Ординатура / Офтальмология / Английские материалы / Tumors of the Eye and Ocular Adnexa_Char_2001

using polymerase chain reaction (PCR) to detect B- and T-cell gene re-arrangements have shown promise, although as high as 30 percent false-nega- tive rate has been reported.92–94 While human herpes virus 8 (HHV-8) and Epstein-Barr virus (EBV) have been found in intraocular lymphoma associated with Kaposi’s sarcoma (KS), it probably is not very important in the pathophysiology of this disease.95 Similarly, while some authors have found that inter- leukin-10 (IL-10) levels tend to be elevated in the vitreous,96 in another study, the IL-10 levels were also elevated in benign conditions.97

We routinely perform a diagnostic vitreous biopsy in all patients. If the visual acuity is less than 20/100 due to vitreous cellular opacification, a vitrectomy is performed at the time of biopsy. The eye is prepared and draped in a sterile manner. If a vitrectomy is indicated, an infusion cannula is sutured into the eye. A 20-gauge sharp needle is placed into the midvitreous through a separate scleral site approximately 3.5 mm posterior to the limbus. One milliliter of liquid vitreous is withdrawn for analysis. The quality of cytologic preparation is superior when vitreous is obtained through a standard needle and syringe, compared

with samples of vitreous cells obtained through the vitrectomy instrument and harvested from the balanced salt solution (BSS)-plus reservoir. In the same patient, we have observed significant cytologic deterioration when the latter method is used. We now also save 0.1 mL undiluted vitreous as well as the vitrectomy specimen for molecular biologic studies.

In all cases, at the time of surgery, bilateral bone marrow biopsies are performed along with a lumbar puncture for cerebrospinal fluid cytology. As previously mentioned, approximately 80 percent of patients eventually develop CNS disease, and historically that has led to their death.

All patients in whom the diagnosis of intraocular lymphoma is suspected, we also have complete CNS imaging studies.98 A T1-weighted MRI, using thin sections and gadolinium, is more sensitive than brain computed tomography (CT) with contrast. A typical CNS lesion associated with intraocular lymphoma is shown on an MRI scan (Figure 10–10). If CT is used, intravenous contrast is mandatory to optimally visualize the lesion.

The treatment of primary intraocular lymphoma is controversial. In 1980, we reported 9 patients with

Figure 10–10. MRI with contrast demonstrating a CNS lymphoma in a patient with primary intraocular and CNS lymphoma.

intraocular lymphomas who had been treated with 35 to 45 Gy of ocular and CNS photon irradiation.71 In 10 of 13 eyes of 8 patients, visual acuity improved. Generally, patients who have initially better vision are more likely to show significant postradiation improvement. Figures 10–11A and B show an intraocular lymphoma before and after radiation treatment. Little ocular morbidity occurred with this dose and fractionation schedule. Unfortunately, most patients treated with just radiation to the eye and CNS had a good initial response but later died of recurrent CNS disease. This led us to treat a series of patients with both eye and CNS disease with a combination of radiation and intrathecal chemotherapy.80

Several chemotherapeutic protocols have been used in only a few patients in different centers.78,99–101 No data have demonstrated the superiority of a given approach. In patients with intraocular and CNS lymphoma, 40 Gy of whole-brain and eye irradiation, with a 5- to 10-Gy boost to the spinal cord, is given along with intrathecal methotrexate. A number of other approaches have been used. Fishburne and colleagues and others have used 400µg intravitreal methotrexate twice weekly to treat intraocular dis-

ease, with promising local results.97,102 Aggressive systemic chemotherapy, with autologous bone marrow transplantation, has also been used with good local control.96,103 The major problem with the latter approach has been morbidity, where over 80 percent of 1-year survivors > 60 years old developed progressive leukoencephalopathy. A recent report using only chemotherapy showed a lower incidence of progressive leukoencephalopathy.104

We have treated a number of patients with longterm (> 10-year) survival. Our best results have been in patients who have minimal CNS disease; vision is restored and life preserved.53 Patients who are initially referred with gross neurologic disease, often succumb to the CNS lymphoma despite radiation and chemotherapy; some have died during initial evaluation or early treatment.77 Rarely, we have seen patients treated elsewhere with this regimen develop radiation retinopathy (Figure 10–12), but that has

A

B

Figure 10–11. A, Pretreatment view of a patient with primary intraocular lymphoma. B, Postradiation response in the same patient.

