This chapter discusses only intraocular masquerade lesions. In previous editions of this chapter, I considered any noninflammatory condition that simulated uveitis to be a masquerade syndrome. In this edition, although I am using this broad definition, I have emphasized neoplastic-simulating lesions because more harm occurs when a malignant process is mistaken for a benign lesion.

Increased awareness that malignant intraocular processes can simulate benign lesions (most commonly in adults as a unilateral media opacity or in children less than 2 years of age with intraocular inflammation), together with the development of better diagnostic techniques, has decreased the frequency of incorrect diagnoses. However, diagnostic problems still occur even with the use of ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI). Occasionally, a correct diagnosis is not established until a cytologic, histopathologic, or newer, molecular-based laboratory examination is performed.

UVEAL MELANOMA

Any elderly patient with a unilateral media opacity and inflammation has a uveal melanoma until proven otherwise with appropriate imaging studies and, when necessary, invasive diagnostic techniques.⁴ Although unapparent intraocular foreign bodies are a much more common cause of unilateral cataract, in as many as 10% of blind eyes submitted to eye pathology laboratories, an undiagnosed uveal melanoma is found. All adults with unexplained unilateral media opacity require a thorough evaluation, including a diagnostic ultrasound examination.^5,6 We have managed many very large uveal melanomas that were discovered only after cataract extraction and were not detected at the time of ultrasonic biometry to measure axial length.

Necrotic melanomas account for approximately 5% of uveal melanomas; in the majority of cases, there is intraocular inflammation accompanying the cataract.^7–9Figures 1 and 2 demonstrate a typical case. The patient had a long history of unilateral decreased vision. The eye had become painful 1 month before admission, and he was referred for evaluation of uveitis. Clinically, there was a dense, unilateral cataract with significant intraocular inflammation, which was manifested as a ciliary flush with 2+ cells and flare. Media opacity obscured all fundus detail. An immersion B-scan demonstrated a large intraocular tumor that was most consistent with a uveal melanoma. The eye was removed, and the diagnosis was confirmed histologically.¹⁰

Unfortunately, imaging studies are not always diagnostic. The A- and B-scans shown in Figures 3 and 4 were from a patient with unilateral media opacity referred for evaluation and treatment of a presumed uveal melanoma. Occasionally, if the cataractous lens is scanned tangentially, artifact can occur. A repeat ultrasound at our institution was negative for tumor, and the referral ophthalmologist who performed a cataract extraction noted that no tumor was present and that the patient has an excellent visual outcome. In contrast, the patient shown in Figure 5 was referred with a presumed uveal melanoma with secondary inflammation and a history similar to that described for the patient shown in Figure 1¹¹ Ultrasound and CT examinations were not diagnostic. Because the eye was blind and painful, it was enucleated, and an extremely necrotic uveal melanoma was noted histologically. In some necrotic melanomas, the fundus cannot be visualized and the diagnosis cannot be established with imaging studies. Very rarely, a necrotic uveal melanoma can produce sufficient pigment dispersion into the vitreous to obscure the correct diagnosis.¹²

The role of MRI in the evaluation of intraocular masquerade syndromes is unclear. There was initial enthusiasm about the possibility of differentiating atypical uveal melanomas from hemorrhagic-simulating lesions based on the unique paramagnetic properties of melanin.¹³ In relation to vitreous, a uveal melanoma typically has a bright signal on a T1 image and a dark signal on a T2 image. In contrast, hemorrhagic processes tend to be either bright or dark on a T1 image and bright on a T2 image.¹⁴

Unfortunately, there are several problems with MRI for uveal melanoma diagnosis. First, several investigators have shown that unless high field-strength, thin-section scans with surface coils are used, the quality of data obtained is suboptimal.¹⁵ Second, even in a state-of-the-art center, we have had a number of cases in which we were unable to differentiate between a uveal melanoma and a simulating lesion on the basis of MRI data. We obtain MRI studies in older patients with opaque media, equivocal ultrasonographic data, and large masses. In some of these cases, the MRI is diagnostic of either a melanoma or an extramacular disciform (hemorrhagic) process. It is also a useful adjunctive study if localized extraocular extension is suspected. In equivocal cases, however, we proceed to using invasive diagnostic techniques, such as fine-needle aspiration biopsy (FNAB) (see Metastatic Tumors).

