原发性中枢神经系统淋巴瘤的诊疗进展
Advances in the Diagnosis and Treatment of Primary Central Nervous System Lymphoma
摘要: 原发性中枢神经系统淋巴瘤(primary CNS lymphoma, PCNSL)是一种主要发病于脑、脊髓、颅神经、软脑膜及眼球的罕见的侵袭性结外非霍奇金淋巴瘤。其发病机制包括多种免疫球蛋白与自体蛋白结合，以及多种信号传导相关基因的改变。原发性中枢神经系统淋巴瘤的临床症状因发病部位不同而展现出不同表现。对于原发性中枢神经系统淋巴瘤，影像学检查、脑脊液检查及病理活检仍是目前主流的诊断手段。其标准治疗中，诱导治疗以高剂量甲氨蝶呤(HD-MTX)为基础，后续根据患者个体情况进行调整的自体造血干细胞移植(HDC-ASCT)。新药如BTK抑制剂和免疫检查点抑制剂等靶向治疗的疗效也正在开展相关研究。
Abstract: Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal non-Hodgkin lymphoma that predominantly arises in the brain, spinal cord, cranial nerves, leptomeninges, and eyes. Its pathogenesis involves the binding of multiple immunoglobulins to autologous proteins, as well as alterations in genes related to cell signal transduction. The clinical manifestations of PCNSL vary depending on the affected anatomical site. Current mainstream diagnostic approaches include neuroimaging, cerebrospinal fluid analysis, and pathological biopsy. Standard treatment involves induction therapy based on high-dose methotrexate (HD-MTX), followed by high-dose chemotherapy consolidated with autologous stem cell transplantation (HDC-ASCT) tailored to patient-specific conditions. Emerging targeted therapies, such as BTK inhibitors and immune checkpoint inhibitors, are being investigated for their therapeutic efficacy.
文章引用：邱浩然, 周慷. 原发性中枢神经系统淋巴瘤的诊疗进展[J]. 临床医学进展, 2025, 15(9): 1034-1043. https://doi.org/10.12677/acm.2025.1592589

参考文献

[1] Ferreri, A.J.M., Calimeri, T., Cwynarski, K., Dietrich, J., Grommes, C., Hoang-Xuan, K., et al. (2023) Primary Central Nervous System Lymphoma. Nature Reviews Disease Primers, 9, Article No. 29. [Google Scholar] [CrossRef] [PubMed]
[2] Villano, J.L., Koshy, M., Shaikh, H., Dolecek, T.A. and McCarthy, B.J. (2011) Age, Gender, and Racial Differences in Incidence and Survival in Primary CNS Lymphoma. British Journal of Cancer, 105, 1414-1418. [Google Scholar] [CrossRef] [PubMed]
[3] Montesinos-Rongen, M., Küppers, R., Schlüter, D., Spieker, T., Van Roost, D., Schaller, C., et al. (1999) Primary Central Nervous System Lymphomas Are Derived from Germinal-Center B Cells and Show a Preferential Usage of the V4-34 Gene Segment. The American Journal of Pathology, 155, 2077-2086. [Google Scholar] [CrossRef] [PubMed]
[4] Hernández-Verdin, I., Kirasic, E., Wienand, K., Mokhtari, K., Eimer, S., Loiseau, H., et al. (2023) Molecular and Clinical Diversity in Primary Central Nervous System Lymphoma. Annals of Oncology, 34, 186-199. [Google Scholar] [CrossRef] [PubMed]
[5] Fukumura, K., Kawazu, M., Kojima, S., Ueno, T., Sai, E., Soda, M., et al. (2016) Genomic Characterization of Primary Central Nervous System Lymphoma. Acta Neuropathologica, 131, 865-875. [Google Scholar] [CrossRef] [PubMed]
[6] Camilleri-Broët, S., Crinière, E., Broët, P., Delwail, V., Mokhtari, K., Moreau, A., et al. (2005) A Uniform Activated B-Cell-Like Immunophenotype Might Explain the Poor Prognosis of Primary Central Nervous System Lymphomas: Analysis of 83 Cases. Blood, 107, 190-196. [Google Scholar] [CrossRef] [PubMed]
