本文選題：顱咽管瘤 + 侵襲性　； 參考：《首都醫(yī)科大學(xué)》2014年博士論文

【摘要】：背景 顱咽管瘤是蝶鞍區(qū)常見的先天性腫瘤，組織學(xué)上可分為造釉細(xì)胞和鱗狀乳頭兩種亞型，二者在臨床特征上存在不同。顱咽管瘤病理學(xué)分類為良性，按照WHO中樞神經(jīng)系統(tǒng)腫瘤分類為Ⅰ級(jí)，但是表現(xiàn)出惡性的生物學(xué)行為，呈侵襲性生長，浸潤粘連周圍重要神經(jīng)血管結(jié)構(gòu)，手術(shù)全切困難，術(shù)后并發(fā)癥多，致死致殘率高，總體預(yù)后不良，即使手術(shù)完全切除后，也會(huì)有較高的腫瘤復(fù)發(fā)率，還有罕見的種植轉(zhuǎn)移現(xiàn)象發(fā)生，這是困擾該腫瘤治療的難題。目前認(rèn)為侵襲性生長是顱咽管瘤不同于蝶鞍區(qū)其他良性腫瘤的最主要特征，也是影響其預(yù)后的重要因素。從分子水平對(duì)顱咽管瘤的侵襲性進(jìn)行研究，明確這一惡性生物學(xué)行為的機(jī)制，有助于加深對(duì)顱咽管瘤這一難治性腫瘤的理解，對(duì)于探索有效的治療方案，降低術(shù)后復(fù)發(fā)率，減少死亡率，提高遠(yuǎn)期生存質(zhì)量具有重要意義。顱咽管瘤種植轉(zhuǎn)移是術(shù)后極其罕見的現(xiàn)象，其發(fā)生的機(jī)制及危險(xiǎn)因素目前尚不明確，現(xiàn)有的治療手段不能有效防止其發(fā)生，需要全面的分析來增加對(duì)該現(xiàn)象的認(rèn)識(shí)，并進(jìn)一步提出可行的防治手段。 第一部分：14-3-3Zeta與顱咽管瘤侵襲性的研究 目的 研究14-3-3Zeta蛋白在顱咽管瘤中的表達(dá)情況，并通過比較該蛋白的表達(dá)與顱咽管瘤臨床病理特征、β-Catenin異常表達(dá)、腫瘤增殖性、p63過表達(dá)之間的關(guān)系，探索14-3-3Zeta蛋白對(duì)顱咽管瘤侵襲性的影響及作用機(jī)制，為進(jìn)一步認(rèn)識(shí)顱咽管瘤的侵襲機(jī)制提供新的線索，為治療顱咽管瘤的新方法提供依據(jù)。 方法 根據(jù)納入標(biāo)準(zhǔn)，由2012年2月至2013年8月間于我院神經(jīng)外科行開顱手術(shù)切除并經(jīng)術(shù)后病理學(xué)確診的顱咽管瘤患者序列中隨機(jī)選取62例進(jìn)行研究，收集患者的臨床資料。取入組62例顱咽管瘤組織石蠟塊，切片行常規(guī)HE染色進(jìn)一步明確腫瘤分型。采用免疫組織化學(xué)的方法，對(duì)62例腫瘤標(biāo)本以及4例正常腦組織標(biāo)本中14-3-3Zeta、β-Catenin、p63及Ki-67表達(dá)水平進(jìn)行研究，分析相應(yīng)指標(biāo)水平與患者臨床及病理特征的關(guān)系。對(duì)術(shù)中液氮快速冰凍并保存于-80℃超低溫冰箱中的62例腫瘤標(biāo)本和4例對(duì)照腦組織標(biāo)本行免疫印跡檢查，比較各組間14-3-3Zeta蛋白表達(dá)水平的差異。對(duì)20例液氮速凍腫瘤標(biāo)本行定量PCR檢查明確顱咽管瘤YWHAZ基因轉(zhuǎn)錄水平。 結(jié)果 62例顱咽管瘤患者中，根據(jù)HE染色分為造釉細(xì)胞型46例，鱗狀乳頭型16例，其中侵襲性顱咽管瘤27例，均為造釉細(xì)胞亞型，非侵襲性造釉細(xì)胞型顱咽管瘤19例。14-3-3Zeta免疫組化顯示：14-3-3Zeta在造釉細(xì)胞型及鱗狀乳頭型顱咽管瘤中表達(dá)水平差異不顯著；侵襲性造釉細(xì)胞型顱咽管瘤中表達(dá)水平顯著高于非侵襲性造釉細(xì)胞型腫瘤及鱗狀乳頭型顱咽管瘤；非侵襲性造釉細(xì)胞型腫瘤與鱗狀乳頭型顱咽管瘤表達(dá)水平差異不顯著。β-Catenin免疫組化顯示：β-Catenin異常表達(dá)率在造釉細(xì)胞型顱咽管瘤顯著高于鱗狀乳頭型顱咽管瘤；在侵襲性造釉細(xì)胞型顱咽管瘤中β-Catenin異常表達(dá)率顯著高于非侵襲性造釉細(xì)胞型腫瘤及鱗狀乳頭型顱咽管瘤；非侵襲性造釉細(xì)胞型腫瘤及鱗狀乳頭型顱咽管瘤異常表達(dá)率差異不顯著。14-3-3Zeta強(qiáng)陽性表達(dá)細(xì)胞與β-Catenin異常表達(dá)細(xì)胞在腫瘤組織內(nèi)相似地分布于漩渦狀細(xì)胞簇中。p63免疫組化顯示：p63陽性表達(dá)于顱咽管瘤的細(xì)胞核中，陽性細(xì)胞彌漫分布于組織內(nèi)，侵襲性顱咽管瘤與非侵襲性顱咽管瘤p63過表達(dá)水平無統(tǒng)計(jì)學(xué)差異。Ki-67的免疫組化顯示：在造釉細(xì)胞亞型Ki-67陽性細(xì)胞主要分布于柵欄狀結(jié)構(gòu)內(nèi)，漩渦狀細(xì)胞簇內(nèi)少見陽性細(xì)胞。在鱗狀乳頭亞型腫瘤中Ki-67陽性細(xì)胞散在分布于腫瘤實(shí)質(zhì)中。侵襲性顱咽管瘤與非侵襲性顱咽管瘤Ki-67標(biāo)記指數(shù)無統(tǒng)計(jì)學(xué)差異。β-Catenin異常表達(dá)組與正常表達(dá)組14-3-3Zeta表達(dá)水平存在顯著差異，而按照年齡、性別、初復(fù)發(fā)、腫瘤大小、p63過表達(dá)、Ki-67指數(shù)分組14-3-3Zeta表達(dá)水平差異無統(tǒng)計(jì)學(xué)意義。