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Masquerade Syndromes: Malignancies Mimicking Inflammation in the Eye

Tsai, Tony M.D.; O'Brien, Joan M. M.D.

International Ophthalmology Clinics: January 2002 - Volume 42 - Issue 1 - p 115-131
Articles

The term masquerade syndrome first appeared in the ophthalmic literature in 1967 to describe a conjunctival carcinoma that had presented as chronic conjunctivitis. 1 Since then, the masquerade syndrome label has been applied to a group of disorders that mimic ocular inflammatory disease. Although some benign conditions can be considered masquerade syndromes, most often the term refers to malignant entities. Ocular oncology, the subspecialty that concerns itself with ocular and orbital malignancies, is by nature a field of uncommon disorders. A discussion of the masquerade syndromes, therefore, becomes a study in uncommon presentations of uncommon diseases. Nevertheless, the subject deserves wide attention because, in many cases, the diseases that masquerade are not only vision-threatening but potentially fatal. Significant morbidity and mortality can be averted by early recognition and diagnosis of the masquerade. This end point can be achieved only when an examiner is familiar with these uncommon presentations and maintains an appropriate index of suspicion.

This brief review concentrates on six malignant conditions that can masquerade as ocular inflammation: sebaceous gland carcinoma, intraocular lymphoma, periocular lymphoma, retinoblastoma, ocular melanoma, and ocular metastases. The aim is to emphasize epidemiological and clinical features that should raise an examiner's suspicion for a masquerade syndrome and then to highlight maneuvers that may assist in making the diagnosis. For brevity, discussions regarding therapeutic choices have been avoided. For these six and many of the rarer masquerade syndromes, the best initial step to therapeutic success is early definitive diagnosis.

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Sebaceous Gland Carcinoma

Although sebaceous gland carcinoma commonly masquerades as benign inflammatory disease, it is a rare malignancy of the eyelid. Sebaceous gland carcinomas comprise between 1% and 5% of all malignant eyelid tumors and represent less than 1% of all eyelid tumors in North America. 2,3 Despite its rarity, sebaceous gland carcinoma commands attention as one of the most lethal of all tumors of the ocular adnexa, second only to melanoma. 4 This is in distinct contrast to sebaceous gland carcinomas arising at other sites, which have a better prognosis, a less aggressive clinical course, and minimal metastatic potential. 5

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Epidemiological Features

Although sebaceous gland carcinoma of the eyelid can occur in any age group, it is predominantly a disease of older adults, occurring with a mean or median age at diagnosis in the sixties in most series. 2–4,6 Many of the younger cases described in the literature have been associated with radiotherapy for patients with bilateral retinoblastoma in childhood, suggesting that sebaceous gland carcinoma is one of the many secondary tumors to which these patients are prone. 7,8 However, sebaceous gland carcinoma has also been reported to occur in association with extensive radiotherapy for a cavernous hemangioma, a benign lesion associated with no known tumor predisposition syndrome. 9 One may consider both bilateral retinoblastoma and irradiation as independent risk factors for the development of sebaceous gland carcinoma, especially in younger age groups. 7

Other epidemiological features of ocular sebaceous gland carcinoma have been more difficult to define. Most series describe a female predominance ranging between 1.4 : 1 and 2.6 : 1, 2,4 but other series demonstrate no such trend. 3 It has been suggested that the incidence in Asia is higher than that in the West, but the relative influences of environment, culture, and race have not been fully studied. 6

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Clinical Features

Although often referred to as meibomian gland carcinoma, the more general terms sebaceous gland carcinoma and sebaceous adenocarcinoma are preferred because the tumor may arise from any sebaceous gland of the ocular adnexa. These include tarsal meibomian glands, glands of Zeis, and sebaceous glands found in the caruncle and eyebrow and associated with the fine hairs on the cutaneous surface of the eyelids. Despite a wide distribution of potential sites, eyelid lesions predominate, with occurrences twice as common on the upper eyelid as compared to the lower lid. 2,4,6,8 Both eyelids are involved in up to 9% of cases. 4,6