In addition to producing media opacity, inflammation, and cataract, uveal melanomas can also produce other signs that may lead to the incorrect diagnosis of uveitis. Anterior melanomas, especially those that involve the ciliary body, often produce dilated episcleral vessels (sentinel vessels) that occasionally have been misdiagnosed as scleritis (Fig. 6).

Iris melanomas can produce anterior chamber cell and flare, and if the tumor is located in the extreme iris periphery, it may be missed during a cursory examination. Iris melanomas, especially those in a circumferential or ring configuration, are often difficult to diagnose and may simulate either an anterior uveitis or glaucoma.¹⁶ Newer, higher-megahertz (high-frequency) ultrasound equipment is better for imaging anterior uveal tumors (Fig. 7).

If direct ophthalmoscopy is used, a circumferential peripapillary melanoma can simulate optic neuritis (Fig. 8).

Pseudomelanoma

Melanomas can masquerade as uveitis, and some inflammations or hemorrhagic processes can simulate melanoma. These processes include posterior scleritis, focal choroidal hemorrhage or detachments, and focal scleral thinning. Figures 9 and 10 demonstrate focal scleral thinning in the area of the superior rectus insertion in a patient with rheumatoid scleritis that produced a pseudomelanoma. An apparent elevated pigmented mass was noted on upgaze, but no tumor was observed when the eye was in primary position. Posterior scleritis is often not painful, although some of these patients have deep, piercing pain and increased discomfort during eye movement. Ultrasound usually is diagnostic, demonstrating fluid inside of Tenon's capsule (Fig. 11). A focal hemorrhagic choroidal detachment after cataract surgery can simulate a melanoma. These lesions usually have a bright area of hemorrhage at their base, whereas melanomas typically do not have associated hemorrhage until they break through Bruch's membrane (most commonly, such tumors are more than 5 mm thick). The differential diagnosis of uveal melanoma is discussed elsewhere in these volumes.

METASTATIC TUMORS

Choroidal metastases can also produce signs that mimic uveitis. As many as 50% of patients with metastases to the eye may present to the ophthalmologist before the primary malignancy is discovered.¹⁷ Patients with renal and lung carcinomas have the highest frequency of presenting with eye symptoms as the initial complaint associated with the neoplasm; in contrast, more than 90% of breast carcinomas have a known primary at the time ocular metastases are noted. Usually, intraocular metastases are solid, posterior, amelanotic, choroidal tumors; however, in less than 10% of cases, they can simulate a benign intraocular inflammation. At least five patterns of inflammatory masquerade syndromes can occur with intraocular metastases.

1. Tumors may produce a pseudoscleritis.
   
2. Patients with metastatic carcinoma may present with a diffuse infiltration of the iris (Fig. 12).
   

   Fig. 12. Breast carcinoma diffusely infiltrating the iris.

3. In rare cases, an optic nerve metastasis can simulate either an optic neuritis or an acute anterior ischemic neuropathy (Fig. 13).
   

   Fig. 13. Bronchiogenic carcinoma metastatic to the optic nerve. (Char DH: Clinical Ocular Oncology. 2nd ed. Philadelphia, Lippincott-Raven, 1996.)

4. Isolated metastatic cells in the vitreous or anterior chamber may occur as the only manifestation of an ocular metastasis.¹⁸
   
5. Figure 14 shows a patient with bilateral pseudohypopyon as the first stigmata of widespread disease.
   

   Fig. 14. Bilateral pseudohypopyon as the initial manifestation of widespread metastases.