232 TUMORS OF THE EYE AND OCULAR ADNEXA

Figure 10–12. Radiation retinopathy without recurrence of intraocular lymphoma in a patient treated elsewhere with eye and brain radiation plus chemotherapy.

not occurred in the approximately 40 patients we have treated at UCSF and Stanford.

A more difficult group of patients to establish treatment guidelines for are those with only intraocular lymphoma.53 In lymphoma localized to the eye, the two options are to radiate only the eye and serially monitor the CNS with brain MRI scans and cerebrospinal fluid cytologies, or to radiate both the eye and brain with or without adjunctive chemotherapy. Significant morbidity, including deterioration of intellectual function, occurs in up to 30 percent of elderly patients treated with both brain irradiation and intrathecal chemotherapy and in up to 80 percent with aggressive systemic chemotherapy.80,103–106 As mentioned above, if radiation and systemic chemotherapy are used in older patients, over 80 percent develop significant intellectual deterioration.97 We, therefore, have been less inclined to aggressively treat very old patients with disease just localized to the eye, and in most of these cases, we treat the eye(s) and monitor such patients expectantly. We have had long-term fol-

low-up of 2 patients treated with only ocular irradiation who are disease-free 7 and 13 years after treatment, respectively.53 In general, most of these patients do eventually develop CNS disease, and at that point, more treatment is undertaken. We believe that the quality of life is better with that approach, and that a number of those patients can be salvaged when they develop CNS disease (unpublished observations).

In 25 percent of ocular lymphoma patients—pre- dominantly those with choroidal infiltrates, as opposed to vitreous disease—systemic non-CNS lymphoma develops. These patients are treated with ocular radiation and systemic chemotherapy.59,99–101

After treatment with radiation, chemotherapy, or both, there is uniform breakdown of the bloodaqueous barrier; all these patients have persistent anterior chamber cell and flare. Similarly, if a central vitrectomy has been performed, the peripheral vitreous opacification remains stationary, despite effective treatment.

All patients are followed up by a medical oncologist. A general physical examination is performed every 3 months, as well as both scans and cerebrospinal fluid cytologic studies on a 6-month basis for the first 5 years after treatment. If relapse or tumor spread occurs, it almost always becomes manifest within 3 years of diagnosis. In our experience, recurrences usually occur within the first year in < 10 percent of treated patients.

Systemic Lymphoma with

Secondary Ocular Involvement

We have seen a number of cases in which patients have presented to the ophthalmologist with anterior segment findings as the initial sign of systemic relapse. Figure 10–13 shows a patient previously

treated with a combination of chemotherapy and radiation for systemic lymphoma. Approximately 3 years after the initial diagnosis of the disease, she presented with persistent, progressive iridocyclitis and was eventually referred for evaluation of a hypopyon. Fine-needle aspiration of the anterior chamber demonstrated lymphoma that responded rapidly to low-dose (10 Gy) irradiation. In our experience, less commonly, systemic lymphoma symptomatically involves the posterior choroid. Figure 10–14 shows a patient who was initially referred for a uveal melanoma. An FNAB demonstrated that this was a lymphoma.107 Figure 10–15 shows a patient who presented with ocular findings from a T-cell lymphoma. Others have noted atypical malignant lymphoma presentations in the eye, including a pattern that simulated a ring melanoma.108,109 A number of rarer lymphomas have been reported, including choroidal infiltrates as an initial manifestation of lymphoma after treatment of arthritis, a primary B- cell lymphoma in a 3-year-old boy, widespread lymphoma in an 11-year-old boy, and T-cell lymphoma involving the anterior chamber.110–113 Similarly, one case report documented choroidal infiltrates as the initial manifestation of lymphoma in a patient with rheumatoid arthritis on methotrexate.110

