Uveitis is an inflammatory disorder, and most cases are considered autoimmune in origin. Yet, occasionally viral, bacterial or parasitic causes may be involved. In older individuals, because of the waning in their immune functions, the frequency of immune-mediated uveitis declines . Instead, infective or neoplastic causes of intraocular inflammation simulating uveitis become more prevalent. This clinicopathologic condition is referred to as the uveitis masquerade syndrome (UMS) [1–3]. We report three cases of UMS due to diffuse large B-cell lymphoma (DLBCL), which illustrated unique features and disease progression.
A 53-year-old woman presented with bilateral blurring of vision. A diagnosis of “pars planitis” (intermediate uveitis) was made. Serologic markers of autoimmune diseases, including antinuclear antibodies, antidouble stranded DNA antibodies, and rheumatoid factor were negative. Topical corticosteroids were ineffective. Treatment with prednisolone and cyclosporine resulted in some improvement. One year later, she complained of frequent headache and short-term memory loss, and was found to have an 8-cm hard irregular right breast mass. Positron emission tomography-computed tomography (PET-CT) showed a large right breast mass associated with right axillary, mediastinal, retroperitoneal, and iliac lymphadenopathy (Fig. 1A). There was also an ill-defined mass in the right frontal lobe with mild midline shift (Fig. 1B). A biopsy of the breast mass showed DLBCL, which was negative for Epstein-Barr virus encoded small RNA on in situ hybridization. There was marrow infiltration. The overall diagnosis was stage IVA DLBCL with central nervous system (CNS) involvement. She was treated with rituximab, methotrexate, bleomycin, cyclophosphamide, vincristine, and dexamethasone (R-M-BACOD) for six courses, resulting in complete clinical and radiologic remission of all lesions. Consolidation radiotherapy was given to the brain and breast, and an allogeneic hematopoietic stem cell transplantation from a sibling was planned.
A 42-year-old woman presented with deterioration of visual acuity, and was diagnosed with bilateral uveitis. She was treated with oral prednisolone with some improvement. Two years later, she developed slurring of speech. Magnetic resonance imaging (MRI) of the brain showed multifocal T2 hyperintensities over the frontal, parietal, and temporal lobes (Fig. 2A,B). Only minimal enhancement was found in some lesions. She declined a histologic examination and was treated conservatively. Six months later, severe abdominal pain developed. At an emergency operation, massive lymphadenopathy with infiltration of the large bowel was found. The right hemicolectomy specimen showed DLBCL. The overall diagnosis was stage IIIB DLBCL. She was treated with rituximab, cytarabine, cisplatin, and dexamethasone (R-DHAP) and achieved a very good partial remission. A repeat MRI of the brain, however, showed no appreciable improvement of the cerebral lesions. She declined treatment, and the disease recurred after 3 months with massive abdominal lymphadenopathy (Fig. 2C). She was then put on palliative chemotherapy.
A 60-year-old woman presented with a sudden decrease of left eye visual acuity. Ophthalmological examination showed severe vitritis with extensive subretinal infiltrates (Fig. 3A,B). A vitrectomy was performed, and the vitreous biopsy showed large atypical lymphoid cells. Further investigations, including an MRI and cerebrospinal fluid (CSF) examination, were normal. Primary intraocular lymphoma (PIOL) was diagnosed. She was treated with intraocular methotrexate (0.4 mg) (13 doses to the left eye, 7 doses to the right eye). There was improvement of left eye visual acuity, and the subretinal infiltrates gradually resolved. About 9 months later, however, she presented with delirium, right arm weakness, and dysphagia. An MRI of brain showed a T1W hypointense and a T2 hyperintense left occipital mass extending to the right side with surrounding vasogenic edema (Fig. 3C). A PET-CT showed extensive and moderately hypermetabolic lymphadenopathy involving the bilateral jugular chains, hilar, mediastinal, axillary, intra-abdominal, pelvic, and bilateral groin areas. An excisional biopsy of the right cervical lymph node showed DLBCL. A bone marrow examination, however, was normal. The overall diagnosis was stage IVA DLBCL with CNS involvement. She was treated with R-M-BACOD chemotherapy for three courses, and received whole brain radiotherapy as consolidation. This was followed by autologous HSCT conditioned by busulfan, cyclophosphamide, and etoposide. At the latest follow-up 5 months post-HSCT, she remained well with no evidence of disease.
These cases illustrate the several different forms of DLBCL that might present as UMS, including PIOL, CNS, and systemic lymphoma. Clinical clues to suggest that the apparent uveitis might be an UMS are its onset after 45 years of age, the insidious deterioration of vision, bilateral involvement, and the presence of additional neurological symptoms [1–4].
Two clinical patterns of UMS were illustrated in our cases. The first pattern was demonstrated by Cases 1 and 2, where an uveitis indistinguishable from autoimmune uveitis preceded the development of systemic DLBCL by 1–2 years. As a vitreous biopsy was not performed, it remained unknown if the ocular lesions were lymphomatous. In both cases, systemic lymphoma was accompanied by CNS lesions. As brain biopsies were also not performed, the nature of the lesions was again undefined. In Case 1, the CNS lesions resolved with chemotherapy, suggesting that they were likely to be lymphomatous. However, in Case 2, the CNS lesions remained static despite the positive partial remission achieved for the systemic lymphoma. Furthermore, the distribution of the lesions was also atypical of CNS lymphoma. This raised the possibility that the brain lesions were best considered demyelinating and paraneoplastic in nature.
The second pattern was seen in Case 3, where a PIOL presenting as refractory uveitis preceded the occurrence of CNS lymphoma and systemic lymphoma. In the World Health Organization classification of lymphoid malignancies, PIOL is grouped under the category of primary CNS lymphoma, underlying their similarities in histological appearance and clinical behavior . Moreover, about 50–80% of PIOL will eventually be associated with CNS lymphoma, while conversely, 15–25% of CNS lymphoma will have intraocular involvement at the time of diagnosis [6–8]. Therefore, for IOL, neurologic imaging is mandatory to exclude CNS involvement, even if symptoms are absent. Cytologic examination of the CSF for lymphoma cells should therefore constitute part of the initial evaluation of PIOL.
Distinguishing UMS from uveitis is very important. UMS due to a systemic or CNS lymphoma requires high dose chemotherapy that may penetrate the CNS . The use of high dose chemotherapy and hematopoietic stem cell transplantation (HSCT) might also be beneficial .
However, UMS due to PIOL may be more difficult to treat. Chemotherapy penetrates the eye poorly. Methotrexate, a very effective drug for systemic and CNS lymphoma, only penetrates the eye at less than 1% of the plasma level . The optimal treatment of IOL has not been determined. A combination of high dose chemotherapy, radiotherapy, and in selected cases high dose chemotherapy and HSCT has been proposed [11, 12].
To conclude, in elderly patients presenting with uveitis, it is important to first exclude UMS, which is often a harbinger of CNS and systemic DLBCL. As the prognosis of CNS lymphoma is considerably worse than nodal DLBCL, an early diagnosis is essential, so that timely and appropriate treatment can be given to improve the patient's outcome.