In 2005, a 60-year-old man presented to the hospital complaining of a 2-month history of headaches and lethargy. His medical history included osteoarthritis and hypertension. From a social perspective, he was married with children, drove a truck for a living, and had never traveled abroad. His family history was unremarkable. Investigations included a brain CT, which highlighted an enhancing, space occupying lesion in the left basal ganglia with associated edema and mass effect (figure, A). He was prescribed high-dose dexamethasone while awaiting a neurosurgical review. One week later, a prebiopsy, contrast-enhanced CT showed a reduction in the size of the caudate head mass (figure, B). MRI brain with gadolinium showed small white matter changes and no mass was evident. He did not proceed to biopsy and was subsequently observed. CSF analysis was abnormal, revealing mature, lymphoid cells and some larger immature cells, some of which appeared plasmacytoid (B cell). Although suspicious for lymphoma, this result was nondiagnostic. The CSF protein level was 331. CSF low-density lipoprotein, Epstein-Barr virus, and flow cytometry were not performed. Theβ2-microglobulin level and serum low-density lipoprotein were normal. Serology for cytomegalovirus and toxoplasma were negative, as were ELISA for Toxocara and HIV screen. Slit-lamp examination was unremarkable. He was discharged, but readmitted 2 weeks later with a deep vein thrombosis. Repeat CSF cytology was again nondiagnostic. CSF was not examined for oligoclonal bands or myelin basic protein. A bone marrow biopsy and staging CT had normal results. Whole body PET/CT was unavailable.
2005年，一名60岁的男子到医院就诊，主诉头痛和嗜睡2个月。患者既往史包括骨关节炎和高血压。社会方面，已婚，育有子女，以开卡车谋生，从未出国旅行。家族史无特殊。检查包括脑部CT，头CT突出表现为左侧基底节区强化占位性病变，伴水肿及占位效应（图，A）。在等待神经外科评估时，医生开具了大剂量地塞米松。一周后活检前，对比增强CT显示尾状核头的占位病灶体积缩小（图，B）。钆增强脑MRI显示白质小灶病变，无明显的肿块。未行活检，随后观察。脑脊液检查异常，显示有成熟的淋巴样细胞和一些较大的未成熟细胞，其中一些呈浆细胞样外观（B细胞）。虽然怀疑淋巴瘤，但结果不具诊断特征。脑脊液蛋白：331，未进行脑脊液低密度脂蛋白、EB病毒和流式细胞术检测。β2微球蛋白水平和血清低密度脂蛋白均正常。巨细胞病毒和弓形虫血清学检测，ELISA 法检测弓形虫和HIV筛查，结果均为阴性。裂隙灯检查无显著异常。患者出院，但是2周后因深静脉血栓形成再次入院。复查脑脊液细胞学，仍旧不能确诊。未检测CSF寡克隆区带或髓鞘碱性蛋白。骨髓活检和CT分期结果正常。未获做全身PET/ CT检查。
Questions for consideration:
1. What is the differential diagnosis for this case presentation?
2. Should steroids be used prior to biopsy of an enhancing CNS lesion?
3. How should this patient be followed?
思考问题：
1.本病例的鉴别诊断是什么？
2.中枢神经系统的强化病灶活检前可使用类固醇吗?
