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Chapter 184 – Masquerade Syndromes: Neoplasms

Chapter 184 – Masquerade Syndromes: Neoplasms

 

RUSSELL W. READ

 

 

 

 

 

DEFINITION

• Simulation of an inflammatory condition by a neoplastic process

 

KEY FEATURES

• Usually bilateral, may have asymmetrical involvement

• Cells in aqueous or vitreous humor or both

• Older age or known history of malignancy elsewhere

 

ASSOCIATED FEATURES

• May respond initially to corticosteroids, but eventually becomes “corticosteroid resistant”

• Usually a lack of inflammatory features such as pain, keratic precipitates and synechiae, but this is not a universal feature

• With primary central nervous system lymphoma: neural retinal infiltration, subretinal pigment epithelial lesions, central nervous system involvement, typically over 50 years of age

 

 

 

INTRODUCTION

A wide variety of entities can produce cells in the intraocular compartments, resulting in what appears to be uveitis. In a review of 828 consecutive patients from a uveitis clinic, Rothova et al.[1] diagnosed a neoplastic masquerade syndrome in 19 patients (2.3%), 13 of whom (68%) had intraocular lymphoma, making it the most common neoplastic masquerader. This text will therefore concentrate on this entity, with other neoplasms that could be considered masquerade syndromes detailed in Table 184-1 .

PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA

INTRODUCTION

Primary central nervous system lymphoma (PCNSL) is usually extranodal, non-Hodgkin’s B cell lymphoma involving the central nervous system (CNS) or eye or both. T cell varieties have been reported, but only account for approximately 2% of intraocular lymphomas. Ocular involvement by PCNSL may affect the vitreous humor, retina, subretinal, or subretinal pigment epithelial spaces. Because the ocular and the CNS components show identical cytologic features and phenotypic expression, these two entities are combined under the heading PCNSL. Some clinicians still refer to this entity as reticulum cell sarcoma, an old term used when understanding of this condition was incomplete.

EPIDEMIOLOGY PATHOGENESIS

PCNSL most commonly affects individuals in the sixth to seventh decades of life, although rarely it may affect children and adolescents. PCNSL is a rare condition, but its incidence is increasing, and the increase does not appear to be solely secondary to the acquired immunodeficiency syndrome (AIDS). It was estimated that PCNSL would occur in 51 of 10 million immunocompetent individuals in 2000.[2]

The site of origin of PCNSL is unknown. Neither the CNS nor intraocular space is known to contain lymphatic tissue. Lymphoma cells might arise in a site external to the CNS or eye, yet they are able to grow only in these two immunologically sequestered locations.[3] Another theory supposes the development of a polyclonal inflammation in which a monoclonal proliferation subsequently develops.[4]

OCULAR MANIFESTATIONS

Patients may seek treatment for either CNS or ocular complaints, or both. Ocular disease has been reported in up to 25% of PCNSL cases affecting the brain or spinal cord.[5] When ocular findings occur first, decreased acuity and floaters are typically present, and the finding of a vitreous cellular infiltration may be the only evidence of disease. In this situation the diagnosis may be missed and an autoimmune or infectious cause presumed. Therapy with corticosteroids or other immunosuppressive agents may result in a decrease in the number of cells, but this response typically does not last, and the “uveitis” becomes resistant to therapy. When the retina is involved, the diagnosis may be more apparent, but it still may be difficult to establish definitively in the absence of CNS findings. The lesions typically are elevated creamy yellow subretinal infiltrates, with overlying retinal pigment epithelial detachments ( Fig. 184-1 , A) and vitreous cells. Keratic precipitates and synechiae may be absent. Findings are usually bilateral but may be asymmetrical.

DIAGNOSIS AND ANCILLARY TESTING

Diagnosis in immunocompetent patients is established by fluid or tissue specimens from the eye (vitreous humor and, rarely, chorioretinal biopsy) or CNS (lumbar puncture or brain biopsy), but ancillary testing can be helpful in supporting the clinical diagnosis.