[7] Chen, R., Zhou, D., Wang, L., Zhu, L. and Ye, X. (2022) MYD88L265P and CD79B Double Mutations Type (MCD Type) of Diffuse Large B-Cell Lymphoma: Mechanism, Clinical Characteristics, and Targeted Therapy. Therapeutic Advances in Hematology, 13, 1-11. [Google Scholar] [CrossRef] [PubMed]
[8] Choi, J., Phelan, J.D., Wright, G.W., Häupl, B., Huang, D.W., Shaffer, A.L., et al. (2020) Regulation of B Cell Receptor-Dependent NF-κB Signaling by the Tumor Suppressor KLHL14. Proceedings of the National Academy of Sciences of the United States of America, 117, 6092-6102. [Google Scholar] [CrossRef] [PubMed]
[9] Montesinos-Rongen, M., Schmitz, R., Brunn, A., Gesk, S., Richter, J., Hong, K., et al. (2010) Mutations of CARD11 but Not TNFAIP3 May Activate the NF-κB Pathway in Primary CNS Lymphoma. Acta Neuropathologica, 120, 529-535. [Google Scholar] [CrossRef] [PubMed]
[10] Chapuy, B., Roemer, M.G.M., Stewart, C., Tan, Y., Abo, R.P., Zhang, L., et al. (2016) Targetable Genetic Features of Primary Testicular and Primary Central Nervous System Lymphomas. Blood, 127, 869-881. [Google Scholar] [CrossRef] [PubMed]
[11] Bruno, A., Alentorn, A., Daniau, M., Labussière, M., Rahimian, A., Tabouret, E., et al. (2015) TERT Promoter Mutations in Primary Central Nervous System Lymphoma Are Associated with Spatial Distribution in the Splenium. Acta Neuropathologica, 130, 439-440. [Google Scholar] [CrossRef] [PubMed]
[12] Muta, H., Sugita, Y., Furuta, T., Shiimura, Y., Ohshima, K., Nakashima, K., et al. (2020) Expression of the Ghrelin/Growth Hormone Secretagogue Receptor Axis and Its Functional Role in Promoting Tumor Growth in Primary Central Nervous System Lymphomas. Neuropathology, 40, 232-239. [Google Scholar] [CrossRef] [PubMed]
[13] Baraniskin, A., Kuhnhenn, J., Schlegel, U., Chan, A., Deckert, M., Gold, R., et al. (2011) Identification of Micrornas in the Cerebrospinal Fluid as Marker for Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System. Blood, 117, 3140-3146. [Google Scholar] [CrossRef] [PubMed]
[14] Thurner, L., Preuss, K., Bewarder, M., Kemele, M., Fadle, N., Regitz, E., et al. (2018) Hyper-N-Glycosylated SAMD14 and Neurabin-I as Driver Autoantigens of Primary Central Nervous System Lymphoma. Blood, 132, 2744-2753. [Google Scholar] [CrossRef] [PubMed]
[15] Ponzoni, M., Berger, F., Chassagne‐Clement, C., Tinguely, M., Jouvet, A., Ferreri, A.J.M., et al. (2007) Reactive Perivascular T‐Cell Infiltrate Predicts Survival in Primary Central Nervous System B‐Cell Lymphomas. British Journal of Haematology, 138, 316-323. [Google Scholar] [CrossRef] [PubMed]
[16] Sugita, Y., Terasaki, M., Nakashima, S., Ohshima, K., Morioka, M. and Abe, H. (2014) The Perivascular Microenvironment in Primary Central Nervous System Lymphomas: The Role of Chemokines and the Endothelin B Receptor. Brain Tumor Pathology, 32, 41-48. [Google Scholar] [CrossRef] [PubMed]
[17] Grommes, C., Rubenstein, J.L., DeAngelis, L.M., Ferreri, A.J.M. and Batchelor, T.T. (2018) Comprehensive Approach to Diagnosis and Treatment of Newly Diagnosed Primary CNS Lymphoma. Neuro-Oncology, 21, 296-305. [Google Scholar] [CrossRef] [PubMed]