3.应该如何对患者随访？
图 神经影像系列突出的表现是初始影像学异常消失，7年后复发，致使诊断为原发性中枢神经系统淋巴瘤
(A) CT的突出表现是左基底节区强化的大占位性病灶，伴有水肿和占位效应。(B) 影像证实在开始类固醇治疗1周后尾状核肿块体积缩小。脑MRI随访，影像学完全缓解（C.a [增强]和C.b [FLAIR]）。(D)症状再发，伴有意识模糊和幻觉，脑MRI检查结果正常。(E) 钆增强T1加权显示左颞叶数个强化病灶。(F)复查脑MRI证实左侧颞叶病变进展，怀疑恶性肿瘤。(G) 完成 4个周期的化疗，脑MRI出现明显的对治疗反应良好的影像学变化。
This case describes a vanishing tumor, an enhancing lesion that characteristically disappears spontaneously or reduces to less than 70% of the initial tumor volume observed radiologically before definitive diagnosis and treatment other than with steroids.1 With respect to vanishing tumors seen within the CNS, the differential diagnosis includes primary CNS lymphoma(PCNSL), inflammatory conditions such as multiple sclerosis, acute disseminated encephalomyelitis or neurosarcoidosis, and cerebral infections (table).1,2 A vanishing tumor is estimated to occur in 1:60,000–1:100,000 patients with other cancers, including renal cell carcinoma and melanoma.1
这个案例描绘了一个消退的肿瘤，一种增强病灶，在确诊前和只是类固醇治疗的情况下，影像观察到增强病灶独特的自发消失，或减少到不足初始肿瘤体积的70%。关于中枢神经系统所见消退的肿瘤，鉴别诊断包括原发性中枢神经系统淋巴瘤（PCNSL），炎症性疾病如多发性硬化症、急性播散性脑脊髓炎或神经结节病和脑感染性疾病（表）。其他癌症患者（包括肾细胞癌和黑色素瘤）出现消退的肿瘤比例为1:60000–1:100000。
表 见于中枢神经系统消退的肿瘤
鉴别诊断 | 表现 | CT特征 | MRI特征 |
继发性CNS淋巴瘤 | 无症状；运动肌无力；感觉症状；痫性发作 | 2 / 3软脑膜受累，1 / 3脑实质病变 | 钆：首选模式，软脑膜，硬脑膜，颅神经强化 |
原发性CNS淋巴瘤 | 男：女 2：1；>50岁，症状：进程短，〈3月；风险因素：HIV，移植后，IgA缺乏；症状：颅内压增高，局灶性神经功能缺损，痫性发作 | 幕上（75%–85%）；单发或多发肿块（高密度[ 70% ]），强化，体积小时占位效应有限，有限的周围水肿 | T1：白质低信号；钆增强T1加权：高级别肿瘤均匀强化（周边厚）；低级别肿瘤：无强化至中度强化；T2：信号多变；DWI：弥散受限；PI：CBV略有增加；波谱：大的胆碱峰，胆碱：肌酐比值倒置 |
脑弓形虫病 | 免疫功能低下，如艾滋病/移植受体，症状模糊 | 多发低密度病灶；位置：基底神经节或皮髓交界处；增强：光滑的环形强化 | T1：难以定性；T2：病灶周围水肿；信号多变：高信号，坏死性脑炎等信号：脓肿；钆增强T1加权：结节/环形强化 |
多形性胶质母细胞瘤 | 局灶性神经功能缺损，症状：颅内压增高，痫性发作 | 不规则不均匀边缘强化，中心坏死，占位效应、周围血管源性水肿；蝶形胶质瘤：累及对侧大脑半球；多灶性（20%） | PI：CBV升高；DWI：无扩散限制；波谱：胆碱峰↑，乳酸峰↑，脂质峰↑，NAA峰↓，肌醇峰↓ |
瘤样脱髓鞘病 | 女>男；青年-中年；非感染后；症状（不典型多发性硬化症）：局灶性神经功能缺损，痫性发作，失语症 | 大（>2厘米），孤立，界定不清，边缘不完整，环形强化病灶；中央坏死；病灶周围水肿；占位效应轻微 | 钆增强T1加权：对比强化（开环），50%；PI：平均相对脑血容量：低于胶质瘤和淋巴瘤；DWI：ADC增加 |
急性播散性脑脊髓炎 | 近期病毒感染或疫苗接种史，通常是儿童和青少年，脑脊液髓鞘碱性蛋白↑ | 小点状低密度，双侧和不对称白质内病灶，±环形强化 | T2：区域性高信号和水肿；钆增强T1加权：±强化；DWI：外周扩散受限 |
多发性硬化 | 多种表现：复发和缓解（70%），继发性或原发性进展（10%）；症状：感觉、运动、或二者混合；病灶时间和空间播散性 | 无特异性 | T1：斑块状：呈等-低信号（慢性）； T2：斑块状：高信号；FLAIR：斑块状：高信号；钆增强T1加权：强化（活动斑块）；DWI：活动斑块：弥散受限；波谱：斑块内NAA峰↓ |
脑脓肿 | 颅内压增高，痫性发作，局灶性神经功能缺损；风险因素：全身性败血症，牙脓肿，细菌性心内膜炎 | 与MRI特征相似，包膜增厚，边缘均匀一致强化，中央囊腔低密度 | T1：中央低信号，周边低信号（水肿），环状强化；T2/FLAIR：中央及周边高信号，脓肿壁薄边缘低信号；DWI：中央弥散受限；PI：周围水肿区域 CBV↓；波谱：琥珀酸峰↑，乳酸峰↑，NAA峰↓ |
神经系统结节病 | 颅内压增高，脑神经麻痹，尿崩症，运动/感觉神经病，脊髓病；孤立的神经系统结节病：罕见 | 假阴性CT 60%；脑积水 | 增强T1加权 均匀强化 |
缩写：ADC=表观扩散系数; ADEM =急性播散性脑脊髓炎; CBV =脑血容量; CNP =颅神经麻痹; DI =尿崩症; DWI =弥散加权成像; FLAIR =液体衰减反转恢复; GBM =多形性胶质母细胞瘤; Gd =钆; ICP =颅内压; IgA =免疫球蛋白A; MBP =髓鞘碱性蛋白; MS =多发性硬化症; PI =灌注成像。
Ideally, glucocorticoid therapy should be avoided prior to biopsy of a lesion that has neuroradiologic characteristics suspicious of PCNSL, as this may prevent histologic confirmation of the diagnosis. With glucocorticoid therapy, complete tumor cell eradication is never achieved and PCNSL inevitably recurs, facilitating the delayed histologic diagnosis.1 However, there are no guidelines available to help determine the appropriate method or duration of follow-up. MRI brain surveillance for a period of 5 years has been suggested.1 This duration is proposed on the basis of a case of PCNSL that entered complete remission for 5 years following glucocorticoid therapy.2 Until now, there has not been a case of vanishing PCNSL reported to recur more than 5 years following initial remission induced by glucocorticoid therapy.
