Chapter 149 – Lymphoma and Leukemia
JAMES J. AUGSBURGER
WILLIAM G. TSIARAS
• Leukocytic malignancies that infiltrate ocular tissues in some affected patients.
• Diffuse, whitish cellular infiltrates that involve retina, vitreous, or optic disc.
• Geographical amelanotic subpigment epithelial infiltrates characteristic of primary intraocular lymphoma.
• Central nervous system involvement.
• Hemorrhagic retinopathy.
• Propensity to develop opportunistic retinitis.
Lymphoma and leukemia are distinct neoplastic disorders that are linked by their common leukocytic basis. Both entities may be associated with various intraocular lesions. Of the two, lymphoma produces intraocular tumors much more commonly. One particularly important subtype of lymphoma that has a strong propensity to produce intraocular tumors is known as primary intraocular lymphoma. Some intraocular lymphomas are metastatic tumors from a solid visceral lymphoma. Tumors of this type exhibit the same general features described in Chapter 148 and are not discussed in this chapter.
PRIMARY INTRAOCULAR LYMPHOMA
Primary intraocular lymphoma is an uncommon but important lymphocytic neoplasia that arises diffusely or multicentrically within the retina or uvea of one or both eyes. Two principal subtypes of primary intraocular lymphoma are currently recognized. Primary vitreoretinal lymphoma is characterized by vitreous cells and geographical subretinal pigment epithelial infiltrative masses. This subtype is regularly associated with independent nonmetastatic foci of primary central nervous system (CNS) lymphoma. Primary uveal lymphoma is characterized by diffuse or multifocal creamy yellow choroidal infiltrates in one or both eyes. This subtype is usually associated with independent foci of visceral non-Hodgkin’s lymphoma. Correct clinical diagnosis of the intraocular disease and awareness of the links with CNS and visceral lymphoma may lead to earlier detection and more effective treatment of this malignancy.
EPIDEMIOLOGY AND PATHOGENESIS
Primary intraocular lymphoma is uncommon, but its precise incidence in the general population is unknown. The principal risk factors for development of primary intraocular lymphoma appear to be older patient age, female gender, and immunosuppression (primary or acquired).
Characteristic clinical manifestations of primary vitreoretinal lymphoma include diffuse cellular infiltration of the vitreous and accumulations of lymphomatous cells in the subpigment epithelial space of the retina ( Fig. 149-1 ).    The subretinal pigment epithelial lesions are yellowish white, geographical infiltrates with clumping of the overlying retinal pigment epithelium. Smaller satellite-type lesions of a similar color and texture often are present adjacent to the principal lesion. Bilateral involvement is present in 80–90% of affected patients. Other less common presenting features of primary vitreoretinal lymphoma include a pattern of chorioretinal spots simulating the multiple evanescent white dot syndrome,  retinal infiltrates with associated intraretinal hemorrhage that resemble cytomegalovirus retinitis,  and retinal artery obstruction. 
The characteristic clinical manifestation of primary uveal lymphoma is a creamy yellow thickening of the choroid diffusely or multifocally ( Fig. 149-2 ).  Few if any vitreous cells are present in this form of primary intraocular lymphoma. Less common features of primary uveal lymphoma include a fundus pattern of orange spots resembling fundus flavimaculatus and disruption and clumping of the retinal pigment epithelium overlying an ill-defined area of uveal thickening.
DIAGNOSIS AND ANCILLARY TESTING
Fluorescein angiography of a typical subretinal pigment epithelial lesion in primary vitreoretinal lymphoma characteristically shows the mass to be hypofluorescent early in the study and hyperfluorescent late. Indocyanine green angiography of such lesions has not yet been reported. Fluorescein angiography of primary uveal lymphoma typically shows an irregular pattern of fluorescence blockage by the orange pigment clumps or disrupted retinal pigment epithelium. Ultrasonography can show diffuse uveal thickening, prominent infiltrative subretinal retinal masses, and intravitreal cells in primary intraocular lymphoma, but these findings are not diagnostic.