The high mortality associated with ocular sebaceous gland carcinoma can be attributed in part to a propensity to masquerade as other, less aggressive, eyelid lesions. Patients most commonly present complaining of a foreign-body sensation or an enlarging painless mass. 3,6 Less commonly, itching, eyelid edema, and proptosis have been reported. 6 In approximately half of all cases, the clinical appearance is mistaken for a chalazion or chronic blepharoconjunctivitis. 2,3 Other misdiagnoses have included conjunctivitis, blepharitis, keratoconjunctivitis, meibomianitis, papilloma, basal cell carcinoma, squamous cell carcinoma, or epithelial carcinoma in situ. 2–4,10 Signs that may raise one's suspicion for sebaceous gland carcinoma include a yellowish appearance of the eyelid mass (due to its high fat content), loss of lashes, or a deep location in the absence of ulceration or papillary masses at the cutaneous surface (as seen in squamous or basal cell carcinoma). 6,11

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Diagnosis

In light of its rarity and its propensity to simulate benign lesions, a high index of suspicion is critical for timely diagnosis of sebaceous gland carcinoma. In as many as 80% of cases, the final diagnosis is not correctly identified preoperatively. 2 Frequently, the time between initial symptoms and diagnosis is a year or more, 3,6,7 an alarming statistic as sebaceous gland carcinoma has a significant malignant potential, and delayed diagnosis is associated with increased mortality. 4 The diagnosis should be seriously considered in all cases of recurrent or atypical chalazion, chronic unilateral unresponsive blepharoconjunctivitis, diffuse or nodular tumors of the upper and lower eyelids, orbital mass developing after removal of an eyelid or caruncular tumor, and any tumor developing in a person with a history of ocular radiotherapy.

If sebaceous gland carcinoma is suspected, definitive histopathological diagnosis must be obtained. Full-thickness biopsy is the most frequent diagnostic procedure, but conjunctival biopsy has been used when the patients present with unresponsive chronic conjunctivitis. 10 Fine-needle aspiration biopsy has been advocated for candidates unsuitable for surgery. 12 Pathological findings include large pleomorphic cells with nucleus-cytoplasm disproportion, brisk mitotic activity, vacuolated cytoplasm, continuity with normal sebaceous glands, and pagetoid involvement of the surface and adnexal epithelium. 3,4,11 Fat stains, such as oil red O, may be useful to demonstrate sebaceous material with high lipid content in the cytoplasm. 12

Unfortunately, difficulties in establishing a histopathological diagnosis are compounded by frequent misdiagnosis at initial biopsy by both general pathologists and ocular pathologists. 3 Therefore, in addition to a high level of clinical suspicion by the examiner, the best pathological diagnosis is highly dependent on the presence of an adequate specimen and on an experienced pathologist who has been alerted to the possible diagnosis. To ensure an adequate specimen, a full-thickness biopsy is necessary. Without it, one may encounter difficulties in differentiating the superficial spread of a squamous cell carcinoma from that of an adnexal neoplasm. The necessity for pathological examination of all chalazia has been debated, but it is generally accepted that atypical or recurrent lesions require pathological examination. 13 When in doubt, specimens should be referred to a center for ophthalmic pathology, and the ocular pathologist should be consulted preoperatively to determine how tissue should be submitted and processed to obtain optimal diagnostic accuracy.

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Intraocular Lymphoma

Both Hodgkin's lymphoma and non-Hodgkin's lymphoma (NHL) can present as inflammation or infection in the eye. All types of intraocular lymphoma are of concern, given their potential lethality if left untreated. Ocular involvement in Hodgkin's lymphoma is relatively rare, often occurring late in the course of the disease. 14 It can manifest as iritis, retinal periphlebitis, and chorioretinitis with an associated vitritis. 14,15 NHL affects the eye more commonly than Hodgkin's lymphoma, and it presents in two clinically distinct forms: systemic NHL with metastases to the eye and NHL of the central nervous system (NHL-CNS).