理想情况下，神经影像学病变特征上怀疑PCNSL时，糖皮质激素治疗应避免先于病灶活检，因其可妨碍组织学证实诊断。糖皮质激素治疗永远不会彻底根除肿瘤细胞并且PCNSL必然复发，这可促使组织学诊断延误。然而，没有可适用的指南来确定随访中适合的方法或期限。建议脑MRI监测的期限为5年。这个期限的提出是基于一个PCNSL病例，患者在糖皮质激素治后进入完全缓解期长达5年。到目前为止，没有糖皮质激素治疗诱导初期缓解、PCNSL消失后可超过5年再发的病例。
One year later, our patient underwent CT and MRI brain, which confirmed a complete radiologic remission of the tumor (figure, C.a and C.b). Lumbar puncture and CSF cytologic assessment was performed 6 times and were all nondiagnostic. The patient did not attend for further follow-up. In December 2011, he re-presented with confusion, impaired hearing, and hallucinations. Repeat CT and MRI brain were unremarkable (figure, D). CSF analysis revealed pleocytosis, an atypical finding, suspicious of lymphoma. In May 2012, he attended with chest pain. A pulmonary embolus (PE) was identified on CT pulmonary angiography. Another MRI brain was performed, which showed numerous foci of enhancement in the left temporal lobe onT1 weighted images taken postgadolinium, suspicious for malignancy (figure, E). His symptom profile evolved. He developed memory loss, complex partial seizures, and ataxia. MRI showed evidence of progression of disease (figure, F). Biopsy of the temporal lobe lesion confirmed non-Hodgkin, diffuse,large B-cell lymphoma. Staging CT ruled out systemic lymphoma, confirming PCNSL. PET/CT was again unavailable.
一年后，病人行CT及脑MRI检查，证实肿瘤影像学完全缓解(图, C.a 和 C.b)。进行6次腰椎穿刺术和脑脊液细胞学评估，均为非诊断性的结果。患者没有参加进一步随访。2011年12月，他再次发病伴有意识模糊、听力受损和幻觉。复查CT与脑MRI无明显异常（图，D）。脑脊液分析显示细胞增多，检查结果不典型，怀疑淋巴瘤。2012年5月，他因胸痛入院，CT肺动脉造影确诊肺栓塞（PE）。另行脑MRI检查，钆增强T1加权像左侧颞叶显示数个强化病灶，怀疑恶性肿瘤（图，E）。患者症状表现发生演变，出现记忆丧失、复杂部分性发作和共济失调。MRI证实疾病在进展（图，F）。颞叶病灶活检证实为非霍奇金弥漫性大B细胞淋巴瘤。CT分期排除系统性淋巴瘤，确诊 PCNSL。PET/ CT 再次因故未做。
Question for consideration:
