今日の臨床サポート

癌性髄膜炎

著者: 内藤陽一 国立研究開発法人 国立がん研究センター東病院 総合内科/先端医療科/腫瘍内科

監修: 田村研治 国立がん研究センター中央病院

著者校正/監修レビュー済:2017/01/26

概要・推奨   

疾患のポイント:
  1. 癌性髄膜炎は、癌細胞が髄膜に転移した状態である。転移性固形癌の約4~15%にみられ、原発巣としては乳癌(12~35%)、肺癌(10~26%)、悪性黒色腫(5~25%)が多く、組織型では腺癌が最も多い。
 
診断:
  1. 癌性髄膜炎は髄液細胞診あるいはMRIなどの画像診断により診断される。髄液細胞診で癌細胞が認められれば確定診断となる。しかし、髄液細胞診は単回では感度は高くなく、繰り返すことで感度が上昇する(1回の細胞診では71%、2回で86%、3回で90%、4回では98%と報告される)。
  1. 癌の診断が確定している患者では、MRI検査による診断も可能である(感度76~87%)。髄膜に沿った造影効果や結節病変などがみられる。
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
内藤陽一 : 講演料(ファイザー,中外製薬,日本イーライリリー),研究費・助成金など(ファイザー,大鵬薬品工業,エーザイ,日本ベーリンガーインゲルハイム)[2021年]
監修:田村研治 : 未申告[2021年]

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 転移性固形癌の約4~15%に診断される。剖検例では20%にのぼる[1][2][3]
  1. 原発巣としては乳癌(12~35%)、肺癌(10~26%)、悪性黒色腫(5~25%)が多く、組織型では腺癌が最も多い[4][5]
  1. HER2陽性乳癌、EGFR遺伝子変異陽性非小細胞肺癌における、分子標的薬剤(trastuzumab、erlotinib、gefitinib)の臨床導入に伴い、これらの癌種における癌性髄膜炎の相対的な増加が問題となってきている。
  1. 多くの症例(>70%)において、癌性髄膜炎は転移性癌の病変の一部としてみられるが、まれには(5~10%)癌性髄膜炎が唯一の癌の症状としてみられ得る[4]
  1. 脳転移を合併することが多い(50~80%)[5]
問診・診察のポイント  
  1. 現在および過去の癌罹患の有無。

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文献 

著者: M C Chamberlain
雑誌名: Arch Neurol. 1997 Jan;54(1):16-7.
Abstract/Text
PMID 9006407  Arch Neurol. 1997 Jan;54(1):16-7.
著者: J P Glass, M Melamed, N L Chernik, J B Posner
雑誌名: Neurology. 1979 Oct;29(10):1369-75.
Abstract/Text We reviewed the correlation between malignant cells in cerebrospinal fluid (CSF) (positive cytology) and pathologic findings at autopsy. The purpose was to discover: (1) the incidence of negative CSF cytology in patients with CNS malignancy, (2) the incidence of false-positive cytology, and (3) the relationship between a true-positive cytology and the distribution of malignant tumor at autopsy. Of 117 patients with CNS tumor and premortem cytologic examination of the CSF, 31 (26 percent) were positive and 86 (74 percent) were negative. Only 1 of 66 patients with tumor that did not reach the leptomeninges had a positive cytology. Of 51 patients with leptomeningeal tumor at autopsy, cytology was positive in 30 (59 percent) and negative in 21 (41 percent). Five potentially "false-positive" cytologies were encountered: three patients were treated, and tumor may have been eradicated; in two patients with lymphoma, inflammatory cells associated with infection were apparently mistaken for malignant cells. These data indicate that a positive CSF cytology is a reliable indicator of CNS malignancy and almost always reflects leptomeningeal tumor.

