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2018欧洲内分泌学会临床实践指南 侵袭性垂体瘤和垂体癌 CK选译版本 Chen Kang 2018.06 介绍 Introduction 有临床意义的垂体瘤的发病率80-100/100 000，年发病率为每10万例新发病例4例。发病率取决于年龄和性别。垂体肿瘤的临床表现变化很大：一些长时间处于静止状态;许多生长缓慢，而在极少数情况下观察到快速肿瘤生长。手术后，存在残余肿瘤的情况下会增加肿瘤进展的风险，大约30％的患者在手术后0.4-37年显示肿瘤再生长。标准治疗结合了手术、药物和放疗，基于药物治疗的抗性和标准治疗后仍多次复发，一小部分垂体肿瘤被分类为侵袭性垂体肿瘤。侵袭性肿瘤的发病率尚不清楚。此类肿瘤通常但不总是会有3种标志物的一种阳性（Ki-67≥3％，和/或增加的有丝分裂和/或p53表达）。2或3个标记阳性的肿瘤在手术系列中占2.5％至10％。由脑脊髓和/或全身转移的存在定义的垂体瘤很少见，据报道占垂体瘤的0.2％。 The prevalence of clinically relevant pituitary tumours is 80–100 cases per 100 000 with an annual incidence of 4 new cases per 100 000. Incidence rates depend on age and sex. The clinical behaviour of pituitary tumours is highly variable: some remain quiescent for long periods of time; many grow slowly, while in rare cases rapid tumour growth is observed. Post-operatively, about 30% of the patients show tumour regrowth 0.4–37 years after surgery, with an increased risk of tumour progression in the presence of residual tumour. A small subset of pituitary tumours has been classified as aggressive pituitary tumours, based on resistance to medical treatment and multiple recurrences despite standard therapies combining surgical, medical and radiotherapy treatment approaches. The prevalence of aggressive tumours is not known. Such tumours often, but not always, exhibit one of the 3 markers (Ki-67 ≥3%, and/or increased mitoses, and/or p53 expression). Tumours exhibiting 2 or 3 markers were found to account from 2.5% to 10% in surgical series. Pituitary carcinomas, defined by the presence of craniospinal and/or systemic metastasis, are rare, and reported to account for 0.2% of pituitary tumours. 侵袭性垂体瘤的早期识别具有挑战性，但具有重要的临床意义，因为它们即使在没有转移的情况下也与发病率和死亡率的增加有关。尽管在预后分类方面进行了大量研究和进展，但没有病理学标记可靠地预测垂体肿瘤行为。本指南提出了一种侵袭性垂体瘤的定义，并为目前的管理提供了建议。 Early identification of aggressive pituitary tumours is challenging, but is of major clinical importance as they are associated with an increased morbidity and mortality even in the absence of metastases. Despite numerous studies and advances in prognostic classification, no pathological marker has been shown as yet to reliably predict pituitary tumour behaviour . This guideline proposes a definition of an aggressive pituitary tumour and provides recommendations for current management. 方法（略） Methods 推荐以及推荐的理由 Recommendations, rationale for the recommendations 1. 概述 General remarks R 1.1.1 我们建议应在多学科专家组会(MDT)上讨论这些患者（内分泌学家，神经外科医生，垂体病理学家，神经放射学家，放射肿瘤学家，肿瘤学家）。 R 1.1.1 We recommend that these patients should be discussed in a multidisciplinary expert team meeting (endocrinologist, neurosurgeon, pituitary pathologist, neuroradiologist, radiation oncologist, medical oncologist). 2. 评估侵袭性 Assessment of aggressiveness 2.1 侵袭性垂体瘤的诊断 2.1 Diagnosis of an aggressive pituitary tumour R 2.1.1 我们建议放射学（影像上的）侵袭性肿瘤和有着异常的快速的肿瘤生长率的患者，或尽管有最佳的标准治疗（手术，放疗和常规药物治疗）但仍有临床相关的肿瘤生长的患者，应考虑到侵袭性垂体瘤的诊断 R 2.1.1 We recommend the diagnosis of an aggressive pituitary tumour be considered in patients with a radiologically invasive tumour and unusually rapid tumour growth rate, or clinically relevant tumour growth despite optimal standard therapies (surgery, radiotherapy and conventional medical treatments). 