Most commonly, pseudohypopyons in adults develop in association with either a systemic lymphoma or leukemic relapse. Rarely, metastatic cutaneous melanoma can produce this pattern; however, usually these later cells are pigmented (Fig. 15). Much more frequently, vitreous cells in patients with known metastases are benign, originating from either infectious or endogenous uveitis.

A masquerade syndrome secondary to a distant malignancy can take several forms. In some metastatic tumor patients, multiple areas of increased choroidal pigmentation develop. Although these paraneoplastic syndromes are rare, a more common form is autoimmune destruction of retinal photoreceptor or ganglion on cells that more commonly occur either with small cell carcinomas of the lung or metastatic cutaneous melanoma.^19–23

The evaluation of patients with metastatic tumors to the eye may be difficult. Approximately 10% of uveal melanoma patients have a history of a systemic malignancy. Approximately 50% of patients with uveal metastases are found to have an elevated plasma carcinoembryonic antigen or cancer antigen 125 level; in contrast, uveal melanoma patients do not have significantly elevated levels.²⁴ Most metastases to the uveal tract can be correctly diagnosed with ultrasonography. In atypical presentations of metastatic tumors in which there is diagnostic uncertainty, we have confirmed the diagnosis with an intraocular FNAB.¹⁸

In several ocular oncology units, FNAB has become an important diagnostic adjuvant in difficult cases.^25–27 We use FNAB in intraocular oncologic cases that cannot be diagnosed with noninvasive techniques.⁴ We have observed no false-positives in uveal melanoma diagnosis, and in that malignancy, we can accurately predict prognosis on the basis of the cellular composition (percentage of epithelioid cells) of the aspirate.²⁷ Rarely in a necrotic melanoma, insufficient viable tumor cells are present to establish a diagnosis with this technique. In several lesions that simulate either retinoblastoma or melanoma, cytologic pattern on FNAB is diagnostic. We have found this technique especially useful in atypical metastatic uveal tumors. Often such patients are incorrectly diagnosed as having either a uveal melanoma or a benign lesion. Establishing the correct diagnosis results in optimum treatment. A misdiagnosis of a uveal melanoma would require a subsequently higher radiation dose with a higher likelihood of radiation vasculopathy. Conversely, a misdiagnosis of a benign process would result in ineffective therapy.

Figure 16 shows a case of what clinically and ultrasonographically appeared to be a uveal melanoma. The FNAB specimen revealed a cellular pattern that was diagnostic of a primary carcinoid (Fig. 17), and the patient responded dramatically with 40 gray of photon radiation. Figure 18 shows the FNAB cytopathology of a typical epithelioid choroidal melanoma; in contrast, a smear of a spindle cell tumor has spindle-shaped cytoplasm and smaller nuclei. Figure 19 shows a benign pigmented mass, such as a retinal pigment epithelial proliferation or a melanocytoma. In contrast to a melanoma, this type of mass has much larger pigment granules and benign cytomorphologic detail. In addition to standard cytopathologic FNAB evaluation, aspirated material may be used for several molecular biology studies (e.g., fluorescence in situ hybridization, comparative genomic hybridization), flow cytometry, special stains, tissue culture, and ultrastructural analyses.

A number of nonuveitis entities can produce vitreous cells, and some of these conditions are listed in Table 1.

Table 1. Vitreous Cells Not Associated With Uveitis

Primary and secondary intraocular lymphomas
Metastatic tumors
Retinoblastoma
Old vitreous hemorrhage (diabetes, retinal detachment)
“Tobacco dust” from retinal detachment
Battered baby syndrome
Retinitis pigmentosa
Asteroid hyalosis
Synchysis scintillans
Familial amyloidosis