The ocular presentation of systemic NHL metastatic to the eye is rarely a diagnostic dilemma because patients are systemically ill with fever, weight loss, and lymphadenopathy. Nevertheless, metastatic NHL lesions presenting as ocular inflammation have been reported as the initial presenting feature. 16 The resulting condition can simulate either posterior uveitis or an anterior uveitis with hypopyon or hyphema in an otherwise inflamed eye. In contrast to the retinal infiltrates seen in NHL-CNS, the infiltrates in systemic NHL with metastases to the eye are, as a rule, centered in the choroid. 17

Of the two forms of NHL affecting the eye, NHL-CNS presents the greater diagnostic challenge. This is the case not only because NHL-CNS often masquerades as ocular inflammation but because it is very rare. In 1951, Cooper and Riker 18 reported the first case of intraocular lymphoma in a 27-year-old patient who presented with uveitis and retinal hemorrhages and eventually died of systemic lymphoma. Since then, fewer than 200 cases have been reported in the literature. 19–21

When NHL-CNS involves the eye, it has been called primary intraocular lymphoma, histiocytic lymphoma, intraocular large-cell lymphoma, and reticulum cell sarcoma. Reticulum cell sarcoma, a misnomer created because the tumor was initially thought to arise from malignant reticulum cells, is a term particularly entrenched in the older ophthalmic literature. With the discovery that the tumor consists of lymphocytes or their precursors, most authors now refer to NHL-CNS of the eye as primary intraocular lymphoma or, more simply, intraocular lymphoma. 19

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Epidemiological Features

Intraocular lymphoma usually presents in the fifth to seventh decade. 19,22–24 It can strike younger patients, but rarely. The youngest reported case occurred in a 15-year old. 20 The literature supports no clear gender or racial predilection. 24 Immunosuppression, whether acquired or inherited, is a risk factor for developing NHL-CNS. Therefore, high-risk groups include transplant recipients, acquired immunodeficiency syndrome patients, and those with congenital immunodeficiencies. 24 Interestingly, the incidence of NHL-CNS is on the rise in the United States, unrelated to any increase in the acquired immunodeficiency syndrome and organ transplant prevalence. 25

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Clinical Features

Intraocular lymphoma may originate in the eye or in other parts of the CNS, including the brain, spinal cord, and leptomeninges. 14 In one report, 50% presented with only ocular disease, but ocular lesions may also develop concurrent with, or following, CNS involvement. 20 Although the initial presentation may be unilateral, involvement is eventually bilateral in 80% of cases. 26 Spread within the CNS is common, with lesions developing in up to 80% of patients. 19 In contrast, systemic metastases outside the CNS occur only rarely. 14

Clinical signs of intraocular lymphoma are nonspecific, and frequently there are no associated systemic findings. Classically, patients present with a refractory uveitis and an associated vitritis. The typical picture of nonspecific uveitis may precede or follow CNS involvement, but ocular symptoms precede CNS symptoms in the majority of patients. 23 These symptoms include eye pain, blurred vision, floaters or, less commonly, a foreign-body sensation. 27 Patients may also present asymptomatically on slit-lamp examination. 20

On ocular examination, vitritis is the only universal finding. Biomicroscopical examination reveals cells, often clumped, without significant flare. The pathognomonic fundus appearance in more advanced cases is one of multiple, small, well-circumscribed, round or oval, yellow-white, creamy, dome-shaped masses in the subpigment epithelial space (Fig 1). 19 Other signs include retinal hemorrhage or exudates, vitreous hemorrhage, hyphema, hypopyon, disc edema, vascular sheathing, vasculitis, and retinitis. 17,19,22,23,28 When disc edema is present, it may be secondary to direct neoplastic transformation, increased intracranial pressure, or hypotony from uveitis. 22 In contrast to the choroidal infiltrates of systemic NHL metastatic to the eye, in NHL-CNS primary to the eye the neoplastic cells lie in the vitreous, retina, or optic nerve. 17,20 Retinal infiltrates usually are associated with a retinochoroiditis. This may lead to marked vitreous clouding and an eventual retinal detachment with secondary glaucoma. 29

Figure 1.