Western Blot結(jié)果顯示：14-3-3Zeta在侵襲性造釉細(xì)胞型顱咽管瘤中相比對(duì)照腦組織表達(dá)顯著增高，，而在非侵襲性造釉細(xì)胞型以及鱗狀乳頭型顱咽管瘤表達(dá)水平增高不顯著，顱咽管瘤病理類型之間以及侵襲性與非侵襲性腫瘤之間表達(dá)水平差異不顯著。RT-PCR顯示：20例顱咽管瘤YWHAZ基因mRNA轉(zhuǎn)錄水平高于對(duì)照腦組織，但病理類型之間、侵襲性與非侵襲性腫瘤之間轉(zhuǎn)錄水平的差異無統(tǒng)計(jì)學(xué)意義。 結(jié)論 14-3-3Zeta在侵襲性顱咽管瘤中存在過表達(dá)現(xiàn)象，其過表達(dá)與腫瘤細(xì)胞的侵襲性相關(guān)而與增殖活性無相關(guān)。14-3-3Zeta的過表達(dá)與Wnt信號(hào)通路核心蛋白β-Catenin的異常表達(dá)呈顯著相關(guān)，在組織中的分布均主要位于造釉細(xì)胞型顱咽管瘤的漩渦狀細(xì)胞簇中，提示14-3-3Zeta過表達(dá)可能通過調(diào)控Wnt通路而影響顱咽管瘤的侵襲性。腫瘤細(xì)胞的增殖活性以及p63表達(dá)水平與顱咽管瘤的侵襲性無相關(guān)。 第二部分：顱咽管瘤種植轉(zhuǎn)移的臨床研究 目的 回顧性研究種植轉(zhuǎn)移顱咽管瘤病例的臨床和病理資料，回顧該罕見現(xiàn)象既往文獻(xiàn)報(bào)告，分析其可能的危險(xiǎn)因素，提出預(yù)防和治療該并發(fā)癥可行的方案。 方法 收集我科治療的4例種植轉(zhuǎn)移顱咽管瘤患者的臨床、影像及病理資料，并結(jié)合文獻(xiàn)回顧總結(jié)歸納該罕見現(xiàn)象的特征及可能的危險(xiǎn)因素，探討可行的防治方法。 結(jié)果 4例種植轉(zhuǎn)移顱咽管瘤患者均為成年男性，種植部位均為前次手術(shù)路徑，本次住院均未發(fā)生原位復(fù)發(fā)。病理類型上3例患者為鱗狀乳頭亞型，1例為造釉細(xì)胞亞型，4例復(fù)發(fā)腫瘤標(biāo)本Ki-67標(biāo)記指數(shù)均不高于5%。 結(jié)論 顱咽管瘤種植轉(zhuǎn)移十分罕見，其發(fā)生的具體機(jī)制目前尚不清楚，囊性腫瘤是該現(xiàn)象發(fā)生可能的危險(xiǎn)因素，術(shù)中嚴(yán)格隔離腫瘤，防止腫瘤破裂及囊液播散可能減少種植轉(zhuǎn)移的發(fā)生，顱咽管瘤術(shù)后需長期密切隨訪以早期發(fā)現(xiàn)和處理種植轉(zhuǎn)移顱咽管瘤，術(shù)后常規(guī)應(yīng)用放射治療預(yù)防顱咽管瘤并非必要，手術(shù)切除種植轉(zhuǎn)移病灶可取得良好的治療效果。
[Abstract]:background
Craniopharyngioma is a common congenital tumor in the sella region. Histologically, it can be divided into two subtypes of enamel and squamous papilla. The two is different in clinical characteristics. The pathological classification of craniopharyngioma is benign. It is classified as grade I according to the WHO central nervous system tumor, but shows malignant biological behavior, invasive growth and infiltration. The important neurovascular structure around adhesion, the operation is difficult to cut, the postoperative complications are more, the death rate is high, the overall prognosis is bad. Even after the operation is completely excised, there will be a high recurrence rate of tumor and rare implant metastasis. This is a difficult problem for the treatment of the tumor. It is considered that invasive growth is not a craniopharyngioma at present. The most important features of other benign tumors in the sella region are also an important factor affecting the prognosis. The study of the invasiveness of craniopharyngioma at the molecular level and the clear mechanism of this malignant biological behavior will help