CAJ | 학술논문

目的探讨睾丸核蛋白(NUT)抗体表达及基因重排在上呼吸道NUT中线癌(NMC)中的应用,以及NMC的发病情况、临床病理学特点、诊断及其鉴别诊断.方法收集北京同仁医院病理科1990年至2010年诊断的上呼吸道小圆细胞型恶性肿瘤163例,包括低分化鳞状细胞癌(31例)及未分化癌(1例)、非角化型未分化鼻咽癌(60例)、小细胞神经内分泌癌(6例)及其他非上皮性小圆细胞型恶性肿瘤(65例).分析其临床特征及病理学特点,行EB病毒编码的小RNA探针(EBER)原位杂交检测及NUT单克隆抗体的免疫组织化学EnVision法染色.NUT抗体阳性表达的病例以荧光原位杂交(FISH)法检测NUT基因重排、以免疫组织化学染色方法标记角蛋白(AEI/AE3、CK7、CK8)、p63及神经内分泌标志物(神经元特异性烯醇化酶、突触素、嗜铬粒素A、S-100蛋白、CD56).结果 (1)3例低分化鳞状细胞癌及1例未分化癌中发现NUT抗体呈强阳性核表达,约占该组病例的12.5％ (4/32),占本组上皮性恶性肿瘤的4.1％ (4/98),全部病例的2.5％ (4/163)；其年龄范围为42～59岁；其他各组病例NUT抗体均为阴性；(2)4例NUT抗体阳性表达的病例其瘤细胞均表达角蛋白及p63,而神经内分泌标志物及EBER检测均阴性；(3)4例NUT阳性表达的病例中2例FISH检测证实有NUT基因重排,此2例患者死亡,另2例未检测到NUT基因重排,患者存活(分别为40及12个月).结论 (1)NMC是发生于上呼吸道的少见小圆细胞型恶性肿瘤,既往被归于低分化鳞状细胞癌及未分化癌中,其NUT抗体阳性表达及NUT基因重排阳性；(2)NMC好发于中线器官,特别是鼻腔鼻窦,与EB病毒感染无关,临床病程及预后有所不同；(3)NUT免疫组织化学染色及FISH检测在其诊断及鉴别诊断中发挥主要作用.
목적 탐토고환핵단백(NUT)항체표체급기인중배재상호흡도NUT중선암(NMC)중적응용,이급NMC적발병정황、림상병이학특점、진단급기감별진단.방법 수집북경동인의원병이과1990년지2010년진단적상호흡도소원세포형악성종류163례,포괄저분화린상세포암(31례)급미분화암(1례)、비각화형미분화비인암(60례)、소세포신경내분비암(6례)급기타비상피성소원세포형악성종류(65례).분석기림상특정급병이학특점,행EB병독편마적소RNA탐침(EBER)원위잡교검측급NUT단극륭항체적면역조직화학EnVision법염색.NUT항체양성표체적병례이형광원위잡교(FISH)법검측NUT기인중배、이면역조직화학염색방법표기각단백(AEI/AE3、CK7、CK8)、p63급신경내분비표지물(신경원특이성희순화매、돌촉소、기락립소A、S-100단백、CD56).결과 (1)3례저분화린상세포암급1례미분화암중발현NUT항체정강양성핵표체,약점해조병례적12.5％ (4/32),점본조상피성악성종류적4.1％ (4/98),전부병례적2.5％ (4/163)；기년령범위위42～59세；기타각조병례NUT항체균위음성；(2)4례NUT항체양성표체적병례기류세포균표체각단백급p63,이신경내분비표지물급EBER검측균음성；(3)4례NUT양성표체적병례중2례FISH검측증실유NUT기인중배,차2례환자사망,령2례미검측도NUT기인중배,환자존활(분별위40급12개월).결론 (1)NMC시발생우상호흡도적소견소원세포형악성종류,기왕피귀우저분화린상세포암급미분화암중,기NUT항체양성표체급NUT기인중배양성；(2)NMC호발우중선기관,특별시비강비두,여EB병독감염무관,림상병정급예후유소불동；(3)NUT면역조직화학염색급FISH검측재기진단급감별진단중발휘주요작용.
Objective To investigate the importance of expression of the NUT gene and its rearrangement in diagnosing NUT midline carcinoma (NMC) of the upper respiratory tract; and to evaluate the prevalence, histological features and differential diagnosis of NMC of the upper respiratory tract.Methods One-hundred and sixty-three small cell malignant tumors of the upper respiratory tract were reviewed at the Beijing Tongren Hospital,Capital Medical University over a 20-year period. These cases included poorly-differentiated squamous cell carcinomas (n =31 ),undifferentiated carcinoma (n =I ),nonkeratizing undifferentiated nasopharyneal carcinomas (n =60 ), small cell neuroendocrine carcinomas ( n =6) and non-epithelial small round cell malignant tumors ( n =65 ).The clinical and pathologic features were investigated. All cases were subjected to Epstein-Barr virus encoded RNA (EBER) in situ hybridization and NUT monoclonal antibody immunohistnchemical staining. Cases positive for NUT immunohistochemistry and negative for EBER in situ hybridization were submitted for fluorescent in situ hybridization (FISH) for rearrangements in both BRD4 and NUT genes,and immunohistochemical staining for a set of cytokeratins ( AE1/AE3,CK7,CK8 ),p63,and neuroendoerine markers ( NSE,Syn,CgA,S-100 protein,CD56 ). Results Three cases of poorrly-differentiated squamous cell carcinomas and one case of undiffereutiated careiuoma showed diffuse nuclear immunohistochemieal staining with antibody against NUT.These positive cases approximately accounted for 12.5％ (4/32) of this group,4.1％ (4/98) of the malignant epithelial carcinomas and 2.5％ (4/163) of all small round cell malignant tumors in the study.The age of these patients were 42-59 years.Other groups were all negative for NUT immunohistochemistry.These four cases also stained for antibodies against cytokeratins and p63, but were negative for neuroendocrine markers and not associated with EBV infection. Only two of these four cases showed rearrangements of the NUT and BRD4 genes by FISH.These two patients died within one year.The other two patients that did not demonstrate NUT rearrangement by FISH were alive and did not have an aggressive clinical course,surviving 40 and 12 mouths respectively. Conclusions NMC is a rare small round cell malignant tumor in the upper respiratory tract.Only in the groups of primary poorly differentiated squamous cell carcinoma and uudifferentiated carcinoma were positive for NUT immunohistochemical staining and NUT rearrangement by FISH. NMC typically occurs in midline organs,and affects the sinonasal tract. It is not associated with EBV infection.There is difference in the clinical course and prognosis among NMC patients.NUT immunohistochemical staining and NUT gene rearrangement analysis can differentiate NMC from other small cell tumors in the upper respiratory tract.