Ultrasonography may reveal vitreous debris, choroidal-scleral thickening, widening of the optic nerve, elevated chorioretinal lesions, and retinal detachment.[6] Fluorescein angiography may reveal punctate hyperfluorescent window defects, round hypofluorescent lesions, “vasculitis,” papilledema, and cystoid macular edema, indicating a disturbance of the retinal pigment epithelium[7] ( Figs. 184-1 , B, C). Computed axial tomography (CAT) scans typically show multiple, diffuse, periventricular lesions with high-density tumor before contrast injection. After contrast injection, dense periventricular enhancement appears and may involve the corpus callosum. Magnetic resonance imaging (MRI) shows isointense lesions on T1, and isointense to hyperintense lesions on T2. Periventricular contrast enhancement is strong. Positron emission tomography and single-photon emission computed tomography (SPECT) may show alterations in brain metabolism, perfusion, and blood–brain barrier permeability. Cerebrospinal fluid (CSF) analysis may allow the diagnosis of

 

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TABLE 184-1 — MALIGNANT CONDITIONS THAT MAY PRODUCE MASQUERADE SYNDROMES

Condition

Epidemiology

Ocular Manifestations

Systemic Associations

Comments

PCNSL in IC

98% B cell, 6th–7th decades of life

Vitreitis, creamy yellow retinal, subretinal, sub-RPE infiltrates, cranial nerve palsies

Behavioral changes, hemiparesis, ataxia

Methotrexate-containing regimens have most success to date

PCNSL in AIDS

12% risk

Similar to IC patients

Diffuse cerebral disease, CD4 typically <100

Positive SPECT and EBV PCR of CSF is diagnostic

SYSTEMIC LYMPHOMA/LEUKEMIA

B cell lymphoma

Rare intraocular involvement, older adults

Vitreitis, retinal vasculitis, necrotizing retinitis, diffuse choroiditis, focal uveal masses, AU, hypopyon

Lymphadenopathy, involvement of retroperitoneum, paranasal sinuses, orbits, meninges, bone marrow

Usually have a known history of systemic lymphoma, but ocular involvement may be initial sign, average longevity of 31 months following ocular diagnosis

T cell lymphoma

2% of intraocular lymphomas

AU, iris thickening, hypopyon, vitreitis, chorioretinitis

May have widespread systemic disease by time of ocular involvement

Ocular involvement usually anterior

Mycosis fungoides

Rare intraocular involvement

AU, vitreitis, KP, papilledema

Typical cutaneous lesions of MF

Reported cases typically had a known history of MF

HTLV-1 lymphoma

Retrovirus endemic in southwest Japan, Caribbean islands, parts of central Africa

Retinal vasculitis, CWS, AU, vitreitis, subretinal infiltrates, retinal hemorrhages, iris nodules, CME

Adult T cell leukemia or lymphoma

 

Ki-1 lymphoma

Single case report, 22-month-old male

Hyphema, fibrin in AC

Fever, adenopathy, hepatosplenomegaly

 

Hodgkin’s disease

Rare intraocular involvement

AU, PU, retinal lesions, CR scarring, optic disc swelling, periphlebitis, chorioretinitis, vitreitis

Lymphadenopathy, fever, nausea, abdominal pain

Reed-Sternberg cells found in AC in one reported case

Richter’s syndrome

Rare intraocular involvement

AU, KP, vitreitis, yellow submacular lesion

Diffuse large cell lymphoma in patients with preexisting chronic lymphocytic leukemia

 

Leukemia

Ocular findings in 28–75% with acute leukemia, less with chronic

Intraretinal hemorrhages, CWS, Roth spots, MA, peripheral NV, vitreitis, exudative RD, AU, hypopyon

Markedly high white blood cell count and other features of leukemia

 

Primary intravascular lymphoma

Older adults

Vitreitis, iridocyclitis, KP, retinal artery occlusion

Tender erythematous nodules on trunk and extremities, CNS disturbances

Commonly fatal within 1 year of diagnosis

Uveal lymphoid proliferations

30–81 years

Multifocal creamy choroidal lesions, AU, KP, hypopyon, serous RD, diffuse choroidal thickening, ocular HTN, epibulbar mass

May be associated with systemic lymphoma

Range from benign to malignant, episcleral biopsy may not be representative[24]

Posttransplantation lymphoproliferative disorder

3% of patients on immunosuppressive agents for liver tx, four cases reported with intraocular involvement

Iris nodules (¾ patients), chorioretinitis (¼)

