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

254 Primary Intraocular Lymphoma

pathologist involved from the very beginning, before any tissues are biopsied. The rate limiting step is not the surgeon’s ability to obtain biopsy tissues, but rather the presence of a pathologist who will perform the histopathologic and molecular examinations that are necessary to establish a diagnosis.9 The eventuation of PIOL to cerebral disease is an unfortunate reality; approximately 80% of cases presenting initially in the eyes progress to involve the brain as well.8,10,11 This case also shows how our treatment of PIOL has progressed. This patient was treated with radiation therapy first and later offered systemic chemotherapy. While PIOL and PCNSL are very radiosensitive, severe adverse effects are common. Recently, high-dose systemic methotrexate was identified as the single most important therapeutic agent in treating PIOL and PCNSL and can be followed, depending on the case, by whole brain radiation therapy if the patient is under 60 years of age. Those over the age of 60 years can suffer significant delayed neurotoxicity if radiation therapy is included after methotrexate administration.12 Complete response in the eye should be assessed by repeat evaluation.13 While the absence of subretinal infiltrates and vitreous cells is a requirement for noting a complete response, some of the chronic changes that occur to the RPE may not resolve in the setting of a complete response.13 If recurrence develops after an initial response with methotrexate, we might consider administering higher doses of systemic methotrexate or intravitreal methotrexate injections, again depending on the case.

Case 3

A 46-year-old woman from Brazil noted floaters in her left eye for two months. She was diagnosed with ocular toxoplasmosis (Fig. 16.7) and started on oral corticosteroids and pyrimethamine. Work up revealed that she had a positive toxoplasmosis titer, but she was VDRLand HIV-negative. Undergoing treatment for toxoplasmosis, the patient showed no improvement from her medication regimen. Therefore, this was discontinued after four weeks. She was then treated for presumed acute retinal necrosis (ARN) with intravenous acyclovir for two weeks followed by oral acyclovir for one week. Despite the antiviral treatment the patient continued to show no improvement. She was put back on toxoplasmosis therapy, including sulfa, pyrimethamine, and corticosteroids, but no improvement was noted. A month later (five months after symptom onset) the patient’s chorioretinitis

Case Illustrations 255

Fig. 16.7 Case 3. Ophthalmoscopic photograph showing huge retinal and subretinal creamy whitish infiltrate in the peripheral retina.

Fig. 16.8 Case 3. Magnetic resonance image (MRI) of the brain showing a lacunar infarct in the cerebellum.

in the left eye progressed, and lesions now appeared in the right eye. An MRI of the brain showed a lacunar infarct (Fig. 16.8), and lumbar puncture with CSF cytopathology revealed no atypical cells. Approximately one month later, the patient developed a retinal detachment in the left eye, and a vitrectomy with silicone oil tamponade was performed. Cytopathology of the vitrectomy specimen failed to show lymphoma cells. The patient was started on intravenous foscarnet, but no improvement was noted. She was then referred to the National Eye Institute (NEI) in the USA where a review of systems revealed a right arm weakness and swaying to the left when she initiated walking. Serological laboratory studies were obtained and were negative

