修回日期: 2011-05-17
接受日期: 2011-05-24
在线出版日期: 2011-05-28
胰腺内分泌肿瘤(pancreatic endocrine tumors, PETs)是一类少见肿瘤, 发病率约占总人口的4-5/100万, 占胰腺肿瘤的1%-2%, 病程缓慢, 最终发生转移致死. 根据其临床表现, PETs分为功能性和无功能性两类. CD10、CD44、CD99、p27、COX2、Ki-67、KIT、CK19、ARHI、RUNX1T1、survivin等基因表达异常、染色体杂合缺失、抑癌基因甲基化及Ghrelin过度表达等因素在PETs的发病机制中发挥重要作用. 铬粒素A(CgA)已作为PETs重要的血清学标志物. KIT和内皮蛋白是PETs新的独立预后指标. CgA的组织病理学阳性结果以及胃泌素、胰岛素原、血管活性肠肽(VIP)、胰高糖素等特异性激素检测可作为PETs的病理和定性诊断依据. 此外, 除标准的定位程序外, 计算机断层扫描(CT)、正电子发射断层成像与计算机断层扫描(PET/CT)、磁共振成像(MRI)、超声(US)、超声内镜(EUS)、腹腔镜超声(LUS)、动态增强螺旋CT扫描、选择性动脉内刺激试验(ASVS)及生长抑素受体闪烁成像(SRS)等技术也用于PETs的定位诊断. 外科手术仍是PETs治疗的首选. 腹腔镜及生长抑素类似物也已常规应用. 上述最新进展为PETs的早期诊断和治疗提供了新的思路.
引文著录: 黄颖秋. 胰腺内分泌肿瘤的研究进展. 世界华人消化杂志 2011; 19(15): 1541-1549
Revised: May 17, 2011
Accepted: May 24, 2011
Published online: May 28, 2011
Pancreatic endocrine tumors (PETs) are uncommon and have an incidence of approximately 4-5 per 1 000 000 people, accounting for 1%-2% of all pancreatic neoplasms. They usually grow slowly, eventually metastasize and lead to death. PETs can be classified as functioning or non-functioning tumors based on clinical manifestation. The pathogenesis of PETs may involve abnormal expression of CD10, CD44, CD99, p27, COX2, Ki-67, KIT, CK19, ARHI, RUNX1T1, and survivin genes, loss of heterozygosity on chromosomes, hypermethylation of tumor suppressor genes, and overexpression of ghrelin. Chromogranin A (CgA) has long been used as an important broad-spectrum marker for the identification of PETs. KIT and endoglin are new independent prognostic markers for PETs. The diagnosis is based on histopathology demonstrating neuroendocrine features such as positive staining for chromogranin A and specific hormones such as gastrin, proinsulin, vasoactive intestinal peptide (VIP) and glucagon. In addition to standard localization procedures, radiology diagnosis including computed tomography (CT), positron emission tomography and computed tomography (PET/CT), magnetic resonance imaging (MRI), ultrasound (US), endoscopic ultrasound (EUS), laparoscopic ultrasound (LUS), dynamic enhanced spiral CT, selective arterial stimulation and venous sampling (ASVS), and somatostatin receptor scintigraphy (SRS) are performed. Surgery is still one of the cornerstones in the management of PETs. Laparoscopy, and drugs of somatostatin analogs are routinely used. Understanding of the recent advances of PETs has important implications for the early diagnosis and treatment of PETs.
