Testicular lymphoma, intraocular (Vitreoretinal) lymphoma, and brain lymphoma: Involvement of three immunoprivileged sites in one patient
Authors: Jacob Pe'er, Jacob M. Rowe, Shahar Frenkel, Eldad J. Dann
Journal: American Journal of Hematology (2010)

The brain, the testicles, and parts of the eye, including, inter alia, the vitreous, and the retina, are immune-privileged organs with relatively sealed blood-tissue barriers. These three organs may, rarely, develop aggressive primary B-cell lymphoma. Vitreoretinal lymphoma is commonly associated with primary central nervous system lymphoma (PCNSL) and with testicular lymphoma, which has a high incidence of relapse, one of the common sites of relapse is the brain. The association of testicular lymphoma with vitreoretinal lymphoma is extremely rare. In these three organs, in treating the lymphoma, the blood-tissue barrier must be overcome. We present a unique case of a patient with testicular lymphoma who 3 years later was diagnosed with monocular vitreoretinal lymphoma, and while being treated for the ocular lymphoma developed PCNSL. The lymphomas in the three organs were treated successfully: the testicular lymphoma by chemotherapy, rituximab, and radiation therapy, with intrathecal methotrexate (MTX) as a preventative measure; the vitreoretinal lymphoma by intravitreal injections of MTX alone; and the PCNSL by intravenous high-dose MTX, rituximab, dexamethasone, procarbazine, and intrathecal MTX. Ten months after completion of the last treatment, there were no signs of systemic, CNS or ocular recurrence. A 51-yr-old man presented to the Department of Hematology at the Rambam Health Care Campus (Haifa, Israel) with a testicular mass in February 2005. Following orchiectomy, a diagnosis of testicular B-lineage diffuse large-cell lymphoma was made. Immunophenotypic characterization of the testicular lymphoma revealed this to be CD20+ with a proliferative index of 90%. Physical examination and laboratory tests, including lactic dehydrogenase, were otherwise unremarkable. Complete systemic staging, including FDG-18-PET/CT, lumbar puncture and bone marrow examination, were all negative. After orchiectomy, the patient was treated with six cycles of rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP). With each cycle, he received intrathecal methotraxate. After the chemotherapy, he received local radiation therapy of 3000 cGy to the contralateral testis and remained in complete remission for 3 years. Because of a complaint of blurred vision in his right eye, he was examined in June 2008 by an ophthalmologist at the Hadassah-Hebrew University Medical Center in Jerusalem, Israel. An elevated white-yellow subretinal lesion was found in the superiotemporal quadrant of the fundus of his right eye (Fig. 1). Only a few cells were seen in the vitreous body. At that time, the visual acuity in his right eye was 1.0 (6/6) and in his left amblyopic eye 0.1 (6/60). Because of the suspicion of vitreoretinal lymphoma, the patient was referred to Hadassah's ocular oncology service for diagnosis and treatment. He underwent diagnostic vitrectomy. The cytopathological examination revealed atypical B-cell lymphoma cells. The IL-10:IL-6 ratio was >1. Molecular evaluation did not demonstrate B-cell rearrangement. Within 2 days of the diagnostic vitrectomy, there was significant progression of the disease in the retina, and with the diagnosis of vitreoretinal lymphoma, he immediately started treatment with intravitreal injections of 400 μg/0.1 ml methotrexate (MTX). Fundus pictures of the patient. The upper left picture shows the retinal lymphoma infiltrate at the time of diagnosis, before the pars plana vitrectomy (PPV). The upper central picture shows further retinal involvement just before beginning the treatment with intravitreal methotraxate. The four remaining pictures show the response to treatment, until complete disappearance of the lymphoma in the retina. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.] The patient was treated according to the Hadassah protocol [1] with 25 injections of intravitreal MTX—during the induction phase, two weekly injections in the first month, in the consolidation phase, a weekly injection for 8 weeks, and in the maintenance phase a monthly injection for an additional 9 months. To prevent keratopathy, which is a common side effect of this therapy, the patient was treated with lubricants, using artificial tears and ointment. The subretinal lesion in the right eye shrank gradually, until its disappearance after 16 injections (Fig. 1). The entire course of 25 injections took almost a year; in the 9-month follow-up after the last injection, there were no signs of intraocular recurrence, and only a gray scar was seen at the site of the lymphoma. During local treatment of the vitreoretinal lymphoma, the patient was also given intravenous high-dose MTX at the Rambam Medical Center to prevent systemic/central nervous system (CNS) recurrence at a dose of 3 g/m2. However, he developed hepatitis and elevation of hepatocellular enzymes to twice the normal limit, and gamma glutamyl transferase to 5 times the upper normal limit. Moreover, after the 18th intravitreal injection and about 4 months from the beginning of the intravitreal MTX injections, the patient developed neurological symptoms. FDG-PET/CT and MRI of the brain revealed involvement of the right temporal lobe of the brain by lymphoma. Lumbar puncture showed lymphoma cells in the CSF. The patient was treated using the Memorial Sloan-Kettering Cancer Center protocol for primary CNS lymphoma [2] that included intravenous high-dose methotraxate, rituximab, dexamethasone, procarbazine, intrathecal MTX together with rituximab. PET/CT MRI and repeated CSF samples demonstrated complete remission. Because of changes in the brain tissue demonstrated on MRI, radiation therapy was omitted, and the patient received another two cycles of high-dose ARA-C according to the protocol. Currently, 8 months after completion of the