摘要
第一部分鼻腔鼻窦内翻性乳头状瘤鼻内镜手术的进路选择与疗效分析研究背景
鼻腔鼻窦内翻性乳头状瘤(Sinonasal inverted papilloma, SNIP)是发生于鼻腔及鼻窦黏膜的上皮源性良性肿瘤,发病率占鼻腔肿瘤的0.4%-4.7%。多发生在中年男性,其临床特征主要表现为术后易复发、周围解剖结构破坏和骨质重塑并与鳞状细胞癌相关,手术是治疗的首选方法。既往多采用鼻侧切开等鼻外手术进路治疗该类疾病,手术损伤较大,出血较多,病人住院时间较长,部分患者遗留面部疤痕等问题。近年来鼻内镜技术的延伸和发展,鼻内镜手术及鼻内镜鼻内外联合入路成为治疗该疾病的主要技术手段,但对不同的肿瘤分级采用何种手术进路以及与临床疗效关系仍需探讨。
目的
本研究主要探讨鼻内镜下切除鼻腔鼻窦内翻性乳头状瘤手术进路的选择及其与疗效的关系。
方法
回顾性分析中山大学附属第三院耳鼻咽喉-头颈外科1996年8月至2008年2月经鼻内镜手术治疗的鼻腔鼻窦内翻性乳头状瘤91例的临床资料。91例患者,男62例,女29例；年龄23-70岁,平均48.6岁。目前国内对SNIP分期主要采用Krouse分期法。Krouse(2000)根据内镜、CT/MRI判断肿瘤的范围而提出了疾病分期系统,Ⅰ级：肿瘤完全局限于鼻腔内,局限于鼻腔的一个壁或一个区,未累及鼻窦及鼻外组织,无恶变；Ⅱ级：肿瘤侵犯窦口鼻道复合体和筛窦,和/或上颌窦内壁及上壁,有/或无鼻腔受累,无恶变；Ⅲ级：病变累及上颌窦外侧壁、下、前、后壁或侵入额窦、蝶窦,无恶变；Ⅳ级：病变侵犯鼻腔鼻窦外结构或恶变者。91例患者按照Krouse分类法分为4级：Ⅰ级18例,Ⅱ级45例,Ⅲ级25例,Ⅳ级3例。其中采用单纯鼻内镜手术组(A组)Ⅰ级18例、Ⅱ级33例、Ⅲ级13例；鼻内镜联合改良柯-陆术式手术组(B组)Ⅱ级12例、Ⅲ级12例；鼻内镜联合鼻外进路手术组(C组)Ⅳ级3例。手术方法：术中根据肿瘤根蒂部的位置和肿瘤侵犯范围来决定手术方法。采取①区段性切除：对于KrouseⅠ级和Ⅱ级的患者,根据肿瘤根蒂所在位置,将蒂所在的解剖单位整块切除。②扩大区段性切除：对于KrouseⅡ级累及上颌窦内侧壁的患者,开放筛窦,扩大上颌窦窦口,酌情切除鼻腔外侧壁,切除上颌窦内及筛窦内肿瘤；对于KrouseⅢ级位于额窦或蝶窦的患者,扩大额隐窝,开放额窦切除额窦内肿瘤；对侵入蝶窦者,咬除蝶窦前壁,切除肿瘤及周围黏膜,开放蝶窦切除其窦内肿瘤。③根治性切除：对于KrouseⅢ级广泛侵及上颌窦外侧壁、下壁、前壁或后壁的患者行鼻内镜联合改良柯-陆术式上颌窦根治术。④扩大根治性切除：对于KrouseⅣ级患者,病变侵及眶顶壁和额窦后壁者,行鼻内镜联合额窦前壁开窗双进路行根治性肿瘤切除术。统计学分析：应用SPSS13.0软件系统,采用Fisher精确概率法分析。以P<0.05为为差异有统计学意义。
结果
术后随访术后随访18-90个月,平均37个月,有15.4%(14/91)复发,其中A组Ⅰ级5.6%(1/18)、Ⅱ级6.1%(2/33)、Ⅲ级53.8%(7/13)；B组Ⅱ级16.7%(2/12)、Ⅲ级8.3%(1/12)；C组Ⅳ级33.3%(1/3)。统计结果提示Ⅱ级病例,A组和B组复发率无差异；而Ⅲ级病例,A组和B组复发率有差异,A组复发率高。复发病例行再次手术,均随访24个月未再复发。
结论
1.鼻内镜技术的优点：无面部切口,面部肿胀轻,住院时间短,可以减少术后疼痛和麻木。
2.鼻内镜手术治疗鼻腔鼻窦内翻性乳头状瘤的复发率处于合理范围,优于鼻外径路手术。
3.鼻内镜手术治疗鼻腔鼻窦内翻性乳头状瘤是一种安全、有效、微创的治疗方法,大部分可以通过单纯鼻内镜进路术式完成,但对于肿瘤涉及上颌窦、额窦等病变广泛的Ⅲ、Ⅳ级患者,采用联合进路可以避免手术盲区,减少肿瘤残留,降低复发率。
1)对于KrouseⅠ级肿瘤,肿瘤位于鼻腔内,若基底部暴露清楚,可以在鼻内镜下行单纯肿瘤切除。
2)对于KrouseⅡ级肿瘤,可考虑行全筛窦切除术,同时尽量扩大上颌窦开口,以利术后随访。在处理眶纸板、筛顶时,既要对病变黏膜彻底清除同时强调保留硬脑膜和眶隔膜的完整性,又要注意不损伤骨质以免出现并发症。
3) KrouseⅢ级肿瘤中①对于侵及鼻腔、筛窦及蝶窦的鼻内翻性乳头状瘤,单纯鼻内镜手术多能彻底切除。②对于KrouseⅢ级肿瘤侵犯上颌窦外侧壁、下壁、前壁的病变,应采取鼻内镜联合改良柯-陆术式,可最大减少复发。③对于大额窦且肿瘤累及额窦外侧或眼眶、前壁,行经鼻内镜联合额窦前壁开窗双进路行根治性肿瘤切除术。
4)对于KrouseⅣ级肿瘤因侵犯鼻外结构如眼眶、颅内者仍需附加鼻外入路联合手术,方能彻底切除肿瘤。
第二部分鼻腔鼻窦内翻性乳头状瘤中Survivin、Caspase-3表达的临床意义研究
研究背景
鼻腔鼻窦内翻性乳头状瘤(Sinonasal inverted papilloma, SNIP)是一种起源于鼻腔鼻窦粘膜上皮的良性肿瘤,但具有局部侵袭性,复发率高和易恶变等特征,其发病及复发和恶变的机制尚未明确。Survivin是新近发现的一种凋亡抑制基因,其表达的蛋白是凋亡抑制蛋白家族的新成员,具有抑制细胞凋亡的作用,并在细胞的有丝分裂及胞质分裂过程中起着重要的作用。研究表明Survivin是在胚胎发育过程中和人的肿瘤组织中表达,而在成熟的终末分化组织中表达降低或缺失。Survivin基因是由DC.Alfirei克隆的抗凋亡基因,在细胞生存和细胞周期进程中发挥着重要作用。Survivin主要功能包括抑制凋亡和调控细胞周期。Survivin属于IAP家族,该家族还包括XIAP, clAP1, elAP2, NIAP, ML. IAP和apollon。IAP家族成员通过杆状病毒IAP重复结构域与Caspase(pro-caspase-9, caspase-3和caspase-7)发生直接或间接作用来抑制凋亡。另一方面,Survivin与内着丝粒蛋白(inner centromere protein), Aurora B激酶和Borealin一起组成染色体过客复合蛋白体,指导姐妹染色单体的精确分离,调控有丝分裂晚期微管的稳定性,促进细胞增殖。在胚胎形成时期,Survivin大量表达,与正常的细胞分裂和组织分化相适应。在终末分化的组织中,Survivin一般很难检测到。但在肿瘤形成过程中,Survivin异常高表达。在多种人类肿瘤中,Survivin的表达量与肿瘤不良预后及高复发率呈正相关相关。目前认为,Survivin过度表达可导致肿瘤对多种化疗药物产生耐受。此外,利用特异的反义核苷酸靶向干扰Survivin的表达能够有效杀伤肿瘤细胞。因此,Survivin作为肿瘤治疗中最具肿瘤特异性的靶点之一受到科学家的密切关注。Caspase-3是Caspase家族最重要成员,引起细胞凋亡的最下游成分,是细胞凋亡的效应分子,参与了一系列与凋亡有关的细胞变化过程,包括细胞内蛋白底物的降解,凋亡抑制的失活,染色后聚集促使凋亡小体形成等,是细胞凋亡的关键酶类。
目的
本研究着重从鼻内翻性乳头状瘤(Sinonasal inverted papilloma, SNIP)的病理形态出发,根据SNIP特有的病理特点及Survivin和Caspase-3的生物学特性及其与肿瘤的关系,采用免疫组织化学方法检测相关因子Survivin及Caspase-3在SNIP中的表达。探讨两者在SNIP中的作用及相互关系,为SNIP的临床监测及预后评估提供新的途径和方法,对SNIP的治疗也提供客观依据。
方法