- Citation: Huang YQ. Recent advances in understanding pancreatic endocrine tumors. Shijie Huaren Xiaohua Zazhi 2011; 19(15): 1541-1549
- URL: https://www.wjgnet.com/1009-3079/full/v19/i15/1541.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v19.i15.1541
胰腺内分泌肿瘤(pancreatic endocrine tumors, PETs)又称胰岛细胞瘤, 是源于胰腺多能神经内分泌干细胞的一类肿瘤, 由良性逐渐发展成恶性, 病程缓慢, 临床少见或罕见, 其发病率约为4-5/100万[1,2]. 根据有无临床症状及其分泌的激素水平, 传统上PETs又分为功能性和无功能性(non-functional, NF)两类: 前者包括胃泌素瘤(gastrinomas)、胰岛素瘤(insulinoma)、胰高血糖素瘤(glucagonoma)、血管活性肠肽(vasoactive intestinal peptide)瘤、生长抑素瘤(somatostatinoma)、生长激素释放因子(growth-hormone releasing factor)瘤、ACTH瘤、胰多肽(pancreatic polypeptide)瘤、致类癌综合征PETs(PETs causing carcinoid syndrome)、致高血钙综合征PETs(PETs causing hypercalcemia)等10种[1,2]; 后者即NFPETs, 无临床症状, 激素分泌水平低[1]. 其中, 胃泌素瘤、胰岛素瘤和NFPETs是发病率最高的3种PETs, 而其他几种功能性PETs发病率很低. 少数PETs患者具有一定的遗传易感性. 多发性内分泌肿瘤1型(multiple endocrine neoplasm type 1, MEN1)的遗传外显率很高. 但大多数PETs为散发, 其分子发生机制和组织来源尚未十分清楚. 晚近, 随着分子生物学和诊断技术的飞速发展, 人们对PETs的组织病理学分类、发病机制及其诊断水平有了更新的认识, 治疗手段也更趋多样化. 了解PETs研究领域的最新进展, 对PETs的早期诊断、治疗方案的选择以及预后评估均有其十分重要的意义.
目前, 预测PETs有无局部浸润或转移等生物学行为仍有难度, PETs的某些临床病理学特征有助于判定肿瘤患者的预后. 据此, 2004年, WHO根据肿瘤大小、血管浸润、核分裂象及Ki-67指数等指标, 制定了PETs新的组织病理学分类标准, 将PETs分为WHO1a, WHO1b, WHO2和WHO3四类. WHO1a是指肿瘤组织分化良好、无临床症状的良性PETs; WHO1b是指肿瘤组织分化良好, 但其良恶性尚未确定的PETs,其肿瘤直径≥2 cm, 有丝分裂象≥2/10高倍视野, Ki-67>2%或肿瘤血管浸润; WHO2是指肿瘤组织分化良好的恶性PETs, 可见局部浸润及转移; WHO3是指肿瘤组织分化差的恶性PETs, 其癌细胞有丝分裂象≥10/10高倍视野[3]. 该分类既考虑了PETs的临床特征, 也兼顾了其病理特征,包括肿瘤大小、肿瘤细胞有丝分裂象的数目、细胞增殖指数、微血管密度、肿瘤的血管浸润及转移等与疾病预后密切相关的因素[3]. WHO的4种分类是独立影响PETs预后的重要因素. 诸多研究发现, 微血管密度在PETs的发生发展中起一定作用, 其显著下降可能表明PETs预后不良[4]. 一般认为, 肿瘤体积的大小与其生物学行为有关, 肿瘤直径≥2 cm无疑增加了PETs恶性的风险, 而肿瘤直径>3 cm应高度怀疑恶性[5]. 一项长期的随访研究证实, 癌细胞有丝分裂象≥10/10高倍视野可预示PETs的高度恶性和较低的生存率[6]. 细胞增殖指标Ki-67>2%已被认为是PETs预后不良的独立危险因素[6,7], 而Ki-67>5%则被证实与NFPETs显著相关[8]. 还有研究发现,另一种细胞增殖指标拓扑异构酶IIα也可作为恶性PETs预后不良的独立危险因素[9]. 此外, 肿瘤组织的血管浸润、周围神经浸润及转移等均可作为PETs不良预后的影响因素[5].