[18] Takase, H., Arai, A., Iwasaki, Y., Imai, A., Nagao, T., Kawagishi, M., et al. (2022) Challenges in the Diagnosis and Management of Vitreoretinal Lymphoma—Clinical and Basic Approaches. Progress in Retinal and Eye Research, 90, Article ID: 101053. [Google Scholar] [CrossRef] [PubMed]
[19] Raval, V., Binkley, E., Aronow, M.E., Valenzuela, J., Peereboom, D.M. and Singh, A.D. (2021) Primary Central Nervous System Lymphoma—Ocular Variant: An Interdisciplinary Review on Management. Survey of Ophthalmology, 66, 1009-1020. [Google Scholar] [CrossRef] [PubMed]
[20] Liu, L., Zhang, H., Zhang, H., Liu, X., Deng, H., Lin, F., et al. (2023) Distinctive Magnetic Resonance Imaging Features in Primary Central Nervous System Lymphoma: A Case Report. World Journal of Radiology, 15, 274-280. [Google Scholar] [CrossRef] [PubMed]
[21] Ambady, P., Hu, L.S., Politi, L.S., Anzalone, N. and Barajas Jr, R.F. (2021) Primary Central Nervous System Lymphoma: Advances in MRI and PET Imaging. Annals of Lymphoma, 5, 27. [Google Scholar] [CrossRef] [PubMed]
[22] Küker, W., Nägele, T., Korfel, A., Heckl, S., Thiel, E., Bamberg, M., et al. (2005) Primary Central Nervous System Lymphomas (PCNSL): MRI Features at Presentation in 100 Patients. Journal of Neuro-Oncology, 72, 169-177. [Google Scholar] [CrossRef] [PubMed]
[23] Helle, T.L., Britt, R.H. and Colby, T.V. (1984) Primary Lymphoma of the Central Nervous System. Journal of Neurosurgery, 60, 94-103. [Google Scholar] [CrossRef] [PubMed]
[24] 何京美, 黄德晖, 吴卫平. 原发性中枢神经系统淋巴瘤的临床特点和影像特征分析[J]. 解放军医学院学报, 2021, 42(3): 291-296.
[25] Capasso, R., Negro, A., Russo, C., Zeccolini, F., Muto, G., Caranci, F., et al. (2023) Conventional and Advanced MRI Techniques in the Evaluation of Primary CNS Lymphoma. Seminars in Ultrasound, CT and MRI, 44, 126-135. [Google Scholar] [CrossRef] [PubMed]
[26] Kim, C., Choi, C., Yi, K.S., Kim, Y., Lee, J., Woo, C.G., et al. (2024) Absence of Enhancement in a Lesion Does Not Preclude Primary Central Nervous System T-Cell Lymphoma: A Case Report. World Journal of Clinical Cases, 12, 374-382. [Google Scholar] [CrossRef] [PubMed]
[27] Park, H.Y., Suh, C.H., Huang, R.Y., Guenette, J.P. and Kim, H.S. (2021) Diagnostic Yield of Body CT and Whole-Body FDG PET/CT for Initial Systemic Staging in Patients with Suspected Primary CNS Lymphoma: A Systematic Review and Meta-Analysis. American Journal of Roentgenology, 216, 1172-1182. [Google Scholar] [CrossRef] [PubMed]
[28] Wang, M., Liu, G., Zhang, N., Li, Y., Sun, S., Tan, Y., et al. (2025) Detecting B-Cell Lymphoma-6 Overexpression Status in Primary Central Nervous System Lymphoma Using Multiparametric MRI-Based Machine Learning. Neuroradiology, 67, 563-573. [Google Scholar] [CrossRef] [PubMed]
[29] Hasner, M.C., van Opijnen, M.P., van der Meulen, M., Verdijk, R.M., Maas, S.L.N., te Boome, L.C.J., et al. (2024) Diagnostics and Treatment Delay in Primary Central Nervous System Lymphoma: What the Neurosurgeon Should Know. Acta Neurochirurgica, 166, Article No. 261. [Google Scholar] [CrossRef] [PubMed]
[30] Bromberg, J.E.C., Breems, D.A., Kraan, J., Bikker, G., van der Holt, B., Smitt, P.S., et al. (2007) CSF Flow Cytometry Greatly Improves Diagnostic Accuracy in CNS Hematologic Malignancies. Neurology, 68, 1674-1679. [Google Scholar] [CrossRef] [PubMed]