实验组(SNIP组)选取2003—-2008年在中山大学附属第三医院耳鼻咽喉科收治的SNIP患者中,手术切除、临床资料及随访记录完整、复习原HE染色病理切片证实的可评价病例46例。其中男性33例,女性13例。年龄39-70岁,平均53.8岁。采用兔抗人Survivin多克隆抗体和兔抗人Caspase-3多克隆抗体,采用免疫组化Envision二步法检测46例SNIP(SNIP组又分为初发组、复发组和恶变组)组织标本中Survivin及Caspase-3的表达；并同时检测10例鼻鳞状细胞癌(Nasal squamous cell carcinoma, NSCC)组织标本及10例正常下鼻甲粘膜组织标本中的Survivin及Caspase-3的表达作为对照研究。统计学处理：所有资料均运用SPSS13.0进行统计分析,率的比较采用Fisher精确概率法分析或X2检验；Survivin与Caspase-3表达相关性采用RXC列表关联性的X2检验用。Survivin与Caspase-3各组间的表达情况比较应用有序多分类资料秩和检验,多重比较方法均采用Bonffroni法。以P<0.05为为差异有统计学意义。
结果
鼻腔鼻窦内翻性乳头状瘤和鼻腔鳞癌组织中Survivin的表达率分别为69.6%、90.0%,均显著高于正常下鼻甲黏膜组织的表达率0%(P<0.01)。鼻腔鳞癌组织中Caspase-3的表达率为20%,显著低于正常下鼻甲黏膜组织的表达率100.00%(P<0.01),鼻腔鼻窦内翻性乳头状瘤组织中Caspase-3的表达率为41.3%,低于正常下鼻甲黏膜,但两者之间的差异无显著性(P>0.05)。Survivin和Caspase-3在鼻腔鼻窦内翻性乳头状瘤中的表达呈负相关(P<0.01)。Survivin在正常鼻粘膜组、SNIP组和SCC组中的表达具有显著差异性。Survivin在SNIP初发组、复发组、恶变组及SCC组中的表达逐渐增强,在各组间表达有差别。经秩和检验两两比较,显示Survivin的表达在SNIP初发组与SCC组,SNIP复发组与SCC组之间均有显著性差异,其它两组之间的表达无明显差异。Caspase-3在正常鼻粘膜组和SNIP组、NSCC组中的表达具有显著性差别。Caspase-3在SNIP初发组、复发组、恶变组及NSCC组中的表达逐渐减弱,在各组间表达差别无显著性。
结论
1.SNIP虽然是良性肿瘤,但其具有高复发、易恶变的特点,在临床治疗上应引起足够的重视。
2.Survivin在SNIP中表达增高,从SNIP初发、SNIP复发到恶变SNIP和SCC组织之间,Survivin的表达逐渐增多,Survivin在鼻腔鼻窦内翻性乳头状瘤和鼻腔鳞癌的发生、发展中起重要作用,可能成为鼻腔鼻窦内翻性乳头状瘤和鼻腔鳞癌基因治疗的靶点。
3.Caspase-3从SNIP初发、SNIP复发到恶变SNIP和SCC组织之间,Caspase-3的表达逐渐减弱,提示Caspase-3可能参与了正常鼻粘膜上皮细胞发育及转化细胞凋亡过程的调节,Caspase-3表达下调在鼻腔鼻窦内翻性乳头状瘤和鼻腔鳞癌的发生、发展中起重要作用。
4.Survivin与Caspase-3之间负性相关,说明在鼻腔鼻窦内翻性乳头状瘤的组织中Survivin直接或间接抑制Caspase-3的表达,减少了细胞的凋亡,同时还可能引起了细胞的增殖,从而通过抑制细胞凋亡和促进细胞增殖的双重作用来促进肿瘤的进展。
5.通过检测Survivin和Caspase-3,对于SNIP的诊断及预后评价有着重要参考价值,并为SNIP的治疗提供了新思路和有效方法。
PartⅠThe Clinical Research of nasal endoscopy Surgical Therapy and Therapeutic Effect of Sinonasal Inverted Papilloma
Background
Sinonasal inverted papilloma (SNIP) is a kind of benign sinonasal tumor which constitutes 0.4% to 4.7% of all nasal tumors and commonly seen in middle aged men. It has a marked tendency to recur after surgical treatment. The tumor is associated with recurrence and malignancy and during growth it can destroy surrounding tissue and correlated with squamous carcinoma. Surgical excision is regarded as the treatment of choice for it. Traditional surgery such as the lateral rhinotomy has served as the standard for surgical management for SNIP, however, the s approach has some questions which have more impaired, more hemorrhagic and more length of hospital stay. All SNIP, arise typically from the lateral nasal wall or within the maxillary sinus. Males are 4-5 times more frequently affected than females. SNIP is prevalent in the fifth and sixth decades of life. The four characteristic attributes of Inverted papilloma are its tendency to recur, its destructive capacity, the associated nasal polyps, and its propensity to be associated with malignancy. The main treatment is surgery. The best surgical approach and the extent of resection are somewhat controversial, as is discussed in the literature. The approaches include conservative intranasal piecemeal excision, Caldwell—Luc surgeries and a more aggressive wide excision by lateral rhinotomy. The above procedure has a high recurrence rate and facial scars. With the development of nasal endoscopy and imaging diagnostic technique, endoscopic surgery or associated with open approaches has been accepted by more and more scholar as the major therapy measure. Endoscopic sinus surgery for nasal inverted papilloma is characterized by a less trauma and the function of nasal cavity and paranasal sinuses were better retained. Endoscopic resection is a favorable treatment option for most cases of sinonasal inverted papilloma. The primary purpose of this research is to investigate the surgical methods and the therapeutic effect of SNIP undergoing endoscopic sinus surgery.