Most common in GI and CNS

Ranges from benign to aggressive multi-system malignancy;presumed EBV-stimulated B cell proliferation

Uveal melanoma

4.9% of 450 enucleation specimens had ocular inflammation initially[25]

Episcleritis, AU, PU, endophthalmitis, panophthalmitis

May have features of metastatic melanoma

Usually necrotic, diffuse, or plaque-like melanomas

Retinoblastoma

Inflammatory appearance in 1–3%, around 6 years old

Lack of calcification, unilateral, nonfamilial, AU, vitreitis, shifting white hypopyon, diffuse involvement

Typically none

 

Juvenile xantho-granuloma

85% of skin lesions present before 1 year of age

Yellowish iris nodule or diffuse thickening, heterochromia, spontaneous hyphema

Raised, reddish-yellowish skin lesions

If eyelid involved, globe usually spared

Metastatic tumors

Most common intraocular malignancy in adults

Usually bilateral, multifocal, plateau-shaped, yellow posterior segment lesions with SRF;anterior segment: AU, iris nodules, NVI

Lung and breast carcinoma most common primary sites

Cutaneous melanoma most common metastasis to retina

PARANEOPLASTIC SYNDROMES

 

 

 

Carcinoma-associated retinopathy/melanoma-associated retinopathy

 

Rapid vision loss, nyctalopia, color vision loss, vitreitis, abnormal ERG, attenuated retinal arterioles

Serum antiretinal antibodies, primary malignancy

 

Bilateral diffuse uveal melanocytic proliferation

 

Rapid vision loss, cataract, multiple pigmentedand nonpigmented placoid iris and choroidalnodules, serous RD

Primary nonocular malignancy

 

AC, Anterior chamber; AIDS, acquired immunodeficiency syndrome; AU, anterior uveitis; CME, cystoid macular edema; CNS, central nervous system; CR, chorioretinal; CSF, cerebrospinal fluid; CWS, cotton-wool spots; EBV, Epstein–Barr virus; ERG, electroretinogram; GI, gastrointestinal; HTLV, human T cell lymphoma virus; HTN, hypertension; IC, immunocompetent; KP, keratic precipitates; MA, microaneurysm; MF, mycosis fungoides; NV, neovascularization; NVI, neovascularization of the iris; PCNSL, primary central nervous system lymphoma; PCR, polymerase chain reaction; PU, posterior uveitis; RD, retinal detachment; RPE, retinal pigment epithelium; SPECT, single-photon emission computed tomography; SRF, subretinal fluid; tx, transplant.

 

 

 

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Figure 184-1 A, Left fundus of patient with primary central nervous system lymphoma involving vitreous and subretinal space. Note cloudiness of view due to vitreous cell, peripapillary involvement (arrowheads), and separate lesion inferotemporal to optic nerve (arrow). B, Fluorescein angiogram of left eye during laminar flow phase, revealing early hypofluorescence of lesions noted in A. C, Fluorescein angiogram of same eye after 6 minutes, revealing intense staining of infiltrates.

 

 

 

Vitreous Humor Sample Processing Options

• Filtration through membrane (Millipore) filters, using negative pressure followed by fixation in 95% alcohol and staining of the filter

• Initial fixation in an equal volume of 95% alcohol followed by

• Centrifugation

• Concentration of cells onto glass slides, air drying, followed by staining

• Paraffin embedding of resultant cellular pellet

• Celloidin bag technique: centrifugation of specimen in a celloidin-coated tube, followed by processing of the celloidin “bag,” paraffin embedding, and sectioning

 

 

 

PCNSL to be made without the need for vitreous humor biopsy, but multiple samples may be needed.

The diagnosis of intraocular PCNSL may be made by cytological examination of a vitreous specimen. Vitrectomy itself does not result in cellular degradation.[8] To ensure that appropriate special staining and studies are performed, the specimen should be examined by an experienced ophthalmic pathologist and the surgeon must communicate directly with the pathologist before surgery to plan such studies. At the beginning of surgery, a 1?ml undiluted vitreous humor sample should be manually aspirated into a syringe before the infusion is started. This sample should be processed rapidly to preserve cellular morphology. Retinal, subretinal, or sub-retinal pigment epithelium (RPE) material biopsy may be required if there is high clinical suspicion but repeatedly negative vitreous biopsy results. Processing options for the vitreous humor sample are detailed in Box 184-1 .

