HPV、CylinD1、p15、EGFR和Bax在鼻腔、鼻窦内翻性乳头状瘤及鼻鳞状细胞癌中的表达及其意义
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摘要
目的
通过对HPV、CyclinD1、p15、EGFR和Bax蛋白在鼻腔、鼻窦内翻性乳头状瘤、鼻鳞状细胞癌及炎性鼻息肉组织中定位表达的比较,分析它们在鼻腔﹑鼻窦内翻性乳头状瘤和鼻鳞状细胞癌发生过程中的作用及相关意义,从而指导临床治疗。
材料方法
收集汕头大学医学院病理教研室及第二附属医院病理科1999年-2009年收检的鼻腔、鼻窦肿瘤临床资料保存完整的手术切除或鼻内活检组织存档蜡块60例,其中11例鼻炎性息肉(INP)、34例鼻腔、鼻窦内翻性乳头状瘤(SNIP)、15例鼻鳞状细胞癌(SCC)。采用免疫组织化学EnVision两步法,检测60例组织标本中HPV、CyclinD1、p15、EGFR及Bax蛋白的表达情况。SPSS17.0统计软件分析结果,各组两两比较用χ~2检验及Fisher精确检验法,各蛋白间相关性用Pearson相关分析法,检验水准α=0.05,P<0.05为差异有统计学意义,P<0.01为差异有高度统计学意义。
结果
1.病理观察结果:
34例SNIP中3例为假复层纤毛柱状上皮乳头状瘤,其余为鳞状上皮乳头状瘤;3例上皮有中、重度不典型增生。15例SCC中有2例中同时含有鳞癌和内翻性乳头状瘤两种肿瘤组织,其余13例为单纯鳞状细胞癌。
2.免疫组织化学检测结果:
⑴光镜下见HPV蛋白阳性定位于细胞核,呈浅黄色或浅棕色;CyclinD1、p15蛋白阳性均定位于细胞核,呈棕黄或棕褐色;EGFR蛋白阳性定位于细胞膜,呈棕黄色;Bax蛋白阳性定位于细胞浆,呈浅黄色或深棕色。
⑵①HPV蛋白在INP、SNIP、SCC组中阳性表达率为0%、38.2%、26.7%。SNIP与INP组间差异有统计学意义(χ~2=5.915,P=0.018<0.05),其余组间均无统计学意义(P>0.05)。
②CyclinD1蛋白在INP、SNIP、SCC组中阳性表达率为18.18%、35.29%、66.67%。SCC与INP组间差异有统计学意义(χ~2=6.003,P=0.017<0.05),其余组间均无统计学意义(P>0.05)。
③p15蛋白在INP、SNIP、SCC组中阳性表达率为90.91%、35.29%、26.67%。SNIP与INP组、SCC与INP组间比较,差异均有高度统计学意义(χ~2=10.288,P=0.001<0.01;χ~2=10.539,P=0.001<0.01),SCC与SNIP组间无统计学意义(P>0.05)。
④EGFR蛋白在INP、SNIP、SCC组中阳性表达率为18.18%、79.41%、93.33%。SCC与INP组、SNIP与INP组间比较,差异均有高度统计学意义(χ~2=15.143,P=0.00016<0.01;χ~2=13.599,P=0.00048<0.01),SCC与SNIP组间无统计学意义(P>0.05)。
⑤Bax蛋白在INP、SNIP、SCC组中阳性表达率为81.82%、70.59%、33.33%。SCC与SNP组、SCC与SNIP组间差异均有统计学意义(χ~2=6.003,P=0.017<0.05;χ~2=5.980,P=0.026<0.05),SNIP与INP组间无统计学意义(P>0.05)。
⑥SNIP和SCC组中HPV、CyclinD1、p15、EGFR和Bax五种蛋白表达强度之间均无相关性(P>0.05)。
结论
1、HPV感染与鼻腔、鼻窦内翻性乳头状瘤的发生密切相关,进一步证实HPV感染是导致鼻腔、鼻窦内翻性乳头状瘤发生的重要病因学因素之一,可以作为鼻腔、鼻窦内翻性乳头状瘤发生的重要辅助指标;
2、CyclinD1蛋白的过度表达与鼻鳞状细胞癌的发生密切相关,提示CyclinD1蛋白的过度表达可能在鼻鳞状细胞癌的发生过程中起着重要作用。CyclinD1蛋白的高表达可能对鼻腔、鼻窦内翻性乳头状瘤癌变有促进趋势,但这还需在扩大样本量进一步证实;
3、p15蛋白低表达与鼻腔、鼻窦内翻性乳头状瘤以及鼻鳞状细胞癌发生和发展密切相关,提示p15蛋白的低表达可能在鼻腔、鼻窦内翻性乳头状瘤的发生及鼻鳞状细胞癌发生、发展复杂过程中有重要作用;
4、EGFR蛋白的过度表达与鼻腔、鼻窦内翻性乳头状瘤以及鼻鳞状细胞癌发生和发展密切相关,提示EGFR蛋白的高表达可能在鼻腔、鼻窦内翻性乳头状瘤的发生及鼻鳞状细胞癌的发生过程中有重要作用。
5、Bax蛋白显著低表达与鼻鳞状细胞癌的发生、发展过程密切相关,提示Bax蛋白低表达可能在鼻鳞状细胞癌的发生、发展过程中起着非常重要的负调控作用并且可能预示着鼻腔、鼻窦内翻性乳头状瘤有恶变倾向;
6、HPV、CyclinD1、p15、EGFR和Bax五种蛋白在鼻腔、鼻窦内翻性乳头状瘤及鼻鳞状细胞癌中的表达无相关性,这有待于进一步研究;
Objective
To investigate the expression of HPV、CyclinD1、p15、EGFR and Bax proteins in thesinonasal inverted papilloma、nasal squamous cell carcinoma and inflammatory nasal polyptissues,study the roles and relationships in the occurrence process of the sinonasal invertedpapilloma and nasal squamous cell carcinoma.
