Clinical features of primary vitreoretinal lymphoma developing extra-central nervous system (CNS)/testicular lymphomas with or without CNS involvement: A single-centre study of 13 cases.

Abstract

Vitreoretinal lymphoma (VRL) is a type of haematologic malignant neoplasm. Among VRLs, primary VRL (PVRL) is a subset of primary central nervous system (CNS) lymphoma (CNSL), which initially manifests in the eye with or without simultaneous CNS involvement. VRL is a rare malignancy typically classified as diffuse large B-cell lymphoma. PVRL most frequently affects older populations and usually develops in the retina, the vitreous chamber, and/or the optic nerve. In a previous report, 65% of patients presenting with PVRL developed CNSL, usually within 29 months, with poor survival outcome.1 PVRL has been reported to have a five-year survival rate of less than 30%.2 On the other hand, a multicentre study in Japan reported that the five-year survival rate of PVRL improved to 61.1% due to earlier diagnosis, new diagnostic tests, and refined diagnostic criteria.3 The reason for the high incidence of CNSL and testicular lymphoma in PVRL is that the eye, CNS, and testis are immune-privileged sites, with similar immune mechanisms.4 On the other hand, extra-CNS/testicular involvement after PVRL is rare. Although some cases have been reported,5-11 there are no cross-sectional or cohort studies. Among 105 patients diagnosed with VRL in our department, some of the patients diagnosed with PVRL subsequently developed lymphomas in organs other than the CNS and testis. In this study, we examined the demographic and clinical features as well as diagnostic findings of these cases. We retrospectively reviewed the medical records of all patients diagnosed with VRL at the Department of Ophthalmology of Tokyo Medical University Hospital. Institutional review board approval was obtained for this retrospective study. The diagnosis of VRL was based on clinical features and test results of diagnostic vitrectomy, comprising cytology, cytokine analysis and polymerase chain reaction analysis, as described previously.12 All patients with ocular lesions were examined by cranial magnetic resonance imaging (MRI) and/or computed tomography (CT) to detect CNSL during the follow-up period. Lymphomas in extra-CNS/testicular organs were detected and diagnosed by biopsy and/or systemic work-up such as systemic CT and/or scintigraphy gallium scintigraphy and/or positron emission tomography (PET)/CT fusion scan. Primary measures in this study were the clinical features of PVRL with subsequent extra-CNS/testicular involvement, including the presence or absence of CNS lesion, number of relapses, and disease duration. Statistical analyses were performed using JMP version 13 (Business Unit of SAS, Cary, NC, USA). Upon testing for normal distribution with the Shapiro–Wilk test, the data were found to be not normally distributed. Thus, non-parametric tests (chi-squared test and Mann–Whitney test) were used to determine significant differences between two groups. The five-year survival rate was defined as the proportion of patients surviving five years or longer after the initial diagnosis of VRL. Survival curves were estimated by the Kaplan–Meier method and analysed using the log-rank test. A p value less than 0.05 was considered statistically significant. A total of 163 eyes of 105 patients diagnosed with VRL during the study period were included in the study. Their demographic and clinical data are shown in Table S1. Thirty-one patients (29.5%) had PVRL only; 53 patients (50.5%) had both VRL and CNSL; and 21 patients (20.0%) had VRL and extra-CNS/testicular lymphoma. Among 21 patients with VRL and extra-CNS/testicular involvement, 13 (12.4% of all VRL patients) had PVRL and subsequent extra-CNS/testicular involvement with/without CNSL; eight patients (7.6% of all VRL patients) had primary extra-CNS/testicular lymphoma with subsequent development of VRL with/without CNSL during the observation period. The clinical features of VRL diagnosed in our institution are summarized in Figure 1 and Table S1. The 13 patients in the PVRL + extra-CNS/testicular involvement group were the subjects of analysis in this study. Table S2 shows the detailed clinical features and relapses in these patients. The sites of involvement were lymph nodes (LN) in five cases; skin in two cases; bone marrow in two cases; and lung, heart, paranasal sinus, buccal region, spleen, ascites, and pleural and pericardial effusion in one case each (with overlap). The imaging findings of representative systemic lymphomas are presented in Figure 2. The