1. What is the management of PCNSL?
思考问题：
1. PCNSL的治疗策略是什么？
The optimal treatment of PCNSL is uncertain and clinical trials should always be considered. Surgical intervention is limited to stereotactic biopsy to make a tissue diagnosis, but may be considered in the setting of impending increased risk of herniation, hydrocephalus, and uncontrolled mass effect. Surgical resection can induce neurologic deficits, can delay treatment, and does not confer a survival benefit.3
PCNSL最佳治疗方案并不确定，应参考临床试验的结果。外科手术限于立体定向活检确定组织学诊断，但在出现即将增加脑疝风险，脑积水和难以控制的占位效应情况下可以考虑外科手术。手术切除可导致神经功能缺损，治疗延期，且不能使生存获益。
For patients with a good performance status, combination chemotherapy is the mainstay of treatment. A combination regimen of high-dose methotrexate (HDMTX) with cytarabine has been shown to improve overall and complete response (CR) rates compared to methotrexate alone.3
状态良好的患者，联合化疗是主要治疗手段。与单用甲氨蝶呤比较，已证明大剂量甲氨蝶呤（HDMTX）与阿糖胞苷联合方案能改善总体及完全缓解（CR）率。
The majority of PCNSL (~95%) express CD20.4 A therapeutic effect of rituximab, a chimeric, monoclonal anti-CD20 antibody, has been suggested. Recently, 2retrospective, observational studies reported improved rates of CR with the addition of rituximab to HDMTX-containing regimens (100% vs 68.4%, p=0.024; 70%vs 36%, p=0.015). One of these studies also reported improved survival data on the addition of rituximab to HDMTX compared to HDMTX alone (median progression-free survival was 26.7 months vs 4.5 months, p = 0.003; median overall survival was 16.3 months in the HDMTX alone group and has not been reached in the HDMTX/rituximab group, P=0.01).5 Although the level of evidence supporting the use of rituximab for treatment of PCNSL is low, its use is encouraged. Two randomized trials currently underway are attempting to establish the exact role of rituximab in the management of PCNSL (NCT01011920; NTR2427).3
多数PCNSL（~ 95%）CD20表达阳性，建议应用利妥昔单抗，其治疗作用为抗CD20嵌合型单克隆抗体。最近，2个回顾性观察研究报道了在HDMTX组成方案中加入利妥昔单抗可提高CR率(100% vs 68.4%, p=0.02; 70% vs 36%, p=0.01)。其中的一个研究还报道了与单独HDMTX相比，将利妥昔单抗添加至HDMTX的方案，生存数据改善（中位无进展生存期为26.7个月vs 4.5个月，p = 0.003；中位总生存期在单独HDMTX组为16.3个月，不及HDMTX /利妥昔单抗组，p = 0.01）。尽管支持应用利妥昔单抗治疗PCNSL证据水平低，但仍鼓励使用。目前进行的两项随机试验正在尝试建立利妥昔单抗在治疗PCNSL中的确切作用(NCT01011920; NTR2427)。
Radiotherapy was the initial treatment of choice prior to studies of HDMTX, which showed superior survival rates over radiotherapy alone. PCNSL is sensitive to radiotherapy and this remains a palliative treatment option.3 Inclusion of the whole brain and eyes in the radiotherapy field is recommended because of the diffuse infiltrative nature of PCNSL. Consolidation, after HDMTX-based chemotherapy, represents the best role for radiotherapy in the management of PCNSL. It is associated with risk for neurotoxicity, with a cumulative 25%–35% incidence at 5 years and related 30% mortality.3,6 Consolidation radiotherapy is particularly challenging in patients aged ≥65 years and radiotherapy is often deferred until disease progression.3 Similarly, in patients who achieve CR to chemotherapy, deferring whole-brain radiotherapy (WBRT) until potential relapse has been proposed in an effort to minimize the neurotoxicity risk. However, this strategy requires validation in randomized trials.6 In contrast, consolidation radiotherapy is unavoidable in those with residual disease after chemotherapy.3 The optimal dose of WBRT is controversial. A dose of 40–50 Gy is recommended.3 Some studies suggest equivalent efficacy and better tolerability when the dose of WBRT is reduced to 23–30 Gy in patients with CR after chemotherapy.6,7
放射治疗是在HDMTX研究之前的初期治疗选择，结果显示HDMTX生存率优于单独放射治疗。PCNSL对放疗敏感，但仍然属于姑息治疗。因PCNSL的弥漫浸润特性，推荐放射野包括全脑及眼部。在HDMTX基础性化疗后，联合巩固性放疗，可体现放疗在治疗PCNSL中的最佳角色。放射治疗与神经毒性风险有关，5年累积发生率25％-35％，相关死亡率30%。巩固性放疗对年龄≥65岁的病人尤具挑战性，通常是推迟到疾病进展再行放疗。同样，化疗取得CR（完全缓解）的患者，可推迟全脑放疗（WBRT）直到医生提出出现潜在的复发风险，以便尽力减少神经毒性风险。然而这种方案需要在随机试验中验证。相比之下，化疗后残留病症的患者巩固放疗是不可避免的。WBRT的最佳剂量有争议，推荐剂量为40-50 Gy。一些研究表明化疗后CR的患者，WBRT剂量降低到23-30 Gy时，疗效相当，耐受性更好。
Systemic chemotherapy (HDMTX/cytarabine) and rituximab was chosen in the case presented. After 4 cycles of treatment, repeat MRI confirmed a good response (figure, G). The treatment course was complicated by febrile neutropenia and recurrent PE. On completion of treatment, active surveillance was undertaken, as opposed to consolidation radiotherapy.