Materials and Methods
Paraffin blocks of surgical specimen of the tumors of nasal cavity and sinus and intranasalbiopsy, including 11 cases of inflammatory nasal polyp(INP),34 of the sinonasal invertedpapilloma (SNIP),15 of nasal squamous cell carcinoma(SCC) were selected from Shantouuniversity medical college pathology staff room and Dept.of pathology of second affiliatedhospital from 1999 to 2009. Expression of HPV、CyclinD1、p15、EGFR and Bax proteins weredetected by immunohistochemistry Envision two-steps method in 60 tissue samples. Statisticalanalysis was performed using SPSS17.0. Chi-square test and Fisher’s exact test were used toobtain statistically significant differences between two groups. Pearson correlation coefficientswere calculated to evaluate the relationships among proteins. The correctedα=0.05. A value ofP<0.05 was considered statistically significant. A value of P<0.01 was considered highlystatiscally significant.
Results
1. Pathological observations：
3 cases of 34 cases SNIP were pseudostratified ciliated columnar epithelium papilloma, therest were squamous papilloma; the epithelials of 3 cases had moderate and severe cervicalsquamous cell dysplasia. 1 case of 15 cases SCC was with a little inverted papillomaorganization, the rest 14 cases were simple squamous cell carcinoma.
2.Immunohistochemical tests：
⑴Under the light microscope, the positive area of HPV protein was located in the nuclears,showing buff or shallow brown; the positive areas of CyclinD1 and p15 proteins were locatedin the nuclears, showing brown-yellow or brown; the positive areas of EGFR protein waslocated in the membranes, showing brown-yellow; positive areas of Bax protein was locatedin the cytoplasm showing light yellow or dark brown.
⑵①Positive expression rates of HPV protein were respectively 0%、38.24%、26.67% in theINP、SNIP、SCC. The difference between SNIP and INP was statistically significant(χ2=5.915，P=0.018<0.05).The rest were no statistically significant among groups(P>0.05).
②Positive expression rates of CyclinD1 protein were respectively 18.18%、35.29%、66.67% inthe INP、SNIP、SCC. The difference between SCC and INP was statistically significant(χ2=6.003，P=0.017<0.05).The rest were no statistically significant among groups(P>0.05).
③Positive expression rates of p15 protein were respectively 90.91%、35.29%、26.67% in theINP、SNIP、SCC. The differences between SNIP and INP and between SCC and INP werehighly statistically significant(χ~2=10.288，P=0.001<0.01；χ~2=10.539，P=0.001<0.01).Thedifference between SCC and SNIP was no statistically significant (P>0.05).
④Positive expression rates of EGFR protein were respectively 18.18%、79.41%、93.33% in theINP、SNIP、SCC. Significant differences were obtained between SCC and INP (χ~2=15.143，P=0.00016<0.01) and between SNIP and INP (χ2=13.599，P=0.00048<0.01).Thedifference between SCC and SNIP was no statistically significant (P>0.05).
⑤Positive expression rates of Bax protein were respectively 81.82%、70.59%、33.33% in theINP、SNIP、SCC. The differences between SCC and INP and between SCC and SNIP werestatistically significan（tχ~2=6.003，P=0.017<0.05；χ~2=5.980，P=0.026<0.05）。The differencebetween SNIP and INP was no statistically significant (P>0.05).
⑥No significant difference was found among the expression of HPV、CyclinD1、p15、Bax、EGFR five kinds of proteins in the SNIP and SCC（P>0.05）.
Conclusions
1. There is relationship between HPV infection and the occurrence of SNIP, to further prove that HPV infection is one of important etiological factors in the occurrence of SNIP and HPVis an important index in the occurrence of SNIP.