lymphomas were diagnosed histopathologically as diffuse large B-cell lymphoma in 12 patients and intravascular large B-cell lymphoma in one patient, while no marginal-zone lymphoma was detected. Only three patients were confirmed to be alive, and the other 10 patients died. The median (first–third quartile) survival time, defined as the duration from the first visit to our ophthalmology department until death, was 53.5 (26.3–87.3) months, and the five-year survival rate was 52.4%. Of the 10 patients who died, six developed CNSL after PVRL diagnosis. The cause of death was CNSL in four cases, pneumonia in one case, disseminated intravascular coagulation in one case, malignant pleural effusion in one case, renal failure due to ascites in one case, and unknown in two cases. Eight of the 13 patients (61.5%) with PVRL + extra-CNS/testicular involvement also had subsequent CNS involvement. Table S3 compares the subgroup with CNSL (n = 8) and the subgroup without CNSL (n = 5). There were no significant differences in patient characteristics and outcomes between the two subgroups. The proportion of VRL with lymphoma development in organs other than the CNS and testis was reported to be 10% of all VRLs by Kimura et al.3 9% by Kao et al.13 and 10% by Karakawa et al.14 In our study, 12.4% of patients with PVRL had relapses involving extra-CNS/testicular organs after the initial diagnosis of PVRL. In our series, extra-CNS/testicular lymphomas secondary to PVRL developed in the skin, LN, and heart, as well as sites not previously reported, including bone marrow, paranasal sinus, buccal region, spleen, ascites, pleural and pericardial effusion. All five patients with LN involvement relapsed three times or more, and all patients except one with lymphomas in two or more extra-CNS/testicular organs had LN involvement. From these results, PVRL is usually an aggressive lymphoma that infiltrates the CNS and relapses in a multitude of systemic organs. Periodic brain MRI is required, and a yearly systemic work-up with PET/CT may be necessary. In the comparison of the presence and absence of CNSL in patients with PVRL and extra-CNS/testicular lymphoma, no significant differences in patient characteristics and outcomes were observed (Table S3). Of eight patients who developed CNSL after PVRL diagnosis, six patients died and the cause of death was CNSL in four patients and deterioration of general condition in two patients. The four cases that died due to CNSL included cases with cognitive dysfunction or pneumonia presumably caused by CNSL. Furthermore, even in patients who did not develop CNSL, the total mortality rate was not significantly different from that in patients who developed CNSL, and the cause of death was deteriorated systemic conditions. Therefore, systemic medical history and work-up including PET/CT for detection of CNSL and/or systemic deterioration would be important in all patients. In conclusion, PVRL patients with secondary systemic lymphoma with or without CNSL may have poor prognosis. This study shows that PVRL may recur not only in the CNS but also in a diversity of organs throughout life. Systemic examinations including systemic CT and/or PET/CT are necessary not only at the initial diagnosis of PVRL but also at the initial diagnosis of systemic lymphoma. Lifelong systemic work-up may be needed in these patients. The corresponding author has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Keiko Kunimi: concept and design; acquisition, analysis, or interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; statistical analysis; and obtained funding. Yoshihiko Usui: Administrative, technical, or material support; supervision. Risa Sugawara, Kinya Tsubota, Masaki Asakage: acquisition of clinical data. Akihiko Gotoh, Hiroshi Goto: Supervision. All authors approved the final paper for submission and publication. The funding organization had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. This work was supported by a Grand-in-Aid for Scientific Research (C) 22K09840 from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and the Japan Agency for Medical Research and Development (AMED) 22Ik0201163h0001. Hiroshi Goto has served on advisory boards for AbbVie. Yoshihiko Usui received financial support from AbbVie, Inc., Eisai, Co. Ltd. and Santen, Inc. The other authors have no conflicts of interest to declare. The study was approved by the institutional review board of Tokyo Medical Hospital Group (No. CRB3180033). Not required. Not commissioned; externally peer reviewed. Table S1. Table S2. Table S3. 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