理由Reasoning 尽管采用了最佳标准治疗，仍然存在临床相关的肿瘤生长是侵袭性的标志。最佳标准治疗，即临床管理指南（补充表5）提出的药物治疗、手术和放疗的组合。标准药物治疗和对这种治疗的抵抗在第3.3节有更详细的讨论。关于手术治疗，重要的是区分非优化手术后复发和专家手术后复发。垂体肿瘤的生长速度受患者和肿瘤特异性特征的影响;这种内在的肿瘤异质性决定了治疗复发和耐药的风险。 The hallmark of aggressiveness is clinically relevant tumour growth despite the use of optimal standard therapies, which entails a combination of medical therapies, surgery and radiotherapy as proposed in clinical management guidelines (Supplementary Table 5). Standard medical therapies and resistance to such treatment are discussed in more detail in Section 3.3. With regard to surgical management, it is important to distinguish between recurrence following non-optimal surgery and recurrence after surgery performed by an expert. The growth rate of pituitary tumours is influenced by patient- and tumour-specific characteristics; this intrinsic tumour heterogeneity determines the risk of recurrence and resistance to treatment . 单纯侵入并不是垂体瘤侵袭性的代名词；然而，入侵是不完全肿瘤切除的主要决定因素。在临床表现上，侵袭性垂体瘤几乎总是大腺瘤。然而，垂体肿瘤大小并不等同于侵袭潜能，就如可能对多巴胺激动剂治疗非常敏感的巨催乳素瘤肿瘤所示。 Invasiveness alone is not synonymous with pituitary tumour aggressiveness ; however, invasion is a major determinant of incomplete tumour resection. Aggressive pituitary tumours are almost always macroadenomas at clinical presentation. However, pituitary tumour size at presentation does not equate to potential for aggressive behaviour, as illustrated by giant lactotroph tumours that may be very sensitive to dopamine agonist treatment . 初次诊断与侵袭性肿瘤行为之间的时间间隔从几个月到10年不等。数年后可能会有长时间的临床静止期，随后是一段快速肿瘤生长、侵袭或转移。 The time interval between the primary diagnosis and the aggressive tumour behaviour varies from months to >10 years. There may be extended periods of clinical quiescence for several years followed by a period of rapid tumour growth, invasion or metastasis. R 2.1.2 我们建议用影像（在大多数情况下是MRI）应用于量化肿瘤大小、侵袭和生长。 R 2.1.2 We recommend that imaging (MRI in most instances) should be used for quantification of tumour dimensions, invasion and growth. 理由（Reasoning）：建议进行可以准确且持续检测肿瘤部位、尺寸和侵入性的影像检查（最好是可以提示骨侵入评估的MRI或CT）。 成像方案应包括薄（2-3毫米）矢状T1，注射钆前后的冠状T1，冠状T2或轴向T1加权。 与前一次和更久远的成像研究进行比较对于识别肿瘤进展和指导适当的治疗至关重要。 An imaging study (preferably MRI or CT where bone invasion assessment is indicated) that enables accurate and consistent measurement of tumour sites, dimensions and invasion is recommended. The imaging protocol should comprise thin (2–3 mm) sagittal T1, coronal T1 before and after gadolinium injection, coronal T2 or axial T1-weighted slices. Comparison with penultimate and prior remote imaging studies is essential to identify tumour progression and to guide appropriate treatment. R 2.1.3 我们建议对侵袭性垂体瘤患者进行全面的内分泌实验室评估。 R 2.1.3 We recommend full endocrine laboratory evaluation in patients with aggressive pituitary tumours. 理由（Reasoning）：评估垂体内分泌功能在识别分泌性肿瘤时至关重要，这些分泌性肿瘤可能提示需要特定的治疗或存在特定的内分泌缺陷，如果不治疗会有致病性。 应该在适当的时间间隔（个体化的基础上3-6个月）进行垂体内分泌功能的评估，既要明确疾病进展的潜在生物标志物，以与影像检查同时进行监测，还要管理内分泌缺陷。 