Figure 1.

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Diagnosis

The evaluation of every suspected case of NHL-CNS should include a full medical history and examination. Associated physical findings are usually absent, but many patients with intraocular lymphoma have CNS disease at the time of presentation. Particular attention should be paid to neurological symptoms and signs such as headaches, focal weakness, sensory deficits, confusion, difficulty with gait, or a recent history of seizure. An evaluation for acquired or inherited immunodeficiency should be undertaken as indicated, to include at a minimum human immunodeficiency virus testing. Peripheral blood, bone marrow cytology, and cellular morphology should be obtained, although these are usually normal. 30 The systemic evaluation should include liver enzyme levels, chest radiography, and nodal biopsies when indicated by the physical examination. Ocular ultrasonography may be helpful for visualizing vitreous debris, choroidal thickening, retinal detachments, and a widened optic nerve. 20 Even in the absence of neurological symptoms, CNS imaging should be obtained to exclude occult CNS involvement.

It must be stressed that early improvement with steroid therapy cannot be used as a diagnostic aid, because either malignancy or chronic inflammation may respond to steroids initially. Many patients will have been treated with corticosteroids prior to definitive diagnosis. Because corticosteroids are lytic for lymphoma cells, these patients may experience a transient improvement, but the “uveitis” typically returns.

A definitive diagnosis requires histological or cytological confirmation of cells having the characteristic appearance of malignant lymphocytes. This often is pursued first by lumbar puncture, with 5 to 10 ml of cerebrospinal fluid obtained for examination. If negative, the diagnosis then is sought by cytological examination of a fine-needle aspiration biopsy specimen of the vitreous or by obtaining a vitrectomy specimen. A standard three-port pars plana vitrectomy can provide the cells necessary to confirm a malignant process, and it has the additional therapeutic value of clearing a clouded visual axis. 20,31,32 Other modalities that have led to the definitive diagnosis of NHL-CNS include anterior chamber tap, CNS biopsy, transscleral biopsy, enucleation and, fortunately less commonly, necropsy. 23,33

Unfortunately, vitreous biopsy is hazardous, may miss the lesion, and yields only a small number of cells. The malignant lymphocytes can be few, friable, and highly sensitive to lysis by the corticosteroid therapy initiated for an apparent chronic uveitis. 20 This mandates careful handling and preparation of the specimen, and some advocate withholding steroids prior to biopsy. 14,20 Complicating matters, the hallmark of a malignant process—monoclonality—can be difficult to determine with traditional methods of histology and cytology because intraocular lymphomas can arise in the setting of previous chronic inflammation or following immunosuppression (as for organ transplantation). 19,27 Although multiple vitreous specimens may be required to make the diagnosis of intraocular lymphoma, the diagnosis can eventually be established in 95% of patients. 19,31

Histopathologically, neoplastic cells infiltrate the optic nerve, vitreous, and retina. The uveal tract exhibits minimal involvement. 29,31 Presence of these tumor cells in the vitreous and retina may elicit a secondary inflammatory response. 27 The malignant cells are typically polymorphic with scanty cytoplasm and eccentric nucleoli. Because the majority of NHLs are B cell in origin, immunocytochemical staining with antibodies to B-cell markers has been recommended to increase the diagnostic yield of routine cytology. 27 Primary intraocular lymphoma has an immunological profile of B lymphocytes with light-chain restriction, in contrast to the predominance of T lymphocytes in uveitis and a predominance of neutrophils and macrophages in infectious processes. 34