2. There is relationship between over-expressed of CyclinD1 protein and SCC; it suggests thatover-expressed of CyclinD1 protein may play an important role in the process of theoccurrence of SCC. High expression of CyclinD1 protein may has the trend to promote thecancerous of SNIP, but it still needs to expand in sample size to further confirmation;
3. There are relationships between low expression of p15 protein and SNIP and SCC; itsuggests that low expression of p15 protein may play important roles in the process of theoccurrence of SNIP and SCC;
4. There are relationships between excessive expression of EGFR protein and SNIP and SCC; itsuggests that excessive expression of EGFR protein may play important roles in the processof the occurrence of SNIP and SCC;
5. There is relationship between significantly low expression of Bax protein and SCC; itsuggests that low expression of Bax protein may have a very importantly negative regulatingrole in the canceration of SCC and indicate that SNIP has the trend of canceration;
6. The expressions of HPV, CyclinD1, p15, Bax and EGFR protein have no correlations in theSNIP and SCC, and this needs to be further study;
通过对HPV、CyclinD1、p15、EGFR和Bax蛋白在鼻腔、鼻窦内翻性乳头状瘤、鼻鳞状细胞癌及炎性鼻息肉组织中定位表达的比较,分析它们在鼻腔﹑鼻窦内翻性乳头状瘤和鼻鳞状细胞癌发生过程中的作用及相关意义,从而指导临床治疗。
材料方法
收集汕头大学医学院病理教研室及第二附属医院病理科1999年-2009年收检的鼻腔、鼻窦肿瘤临床资料保存完整的手术切除或鼻内活检组织存档蜡块60例,其中11例鼻炎性息肉(INP)、34例鼻腔、鼻窦内翻性乳头状瘤(SNIP)、15例鼻鳞状细胞癌(SCC)。采用免疫组织化学EnVision两步法,检测60例组织标本中HPV、CyclinD1、p15、EGFR及Bax蛋白的表达情况。SPSS17.0统计软件分析结果,各组两两比较用χ~2检验及Fisher精确检验法,各蛋白间相关性用Pearson相关分析法,检验水准α=0.05,P<0.05为差异有统计学意义,P<0.01为差异有高度统计学意义。
结果
1.病理观察结果:
34例SNIP中3例为假复层纤毛柱状上皮乳头状瘤,其余为鳞状上皮乳头状瘤;3例上皮有中、重度不典型增生。15例SCC中有2例中同时含有鳞癌和内翻性乳头状瘤两种肿瘤组织,其余13例为单纯鳞状细胞癌。
2.免疫组织化学检测结果:
⑴光镜下见HPV蛋白阳性定位于细胞核,呈浅黄色或浅棕色;CyclinD1、p15蛋白阳性均定位于细胞核,呈棕黄或棕褐色;EGFR蛋白阳性定位于细胞膜,呈棕黄色;Bax蛋白阳性定位于细胞浆,呈浅黄色或深棕色。
⑵①HPV蛋白在INP、SNIP、SCC组中阳性表达率为0%、38.2%、26.7%。SNIP与INP组间差异有统计学意义(χ~2=5.915,P=0.018<0.05),其余组间均无统计学意义(P>0.05)。
②CyclinD1蛋白在INP、SNIP、SCC组中阳性表达率为18.18%、35.29%、66.67%。SCC与INP组间差异有统计学意义(χ~2=6.003,P=0.017<0.05),其余组间均无统计学意义(P>0.05)。
③p15蛋白在INP、SNIP、SCC组中阳性表达率为90.91%、35.29%、26.67%。SNIP与INP组、SCC与INP组间比较,差异均有高度统计学意义(χ~2=10.288,P=0.001<0.01;χ~2=10.539,P=0.001<0.01),SCC与SNIP组间无统计学意义(P>0.05)。
④EGFR蛋白在INP、SNIP、SCC组中阳性表达率为18.18%、79.41%、93.33%。SCC与INP组、SNIP与INP组间比较,差异均有高度统计学意义(χ~2=15.143,P=0.00016<0.01;χ~2=13.599,P=0.00048<0.01),SCC与SNIP组间无统计学意义(P>0.05)。
⑤Bax蛋白在INP、SNIP、SCC组中阳性表达率为81.82%、70.59%、33.33%。SCC与SNP组、SCC与SNIP组间差异均有统计学意义(χ~2=6.003,P=0.017<0.05;χ~2=5.980,P=0.026<0.05),SNIP与INP组间无统计学意义(P>0.05)。
⑥SNIP和SCC组中HPV、CyclinD1、p15、EGFR和Bax五种蛋白表达强度之间均无相关性(P>0.05)。
结论
1、HPV感染与鼻腔、鼻窦内翻性乳头状瘤的发生密切相关,进一步证实HPV感染是导致鼻腔、鼻窦内翻性乳头状瘤发生的重要病因学因素之一,可以作为鼻腔、鼻窦内翻性乳头状瘤发生的重要辅助指标;
2、CyclinD1蛋白的过度表达与鼻鳞状细胞癌的发生密切相关,提示CyclinD1蛋白的过度表达可能在鼻鳞状细胞癌的发生过程中起着重要作用。CyclinD1蛋白的高表达可能对鼻腔、鼻窦内翻性乳头状瘤癌变有促进趋势,但这还需在扩大样本量进一步证实;
3、p15蛋白低表达与鼻腔、鼻窦内翻性乳头状瘤以及鼻鳞状细胞癌发生和发展密切相关,提示p15蛋白的低表达可能在鼻腔、鼻窦内翻性乳头状瘤的发生及鼻鳞状细胞癌发生、发展复杂过程中有重要作用;
4、EGFR蛋白的过度表达与鼻腔、鼻窦内翻性乳头状瘤以及鼻鳞状细胞癌发生和发展密切相关,提示EGFR蛋白的高表达可能在鼻腔、鼻窦内翻性乳头状瘤的发生及鼻鳞状细胞癌的发生过程中有重要作用。
5、Bax蛋白显著低表达与鼻鳞状细胞癌的发生、发展过程密切相关,提示Bax蛋白低表达可能在鼻鳞状细胞癌的发生、发展过程中起着非常重要的负调控作用并且可能预示着鼻腔、鼻窦内翻性乳头状瘤有恶变倾向;
6、HPV、CyclinD1、p15、EGFR和Bax五种蛋白在鼻腔、鼻窦内翻性乳头状瘤及鼻鳞状细胞癌中的表达无相关性,这有待于进一步研究;
Objective
To investigate the expression of HPV、CyclinD1、p15、EGFR and Bax proteins in thesinonasal inverted papilloma、nasal squamous cell carcinoma and inflammatory nasal polyptissues,study the roles and relationships in the occurrence process of the sinonasal invertedpapilloma and nasal squamous cell carcinoma.