Assessment of pituitary endocrine function is essential at presentation to identify secretory tumours that may indicate specific therapies or endocrine deficiencies, which if left untreated would contribute to patient morbidity. Assessment of pituitary endocrine function should be performed, at appropriate intervals (3–6 months on an individualised basis), both to characterise potential biomarkers of disease progression to monitor in parallel with imaging studies, and to manage endocrine deficiencies. R 2.1.4 对于侵袭性垂体肿瘤患者，同时有部位特异性症状，或生化与放射学结果不一致的情况，我们建议筛查转移性疾病。 R 2.1.4 In patients with aggressive pituitary tumours, and either site-specific symptoms or discordant biochemical and radiological findings, we recommend screening for metastatic disease. 理由（Reasoning）：鉴于侵袭性垂体瘤常常进展并且偶尔有转移风险，因此需警惕，并且应该考虑适当的结构影像（MRI和CT）和/或功能影像（FDG和/或SSTR-PET），尤其是出现局部症状（颈部/背部疼痛或神经系统症状），和/或实验室检查结果与已知的可见疾病程度不一致（激素水平升高而肿瘤大小没有相应增加）。 转移性疾病的常见部位包括脑脊髓、颈淋巴链以及少见的肝，骨和肺。 Reasoning：Given that aggressive pituitary tumours often progress and occasionally metastasize insidiously over several years, attention should be paid and appropriate structural (MRI and CT) and/or functional (FDG- and/or SSTR-PET) imaging studies should be considered, in the setting of site-specific symptoms (neck/back pain or neurological complaints), and/or where laboratory measures are discordant with known visible extent of disease (increase in hormone levels without corresponding increase in tumour size). Common sites for metastatic disease include craniospinal deposits, neck lymphatic chains and less commonly liver, bone and lung. 2.2 垂体瘤侵袭性的潜在预测因素 2.2 Potential predictors of aggressiveness in pituitary tumours R 2.2.1 我们建议所有垂体肿瘤应进行组织病理学分析，其中应包括最低限度的垂体激素免疫检测和Ki-67增殖指数评估。当Ki-67指数≥3％时，至少应评估p53免疫检测和有丝分裂计数。（+000） R 2.2.1 We recommend that all pituitary tumours should undergo histopathological analysis, which should include a minimum immunodetection of pituitary hormones and Ki-67 proliferative index evaluation. The p53 immunodetection and the mitotic count should be evaluated at least, when the Ki-67 index is ≥3% (+000). 理由 Reasoning 根据免疫组织化学（IHC），将垂体瘤分为
转录因子染色可能有助于免疫阴性肿瘤，但不能评估侵袭性。 Based on immunohistochemistry (IHC), pituitary tumours are classified into somatotroph (GH, Pit 1 positive), lactotroph (PRL, Pit1 and ER positive), corticotroph (ACTH, Tpit positive), thyrotroph (TSH, Pit1 positive), gonadotroph (FSH/LH, SF1 positive), null cell (negative for hormones and transcription factors) tumours and plurihormonal and double tumours. Transcription factors staining could be helpful for immunonegative tumours but not for the assessment of aggressiveness. 使用增殖标志物作为评估垂体瘤的预后指标是有争议的。然而，一些标准