It has been suggested that the diagnostic value of vitrectomy may be further improved by adding analysis for interleukin-10 (IL-10) and interleukin-6 (IL-6). Whitcup and colleagues 35 demonstrated that the IL-10/IL-6 ratio was greater than 1 in all of 5 patients with intraocular lymphoma and in none of 13 control patients with intraocular inflammation unrelated to a malignant process. The diagnostic value of the vitreous IL-10 level must be tempered by the knowledge that, like the malignant cells, it is sensitive to steroid therapy. Also, other investigators have reported cases of nonneoplastic uveitis in which the ratio was greater than 1 and cases of NHL-CNS in which the ratio was less than 1. 36 Elevated levels of IL-10 relative to IL-6 may serve best to increase the suspicion for primary intraocular lymphoma. 35,36 It must be maintained that definitive diagnosis requires histopathological confirmation of malignant cells.

Untreated, NHL-CNS primary to the eye is blinding and spreads extraocularly within 20 to 36 months. Typically, survival without treatment is measured in weeks after the CNS becomes involved, 37 but the disease can have a fulminant course with mortality in a matter of days. Some still consider the disease uniformly fatal, but accurate diagnosis is important because treatment can delay mortality and improve the remaining quality of life. 37

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Periocular Lymphoma

In addition to intraocular disease, lymphoma may also affect the conjunctivae in multiple forms, including Hodgkin's lymphoma, Burkitt's lymphoma, and lymphomas arising from mucosal-associated lymphoid tissue (MALT). MALT, best described in the gastrointestinal tract, is an afferent arm of the mucosal defense system and has been suggested as the origin for most primary conjunctival lymphomas. 38,39 These conjunctival lymphomas are B cell in origin. Further histological classifications using accepted guidelines for NHL are difficult. 40

Hoang-Xuan and associates 41 in 1996 reported a case of MALT lymphoma presenting as scleritis, a “new masquerade syndrome.” The presenting symptoms included decreased vision and redness, and on initial evaluation the patient had biopsy-proven anterior and posterior scleritis in addition to yellow-white choroidal infiltrates. Failure to respond to immunosuppressive therapy prompted a second biopsy, in which immunostaining for lymphocyte markers confirmed the diagnosis of MALT lymphoma. It has since been seen that an initial presentation of MALT lymphoma that mimics inflammation of the conjunctiva is not uncommon (Fig 2).

Figure 2.

Figure 2.

Although other forms of lymphoma may affect the eye, it is important to diagnose conjunctival MALT lymphoma accurately, because in contrast to the intraocular lymphomas, these tend to remain localized for long periods and to respond well to radiotherapy. This diagnosis carries a much better prognosis than do nodal tumors of the same grade. 40 However, one must be highly vigilant for a more malignant disease. Therefore, all patients with conjunctival lymphomas deserve a thorough evaluation, including a hematological evaluation, plasma protein electrophoresis, radiological evaluation for systemic disease, and bone marrow biopsies. 21

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Retinoblastoma

Retinoblastoma, an uncommon but important childhood malignancy, represents the phenotypic expression of an absent or abnormal tumor suppressor gene, RB1. Tumors arise from loss or mutation of both RB1 alleles. In the heritable form of the disease, one allele is inactivated in the germline, and loss or mutation of the second allele occurs somatically within a retinal cell. In the sporadic form of the disease, both alleles are inactivated somatically to produce a retinal tumor. 21 Prior to 1900, the disease was uniformly fatal, 42 but advances in ophthalmic care have improved survival rates to exceed 90% in the United States. 43

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Epidemiological Features

With approximately 300 new children affected each year, retinoblastoma accounts for 11% of infant cancers in the United States. 43 The average age at diagnosis is 18 months, and most cases of retinoblastoma are diagnosed before age 5. 21 Older children, however, are more likely to have an unusual presentation. 44–48 To date, no gender or racial predilection has been documented for this disease. The disease is bilateral in 30% and, in unilateral cases, right and left eyes are affected equally. 43

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Clinical Presentation

Classically, retinoblastoma presents as leukocoria, strabismus, or decreased vision. On indirect ophthalmoscopy, early lesions appear as flat, transparent or slightly white, placoid masses within the neurosensory retina. With enlargement, these tumors have a white appearance with flecks of intrinsic calcification. Growth of the tumor can either be endophytic, with extension into the vitreous, or exophytic, with spread under the neurosensory retina.