INTRAOCULAR LYMPHOMA

Intraocular lymphoma is usually initially misdiagnosed in older patients as a chronic diffuse uveitis.²⁸ In a series of 828 consecutive patients at the uveitis center, approximately 1.5% of cases (13), had intraocular lymphomas.²⁹ In any patient more than 50 years of age with an onset of a diffuse uveitis or vitritis, the diagnosis of intraocular lymphoma must be excluded. The classification and nomenclature of intraocular lymphomas is in flux.^28,30,31 Erroneously termed ocular reticulum cell sarcoma, this neoplastic disease is usually limited to the eye and central nervous system (CNS). This process was initially thought to be due to a proliferation of malignant reticulum cells, but more recent studies have shown that this is usually a malignant B-cell lymphoma.³⁰ Most investigators have adopted the term primary central nervous system lymphoma (PCNSL). The incidence of this disease has increased, although reasons for the rise are unclear.³² Ocular involvement occurs between 12% and 25% of patients. There are three types of intraocular lymphomas.

1. The intraocular findings in primary intraocular–CNS lymphoma may simulate a diffuse uveitis, usually with a plethora of vitreous cells and often with virtually pathognomonic yellowish white chorioretinal infiltrates (Fig. 20). Less common clinical presentations can mimic toxoplasmosis, acute retinal necrosis, a branch vein occlusion, or various forms of retinal vasculitis.
   

   Fig. 20. Yellowish white chorioretinal infiltrate typical of primary intraocular lymphoma (erroneously termed ocular reticulum cell sarcoma). (Char DH: Clinical Ocular Oncology. 2nd ed. Philadelphia, Lippincott-Raven, 1996.)

2. A less common form of primary ocular lymphoma consists of lesions in the choroid with fewer vitreous cells. Systemic, non-CNS lymphoma usually develops in these patients.³³ Rarely, we have observed a variant of this second group, in which a patient has a solid intraocular lymphoma that involves the choroid as the first manifestation of widespread disease.³⁴
   
3. Intraocular involvement may occur as a sequela of systemic lymphoma, often as the first sign of reactivation after therapy. Such patients usually present with a malignant hypopyon (Fig. 21). In very rare cases, a patient with mycosis fungoides, a cutaneous T cell lymphoma, is found to have an associated anterior or posterior uveal involvement.
   

   Fig. 21. Malignant hypopyon in a patient with systemic lymphoma.

In all three forms of intraocular malignant lymphoma, the diagnosis is made with FNAB. In rare instances, a chorioretinal biopsy is necessary.^35,36 In 15% of cases, a single vitreous biopsy may not demonstrate malignant cells, and multiple biopsies may be required.²⁸

All patients with intraocular lymphoma require a thorough systemic evaluation, including examination of cerebral spinal fluid cytology, gadolinium-enhanced brain MRI, abdominal-chest CT, routine blood studies, and bone marrow biopsies. Probably, positron emission tomography scans will supplant some of these studies, but at present, data from this entity are insufficient. Historically, primary intraocular–CNS lymphomas were almost uniformly fatal, but newer, aggressive therapies with either intrathecal or systemic chemotherapy plus eye and CNS irradiation have produced long-term survival in some patients. Early diagnosis and treatment are associated with better prognosis, so patients should be evaluated promptly.²⁸

The diagnostic evaluation of these patients continues to evolve. Superb cytologic analysis remains the central diagnostic test. Several approaches can be used to assess monoclonality (usually associated with lymphoma) versus polyclonality (usually associated with benign processes). The major problem with all of these techniques is that the vitreous sample is limited, and all of these ancillary assays may have false-positive and false-negative results. Flow cytometric features of lymphoma include an abnormal kappa-lambda ratio of either greater than 3 or less than 0.33, and monoclonal expansion of either B cells (more common) or T cells.^37,38 A more elegant technique is to adapt a variation of polymerase chain reaction assay to identify a clonal B or T cell expansion, gene rearrangements, or oncogenes. However, errors do occur even with these sensitive assays.^39,40 A few vitrectomy specimens that were not diagnosed cytologically were correctly diagnosed with these techniques.^41,42 In addition, often the vitreous ratio of two cytokines, interleukin (IL)-10 and IL-6, is increased in lymphoma; however, exceptions occasionally have been reported.^43,44

Pseudolymphoma

A benign variant of intraocular lymphoid tumors may occur in either an isolated form or, more commonly, a diffuse form involving both the intraocular contents and contiguous sclera and orbit.⁴⁵ Usually these lesions simulate a solid intraocular neoplasm (e.g., melanoma), and they may occur with or without pain (Fig. 22). Most of these patients have an ultrasound pattern consistent with a melanoma, and the correct diagnosis is established with FNAB. As Cockerham and colleagues⁴⁶ noted, the episcleral lesion may appear benign, whereas the intraocular component demonstrates lymphoma.