PMID 573381  Neurology. 1979 Oct;29(10):1369-75.
著者: Giuseppe Lombardi, Fable Zustovich, Patrizia Farina, Alessandro Della Puppa, Renzo Manara, Diego Cecchin, Antonella Brunello, Alessandro Cappetta, Vittorina Zagonel
雑誌名: Oncologist. 2011;16(8):1175-88. doi: 10.1634/theoncologist.2011-0101. Epub 2011 Jul 27.
Abstract/Text Neoplastic meningitis is a result of the spread of malignant cells to the leptomeninges and subarachnoid space and their dissemination within the cerebrospinal fluid. This event occurs in 4%-15% of all patients with solid tumors and represents an important prognostic factor for poor survival. Neoplastic meningitis should be diagnosed in the early stages of disease to prevent important neurological deficits and to provide the most appropriate treatment. Despite new diagnostic approaches developed in recent years, such as positron emission tomography-computed tomography and new biological markers, the combination of magnetic resonance imaging without and with gadolinium enhancement and cytology still has the greatest diagnostic sensitivity. Recently, no new randomized studies comparing intrathecal (i.t.) with systemic treatment have been performed, yet there have been a few small phase II studies and case reports about new molecularly targeted substances whose successful i.t. or systemic application has been reported. Trastuzumab, gefitinib, and sorafenib are examples of possible future treatments for neoplastic meningitis, in order to better individualize therapy thus allowing better outcomes. In this review, we analyze the most recent and interesting developments on diagnostic and therapeutic approaches.

PMID 21795431  Oncologist. 2011;16(8):1175-88. doi: 10.1634/theoncolog・・・
著者: Marc C Chamberlain
雑誌名: Oncologist. 2008 Sep;13(9):967-77. doi: 10.1634/theoncologist.2008-0138. Epub 2008 Sep 5.
Abstract/Text BACKGROUND: Neoplastic meningitis (NM) is a common problem in neuro-oncology, occurring in approximately 5% of all patients with cancer.
METHODS: Notwithstanding frequent focal signs and symptoms, NM is a disease affecting the entire neuraxis, and therefore staging and treatment need encompass all cerebrospinal fluid (CSF) compartments.
RESULTS: Central nervous system staging of NM includes contrast-enhanced cranial computerized tomography or magnetic resonance imaging (MR-Gd), contrast-enhanced spine magnetic resonance imaging or computerized tomographic myelography and radionuclide CSF flow study. Treatment of NM incorporates involved-field radiotherapy of bulky or symptomatic disease sites and intra-CSF drug therapy. The inclusion of concomitant systemic therapy may benefit patients with NM and may obviate the need for intra-CSF chemotherapy. At present, intra-CSF drug therapy is confined to three chemotherapeutic agents (i.e., methotrexate, cytosine, arabinoside, and thio-TEPA) administered by a variety of schedules either by intralumbar or intraventricular drug delivery.
CONCLUSIONS: Although treatment of NM is palliative with an expected median patient survival of 2 to 6 months, it often affords stabilization and protection from further neurologic deterioration in patients with NM.

PMID 18776058  Oncologist. 2008 Sep;13(9):967-77. doi: 10.1634/theonco・・・
著者: M J Glantz, B F Cole, L K Glantz, J Cobb, P Mills, A Lekos, B C Walters, L D Recht
雑誌名: Cancer. 1998 Feb 15;82(4):733-9.
Abstract/Text BACKGROUND: Detection of malignant cells on cytologic examination of the cerebrospinal fluid (CSF) is the diagnostic gold standard for leptomeningeal carcinomatosis. The absence of cells is a primary endpoint for most therapeutic trials. Unfortunately, false-negative results are common. Practical strategies are necessary to remedy this problem.
METHODS: Four physician-dependent variables (CSF sample volume, site of CSF sampling, processing time, and frequency of CSF sampling) were identified, and their contributions to the false-negative rate of CSF cytology were evaluated prospectively in 39 patients with leptomeningeal carcinomatosis. Retrospective data were analyzed to estimate the importance of these variables in daily practice.
RESULTS: False-negative CSF cytology results correlated with small CSF volume (P < 0.001), delayed processing (P < 0.001), not obtaining CSF from a site of symptomatic or radiographically demonstrated disease (P = 0.02), and sampling fewer than two times (P < 0.001). In 1 year, 97% of CSF specimens at the study institution were of inadequate volume; >25% were processed too slowly.
CONCLUSIONS: False-negative CSF cytology results are common, but can be minimized by: 1) withdrawing at least 10.5 mL of CSF for cytologic analysis; 2) processing the CSF specimen immediately; 3) obtaining CSF from a site of known leptomeningeal disease; and 4) repeating this procedure once if the initial cytology is negative.