Despite widespread knowledge of this classic presentation, retinoblastoma can simulate many lesions and many lesions can simulate retinoblastoma. 49 Advanced tumors can present with spontaneous hyphema or secondary glaucoma. Tumor necrosis may produce anterior or posterior inflammation, masking the underlying diagnosis. 45 Advanced cases may present with flare, cells, and a grayish white pseudohypopyon, so-called because the cells layered in the anterior chamber are tumor cells rather than inflammatory leukocytes. 48,50 Tumor seeding into the vitreous cavity may be confused with inflammatory vitritis or retinal exudates, producing a “pseudoinflammatory” vitreous. 50 Intraocular tumor necrosis in retinoblastoma can produce an orbital inflammation resembling panophthalmitis or orbital cellulitis. 51

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Diagnosis

An experienced examiner can make the clinical diagnosis of retinoblastoma by indirect ophthalmoscopy. When the fundus view is obscured by hemorrhage, ultrasonography and computed tomography are mandatory. Calcification is characteristic of retinoblastoma and is not frequently seen in the other entities considered in the differential diagnosis, such as Coat's disease, toxoplasmosis, toxocariasis, pars planitis, and persistent hyperplastic primary vitreous.

The diagnosis of retinoblastoma as a masquerade syndrome, however, is complicated by the fact that fewer than 10% of all retinoblastoma cases present as inflammation. 52 In one study, retinoblastoma manifesting as a form of primary ocular inflammation accounted for almost half of all cases of misdiagnosed retinoblastoma. 52 Furthermore, when retinoblastoma presented as an inflammatory disease, 50% of cases simulated orbital cellulitis. Other inflammatory presentations of retinoblastoma include exophthalmos, eyelid edema, conjunctivitis, hypopyon iritis, and granulomatous uveitis. 45 In practice, if retinoblastoma is suspected, identifying the apparent cellulitis as a masquerader is often straightforward. Children with true orbital cellulitis exhibit fever, leukocytosis, and sinusitis. These findings are absent in retinoblastoma; normal sinuses and the intraocular mass are seen easily with computed tomography. 50,51

In contrast to the relative ease of diagnosing a retinoblastoma mimicking cellulitis, the masquerade can be especially difficult to recognize in the diffuse form of retinoblastoma, which accounts for approximately 1% to 2% of all cases. 47,50 In diffuse retinoblastoma, symptoms may include a mild conjunctivitis with hyperemia and pseudohypopyon. 46,47 Funduscopic examination will reveal a diffuse gray-white opacification and retinal thickening with vitreous seeds (Fig 3). Computed tomography and magnetic resonance imaging are less helpful in this diffuse form, given the absence of a well-defined mass and a lower incidence of calcification. 47 Because of the lower likelihood of calcification, ultrasonography often is also not diagnostic in these cases. 46 Iatrogenic extraocular spread can produce fatality in this disease. Therefore, all intraocular diagnostic procedures are contraindicated.

Figure 3.

Figure 3.

When, if necessary, a therapeutic enucleation is performed, the clinical diagnosis can be confirmed histopathologically. Most tumors are composed of undifferentiated cells with hyperchromatic nuclei and scant cytoplasm. The mitotic rate is high, and the tumors often outgrow their blood supply, leading to necrosis beyond 90 to 110 μm from nutrient vessels. 53 Focal signs of retinal differentiation, such as rosettes and fleurettes, are common but have little prognostic importance. The most important pathological finding for prognosis is the depth and extent of tumor invasion at the optic nerve, which correlates strongly with survival. 54

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Ocular Melanoma

Melanoma, while typically well recognized, is nevertheless important because of its potential for mortality. Diagnostic delay because of failure to recognize a masquerading presentation may transform a small tumor with a relatively good prognosis into a tumor with extraocular extension and a dismal prognosis. Ocular melanomas include lesions of the uvea, conjunctivae, and eyelid. More than 85% of all ocular melanomas are uveal, 55 and these are the tumors that most frequently masquerade as inflammation.