分子生物学技术的日臻成熟, 使人们更有机会从基因角度关注PETs的发病机制以及其生物学行为对疾病预后的影响. CD10、CD44、CD99、p27、COX2等基因可能与PETs的良恶性及预后密切相关. 研究显示, CD10的阳性染色与PETs的细胞增殖指标、肿瘤大小、肝转移及其生存率下降显著相关[10], CD44的变异亚型v6和v9可作为判定PETs良性及预后良好的一项指标[11]. 而CD99、p27的表达下调, 以及COX2的表达上调与细胞增殖指标Ki-67显著相关[3,12-14]. 此外, 血管内皮生长因子(vascular endothelial growth factor, VEGF)的过度表达与PETs的浸润性生长以及肝转移显著相关[15]. 但最近研究发现, 内皮蛋白(endoglin)在胃肠胰腺神经内分泌肿瘤中过度表达, 并与肿瘤的大小、转移及浸润程度显著相关, 但却与VEGF无关, 提示, 内皮蛋白可能是PETs的一种潜在标志物[16]. 表皮生长因子受体(epidermal growth factor receptor, EGFR)、肝细胞生长因子受体(hepatocyte growth factor receptor, HGFR)在胃泌素瘤中呈过度表达, 并与胃泌素瘤的肝转移及治愈率降低显著相关, 其中EGRF的过度表达还与胃泌素瘤的进行性生长及瘤体大小有关[17]. 癌基因HER2/neu(EGFR家族成员)的mRNA在胃泌素瘤中呈过度表达, 也与胃泌素瘤的肝转移显著相关, 但与瘤体大小无关[18]. Nasir等[19]研究发现, RUNX1T1蛋白的表达下调可作为预测PETs肝转移的一种新的标志物. 业已证实, 细胞角蛋白CK8、CK18、CK19在源于上皮组织的恶性细胞中广泛表达, 近年研究发现, 上述细胞角蛋白基因也存在于PETs患者[5,20]. CK19的阳性染色不仅可以区别PETs的良恶性, 还可作为PETs患者的预后指标[3,20,21]. 最近, Zhang等[21]采用免疫组织化学染色检测了包括Ki-67、KIT、CK19、Pdx-1、Pax4和Pax6等胰岛细胞分化指标, 应用Cox风险比例回归分析了PETs患者的临床病理特征、免疫组织化学结果与预后的关系. 多变量分析发现, 只有WHO分类标准和KIT表达可作为PETs的独立预后因素. 依据KIT和CK19的表达情况, 他们提出了PETs的免疫组化分类标准: 低风险肿瘤(KIT-/CK19-)、中度风险肿瘤(KIT-/CK19+)和高风险肿瘤(KIT+/CK19+). 该研究认为, KIT是一种新的、独立的PETs预后标志物[21]. 值得一提的是, 作为Ras家族成员之一的ARHI, 与其他家族成员不同, 他具有抑制肿瘤细胞生长的作用, 相当于抑癌基因. 研究发现, ARHI的mRNA表达下调与PETs的生存期下降显著相关[22]. 业已证实, Survivin基因抑制细胞凋亡, 促进肿瘤细胞的发生发展. 研究显示, 在发生肝转移的胃肠胰腺神经内分泌肿瘤患者中, Survivin基因表达阳性与预后不良显著相关[23].
Ghrelin是一种新的脑肠肽, 是迄今发现的唯一的生长激素促分泌素受体(GHS-R)的内源性配体. 根据氨基酸的羧基端序列不同, GHS-R分为GHS-R1a和GHS-R1b 2种类型[2,24]. GHS-R1a是GHS-R的活性形式, 而GHS-R1b受体仅由第一外显子编码, 是GHS-R1a受体的羧基端被剪切后的一种形式, 因而不具有生物活性[24]. GHS-R在胰腺组织、腺泡细胞及胰岛的α细胞和β细胞中均呈阳性表达[25-27]. Ghrelin与其受体结合后发挥其生物学效应. 业已证实, 胰腺和胰岛细胞均可分泌Ghrelin[28], 少量Ghrelin免疫活性细胞散在分布于与胰腺导管相连的区域内[29]. 研究发现, 胰腺的腺泡细胞中, Ghrelin蛋白和Ghrelin mRNA均呈阳性表达[26]. Ghrelin与其受体结合后除了能促进生长激素(GH)释放外, 还可能在PETs的发生发展中起重要作用[30]. Volante等[31]应用免疫组织化学、原位杂交及RT-PCR法分别检测了28例PETs组织中的Ghrelin蛋白和mRNA的表达情况, 结果显示, 39%的PETs的Ghrelin蛋白表达阳性, 而原位杂交及RT-PCR法测定的Ghrelin mRNA的阳性结果分别高达68%和79%. 此研究还发现, PETs组织中GHS-R1a和GHS-R1b的阳性表达分别为25%和50%, 其中, GHS-R1a阳性者均为胰岛素瘤, 且其GHS-R1b也呈阳性表达. 另有研究显示, PETs组织中Ghrelin蛋白和Ghrelin mRNA的阳性表达率分别为68%和95%, GHS-R蛋白和mRNA的阳性表达率分别为70%和100%, 但其血浆中的Ghrelin水平与正常对照组无显著差别, 其原因尚不清楚[32]. 此外, 胰高血糖素瘤患者的肿瘤组织中Ghrelin mRNA也呈阳性表达[33], 而作为NFPETs中的一种特殊类型Ghrelinoma, 不仅其肿瘤组织中的Ghrelin蛋白呈过度表达, 血浆中的Ghrelin水平也显著高于正常对照组, 但血浆中的GH水平与却正常对照组无显著差异[34], 因迄今仅见一例报道, 相关机制有待于进一步研究. 最近, 有人成功建立了Ghrelinoma的小鼠模型, 为相关研究提供了实验基础[35,36].