被纳入2004年WHO分类。然而，这种分类的解释存在困难，并且从未在临床情况下得到验证。对Ki-67指数仍然没有明确的一致意见，该指标可能鉴别复发风险高的肿瘤，但指数的切点各异，范围从1.3％到10％，有时适用于肿瘤亚型。但是，大多数情况下使用切点为≥3％。大多数研究仅基于数量有限的病例，仅有短期随访或专家意见。一些作者认为Ki-67> 10％是恶性肿瘤的标志，但同样没有进行前瞻性验证。 The use of proliferative markers as prognostic tools in the assessment of a pituitary tumour is controversial. Nevertheless, some criteria (Ki-67 >3%, extensive p53 immunoreactivity and increased mitotic activity) were incorporated into the 2004 WHO Classification. However, there are difficulties with the interpretation of this classification, and it has never been validated in a clinical context. There remains no clear consensus on the Ki-67 index that may identify tumours at a high risk of recurrence, with widely different cut-offs proposed, ranging from 1.3% to 10%, sometimes adapted to the tumour subtype. However, a cut-off ≥3% is mostly used. Most studies are based on a limited number of cases, short follow-up or expert opinion only. Some authors consider that a Ki-67 >10% is a sign of malignancy, again without prospective validation. 最近重新评估了有丝分裂计数，有丝分裂计数> 2表明有复发风险。 p53的预后价值也有争议，因为可靠的定量方法尚未得到验证。然而，对于阳性染色（每10个HPF> 10个强阳性核）的共同定义已经达成一致。 Mitotic count has been recently re-evaluated and mitotic count >2 is suggestive of risk of recurrence. The prognostic value of p53 is also debated because a reliable method of quantification has not been validated. However, a common definition of positive staining (>10 strongly positive nuclei per 10 HPFs) has been agreed upon. 结合侵袭性（影像）、增殖性标志物（Ki-67指数≥3％和有丝分裂计数> 2）和p53（通过IHC病理学评估）已经提出用于鉴别具有更高风险的垂体瘤进展/复发。 The combination of invasion (determined radiologically) and use of proliferative markers (Ki-67 index ≥3% and mitotic count >2) and p53 (assessed by IHC pathologically) has been proposed to be superior in identifying pituitary tumours with a higher risk of progression/recurrence. 我们认为没有标志物能足以单独预测肿瘤行为。然而，在最近的ESE调查中，97例侵袭性垂体瘤和34例（垂体）癌（未发表的ESE调查）至少有一个可用的病理学标记。 Ki-67≥3％是侵袭性垂体瘤（79 / 97,81％）和癌（29 / 34,85％）中最常见的阳性标记;也常可观察到p53阳性（分别为35/48; 73％和18/23; 78％）和有丝分裂计数> 2有丝分裂/ 10HPF（分别为26/41,63％和18/20,90％ P = 0.03）。这些标记的频率在侵袭性垂体肿瘤和癌之间没有差异，但高于外科系列中观察到的（其他肿瘤）。 We acknowledge that no marker alone is sufficient to predict tumour behaviour. However, in the recent ESE survey at least one pathology marker was available for 97 aggressive pituitary tumours and 34 carcinomas (unpublished ESE survey). Ki-67 ≥3% was the most frequent positive marker in aggressive pituitary tumours (79/97, 81%) and carcinomas (29/34, 85%); also p53 positivity (35/48; 73% and 18/23; 78%, respectively) and a mitotic count >2 mitoses/10HPFs were also frequently observed (26/41, 63% and 18/20, 90%, respectively, P = 0.03). The frequency of these markers was not different between aggressive pituitary tumours and carcinomas, but higher than observed in surgical series. 根据这些结果以及世界卫生组织关于垂体瘤的最新分类，我们推荐应至少评估Ki-67指数，当Ki-67指数≥3％时，应评估p53免疫检测和有丝分裂计数。 Based on these results, and the last WHO classification on pituitary tumour, we recommend the evaluation of Ki-67 index at minimum, the p53 immunodetection and the mitotic count when the Ki-67 index is ≥3%. R 2.2.2 我们建议结合患者的个体化临床情况对组织病理学结果进行解释（+000） R 2.2.2 We suggest interpretation of histopathological results in the clinical context of the individual patient (+000). 理由 Reasoning 在Trouillas等人的研究中，与非侵入性和非增殖性肿瘤（1a级）相比，侵袭性和增殖性（Ki-67> 3％和p53阳性或有丝分裂数> 2）肿瘤（等级2b）表现出较差的预后，肿瘤进展/ 复发的可能性增加（12倍）。 