Objective
The objective of this study was to compare the endoscopic with tradition and associated with open approaches for surgical management of SNIPs. Operative parameters included the operated time(OT), estimated blood loss(EBL), length of hospital stay(HS)were al so compared.
Methods
A retrospective analysis was performed of medical records for 91 cases treated with endoscopic resection of sinonasal inverted papilloma at the Department Otorhinolaryngology Head and Neck Surgery of the 3rd hospital affiliated Sun-Yet Sen University from August 1996 to February 2008. There were 62 males and 29 females in the study group. The patient ages ranged from 23 to 70 years, with an average age of 48.6 years. All patients were classified according to the staging systems separately reported Krouse specifically for SNIP. In 2000, Krouse developed a staging system based on the extent of tumor involvement depending on endoscopic, CT, and MRI examinations. The importance of this classification is because of the impact of the portion or portions of the antrum involved and/or extra sinonasal extensions on surgical plan:T1:tumor totally confined to the nasal cavity; the tumor Can be localized to one wall of the nasal cavity or can be extensive within the nasal cavity;T2:tumor limited to the medial and superior portions of the maxillary sinus. And/or involving the ethmoid sinus, with or without involvement of the nasal cavity; T3:tumor involving the lateral inferior; anterior; or posterior walls of the maxillary sinus, the sphenoid sinus, and/or the frontal sinus, with or without involvement of the ethmoid sinuses, or the nasal cavity;T4:tumor extending outside the confines of the nose and/or paranasal sinuses to involve adjacent, contiguous structures(e.g., the orbit, intracranial compartment, or the pterygomaxillary space) Nowadays, Krause's system is used to be the standard of the classification for SNIP. The staging was summarized as following:18 pts in gradeⅠ,45 pts in gradeⅡ,25 pts in gradeⅢ,3 pts in gradeⅣ. Simple endoscope approach group(A group):18 cases in gradeⅠ ,33 cases in gradeⅡand 13 cases in gradeⅢ. Endoscopic surgery combined with Caldwell-luc approach group (B group),12 cases in gradeⅡand 12 cases in gradeⅢ. Endoscopic surgery combined with external approach group(C group):3 cases in gradeⅣ. The classification system based on the origin of SNIP is helpful in planning surgery and evaluating results:①In gradeⅠandⅡ, we performed with conservative transnal endoscopic en bloc excision and according to the root of the tumor;②In gradeⅡand cases involved the media wall of maxillary sinus, we performed with extend local-excision;③In gradeⅢand cases involve the lateral, front, media and rear wall of maxillary, we performed with radical excision by endoscopic combined with improved Caldwell-luc procedure to remove the tumor in ethmoidal and maxillary sinus;④In gradeⅣand cases involved superior wall of orbit and rear wall of frontal sinus, we performed radical excision by endoscopic surgery combined with anterior wall fenestration of frontal sinus. Statistical analysis:All the data were analyzed by the software SPSS 11.0. Ratio comparison is done by chi-square and Fish's methods.