肿瘤的发生、发展是一个多阶段多基因变化的过程, 涉及许多癌基因的活化和抑癌基因的失活. 这些基因事件可发生在单碱基水平, 但更多是发生在染色体水平, 其中包括染色体整条或区域性的缺失.所谓杂合性缺失(loss of heterozygosity, LOH)即指一个位点上两个多态性的等位基因中的一个出现缺失. LOH在肿瘤细胞中是一种十分常见的DNA变异. 等位基因已经异常的抑癌基因发生LOH可导致基因的失活, 进而导致肿瘤的发生发展.研究显示, 1号染色体的LOH与PETs患者的生存期缩短、肿瘤的进行性生长及肝转移密切相关, 在肝转移的PETs患者中1号染色体的LOH的发生率显著高于无肝转移PETs患者就是一个例证[37]. Chen等[38]研究发现, 胃泌素瘤患者存在1q21-25和1q31-32两个1q LOH的频发区, 此区域的LOH与肿瘤的进行性生长及肿瘤术后的肝转移显著相关. 1q21.3-23.2、1q31.3及22q12.2-12.3三个区域的LOH可能与MEN1基因无关的独立的胰岛素瘤的发病相关, 而1q21.3-23.2与22q12.3两个区域的LOH均与散发型恶性胰岛素瘤的发病有关[39], MEN1基因的LOH发生在43%的散发型胃泌素瘤和17%的散发型胰岛素瘤中[20,40]. 3号染色体的LOH与PETs的肝转移密切相关.研究显示, 50%的肝转移PETs患者发生3号染色体LOH, 而无肝转移PETs患者未出现LOH[41]. 此外, 6q22和6q23-24两个区域的LOH与PETs的恶性程度有关[42]. 性染色体中X染色体的LOH与PETs的恶性进展相关. 研究显示, 56%的女性散发型胃泌素瘤患者发生X染色体LOH, 且与胃泌素瘤手术后的肿瘤进行性生长及肿瘤大小显著相关[43], 女性胃泌素瘤患者中频发X染色体LOH可能是导致女性患者预后不良的因素之一.
甲基化是由酶介导的一种化学修饰, 即将甲基选择性地添加到蛋白质、DNA 或RNA上, 虽未改变核苷酸顺序及组成, 但基因表达却受影响. DNA甲基化能引起染色体结构、DNA构象、DNA稳定性及DNA与蛋白质相互作用方式的改变, 从而控制基因表达.甲基化位点可随DNA的复制而遗传, 因为DNA复制后, 甲基化酶可将新合成的未甲基化的位点进行甲基化. DNA甲基化模式的改变, 尤其是某些抑癌基因局部甲基化水平的异常增加, 在PETs的发生和发展过程中起到了不容忽视的作用[39]. 研究显示, PETs中的多种抑癌基因由于启动子甲基化而失活[40]. 其中, RASSF1A、p16、MGMT、RAR-β及MLH1是甲基化发生频率最高的抑癌基因[44], PETs患者中MLH1抑癌基因的甲基化可导致微卫星不稳定现象, 并与患者的预后相关[45]. 此外, CpG岛甲基化表型(CpG island methylator phenotype, CIMP)涉及到多个基因启动子同时甲基化, 具有肿瘤特异性, 与多种肿瘤的发生或预后相关, 但有关PETs的CpG岛甲基化表型的研究却罕见报道[2]. 最近, Liu等[46]对一组神经内分泌肿瘤的RASSF1A、p14、p16、MGMT四个基因的甲基化研究发现, CpG岛甲基化表型与肿瘤的预后可能有关, 二个或二个以上基因发生甲基化者与肿瘤的肝转移显著相关.
