Ординатура / Офтальмология / Английские материалы / Primary Intraocular Lymphoma_Chan, Gonzales_2007

54 Primary Intraocular Lymphoma

by the time the diagnosis of PIOL was made. Five other patients eventuated to CNS disease as determined by CSF cytology after PIOL had been diagnosed. One patient refused lumbar puncture for CSF cytology altogether.

When the systemic disease metastasizes to the leptomeninges, cranial nerve, spinal cord, and radicular symptoms can occur.30 Primary lymphoma of the leptomeninges is less common, but would manifest in much the same way as a metastasis from a systemic source.31 Thus, visual and auditory deficits might be present, or facial nerve parasthesias or pain might occur. Compression of the spinal cord or dorsal or ventral roots may manifest as incontinence or limb parasthesias, though primary lymphomatous involvement of the spinal cord is quite rare.32 While immunocompetent patients seem to have focal lesions, AIDS patients can present with multifocal lesions that can be more complex and diffuse neurologic manifestations.27,33 In Bataille’s examination of CNS symptoms manifesting from PCNSL, the most common finding (70% of cases) was a focal neurologic deficit, such as aphasia, ataxia, or a hemiparesis. Psychiatric manifestations, including depression, slowed mentation, and confusion were seen in 43% of the cases upon first presentation. Gastrointestinal symptoms, such as nausea and vomiting, were also common (33% in association with increased intracranial pressure).

Ocular Manifestations, Symptoms, and Complaints. More typically, a patient with PIOL will present with ocular complaints of blurred vision or decreased visual acuity.11–13,16,29,34–42 The patient may note a new onset of metamorphopsias or “floaters.” Photopsias, or “flashes,” seems to be described infrequently in the literature. These complaints almost reflexively bring uveitis to the forefront of an ophthalmologist’s differential diagnosis. Less often, patients complain of discharge and photophobia. Ocular pain or foreign body sensation is also infrequently a complaint of patients with PIOL, but is not unheard of.29,43 Occasionally, periorbital swelling may be a complaint.41.

Iris involvement has been documented in PIOL. While posterior synechiae may be a common finding in uveitis, such iris lesions are not common in PIOL patients. For example, in Matsuo’s case series of 10 consecutive patients with PIOL over a 16-year period, two patients were noted

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to have posterior synechiae.44 In Velez and colleagues’ review of the previous literature accounting for 163 cases of PIOL, only five cases were noted, on clinical examination, to have posterior synechiae.45 Likewise, iris infiltration with lymphomatous cells was a rare occurrence, with five cases exhibiting it. Velez and colleagues reported two patients from the National Eye Institute (NEI) who exhibited infiltration of the iris by PIOL.45 One patient, a 51-year-old Caucasian male, had an eight-year history of decreased vision and floaters bilaterally. Through the years he had been diagnosed as having intermediate uveitis and had bilateral pars plana vitrectomies with scleral buckles. Prior to presentation at the NEI, this patient was noted to have anterior chamber cells in the right eye and cell and flare in the vitreous. Subretinal lesions whitish in color were noted upon funduscopic examination of the right eye. When the patient was examined at the NEI, iris heterochromia of the right eye was noted. The right eye’s iris had lost the varied hues of grey and blue that characterized the left eye. Instead, the right eye appeared more uniformly greyish-white, and there were engorged circumcorneal vessels. Findings on slit lamp examination suggestive of iris involvement in PIOL include a thickened cornea, engorged iridal vessels, and iris nodules.45 Gonioscopy may reveal cellular infiltration as well.45

An ophthalmologist must have a high index of suspicion that a uveitic process may be a hint of a lymphomatous process. Etiological factors involved in the production of uveitis serve to point one’s clinical suspicions toward a possible PIOL diagnosis or at least a diagnosis of “rule out PIOL.”13 Often in medicine, when a disease follows a pattern or clinical script, the ability to tease out a diagnosis from characteristic clinical nuances can help rule in or rule out certain disease processes. Such is the case with PIOL. When a patient who is middle-aged or older arrives at his or her ophthalmologist’s office with complaints of blurred vision and possibly floaters, perhaps two thoughts should spring to the mind of the ophthalmologist: the patient may have a uveitic process occurring, but perhaps a process more sinister, such as PIOL, could potentially, albeit much less frequently, be producing such complaints in the patient. On the basis of a patient’s clinical history, slit lamp and dilated fundus examinations, ultrasonographic and photographic (including fluorescein angiography or indocyanine green) examinations, and lab work, such as serologies for infectious or autoimmune markers (e.g. CBC; VDRL; Toxoplasma, Histoplasma, and

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cat scatch titers; tuberculin skin tests; angiotensin converting enzyme; and HLA-typing), an ophthalmologist can substantiate his or her suspicion about the cause of a patient’s uveitis. In addition, chest X-ray or CT scan may help rule out other causes of uveitis, such as sarcoidosis.46,47 Thus, a patient’s clinical history and physical exam findings will help dictate the tests that should be ordered. If PIOL is suspected, brain MRI and lumbar puncture for CSF examination and cytology should be arranged.