OTHER INTRAOCULAR LYMPHOID TUMORS

Benign and malignant lymphoid tumors involving the uveal tract have been reported since 1920.114–116 There have been approximately 50 cases of benign intraocular lymphoid tumors reported.114 These tumors can be localized choroidal lymphomas, consist of a benign uveal infiltrate, or involve the uveal tract, sclera, optic nerve, and orbit.116–118 Crookes and Mullaney first reported a case of lymphoid hyperplasia of the uveal tract in 1967.118 Ryan and co-workers retrospectively analyzed histologic data on 19 cases that exhibited massive lymphoid uveal involvement without inflammation of the sclera.119 Seventeen of the 19 patients had unilateral disease, and this process simulated a melanoma. The mean age at onset was 55 years, the range being 30 to 94 years. Most patients presented because of decreased vision; however, retinal detachment with glaucoma and/or iridocyclitis occurred, and some

Figure 10–14. Patient presented with a uveal parapapillary tumor that simulated a choroidal melanoma. FNAB was positive for lymphoma.

patients initially sought care because of inflammation or pain. Histologically, mature lymphocytes were observed in the uveal tract of all cases, and most also had plasma cells. Only one patient had an abnormality on serum protein electrophoresis.119 A recent Armed Forces Institute of Pathology (AFIP) report reviewed 10 of these cases and, using molecular techniques, noted that 8 of the 10 were well-dif- ferentiated small cell lymphomas.120 None of these patients died from systemic lymphoma; as others have noted, lymphoma was more common in the posterior segment, and the extrascleral component appeared to have a more benign cytology.120 Rarely, there are intraocular benign EBV driven lymphoproliferative disorder in post-transplant patients.121 Very few clinical reports of this entity have been published. Usually, there is associated localized extraocular lymphocytic infiltration.121,122 A case of benign lymphoid hyperplasia of the uveal tract, confirmed with FNAB, is shown in Figure 10–16.

Many patients with benign uveal lymphoid lesions will respond to steroids.121,123 In a single case report, radiation also appeared effective, and we have had good results in 3 patients treated with 20 Gy of photons.

The benign uveal lymphoid lesions may also occur as part of the spectrum of conditions associated with idiopathic posterior scleritis. Most patients

Figure 10–16. Benign lymphoid hyperplasia of the uveal tract confirmed with FNAB.

Figure 10–17. Choroidal detachment and transient uveal mass in which the patient had a history of pain without a red eye. Clinical and ultrasound findings simulated a ciliary body melanoma. The presence of a ring of choroidal detachment and pain prompted oral steroid therapy. The eye became completely normal 1 week after treatment.

have an exudative detachment without an obvious mass. The patient shown in Figure 10–17 was referred with the diagnosis of a ciliary body melanoma. This exudative retinal detachment disappeared during a 2-week course of oral steroids (see Figure 10–17).124 Many posterior scleritis patients have little anterior segment inflammation; a number have been reported with false-positive radioactive phosphorus uptake tests.110–129

The management of either posterior scleritis or benign lymphoid uveal lesions is unclear. Some patients respond to oral steroids.130 Others have a varied course.116,123–131

Finally, it is important to stress that intraocular inflammation does not exclude the diagnosis of a uveal melanoma. A small percentage of patients, generally with large, necrotic uveal melanomas, can have intraocular inflammation as their presenting sign.132 Figure 10–18 shows a patient who had a negative ultrasound for tumor but had a blind, painful eye that, on histologic examination, had a necrotic melanoma with substantial inflammation.

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122.Grossniklaus HE, Martin DF, Avery R, Shields JA. Uveal lymphoid infiltration. Report of four cases and clinicopathologic review. Ophthalmology 1998; 105:1265–73.

123.Desroches G, Abrams GW, Gass JD. Reactive lymphoid hyperplasia of the uvea. A case with ultrasonographic computed tomographic studies. Arch Ophthalmol 1983;101:725–8.