Result
The patients were following up for 18 to 90 months, average 37 months. The total recurrence rate is 15.4%(14/91). The recurrence rate for A group:gradeⅠis 5.6%(1/18)、gradeⅡis 6.1%(2/33)、theⅢgrade is 53.8%(7/13); The recurrence rate for B group:gradeⅡis 16.7%(2/12), theⅢgrade is 8.3%(1/12); The recurrence rate for C group:gradeⅣis 33.3%(1/3). The main complaint was unilateral nasal obstruction and epitasis. Lesions arising from the nasal septum or lateral nasal wall presenting the nasal cavity resulting in the nasal obstruction and early diagnosis while the lesion is relatively small and limited. Tumors originating from the maxillary sinus give vague symptoms and result in late diagnosis while the lesion is large and extensive. SNIP regardless of its size, location, and/or extent could be traced to its origin. In gradeⅠ, the origin of the lesion was localized in most of the cases and pedicled in about 60% cases. In gradeⅡ, the origins were wide and diffuse in all cases. All cases were unilateral with no secondary attachment and/or multicentricity. In gradeⅡ, medial wall was involved in all cases, inferior involved in some cases, anterior, lateral, posterior, superior wall. In most case, tumors were found in nose cavity. In gradeⅠ, maxillary sinus was involved in four cases that were origined from lateral nasal wall. Nasolacrimal duct was involved in more than half. The extension of tumor beyond the confines of the nasal cavity and paranasal sinuses(e.g., orbit, nasopharynx, dura, or soft tissue of nose or face) were not found in all cases. With recent advances in transnasal endoscopic sinus surgery and CT/MRI, in KrouseⅡ cases, the difference was not statistically significant in rate of recurrence between A and B group. However, the recurrence rate is higher in the group of A than that of group B in KrouseⅢcases. The cases of recurrence required additional surgery and there were no relapse for following-up 24 months.
Conclusion
With nasal endoscopy and CT/MRI, we can trace the origin of NIE The classification system based on the origin of SNIP is helpful in planning surgery and evaluating results. Lesions arising from the nasal septum or lateral nasal wall present in the nasal cavity resulting in nasal obstruction and early diagnosis while the lesion is relatively small and limited. Tumors originating from the maxillary sinus give vague symptoms and result in late diagnosis while the lesion is large and extensive. It may get the better therapeutic effect in patients with Endoscopic nasal surgery, if the indications are appropriate. And the patient's quality of life may be improved significantly. Endoscopic sinus surgery is an excellent procedure for treating SNIP who have limited disease that involves the lateral nasal wall. the anterior and posterior ethmoid sinuses, and the medial maxillary wall(KrouseⅠ,Ⅱand parts ofⅢ). It can completely remove the tumor and the nasal function can be retained.
1. The endoscopic surgery is the preferred method which has less bleeding, fewer complications and shorter hospitalization time and reduce the financial burden of patients.
2. The recurrence of the inverted papilloma undergoing endoscopic surgery is in a reasonable range and better than the external approach.
3. The endoscopic surgery is a safe, economical and effective method for the SNIPs cases in Krouse gradeⅠandⅡFor the KrouseⅢor/andⅣcases in recurrence or extensive disease, endoscopic surgery combined with external approach is a better choice which should be studied in clinical practice.
1) In gradeⅠ, we performed with conservative transnal endoscopic en bloc excision if the tumor located in the nasal cavity.8. We performed with conservative transnasal endoscopic excision and with performed conservative transnasal endoscopic excision, radical transnasal endoscopic medial maxillectomy, combined approach, Lateral rhinotomy.
2) For gradeⅡ, we performed ethmoidectomy and enlarged the ostia of maxillary as impossible for promoting the postoperative follow-up. At the same time, the favorable operation effect requires not only making a clean sweep of tumor, but also maintaining the integrity of the normal mucosa.
3) For gradeⅢ, the patients should be operated by the combination of endoscopic surgery and anterior wall fenestration of frontal sinus procedure, when the tumor involved the lateral wall of frontal sinus or the anterior wall of orbit.
4) For gradeⅣ, the patients should be performed with endoscopic surgery and external approach, when the tumor involved the external nasal including orbit and the skull base.