本病例选择全身化疗（HDMTX /阿糖胞苷）和利妥昔单抗。 经过4个周期的治疗，复查MRI证实反应良好（图，G）。治疗过程并发发热性中粒细胞减少和复发肺栓塞。化疗结束后，进行主动监测，未行巩固性放疗。
Question for consideration:
1. Is there a known association between venothromboembolism (VTE) and PCNSL?
思考问题：
1. 静脉血栓栓塞(VTE)和PCNSL之间是否有已知的关系？
The association between malignancy and thrombosis is well-recognized and occurs in 15% of all cancer patients. 8 The risk of VTE in the setting of a brain tumor is high, affecting 28% of patients with malignant gliomas.8 Predisposing risk factors other than the inherent risk of malignancy include the presence of leg paresis, histologic diagnosis of glioblastoma multiforme, age ≥ 60 years, large tumor size, and use of chemotherapy. One study found an incidence of VTE of 60% (25/42) in patients with PCNSL. Almost all events occurred in the first 3 months of treatment.8
恶性肿瘤和血栓形成之间的关系是公认的，所有癌症患者中15％发生血栓。脑肿瘤的情况下发生VTE的风险很高，恶性胶质瘤患者28％可发生VTE。除了恶性肿瘤的固有风险外，易患风险因素包括：存在腿部麻痹、组织学诊断多形性胶质母细胞瘤、年龄≥60岁、肿瘤体积大和应用化疗。一项研究发现PCNSL患者的VTE发生率为60％（25/42）。几乎所有的血栓事件都发生在治疗的前3个月。
A vanishing tumor is a complex diagnostic dilemma and is not specific for one disease. The clinical course of a vanishing tumor, with the exception of PCNSL, has not been completely described. In the case of PCNSL, the diagnosis is made at the time of recurrence. Literature suggests that surveillance of a vanishing tumor should take the form of regular MRI for a duration of 5 years. However, in the case presented, the vanishing tumor remained in complete remission for a 7-year period with steroid treatment alone, at which point it recurred and was definitively diagnosed as a PCNSL.
消失的肿瘤是一种复杂的诊断难题，不是一种疾病所特有。除PCNSL外，消退的肿瘤临床过程尚未被完全阐明。至于PCNSL而言，是在复发时做出诊断。文献建议，消失的肿瘤应采取为期5年的常规MRI监测形式。然而，在本文案例中单用类固醇治疗，这个消失的肿瘤保持完全缓解7年时间，此时复发被确诊为PCNSL。
A similar case reported symptomatic recurrence after 5 years in remission, which led to the radiologic diagnosis of recurrence.2 Relapse generally occurs within 18 months in 80% of patients with PCNSL vanishing tumors, with a median remission duration of 7 months for PCNSL (range 1–54 months).9 Late recurrence (≥5 years from initial diagnosis) in appropriately treated PCNSL is a rare event. One large series identified a late relapse rate of 4% in patients who achieved CR following appropriate treatment.10The median time to first relapse was 7.4 years (range 5.2–14.6 years).10 Sustained clinical follow-up is therefore recommended given the incidence of late recurrence as demonstrated by this case and those reported in literature.
有一类似的病例报告，缓解5年后症状再发，影像诊断复发。80%PCNSL肿瘤消退的患者复发通常发生在18个月内，中位缓解持续时间为7个月（范围1-54个月）。妥善治疗的PCNSL远期复发（从开始诊断起≥5年）是罕见事件。一个大的系列研究结论是在适当治疗后达到CR的患者，远期复发率为4％，首次复发的中位时间为7.4年（范围5.2-14.6年）。鉴于本病例和文献报道的远期复发率，因此推荐持续的临床随访。
（全文终）
诗 句 赏 析
见贤思齐焉，见不贤而内自省也。
On seeing a man of virtue, try to become his equal; on seeing a man without virtue, examine yourself not to have the same defects.
编辑：李会琪
：李神经群招贤榜--招募病历讨论总结员，公众号编辑的通知【公告】
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