PETs可分泌多种神经内分泌标志物, 如神经元特异性烯醇化酶(neuron-specific enolase, NSE)、突触素(synaptophysins, SYN)和铬粒素A(chromogranin A, CgA). NSE是参与糖酵解途径的烯醇化酶中的一种, 存在于神经组织和神经内分泌组织中. 神经内分泌肿瘤和PETs的血清中NSE可显著增高. SYN是一种与突触结构和功能密切相关的囊泡吸附蛋白, 有调节神经递质释放的作用. CgA是一种分子量为77 000 Da的酸性蛋白, 存在于嗜铬颗粒中, 大多数PETs患者血清CgA 水平升高[47,48], 被认为是目前最有价值的PETs血清标志物[49], 血清CgA的敏感性与肿瘤类型、分化程度及大小有关. 上述三种标志物常被用于PETs的血清学诊断指标. 而细胞角蛋白CK8、CK18、CK19以及神经细胞内微管、微丝等细胞骨架中间丝蛋白也在PETs中显著表达[5,20], 他们可能成为PETs潜在的血清学诊断标志物. 此外, Ghrelin作为一种新的脑肠肽虽然在PETs的肿瘤组织中呈过度表达, 但血浆中Ghrelin水平却与正常对照组无显著差异[32]. 而作为无功能性PETs中的一种特殊类型Ghrelinoma, 不仅其肿瘤组织中的Ghrelin蛋白呈过度表达, 其血浆中的Ghrelin水平也显著高于正常对照组[34], 提示Ghrelin可能成为Ghrelinoma这种特殊类型PETs的潜在血清学标志物.
PETs的定位诊断方法很多, 包括螺旋CT(helical computed tomography, hCT)、正电子发射断层成像与计算机断层扫描(PET/CT)、磁共振成像(MRI)、超声(US)、超声内镜(EUS)、腹腔镜超声(laparoscopic ultrasound, LUS)、开腹术中超声(IOUS)、血管造影(DSA)、选择性动脉内刺激试验(ASVS)等[1,2,50]. 单纯的US定位诊断其阳性率相对较低, 一般在9%-63%, 若US和CT联合应用可显著提高诊断的阳性率, 其敏感性高达84%[51]. 在全部的影像定位技术中, CT联合EUS或联合EUS引导下的细针穿刺(EUS-FNA)被认为是最有效的检查手段, 尤其对胰岛素瘤的诊断, 其敏感性可高达100%[51]. 而胃泌素瘤最有效的定位诊断方法是EUS与奥曲肽受体显像的联合应用[51]. 研究证实, EUS对PETs的总体敏感性可高达95.8%[52], 且EUS-FNA可用于组织学诊断, 对于不能手术治疗的患者, 还可以在EUS引导下注射无水乙醇治疗[52]. EUS-FNA活检具有分辨率高、穿刺针短、能实时超声显影避开血管等优势, 是一种安全有效的定位和组织学诊断方法, EUS-FNA不仅能确定PETs的恶性度, 还可以预测PETs的5年生存率[53,54]. 但因EUS-FNA标本常导致微小的碎片组织也使其诊断具有局限性, 倘若在EUS-FNA检查的同时, 进行一些标志物的免疫组化分析无疑可显著提高诊断的准确性. 最近, Hosoda等[55]应用CK7、CDX2免疫组织化学染色、神经内分泌标志物及KRAS基因突变等指标进行了相关研究, 他们采用如下的诊断标准:神经内分泌标志物阴性, CK7阳性, KRAS基因突变为浸润性胰管癌; 神经内分泌标志物广泛阳性, CK7、CDX2阴性, 野生型KRAS基因为PETs; 神经内分泌标志物阳性不超过病灶范围, CK7、CDX2染色呈多样性, 野生型KRAS基因为胰腺腺泡细胞瘤. 按上述标准, 他们分别对25例浸润性胰管癌患者、25例PETs患者及11例胰腺腺泡细胞瘤患者的手术切除标本及51例EUS-FNA的细胞组织标本进行了对比研究. 