PartⅡExpression of Survivin and Capase-3 in Sinonasal inverted papilloma and their clinical significance
Background
Sinonasal inverted Papilloma (SNIP) is a kind of benign tumor originated in nasal sinus mucosa, but characterized by aggressive nature and high recurrence rate and malignant transformation potential. Its incidence and recurrence and malignant transformation mechanism is not clear. Survivin is a new antiapoptosis gene, which is discovered recently. And survivin protein is a new member of inhibition of apoptosis protein (IAP) family. It can inhibit cell apoptosis, and play a significant role in cell mitosis and cytoplastic cleavage. Research shows that survivin is a tumor specific apoptosis gene, which is expressed in the process of embryonic development and human tumor tissue, but in the mature terminal differentiation organization in reducing loss or cannot be found. Survivin is an anti—apoptosis gene which is cloned by DC.Altirei. Survivin plays a pivotal role in not only cell survival but also cell cycle progression. Survivin is a potent inhibitor of apoptosis; being a member of inhibitors of apoptosis proteins (tAP) family which also includes XIAP, clAP1, clAP2, NIAP, ML-IAP and apollon. The lAP family members inhibit apoptosis via the baculovims IAP repeat domains which can directly or indirectly interact with caspases (pro-caspase-9, caspase-3 and caspase-7). In addition, Survivin may promote proliferation by facilitating accurate sister chromatid segregation and stabilization of microtubules in late mitosis where it forms a complex with the inner centromere protein, Aurora B kinase and Borealin. Survivin is normally expressed in abundance during embryonic development, coordinating cell divisions of normal growth and tissue differentiation. Survivin often becomes undetectable in terminally differentiated tissues. However, during carcinogenesis, survivin is often highly expressed. High expression of survivin is associated with poor prognosis and increased frequency of relapse in many common human cancers(e.g. colorectal cancer, acute myeloid leukemia and prostate cancer). In addition, targeting survivin by specific antisense oligonucleotides can effectively kill tumor cells. Overexpression of survivin has been suggested to cause resistance to various chemotherapeutic compounds in cancers. Therefore, survivin has been hailed by scientists as one of the most cancer-specific targets for cancer therapeutics. The capase-3 is a member of the cysteine-aspartic acid protease (caspase) family. The occurrence of apoptosis is a complicated protease cascade process that is guided by the caspase family group, Activation of effector caspases is a central and ultimate step in many apoptosis pathways. Caspase-3 is the key executioner caspase, it exists as an inactive zymogen that is activated by upstream signals. Several groups have considered using the human caspase-3 gene as a novel form of anticancer gene therapy. However, overexpression of the wild-type caspase-3 in mammalian cells does not induce apoptosis, which is due to their inability to undergo autocatalytic processing without upstream caspase for activation. Recently, constitutively active recombinant caspase-3(re-caspase-3)has been was generated by making its small subunit preceding its large subunit. Unlike its wild-type counterpart that is the large subunit preceding the small subunit, the re-caspase-3 is capable of autocatalytic processing and inducing apoptosis independent of the upstream initiator caspase molecules. In addition, it could resist the effect of some apoptosis restraining genes. As caspase-3 is the most downstream executioner of apoptosis, the re-caspase-3 could be used at very low concentrations to induce apoptosis in target cells. To determine the effect of inhibit apoptosis and proliferative activity in SNIP and the relations of each others, and to Provide a new way of the clinical monitoring and prognostic evaluation of SNIP, and also provide an objective basis for treatment on the SNIP.
Objective
This study focused on the pathological form of the SNIP, according to the relationship between the SNIP unique features and caspase-3 and survivin's biological characteristics of the tumor, to detect the expression of the caspase-3 and survivin in the SNIP using the immunohistochemical methods.
Methods
The experimental group was selected from SNIP patients in Otorhinolaryngology of the 3rd affiliated hospital of Sun-Yet Sen University during 2003-2008, surgical excision, clinical data and follow-up records are all integrity, reviewing the original HE dying pathological section confirmed cases can be evaluation 46 cases. Among these cases,33 cases was male,13 cases was female. Their age was between 39 to 70 years old, average 53.8 years. To detect the expressing of caspase-3 and survivin in tissue of 46 cases of SNIP using immunohistochemistry methods with mouse anti-human monoclonal antibody caspase-3 and Rabbit anti-human polyclonal antibody Survivin. At the same time, to detect the expression of Caspase-3 and Survivin in tissue samples of 10 cases of SCC (squamous cell carcinoma,SCC) and 10 patients with normal nasal mucous as the control group.(The SNIP group was subdivided into the new-onset group, the recurrence group and the malignant group).
Statistical treatment
All data processing used statistical software SPSS 13.0, and p<0.05 was significant for the difference. The comparison between constituent ratios was made with Chi-square test. We used Spearman rank correlation to analysis the correlation of Survivin and Caspase-3, significance level was set to a=0.05. To compare the expression of Survivin and Caspase-3 in the three group of SNIP and the SCC group, ordinal multi-categorical data and the two categorical data was described by Wilcoxon signed rank test.
Result
Survivin was expression in 69.6% cases of SNIP,90.0% cases of SCC and not expressed in 0% cases of normal inferior concha tissues. Caspase-3 was expressed in 20% cases of SCC, which is significantly lower than cases of normal nasal mucosa(P<0.01). Caspase-3 was expressed in 41.3% cases of SNIP, which is lower than that in normal tissues 100%(P<0.01), but there was no significant difference between them(P>0.05). Expression of Survivin and Caspase-3 was negatively related to expression of survivin in SNIP. The expression of Survivin in the normal mucosa group, SNIP and SCC group had significant differences. The expression of Survivin in the SNIP new-onset group, the recurrence group, the malignant group and SCC group were all gradually increased, and the expression among these groups were significant differences. Rank test showed that Survivin in the SNIP new-onset group and the recurrence group, the malignant group and SCC group were significant difference between each two groups, there was no significant difference in the other groups. The expression of caspase-3 in the normal mucosa group, SNIP and SCC group had significant differences. The expression of Caspase-3 in the SNIP new-onset group, the recrudescent group, malignant group and SCC group were all gradually decreased, and the expression among these groups were no significant differences.
Conclusion
The results are significantly different between the expression Survivin and Caspase-3 in tissue samples of SNIP, SCC and normal mucosa, and the two results have closed relations. The results showed that the development process of SNIP involved the activation of apoptosis inhibitory factor Survivin and the altered function of Caspase-3.
1. SNIP is a benign tumor, but with high recurrence and malignant transformation in the clinical characteristics, which should cause enough attention. Survivin may play an important role in the pathway of progressing of SNIP and SCC. It may be identified as a new therapeutic target.
2. The expression of Survivin increased in the SNIP. The expression of Survivin in the SNIP new-onset group, the recrudescent SNIP, the malignant SNIP and SCC group gradually increase.
3. From the new-onset SNIP, the recrudescent SNIP and the malignant SNIP to SCC organizations, Caspase-3 expression gradually decrease. Prompting that Caspase-3 may regulate the homeostasis of normal nasal mucosa and the apoptosis of transformed cells. The expression of Caspase-3 may play important role in the pathogenesis of sinonasal inverted papilloma and squamous cell carcinoma.
