本文選題：橋本氏甲狀腺炎　切入點：甲狀腺乳頭狀癌　出處：《浙江大學(xué)》2016年博士論文　論文類型：學(xué)位論文

【摘要】：背景和目的：橋本氏甲狀腺炎(HT)癌變問題是近年一個研究的熱點,很多機制尚不明朗,而且治療方案存在爭議。以往認為橋本氏甲狀腺炎是良性病變且會引起甲狀腺功能減低故不宜手術(shù)治療,但近年發(fā)現(xiàn)HT可能為癌前病變,如有癌變跡象需積極手術(shù)治療。已有報告顯示,HT伴PTC發(fā)生率由過去的23%上升為近年的58.3%,所以橋本氏甲狀腺炎與癌變有非常大的關(guān)系。近年來HT伴發(fā)甲狀腺癌的發(fā)病率呈上升趨勢,尤以HT伴發(fā)甲狀腺乳頭狀癌(PTC)發(fā)病率增長明顯,且往往伴發(fā)多灶性PTC。如HT伴發(fā)多灶性癌變應(yīng)行甲狀腺全切,但目前尚無明確指標能預(yù)先判斷HT伴發(fā)的是單發(fā)癌灶還是多灶性癌變。術(shù)中冰凍切片往往會遺漏微小癌灶,只有行甲狀腺全切進行常規(guī)病理檢查才能明確是否存在多灶癌,但這樣做可能使低危的單發(fā)癌患者接受了過度治療,且增加了術(shù)后并發(fā)癥的發(fā)生幾率。因此進行HT多灶性癌變預(yù)警信號的研究對指導(dǎo)臨床治療方案具有重要意義。方法：1.回顧性分析2008年6月至2013年6月期間行甲狀腺手術(shù)的HT伴PTC及單純HT患者808例病例資料,其中男性206例,女性602例,患者均為體檢彩超發(fā)現(xiàn)甲狀腺結(jié)節(jié)因懷疑惡性或因結(jié)節(jié)較大有癥狀而行手術(shù)治療。所有因具備甲狀腺手術(shù)指征行手術(shù)治療而術(shù)后病理證實為HT伴PTC或單純HT的病例均納入,但要排除有甲亢、亞急性甲狀腺炎、結(jié)核病史或有其他惡性腫瘤病史、免疫功能低下、其他重大疾病史的病例,所有患者術(shù)前均未行化療、放療及無免疫治療史。根據(jù)術(shù)后病理結(jié)果將其分為3組：A組(HT伴多灶性PTC)、B組(HT伴單發(fā)PTC)、C組(單純HT)。將術(shù)后常規(guī)病理結(jié)果與術(shù)前TPOAb檢測結(jié)果進行比對分析,并將術(shù)后病理結(jié)果與術(shù)前患者基礎(chǔ)情況、TSH等化驗結(jié)果進行對比分析。分析與單發(fā)癌、多灶癌的相關(guān)性以及與淋巴結(jié)轉(zhuǎn)移的相關(guān)性。2.取我院2012年6月至2014年6月甲狀腺手術(shù)患者術(shù)后常規(guī)病理確診HT(30例)、HT單發(fā)癌(30例)及HT多灶癌(30例)病例的病理標本制成的石蠟切塊共90例。所有病例均經(jīng)病理診斷證實,且術(shù)前均未行化療、放療及無免疫治療史。按要求對HT單發(fā)癌、HT多灶癌、HT組織蠟塊進行切片,分別進行CK-19、COX2、 Galectin-3、HBME-1四個蛋白的免疫組化IHC實驗。3.取我院2012年6月至2014年6月甲狀腺手術(shù)患者術(shù)后常規(guī)病理確診HT(10例)、HT單發(fā)癌(40例)及HT多灶癌(30例)病例的病理標本制成的石蠟切塊進行DNA提取,然后進行PCR及基因測序?qū)嶒灆z測BRAF基因突變。結(jié)果：1.232例HT伴多灶性PTC(A組)患者中有196例TPOAb指標明顯升高1300IU/mL；另外469例HT伴單發(fā)PTC(B組)患者中有416例TPOAb指標1000 IU/mL(多數(shù)在400-600之間)；其余107例HT患者TPOAb指標差異較大；TPOAb指標在HT伴單發(fā)和多灶性PTC患者之間有顯著差異(P0.01)。2.C組免疫組化指標表達最低,與各組有顯著差異(P0.05)。CK19:A組明顯高于B組,有顯著差異(P0.05)。COX-2:A組與B組沒有顯著差異(P0.05)。Galectin-3:A組與B組沒有顯著差異(P0.05)。HBME-1:A組與B組沒有顯著差異(P0.05)。CK19免疫組化平均光密度定量0.007時A、B兩組差異最大(P0.001),根據(jù)ROC曲線0.007可作為區(qū)分HT單發(fā)癌和多灶癌的界點。3.A組(HT伴多灶性PTC)BRAF基因突變明顯高于B組(HT伴單發(fā)PTC),而C組(單純HT)無BRAF基因突變,A組有29.63%出現(xiàn)BRAF基因突變,B組有10.26%出現(xiàn)BRAF基因突變,各組有顯著差異(P0.05)。結(jié)論：1. TPOAb1300IU/mL是HT伴多灶性PTC的高危因素,對術(shù)中冰凍病理報告為HT伴PTC(而術(shù)前TPOAb1300 IU/mL)的患者建議行甲狀腺全切除術(shù)。但TSH增高伴TPOAb輕中度升高(1300 IU/mL)并不能作為判斷HT伴發(fā)多灶性PTC的高危風(fēng)險因素,TSH增高只能作為輔助參考因素。在HT伴發(fā)多灶性PTC中TPOAb指標的高低對頸中央?yún)^(qū)淋巴結(jié)轉(zhuǎn)移陽性率無影響,但多灶癌比單發(fā)癌轉(zhuǎn)移陽性率要高,因此無論TPOAb指標高低都建議行中央?yún)^(qū)淋巴結(jié)清掃。2.僅發(fā)現(xiàn)CK19在HT伴多灶性PTC組免疫組化呈強陽性表達,明顯高于HT伴單發(fā)癌組,有顯著差異,其余指標無顯著差異。如術(shù)前或術(shù)中CK19免疫組化平均光密度定量0.007則很有可能是HT伴多灶癌,結(jié)合術(shù)中冰凍切片建議行甲狀腺全切。3.HT伴多灶癌的BRAF基因突變率明顯高于HT伴單發(fā)癌,HT伴PTC患者如檢測發(fā)現(xiàn)有BRAF基因突變則很有可能為HT伴多灶癌,結(jié)合術(shù)中冰凍切片建議行甲狀腺全切。
[Abstract]:Background and objective: Hashimoto's thyroiditis (HT) cancer problem is a hot research topic in recent years, many mechanisms are still unclear, but controversial treatment. The past that Hashimoto's thyroiditis is a benign lesion and cause hypothyroidism is not suitable for surgery, but in recent years HT may be precancerous lesions, such as there are signs of cancer need surgical treatment. The report shows that HT with the incidence of PTC increased from 23% to 58.3% in the past, so there is a very large Hashimoto's thyroiditis and cancer. In recent years, HT