在大多数的配对研究中, 两种标本的检测结果显示出高度的一致性. 除了KRAS基因突变外, CK7和/或CDX2表达仅在恶性PETs中偶然看到, 但并不存在于高分化的PETs中, 提示PETs的胰管变异可作为浸润性疾病的一个预测指标, 这些标志物的检测不仅有助于EUS-FNA对PETs诊断, 同时也有助于与其他胰腺肿瘤的鉴别. 近年研究发现, 应用PET/CT技术可显著提高无症状微小PETs的检出率[51]. Inagaki等[56]通过内镜逆行胰管造影(endoscopic retrograde pancreatography, ERP)和EUS检查发现了一例胰管梗阻的特殊患者, 后经PET/CT确诊为是一种十分罕见和独特的以肿瘤组织在胰管内广泛生长为特征的恶性NFPETs, 由于术前的精确诊断使保留胃窦的胰十二指肠切除和局部淋巴结清除术得以成功实施, 提示PET/CT有助于NFPETs的恶性程度预测和术前诊断. Toshikuni等[57]也证实了PET/CT是NFPETs的可靠诊断方法. 此外, PET/CT也是胃泌素瘤的准确定位手段之一[51]. 由于PETs为血运丰富的肿瘤, 选择性血管造影可用于PETs的定位诊断, 其对胰岛素瘤和胃泌素瘤的检出率分别为88%和40%[50]. 此外, 因多数PETs患者存在生长抑素受体(somatostatin receptor, SSTR)过度表达, SSTR有多种亚型, 其中的SSTR2、SSTR3、SSTR5三种亚型与生长抑素类似物(SSTA)具有很强的结合力和亲和力[58,59]. 体内注射111In标记的SSTA, 可与PETs的SSTR2、SSTR3、SSTR5靶向结合, 由此形成同位素显像协助诊断[60]. 生长抑素受体闪烁成像(SRS)的敏感性可根据肿瘤的类型而有所不同, 其对胰腺内分泌肿瘤的总体敏感性高达89%, 显著优于血浆CgA检查79%的阳性结果[61]. SRS不仅显著提高了胰腺肿瘤的检出率, 而且还能区分胰腺癌和PETs[59], 其对PETs的敏感性远大于上述的常规影像定位诊断, 敏感性依次为[60]:SRS>EUS>DSA>MRI>hCT>US. 此外, 因多数胰岛素瘤直径小于2 cm, CT、MRI、US和SRS等非侵入性成像技术对肿瘤的定位和敏感性相对较低, 而ASVS的侵入性检查对胰岛素瘤的诊断准确性可高于95%[62], 被认为是隐匿性胰岛素瘤和胃泌素瘤最有效的定位方法. LUS可直接置于胰腺表面定位, 对胰岛素瘤的探查成功率高达86%, 并可行腹腔镜下胰岛素瘤切除术[63].
根据临床表现, 检测患者血液及组织中相应的异常激素水平, 如胃泌素、血管活性肠肽(vasoactive intestinal peptide, VIP)、胰高糖素、生长抑素、胰多肽等, 可用于PETs的定性诊断. 患者出现顽固性消化系溃疡和腹泻症状, 胃酸显著增高, 血浆基础胃泌素水平>1 000 ng/L, 即可确诊胃泌素瘤[64], 患者出现顽固性周期性水样腹泻和低钾血症, 血浆VIP水平>100 μg/g, 即可确诊VIP瘤[65], 患者出现Whipple三联征, 血清胰岛素水平>36 pmol/L, 血清胰岛素水平/血糖>0.3; C反应肽浓度>200 pmol/L, 胰岛素原>5 pmol/L可确诊胰岛素瘤[66], 患者出现对称性、坏死性、游走性红斑及顽固性贫血等症状, 血清胰高糖素浓度>800 ng/L, 可确诊胰高糖素瘤[67], 患者出现脂肪泻、糖尿病、胃酸过少和胆石症等综合征, 胃肠激素免疫组化显示肿瘤主要产生生长抑素, 可确诊生长抑素瘤[68]. 此外, 一旦诊断为PETs, 必须注意MEN1的可能性, 还应同时检测血清钙、降钙素、甲状旁腺素、生长激素、催乳素等激素水平, 以除外MEN1.
