无功能性腺瘤

有大约50%的垂体瘤患者没有明显的内分泌改变，而一些非垂体组织起源的肿瘤虽然会影响激素的分泌，但一般不是增强作用。

无功能性腺瘤以大腺瘤为主，临床缺乏激素过多的确切证据，常伴随视力受损和（或）不同程度垂体功能低下，占整个垂体腺瘤的25%～30%。根据形态学异质性分成两类：一类是具有相同激素免疫反应性和形态学特征的腺垂体细胞型，但临床上处于“沉默”状态，另一类无任何特殊标记。前者包括沉默型的生长激素细胞腺瘤、促皮质素细胞腺瘤、促甲状腺素细胞腺瘤和促性腺激素细胞腺瘤；后者包括裸细胞瘤、嗜酸细胞瘤和沉默性亚型3腺瘤。散发病例中垂体瘤转化基因（pituitary tumour transforming gene，PTTG）和磷脂酰肌醇激酶/蛋白激酶B（Akt）途径增量调节以及成纤维细胞生长因子受体-4（FGFR-4）组成型表达在无功能腺瘤病理改变中扮演重要角色，近来研究表明MAPK通路和Wnt信号通路与肿瘤发生关系密切。

在一些研究系列中，有超过90%的患者术前至少有一种垂体激素缺乏，其中以性腺功能减退最常见，可以是垂体糖蛋白多肽激素过量分泌引起，更普遍的是这些激素的单体亚单位。约1/3的患者β-FSH基线水平升高，约1/5的患者α亚单位升高，FSH过量分泌较少出现，在极少情况下，LH分泌过多可能导致睾酮水平异常升高。

多重因素可导致继发性性腺功能减退，例如大腺瘤直接压迫，或因下丘脑垂体神经束受压导致下丘脑多巴胺能神经元抑制性递质传递受阻，即所谓的“垂体柄效应”。垂体无功能腺瘤与PRL腺瘤的鉴别诊断研究已较深入，目前，两者间催乳素水平临界值多趋向于3 000 mU/l（150 ng/ml），Karavitaki等在排除GH和ACTH腺瘤基础之上，认为PRL水平达到2 000 mU/l（100 ng/ml）水平时诊断即可确定下来，因为此时绝大多数都表现为PRL大腺瘤。另外，PRL腺瘤患者其PRL水平与肿瘤直径关联密切。

术后垂体功能缺失各家报道差异较大，从16%～60%不等，一般来说，甲状腺轴和肾上腺轴功能恢复可能性最大，GH恢复正常分泌几乎为零。术前部分垂体功能保存良好者（GnRH或TRH激发试验存在应答）预示术后能较好恢复激素分泌，当肿瘤直径＜2.5cm时垂体功能恢复可能性较大。垂体无功能性腺瘤多具有多巴胺受体，生长抑素受体，但给药后肿瘤很少有缩小，通常情况药物治疗并不推荐。

对于这些患者的内分泌检查包括了解详细的内分泌病史，检测PRL，ACTH，GH，FSH，LH的基础水平，了解甲状腺功能，检测凌晨皮质醇水平，以及在男性病人中检测睾酮水平。在垂体巨腺瘤的患者，即使没有明显的内分泌症状，FSH和LH也应进行检测，这并非一定是为了改变治疗方案，而是为了区别肿瘤类型，为治疗后的疗效评估提供依据。

如果患者确实没有任何临床内分泌功能紊乱并且激素的基础水平检测都正常的话，就不需要做进一步检查。但必须指出的是，术前对病人的甲状腺和肾上腺轴的功能进行评估是十分重要的，因为这些脏器的功能低下将导致严重的生命危险。对于甲状腺和肾上腺功能处于临界状态或低下，以及＞10 cm的垂体巨腺瘤，有必要对患者进行甲状腺和肾上腺功能的动态监测。

电镜发现几乎没有临床上的无功能腺瘤是真正的胞质内没有分泌颗粒的裸细胞腺瘤，这些颗粒内部所含成分尚不清楚。Asa等通过体外培养研究无功能性腺瘤，发现大部分这类肿瘤能分泌少量的FSH，LH和α亚单位，并对GnRH反应，免疫组化染色显示瘤组织内仅有少量散在的细胞染色。活体外实验证实大多数无功能性腺瘤既分泌完整的糖蛋白激素（FSH，LH，TSH）也分泌合成此类糖蛋白激素的游离亚单位（α-subunit，β-FSH，β-LH，β-TSH），少数情况下可见到具有免疫反应的PRL，ACTH或GH，不到30%的无功能性腺瘤无分泌功能。尽管在这些无功能性腺瘤患者中，许多激素分泌的量很少，以致相对于临床症状无关紧要，但随着检测水平的提高，将来这些轻微的激素改变都能够成为术后随访和切除率、治愈率评价，以及早期复发的标准。近年来，许多实验证据显示腺垂体细胞并非一成不变地限于一种类型，在特定条件及治疗后经诱导分化而具有多种内分泌特性，其促发因素仍需进一步鉴定。

由于α亚单位在各类型垂体瘤中都有分泌，应用放射免疫学方法对它进行检测，在确定是否有手术残留和复发中，已显得越来越重要。另外，目前在无功能性腺瘤中发现有嗜铬粒蛋白A分泌，这被认为是此类型腺瘤的特殊标志，但是否在临床上具有重要意义尚不明确。

（高　恒　惠国桢）

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