PMID 9477107  Cancer. 1998 Feb 15;82(4):733-9.
著者: C S Straathof, H G de Bruin, D W Dippel, C J Vecht
雑誌名: J Neurol. 1999 Sep;246(9):810-4.
Abstract/Text Diagnostic decision making in the case of patients suspected of having leptomeningeal metastasis (LM) can be very difficult. The results of cerebrospinal fluid (CSF) cytology can be repeatedly negative, and the predictive value of gadolinium-enhanced magnetic resonance imaging (MRI) is not well known. We report the results of CSF cytology and Gd MRI in 61 patients with known cancer, suspected of having LM. We combined our data with those from a similar study and calculated the sensitivity and specificity of CSF and Gd MRI, in the absence of a "gold standard diagnosis." CSF cytology was positive for LM in 35 patients and MRI in 38. With CSF cytology sensitivity 75% and specificity 100%, with Gd MRI sensitivity was 76% but specificity only 77%. We conclude that Gd MRI provides strong support in the diagnosis of LM in patients with cancer who have negative results on CSF cytology.

PMID 10525979  J Neurol. 1999 Sep;246(9):810-4.
著者: R J Freilich, G Krol, L M DeAngelis
雑誌名: Ann Neurol. 1995 Jul;38(1):51-7. doi: 10.1002/ana.410380111.
Abstract/Text The diagnosis of leptomeningeal metastasis is often difficult and usually requires the demonstration of malignant cells in the cerebrospinal fluid. Neuroimaging, however, may establish or support the diagnosis in some patients. Radiographic abnormalities consistent with or suggestive of leptomeningeal metastasis include leptomeningeal, subependymal, dural, or cranial nerve enhancement; superficial cerebral lesions; and communicating hydrocephalus. We evaluated 137 cancer patients with clinical symptoms suspicious for leptomeningeal metastasis with neuroimaging or cerebrospinal fluid cytology or both. Neuroimaging findings were abnormal in 70 of 128 tested patients; cytology was performed in 58 of these 70 and the results were positive in 37. Conversely, cytological findings were positive in 53 of 115 tested patients; neuroimaging was performed in 49 of these 53 and the findings were abnormal in 37 (26/29 solid tumors and 11/20 hematological tumors). Of the total series of 137 patients, leptomeningeal metastasis was diagnosed in 77; in 24 (31%) the diagnosis was made on the basis of clinical picture and abnormal neuroimaging alone. Neuroimaging is a valuable tool in the investigation of leptomeningeal metastasis in the cancer population, and the presence of typical clinical features together with appropriate neuroimaging abnormalities is adequate to make the diagnosis of leptomeningeal metastasis even if cerebrospinal fluid cytological results are negative.

PMID 7611725  Ann Neurol. 1995 Jul;38(1):51-7. doi: 10.1002/ana.41038・・・
著者: M C Chamberlain, A D Sandy, G A Press
雑誌名: Neurology. 1990 Mar;40(3 Pt 1):435-8.
Abstract/Text We evaluated 14 consecutive patients with leptomeningeal metastasis prospectively, using both T1-weighted (T1W) gadolinium-DTPA-enhanced MR (Gd-MR) and contrast-enhanced CT (CE-CT). Thirteen had positive CSF cytology; the remaining patient had an atypical CSF lymphocytosis and primary CNS lymphoma. The patients (8M/6F) ranged in age from 8 to 70 years (median, 42 years). Tumor histology included 3 systemic and 2 primary CNS lymphomas, 3 breast carcinomas, 2 leukemias, 1 malignant schwannoma, 1 small cell lung cancer, 1 prostate cancer, and 1 melanoma. Both imaging methods demonstrated parenchymal volume loss equally well in all patients. Gd-MR revealed abnormal enhancement of meninges or parenchyma in 10 patients, including all 5 patients with positive CE-CT. Neither technique revealed any foci of abnormal enhancement in 4 patients. Gd-MR was superior to CE-CT in demonstrating and quantifying enhancing subarachnoid and parenchymal nodules in 6 patients and in demonstrating sulcal, dural, cisternal, tentorial, and ependymal enhancement. Our findings indicate that T1W Gd-MR is the preferred imaging modality in leptomeningeal metastasis and suggest that CE-CT is unnecessary.