Because several non-neoplastic conditions can simulate primary intraocular lymphoma quite closely, biopsy of an appropriate tissue is usually performed to confirm the diagnosis before treatment. If a cellular infiltrate in the vitreous is a prominent aspect of the disorder, the diagnosis can be confirmed by cytological examination of vitreous fluid removed by pars plana vitrectomy.    Occasionally, the vitreous specimen from the initial vitrectomy contains only activated lymphocytes.  If primary intraocular lymphoma is still strongly suspected, a second vitrectomy should be considered. The second vitrectomy specimen may contain lymphoma cells even when none were present in the
Figure 149-1 Primary vitreoretinal lymphoma. Typical geographical subretinal pigment epithelial lesion. This eye had relatively few vitreous cells.
Figure 149-2 Primary uveal lymphoma. Diffuse, creamy uveal infiltration with focal nodular accentuation inferotemporal to macula.
original one. In patients with a subretinal pigment epithelial lesion or infiltrative choroidal or retinal lesion, the diagnosis of lymphoma can be confirmed pathologically by examination of a fine-needle aspirate or incisional chorioretinal biopsy specimen.  An alternative method that may be useful for confirming primary intraocular lymphoma in uncertain cases is determination of the relative concentrations of interleukin-10 and interleukin-6 in the fluid specimen. An interleukin-10–to–interleukin-6 ratio substantially greater than 1.0 is strongly suggestive of lymphoma, while a ratio substantially less than 1.0 is more suggestive of intraocular inflammation.
Several of the more important lesions and disorders in the differential diagnosis of primary intraocular lymphoma are listed in Box 149-1 .
As noted earlier, patients with primary vitreoretinal lymphoma frequently develop independent primary foci of lymphoma within the CNS.    The lymphomatous brain tumors can appear before, concurrent with, or after the development of primary intraocular lymphoma. Unfortunately, these brain lesions frequently prove fatal. In contrast, patients with primary uveal lymphoma are unlikely to have associated primary CNS lymphoma but are highly likely to have or develop visceral non-Hodgkin’s lymphoma in the abdomen or pelvis.  Not surprisingly, some overlap of these subtypes has been reported. 
DIFFERENTIAL DIAGNOSIS OF PRIMARY INTRAOCULAR LYMPHOMA
PRIMARY VITREORETINAL LYMPHOMA
• Chronic idiopathic vitritis
• Vitiliginous choroiditis
• Vitreous amyloidosis
• Metastatic carcinoma
• Pars planitis (intermediate uveitis)
• Leukemic intraocular infiltration
PRIMARY UVEAL LYMPHOMA
• Metastatic carcinoma
• Pneumocystis carinii choroiditis
• Other microbial choroiditis
• Benign reactive lymphoid hyperplasia
• Posterior scleritis
• Harada’s disease
• Syndrome of bilateral diffuse uveal melanocytic proliferation associated with systemic carcinoma
TREATMENT OPTIONS FOR PRIMARY INTRAOCULAR LYMPHOMA
• External beam radiation therapy
• Plaque radiotherapy
• Intravenous chemotherapy
• Intravitreal chemotherapy
The infiltrative subretinal pigment epithelial and retinal lesions of primary vitreoretinal lymphoma are usually composed of malignant lymphoid cells that have the cytological features of diffuse large cell lymphoma.  The cells that infiltrate the vitreous appear in cytological preparations as lymphoid cells that have pleomorphic nuclei and scanty cytoplasm.  These cells occur singly or in small clusters and are frequently associated with many necrotic lymphocytes. Immunocytochemical stains and flow cytometry can be used to identify the cell of origin in most cases. Most of the abnormal lymphoid cells in such cases appear to be B-cell derived.
The tumor cells that infiltrate the uvea in primary uveal lymphoma are more likely to be well-differentiated small lymphoma cells than cells of diffuse large cell lymphoma.  The lymphoid cells in such cases may be either B-cell or T-cell derived.
