Abstract
北京大学第三医院神经外科2017年收治1例颈椎管内腺泡状横纹肌肉瘤(alveolar rhabdomyosarcoma,ARMS)转移病例,回顾其临床病理特征,手术治疗、化疗及预后情况,并复习国内外文献报道,对该病的诊断、鉴别诊断以及治疗预后进行综合分析,以提高临床医生对这一罕见疾病的认识。本例患者病情发展快,原发病灶为无痛性包块,1年余出现椎管内转移,有明显的疼痛。给予手术切除,病理诊断为小细胞恶性肿瘤,免疫组织化学Myogenin(+)、MyoD1(+)。FOXO1基因FISH检测阳性,>50%的细胞核显示红绿信号分离,且红绿信号之间的距离大于两个信号点的直径,支持腺泡状横纹肌肉瘤的诊断。全切椎管内肿瘤并术后化疗,但肿瘤药物反应差,病情进展快,迅速出现椎管内播散转移。ARMS少见,侵袭性强,预后不佳,硬膜下转移罕见,临床医生要充分利用现代分子生物学诊断方法,做出正确的诊断和分型,才能有效指导治疗。
Keywords: 横纹肌肉瘤, 腺泡状横纹肌肉瘤, PAX-FKHR
Abstract
This paper reported a case of cervical intraspinal metastasis of alveolar rhabdomyosarcoma (ARMS). The clinicopathological features,surgical treatment,chemotherapy and prognosis were introduced and the current literature was reviewed. The diagnosis,differential diagnosis,treatment,molecular features and prognosis of the disease were comprehensively analyzed to improve clinicians’ knowledge of this rare disease. The primary lesion appeared about 1 year ago which was painless mass of left hand whose size was about 2 cm×2 cm. After conservative treatment;,the mass gradually enlarged and the mass was resected. Postoperative pathology revealed embryonic rhabdomyosarcoma. Postoperative chemotherapy with recombinant human endostatin,liposomal doxorubicin and ifosfamide was performed. The left neck mass was found about 3 months ago,and then the left neck mass was resected under general anesthesia. Postoperative pathological examination showed small round cell malignant tumors. Severe left upper extremity pain began about 2 weeks ago with nocturnal pain and supine pain. Non-steroidal anti-inflammatory drugs were needed to relieve pain which was accompanied by numbness and weakness of the left upper extremity. MRI showed a intraspinal tumor at C5. The left thumb and index finger were absent. Hypoesthesia,muscle atrophy and hypotonia of the left upper limb were confirmed. The muscle strength of biceps brachii and deltoid muscle of the left upper limb was grade 0,the muscle strength of extensor carpus and interphalangeal muscle was grade Ⅱ,the muscle strength of intrinsic muscles of hands was grade Ⅰ. The tendon reflex of the left upper limb disappeared. Intraspinal mass was removed and the pain was relieved. But there was no significant change in the muscle strength of the left upper limb. Pathological examination revealed small cell malignancies which were poorly differentiated with diffuse patchy distribution and disordered arrangement. The tumor cells had round,oval or irregular nuclei,and few cytoplasms were positive for Myogenin and MyoD1. FISH test of FOXO1 gene was positive. More than 50% of nuclei showed red-green signal separation,and the distance between red-green signals was larger than double diameter of the signal points,which supported ARMS. Total resection of intraspinal tumors was achieved and postoperative chemotherapy was admitted. But intraspinal disseminated metastasis occurred rapidly. ARMS was rare,aggressive tumor with poor prognosis. Subdural metastasis was rare. Correct diagnosis and classification can be made only with help of modern molecular diagnostic methods,which is effective to guide the treatment.