PMID 2314584  Neurology. 1990 Mar;40(3 Pt 1):435-8.
著者: M C Chamberlain
雑誌名: J Neurooncol. 1995;23(3):233-8.
Abstract/Text Sixty-one patients (34 men; 27 women) ranging in age from 1-74, median 40 years with leptomeningeal metastases (LM) as defined by either positive CSF cytology (85%) or a clinical syndrome and compatible neuroradiographic findings (15%) underwent CT-myelographic (CT-M), spine MR (S-MR) and 111Indium-DTPA CSF flow studies (FS). Each patient underwent sequential spine imaging (CT-M, S-MR and FS) over a median of 5 days. In 57% of patients, all 3 spine imaging modalities were normal. 43% of patients demonstrated abnormalities on spine imaging; 33% had abnormal FS, 34% showed abnormalities on S-MR and 33% had abnormalities by CT-M. FS were most sensitive for detecting interruption of CSF flow whereas CT-M and S-MR better demonstrated nerve root thickening (CT-M approximately S-MR), cord enlargement (CT-M > S-MR), subarachnoid nodules (S-MR > CT-M), intraparenchymal cord tumor (S-MR > CT-M) and epidural spinal cord compression (S-MR = CT-M). In conclusion, patients with LM frequently require spine imaging and the results of this study suggest both S-MR and FS provide the best radiographic assessment wherein S-MR is superior for detecting bulky disease and FS best demonstrates interruption of CSF flow.

PMID 7673985  J Neurooncol. 1995;23(3):233-8.
著者: B K Kleinschmidt-DeMasters, Denise M Damek
雑誌名: J Neurooncol. 2010 Feb;96(3):375-84. doi: 10.1007/s11060-009-9969-2. Epub 2009 Jul 16.
Abstract/Text Bevacizumab (Avastin, Genetech/Roche) is an anti-angiogenic drug approved for treating patients with malignant gliomas that reduces edema and mass effect, but has been suggested to promote multifocal tumor spread within the brain. Patients with systemic malignancies are also treated with bevacizumab, but there is limited information regarding effects of the drug on the neuroimaging or neuropathological features of metastatic CNS disease. We report 2 patients with non-small cell lung carcinomas who had received bevacizumab for their systemic cancers and then developed cognitive deficits consistent with white matter dementia. Diagnosis of leptomeningeal carcinomatosis (LC) was confounded and delayed by the finding of atypical neuroimaging features, including minimal to absent leptomeningeal enhancement and unusual perivascular and punctate hemorrhagic lesions and multifocal subgyral signal abnormalities suspicious for vasculitis or small vessel vasculopathy. Neuropathological assessment confirmed LC but, in the autopsy case also disclosed extraordinary perivascular spread of individual metastatic tumor cells to the depth of capillaries. The pattern was reminiscent of vascular "cooption" by tumor seen in experimental animals in preclinical trials of bevacizumab. Small infarctions were associated with perivascular tumor and vasculopathy, unusual features of LC in patients who do not receive bevacizumab. In the biopsied patient, multiple perivascular tumor nodules were identified in superficial cortex. In these two patients, bevacizumab appeared to alter neuroimaging characteristics of LC, confounded diagnosis and possibly also influenced the pattern of tumor spread of LC. More cases will need to be studied to confirm this latter finding.