In a study by Trouillas et al., invasive and proliferative (Ki-67 >3% and p53 positive or number of mitosis >2) tumours (grade 2b) demonstrated a poorer prognosis with an increased probability (12 fold) of tumour progression/recurrence compared to non-invasive and non-proliferative tumours (grade 1a). 还认识到，男性泌乳素瘤和静寂型ACTH瘤（ACTH阳性，但无分泌）表现出更具侵袭性的病程，并且可能比静寂型的促性腺激素瘤更早复发。最初为垂体静寂型ACTH瘤在多年随访过程中很少会发展为分泌ACTH的垂体瘤，如果出现这种转变也可能预示着更具侵袭性的肿瘤行为。 静寂亚型III型或多激素静寂型肿瘤也可能表现出比无症状促性腺激素肿瘤更具侵袭性的临床过程。 It is also recognised that lactotroph tumours in men and silent corticotroph (ACTH positive) tumours demonstrate a more aggressive course, and may recur earlier than silent gonadotroph tumours. Rarely, initially silent corticotroph tumours may evolve to secrete ACTH after many years of follow-up, and this transformation may also herald more aggressive tumour behaviour. Silent subtype III or plurihormonal silent tumours also may exhibit a more aggressive clinical course compared with silent gonadotroph tumours. R 2.2.3 对于侵袭性垂体瘤患者，建议根据垂体瘤或内分泌瘤发病年龄（较小）或家族史进行种系细胞基因检测（+000），这一适应症同非侵袭性垂体瘤患者一样。 R 2.2.3 In patients with aggressive pituitary tumours, we suggest germline genetic testing based on young age at presentation or family history of pituitary or endocrine neoplasia, as recommended for patients with nonaggressive pituitary tumours (+000). 理由 Reasoning 目前有关垂体瘤患者基因检测的建议没有专门针对侵袭性肿瘤进行阐述。 在这方面缺乏足够数据的情况下，我们建议进行基因检测的适应症与非侵袭性垂体瘤患者相同。 Current suggestions on genetic testing in patients with pituitary tumours do not elaborate specifically on aggressive tumours (15, 47, 48). In the absence of sufficient data in this regard, we suggest that indications for genetic testing should be applied as for non-aggressive pituitary tumours. 一些研究表明，与MEN1和AIP相关患者垂体瘤更具侵袭性。 MEN1阳性的垂体肿瘤与未选择的非MEN1散发性垂体腺瘤组比较，显示MEN1肿瘤较大且于组织学侵袭性更常见。在另一项研究中，年轻的垂体肿瘤患者（主要是生长激素瘤）被发现更可能在明显散发的人群中携带AIP突变。涉及垂体肿瘤易感性的其他基因包括GPR101（XLAG），p27Kip1（多发性内分泌瘤病4型（MEN4）），PRKAR1A（卡尼综合征），GNAS（McCune-Albright综合征），1型神经纤维瘤病，SDHx突变和DICER1综合征）。然而，目前对这些情况下潜在的更具侵袭性的垂体肿瘤行为知之甚少。 Some studies have suggested that more aggressive pituitary tumours may be found in association with MEN1 and AIP patients. Comparison of MEN1-positive pituitary tumours with an unselected group of non-MEN1 sporadic pituitary adenomas revealed that MEN1 tumours were larger and more often histologically invasive (49). In another study, young patients with pituitary tumours (mostly somatotroph tumours) were found to be more likely to carry AIP mutations among apparently sporadic populations (48). Other genes implicated in pituitary 3. 治疗选择 Therapeutic options 3.1手术的作用 3.1 Role of surgery R 3.1.1我们建议手术应由具有丰富垂体手术经验的神经外科医生进行（++ 00）。 R 3.1.1 We recommend that surgery should be performed by a neurosurgeon with extensive experience in pituitary surgery (++00). R 3.1.2 在考虑其他治疗方案之前，我们建议与专家神经外科医生就（是否）再次手术进行讨论（++ 00）。 R 3.1.2 We recommend discussion with an expert neurosurgeon regarding repeat surgery prior to consideration of other treatment options (++00). 建议所有患者在选择放疗、药物治疗前，多学科讨论是否可以手术及手术方式，手术方式包括经蝶窦 vs 开颅，全切 vs 大部分切除（减压手术）。如果手术能达到减压目的，即解除肿瘤压迫视神经视交叉、下丘脑、脑积水以及剧烈的头痛；或者手术能达到近全切的可能，则建议手术，并由相关手术经验丰富的神经外科医生主刀。丰富的手术经验有助于降低手术并发症和死亡率。