4. There was negative significant correlations between the expression of Survivin protein and the expression of Caspase-3, thus the results had shown that survivin was a bifuntional protein capable both of suppressing apoptotic cell death and regulating cell proliferation, and it could promote the neoplastic progression by both inhibition of cell apoptosis and progress of cell proliferation.
5. By the detection of Survivin and Caspase-3 there is an important reference value for the diagnosis and prognosis of SNIP.
引文
[1]Krouse JH. Endoscopic Treatment of inverted papilloma:safety and efficacy [J]. AmJ Otolaryngol,2001,22 (2):87299.
[2]Von Buchwald C,Bradley P J.Risks of maliganancy in inverted papilloma of the nose and paranasal sinuses.Curr Opin Otolaryngol Head Neck Surg 2007,15:95-98.
[3]Chiu A G, Jackman A H,Antunes M B, et al. Radiographic and histologic analysis of the bone underlying inverted papillomas [J]. Laryngoscope,2006, 116:1617-1620.
[4]袁虎,王荣光.鼻腔鼻窦内翻性乳头状瘤复发与恶变[J].国外医学耳鼻咽喉科学分册,2002,26(1)：30-33.
[5]Waitz G, Wiyand M E. Resluts of endoscopic sinus surgery for the treatment of inverted papillomas [J]. Laryngoscope,1992,102:917-922.
[6]Mccraryws, Grosscw,Reibelj F,etal. Preliminary report:endoscopic versus external surgery in the management of inverting papilloma [J]. Laryngoscope, 1994,104:415-419.
[7]许庚,李源.鼻窦内窥镜手术治疗鼻腔、副鼻窦内翻性乳头状瘤[J].中华耳鼻咽喉科杂志,1996,31(4)：237-239.
[8]Krouse JH. Development of a staging system for inverted papilloma [J] Laryngoscope,2000,110(6):965-968.
[9]Mirza S, Bradley PJ, Acharya A, Stacey M, Jones NS. Sinonasal inverted papillomas:recurrence, and synchronous and metachronous malignancy. Journal of Laryngology & Otology 2007;121(9):857-64.
[10]Lampertico P, Russell W, MacComb W. Squamous papilloma of upper respiratory epithelium. Archives of Pathology & Laboratory Medicine 1963;75:293-302.
[11]Skolnik EM, Loewy A, Friedman JE. Inverted papilloma of thenasal cavity. Archives of Otolaryngology 1966;84(1):61-7.
[12]Buchwald C, Franzmann MB, Tos M. Sinonasal papillomas:areport of 82 cases in Copenhagen County, including a longitudinal epidemiological and clinical study. Laryngoscopel995;105(1):72-9.
[13]Outzen KE, Grontveld A, Jorgensen K, Clausen PP, Ladefoged C. Inverted papilloma:incidence and late results of surgical treatment. Rhinology 1996;34(2):114-8.
[14]Bielamowicz S, Calcaterra TC, Watson D. Inverting papilloma of the head and neck:the UCLA update. Otolaryngology-Head & Neck Surgery 109(1):71-6, 1993;109(1):71-6.
[15]Phillips PP, Gustafson RO, Facer GW. The clinical behavior of inverting papilloma of the nose and paranasal sinuses:report of 112 cases and review of the literature. Laryngoscope 1990;100(5):463-9.
[16]Lawson W, Patel ZM. The evolution of management for inverted papilloma:an analysis of 200 cases. Otolaryngology-Head & Neck Surgery 2009; 140 (3):330-5.
[17]Bhandary S, Singh RK, Sinha AK, Badhu BP, Karki P. Sinonasal inverted papilloma in eastern part of Nepal. Kathmandu University Medical Journal 2006;4(4):431-5.
[18]Garavello W, Gaini RM. Incidence of inverted papilloma in recurrent nasal polyposis. Laryngoscope 2006; 116(2):221-3.
[19]Weissler MC, Montgomery WW, Turner PA, Montgomery SK, Joseph MP. Inverted papilloma. Annals of Otology, Rhinology & Laryngology 1986;95(3 Pt 1):215-21.
[20]Busquets J M, HWAN G P H. Endoscopic resection of sinonasal inverted papilloma:a meta-analysis[J]. Otolaryngol Head Neck Surg,2006,134:476-482.
[21]Constantino G T, ABDO T T, ROMANO F R,et al. The role of endoscopic surgery in the t reatmentof nasal inverted papilloma [J]. Rev Bras Otorrinolaringol,2007,73:65-68.
[22]Baruah P, Deka RC. Endoscopic management of inverted papillomas of the nose and paranasal sinuses. Ear, Nose,& Throat Journal 82(4):317-20, 2003;82(4):317-20.
[23]Hymas V.J papillomas of the nasal cavity and Paranasal sinuses.A clinieoPathological study of 315 cases.Am.Otol.Rhinol.Laryngol.1971;80,192 —206.
[24]Weissler M.C. etal.Inverted PaPilloma.Ann Otol Rhinol Laryngol,1986, 95:215.
[25]Wbodson GE,Robbins MiehaelsL.Inverted PaPilloma.Considerations intreatment.Arch Otolaryngol.1985 Dee:111(12):806—811.
[26]Beek JC, MeClatehey KD, LesPeranee MM.el al.Presence of human PaPillonavirus Prediets reeurrence of inverted PaPilloma.Oto Head Neek Surg, 1995,113(3):49.
[27]刘翠苓 等鼻内翻性乳头状瘤与人类乳头状瘤病毒的关系北京医科大学学报1998.6月,30(3).
[28]高鹏飞,陈文弦等EB病毒和人乳头状瘤病毒感染与鼻、鼻窦内翻性乳头 状瘤的关系西南国防医药2000,10(2)：68—70.
[29]Lawson W, Kaufman MR, Biller HF. Treatment outcomes in the management of inverted papilloma:an analysis of 160 cases. Laryngoscope 2003;113(9): 1548-56.