Treatment of the intraocular lesions of primary intraocular lymphoma generally consists of whole eye irradiation by fractionated external beam radiation therapy ( Box 149-2 ).   The typical target dose of radiation is 30–45?Gy. The fundus lesions usually respond promptly to radiotherapy ( Fig. 149-3 ). If concurrent CNS lymphoma exists, aggressive intravenous and intrathecal chemotherapy   and occasionally whole brain irradiation are usually recommended. Bone marrow transplantation has been used with some success in selected patients.  The role of chemotherapy in primary intraocular lymphoma without evidence of CNS lymphoma or visceral lymphoma is controversial. Intravitreal chemotherapy has been given to a few patients with residual or recurrent vitreoretinal lymphoma after conventional therapy and has reportedly been effective, at least through short-term follow-up.
Figure 149-3 External beam radiation therapy for primary vitreoretinal lymphoma. The same lesion shown in Figure 149-1 underwent complete regression 2 months after radiation therapy.
COURSE AND OUTCOME
Primary intraocular lymphoma has a highly variable clinical course that ranges from an indolent waxing and waning to an aggressive progression that results in a completely blind eye. Patients who develop primary intraocular lymphoma in the context of the acquired immunodeficiency syndrome (AIDS) tend to have an extremely virulent and rapidly progressive form of the disease.
Following chemotherapy or ocular irradiation, subretinal pigment epithelial lesions of primary vitreoretinal lymphoma typically become totally atrophic (see Fig. 149-3 ), and the vitreous infiltration usually clears. Unfortunately, the vitreous cellular infiltration sometimes relapses within a few months after initially effective therapy. Diffuse uveal infiltrates also typically regress completely following chemotherapy, radiation therapy, or a combination of these therapies. Extensive retinal pigment epithelial degeneration and pigment clumping are usually evident at sites of prior uveal infiltration.
Patients with primary intraocular lymphoma must be followed on a regular basis after their treatment to monitor for local ocular relapse or the development of extraophthalmic disease in the CNS or elsewhere. If primary CNS lymphoma develops, the patient’s prognosis for long-term survival is poor.  The survival prognosis of patients with visceral non-Hodgkin’s lymphoma is generally substantially better than that of patients with primary CNS lymphoma ; however, patients with aggressive forms of non-Hodgkin’s lymphoma also have substantially shortened survival.
Intraocular leukemia is an uncommon ophthalmic disorder due to accumulation of circulating leukemic cells in the uvea, neural retina, optic disc, vitreous, or other intraocular tissues and fluids. Although leukemic patients frequently develop hemorrhagic retinopathy and occasionally develop microbial intraocular lesions, true leukemic intraocular lesions occur in only a small proportion of patients who have leukemia. Unfortunately, leukemic intraocular infiltrates are a poor prognostic sign for survival.
EPIDEMIOLOGY AND PATHOGENESIS
The cumulative lifetime incidence of intraocular leukemic infiltration in the general population of the United States, based on published data on the annual incidence of new cases of leukemia
Figure 149-4 Leukemic retinal infiltrate. The patient was a 76-year-old woman who had chronic myelogenous leukemia.
Figure 149-5 Leukemic optic disc infiltration. The patient was a 37-year-old man who had chronic myelogenous leukemia.
and death from leukemia and the percentage of leukemic patients dying of the disease who have intraocular lesions (infiltrative or other) at the time of death, is approximately 1 case per 2000–2500 persons. Because only about one out of every six patients dying of leukemia develops ophthalmic symptoms that necessitate referral to an ophthalmologist, and because only about 10% of all clinically detected intraocular lesions in leukemic patients are infiltrative in nature, one can further estimate that the incidence of clinically important intraocular infiltrative leukemic lesions is 1 per 12,000–13,000 persons.
Infiltrative intraocular lesions can occur in individuals of any age, but peaks of incidence mirror those of leukemia in general. Intraocular leukemic lesions are usually not a presenting feature of the disease but are more likely to occur during leukemic relapse.
The most characteristic clinical intraocular lesion of leukemia is the leukemic retinal infiltrate. The typical lesion of this type is a fuzzy, flat, white retinal patch ( Fig. 149-4 ) that is frequently associated with retinal hemorrhages and overlying intravitreal cells. Leukemic retinal infiltrates can be unifocal or multifocal and can present in one eye or both eyes. Other recognizable intraocular infiltrative lesions of leukemia include cells in the vitreous, sheathing of retinal blood vessels, optic disc infiltration ( Fig. 149-5 ), retinal pigment epithelial detachment, nonrhegmatogenous retinal detachment, localized or diffuse choroidal infiltration, neoplastic pseudohypopyon, and iris infiltration. 