PMID 19609489  J Neurooncol. 2010 Feb;96(3):375-84. doi: 10.1007/s1106・・・
著者: Michael J Glantz, Alixis Van Horn, Rebecca Fisher, Marc C Chamberlain
雑誌名: Cancer. 2010 Apr 15;116(8):1947-52. doi: 10.1002/cncr.24921.
Abstract/Text BACKGROUND: A study was undertaken to determine whether route (intraventricular vs intralumbar) of intracerebrospinal fluid (intra-CSF) drug administration influences progression-free survival in the treatment of patients with neoplastic meningitis, which occurs in 1% to 5% of patients with known cancer. Currently available treatment options result in modest responses, which is in part a reflection of obstacles to drug delivery into the leptomeningeal space.
METHODS: One hundred patients with clinically and cytologically or radiographically documented neoplastic meningitis because of solid cancers received intra-CSF liposomal cytarabine or methotrexate as specified in a randomized phase 4 trial. The 2 treatment arms were well balanced for demographic and tumor-related characteristics of known prognostic importance, including age, performance status, tumor type, extent of systemic and other central nervous system (CNS) disease, prior CNS therapy, and concurrent systemic chemotherapy.
RESULTS: One hundred patients were randomized and treated (52 with sustained-release cytarabine, and 48 with methotrexate). Progression-free survival (the primary study endpoint) was identical between the sustained-release cytarabine and methotrexate treatment arms for all 100 patients (35 vs 37.5 days, P = .79). When progression-free survival was examined as a function of route of chemotherapy administration (lumbar vs ventricular), there was no difference for patients treated with sustained-release cytarabine (29 vs 43 days, P = .35). For patients treated with methotrexate, however, there was a statistically significant difference favoring patients receiving intraventricular therapy (19 vs 43 days, P = .048).
CONCLUSIONS: Site of intra-CSF chemotherapy drug administration is clinically relevant with short half-life drugs such as methotrexate.

(c) 2010 American Cancer Society.
PMID 20151421  Cancer. 2010 Apr 15;116(8):1947-52. doi: 10.1002/cncr.2・・・
著者: R N Hitchins, D R Bell, R L Woods, J A Levi
雑誌名: J Clin Oncol. 1987 Oct;5(10):1655-62.
Abstract/Text Forty-four patients with documented meningeal carcinomatosis (small-cell lung carcinoma [SCLC], 29%; breast carcinoma, 25%) were treated in a prospective randomized trial with intrathecal methotrexate (MTX) 15 mg or MTX plus cytosine arabinoside (Ara-C) 50 mg/m2. Most patients received intrathecal hydrocortisone (HC) each treatment to minimize arachnoiditis. Overall response was 55%. Seven patients achieved complete response. Response to MTX was superior to combined MTX/Ara-C, but not significantly so (61% v 45%; P greater than .10). Response was more frequent if drugs were administered via Ommaya reservoir than by lumbar puncture (65% v 48%; P greater than .10). Concurrent radiotherapy to the CNS was associated with significantly better response (73% v 35%; P less than .05). Small-cell lung carcinoma patients showed the best response (69%). Overall median survival for the whole group was 8 weeks, but responders fared better than nonresponders (median survival, 18 v 7 weeks; P less than .05). Nausea and vomiting were the most common toxicities encountered (45%), but rarely proved limiting. An unusual, previously undocumented reaction to intrathecal HC was noted. MTX is moderately effective in nonleukemic meningeal carcinomatosis, but the addition of Ara-C does not appear to improve results. Pretreatment factors did not predict outcome in this trial.

PMID 3309199  J Clin Oncol. 1987 Oct;5(10):1655-62.
著者: T Siegal, A Lossos, M R Pfeffer
雑誌名: Neurology. 1994 Aug;44(8):1463-9.
Abstract/Text Thirty-one (23%) of 137 patients treated for leptomeningeal metastases (LM) achieved a sustained off-therapy response of at least 6 months' duration following treatment by a standard protocol. Of the 31 patients, equal distribution was found among various tumors: lymphoma, 13/44 (29%); breast carcinoma, 10/51 (20%); and other tumors, 8/42 (19%). Neuroimaging of the neuraxis disclosed subarachnoid deposits in 70%, with unexpected findings in 55%. At withdrawal of therapy, all 13 patients with lymphomas had achieved a complete response, and for those with the other tumors, 61% had a partial response. Off-therapy relapse was unrelated to the type of attained response and occurred in nine patients (29%) after a median time of 12 months. Five patients obtained a second prolonged response, mainly by systemic therapy. All eight patients who received only systemic therapy for their LM responded to treatment, four with a complete response. All others received both systemic and intra-CSF treatment and maintained a systemic response. Delayed complications occurred in 58%, with leukoencephalopathy equally affecting patients exposed and patients not exposed to cranial irradiation. The median survival of the whole group was 23 months. We conclude that in LM (lymphomas excluded), a partial response is compatible with a prolonged off-therapy response. Since LM may respond to systemic treatment, the role of intra-CSF therapy, with its associated complications, deserves a prospective reevaluation.

PMID 8058150  Neurology. 1994 Aug;44(8):1463-9.

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