome

• Are congenital

• Accidental finding or until the patient develops symptoms, when secondary changes associated with the tumor develop

CIRCUMSCRIBED CHOROIDAL HEMANGIOMA

CLINICAL FEATURES

• Are located posterior to the equator and generally are situated near the optic disc

• Solitary tumors are the rule

• Tumors close to the macula lead to the symptoms associated with exudative retinal detachment

CLINICAL FEATURES

• Are elevated and usually round or oval

• The color is pinkish or orange-red – Flecks of pigment may be

present over the surface of the tumor

– Gray or whitish gray color associated with plaque formation probably develop over time

• Tend to have indistinct margins

• The tumors transilluminate easily

FFA

– Is not pathognomonic

– Irregular hyperfluorescence of the choroidal vessels before the filling of the retinal arterioles

– In early phases hyperfluorescence increases and the mottling pattern becomes more confluent

– In the later stages, there is accumulation of dye in the outer retina

ICG

• It shows a well defined area of an early, intense and uniform hyperfluorescence

• Intrinsic vessels can be seen

• Late a characteristic ‘’dye wash out’’ is noted with the tumor rapidly losing its fluorescence

AF

Acoustic solidatarityHigh internal reflectivity by the multiple vascular channelsNo spontaneous vascular movements are present

TREATMENT

• Observation if there are no symptoms

• PDT

• Radiation

TREATMENT

PDT EBRT

STURGE WEBER SYNDROME

• Is characterized by

– Facial hemangioma

– Bupthalmos

– Seizures

– Evidence of intracranial calcification

STURGE WEBER SYNDROME

• Choroidal hemangioma– Diffuse type

– Intense red reflex –tomato ketchup

– Thickened choroid

• Exudative retinal detachment

• Glaucoma

TREATMENT

• Observation

• PDT

• Radiation

• Enucleation

CHOROIDAL METASTASES

• It may be the first manifestation of systemic relapse

• A choroidal tumor that involves the macular area leads to painless visual loss due to an associated exudative retinal detachment

– Retinal detachment is out of proportion to the size of the lesion

• An anteriorly located tumor may cause visual loss by tilting the lens

• Rarely, there can be neovascularglaucoma or metastatic iritis

• Multiple foci and bilaterality are important features

• Typically are in the posterior pole

• Usually they have a yellow appearance and are flatter

Demonstrates moderate to high internal reflectivityVascularity is not prominent

Consistency is solid

LUNG CA

PRIMARY SITES FOR CHOROIDAL METASTASES

• FEMALE– Breast– Lung– Unknown primary– Gastrointestinal – Skin melanoma– Other sources

• MALE– Lung– Unknown– Gastrointestinal– Prostate– Kidney– Skin melanoma

Intraocular Lymphoma

• Intraocular Lymphoma is almost always non Hodgkin large cell lymphoma of the B cell type

• T cell lymphoma involves the eye only rarely

• Two types of lymphoma may involve intraocular structures

• The much more common one is the primary central nervous system lymphoma (PCNSL), in which approximately one quarter of the patients have intraocular involvement• In these cases, the vitreous and the retina are involved

• More rarely, the eye can be involved in systemic/nodal lymphoma• In these cases, the uveal tract is more commonly involved

PRIMARY INTRAOCULAR LYMPHOMA

• Primary intraocular lymphoma (PIOL) is an ocular malignancy that is subset of primary central system lymphoma

• Although rare, the incidence has been rising in both immunocompromised and immunocompetent populations

• The incidence has tripled over the past 15 years

EPIDEMIOLOGY

• Is now considered to be a variant of extranodal non-Hodgkin’s lymphoma that arises from specific sites such as the brain, spinal cord, meninges or eyes and is called primary CNS lymphoma.