chemotherapy, there are no signs of systemic or CNS recurrence. Testicular lymphomas are rare tumors that account for ∼5% of testicular neoplasms and are the most common testicular malignancies in men during the age of 60 years [3]. It comprises ∼0.6% of all patients with non-Hodgkin lymphoma in the USA [4]. Testicular lymphoma is associated with a high incidence of relapses (52%) and up to 72% of the relapses were extranodal [5]. The CNS, both parenchymal brain tissue and leptomeningis, are common sites for such an involvement [5, 6]. In most cases, testicular lymphoma is a B-cell non-Hodgkin lymphoma, although cases of testicular T-cell lymphoma have been reported as well [7]. Primary central nervous system lymphoma (PCNSL) is also a rare disease, mostly of the B-cell type that, like testicular lymphoma, affects mainly the elderly population [8]. It is an aggressive disease, with survival of a few months, if not treated. Intraocular lymphoma may arise in different parts of the eye, expressing various clinical manifestations [9]. Vitreoretinal lymphoma, which is mostly a high-grade B-cell malignancy, is the most common and most aggressive one and predicts for a poor prognosis. It is usually associated with PCNSL and occurs in ∼15 to 25% of the patients with PCNSL [8, 10]. On the other hand, over 50% of vitreoretinal lymphomas appear in association with PCNSL [11, 12] and may be considered as a subset of PCNSL [10]. The association of testicular and vitreoretinal lymphomas is extremely rare, and only seven cases have been reported to date at 2 months to 10 years from diagnosis [7, 13-17]. We reported a case of a patient with testicular lymphoma who, after remission of 3 years, developed vitreoretinal lymphoma with subsequent brain lymphoma. Testicular lymphoma was reported as an entity with inferior prognosis compared with other early-stage lymphomas (Table I). It is treated with combination therapy and local radiotherapy [18]. In the cohort of patients treated in British Columbia during 1980–1998, there were 27 patients with testicular lymphoma and 12 of them had disease progression after brief chemotherapy and radiotherapy to the contralateral testis. Four of these relapses were to the brain parenchyma. The International Extranodal Lymphoma Group reported 10-year progression-free survival (PFS) rate of only 33%, and continuous relapses occurring up to 10 years from diagnosis in 15% of patients [5]. However, it should be noted that in this study, only 20% of 373 patients received prophylactic intrathecal therapy and only 8% were given high-dose MTX as part of their therapy. Because of the relatively frequent relapse of testicular lymphoma in the CNS [14] in patients treated with orchiectomy and local radiation, intrathecal prophylaxis was added to various treatment protocols. However, there are debates about the effectiveness of prophylactic intrathecal chemotherapy to the brain, because in the majority of cases, CNS recurrences involve the brain parenchyma [6]. Several study groups added prophylactic cranial irradiation and in this cohort of patients CNS relapse was reduced [19]. Although addition of rituximab, an anti-CD20 monoclonal antibody, improved the PFS of elderly patients with aggressive CD20 positive lymphoma, such an effect was not observed in patients with testicular lymphoma [4]. The brain, testicles, and parts of the eye including, inter alia, the vitreous humor, and the retina, are immune privileged or sanctuary organs with strong blood-tissue barriers: the blood-brain barrier, the blood-retinal barrier, and the blood-tubular barrier [20, 21]. These barriers impair drug entrance and reduce effectiveness of monoclonal antibodies. An altered immune response allows cells, including certain malignant cells expressing nonself antigen, to escape destruction by the immune system [20-22]. The uniqueness of these three organs may partially explain the development of primary B-cell lymphoma in multiple immunoprivileged sites at different times or parallel to each other and may hint at specific features of this type of lymphoma. Batchelor et al. [23] showed that measurement of intravitreous levels of MTX after the administration of 8 g/m2 of MTX demonstrated a therapeutic dose at 4 hours after end of therapy; however, in their study, only four of nine patients had a sustained response. However, such high dose may not be tolerated by elderly patients. A therapeutic dose of >1 μM was obtained for 48 to 72 hours following intravitreal MTX [24]. The use of high dose of MTX (3 g/m2) should be evaluated in a randomized controlled study even for patients with Stage I testicular lymphoma. A high index of suspicion for intraocular lymphoma (IOL) must be maintained because early visual symptoms are not specific. Because eye examination is abnormal in >90% of patients with IOL revealing vitreous cells and retinal or subretinal infiltrate, it should be added to routine follow-up of testicular lymphoma patients. In summary, patients with testicular lymphoma are at high risk for extranodal disease progression, especially for CNS involvement. Any visual disturbance or uveitis should raise the suspicion of IOL. Routine eye examination should be considered as part of the follow-up because of reported IOL up to 10 years from the diagnosis of testicular lymphoma. This is an observational case study. The patient has been followed routinely for the three sites of involvement, including imaging studies. The data on the patient were collected from the patient's files in the Department of Hematology and Bone Marrow Transplantation of the Rambam Medical Center in Haifa, Israel, and at the Department of Ophthalmology of the Hadassah-Hebrew University Medical Center in Jerusalem, Israel. Jacob Pe'er*, Jacob M. Rowe , Shahar Frenkel*, Eldad J. Dann , * Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel, Department of Hematology and Bone Marrow Transplantation, Rambam Medical Center, Haifa, Israel, Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.