124.Kannan KA. Lymphomatous pseudotumour of the choroid with secondary retinal detachment. Ind Ophthalmol 1976;23:28–31.

125.Feldon SE, Sigelman J, Albert DM, Smith TR. Clinical manifestations of brawny scleritis. Am Ophthalmol 1978;85:781–7.

126.Goder G. Scleritis posterior pseudotumorosa. Klin Monat 1969;155:200–14.

127.Singh G, Guthoff R, Foster CS. Observation on longterm follow-up of posterior scleritis. Am J Ophthalmol 1986;101:570–5.

128.McGavic JS. Lymphomatoid diseases involving the eye and its adnexa. Arch Ophthalmol 1943;30:179–93.

129.Schwarze E-W, Radaszkiewicz T, Pulhorn G, et al. Maligne and benigne Lymphome des Auges der Lid und Orbitalregion. Virchows Arch Pathol Anat und Histol 1976;370:85–96.

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There are relatively few retinal neoplasms. Retinoblastoma is the most common retinal malignancy and is discussed in the chapters on retinal tumors and retinoblastoma. Metastatic lesions involving the retina are quite rare and much less frequent than uveal tract metastases. Retinal and retinal pigment epithelial (RPE) hamartomas occur, and both neoplasms and malformations of the retinal vasculature and pigment epithelium have been reported. This chapter discusses retinal tumors and simulating lesions that are important in ocular oncology; discussion of other retinal problems can be found in textbooks on retinal disease.

VON HIPPEL-LINDAU SYNDROME AND ISOLATED RETINAL ANGIOMAS

In retrospect, probably the first clinical description of von Hippel-Lindau syndrome (VHL) was by Treacher Collins in 1894.1 Von Hippel first described vascular tumors of the retina in 1904; Lindau observed their association with cerebellar tumors in 1926.2–4 In addition to central nervous system (CNS) findings, both visceral carcinomas and cysts occur as part of this syndrome.5 Renal cell carcinoma, pancreatic carcinoma, pheochromocytoma, endolymphatic sac tumor, islet cell tumor, and meningiomas have been reported with the syndrome, as have cysts in the pancreas, kidney, epididymis, liver, lung, adrenal glands, bone, omentum, and mesocolon.6–15 The life-time risk of renal cell carcinoma is approximately 70 percent and is the most common cause of death.15

Isolated retinal hemangioblastomas (angiomatosis retinae, capillary hemangiomas, or VHL lesions) or those in association with systemic and CNS findings

(VHL) occur either as a sporadic, isolated, nonheritable condition or as an autosomal-dominant disease.16 Isolated retinal capillary angiomas can be the presenting sign of VHL disease in as many as 43 percent of cases.17 In one meta-analysis, the authors found that isolated angiomas occurred in statistically significantly older age groups than the retinal hemangioblastoma in association with VHL syndrome (48 years versus 25 years).18 In contradiction, in a prospective study from the United Kingdom, of 32 patients referred with solitary angiomas, 17 had no evidence in themselves or family members of VHL, nor were there any germline VHL mutations noted.19 In that latter analysis, the age of the patients with isolated disease was 27.5 years, and the prevalence was less than that of VHL, approximately 1 in 110,000 patients. In a German study of 20 patients with retinal angiomas, 16 had VHL. Interestingly, on the basis of clinical findings or family history, 15 of the 16 could

be documented without molecular studies.20

Most patients with VHL syndrome have a positive family history. The most common initial presentation is decreased vision in the second or third decade of life. Less frequently, in the VHL syndrome, either CNS involvement or a systemic carcinoma can be the presenting sign; visceral cysts and angioma are usually asymptomatic. Retinal lesions occur in one-half to two-thirds of patients with VHL disease.12,21

In a large cross-sectional clinical and molecular study of 183 patients reported from England, the prevalence of ocular lesions in VHL disease was 68 percent (124 of 183) and the mean number of angiomas was 1.85. Neither the occurrence nor number of angiomas appeared to increase with age. They estimated the cumulative probability of vision