[30]Lawson W, Ho BT, Shaari CM, Biller HF. Inverted papilloma:a report of 112 cases. Laryngoscope 1995;105(3 Pt 1):282-8.
[31]Myers EN,Schramm VL Jr,Barmes EL Jr.Management of inverted papilloma of the nose and paranasal sinuses.Laryngoscope,1981,91:2071-2084.
[32]CannadY SB,Batra PS,Sautter NB,et al.New staging system for sinonasal inverted papilloma in the endoscopic era, Laryngoscope,2007,117:1283 1287.
[33]Woodworth BA, Bhargave GA, Palmer JN, Chiu AG, Cohen NA, Lanza DC, et al. Clinical outcomes of endoscopic and endoscopic-assisted resection of inverted papillomas:a 15-year experience.[erratum appears in Am J Rhinol. 2008 Jan-Feb;22(1):97]. American Journal of Rhinology 2007;21(5):591-600.
[34]Buchwald C, Larsen AS. Endoscopic surgery of inverted papillomas under image guidance--a prospective study of 42 consecutive cases at a Danish university clinic. Otolaryngology-Head & Neck Surgery 2005;132(4):602-7.
[35]Landsberg R.Attachment-oriented endoscopic surgical approach for sinonasal inverted papilloma.Oper Tech Otolaryngol Head Neck Surg,2006,17:87-96.
[36]Phillips PP,Gustafson RO,Facer GW.The clinical behavior of inverting papilloma of the nose and paranasal sinuses:report of 112 cases and review of the literature. Laryngoscope,1990,100:463-469.
[37]Kraft M,Simmen D,Kaufmann T,et al. Long-term results of endonasal sinus surgery in sinonasal papillomas.
[38]Hwang CS, Yang HS, Hong MK.Deteetion of human PaPillomavirus(HPV) in sinonasal Inverted Papillomas using Polymerase chain reaetion(PCR).Am J Rhinol.1998 SeP-Oct; 12(5)363-6.
[39]Bernauer HS, WeIkoborsky HJ, Tilling A, Amedee RG, Mann WJ.Inverted PaPillomas of the paranasl sinuses and the nasal eavity:DNA indiees and HPV infeetion. Am J Rhinol.1997Mar-APr;11(2):155—60.
[40]Fan SY,Yan JJ, Ohyama M.Immunohistoehemistry of P53 in sinonasal inverted Papilloma and assoeiated squamous cell carcinoma.Am J Rhinol.1998 Mar-Apr:12(2):119-24
[41]卓明英,杨军等鼻腔鼻窦内翻性乳头状瘤CD44蛋白的表达及意义临床肿瘤学杂志2005,10(4)：399-403
[42]Karkos PD,Fyrmpas G,Carrie SC,et al.Endoscopic versus open surgical interventions For inverted nasal papilloma:asystematic review. Clin Otolaryngol,2006,31:499-503.
[43]曲永辉,邹昕,李博颐,等189例鼻腔及鼻窦内翻性乳头状瘤CT检查的价值.临床放射学杂志,1998,17：139
[44]Woodruff WW, Vrabec DP. Inverted papilloma of the nasal vault and paranasal sinuses:spectrum of CT findings. AJR,1994,162:419
[45]Kmael RH.TrnasnasalendoseoPiemedialmaxilleetomyininvertedPpailloma[J]. LayrngoscoPe,1995,105:847—853.
[46]Fakhri S,Citardi MJ,Wolfe S,et al.Challenges in the management of sphenoid inverted papilloma.Am J Rhinol,2005,19:207-213.
[47]李源,周兵主编。实用鼻内窥镜外科学技术及应用[M]。北京：人民卫生出版社,2009.342-344.
[48]骆云珍,钱林荣,杨雪明等鼻内镜下内翻性乳头状瘤切除术治疗53例回顾分析[J].中国内镜杂志,2009,15(2)：152-153.
[1]Krouse JH. Endoscopic Treatment of inverted papilloma:safety and efficacy [J]. AmJ Otolaryngol,2001,22 (2):87299.
[2]AmbrosiniQAdida C,AltieriDC.A novel anti-apoptosis gene,survivin, expressed in cancer and lymphoma [J]. Nature Med,1997, (8):917-921.
[3]MaH,Nguyen C,LeeKS,et al.Differential roles for the coactiva-torsCBP and p300 on TCF/beta-catenin-mediated Survivin geneexpression[J].Oncngene, 2005,24(22):3619-3631.
[4]LiF.Role ofSurvivin and its splice variants in tumorigenesis[J].Br JCancer,2005, 92(2):212-216.
[5]McNeish IA,LopesR, BellSJ,etal. Survivin interactswith Smac/DIABLO in ovarian carcinoma cells but is redundant in Smacme-diated apoptosis[J].Exp CellRes,2005,302(1):69-82.
[6]Chiou SK,Jones MK,Tarnawski AS,et al.Survivin-an anti-apoptosis protein:itsbiological roles and implications for cancer and beyond.[J].Medical Science Monitor,2003,9(4):125-129.
[7]Suzuki A,Hayashida M,Ito T,et al.Survivin initiates cell cycle entry by thecompetitive interaction with Cdk4/p16(INK4a)and Cdk2/cyclin E complex activation.[J].Oncogene,2000,19(29):3225-3234.