Materials and Methods
Paraffin blocks of surgical specimen of the tumors of nasal cavity and sinus and intranasalbiopsy, including 11 cases of inflammatory nasal polyp(INP),34 of the sinonasal invertedpapilloma (SNIP),15 of nasal squamous cell carcinoma(SCC) were selected from Shantouuniversity medical college pathology staff room and Dept.of pathology of second affiliatedhospital from 1999 to 2009. Expression of HPV、CyclinD1、p15、EGFR and Bax proteins weredetected by immunohistochemistry Envision two-steps method in 60 tissue samples. Statisticalanalysis was performed using SPSS17.0. Chi-square test and Fisher’s exact test were used toobtain statistically significant differences between two groups. Pearson correlation coefficientswere calculated to evaluate the relationships among proteins. The correctedα=0.05. A value ofP<0.05 was considered statistically significant. A value of P<0.01 was considered highlystatiscally significant.
Results
1. Pathological observations：
3 cases of 34 cases SNIP were pseudostratified ciliated columnar epithelium papilloma, therest were squamous papilloma; the epithelials of 3 cases had moderate and severe cervicalsquamous cell dysplasia. 1 case of 15 cases SCC was with a little inverted papillomaorganization, the rest 14 cases were simple squamous cell carcinoma.
2.Immunohistochemical tests：
⑴Under the light microscope, the positive area of HPV protein was located in the nuclears,showing buff or shallow brown; the positive areas of CyclinD1 and p15 proteins were locatedin the nuclears, showing brown-yellow or brown; the positive areas of EGFR protein waslocated in the membranes, showing brown-yellow; positive areas of Bax protein was locatedin the cytoplasm showing light yellow or dark brown.
⑵①Positive expression rates of HPV protein were respectively 0%、38.24%、26.67% in theINP、SNIP、SCC. The difference between SNIP and INP was statistically significant(χ2=5.915，P=0.018<0.05).The rest were no statistically significant among groups(P>0.05).
②Positive expression rates of CyclinD1 protein were respectively 18.18%、35.29%、66.67% inthe INP、SNIP、SCC. The difference between SCC and INP was statistically significant(χ2=6.003，P=0.017<0.05).The rest were no statistically significant among groups(P>0.05).
③Positive expression rates of p15 protein were respectively 90.91%、35.29%、26.67% in theINP、SNIP、SCC. The differences between SNIP and INP and between SCC and INP werehighly statistically significant(χ~2=10.288，P=0.001<0.01；χ~2=10.539，P=0.001<0.01).Thedifference between SCC and SNIP was no statistically significant (P>0.05).
④Positive expression rates of EGFR protein were respectively 18.18%、79.41%、93.33% in theINP、SNIP、SCC. Significant differences were obtained between SCC and INP (χ~2=15.143，P=0.00016<0.01) and between SNIP and INP (χ2=13.599，P=0.00048<0.01).Thedifference between SCC and SNIP was no statistically significant (P>0.05).
⑤Positive expression rates of Bax protein were respectively 81.82%、70.59%、33.33% in theINP、SNIP、SCC. The differences between SCC and INP and between SCC and SNIP werestatistically significan（tχ~2=6.003，P=0.017<0.05；χ~2=5.980，P=0.026<0.05）。The differencebetween SNIP and INP was no statistically significant (P>0.05).
⑥No significant difference was found among the expression of HPV、CyclinD1、p15、Bax、EGFR five kinds of proteins in the SNIP and SCC（P>0.05）.
Conclusions
1. There is relationship between HPV infection and the occurrence of SNIP, to further prove that HPV infection is one of important etiological factors in the occurrence of SNIP and HPVis an important index in the occurrence of SNIP.
2. There is relationship between over-expressed of CyclinD1 protein and SCC; it suggests thatover-expressed of CyclinD1 protein may play an important role in the process of theoccurrence of SCC. High expression of CyclinD1 protein may has the trend to promote thecancerous of SNIP, but it still needs to expand in sample size to further confirmation;
3. There are relationships between low expression of p15 protein and SNIP and SCC; itsuggests that low expression of p15 protein may play important roles in the process of theoccurrence of SNIP and SCC;
4. There are relationships between excessive expression of EGFR protein and SNIP and SCC; itsuggests that excessive expression of EGFR protein may play important roles in the processof the occurrence of SNIP and SCC;
5. There is relationship between significantly low expression of Bax protein and SCC; itsuggests that low expression of Bax protein may have a very importantly negative regulatingrole in the canceration of SCC and indicate that SNIP has the trend of canceration;
6. The expressions of HPV, CyclinD1, p15, Bax and EGFR protein have no correlations in theSNIP and SCC, and this needs to be further study;
引文
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[11] Mendenhall W M, Hinerman R W, Malyapa R S, et al. Inverted papilloma of thenasal cavity and paranasal sinuses [J]. Am J Clin Oncol，2007，30(5):560-563.