Keywords: Rhabdomyosarcoma, Alveolar rhabdomyosarcoma (ARMS), PAX-FKHR
横纹肌肉瘤(rhabdomyosarcoma,RMS)是起源于间叶组织具有骨骼肌分化特征的软组织恶性肿瘤,临床罕见。北京大学第三医院神经外科2017年收治1例首发于上肢的RMS,外院初次诊断为胚胎性横纹肌肉瘤(embryonal rhabdomyosarcoma,ERMS),患者有远处转移,并累及椎管内,经历多次手术和化疗等治疗,最终通过免疫组织化学及基因检测明确诊断为腺泡状横纹肌肉瘤(alveolar rhabdomyosarcoma,ARMS)。
1. 病例资料
患者男性,18岁,左手肿物术后1年余,左侧颈部肿物术后3月余,左上肢疼痛,发现颈椎肿瘤复发可能2周,于2017年5月2日入北京大学第三医院神经外科治疗。患者于1年余以前发现左手虎口肿物,大小约2 cm ×2 cm,就诊于当地医院,给予保守治疗,效果欠佳,肿物逐渐增大,遂于2016年4月行左手肿物切除术,术后病理诊断为ERMS。术后行重组人血管内皮抑制素(恩度)+盐酸多柔比星脂质体+异环磷酰胺方案化疗。此后定期复查,3月余前发现左侧颈部肿物,遂于当地医院全身麻醉下行左侧颈部肿物切除术(2017年1月),术后病理诊断为小圆细胞恶性肿瘤。约2周前开始出现左上肢疼痛,程度较重,有夜间痛及平卧痛,需服用非甾体类抗炎药止痛,伴有左上肢肢体麻木无力。复查核磁提示颈5椎管内肿物(图1)。查体左颈部及左手可见手术瘢痕,左手拇指及食指缺如,左上肢活动受限,左上肢针刺觉及触觉减退,左上肢肌肉萎缩,肌张力降低,左上肢肱二头肌及三角肌肌力0级,伸腕肌及指间肌肌力Ⅱ级,握力Ⅰ级,左上肢腱反射消失,颈椎JOA评分12分,Frankel分级C级。完善检查及准备后于2017年5月3日行手术治疗,术中见肿瘤位于脊髓左腹侧,呈黄白色,大小约1 cm ×1 cm,生长于腹侧神经根,供血来源于神经根动脉,与脊髓及硬膜有粘连,质脆,分离粘连,电凝切断供血血管后全切肿瘤。术后疼痛有所减轻,但仍有疼痛。患者肌力等无明显变化。术后病理切片提示为小细胞恶性肿瘤,分化极低,弥漫片状分布,无明显排列,肿瘤细胞核呈圆形、椭圆形或不规则形,胞浆少,诊断ARMS(图2)。免疫组织化学发现:Desmin(+),CD56(+),Myogenin(+)(图3),MyoD1(+),CgA(-),Syn(-),S-100(-),Ki67(50%+),LCA(-),CD99(-),Myoglobin(-),Myosin(-),Ini1(+),CK混(+)。FOXO1基因FISH检测阳性,>50%的细胞核显示红绿信号分离,且红绿信号之间的距离大于两个信号点的直径,支持ARMS的诊断(图4)。术后1周复查磁共振显示颈椎管肿瘤全切(图5), 转肿瘤科行进一步的化疗治疗。
1.
术前磁共振检查结果(2017-04-15)
2.
术后病理(HE染色 ×100)
3.
Myogenin免疫组化染色(×200)
4.
FOXO1 FISH检测
5.
术后1周复查磁共振(2017-05-09)
术后5个月,患者出现双下肢无力,迅速进展,出现不全截瘫及大小便功能障碍,2017年10月16日再次复查磁共振显示胸腰椎椎管内弥漫性病变(图6),考虑肿瘤播散转移可能。因患者家属拒绝,未行进一步治疗。
6.