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for RPR, ANA, c-ANCA, p-ANCA, HIV, lyme titer, and hepatitis. The patient did have a positive toxoplasmosis IgG titer. A fluorescein angiogram was obtained that showed areas of hyperfluorescence at the level of the RPE. A lumbar puncture was performed, and CSF cytology revealed cells suspicious for lymphoma. An infectious disease consult agreed with having the patient on therapy for toxoplasmosis (pyrimethamine and corticosteroids) and acute retinal necrosis (acyclovir). A neurology consultation resulted in a diagnosis of Parkinson’s disease. Visual acuity in the right eye was stable, and the left eye was now non-light perception. The chorioretinitis showed progression in the right eye upon ophthalmoscopic examination. To better determine the nature of the patient’s ocular processes, whether malignant or infectious, a diagnostic enucleation of the blind left eye was performed. The pathology of the eye disclosed sheets of vitreous condensation, fibrin strands and debris underlying the peripheral retina, pars plana, and pars plicata. Retinal detachment was noted in several places, including the macula, and white-yellowish infiltrates arose between the RPE and neuroretina in several areas, particularly the posterior pole. In the periphery, there were foci of chorioretinal scars with pigmentary demarcation and deposits. The optic disc was flat. Microscopically, the retina was completely detached, except for a few foci in the periphery that had chorioretinal adhesions and scarring. There was also serosanguinous material containing clumps of atypical lymphoid cells and inflammatory cells in the subretinal space. In some areas, fibrovascular inflammatory membrane was formed. Except for the temporal anterior region, the RPE was detached by tightly packed tumor cells characterized by large hyperchromatic and pleomorphic nuclei, and prominent nucleoli (Fig. 16.9). Mitoses were also noted. The RPE cells showed various degrees of atrophy and alternation, and they were infiltrated by tumor cells. In some areas, the tumor cells infiltrated the neuroretina. Bruch’s membrane was intact in most places, except at the nasal periphery where there was a small necrotic focus. Some of the ganglion cells were enlarged and had swollen cytoplasm. Moderate-to-intense inflammation was present throughout the choroid. The optic nerve, however, was free of tumor infiltration. Immunohistochemistry was performed, and it revealed that the lymphomatous B-cells were monoclonal κ, rather than λ, light chain positive (Fig. 16.10). Microdissection of the infiltrating B-cells showed that they were monoclonal, having the same IgH gene rearrangement as found by PCR (Fig. 16.3).

Case Illustrations 257

Fig. 16.9 Case 3. Photomicrograph showing PIOL cells located in the subretina between the destroyed retinal pigment epithelium (RPE) and fragmented Bruch’s membrane (hematoxylin and eosin, original magnification × 50).

Fig. 16.10 Case 3. Photomicrographs showing PIOL cells staining positive for κ light chain (left) and negative for λ light chain (right) (avidin-biotin complex immunoperoxidase, original magnification × 200).

Commentary. This patient was younger than we typically would expect for PIOL. However, it is important to consider PIOL even in younger patients.3,14 Note the typical pathology of PIOL, in which there is subretinal infiltration between Bruch’s membrane and the RPE (Fig. 16.9). Lymphomatous infiltration can make its way into the retina as well, as evidenced by this case. Frequently a reactive inflammatory infiltrate is found in the choroid, and these lymphocytes are typically smaller than the PIOL cells. The overwhelming majority of PIOLs are of B-cell origin and that is demonstrated here by immunohistochemistry. It is important to realize that CSF and

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vitrectomy cytology may not always provide a definitive diagnosis, even if we repeat these tests. Despite this fact, it is important not to become dismayed with initially negative biopsies. Often, a repeat diagnostic vitrectomy is necessary to make the diagnosis of PIOL.10 However, if vitrectomies prove nondiagnostic and there remains a strong suspicion for PIOL, we may turn to a retinochoroidal biopsy. This is done when there are obvious lesions that can be submitted to sampling and when these lesions fail to respond to therapy and are threatening to advance upon the macula. Alternatively, enucleation may be performed, especially when there is no possibility (as in this case) of restoring vision due to extensive disease progression, and the patient’s course can be improved (through treatment) by making a definitive diagnosis. This case also illustrates that while PIOL can frequently be a deadly disease, confinement to the eye without cerebral involvement may prove to be a relatively advantageous situation compared to oculocerebral or solely cerebral disease.

Case 4

A 51-year-old man complained of floaters and decreased vision initially appearing in the right eye and, later, in the left eye.15 An intermediate uveitis was diagnosed, and was treated with bilateral vitrectomy and scleral buckling over a period of two years. Five years later, the right eye developed episodic increases in intraocular pressure that seemed to correlate with the degree of intraocular inflammation. Importantly, this inflammation would often respond to topical corticosteroids. Eventually the patient developed bilateral multiple white subretinal lesions. An MRI of the brain revealed that there were contrast-enhancing lesions in the left caudate nucleus, and PCNSL with intraocular involvement was suspected. The iris in the right eye had diffuse infiltrative nodules (Fig. 16.11). Ophthalmoscopy revealed a bilateral vitritis, diffuse RPE changes, and macular thickening by dilated ophthalmoscopic examination. A diagnostic vitrectomy showed a B-cell PIOL, and iris biopsy revealed that the stroma was likewise infiltrated with B-cell lymphoma. Microdissection and PCR of the PIOL cells in the iris and vitreous, revealed monoclonal rearrangement of the IgH gene (Fig. 16.3). The patient was submitted to both systemic and intrathecal chemotherapy and radiation treatment and showed improvement (Fig. 16.12). Over six years, this patient also had intravitreal injections of methotrexate, allowing for the vitreous to be sampled prior to drug injection for cytokine analysis. When IL-10 levels were