内镜下广泛暴露能有助于海绵窦侵袭及其他部分肿瘤的切除。 开颅手术适用于鞍上生长为主的肿瘤。肿瘤巨大、造成脑积水、下丘脑压迫症状时，可先行脑室分流术，待症状好转后，再进一步治疗。 3.2 放射治疗的作用 3.2 Role of radiotherapy R 3.2.1 不论非功能肿瘤手术、或功能性肿瘤的标准药物治疗+手术，（如治疗后）临床可见相关肿瘤生长，我们建议对其进行放疗（++ 00）。 R 3.2.1 We recommend radiotherapy in patients with clinically relevant tumour growth despite surgery in nonfunctioning tumours or surgery and standard medical treatment in functioning tumours (++00). R 3.2.2 我们建议在临床相关浸润性肿瘤残留时，病变标志物（Ki- 67指数，有丝分裂计数，p53免疫检测）强烈指示侵袭性行为，应考虑辅助放疗，（+000）。 R 3.2.2 We suggest that adjuvant radiotherapy should be considered in the setting of a clinically relevant invasive tumour remnant with pathological markers (Ki- 67 index, mitotic count, p53 immunodetection) strongly indicating aggressive behaviour (+000). R 3.2.3 我们建议与专家放射肿瘤学家就不同的放疗方案进行讨论，考虑肿瘤的大小和部位，以及放疗前和放疗前的病理。 R 3.2.3 We suggest discussion with an expert radiation oncologist regarding the different radiotherapeutic options taking into consideration tumour size and location, as well as pathology, prior RT and dose. 放疗手段包括普通分割外照射放疗和立体定向放疗。普通分割外照射总剂量为45-54Gy，分25-30次，对正常组织损伤较小，主要用于形状不规则的肿瘤，特别是侵犯视路垂体柄即脑干等重要结构时为首选。立体定向放疗可1次完成，常规剂量12-14Gy, 最高可达16Gy。此方式一般要求肿瘤边缘距离视路至少3-5mm，切肿瘤直径最大不超过3cm，当射线可能损伤视路，可分为5个单元，总剂量25Gy。 3.3 标准药物治疗（内分泌科重点） 3.3 Standard medical therapies R 3.3.1 按照当前指南，我们推荐标准的最大耐受剂量的药物治疗来控制肿瘤的生长。 R 3.3.1 We recommend standard medical treatment with maximally tolerated doses in order to control tumour growth, as per current guidelines. 理由：Reasoning 泌乳素瘤 Prolactinoma 卡麦角林是治疗泌乳素瘤最有效且最好的耐受药物（补充表5）。 在大多数泌乳素瘤中，正常血泌乳素和肿瘤体积减少可以在≤2mg/周的剂量下实现。 男性中，侵袭性生长和巨大肿瘤（即直径> 4 cm）与较差的（治疗）反应相关。 这些肿瘤通常可以通过增加卡麦角林的每周剂量（每1-3个月增加0.5mg，最多3.5mg）来控制。 但一些大的肿瘤也可能对多巴胺激动剂敏感。 一些泌乳素瘤反应较缓慢，最终可以使用相同剂量的卡麦角林进行治疗。 在一部分患者中，催乳素水平可以正常化但肿瘤大小不减; 这种现象的机制还有待澄清。 Cabergoline is the most effective and best tolerated drug for treating prolactinomas (Supplementary Table 5). In most prolactinomas, normoprolactinemia and a reduction of tumour volume can be achieved with a dose ≤2 mg/week. Male gender, invasive growth and giant tumours (i.e. diameter >4 cm) are associated with a lower response. These tumours can often be controlled by increasing the weekly dose of cabergoline, by 0.5 mg every 1–3 months, up to 3.5 mg. However, some large tumours may be exquisitely sensitive to dopamine agonists. Some prolactinomas respond slowly and can eventually be managed using the same dose of cabergoline. In a subset of patients, prolactin levels may be normalised without a decrease in tumour size; the mechanism for this phenomenon remains to be clarified. 肢端肥大症 Acromegaly 生长激素瘤表达生长抑素受体（sst），主要是sst2和sst5，sst1和sst3少量表达。生长抑素类似物的第一代（兰瑞肽，奥曲肽）和第二代（帕瑞肽）可用于治疗肢端肥大症（补充表5）。在最近一项治疗初治患者的研究中[PRIMARYS研究（Lanreotide Autogel）研究]显示，27/63（43.5％）患者IGF-I得以正常化且GH水平<2.5μg/ L。在另一项针对358名未接受治疗的患者的较大样本研究中，将奥曲肽LAR与帕瑞肽LAR（可作用于sst1-3、尤其是sst5的多sst配体）进行比较。在给予奥曲肽LAR的患者中有19％的IGF-I正常化且GH水平<2.5μg/ L，而给予帕瑞肽LAR的患者为31％。生长抑素类似物治疗可以使20％的患者肿瘤体积缩小> 25％。这一比例在大腺瘤中更高，89例大腺瘤患者有63％（95％CI 52.0-72.9）的患者在PRIMARYS研究中肿瘤体积减少≥20％，在治疗头6个月内体积减少最快。已有报道使用奥曲肽的反应类似。然而，在使用生长抑素类似物治疗时，约1-2％的患者肿瘤体积增加，这种情况可能与肿瘤本身更具侵袭性的肿瘤行为有关。 