[31] Ferreri, A.J.M., Calimeri, T., Lopedote, P., Francaviglia, I., Daverio, R., Iacona, C., et al. (2021) MYD88 L265P Mutation and Interleukin‐10 Detection in Cerebrospinal Fluid Are Highly Specific Discriminating Markers in Patients with Primary Central Nervous System Lymphoma: Results from a Prospective Study. British Journal of Haematology, 193, 497-505. [Google Scholar] [CrossRef] [PubMed]
[32] Bravetti, C., Degaud, M., Armand, M., Sourdeau, E., Mokhtari, K., Maloum, K., et al. (2023) Combining MYD88 L265p Mutation Detection and Clonality Determination on CSF Cellular and Cell‐Free DNA Improves Diagnosis of Primary CNS Lymphoma. British Journal of Haematology, 201, 1088-1096. [Google Scholar] [CrossRef] [PubMed]
[33] Yamaguchi, J., Ohka, F., Kitano, Y., Maeda, S., Motomura, K., Aoki, K., et al. (2023) Rapid Detection of the MYD88 L265p Mutation for Pre‐ and Intra‐Operative Diagnosis of Primary Central Nervous System Lymphoma. Cancer Science, 114, 2544-2551. [Google Scholar] [CrossRef] [PubMed]
[34] Ma, J., Lin, Z., Zhang, Y., Ding, Y., Tang, Q., Qian, Y., et al. (2024) Targeted Multiplex Validation of CSF Proteomic Biomarkers: Implications for Differentiation of PCNSL from Tumor-Free Controls and Other Brain Tumors. Frontiers in Immunology, 15, Article 1343109. [Google Scholar] [CrossRef] [PubMed]
[35] Kim, J.H., An, Y.J., Kim, T.M., Kim, J.E., Park, S. and Choi, S.H. (2022) Ex Vivo NMR Metabolomics Approach Using Cerebrospinal Fluid for the Diagnosis of Primary CNS Lymphoma: Correlation with MR Imaging Characteristics. Cancer Medicine, 12, 4679-4689. [Google Scholar] [CrossRef] [PubMed]
[36] Ganau, M., Zaed, I., Todeschi, J., Prisco, L., Cebula, H., Bruno, C., et al. (2022) Efficacy of Endoscopic Management of Primary Central Nervous System Lymphoma: A Multicentric Study and Literature Review. Journal of Neuro-Oncology, 159, 457-468. [Google Scholar] [CrossRef] [PubMed]
[37] Li, G., Hou, X., Fu, Y., He, D. and Zhang, D. (2025) Association between Surgery and Increased Survival in Primary Central Nervous System Lymphoma: A Retrospective Cohort Study. Scientific Reports, 15, Article No. 3816. [Google Scholar] [CrossRef] [PubMed]
[38] Chojak, R., Koźba-Gosztyła, M., Polańska, K., Rojek, M., Chojko, A., Bogacz, R., et al. (2022) Surgical Resection versus Biopsy in the Treatment of Primary Central Nervous System Lymphoma: A Systematic Review and Meta-Analysis. Journal of Neuro-Oncology, 160, 753-761. [Google Scholar] [CrossRef] [PubMed]
[39] Lee, C., Byeon, Y., Kim, G.J., Jeon, J., Hong, C.K., Kim, J.H., et al. (2025) Assessing the Effect of Cytoreduction on Solitary, Resectable Lesions in Primary Central Nervous System Lymphoma. Cancers, 17, Article 917. [Google Scholar] [CrossRef] [PubMed]
[40] Heming, M., Haessner, S., Wolbert, J., Lu, I., Li, X., Brokinkel, B., et al. (2022) Intratumor Heterogeneity and T Cell Exhaustion in Primary CNS Lymphoma. Genome Medicine, 14, Article No. 109. [Google Scholar] [CrossRef] [PubMed]