Rarely, after liver transplantation, patients develop a spectrum of post-transplantation lymphoid proliferative disorders that may range from benign to malignant lymphomas and have involved the eye.^47–49

Medications can alter the normal clarity of the anterior chamber and produce a pattern that may be mistaken for an anterior uveitis. For example, patients, especially those with a dark iris on dilation with phenylephrine hydrochloride, may have a transient appearance of anterior chamber pigmented cells that may last for up to 24 hours. Administering drops before performing an anterior segment examination can impair the clinician's ability to grade aqueous cell and flare.^50,51 Similarly, occasionally Krukenberg spindles with pigment dispersion may also mimic uveitis. Anterior uveitis has developed in several acquired immunodeficiency syndrome patients receiving rifabutin therapy.⁵²

A number of adult cardiovascular diseases can produce ophthalmic manifestations that simulate uveitis. In severe hypertension, retinal detachment, small choroidal vascular insults, cotton wool spots, and hemorrhages may occur, simulating posterior uveitis (Fig. 23). In patients with carotid artery disease, anterior segment ischemia similar to mild anterior uveitis may be observed. This pattern may also occur after either extensive ocular irradiation or disinsertion of more than two extraocular muscles during retinal or strabismus surgery.

A number of retinal lesions can either produce or simulate uveitis. Retinal detachments can occasionally produce enough inflammation for anterior uveitis to obscure both fundus detail and the correct diagnosis. In a patient with markedly decreased vision and media opacification, an ultrasonographic evaluation is mandatory to rule out a neoplastic or foreign body process. Cases of inapparent retinal detachment also can be correctly diagnosed with ultrasonography. Uncommonly in central serous choroidopathy, protein deposition at the leakage point can simulate a focal choroiditis. Medullated nerve fibers can simulate retinochoroiditis, but the shape, corresponding to the nerve fiber layer with the absence of other signs of inflammation, usually allows a clear-cut differentiation.⁵³

Some retinal dystrophies and degenerative processes can simulate a retinochoroiditis. Vitreous cells may occur in cases of retinitis pigmentosa. Pigmented paravenous retinochoroidal atrophy has a distinctive pattern of pigmentary deposits surrounding retinal veins; it may occur as an idiopathic degenerative disorder or sometimes as a sequela of ocular sarcoid. Fundus flavimaculatus is a rare autosomal recessive dystrophy that is usually detected in the third decade of life. It produces typical comma-shaped, yellowish retinal pigment epithelial opacities in the posterior pole, but it does not involve the macula. It can simulate a diffuse choroiditis (Fig. 24). Myopic degeneration can produce small, white, posterior pole spots that can simulate a posterior choroiditis. Peripheral fundus “paving stone” degeneration is rarely confused with an inflammatory process. These lesions show no evidence of retinal or vitreal inflammation and are quite common.⁵⁴

RETINOBLASTOMA

Retinoblastoma is the most common childhood intraocular malignancy. More than 98% of patients present before the age of 5 years, and any child less than 3 years of age presenting with leukocoria, strabismus, or intraocular inflammation must have retinoblastoma excluded from the differential diagnosis by a thorough fundus evaluation. At least three patterns of retinoblastoma can simulate a benign inflammatory process.

1. Inflammatory signs occur in as many as 10% of retinoblastomas; the child presents with redness and ciliary flush. In any child less than 2 years of age who has evidence of intraocular inflammation, either a tumor or a trauma must be ruled out.
   