[12]孔维佳，周梁，许庚，等．耳鼻咽喉头颈外科学[M].北京:人民卫生出版社, 2005：107-108．
[13] Stephen J K，Vaught L E，Chen K M．Epigenetic events underlie the pathogenesisof sinonasal papillomas[J]．Modern Pathology，2007，20:1019-1027．
[14]杜宜刚，徐永向．家族鼻腔鼻窦内翻乳头状瘤2例报告[J]．山东大学耳鼻喉眼学报，2007，21(5)：453-454．
[15] Weber R S，Shillitoe E J，Robbins K T，et al．Prevalence of Human Papillomavirus in inverted nasal papillomas[J]．Arch Otolaryngol Head Neck Surg，1998，114：23-26．
[16] Bemauer H S，Welkoblmky H J，Tilling A，et al．Inverted papillomas of theparanasal sinuses and the nard cabity DNA indices[J]．Minfoction Amurhinol，1997，11(4)：155-160．
[17] Fiehelson P，Audibert A，Simon F，etal.Cell cycle and cell-fate determinationin Drosophila neural cell lineages[J].Trends in Geneties，2005，21(7):413-420.
[18] James A Coffman.Cell Cycle Development[J].Developmental Cell，2004，6(3):321-327.
[19] Lovec H，Sewing A，Lucibello F C，et al．Oncogenic activity of cyclinD1 revealedthrough cooperation with Ha-ras：link between cell cycle control and malignanttransformation[J]．Oncogene, 1994, 9(1):323.
[20] Nawroz H, van der Riet P, Hruban R H, et al. Allelotype of head and necksquamous cell carcinoma [J]. Cancer Rer, 1994, 54:1152-1155.
[21] Huang D P, Lo K W, Van Hasselt C A, et al. A region of homozygous delectionon chromosome 9p21-22 in primary nasopharyngeal carcinoma [J]. Cancer Res，1994，54:4003-4006.
[22] Paise J O，Carvalho L V，Miguel R E，etal.Prognostic impact of P53、c-erbB2and epidermal growth factor receptor in head and neckCarcinoma[J].Sao PauloMed J，2004，122(6):264-269.
[23] Hitt R，Ciruelos E，Amador M L，et al.Prognostic value of the epidermal growthfactor receptor(EGFR) and p53 in advanced head and neek squamous cellcarcinoma patients treated with induction chemotherapy[J].Eur Cancer2005，41(3):453-460
[24] Ullrieh A，Coussens L，Hayfliek J S，et al.Human epidermal growth factorreceptor cDNA sequence and aberrant expression of the amplified gene in A431epidermoid carcinoma cells[J].Nature，1984，309(5967):418-425.
[25] Chang M S，Lee H S，Lee B L，et al. Differential protein expression betweenesophageal squamous cell carcinoma and dysplasia，and prognosticsignificance of protein markers[J].Pathol ResPraet，2005，201(6):417-425.
[26] Gibaul T L，Metges J P，Conan C V，et al.Diffuse EGFR staining is associatedwith reduced overall survival in locally advanced oesophageal squamous cellcancer[J].Br J Cancer，2005，93(1):107-115.
[27] Baumann M，Krause M，Zips D，etal.Seleetive inhibition of the epidermal growthfaetor receptor tyrosine kinase by BIBX1382BS and the improvement of growthdelay，but not local control，after fractionated irradiation in human Fadusquamous cell carcinoma in the nude mouse[J].Int J Radiat Biol，2003，79(7):547-559.
[28] Gale N，Kambie V，Poljak M，etal.Chromosome 7，17polysomies andoverexpressionof epidermal growth factor receptor and P53 Protein in epithelialhyperplastic laryngeal lesions[J].Oneology，2000，58(2):117-125
[29] Van der Woude C J, Kleibeuker J H, Tiebosch A T, et al. Diffuse and intestinaltype gastric carcinomas differ in their expression of apoptosis relatedproteins [J]. J Clin Pathol, 2003, 56(9):699-702.
[30] BuehwalD C，Franzmann M B，Tos M.Sinonasal papillomas:a report or 82 casesin Copenhagen County,in cluding a Longitudinal epidemiological and Clinicalstudy[J].Laryngoscope，1995，105:72-79.
[31]卜国铱.耳鼻咽喉科学全书(鼻科学)[M].上海：上海科学技术出版社，1997，529.
[32]KrouseJH.Development of a staging system for invertedpapilloma[J].Laryngoscope，2000，110:965-968.
[33] Shanmugaratnam K，Sobin L H.Histological Typing of Turners of the UpperRespiratory Tract and Ear[J].Springer Verlag Berlin，1991:20-21.
[34] Buehwald C Lindeberg H，Pedersen B L，Franzmann M B. Human papilloma virusand P53 expression in carinomas associated with sinonasal papillomas: ADanish Epidemiological study 1980-1998[J].Laryngoscope，2001，111(6):1104-1110.
[35] Katori H，Nozawa A，Tsukuda M. Histopathological Parameters of recur-renceand malignant transformation in sinnasal inverted papilloma[J].ActaOtolaryngol，2006，126(2):214-218.
[36] WEBER R S，SHILLITOE E J，ROBBINS K T，et al．Prevalence of Human Papillomavirus in inverted nasal papillomas[J]．Arch Otolaryngol Head Neck Surg，1998，114：23-26．
[37]吴先光,姚卓华,吴南娇，等.鼻腔、鼻窦内翻性乳头状瘤癌变过程PCNA和PTEN蛋白表达的意义[J].现代医院,2009, 9(1)：14-16.
[38] Heley S.Human papilloma virus:beware the infection you can’t see[J]. AustFam Physician, 2003, 32(5)：311-315.
[39] Burd E M.Human papilloma virus and cervical cancer [J].Clin Microbiol Rev,2003, 16(1):1-17.
