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Ⅰ型神经纤维瘤病多学科诊治指南(2023版)
doi: 10.12376/j.issn.2097-0501.2023.02.009
通信作者：朱以诚，E-mail：zhuych910@163.com
Guidelines for the Multidisciplinary Diagnosis and Treatment of Neurofibromatosis Type 1(2023 Version)
Corresponding author: ZHU Yicheng, E-mail: zhuych910@163.com
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摘要: Ⅰ型神经纤维瘤病(NF1)是由于NF1基因突变引起的常染色体显性遗传性肿瘤性疾病。患者多幼年起病，临床表现复杂，以神经纤维瘤为特征性表型，可伴多系统受累，且存在肿瘤恶变风险。NF1诊断难度大，其治疗、随访、管理等多方面存在挑战，多学科协同诊治及流程的制定势在必行。因此中国罕见病联盟Ⅰ型神经纤维瘤病多学科诊疗协作组联合国内相关专业人士，共同制定本指南，旨在提高NF1诊疗水平，为患者提供同质化医疗服务。Abstract: Neurofibromatosis type 1(NF1) is an autosomal dominant hereditary neoplastic disease caused by mutations in the NF1 gene. Features of disorder typically appear in early childhood. The clinical phenotypes of the patients are diverse but neurofibromas is the main feature. Patients with NF1 also suffer from multi-system involvement and have high risk of malignant tumor. NF1 poses significant challenges for diagnosis, treatment, follow-up and patients management. Therefore, it is imperative to develop a multidisciplinary collaborative diagnosis and treatment protocol. Under the leadership of China Alliance for Rare Diseases, a multidisciplinary diagnosis and treatment collaborative team for NF1 has been formed and worked out the guideline. This guideline intends to lift the diagnosis and treatment level for NF1 and to provide the guideline for standardized treatment for NF1 patients in China.
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Key words:
- neurofibromatosis type 1 /
- multi-discipline /
- guideline
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图 1 NF1多学科诊治流程
*儿童于儿科（儿童肿瘤科）诊治、随访
Figure 1. Multidisciplinary approach to care for NF1 patients
表 1 Ⅰ型神经纤维瘤病(NF1)的鉴别诊断
Table 1. Differential diagnosis of neurofibromatosis type 1(NF1)
诊断 临床特征 发病机制 Legius综合征 有CALMs和双侧腋窝/腹股沟雀斑，无神经纤维瘤和OPG等其他NF1临床表现 15号染色体SPRED1双等位基因失活，导致Ras-MAPK信号通路上调[3] McCune-Albright综合征 锯齿状CALMs，多发性骨纤维性发育不良，性早熟；无神经纤维瘤 GNAS基因体细胞突变，尤其cAMP调节蛋白Gas突变[6] Ⅱ型神经纤维瘤病 CALMs偶见，无Lish结节；双侧前庭神经鞘瘤、脑膜瘤、室管膜瘤 22号染色体NF2双等位基因失活[7] Noonan综合征 典型CALMs，数量少；先天性心脏病；凝血功能障碍；矮小，性发育延迟；特殊面容；认知障碍 Ras信号通路若干基因胚系突变，尤其PTPN11基因[8] 结构性错配修复缺陷综合征 典型或非典型CALMs；高恶性风险 罕见的儿童肿瘤易感综合征，4个错配修复基因(MLH1、MSH2、MSH6、PMS2)之一的双等位基因缺失突变所致[9] CALMs: 咖啡牛奶斑；OPG: 视路胶质瘤 
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表 2 良性神经纤维瘤的病理学分类及特征
Table 2. Histopathological classification and characteristics of benign neurofibroma
分类 大体病理特征 组织病理特征 免疫组化特征 局限/结节型神经纤维瘤 界限分明的真皮/皮下结节；
切面发亮，呈棕褐色；
累及主要神经时表现为有包膜的梭形肿块。低至中等的细胞密度；
细胞为梭形，核呈波浪状或逗号状，细胞质界限不清；
细胞排列混乱；
纤维-黏液样基质。弥漫性表达
S-100和SOX-10；
上皮膜抗原和CD34表达水平多变。弥漫型神经纤维瘤 边界不清的真皮/皮下结节；
切面呈棕褐色。低至中等的细胞密度；
细胞为梭形，核呈深染波浪状或逗号状；
细胞排列混乱；
间质细纤维样或黏液样；
假meissner小体状结构；
伴皮下脂肪组织浸润，局灶呈蜂窝状。弥漫性表达
S-100和SOX-10；
上皮膜抗原和CD34表达水平多变。丛状神经纤维瘤 伴有多发结节的肿块；