与其他肿瘤的病理诊断不同, 目前仅依靠瘤体的组织病理形态学检查, 尚无法鉴别PETs的良恶性. 肿瘤对周围组织器官的浸润、转移或复发依然是诊断恶性PETs的可靠指标[2,69]. PETs的大体标本多呈褐色、粉红色或灰白色, 与周围组织界限清楚, 部分可有完整的包膜. 组织病理切片下瘤细胞为相对一致的小圆形细胞, 核居中, 核染色质呈细颗粒状, 核分裂象少见, 瘤细胞多呈小梁状、腺泡状排列, 间质内血管丰富[5,6,70]. 多数PETs分化较好, 分化差者少见. 此外, 肿瘤内分泌源性的诊断还有赖于免疫组织化学分析, 多数肿瘤的SYN、NSE、CgA免疫组织化学反应阳性[47,70].
外科手术目前仍是PETs的首选治疗方法. 根据肿瘤大小和位于胰腺的部位不同, 而采取不同的手术方式. 其主要术式包括肿瘤局部切除术、区域淋巴结清除术、胰体尾切除术、胰腺节段切除术及胰十二指肠切除术等[71]. 对于伴有肝转移而不能根治性切除的恶性PETs患者, 可行减瘤术、胃肠道短路术或肝移植术[72], 但对MEN1相关的PETs患者, 因其病灶常多源发生, 术后易复发, 尤其对MEN1相关的胃泌素瘤患者还可用质子泵抑制剂治疗, 因此手术更应慎重保守. 但也有学者认为, 根据SRS的准确定位而采取积极的手术切除病灶有助于MEN1相关的胃泌素瘤患者的生化治疗[73]. 一般认为, 术前的准确定位有利于确定肿瘤与胰管胆管的关系, 不仅对选择术式和切口十分重要, 也避免了盲目手术或再次手术的风险[74,75]. 研究显示, 术前采用胰腺动态增强螺旋CT扫描和灌注成像, 有利于病灶的准确定位, 并显著提高了体积较小PETs的检出率[76]. 但也有观点认为, 对于散发的PETs, 尤其是胰岛素瘤, 经验丰富的外科医生完全不需要术前定位即可达到术中的准确探查率在90%以上[77]. 此外, 腹腔镜技术的进步使PETs的微创治疗成为可能. 腹腔镜可将超声探头置于胰腺表面进行PETs定位, 并且实施瘤体摘除和胰体尾切除术, 还可根据情况决定是否切除脾脏, 应用前景值得期待[63,78].
前已述及, 多数PETs患者存在SSTR过度表达, 这不仅奠定了SRS的分子诊断学基础, 也为SSTA对PETs的治疗提供了重要的分子靶点. 业已证实, SSTA对SSTR的五种受体亚型均具有很强的亲和力[59], 对生长激素、胰岛素、胃泌素等多种人体激素具有抑制作用, 采用SSTA的生物治疗目前已广泛用于PETs, SSTA不仅能有效抑制PETs病理性激素分泌所引发的相应症状, 还能抑制肿瘤的生长[79]. 更高剂量的SSTA或SSTR新亚型选择性受体激动剂的应用可改善对标准剂量SSTA治疗无效的PETs患者的症状[80]. 低分子多激酶抑制剂, 能靶向作用于肿瘤细胞和肿瘤血管上的丝氨酸和/或苏氨酸及受体酪氨酸激酶, 阻断信号传导, 从而抑制肿瘤细胞生长. 最近, 经三期临床试验证实, 低分子多激酶抑制剂苏尼替尼(sunitinib)对胰腺神经内分泌肿瘤具有显著疗效[80]. 此外, 影响血管内皮生长因子受体的单克隆抗体贝伐单抗(bevacizumab)不论其独立治疗还是其与SSTA或与奥沙利铂(oxaliplatine)和卡培他滨(capecitabine)的联合治疗均取得了良好的效果[80].