[40]Ishiji T.Molecular mechanism of carcinogenesis by humanpapillomavirus-16[J].J Dermatol, 2000, 27(2):73-86.
[41]王德辉，李玉茹，孙克敏．人乳头状瘤病毒与鼻内翻性乳头状瘤的关系[J]．临床耳鼻咽喉科杂志，1998，12(3)：118-119．
[42] Viallard J F, Lacombe F, Belloc F, et al.Molecular mechanisms controllingthe cell cycle: fundamental aspects and implications for oncology [J].CancerRadiother, 2001, 5(2):109-129.
[43] Hortwell L H, Kastan M B.Cell cycle control and cancer[J].Science, 1994,266(5192):1821.
[44] Schrump D S, Chen A, Consoli C.Inhibition of lung cancer proliferation byantisense CyclinDl[J].Cancer Gene Ther, 1996, 3(2):131-135.
[45] Huang D P, Lo K W, van Hasselt C A, et al. A region of homozygous delectionon chromosome 9p21-22 in primary nasopharyngeal carcinoma [J].Cancer Res,1994, 54:4003-4006.
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[48] Galm O, Wilop S, Reichelt J, et al. DNA methylation changes in multiplemyeloma[J]. Leukemia, 2004, 18:1687-1692.
[49] Chang H W, Ling G S, Wei W I, et al. Smoking and drinking can induce p15methylation in the upper aerodigestive tract of healthy individuals andpatients with head and neck.squamous cell carcinoma[J].Cancer,2004,101:125-132.
[50] Wang S E, Narasanna A, Perez T M, et al.HER2 kinase domain mutation resultsin constitutive phosphorylation and activation of HER2 and EGFR andresistance to EGFR tyrosine kinase inhibitors[J].Cancer Cell,2006,10(1):25-38.
[51] Pedersen M W, Meltorn M, Damstrup L, et al. The typeⅢepidermal growth factorreceptor mutation biological significance and potential target foranticancer therapy[J]. Ann Oncol, 2001, 12(6):745-760.
[52]孔慧，孙秀珍，乌肠旭，等.鼻内翻性乳头状瘤中表皮生长因子及受体的表达与恶变的关系[J].临床耳鼻咽喉科杂志，2005，19(5):193-197.
[53] Katori H，Nozawa A，Tsukuda M. Markers of malignant transformation of sinonasalinverted papilloma[J].Eur J Surg Oneol，2005，31(8):905-911.
[54] Holland E C, Hively W P, DePinho R A, et al. A constitutively active epidermalgrowth factor receptor cooperates with disruption of G1 cell-cycle arrestpathways to induce gliom a-like lesions in mice[J].Genes Dev，1998，12(23):3675-3685.
[55] Aptes S S, Mattei M G, Olsen B R, Mapping of the human Bax gene to chromosome19q13.3-q13.4 and isolation of a novel alternatively spliced transcript, Baxdelat[J]. Genomics，1995，26:592-594.
[56] Krajewski S,Krajewska M,Shabaik A, et al. Immunohistochemical determinationof in vivo distribition of Bax, a dominant inhibitor of Bcl-2[J].Am J Pathol，1994，145:1323-1336.
[1] KARKOS P D，FYRMPAS G，CARRIE S C，et al．Endoscopic versus open surgicalinterventions for inverted nasal papilloma: a systematic review [J]．ClinicOtolaryngol，2006，31：499-503.
[2]孔维佳，周梁，许庚，等．乳头状瘤[M]．孔维佳主编：耳鼻咽喉头颈外科学．北京：人民卫生出版社，2005：107-108．
[3] STEPHEN J K，VAUGHT L E，CHEN K M．Epigenetic events underlie the pathogenesisof sinonasal papillomas[J]．Modern Pathology，2007，20：1019-1027．
[4]杜宜刚，徐永向．家族鼻腔鼻窦内翻乳头状瘤2例报告[J]．山东大学耳鼻喉眼学报，2007，21(5)：453-454．
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[7] HAN J K，SMITH T L，LOEHRL T，TOOHILL RJ，et al．An evolution in the managementof sinonasal inverting papilloma[J]．Laryngoscope，2001，111(8)：1395-1400．
[8] KROUSE J H．Endoscopic treatment of inverted papilloma：safety and efficacy[J]．Am J Otolaryngol，2001，22(2)：87-99．
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[14]李毅民，崔惠文，等．人乳头状瘤病毒与呼吸道肿瘤关系的研究：HPV与人鼻腔内翻性乳头状瘤的关系[J]．耳鼻喉学报，1995，9（1）：4．
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[2]邬旭，韩德民.鼻腔、鼻窦内翻性乳头状瘤的研究进展[J].国外医学耳鼻咽喉科学分册，2002，26(2):95-97.
[3] KrouseJH．Endoscopic treatment of inverted papilloma:safety and efficacy[J]．Am J Otolaryngol，2001，22(2):87-99．
[4] Phillips P P，Gustafson R O，Facer G W．The clinical behavior of invertingpapilloma of the nose and paranasal sinuses: report of 112 cases and reviewof the literature[J]．Laryngoscope，1990，100(5):463-469．
[5] Han J K，Smith T L，Loehrl T，Toohill R J，et al．An evolution in the managementof sinonasal inverting papilloma[J]．Laryngoscope，2001，111(8):1395-1400．
[6] BusquetsJM, HwangPH. Endoscopic resection of nasal inverted papilloma: ameta-analysis[J].Otolaryngol Head Neak surg，2006，134:476-482.