One diagnostic algorithm for the evaluation of suspected PCNSL begins with cerebral MRI and lumbar puncture. If a definitive diagnosis is not made by the demonstration of malignant cells in the CSF, then a vitreous humor biopsy is performed. If these techniques fail to yield the diagnosis, repeat vitrectomy, with or without chorioretinal biopsy, is considered. If MRI revealed the presence of brain lesions and the vitreous humor biopsy result is unrevealing yet suspicion remains high, then stereotactic brain biopsy is considered.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of PCNSL includes all forms of ocular inflammatory disease that produce cells within the eye, including true uveitis and scleritis. Especially difficult to differentiate are those with concurrent retinal lesions, such as toxoplasmosis and acute retinal necrosis, although these two entities tend to have characteristic features described elsewhere in this text. Other neoplastic conditions which may masquerade as uveitis are covered in Table 184-1 .

SYSTEMIC ASSOCIATIONS

The finding of intraocular PCNSL mandates a systemic evaluation, because it is the CNS involvement which results in the high mortality rate produced by this condition. When CNS involvement is present, patients may exhibit both general and focal signs and symptoms. The most frequent symptom reported at time of admission is behavioral changes. Focal neurological signs include hemiparesis, cerebellar signs (including ataxia), and cranial nerve palsies.[9] The mnemonic “GUN” syndrome has been proposed to emphasize the frequent occurrence of glaucoma, uveitis, and neurological symptoms in PCNSL.[10]

PATHOLOGY

With increased awareness and better diagnosis based on vitrectomy specimens, enucleation for PCNSL is not common. When enucleation is performed, gross examination reveals vitreous humor

 

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Figure 184-2 Gross photograph of enucleated globe with primary central nervous system lymphoma, revealing retinal thickening, hemorrhage, and subretinal pigment epithelial involvement.

opacification, retinal thickening, and subretinal elevations ( Fig. 184-2 ). Microscopic examination may reveal compartmentalization of malignant B cells from reactive T cells, with the former found in the retina, the latter in the choroid. This is in contrast to pathological findings in ocular involvement in systemic lymphoma, when the malignant infiltrate is within the uvea. Vitreous humor specimens typically produce much less cellular material, with an admixture of neoplastic and reactive lymphocytes. The neoplastic B lymphocytes are pleomorphic cells with hyperchromatic nuclei and an elevated nuclear-to-cytoplasm ratio. Nuclear membranes may show finger-like projections or folds and an irregular contour. Multiple nucleoli may be seen, and nuclear chromatin is coarse ( Figs. 184-3 and 184-4 ). Also typical is the presence of necrotic cellular debris in the background (see Fig. 184-3 ).

False-negative reports may occur from improper or delayed fixation of the sample, which either damages or alters the staining properties of the neoplastic cells. Other factors that may lead to diagnostic pitfalls include the distribution of variable proportions of neoplastic and inflammatory cells in the vitreous humor. This variable distribution may mask the true pathology. Neoplastic cells may be concentrated in the subretinal and sub-RPE spaces, with the vitreous containing only inflammatory cells. In several reported cases, repeated vitrectomies showed negative cytology findings, and only a later vitrectomy or chorioretinal biopsy of subretinal lesions provided the diagnosis.[11] Prior use of systemic corticosteroids may produce false-negative results due to corticosteroid-induced cell loss.

Molecular pathology with immunophenotypic and genetic tests may be helpful in determining clonality. Although clonal expansion is part of a normal immune response, benign lymphoid lesions generally should not contain one dominant clone. Demonstration of an abnormal ? or ? light chain predominance helps to establish B lymphocyte clonality. Some B cell lymphomas may not express detectable surface immunoglobulins, a finding which itself is correlated with malignancy. Immunophenotyping can be carried out by immunohistochemistry or flow cytometry. Both use antibodies directed against specific cellular markers. Immunohistochemistry uses tissue sections on a microscope slide, while flow cytometry uses fresh cells labeled with fluorescent antibodies which are passed through a computerized cell counter. Gene rearrangement studies may enable determination of the clonality and lineage of lymphoid lesions as well.

 

 

Figure 184-3 Photomicrograph of primary central nervous system lymphoma, revealing large neoplastic cells with necrosis.