Hemorrhagic retinal lesions are much more common in leukemic patients than are true malignant infiltrates. These
lesions are frequently multifocal and bilateral. They are usually attributable to associated anemia and thrombocytopenia rather than to the leukemia per se. Larger intraretinal hemorrhages sometimes have prominent white centers (Roth’s spots). If the anemia and thrombocytopenia are addressed, the extravasated blood gradually resolves in most patients.
Because patients who have leukemia are commonly immunosuppressed (either because of their malignancy or, more often, because of the effects of chemotherapy), it is sometimes difficult, if not impossible, to tell clinically whether a fundus lesion is truly a leukemic infiltration or a microbial focus caused by an opportunistic organism. In such cases, fine-needle aspiration biopsy or another specimen-generating technique may be of great value in establishing the correct diagnosis.
In patients who have chronic myelogenous leukemia, peripheral retinal capillary obstruction and microaneurysm formation have been observed. In a few patients who have leukemia, neovascularization of the optic disc and retina has been reported.
DIAGNOSIS AND ANCILLARY TESTING
All patients who have suspected leukemic intraocular infiltration should be evaluated thoroughly from a hematological perspective. This evaluation should include a complete blood count with differential, bone marrow aspiration or biopsy, complete systemic staging evaluation, and probably lumbar puncture for cerebrospinal fluid cytology. If monocular or binocular optic disc edema or infiltration is present, computed tomography or magnetic resonance imaging of the orbits and brain is indicated (see Systemic Associations below). If uncertainty still exists about the ocular diagnosis, and if vitreous cells and retinal infiltrates are prominent features of the clinical presentation, one should consider pars plana vitrectomy or fine-needle aspiration biopsy to confirm the diagnosis. Biopsy is most appropriate if the patient has no clinical evidence of leukemic relapse elsewhere and is believed to be in clinical remission.
The principal lesions in the differential diagnosis of intraocular leukemia are listed in Box 149-3 .
Concurrent CNS leukemia is common in patients who develop an intraocular leukemic infiltrate. This relationship is particularly strong in patients who have infiltrative lesions of the optic disc. Consequently, CNS imaging and lumbar puncture are especially indicated in any patient suspected of having leukemic relapse in the eye.
DIFFERENTIAL DIAGNOSIS OF INTRAOCULAR LEUKEMIA
Microbial infiltrate (e.g., Candida, Nocardia, Cryptococcus)
Nonmicrobial intraocular inflammation (e.g., sarcoid granuloma, pars planitis)
Primary vitreoretinal lymphoma
TREATMENT OPTIONS FOR INTRAOCULAR LEUKEMIA
Chemotherapy (regimen appropriate to specific type of leukemia)
Radiotherapy (fractionated low-dose external beam radiation therapy)
Pathologically, the infiltrated uvea, optic disc, retina, and overlying vitreous contain leukemic cells in various quantities. In reported autopsy series, choroidal infiltration is much more frequent than infiltration of any other intraocular tissue. Leukemic cells are also commonly observed in the lumina of choroidal and retinal blood vessels.
Infiltrative intraocular leukemia is generally treated by a combination of systemic chemotherapy appropriate to the particular type of leukemia and external beam radiation therapy to the involved eye or eyes ( Box 149-4 ).  The dose of radiation required is usually much less than that recommended for intraocular lymphoma and may be as low as 12–20?Gy.
COURSE AND OUTCOME
Untreated leukemic infiltrates usually progress relentlessly and ultimately cause profound visual loss in the affected eye or eyes. Fortunately, most retinal lesions respond promptly and completely to low-dose external beam radiation therapy, appropriate chemotherapy, or both. Massive optic disc infiltration that causes visual loss also commonly responds to this treatment, but the vision in such eyes often does not improve. Unfortunately, the survival prognosis of leukemic patients who develop intraocular infiltrative tumors is extremely poor. The median survival time after detection of infiltrative intraocular lesions in most series is 3–5 months.
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