宛如“一袋蠕虫”样的外观。低至中等的细胞密度；
细胞为圆形或梭形，核呈深染波浪状或逗号状；
多发结节和迂曲神经样结构；
丰富的黏液水肿基质，胶原纤维粗大、排列随意；
偶尔延伸至周围组织。弥漫性表达
S-100和SOX-10；
上皮膜抗原和CD34表达水平多变。
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表 3 丛状神经纤维瘤(pNF)患者术后复发风险评估
Table 3. Risk of postoperative recurrence in patients with plexiform neurofibroma(pNF)
危险因素 完全切除/近全
切除(切除范围≥90%)次全切除
(50%≤切除范围＜90%)部分切除
(切除范围＜50%)患者年龄 部位 21岁以上 四肢 低危 低危 中危 10~21岁 四肢 低危 低危 中危 10岁以下 四肢 低危 中危 中危 21岁以上 躯干 中危 中危 高危 10~21岁 躯干 中危 中危 高危 10岁以下 躯干 中危 高危 高危 所有年龄段 面部 高危 高危 高危
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表 4 外科分期系统(surgical staging system，SSS)或骨与软组织肿瘤外科分期系统(musculoskeletal tumor society, MSTS分期)
Table 4. Surgical staging system(SSS) or the musculoskeletal tumor society(MSTS)
分期 病理分级 部位 转移 ⅠA期 低恶(G1) 间室内(T1) 无转移(M0) ⅠB期 低恶(G1) 间室外(T2) 无转移(M0) ⅡA期 高恶(G2) 间室内(T1) 无转移(M0) ⅡB期 高恶(G2) 间室外(T2) 无转移(M0) Ⅲ期 任何G 任何T 区域或远处转移(M1)
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表 5 外科边界的定义
Table 5. Definition of surgical margin
分层 切除平面 切缘显微镜下表现 囊内切除 经病灶切除 切缘阳性 边缘切除 包膜外反应区内切除 切缘为反应区组织(内可含卫星灶) 广泛切除 反应区外正常组织内切除 切缘为正常组织(可含跳跃灶) 根治切除 间室外正常组织内切除 正常组织
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表 6 NF1患者肿瘤的监测及早期识别
Table 6. Surveillance and early identification of tumors in NF1 patients
病种 良恶性 发病年龄 早期征象 监测手段 皮肤型神经纤维瘤 良性 儿童期发病，可伴随终身 主要分布于躯干和面部皮肤，也见于四肢，多呈粉红色，数量可达数百乃至上千，大小不等，部分瘤体可引起疼痛、压痛、放射痛或感觉异常 定期体格检查 幼年性黄色肉芽肿 良性 多发生于婴儿和儿童 多见于头部、颈部、躯干上部或四肢的为无症状、界限分明的皮肤黄色丘疹。可单发也可成簇发生，并可能累及多个器官 对于3岁以下或存在10个以上皮肤病变的患者，建议定期进行腹部超声检查，特别是伴有肝肿大或黄疸的婴儿。对于全身受累较少的患者，建议每年随访1次，监测其病灶消退情况。如果发现内脏病变，应根据累及的器官和临床症状，制订每1~3个月的频繁随访和相应的治疗策略 丛状神经纤维瘤 良性肿瘤但术后容易复发 可自婴儿期发病，在儿童期和青春期也可快速增长，成年后相对保持稳定 大多数丛状神经纤维瘤发生在机体内部，因早期多无症状，常导致诊断延迟。随着瘤体向邻近组织浸润，可引发疼痛及神经功能障碍导致的行为异常。巨大瘤体可造成严重的毁容 除CT作为丛状神经纤维瘤的常规监测手段外，MRI扫描可显示丛状神经纤维瘤的大小和严重程度，可作为定期评估丛状神经纤维瘤生长状态的常规监测手段。磁共振血管造影对于评估NF1血管病变很有价值。在接受骨病变的手术治疗前，推荐进行CT成像或三维CT重建 嗜铬细胞瘤 多良性，恶性占10% 发病高峰为20~50岁 血压升高、头痛、心悸、多汗 血、尿儿茶酚胺及其代谢物测定可作为定性诊断；B超、CT、MRI和MIBG扫描用于定位诊断 视路胶质瘤 低度恶性 通常在6岁以下 15%~20% NF1儿童可发生视路胶质瘤，可终生无症状，即使出现症状也比不伴有NF1的患儿轻，患有脑干和小脑胶质瘤的NF1患者也比非NF1患者的病症更轻。20%以上在儿童期被诊断患有视路胶质瘤且接受放疗的NF1患者可发生继发性中枢神经系统胶质瘤[70] 可采用MRI动态随访 恶性外周神经鞘瘤 是NF1相关的最常见恶性肿瘤 青春期或成年早期 患病风险为：非体表的丛状神经纤维瘤且数目较多、瘤体较大、年龄较小、整个NF1基因缺失的NF1患者。当原有的肿块大小或疼痛出现明显变化，或神经功能障碍迅速进展时，应警惕发生了恶性转化，尤其是肿瘤大小的变化最能预测肿瘤的恶性程度 超声检查可清楚显示肿块部位、大小、性质、血流情况、与周围组织毗邻关系、周围淋巴结是否肿大等。MRI对于MPNST的诊断、临床分期、治疗及预后评估方面具有很高价值，为其首选的影像学检查手段。筛查有无肺转移首选胸部CT平扫，而骨扫描有助于判断有无骨转移。确诊MPNST仍需要活检，推荐进行开放式、且包括多个不同的肿瘤部位活检 幼年型粒-单核细胞白血病 恶性 婴幼儿期，中位发病年龄为2岁 常见临床表现为皮肤损害、发热、贫血、出血、肝脾肿大和肺部浸润等症状 血常规、外周血涂片、骨髓细胞学检查结果、免疫分型、细胞遗传学特征、基因检测 横纹肌肉瘤 恶性 发病高峰年龄为2~5岁及15~19岁两个年龄段 在头颈部、躯干四肢、泌尿生殖道等部位出现肿块，或出现涕中带血伴鼻塞、外耳道脓性分泌物、吞咽困难、排便困难、血尿等 B超、CT、MRI，肿块活检或手术切除，病理诊断为金标准 乳腺癌 恶性 25岁后逐渐增多，50~54岁达高峰 在乳腺上摸到无痛性肿块，或同时伴有与月经周期无关的乳腺胀痛；或乳头溢液、酒窝征，或乳头皮肤瘙痒、糜烂、破溃、结痂、脱屑等 乳腺超声、X线钼靶、磁共振增强扫描。活检是确诊乳腺癌的唯一确切方法 MIBG: 间碘苄胍；MPNST：恶性外周神经鞘瘤
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