• Primary intraocular lymphoma is a variant with predominantly ophthalmic involvement

• Approximately 1/3 of patients with PIOL will have concurrent PCNSL at presentation and 42-92% will develop PCNSL within a mean of 8-29 months

• The majority is diffuse large B-cell lymphoma and rarely T-cell variants

CLINICAL FEATURES

• The brain, spinal cord and meninges either separately or in various combinations can be involved

• Solitary involvement of the spinal cord is rarely seen

• Personality changes are a common presenting feature because the frontal lobe is the most frequently involved region of the brain

• Seizures may develop

• Intraocular involvement may precede, occur simultaneously or follow the CNS disease

CLINICAL FEATURES

• PIOL usually occurs in adults from the third to the eighth decades of life, although some cases in infants and young adults are documented

• The mean age of presentation is in fifth and sixth decades of life

• Ocular disease may manifest as a masquerade syndrome, simulating nonspecific uveitis

• There may be an initial response to steroid therapy

CLINICAL FEATURES

• Bilateral involvement occurs in up to 80%

• The most frequent symptoms are of painless blurred vision, floaters or both

• Some patients are asymptomatic and are diagnosed only when examined for suspected CNS involvement

• The most common manifestations are of a posterior uveitis or vitritis, combined anterior or posterior uveitis, chorioretinitis or subretinal infiltrates

CLINICAL EVALUATION

• Anterior segment inflammatory findings are frequently absent, particularly scleral redness or posterior synechiae

• There may be cells in the anterior chamber and keraticprecipitates

• In rare cases can present infiltration of the iris or angle or even pseudohypopyon

CLINICAL FEATURES

• The presence of vitreous cells is a common finding. May form clumps, strands or sheets with mild to moderate haze

• CMO is usually absent

• Vision is better than expected for the degree of vitritis

CLINICAL FEATURES

• Multifocal or diffuse chorioretinalinfiltrates may be seen with or without vitreous cells. • Creamy lesions with orange

infiltrates that are deep to the retina or RPE

• ‘leopard skin’ pigmentation

• There may be isolated subretinal lesions with associated RD

• Spontaneous resolution may lead to RPE atrophy with subretinal fibrosis

TAKE HOME MESSAGE

• The onset of bilateral posterior uveitis in patients over the age of 50 years should be considered suggestive of large cell lymphoma, as should ‘’chronic’’ uveitis in patients in their fifth to seventh decades

• Although 30% of patients present with unilateral involvement, delayed involvement of the second eye occurs in approximately 85% of patients

IMAGING

• FFA:• Punctate hyperfluorescent

window defects• Round hypofluorescent lesions• Vasculitis • Granularity, blockage and late

staining at the level of the RPE with lack of angiographic signs of inflammation

• ICG:• Small hypofluorescent lesions in

the early phase becoming less apparent in late stages

IMAGING

• OCT

• Hyperreflective lesions in RPE layer

• Lymphomatous subretinal or sub-RPE deposits

IMAGING

• Fundus autofluorescence

• The clinically observed brown ‘’leopard spotting’’ over yellow lesions beneath the RPE had a bright hyperautofluorescenceappearance

• White lesions above the RPE were hypoautofluorescent

NEUROIMAGING

• Magnetic resonance imaging (MRI) with contrast is more sensitive than computed tomography (CT) for detecting lymphomatous lesions in the CNS, but both are limited in evaluating ophthalmic disease

• MRI and CT show multifocal periventricular, homogenously enhancing lesions

• With CT the lesions are isodense or hypodense• With MRI the lesions are hypodense on T1 weighted and

hyperdense on T2 weighted images

• PET/CT has been used to identify CNS lesions as well as ocular activity

NEUROIMAGING

DIAGNOSIS

• Biopsy remains the hallmark

• Tissue biopsy, especially of the vitreous, is performed, especially if PCNSL lesions can not be found on neuroimaging

• Multiple biopsies may be required to reach a definite diagnosis

• Lymphoma cells undergo morphological degradation within 60 minutes so specimens need to be transported quickly and gently

• Steroids should stop 2 weeks before the procedure

VITREOUS BIOPSY

• Fine Needle Aspiration of the vitreous is performed through the pars plana

• Generally, this is a safe clinical procedure, with a high success rate in differentiating between infectious, inflammatory and malignant causes of uveitis

VITREOUS BIOPSY

• Pars plana vitrectomy for undiluted specimen has several advantages, including improved vision by clearance of vitreous debris and maximizing the sample size

• Extension of the lymphoma through the sclerotomy port to the epibulbar space following vitrectomy may occur

RETINAL BIOPSY

• If subretinal lesions are present, a retinotomy can be performed

CYTOLOGY AND HISTOLOGY

• Preferably, a pathologist familiar with the diagnosis of intraocular large cell lymphoma should evaluate the specimen