SSTR靶向放射核素治疗也常用于PETs患者. 业已证实, 体内注射111In标记的SSTA, 并与SSTR靶向结合后经同位素放射治疗对多数PETs患者取得了较好的疗效[1,60]. Kaemmerer等[58]报道, 对1例因腹主动脉旁淋巴结及肠系膜血管受累, 而无法实施手术切除的恶性PETs患者, 首先采用肽受体放射性核素治疗(PRRT)作为新的一线辅助治疗, 待腹腔淋巴结转移及肠系膜血管浸润程度显著降低后再行后续的手术切除, 18 mo后随访发现, 患者病情完全缓解. 提示对于SSTR过度表达而不能手术切除的PETs患者, 采用PRRT这种新的辅助治疗无疑是PETs一种全新的有效治疗手段.
PETs的发病机制尚未十分清楚, 由于此类肿瘤发病率很低, 使得系统研究其发病机制仍面临不少困难. 在其他消化系肿瘤常见的抑癌基因和癌基因在PETs中却很少发生变化. 近年来的研究发现, 一些特殊基因的表达异常、等位基因染色体的杂合缺失、抑癌基因的甲基化以及新的脑肠肽Ghrelin等在PETs的发病机制中可能发挥重要作用, 这无疑为该领域的深入研究开启了新的思路. 而PETs新的组织病理学分类标准的制定也对评估PETs的生物学行为提供了帮助. 此外, 随着肿瘤分子生物学、分子病理学及遗传学研究领域的飞速发展, 用基因分子生物学标志物作为PETs的临床预后观察指标已成为可能. 尽早确定PETs的预后指标并准确预测肿瘤的生长方式, 无疑对治疗方案的选择有十分重要的参考价值. EUS-FNA、PET/CT等影像检查技术的进步对PETs的术前精确定位及组织学诊断提供了保障. 外科手术、腹腔镜切除、SSTA治疗等诸多治疗方法的日臻成熟使患者的生存期明显改善. 总之, 尽管PETs的相关研究已取得较大进展, 但关于其发病机制、遗传学及分子生物学的临床预后指标仍有待于进一步的深入研究, 前景值得期待.
胰腺内分泌肿瘤是一类少见的肿瘤, 源于APUD系统, 能分泌多种神经内分泌标志物和相应的胃肠激素, 临床表现各异. 发病机制尚不十分清楚. 基因表达异常、染色体缺失、抑癌基因甲基化、Ghrelin等可能在其发病机制中起重要作用. 新的组织病理学诊断标准及分子生物学、遗传学标志物的发现对其预后评估有重要参考价值.
郝建宇, 教授, 首都医科大学附属北京朝阳医院消化内科
分子生物学技术的进步, 从基因角度研究PETs的发病机制已成为目前关注的焦点. CD10、CD44、CD99、 p27、COX2、Ki-67、KIT等相关基因表达异常可能在肿瘤的发生发展及预后评估中发挥重要作用. 寻找PETs新的血清学标志物是目前努力的方向.
Corbetta等发现了一种新的无功能胰腺内分泌肿瘤Ghrelinoma, 目前世界上也仅见一例报道. 其主要表现为血浆Ghrelin水平高于正常对照组50倍以上, Ghrelin蛋白在肿瘤组织中显著表达, 血浆GH、IGF-1水平正常, 除肥胖外, 无其他激素引起的临床症状.
本文创新性地综述了多种基因在PETs发生发展中的作用机制, 着重介绍了多种分子生物学、遗传学标志物的研究进展, 为基础研究和临床治疗提供了新的思路.
本文全面系统阐述了PETs在发病机制、组织病理学诊断标准、肿瘤转移及预后的分子生物学、遗传学指标、血清学和影像学诊断以及内外科治疗方面的相关进展, 为基础研究及临床工作提供了有价值的信息.
本文总体科学性较好, 较全面地综述了胰腺内分泌肿瘤的概况, 对临床工作有指导意义.
编辑:李军亮 电编:李薇
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