[8]Sun C,Nettesheim D,Liu Z,et al.Solution structure of human surviving and itsbinding interface with Smac/Diablo.[J].Biochemistry,2005,44(1):11-1723
[9]O'Connor DS, SchechnerJS, Adida C, et, al. Control of apoptosis during angiogenesis by survivin expression in endothelial cells. Am J Path01.2000, 156(2):393-398
[10]Kishi H, Igawa M, Kikuno, N,et, al. Expression of the survivin gene in prostate cancer:correlation with clinicopathological characteristics, proliferative activity and apoptosis,J Urol,2004,171(5):1855-1859
[11]Swarm HS, Grossman D, Anthony JN, et al. Tunor content of the antiapoptosis molecule survivin and recurrence of bladder cancer. N Engl J Med,1999, 34 1(6):452-453
[12]Sarela Al, Macadam RC, Farmery. SM, et al. Expression of the antiapoptosis gene, survivin, predicts death from recurrent colorectal carcinoma. Gut.2000,46(5):645-650
[13]Kawasaki H, Alfieri DC, Lu CD, et al. Inhibiter of apoptosis by sutvivin predicts shorter Survival rates in colorectal cancer. Cancer Res,1998.5 8(22):5017-5074
[14]Mpnzo M, Rosell 1LFelip E, et al. A novel anti-apoptosis gene:Re-expression of survivin messenger RNA as a prognosis marker in non-small-cell lung cancers. J Clin Oncol,1999,17(7):2100—2104.
[15]Tanaka K,Iwamoto S,Gon G, et al. Expression of survivin and its relationship to loss apoptosis in breast carcinomas. Clin Cancer Res,2000,6(1):127-134-40.
[16]Bernaue R, et al Am J Rhinol,1997,11:155.160
[17]Harris MO, et al Otolaryngol Head Neck Surg 1998,118:312-318
[18]Garavello W:Gaini RM, Incidence of inberted papilloma in recurrent nasal polyposis[JLaryngoscope,2006,116(2):221—3
[19]G. Qi, Y. Kudo, T. Ando, T. Tsunematsu, N. Shimizu, S.B. Siriwardena, M. Yoshida, M.R. Keikhaee, I. Ogawa, T. Takata, Nuclear Survivin expression is correlated with malignant behaviors of head and neck cancer together with Aurora-B, Oral Oncol 46 (2010) 263-270.
[20]S. Mega, M. Miyamoto, L. Li, M. Kadoya, R. Takahashi, R. Hase, H. Kaneko, T. Shichinohe, Y. Kawarada, T. Itoh, T. Morikawa, S. Kondo, Immunohistochemical analysis of nuclear survivin expression in esophageal squamous cell carcinoma, Dis Esophagus 19 (2006) 355-359.
[21]Oconnor DS, Schechner JS, Adida C,et al.Angioptosis during angiogenesis by Surviving express in endothelial cell.Am J Pathol,2000,156(6):393
[22]Papapetropoulos A,Fulton D,Mubboubi K,et al.Angiopioetin-1 inhibits endothelial cell.J Biol Chem,2000,275(13):91-92
[23]Alticri DC.Validating Surviving as a cancer therapeutic target.Nat Rev Cancer, 2003,3:46-54
[24]O'Connor DS, Schechner JS. Control of apoptosis during angiogenesis by Survivin expression in endothelial cells. Am J Pathol,2000,156(2):393-398
[25]HasegawaM,YagiK, Iwakawa S, eta.l Chitosan induces apoptosisvia Caspase-3 activation in bladder tumor cell [J]. Jap JCanc-erRes,2001,92(4):459-466.
[26]Wang J,LenardoMJ.Roles ofcaspases in apoptosis, development,and cytokinematuration revealed by homozygous gene deficiencies[J]. JCellSc,i 2000,113(5):753-757.
[27]Bratton SB,MacFarlaneM, Cain K, et a.l Protein complexes acti-vate distinctcaspase cascades in death receptorand stress inducedapoptosis [J].Exp CellRes,2000, (256):27-33.
[28]Tschopp J,Martiron F,et al.Mechanisms of caspase activation Kelly M Boatright and Guy S Salvesen Current Opinion in Cell[J].Biology,2003, 15:725-731.
[29]Chang DW,Xing Z,Capacio VL,Peter ME,Yang X.Inter-dimer processing mechanism of procaspase-8 activation[J].EMBO,2003,22:4132-4142.
[30]Green DR,Reed JC.Mitochondria and apoptosis[J].Science,1998,281(5381): 1309-1312.
[31]Saikumar P,Dong Z,Mikhailov V,et al.Apoptosis:definition,mechanism, and relevance to disease[J].Am J Med,1999,107(5):489-506.
[32]Budihardjo I,Oliver H,Lutter M,et al.Biochemical pathways of caspase activation during apoptosis[J].Annau Rev Cell Dev Biol,1999,15:269-290.
[33]Tamm I,Wang Y,Sausville E,et al.IAP-family protein survivin inhibits caspaseactivity and apoptosis induced by Fas(CD95),Bax,caspases,and anticancer dru [J].Cancer Res,1998,58(23):5315-5120
[34]Kim HS,Shiraki K,Park SH.Expression of survivin in CIN and invasive squamous cell carcinoma of uterine cervix.[J].Anticancer Res,2002,22(2A): 805-808
[35]陈余清,李伟,周继红,等.Survivin抗肺癌细胞凋亡的分子机制.[J].中华肿瘤杂志,2006,28(6)：413-417.
[36]Pennati M, Binda M, DeCesare M, et al. Ribozyme mediated down—regu lation of survivin expression sensitizes human melanoma cells topotecan in vitro and in vivo[J]. Carcino. genesis,2004,25(7):1129—1136.
[37]Mesri M,Wall NR,Li J,et al.Cancer gene therapy using a Survivin mutantadenovirus.[J].J Clin Invest,2001,108(7):981-990.
[38]Yonesaka K, Tamura K, Kurata T, et al. Small interfering RNA targeting survivingsensitizes lung cancers cell with mutant p53 to Adriamycin.[J]. Int J Cancer,2006,118(4):812—820.
[39]Reker S,Becker JC,Svane IM,et al.HLA-B35-restricted immuneresponses against surviving in cancer patients[J].Int J Cancer,2004,108(6):937-941.
[40]FuesselS,Herrmann J,Ning S,et al. Chemosensitization ofbladdercancer cells by Survivin-directed antisenseoligodeoxynucleotidesand siRAN[J].CancerLett, 2006,232(2):243-254.