[7] Lawson W, Kaufman M R, Biller H F.Treatment outcomes in the management ofinverted papilloma: an analysis of 160 cases [J]. Laryngoscope，2003，113:1548-1556.
[8] Wbodworth B A，Bhargave G A，Palmer J N，et al.Clinical outcomes of endoscopicandendoscopic-assisted:resection of inverted papillomas:a 15-year experience[J].Am J Rhinol，2007，21:591-600.
[9] Ikeqawa K, Matsukuma S. Immunohistochemical study of p53 and ki-67 in invertedpapillomas and nasal polyps arising from or paranasal regions[J]. Rinsho Byori,2005, 53(6):499-503.
[10] Gaio E, Marioni G, Blandamura S,et al. Inverted papilloma involving thetemporal bone and its association with squamous cell carcinoma: criticalanalysis of the literature[J].Expert Rev Anticancer Ther, 2005,5(2):391-397.
[11] Mendenhall W M, Hinerman R W, Malyapa R S, et al. Inverted papilloma of thenasal cavity and paranasal sinuses [J]. Am J Clin Oncol，2007，30(5):560-563.
[12]孔维佳，周梁，许庚，等．耳鼻咽喉头颈外科学[M].北京:人民卫生出版社, 2005：107-108．
[13] Stephen J K，Vaught L E，Chen K M．Epigenetic events underlie the pathogenesisof sinonasal papillomas[J]．Modern Pathology，2007，20:1019-1027．
[14]杜宜刚，徐永向．家族鼻腔鼻窦内翻乳头状瘤2例报告[J]．山东大学耳鼻喉眼学报，2007，21(5)：453-454．
[15] Weber R S，Shillitoe E J，Robbins K T，et al．Prevalence of Human Papillomavirus in inverted nasal papillomas[J]．Arch Otolaryngol Head Neck Surg，1998，114：23-26．
[16] Bemauer H S，Welkoblmky H J，Tilling A，et al．Inverted papillomas of theparanasal sinuses and the nard cabity DNA indices[J]．Minfoction Amurhinol，1997，11(4)：155-160．
[17] Fiehelson P，Audibert A，Simon F，etal.Cell cycle and cell-fate determinationin Drosophila neural cell lineages[J].Trends in Geneties，2005，21(7):413-420.
[18] James A Coffman.Cell Cycle Development[J].Developmental Cell，2004，6(3):321-327.
[19] Lovec H，Sewing A，Lucibello F C，et al．Oncogenic activity of cyclinD1 revealedthrough cooperation with Ha-ras：link between cell cycle control and malignanttransformation[J]．Oncogene, 1994, 9(1):323.
[20] Nawroz H, van der Riet P, Hruban R H, et al. Allelotype of head and necksquamous cell carcinoma [J]. Cancer Rer, 1994, 54:1152-1155.
[21] Huang D P, Lo K W, Van Hasselt C A, et al. A region of homozygous delectionon chromosome 9p21-22 in primary nasopharyngeal carcinoma [J]. Cancer Res，1994，54:4003-4006.
[22] Paise J O，Carvalho L V，Miguel R E，etal.Prognostic impact of P53、c-erbB2and epidermal growth factor receptor in head and neckCarcinoma[J].Sao PauloMed J，2004，122(6):264-269.
[23] Hitt R，Ciruelos E，Amador M L，et al.Prognostic value of the epidermal growthfactor receptor(EGFR) and p53 in advanced head and neek squamous cellcarcinoma patients treated with induction chemotherapy[J].Eur Cancer2005，41(3):453-460
[24] Ullrieh A，Coussens L，Hayfliek J S，et al.Human epidermal growth factorreceptor cDNA sequence and aberrant expression of the amplified gene in A431epidermoid carcinoma cells[J].Nature，1984，309(5967):418-425.
[25] Chang M S，Lee H S，Lee B L，et al. Differential protein expression betweenesophageal squamous cell carcinoma and dysplasia，and prognosticsignificance of protein markers[J].Pathol ResPraet，2005，201(6):417-425.
[26] Gibaul T L，Metges J P，Conan C V，et al.Diffuse EGFR staining is associatedwith reduced overall survival in locally advanced oesophageal squamous cellcancer[J].Br J Cancer，2005，93(1):107-115.
[27] Baumann M，Krause M，Zips D，etal.Seleetive inhibition of the epidermal growthfaetor receptor tyrosine kinase by BIBX1382BS and the improvement of growthdelay，but not local control，after fractionated irradiation in human Fadusquamous cell carcinoma in the nude mouse[J].Int J Radiat Biol，2003，79(7):547-559.
[28] Gale N，Kambie V，Poljak M，etal.Chromosome 7，17polysomies andoverexpressionof epidermal growth factor receptor and P53 Protein in epithelialhyperplastic laryngeal lesions[J].Oneology，2000，58(2):117-125
[29] Van der Woude C J, Kleibeuker J H, Tiebosch A T, et al. Diffuse and intestinaltype gastric carcinomas differ in their expression of apoptosis relatedproteins [J]. J Clin Pathol, 2003, 56(9):699-702.
[30] BuehwalD C，Franzmann M B，Tos M.Sinonasal papillomas:a report or 82 casesin Copenhagen County,in cluding a Longitudinal epidemiological and Clinicalstudy[J].Laryngoscope，1995，105:72-79.
