Table 1. Reported cases of primary central nervous system methotrexate-associated lymphoproliferative disorder.
| Study | Age/ sex | MTX mg/week (yr) | Other immune suppressors | Neurological symptoms | LPD site/properties | Biopsy site | Histopathology | EBER | Regression after MTX withdrawal | Additional LPD treatment | Outcome | Follow-up duration | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Kleinschmidt 2008.7) | 78/F | Standard dose (>10) | NA | NA | Cerebrum, multiple lesions | Cerebrum | P/L LPD | Yes | Yes | No | Died 3 mo later; multi-organ failure attributable to RA | 3 mo |
| 2 | Fukushima 2013.8) | 64/F | 6 (4) | No | Headache, dementia | Cerebrum, multiple lesions | Cerebrum | PTCL-NOS | Yes | Yes (transient) | High-dose MTX with leucovorin rescue | Good | 1 yr |
| 3 | Migita 2013.9) | 53/F | 8 (1) | Bucillamine, PRD | Nausea, vomiting, vertigo, double vision | Medulla, single lesion | Medulla | DLBCL | Yes | Yes | Resection of mass | Good | 8 yr |
| 4 | Liu 2015.10) | 58/M | 10 (2) | No | Depression, nausea, vomiting | Cerebrum, multiple lesions | Cerebrum | DLBCL | No | NA | Radiotherapy | Good | 1 yr |
| 5 | Shimada 2015.11) | 60s/F | 14 (7) | ETN, ADL, PRD | Convulsion | Cerebrum, multiple lesions | Cervical lymph node | NC (dispersed Hodgkin-like large cells with CD20+ lymphocytes) | Yes | Yes | No | Good | >1 yr |
| 6 | Kikuchi 2016.12) | 50/F | 8 (3) | ETN, ADL | No | Hypertrophy of frontal dura mater | Skin, subcutaneous | IVLBCL | No | Partial improvement | R-CHOP + intrathecal CT (PRD+ MTX + cytarabine) | Good | 2 yr |
| 7 | Matsuda 2018.13) | 76/F | NA (2) | No | Staggering gait | Cerebrum, multiple lesions | Cerebrum | NC (perivascular proliferation of CD20+ lymphoid cells) | Yes | Yes | NA | NA | NA |
| 8 | Uchida 2018.14) | 52/F | 8 (4) | ETN | Dementia, hemiparesis | Cerebrum, multiple lesions | Cerebrum | DLBCL | No | No | Rituxan + high-dose MTX + cytarabine, RT | Died 17 mo after onset | 17 mo |
| 9 | Miyaza 2019.15) | 68/F | 16 (5) | No | Hemiparesis, dysgraphia, speech disturbance | Cerebrum, single lesion | Cerebrum | NC (dense proliferation of CD20+ lymphocytes with atypical nuclei in perivascular lesion) | Yes | Yes | No | Good | >3 yrs |
| 10 | Present case | 68/F | 8 (>10) | No | Motor aphasia, hemiparesis | Cerebrum, multiple lesions | Cerebrum | DLBCL | Yes | Yes | No | Good | 8 mo |
All patients’ primary disease was RA.
ADL: adalimumab, CT: chemotherapy, DLBCL: diffuse large B-cell lymphoma, EBER: Epstein-Barr virus-encoded small RNA, ETN: Etanercept, F: female, HL LPD: Hodgkin’s lymphoma–like lymphoproliferative disorder, IVLBCL: intravascular large B-cell lymphoma, LPD: lymphoproliferative disorder, M: Male, mo: months, MTX: Methotrexate, NA: not available, NC: non-classifiable, P/L LPD: polymorphic/lymphoplasmacytic lymphoproliferative disorder, PRD: Prednisolone, PTCL-NOS: peripheral T-cell lymphoma, not otherwise specified, RA: rheumatic arthritis, R-CHOP: rituximab + cyclophosphamide + vincristine + adriamycin + prednisolone, RT: radiotherapy, yr: years.