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Epidemiological Features

Malignant melanoma of the uveal tract is the most common primary intraocular tumor in adults. In the United States and Western Europe, the estimated incidence is 5 to 7 per million persons, which translates to approximately 1,200 to 1,500 new cases in the United States each year. 21 This is in contrast to the much higher incidence of cutaneous melanoma, which affects 32,000 new patients each year. 55

Uveal melanoma occurs most commonly among middle-aged and older whites. 55 It rarely presents in darker-pigmented patients or in patients younger than 20 years. 56,57 There is a slight increase in incidence with increased sun exposure. 58 Other risk factors include the presence of ocular or oculodermal melanosis in white patients. 59 Interestingly, although increased numbers of uveal nevi are noted in patients with dysplastic nevus syndromes, there is no apparent increase in the incidence of uveal melanoma in this population. 21

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Clinical Features

Melanoma can present anywhere along the uveal tract. The choroid, however, is the most frequent location, representing 80% of cases. Between 10% and 15% present in the ciliary body, and the remaining 5% to 8% involve the iris. 21

Nearly one-third of all uveal melanoma cases present asymptomatically. 21 Those patients who have symptoms may report flashing lights or scotomas. 55 If the macula is affected, the patient may describe metamorphopsia, an increase in hyperopia, or a decrease in myopia. When masquerading as ocular inflammation, uveal melanoma may present as unilateral uveitis. Iris lesions may produce anterior chamber cell and flare. Ciliary body melanomas may produce dilated episcleral vessels, classically termed sentinel vessels. These patients may present for evaluation of a red eye and receive a misdiagnosis of episcleritis or scleritis. 60 Posterior melanomas are less often mistaken for ocular inflammation but can produce a focal choroidal mass that resembles a sarcoid or tuberculous granuloma or posterior scleritis. The presence of associated exudative retinal detachment may further complicate clinical evaluation.

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Diagnosis

The diagnostic accuracy of an experienced examiner is excellent for typical uveal melanomas, and this accuracy has been improving. The Collaborative Ocular Melanoma Study reported a misdiagnosis rate of less than 1% in 1990. 61 Few findings are absolutely pathognomonic, the closest being the development of a collar-button or mushroom-shaped configuration because of tumor rupture through Bruch's membrane. Other features suggestive of melanoma include associated subretinal fluid and the presence of orange pigmentation, visualized because of the contrast between lipofuscin and melanin. 21

In atypical, masquerading cases, the diagnosis is more difficult. The diagnostic accuracy of fluorescein has been estimated at less than 50%, but the presence of punctate hot spots, intrinsic vasculature, or blockage by overlying orange pigment may assist in making a diagnosis. 21,62 Ultrasonography is most useful in thicker lesions where the characteristic findings include vascular pulsations, an intratumoral acoustic quiet zone, medium to low internal reflectivity, choroidal excavation, and orbital shadowing. Magnetic resonance imaging has been employed but is generally less cost-effective and, in most cases, does not offer more information than does ultrasonography. In smaller lesions, the diagnosis may be made only on close follow-up, during which evidence of growth, the development of substantial subretinal fluid, or associated symptoms suggest a progressive malignant process. An intraocular malignancy should always be considered in the differential diagnosis of any patient with unilateral cataract or opaque media. Ultrasonography should be performed to exclude this possibility.