• If an adequate specimen is obtained, multiple pathologic approaches may be employed

• Cytologic evaluation is essential in establishing the diagnosis, with flow cytometry and PCR serving as ancillary studies

• Specimens that reveal malignant lymphocytic cells establish the diagnosis

• Evaluation of cell surface markers may allow for subclassification of the tumor

IMMUNOCYTOCHEMISTRY

• CD20, CD19, CD22

• PCR• Immunoglobulin heavy chain (IgH) gene sequences,

region (CDR3) of the variable region of IgH

• Marker of clonality and not of malignancy

• IL 10:6 ratio• High in PIOL

• But can be high in uveitis

TREATMENT

• Ocular irradiation with prophylactic CNS treatment is used in an attempt to control PIOL, maintain vision and prevent CNS involvement if the general condition allows

• Systemic chemotherapy methotrexate-based or intrathecal may be combined with radiation

• In cases of local relapse without generalized involvement, then intravitreal methotrexate injections are performed

• Successful treatment modalities for PCNSL do not automatically translate into successful therapies for PIOL

TREATMENT

• INTRAVITREAL INJECTIONS OF 400 ug/0.1 ml of methotrexate• Twice weekly for 4 weeks• Once weekly for 8 weeks• Once monthly for 9 months• Total of 25 injections• Remission usually after a mean of 6.4 injections• Side effects included corneal epitheliopathy

• Intravitreal rituximab 1mg in 0.1 ml• Anti CD 20 monoclonal antibody• Good initial response, but subsequent relapse

UVEAL LYMPHOPROLIFERATIVE TUMORS

• Lymphoid proliferations of the uvea can be divided into primary uveal tumors and secondary intraocular manifestations of systemic lymphoma• Particular in leukemia intraocular involvement

may occur in as many as 80-90% of patients at some point in the course of the disease

• The majority of these tumors represent low-grade B-cell lymphoma

PRIMARY UVEAL LYMPHOMA

• Extranodal marginal zone lymphoma (mucosa associated lymphoid tissue B cell lymphomas) can also present with intraocular features

• Often they present with a localized uveal mass with extraocular extension and is termed primary uveal lymphoma

SECONDARY INTRAOCULAR LYMPHOMA• Secondary intraocular lymphoma arises outside the

central nervous system and metastasizes to the eye

• This type has different clinical features and prognosis

• The lymphoma cells are present mainly in the uvea

• Systemic T-cell lymphoma with intraocular involvement shares some of the ocular clinical features of typical B cell PIOL

CLINICAL FEATURES

• Usually occur in men in the fifth decade

• Typical presenting symptoms include

• recurrent episodes of blurred vision,

• painless loss of vision and

• metamorphopsia due to secondary serous detachment of the macula

• Late forms of the disease are characterized by symptoms such as narrow-angle glaucoma and eye pain, total RD and reduced visual acuity

CLINICAL FEATURES

• The key early features of PCL include

creamy choroidal infiltrates with low

echogenicity on ultrasound

• Ultimately, a diffuse thickening of the

uveal tract

• Thickened uveal tract with confluent

or non- confluent creamy yellow

lesions

CLINICAL FEATURES

• In some cases subconjunctival or episcleral extension can occur in the form of fixed salmon- colored epibulbarmasses with fine intrinsic vascularity

Occasionally, depigmentation of the retinal pigment epithelium with loss of normal choroidal markings

IMAGING - FFA

• early mottled or pinpoint areas of hyperfluorescence of the lesions with late staining at the level of RPE

IMAGING- ICG

IMAGING - OCT

IMAGING - US

• Choroidal thickening with decreased echogenicity and extrascleral extension with an intact scleral layer.

• Absence of scleral thickening or retrobulbaredema

IMAGING

• CT: thickening in the region of the mass without calcification, with a corresponding reduction in size of the vitreous cavity

• MRI: thickening in the region of the mass with a decrease in size of the vitreous cavity

TREATMENT

• It is essential to perform a complete staging investigation

• If no systemic disease is found, local treatment is appropriate

• Excisional biopsy of any epibulbar mass, cryotherapy and low-dose radiation in fragments

• Prognosis: are less aggressive in their clinical course, with the overall survival of patients being very good