to deepen the understanding of the intractable tumor of the craniopharyngioma, to explore the effective treatment and to reduce the postoperative recovery. The occurrence of craniopharyngioma implantation metastasis is an extremely rare phenomenon after operation. The mechanism and risk factors of the occurrence of craniopharyngioma are not clear, the existing treatment means can not effectively prevent it from happening. It needs comprehensive analysis to increase the understanding of this phenomenon and further put forward the feasibility. The means of prevention and control.
Part I: 14-3-3Zeta and craniopharyngioma invasiveness
objective
To investigate the expression of 14-3-3Zeta protein in craniopharyngioma, and compare the relationship between the expression of the protein and the clinicopathological features of craniopharyngioma, abnormal expression of beta -Catenin, tumor proliferation, and p63 overexpression, explore the influence and mechanism of 14-3-3Zeta protein on the invasiveness of craniopharyngioma, in order to further understand the invasion of craniopharyngioma. The mechanism provides new clues for providing new evidence for the treatment of craniopharyngioma.
Method
According to the inclusion criteria, 62 cases of craniopharyngioma in the Department of Neurosurgery of our hospital from February 2012 to August 2013 were selected randomly and 62 cases were selected randomly to collect the clinical data of the patients. 62 cases of craniopharyngioma tissue paraffin block were taken into the group, and the sections were stained by conventional HE staining to further clarify the tumor classification. The expression of 14-3-3Zeta, beta -Catenin, p63 and Ki-67 in 62 cases of tumor and 4 normal brain tissue were studied by immunohistochemistry. The relationship between the level of the corresponding index and the clinical and pathological features of the patients was analyzed. 62 cases of tumor specimens and 4 in the cryopreservation of cryopreservation at -80 C were frozen and 4 were frozen in the intraoperative liquid nitrogen. The difference in the expression of 14-3-3Zeta protein was compared between the specimens of the brain tissue and the difference of the expression level of 14-3-3Zeta protein in each group. The transcriptional level of the YWHAZ gene in the craniopharyngioma was determined by quantitative PCR examination.