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Ocular Metastases

Metastatic cancer is likely the most common intraocular malignancy. In practice, however, many patients with metastatic ocular lesions are systemically ill with advanced disease and do not come to ophthalmic attention. 63 Nevertheless, in some series, almost half of all ocular metastases are recognized before the primary malignant process is known. 64

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Epidemiological Features

Carcinomas predominate as the primary lesions that produce ocular metastases. Breast cancer in women and lung cancer in men are the most frequent, other common primary sites being the kidney and gastrointestinal and genitourinary tracts. 64–66 Although breast cancer commonly metastasizes to the eye, the primary tumor has been treated in 90% of cases by the time the ocular lesion is first noted. 21 This is in contrast to ocular metastases from renal and pulmonary malignancies, in which ocular metastases are the first presentation of disease in 80% of cases. 21

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Clinical Features

Ocular metastases are hematogenously disseminated and most commonly affect the uveal tract. These lesions present in the choroid in 90% of patients, manifesting bilaterally or multifocally in more than 25%. 66 Choroidal metastases are generally creamy yellow subretinal masses that produce a secondary retinal detachment. With regard to masquerade syndromes, the 10% of metastases that involve the iris or ciliary body produce greater diagnostic difficulty. Iris lesions present as one or more yellow, white, or pink stromal nodules (Fig 4). Aside from visible iris masses, patients may report blurred vision, pain, redness, and photophobia. These tumors can be friable and seed to the aqueous, causing an anterior chamber inflammatory reaction. 65 Ciliary body tumors, which typically present as yellow sessile or dome-shaped masses, may induce iridocyclitis and spontaneous hyphema. 67

Figure 4.

Figure 4.

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Diagnosis

The maneuver most critical to making the correct diagnosis is obtaining a careful medical history. Ocular metastases have been known to occur years after the removal of the primary tumor, especially with carcinoids and renal cell cancers. Beyond a thorough history, complete examination with slit-lamp biomicroscopy and indirect ophthalmoscopy will suggest the correct diagnosis (in most cases) if the examiner has an appropriate index of suspicion.

Identification of the primary tumor demands consultation with medical oncologists. Few clues from the ophthalmic examination are of much diagnostic assistance in the search, except in the rare event of a skin melanoma metastatic to the eye, in which brown pigment may be visible. Of the patients with no known primary cancer at the time of ophthalmic presentation, the site of origin will never be identified in one-half. 66

Ultrasound examination is a useful diagnostic aid that can help to distinguish a choroidal metastatic lesion from an amelanotic melanoma. Metastatic lesions characteristically exhibit a solid profile with medium to high internal reflectivity and a negative angle kappa. In contrast to melanoma, such lesions do not demonstrate an acoustic quiet zone, choroidal excavation, or orbital shadowing. In difficult cases, fine-needle aspiration biopsy is useful in making the diagnosis. 65,68

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Conclusion

Sebacous cell carcinoma, intraocular lymphoma, periocular lymphoma, retinoblastoma, uveal melanoma, and ocular metastases are by no means the only malignancies that masquerade as ocular inflammation. In the adult population, additional malignant diagnoses to consider when faced with idiopathic uveitis include paraneoplastic syndromes, such as bilateral diffuse uveal melanocytic proliferation and cancer-associated retinopathy. In addition to retinoblastoma, children may present with idiopathic uveitis when leukemia, medulloepithelioma, and juvenile xanthogranuloma masquerade. A host of nonmalignant etiologies ranging from foreign bodies to drug reaction may also present as ocular inflammation. Masquerade syndromes represent the uncommon presentation of rare disease. In practice, true masquerades will be encountered infrequently. Nevertheless, knowledge of the key clinical and diagnostic features of the masquerade syndromes presented in this brief review, when coupled with a disciplined approach to forming a differential diagnosis, will lead to earlier recognition when a true masquerade is present, with potentially life-saving benefit to the patient.

This work was supported by the Giannini Foundation, the Knights Templar Eye Foundation, Inc., and That Man May See, Inc.

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