 

 

Figure 184-4 Vitreous cytology in primary central nervous system lymphoma, showing large neoplastic cells.

An increased ratio of vitreous interleukin-10 to interleukin-6 has been proposed as suggestive of lymphoma,[12] but the diagnostic usefulness of this ratio remains to be verified.[13]

TREATMENT

The evaluation and treatment of PCNSL is best accomplished by practitioners at large centers with extensive experience, because of the condition’s relative rarity and the need for coordination with a neuro-oncologist familiar with its treatment. Median survival with supportive care alone is 1.9–3.3 months. [14]

Surgery

PCNSL involvement in the CNS is multifocal, diffuse, and infiltrative in nature, therefore neurosurgical extirpation is not feasible and is indicated only to establish the diagnosis. Median survival following surgery alone ranges from 1–4.6 months.[14] Likewise vitrectomy surgery is indicated only to establish the diagnosis.

Medical Treatment

Isolated radiotherapy for PCNSL achieves a high rate of successful initial control of disease. However, in contrast to the long-term good results in non-Hodgkins lymphomas outside the CNS, radiotherapy produces short survival times when used in PCNSL[15] and is no longer standard as an isolated treatment in immunocompetent patients. For patients with CNS lymphoma

 

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who have advanced AIDS, radiotherapy remains a central therapeutic modality.

Multiple chemotherapeutic agents and regimens have been used in PCNSL, including chemotherapy alone and in combination with radiotherapy. Those chemotherapy protocols effective in systemic lymphoma have been found ineffective in PCNSL. Corticosteroids typically provide a dramatic clinical improvement, in part due to their lympholytic action. Regardless of their benefits, corticosteroids should be withheld until the diagnosis is established, due to the adverse impact they have on the establishment of the diagnosis through biopsy. Regimens containing methotrexate have been found to be the most effective. Two routes of methotrexate administration have shown the most promise, one using combination high-dose intravenous plus intrathecal methotrexate with subsequent cytarabine and radiotherapy,[16] and another using mannitol-induced blood–brain barrier disruption followed by intraarterial methotrexate and intravenous cyclophosphamide, with radiotherapy variably used.[17] No studies have been published comparing these regimens directly. Each has advantages and disadvantages relating to toxicity and protocol difficulty, while achieving similar long-term patient survivals. Chemotherapy alone may be preferable as the initial treatment in patients 60 years and older.[18]

Whether patients with isolated ocular disease are treated adequately with local therapy alone (such as intravitreal methotrexate or ocular irradiation) is unknown, but some advocate prophylactic CNS treatment even with apparently isolated ocular disease.[19]

Following initially successful treatment, a recurrence of ocular cells requires reevaluation to determine if CNS disease is recurrent as well. If so, therapy is directed at the entire CNS again. If CNS disease is absent, then intravitreal methotrexate can be considered.[20] [21]

COURSE AND OUTCOME

The long-term prognosis for patients with PCNSL remains poor, with the longest median disease-free survivals reported to date of approximately 40 months.[22] [23] Multiple factors have been found to be of significance in predicting outcomes and survival in patients with PCNSL, including age, performance status, neurological function, single versus multiple lesions, and superficial cerebral and cerebellar hemisphere lesions versus deep nuclei and periventricular region lesions.

OTHER SYSTEMIC CONDITIONS PRODUCING MASQUERADE SYNDROMES

Multiple other neoplastic conditions may result in confusion with an ocular inflammatory disease. These are detailed in Table 184-1 .

 

 

REFERENCES

 

1. Rothova A, Ooijman F, Kerkhoff F, et al. Uveitis masquerade syndromes. Ophthalmology. 2001;108:386–99.

 

2. Corn BW, Marcus SM, Topham A, et al. Will primary central nervous system lymphoma be the most frequent brain tumor diagnosed in the year 2000? Cancer. 1997;79:2409–13.

 

3. Paulus W. Classification, pathogenesis and molecular pathology of primary CNS lymphomas. J Neurooncol. 1999;43:203–8.

 

4. Alderson L, Fetell MR, Sisti M, et al. Sentinel lesions of primary CNS lymphoma. J Neurol Neurosurg Psychiatry. 1996;60:102–5.