Result
62 cases of craniopharyngioma were divided into 46 cases of enamel cell type, 16 cases of squamous papilla type, 27 cases of invasive craniopharyngioma, and 27 cases of invasive craniopharyngioma, all of which were the subtypes of enamel cells, and 19 cases of non aggressive actin craniopharyngioma in 19 cases of.14-3-3Zeta immunohistochemistry showed that the expression level of 14-3-3Zeta in the enamel fine cell type and the squamous papillary craniopharyngioma was poor. The expression level of the invasive enamel type craniopharyngioma was significantly higher than that of non invasive apioid tumor and squamous papillary craniopharyngioma, and the expression level of non invasive apioid tumor and squamous papillary craniopharyngioma was not significant. Beta -Catenin immunohistochemical staining showed that the abnormal expression rate of beta -Catenin was in the formation. The enamel type craniopharyngioma was significantly higher than that of the squamous papillary craniopharyngioma, and the abnormal expression rate of beta -Catenin in the invasive enamel type craniopharyngioma was significantly higher than that of non invasive enamel type tumor and squamous nipple type craniopharyngioma, and the abnormal expression rate of noninvasive apex type and squamous papillary craniopharyngioma was different. The abnormal expression of.14-3-3Zeta strong positive expression cells and beta -Catenin cells in the tumor tissues resemble in the swirling cell cluster in.P63 immunohistochemical staining: p63 positive expression in the nucleus of craniopharyngioma, positive cells diffuse in the tissue, invasive craniopharyngioma and non invasive craniopharyngioma p63 overexpression of water The immunological histochemistry of.Ki-67 without statistical difference showed that the Ki-67 positive cells in the apioma subtype were mainly distributed in the palisade structure, and the positive cells were rare in the vortex cell cluster. In the squamous papillary subtype tumor, Ki-67 positive cells were scattered in the tumor parenchyma. Invasive craniopharyngioma and non invasive craniopharyngioma Ki-67 standard There was no significant difference in the index of the expression of 14-3-3Zeta in the abnormal expression group of beta -Catenin and the normal expression group, while the age, sex, initial recurrence, tumor size, p63 overexpression, and the 14-3-3Zeta expression level of the Ki-67 index group were not statistically significant.Western Blot results showed that 14-3-3Zeta was in the invasive enamel cell type. The expression of the craniopharyngioma was significantly higher than that of the control brain tissue, but the expression level of the noninvasive enamel type and the squamous papillary craniopharyngioma was not significant. There was no significant difference in the expression level between the pathological types of craniopharyngioma and the invasive and non invasive tumor.RT-PCR: 20 cases of craniopharyngioma YWHAZ gene mRNA turn The level of transcription was higher than that of control brain tissue, but there was no significant difference in the transcriptional level between invasive and noninvasive tumors.
conclusion
The overexpression of 14-3-3Zeta in invasive craniopharyngioma is associated with the invasiveness of the tumor cells and the overexpression of.14-3-3Zeta, which is not related to the proliferation activity, is significantly related to the abnormal expression of the core protein beta -Catenin of the Wnt signaling pathway, and the distribution in the tissue is mainly located in the whirlpool of the enamel type craniopharyngioma. In the cell clusters, the overexpression of 14-3-3Zeta may affect the invasiveness of craniopharyngioma by regulating the Wnt pathway. The proliferation activity of the tumor cells and the level of p63 expression are not related to the invasiveness of the craniopharyngioma.
The second part: clinical study of craniopharyngioma implant metastasis.
objective
To review the clinical and pathological data of the cases of metastatic craniopharyngioma, review the previous literature report on the rare phenomenon, analyze the possible risk factors, and propose a feasible scheme to prevent and treat the complications.
Method
The clinical, imaging and pathological data of 4 patients with metastatic craniopharyngioma treated by our family were collected, and the characteristics and possible risk factors of the rare phenomenon were summarized and summarized in the literature review. The feasible methods of prevention and treatment were discussed.
Result
4 patients with metastatic craniopharyngioma were all adult male, and the implant site was the first operation route. There were no recurrence in this hospital. 3 cases were squamous papillary subtype, 1 cases were apioform subtype, and 4 cases of recurrent tumor specimens were not higher than 5%. Ki-67 markers.
conclusion
Craniopharyngioma implantation metastasis is very rare, and the specific mechanism of its occurrence is unclear. Cystic tumor is a possible risk factor for this phenomenon. Intraoperative strict isolation of tumor, prevention of tumor rupture and cystic fluid dissemination may reduce the occurrence of implant metastasis. Long term close follow-up after craniopharyngioma is needed to identify and deal with early metastasis. Craniopharyngioma is not necessary for routine postoperative radiotherapy to prevent craniopharyngioma. Surgical removal of the metastatic lesion can achieve good results.
【學(xué)位授予單位】：首都醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R739.41

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本文編號(hào)：2050804