associated with thyroid cancer incidence is rising, especially in HT associated with thyroid papillary carcinoma (PTC) the incidence rate increased significantly, and often accompanied by multifocal PTC. HT with multifocal carcinoma should be underwent total thyroidectomy, but there is no clear indicators to judge beforehand associated with HT is a single tumor or multi focal cancer surgery. Frozen sections often left small foci, only underwent total thyroidectomy for routine pathological examination to confirm the existence of multifocal carcinoma, but this may lead to low-risk single cancer patients received excessive treatment, and increase the incidence of postoperative complications. Therefore HT multifocal carcinogenesis with early warning signals an important significance for guiding the clinical treatment. Methods: a retrospective analysis of 1. during the period from June 2008 to June 2013 for thyroid surgery with HT PTC and the HT patients 808 cases, including 206 cases of male, female 602 cases, patients were found by ultrasound examination of thyroid nodules or suspected malignant nodules due to larger symptoms and surgical treatment all due to have thyroid surgery indications for surgery and postoperative pathology confirmed HT with PTC or HT alone were included, but to exclude hyperthyroidism and subacute thyroiditis. The history of nuclear or other malignant tumor history, immune dysfunction, other major disease cases, all patients had not received chemotherapy, radiotherapy and immunotherapy. According to the postoperative pathological results, it can be divided into 3 groups: group A (HT with multifocal PTC), group B (with HT single PTC), C group (HT alone). The routine pathological results with preoperative TPOAb detection results were compared and analyzed, and the postoperative pathological results and preoperative patients, TSH test results were analyzed. Correlation analysis and single cancer, multifocal carcinoma and lymph node.2. correlation the transfer of the conventional HT diagnosed in our hospital from June 2012 to June 2014 in thyroid surgery patients (30 cases), HT single cancer (30 cases) and HT multifocal carcinoma (30 cases) were made of paraffin slice specimens were 90 cases. All cases were confirmed by pathological diagnosis, and no preoperative chemotherapy, radiotherapy and Immunotherapy. According to the requirements of the HT single cancer, HT multifocal carcinoma, HT biopsy tissue blocks, respectively CK-19, COX2, Galectin-3, HBME-1 four protein immune group IHC experimental.3. conventional HT diagnosed in our hospital from June 2012 to June 2014 in thyroid surgery patients (10 cases), HT single cancer (40 cases) and HT multifocal carcinoma (30 cases) were made of paraffin slice specimens for DNA extraction and detection of BRAF gene and PCR gene sequencing the mutation. Results: 1.232 cases of HT with multifocal PTC (A group) of 196 patients with TPOAb significantly increased 1300IU/mL; the other 469 cases of HT patients with single PTC (B group) of 416 patients with TPOAb index of 1000 IU/mL (mostly in 400-600); the remaining 107 cases