Case Illustrations 259

Fig. 16.11 Case 4. Slit lamp photograph showing diffuse infiltrative nodules in the iris.

Fig. 16.12 Case 4. Ophthalmoscopic photograph showing small, atrophic chorioretinal scars with some pigmentation representing old PIOL lesions.

high (see Table 16.1), we would treat with intravitreal methotrexate, and the patient would respond. Unfortunately, the patient eventually developed a new cerebral parenchymal lesion after six years and died.

Commentary. This case is an almost classical presentation of PIOL in an immunocompetent patient, but with a twist. While the patient was in his 50s, complaining of decreased vision and floaters, iris stromal involvement eventually occurred, which is extremely rare.15 This patient had extensive follow up with us at the NEI, and we were able to obtain vitreous

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Table 16.1 Vitreous IL-10 and IL-6 Levels in Case 4

1ND = not determinable.

or aqueous for assay of IL-10 and IL-6 levels during his visits for intravitreal methotrexate administration. As Table 16.1 shows, we were able to follow this patient’s cytokine levels and treated it accordingly over six years. High IL-10 levels, suggesting active disease, prompted intravitreal injection of methotrexate with a subsequent response in the injected eye. Thus, following IL-10 levels can give us an indication as to the adequacy of our treatment regimen. For example, high IL-10 levels that fall in response to methotrexate treatment and stay low (or IL-10/IL-6 ratios less than 1.0) inform us that our treatment regimen is producing some benefit. On the other hand, IL-10 levels that only minimally respond to methotrexate or are refractory to treatment may indicate that the mode of treatment, the

Case Illustrations 263

immunocompetent patients who develop PIOL. In addition, AIDS patients, as this case reveals, often have multiple opportunistic infections that have their own unique presentations in the eye and can mask the presence of concurrent conditions, such as malignant ocular processes. Unfortunately, this patient succumbed to systemic complications arising from multiple opportunistic infections before a malignant ocular disease could be identified. If PIOL had been discovered in this patient prior to death, what treatment might have been initiated? This is not an easy question to answer. Certainly, an idea is developing of how to treat PIOL in immunocompetent patients (see Chapter 10). In AIDS patients, however, it seems that the most important issue regarding treatment is the immunodeficiency itself. The CD4 count must be addressed and typically involves the use of HAART. This patient, however, was being treated before the availability of HAART. Improving the CD4 population in terms of number improves the quality of the immune system and is perhaps the most important factor impacting the development of malignancies in AIDS patients.

Case 6

A 78-year-old pseudophakic man complained of a four-month history of blurry vision in the left eye. His past medical history was ominous, with cutaneous T-cell lymphoma of the leg (three years prior to presentation) and lung cancer being especially prominent. The patient had been treated with radiation for the cutaneous T-cell lymphoma (CTCL) and was status post lobectomy for the lung cancer (the patient had a history of smoking). Visual acuity was measured as 20/25 in the right eye and light perception in the left. Dilated ophthalmoscopy showed that there were trace cells and RPE atrophy superonasal to the fovea in the right eye and 2+ cell 3+ haze with no obvious retinal lesions in the left eye; the view of the fundus in the left, however, was hazy (Fig. 16.17). A fluorescein angiogram was obtained and showed no changes at the level of the RPE. Because of the patient’s past history of CTCL and his current ocular presentation with bilateral vitritis, PIOL was suggested. An MRI was obtained and showed no lesions in the brain. A lumbar puncture was performed, and CSF cytology showed that there was a lymphocytosis, but rarely malignant cells were identified (Fig. 16.18). A vitrectomy was then performed and revealed atypical intermediate to