Masquerade Syndrome. When PIOL presents as a “uveitis,” several key features allow an ophthalmologist to pursue the possibility of this diagnosis further.11–13,16,29,34–42 PIOL should be considered when an elderly patient presents with chronic uveitis unresponsive to corticosteroid therapy.

As noted previously, inflammatory infiltrates simulating uveitis can make the diagnosis of PIOL elusive. However, the presence of a dense vitritis and intraretinal or subretinal lesions appearing as creamy, yellow-to- white infiltrates may provide convincing evidence that a more malignant process is occurring. Other retinal lesions that may be noted include retinal hemorrhages,48 birdshot chorioretinopathy,49 and punctate inner choroidopathy.43,50

Ocular Examinations

Slit Lamp Biomicroscopy. The most common findings seen on slit lamp biomicroscopy include anterior chamber cells (simply called “cell”) and protein (known as “flare”). Collections of cells that accumulate on the corneal endothelium, known as keratic precipitates (KP), may also be seen on slit lamp examination.13 Such keratic precipitates may be small or can be larger, forming mutton fat keratic precipitates.51 Anterior chamber inflammation composed of many PIOL cells may be so pronounced as to simulate a hypopyon (termed pseudohypopyon secondary to the collection of tumor cells, not inflammatory cells).37–39 Anterior chamber cells may even collect within the canal of Schlem blocking the flow of aqueous humor and resulting in increased intraocular pressure39 and secondary glaucoma. Velez and colleagues’ extensive review of case reports of PIOL showed that 43% of the total 163 patients exhibited anterior chamber cells.45 Indeed, in the series of nine patients by Char et al., four exhibited minor or no anterior chamber cells,37 and in Siegel and colleagues’ series of 14 patients observed

Clinical Manifestations of PIOL 57

over 10 years, only three exhibited trace to obvious anterior uveitis.42 Thus, when a patient complains of a blurring of visual acuity, the ophthalmologist should pursue a dilated ophthalmoscopic examination to investigate the lack of anterior chamber cell and flare.

Dilated Fundus Examination. Dilated fundus examination often shows a vitritis (vitreous cells and haze), further suggesting uveitis. This is the most common ocular finding in PIOL. For example, in a review of 163 cases from the literature, 66% of patients were noted to have a vitritis.45 At times the opacities in the vitreous may be so dense that they preclude a clear view of the fundus.37 The vitritis can exhibit many cells in sheets and clumps, and there may be haze, but this finding is less common than in uveitis. In our extensive knowledge and experience of the unique clinical characteristics of PIOL, the simple office technique of having a patient with vitreous cells shake his or her head can be very telling. In PIOL, visual acuity can show temporary improvement as the vitreous cells and necrotic debris are dislodged from their position in the vitreous humor and settle toward the bottom of the globe. In uveitis, such a maneuver may not improve visual acuity, especially when vitreous hazing and stranding is a major component of the uveitic process. Despite the vitritis noted on ophthalmoscopic examination, the visual acuity can actually be much better than expected.11 In a series of 12 patients, Whitcup et al. reported eight patients with bilateral involvement. Visual acuities in these patients were good, ranging most frequently from 20/20 to 20/40.29 There were two eyes in two patients that exhibited HM vision or NLP.

Another important finding during the examination of the fundus is subretinal lesions. Classically, these lesions have been described as being whitish-yellow to slightly orange in color, with a fluffy appearance. In addition, the subretinal infiltrates may have distinct or lobulated borders. As the tumor initially infiltrates the space between the retinal pigment epithelium (RPE) and Bruch’s membrane, causing RPE detachments, the tumor mass can sometimes be visualized with marked contrast to the remaining attached RPE.52,53 The involvement of the retina by the tumor can produce RPE detachments9,54 in addition to exudative retinal detachments.53,55 The detachment of the RPE from Bruch’s membrane may lead to RPE atrophy in areas associated with tumor infiltration; these areas of atrophy may show scarring.52 Pigment epithelium not directly involved or

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detached by the tumor may exhibit foci of hypertrophy. Often, these lesions may be multiple in numbers and begin as round to oval in shape. As they enlarge, the lesions may become confluent10,11,13 and their borders may become more indistinct and ragged as they extend through the RPE.