2. Very large retinoblastomas can contiguously involve the anterior segment and produce a pseudohypopyon (Fig. 25). Unlike a benign collection of white cells, a pseudohypopyon is made up of malignant cells, and clinically it is not as mobile as an inflammatory hypopyon. Usually the diagnosis in these cases is relatively straightforward because the large retinoblastoma can be either seen ophthalmoscopically or imaged with CT or ultrasound.
   

   Fig. 25. Large retinoblastoma with “spillover” pseudohypopyon.

3. Diffuse retinoblastoma, which accounts for less than 2% of cases, often does not produce a discrete tumor (Fig. 26). The diffuse cases I have managed have had atypical retinal detachments without clinical, CT, or ultrasonographic evidence of a calcified tumor mass. Diagnosis has been established with an intraocular FNAB.⁵⁵
   

   Fig. 26. Diffuse retinoblastoma without an obvious tumor mass.

Pseudoretinoblastoma

The diagnosis and classification of pseudoretinoblastoma lesions are evolving. Genetic tests will more precisely differentiate among several entities grouped under the rubrics of either retinal dysplasia or atypical persistent hyperplastic primary vitreous. In children with lesions that produce leukocoria, such molecular biologic testing for several diseases is often useful (see http://www.genetests.org). A recent example in which such tests altered our clinical impression is the case of a young female patient referred to us to rule out retinoblastoma. Our findings on clinical examination were consistent with an atypical retinal dysplasia. There was no family history, but genetic testing demonstrated that she was a mosaic for Norrie's disease.⁵⁶ It is likely that such types of studies will help to clarify the nature of many of the pseudoretinoblastomas that have been classified clinically as variants of either persistent hyperplastic primary vitreous or retinal dysplasia.

LEUKEMIA

Ocular involvement is a common presentation of acute myelomonocytic leukemia in children from the Mediterranean area.⁵⁷ These children often present with simultaneous ocular and orbital tumor.^58,59 In a few cases, we have established the correct diagnosis with an anterior chamber paracentesis. Most American children managed for leukemia-associated ocular problems, however, have the acute form of lymphocytic disease, and ocular problems usually develop as a sign of systemic or CNS relapse. In rare cases, an anterior chamber collection of malignant cells (similar in appearance to Fig. 21) or tumor infiltrating the optic nerve head can be the presenting sign of this disease.^58,59 Rarely, where the possibility of intraocular recurrence of acute lymphocytic leukemia is not recognized and topical corticosteroids are given for presumed anterior uveitis, the anterior chamber clears and the patient presents with a ciliary body mass (Fig. 27).

RARE PEDIATRIC INTRAOCULAR NEOPLASMS

Less common neoplasms in children can also simulate benign forms of inflammation. Medulloepithelioma is a rare tumor that can affect different intraocular structures but most commonly involves the iris-ciliary body. This tumor has a typically velvety surface⁶⁰ and may present with intraocular inflammatory signs (Fig. 28).

Juvenile xanthogranuloma, a benign lesion, usually presents in children less than 1 year of age; it is characterized by a spontaneous hemorrhage and a poorly demarcated yellowish iris tumor.^61–64 Only about-one third of children have the complete form of this disease.⁶⁴

Combined retinal and retinal pigment epithelial hamartomas can also produce a pattern that simulates retinitis (Fig. 29). The pigment at the level of the retinal pigment epithelium, the surface fibrosis, and the vascular changes are typical features of this entity.

A number of macular dystrophies can be mistaken for a central choroiditis. Best's vitelliform macular dystrophy is often referred to as a focal macular choroiditis. This dystrophy is autosomal dominantly inherited and has variable penetrance and expressivity. An “egg yolk” lesion in the fovea is a classic sign, but this characteristic is not always observed. In difficult cases of Best's vitelliform macular dystrophy, an electro-oculogram may be performed and will be abnormal, even in normal-appearing disease carriers.

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