 

5. Hochberg FH, Miller DC. Primary central nervous system lymphoma. J Neurosurg. 1988;68:835–53.

 

6. Ursea R, Heinemann MH, Silverman RH, et al. Ophthalmic, ultrasonographic findings in primary central nervous system lymphoma with ocular involvement. Retina. 1997;17:118–23.

 

7. Cassoux N, Merle-Beral H, Leblond V, et al. Ocular and central nervous system lymphoma: clinical features and diagnosis. Ocul Immunol Inflamm. 2000;8:243–50.

 

8. Conlon MR, Craig I, Harris JF, et al. Effect of vitrectomy and cytopreparatory techniques on cell survival and preservation. Can J Ophthalmol. 1992;27:168–71.

 

9. Herrlinger U, Schabet M, Clemens M, et al. Clinical presentation and therapeutic outcome in 26 patients with primary CNS lymphoma. Acta Neurol Scand. 1998;97:257–64.

 

10. Kim EW, Zakov ZN, Albert DM, et al. Intraocular reticulum cell sarcoma: a case report and literature review. Graefes Arch Klin Exp Ophthalmol. 1979; 209:167–78.

 

11. Akpek EK, Ahmed I, Hochberg FH, et al. Intraocular-central nervous system lymphoma: clinical features, diagnosis, and outcomes. Ophthalmology. 1999; 106:1805–10.

 

12. Whitcup SM, Stark-Vancs V, Wittes RE, et al. Association of interleukin 10 in the vitreous and cerebrospinal fluid and primary central nervous system lymphoma. Arch Ophthalmol. 1997;115:1157–60.

 

13. Akpek EK, Maca SM, Christen WG, Foster CS. Elevated vitreous interleukin-10 level is not diagnostic of intraocular-central nervous system lymphoma. Ophthalmology. 1999;106:2291–5.

 

14. Jellinger K, Radaskiewicz TH, Slowik F. Primary malignant lymphomas of the central nervous system in man. Acta Neuropathol Suppl (Berl). 1975;(Suppl):95–102.

 

15. Nelson DF. Radiotherapy in the treatment of primary central nervous system lymphoma (PCNSL). J Neurooncol. 1999;43:241–7.

 

16. Nasir S, DeAngelis LM. Update on the management of primary CNS lymphoma. Oncology (Huntingt). 2000;14:228-34; 237–42; 244.

 

17. Neuwelt EA, Goldman DL, Dahlborg SA, et al. Primary CNS lymphoma treated with osmotic blood-brain barrier disruption: prolonged survival and preservation of cognitive function. J Clin Oncol. 1991;9:1580–90.

 

18. Freilich RJ, Delattre JY, Monjour A, DeAngelis LM. Chemotherapy without radiation therapy as initial treatment for primary CNS lymphoma in older patients. Neurology. 1996;46:435–9.

 

19. Read RW, Zamir E, Rao NA. Neoplastic masquerade syndromes. Surv Ophthalmol. 2002;2:81–124.

 

20. de Smet MD, Vancs VS, Kohler D, et al. Intravitreal chemotherapy for the treatment of recurrent intraocular lymphoma. Br J Ophthalmol. 1999;83:448–51.

 

21. Fishburne BC, Wilson DJ, Rosenbaum JT, Neuwelt EA. Intravitreal methotrexate as an adjunctive treatment of intraocular lymphoma. Arch Ophthalmol. 1997;115:1152–6.

 

22. Abrey LE, DeAngelis LM, Yahalom J. Long-term survival in primary CNS lymphoma. J Clin Oncol. 1998;16:859–63.

 

23. McAllister LD, Doolittle ND, Guastadisegni PE, et al. Cognitive outcomes and long-term follow-up results after enhanced chemotherapy delivery for primary central nervous system lymphoma. Neurosurgery. 2000;46:51–61.

 

24. Cockerham GC, Hidayat AA, Bijwaard KE, Sheng ZM. Re-evaluation of “reactive lymphoid hyperplasia of the uvea”: an immunohistochemical and molecular analysis of 10 cases. Ophthalmology. 2000;107:151–8.

 

25. Fraser DJ Jr, Font RL. Ocular inflammation and hemorrhage as initial manifestations of uveal malignant melanoma. Incidence and prognosis. Arch Ophthalmol. 1979;97:1311–4.

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