[41] Tang, Y., Shi, Y., Wang, L., Qian, Z., Fan, Y., Wu, H., et al. (2022) Preliminary Clinical Application of Multimodal Imaging Combined with Frameless Robotic Stereotactic Biopsy in the Diagnosis of Primary Central Nervous System Lymphoma. Heliyon, 8, e12162. [Google Scholar] [CrossRef] [PubMed]
[42] Dellaretti, M., de Lima, F.B.F., de Sena, P.H.V.P., Figueiredo, H.P.G., Albuquerque, J.P.S., Gomes, F.C., et al. (2024) Efficacy, Safety, and Impact of Fluorescein in Frameless Stereotactic Needle Biopsies—A Case Series. Neurosurgical Review, 47, Article No. 523. [Google Scholar] [CrossRef] [PubMed]
[43] Mazzucchi, E., Galieri, G., Pignotti, F., Rinaldi, P., Sabatino, G. and La Rocca, G. (2024) Combination of Tractography, Intraoperative Computed Tomography and 5-Aminolevulinic Acid Fluorescence in Stereotactic Brain Biopsies: A Case Series. Journal of Personalized Medicine, 14, Article 357. [Google Scholar] [CrossRef] [PubMed]
[44] Zhou, Z., Li, T., Zhang, Y., Zhou, X., Wang, X., Cui, D., et al. (2025) Biplanar or Monoplanar Prostate Biopsy: Should Transrectal and Transperineal Approaches Be Combined for Prostate Cancer Detection? International Brazilian Journal of Urology, 51, e20240630. [Google Scholar] [CrossRef] [PubMed]
[45] Malaizé, H., Laigle-Donadey, F., Riche, M., Marijon, P., Mokhtari, K., Bielle, F., et al. (2022) Roles and Outcomes of Stereotactic Biopsy for Adult Patients with Brainstem Lesion. Journal of Neuro-Oncology, 160, 159-170. [Google Scholar] [CrossRef] [PubMed]
[46] Tosefsky, K., Rebchuk, A.D., Martin, K.C., Chen, D.W., Yip, S. and Makarenko, S. (2024) Preoperative Corticosteroids Reduce Diagnostic Accuracy of Stereotactic Biopsies in Primary Central Nervous System Lymphoma: A Systematic Review and Meta-Analysis. Neurosurgery, 95, 740-750. [Google Scholar] [CrossRef] [PubMed]
[47] Chen, T., Liu, Y., Wang, Y., Chang, Q., Wu, J., Wang, Z., et al. (2022) Evidence-Based Expert Consensus on the Management of Primary Central Nervous System Lymphoma in China. Journal of Hematology & Oncology, 15, Article No. 136. [Google Scholar] [CrossRef] [PubMed]
[48] Soussain, C., Malaise, D. and Cassoux, N. (2021) Primary Vitreoretinal Lymphoma: A Diagnostic and Management Challenge. Blood, 138, 1519-1534. [Google Scholar] [CrossRef] [PubMed]
[49] Nezu, N., Usui, Y., Saito, A., Shimizu, H., Asakage, M., Yamakawa, N., et al. (2021) Machine Learning Approach for Intraocular Disease Prediction Based on Aqueous Humor Immune Mediator Profiles. Ophthalmology, 128, 1197-1208. [Google Scholar] [CrossRef] [PubMed]
[50] Tan, W.J., Wang, M.M., Castagnoli, P.R., Tang, T., Chan, A.S.Y. and Lim, T.S. (2021) Single B-Cell Genomic Analyses Differentiate Vitreoretinal Lymphoma from Chronic Inflammation. Ophthalmology, 128, 1079-1090. [Google Scholar] [CrossRef] [PubMed]
[51] Wang, X., Su, W., Gao, Y., Feng, Y., Wang, X., Chen, X., et al. (2022) A Pilot Study of the Use of Dynamic Analysis of Cell-Free DNA from Aqueous Humor and Vitreous Fluid for the Diagnosis and Treatment Monitoring of Vitreoretinal Lymphomas. Haematologica, 107, 2154-2162. [Google Scholar] [CrossRef] [PubMed]
[52] de Koning, M.E., Hof, J.J., Jansen, C., Doorduijn, J.K., Bromberg, J.E.C. and van der Meulen, M. (2023) Primary Central Nervous System Lymphoma. Journal of Neurology, 271, 2906-2913. [Google Scholar] [CrossRef] [PubMed]