术后5个月复查磁共振(2017-10-16)
2. 分析与讨论
RMS根据其组织学和遗传学特点可分ERMS、ARMS和多形性横纹肌肉瘤(pleomorphic rhabdomyosarcoma,PRMS)[1,2,3]。不同的RMS在预后上有着很大的差异,因此明确诊断,给予针对性治疗显得尤为重要。ERMS和ARMS是最多见的两种亚型。ERMS好发于儿童,最常见的发病部位是头颈部和泌尿生殖道; ARMS比ERMS更具侵袭性,以青少年和年轻人多见,常见年龄为10~25岁[4],常好发于四肢深部软组织,其次为头颈部、躯干、会阴、盆腔和腹膜后,临床表现为迅速生长的肿块,可伴有疼痛,肿瘤呈浸润性生长,边界不清,平均直径为7 cm,肿瘤较大的可见出血和坏死,相当比例的患者在诊断时就已有转移,常见的转移部位是肺、骨髓和淋巴结。硬膜下脊髓或神经根转移非常罕见,可能与肿瘤累及头颈部后进一步播散转移有关[5]。本例患者首发症状为左手的无痛性包块,生长迅速,与ARMS特点相符,但是不确定是诊断时就已经有远处转移还是术后发生的转移,但是颈椎硬膜下转移极有可能是由颈部肿瘤引起的二次转移。虽然颈椎硬膜下肿瘤得到了全切,但在术后仍出现胸腰椎管内的广泛病变,有可能是肿瘤沿脑脊液播散引起的第3次转移。
病理形态上,ARMS呈小圆细胞恶性肿瘤,并具有原始骨骼肌样分化[3]。根据纤维血管间质的多少,可以分为经典型、实性型和胚胎性-腺泡状混合型,经典型ARMS瘤细胞排列成片状和巢状,可见特征性的腺泡状结构,其间为纤维血管间隔。实性型由一致的实性细胞巢组成,不见腺泡状结构。胚胎性-腺泡状混合型在经典的ARMS的局部区域可见胚胎性横纹肌肉瘤的形态。ARMS和ERMS两者常规组织学一般难以鉴别,部分ARMS在常规病理上可能会误诊断为ERMS[6]。分子遗传学检测对病理明确诊断有重要作用[6,7]。在细胞遗传学或分子生物学研究中,70%~80%的ARMS可检测到特异性染色体易位[t(2;13)(q35;q14)易位和t(1;13)(p36;q14)易位][8],两种易位分别形成相应的融合基因PAX3-FKHR(也称为PAX3-FOXO1)或PAX7-FKHR(也称为PAX7-FOXO1)。虽然不是所有的ARMS都表现为PAX-FKHR阳性,但PAX-FKHR阳性却一定能诊断ARMS[9]。本例患者初次手术时根据常规病理诊断为ERMS,第2次手术病理为小圆细胞恶性肿瘤。北京大学第三医院手术后通过免疫组织化学Myogenin(+)和MyoD1(+),以及FISH基因检测FOXO1基因阳性,最终诊断应为ARMS。
PAX-FKHR 融合蛋白表达与预后不良相关并常常出现在转移的患者[2],因此PAX-FKHR阳性的患者需要强化治疗,可能改善患者的预后[6]。本例患者如果能早期明确属于PAX-FKHR阳性,给予更积极的治疗,有可能降低其转移的风险。
已有转移的ARMS的标准治疗为包括长春新碱、多柔比星和环磷酰胺的联合化疗。但是否需要放疗仍有争议,有的学者认为不需要同步放疗[5],有的则认为联合质子束放疗能改善患者的预后[6],但是由于同步放、化疗可能会加重免疫抑制,且目前文献大多为个案报道,故仍需进一步的临床病例对照研究来确定联合放化疗的利弊,但目前认为至少应给予积极的化疗,并注意防治化疗相关并发症。
综上所述,ARMS是少见的软组织肿瘤,临床上有很强的侵袭性,预后不佳,硬膜下转移罕见。诊断上要充分利用现代分子生物学诊断方法,做出正确的诊断和分型,才能有效指导后续治疗,为患者争取最佳的预后。
Funding Statement
首都临床特色应用研究项目（Z171100001017120）
Supported by the Capital Foundation for Clinical Characteristics and Application Research(Z171100001017120)
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