[31]卜国铱.耳鼻咽喉科学全书(鼻科学)[M].上海：上海科学技术出版社，1997，529.
[32]KrouseJH.Development of a staging system for invertedpapilloma[J].Laryngoscope，2000，110:965-968.
[33] Shanmugaratnam K，Sobin L H.Histological Typing of Turners of the UpperRespiratory Tract and Ear[J].Springer Verlag Berlin，1991:20-21.
[34] Buehwald C Lindeberg H，Pedersen B L，Franzmann M B. Human papilloma virusand P53 expression in carinomas associated with sinonasal papillomas: ADanish Epidemiological study 1980-1998[J].Laryngoscope，2001，111(6):1104-1110.
[35] Katori H，Nozawa A，Tsukuda M. Histopathological Parameters of recur-renceand malignant transformation in sinnasal inverted papilloma[J].ActaOtolaryngol，2006，126(2):214-218.
[36] WEBER R S，SHILLITOE E J，ROBBINS K T，et al．Prevalence of Human Papillomavirus in inverted nasal papillomas[J]．Arch Otolaryngol Head Neck Surg，1998，114：23-26．
[37]吴先光,姚卓华,吴南娇，等.鼻腔、鼻窦内翻性乳头状瘤癌变过程PCNA和PTEN蛋白表达的意义[J].现代医院,2009, 9(1)：14-16.
[38] Heley S.Human papilloma virus:beware the infection you can’t see[J]. AustFam Physician, 2003, 32(5)：311-315.
[39] Burd E M.Human papilloma virus and cervical cancer [J].Clin Microbiol Rev,2003, 16(1):1-17.
[40]Ishiji T.Molecular mechanism of carcinogenesis by humanpapillomavirus-16[J].J Dermatol, 2000, 27(2):73-86.
[41]王德辉，李玉茹，孙克敏．人乳头状瘤病毒与鼻内翻性乳头状瘤的关系[J]．临床耳鼻咽喉科杂志，1998，12(3)：118-119．
[42] Viallard J F, Lacombe F, Belloc F, et al.Molecular mechanisms controllingthe cell cycle: fundamental aspects and implications for oncology [J].CancerRadiother, 2001, 5(2):109-129.
[43] Hortwell L H, Kastan M B.Cell cycle control and cancer[J].Science, 1994,266(5192):1821.
[44] Schrump D S, Chen A, Consoli C.Inhibition of lung cancer proliferation byantisense CyclinDl[J].Cancer Gene Ther, 1996, 3(2):131-135.
[45] Huang D P, Lo K W, van Hasselt C A, et al. A region of homozygous delectionon chromosome 9p21-22 in primary nasopharyngeal carcinoma [J].Cancer Res,1994, 54:4003-4006.
[46] Hamada J，Cavanaugh P G,Lotan O.Seperable growth and migration factors forlarge cell lymphoma.factors secreted by microvascular endo-thelial cellsderived from target organs for metastasis [J].BrJ Caneer1992, 66(2):349-354.
[47] Xu XL, Yu J, Zhang H Y, et al. Methylation profile of the promoter CpG islandsof 31 genes that may contribute to colorectal carcinogenesis[J].WorldGastroenterol,2004,10:3441-3454.
[48] Galm O, Wilop S, Reichelt J, et al. DNA methylation changes in multiplemyeloma[J]. Leukemia, 2004, 18:1687-1692.
[49] Chang H W, Ling G S, Wei W I, et al. Smoking and drinking can induce p15methylation in the upper aerodigestive tract of healthy individuals andpatients with head and neck.squamous cell carcinoma[J].Cancer,2004,101:125-132.
[50] Wang S E, Narasanna A, Perez T M, et al.HER2 kinase domain mutation resultsin constitutive phosphorylation and activation of HER2 and EGFR andresistance to EGFR tyrosine kinase inhibitors[J].Cancer Cell,2006,10(1):25-38.
[51] Pedersen M W, Meltorn M, Damstrup L, et al. The typeⅢepidermal growth factorreceptor mutation biological significance and potential target foranticancer therapy[J]. Ann Oncol, 2001, 12(6):745-760.
[52]孔慧，孙秀珍，乌肠旭，等.鼻内翻性乳头状瘤中表皮生长因子及受体的表达与恶变的关系[J].临床耳鼻咽喉科杂志，2005，19(5):193-197.
[53] Katori H，Nozawa A，Tsukuda M. Markers of malignant transformation of sinonasalinverted papilloma[J].Eur J Surg Oneol，2005，31(8):905-911.
[54] Holland E C, Hively W P, DePinho R A, et al. A constitutively active epidermalgrowth factor receptor cooperates with disruption of G1 cell-cycle arrestpathways to induce gliom a-like lesions in mice[J].Genes Dev，1998，12(23):3675-3685.
[55] Aptes S S, Mattei M G, Olsen B R, Mapping of the human Bax gene to chromosome19q13.3-q13.4 and isolation of a novel alternatively spliced transcript, Baxdelat[J]. Genomics，1995，26:592-594.
[56] Krajewski S,Krajewska M,Shabaik A, et al. Immunohistochemical determinationof in vivo distribition of Bax, a dominant inhibitor of Bcl-2[J].Am J Pathol，1994，145:1323-1336.
[1] KARKOS P D，FYRMPAS G，CARRIE S C，et al．Endoscopic versus open surgicalinterventions for inverted nasal papilloma: a systematic review [J]．ClinicOtolaryngol，2006，31：499-503.
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