[53] Scordo, M., Wang, T.P., Ahn, K.W., Chen, Y., Ahmed, S., Awan, F.T., et al. (2021) Outcomes Associated with Thiotepa-Based Conditioning in Patients with Primary Central Nervous System Lymphoma after Autologous Hematopoietic Cell Transplant. JAMA Oncology, 7, 993-1003. [Google Scholar] [CrossRef] [PubMed]
[54] Arshad, S., Fang, X., Ahn, K.W., Kaur, M., Scordo, M., Sauter, C.S., et al. (2023) Impact of Thiotepa Dose-Intensity in Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System Undergoing Autologous Hematopoietic Cell Transplant with Thiotepa/Carmustine Conditioning. Bone Marrow Transplantation, 58, 1203-1208. [Google Scholar] [CrossRef] [PubMed]
[55] Aquilanti, E., Herrity, E. and Nayak, L. (2024) Novel Therapies for Primary Central Nervous System Lymphomas. Current Neurology and Neuroscience Reports, 24, 621-629. [Google Scholar] [CrossRef] [PubMed]
[56] Habot‐Wilner, Z., Frenkel, S. and Pe’er, J. (2021) Efficacy and Safety of Intravitreal Methotrexate for Vitreo‐Retinal Lymphoma—20 Years of Experience. British Journal of Haematology, 194, 92-100. [Google Scholar] [CrossRef] [PubMed]
[57] Bromberg, J.E.C., Issa, S., van der Holt, B., van der Meulen, M., Dirven, L., Minnema, M.C., et al. (2023) Survival, Neurocognitive Function, and Health-Related Quality of Life Outcomes after Rituximab—Methotrexate, BCNU, Teniposide, and Prednisolone for Primary CNS Lymphoma: Final Results of the HOVON 105/ALLG NHL 24 Study. Neuro-Oncology, 26, 724-734. [Google Scholar] [CrossRef] [PubMed]
[58] Sheng, L., Liu, H., Zhang, X., Ding, K., Ma, J., Peng, H., et al. (2025) Prospective Phase II Trial of First-Line Rituximab, Methotrexate, and Orelabrutinib (R-MO) in Primary Central Nervous System Lymphoma. Blood Cancer Journal, 15, Article No. 81. [Google Scholar] [CrossRef] [PubMed]
[59] Schaff, L.R., Piotrowski, A.F., Pentsova, E., Gavrilovic, I.T., Lin, A., Kaley, T.J., et al. (2025) Phase Ib Study with Expansion of Ibrutinib, Lenalidomide, and Rituximab in Patients with Relapsed/Refractory Central Nervous System Lymphoma. Neuro-Oncology. [Google Scholar] [CrossRef] [PubMed]
[60] Grommes, C., Nandakumar, S., Schaff, L.R., Gavrilovic, I., Kaley, T.J., Nolan, C.P., et al. (2024) A Phase II Study Assessing Long-Term Response to Ibrutinib Monotherapy in Recurrent or Refractory CNS Lymphoma. Clinical Cancer Research, 30, 4005-4015. [Google Scholar] [CrossRef] [PubMed]
[61] Zeng, Z., Yang, A., Yang, J., Zhang, S., Xing, Z., Wang, X., et al. (2024) Sintilimab (Anti-Pd-1 Antibody) Combined with High-Dose Methotrexate, Temozolomide, and Rituximab (Anti-CD20 Antibody) in Primary Central Nervous System Lymphoma: A Phase 2 Study. Signal Transduction and Targeted Therapy, 9, Article No. 229. [Google Scholar] [CrossRef] [PubMed]
[62] Cook, M.R., Dorris, C.S., Makambi, K.H., Luo, Y., Munshi, P.N., Donato, M., et al. (2023) Toxicity and Efficacy of CAR T-Cell Therapy in Primary and Secondary CNS Lymphoma: A Meta-Analysis of 128 Patients. Blood Advances, 7, 32-39. [Google Scholar] [CrossRef] [PubMed]

为你推荐