Though chorioretinal lesions might be found rarely in patients with PIOL, they may not always be in the orange-yellow-white color recognized as being the characteristic of PIOL. For example, in the series by Vogel et al., one patient had a rather uncharacteristically colored lesion of greyishwhite, though the fluffy borders of this lesion were similar to the classically described borders of PIOL subretinal lesions.8 In a cohort of 10 patients, 60% of patients exhibited sub-RPE infiltrates that were yellowish in color, with the distinguishing fluffy border. In Siegel and colleagues’ description of 14 cases of PIOL over 10 years, none were noted to have fluffy subretinal infiltrates of any color.42 Such lesions may look obscure due to the overlying vitritis.35 When lesions of the fundus are noted, it is important to document them with photography. This can help to track changes in the size of the tumor. Small punctate retinal lesions may grow over time so that some may actually coalesce forming an even larger lesion. While it is known that tumor infiltrates in such a way that a confluence between the different foci occurs, the rapidity with which this process occurs is difficult to ascertain as there are no studies documenting this with respect to discrete time intervals. In addition, treatment with corticosteroids for presumed uveitis can lead to a reduction in tumor size and some lesions may spontaneously resolve. However, maintaining records using fundus photography and fluorescein angiography (to be discussed in Chapter 6, “Imaging”) can help follow the progression of lymphomatous involvement. Tumor infiltration seems to exhibit a spread from the sub-RPE to the retina, with some cases eventuating to the involvement of the optic nerve.

In 1989, Siegel and colleagues presented their experience with 14 patients with primary intraocular lymphoma (the term, “reticulum cell sarcoma” was still being used at the time) over a 10-year period.42 Ocular findings in their patients at presentation displayed a uveitic picture. Anterior uveitis was noted in three patients, bilaterally in two and unilaterally in one. Vitreous cells were present in all patients, bilaterally in 10 patients and unilaterally in two patients. A 27-year-old female patient, in addition to having bilateral vitreous cells, exhibited RPE atrophy in her left eye. Another patient, a 66-year-old female had bilateral posterior detachments.

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A 55-year-old female exhibited a Koeppe nodule (iris nodule at the pupil’s border) as well as retinal masses and infiltrates in her right eye. Three other patients had unilateral retinal exudates and another had unilateral subretinal lesions. A 64-year-old female had unilateral cystoid macular edema and retinal exudates. In Char and colleagues’ retrospective series of 20 patients,53 ocular involvement was bilateral in 18 patients. Ophthalmic examination revealed vitreous cells in all patients. Anterior chamber cells were present in 15 patients. Chorioretinal lesions were noted in 16 patients. Two patients had retinal hemorrhages in addition to chorioretinal lesions, and another patient had an exudative retinal detachment. Four patients showed negative results for chorioretinal lesions, while one patient had a fundus that could not be visualized due to very dense media opacities.53 Chorioretinal lesions displayed areas of RPE hyperplasia, and some cases exhibited the classical diffuse and creamy infiltration. Char et al. noted that the time interval between symptoms and diagnosis of PIOL ranged from 0 to 60 months, with 11 patients examined prior to 1980 having a mean interval between symptoms and diagnosis of 24.3 months. Nine patients examined after 1980 had a mean interval of 5.8 months. Asymmetrical cellular involvement (both anterior chamber and vitreous) and chorioretinal lesions were the rule in these cases. PIOL eventuated to CNS disease in 16 of the cases. Three other patients developed systemic lymphoma between one-and-a-half to three years after being diagnosed with PIOL. In the series of 12 cases recorded by Whitcup and colleagues,29 visual acuity ranged from unilateral NLP and HM in two patients to 20/20 or 20/16 in some. In fact, though dense vitritis and retinal lesions were present, six patients had visual acuities that were 20/40 or better. Some of the retinal lesions are described as multiple and punctate located in the subretina and being yellow in color. Table 5.2 shows that the most common presenting ocular complaint in PIOL is blurred vision or metamorphopsias. Lymphomatous infiltration of the optic nerve can produce optic neuritis, and optic nerve atrophy can also be a manifestation.43 Acute retinal necrosis (ARN) presentation has also been documented in the case of some patients,43,56 developing from lymphomatous infiltration of a retinal artery and leading to thrombosis. It is important, however, that ARN due to viral etiologies be ruled out. This may be done by using genotypic profiling via the polymerase chain reaction (PCR) amplification on ocular biopsies to detect viral DNA.57,58 In addition, using older but important techniques of viral culture and