TPOAb index in patients with HT are different; the TPOAb index in HT with a significant difference between solitary and multifocal PTC patients (P0.01 group.2.C) immunohistochemical expression index Low, there was significant difference in each group (P0.05) of.CK19:A group was significantly higher than that in B group, there was significant difference (P0.05) of.COX-2:A group had no significant difference with group B (P0.05).Galectin-3:A group had no significant difference with group B (P0.05).HBME-1:A group had no significant difference with group B (P0.05).CK19 immunohistochemistry. The average optical density quantitative 0.007 A, B two group (P0.001), the biggest difference according to the ROC curve of 0.007 can be used as the dividing points between.3.A group and HT single cancer multifocal carcinoma (HT with multifocal PTC) BRAF gene mutation was significantly higher than B group (HT with single PTC) C group, (HT only) BRAF gene the A group had 29.63% mutations, BRAF gene mutation, B group had 10.26% BRAF mutations in each group have significant difference (P0.05). Conclusion: 1. TPOAb1300IU/mL is a high risk factor of HT with multifocal PTC, the intraoperative frozen pathology report with HT PTC (preoperative TPOAb1300 IU/mL) were recommended for total thyroidectomy but TSH. TPOAb increased with mild to moderate increase (1300 IU/mL) and high risk factors and can't be judged as HT associated with multifocal PTC, TSH increased only as auxiliary reference factors. In the HT TPOAb index with multiple focal PTC in the level of central neck lymph node metastasis positive rate has no effect, but more than single foci the positive rate of cancer metastasis is higher, so both TPOAb index level recommended for central lymph node dissection.2. found only in HT CK19 with multifocal PTC immunohistochemical expression was strongly positive, HT was significantly higher than that of patients with single cancer group, there are significant differences, other indexes had no significant difference. As before or during operation average optical density of CK19 immunoreactivity quantitative 0.007 is likely to be HT with multifocal carcinoma, with sections suggested BRAF gene.3.HT underwent total thyroidectomy with multifocal carcinoma and the mutation rate was significantly higher than that of HT with single cancer intraoperatively, HT patients with PTC such as the detection of BRAF gene mutation It is likely to be HT with multiple cancer, combined with intraoperative frozen section recommended for total thyroidectomy.

【學(xué)位授予單位】：浙江大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R736.1;R581.4

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5 宋廣昊;TXNIP在甲狀腺乳頭狀癌組織中的表達及臨床意義[D];河北醫(yī)科大學(xué);2015年

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7 高彬;HIF-2α與CITED2、PTPRZ1基因在甲狀腺乳頭狀癌中的表達及意義[D];河北醫(yī)科大學(xué);2015年

8 孫靜秋;雌激素受體在甲狀腺乳頭狀癌中的表達及意義[D];青海大學(xué);2016年

9 茅建婭;甲狀腺乳頭狀癌合并橋本氏甲狀腺炎的臨床病理研究[D];新疆醫(yī)科大學(xué);2016年

10 張磊;預(yù)防性頸Ⅵ區(qū)淋巴結(jié)清掃術(shù)與傳統(tǒng)甲狀腺全切術(shù)在治療cN0期甲狀腺乳頭狀癌安全性、有效性的meta分析[D];新疆醫(yī)科大學(xué);2016年

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