Somatotroph tumours express somatostatin receptors (sst), predominantly sst2 and sst5 and less abundantly sst1 and sst3 . First (lanreotide, octreotide) and second generations (pasireotide) of somatostatin analogues are available (Supplementary Table 5) for treating acromegaly. In a recent study in treatment of naive patients, the PRIMARYS study (Lanreotide Autogel), normalisation of IGF-I combined with GH levels <2.5 μg/L was achieved in 27/63 (43.5%) of the patients. In a larger study of 358 medically naive patients, octreotide LAR was compared to pasireotide LAR, a multi-sst ligand acting on sst1–3 and particularly sst5. Normal IGF-I combined with GH levels <2.5 μg/L was achieved in 19% of the patients given octreotide LAR vs 31% given pasireotide LAR. Treatment with somatostatin analogues leads to tumour volume reduction by >25% in 20% of the patients. A higher proportion, 63% of 89 patients with macroadenomas (95% CI 52.0–72.9), achieved ≥20% tumour volume reduction in the PRIMARYS study, the maximal decrease occurring within the first six months. Similar responses have been reported using octreotide. An increase in tumour volume while on treatment with somatostatin analogues has been observed in 1–2% patients, and is related to more aggressive tumour behaviour. 据报道，GH受体拮抗剂培维索孟可以使63-93％的患者IGF-I正常化，效果取决于临床情况，而对肿瘤大小的影响则呈中性。在部分由生长抑素类似物控制的垂体瘤的情况下，与培维索孟联合应用可使大多数患者的IGF-I正常化。尽管多巴胺激动剂单独应用或与生长抑素类似物或培维索孟联合应用可能有潜在的获益，但没有前瞻性研究证明其对未选择或初始治疗患者的肿瘤生长的作用。 Pegvisomant, a GH receptor antagonist, is reported to normalise IGF-I in 63% and 93% of the patients depending on the clinical setting, whereas the effect on tumour size appears neutral. In the setting of a pituitary tumour partially controlled by somatostatin analogues, combination with pegvisomant could lead to IGF-I normalisation in most patients. Despite a potential benefit of dopamine agonist therapy alone or in additionto somatostatin analogue or pegvisomant, there are no prospective studies demonstrating its action on tumour growth in unselected or naive patients. 库欣病 Cushing’s disease 垂体ACTH瘤表达sst5受体，少数可表达sstr2和多巴胺受体（补充表5）。目前，帕瑞肽是唯一被批准用于治疗库欣病的垂体靶向药物。在一项对162名患者的研究中，26％使用帕瑞肽的患者UFC正常化。关于对肿瘤大小的影响的数据有限。多巴胺激动剂尚未被证实对垂体ACTH瘤的生长有任何作用。 Corticotroph tumours express sst5 receptors, and less frequently sstr2 and dopamine receptors (Supplementary Table 5). Pasireotide is presently the only drug targeting the pituitary that is approved for treatment of Cushing’s disease. In a study on 162 patients, pasireotide led to normalisation of UFC in 26% of the patients. There are limited data regarding the effect on tumour size. Dopamine agonists have not been confirmed to have any effect on corticotroph tumour growth. 促甲状腺素瘤 Thyrotroph tumours 垂体TSH瘤SSTR2高表达，因此超过90％的垂体TSH瘤对生长抑素类似物治疗有反应，73-100％的病例治疗后可恢复甲状腺功能状态，肿瘤大小缩小20-70％（补充表5）。多巴胺受体激动剂对该肿瘤的TSH分泌和肿瘤缩小的治疗反应各异，效果最好的是TSH/泌乳素混合分泌瘤。 Related to the high expression of SSTR2 in these tumours, more than 90% of thyrotroph tumours respond to somatostatin analogues with restoration of a euthyroid state in 73–100% of cases, and a reduction in tumour size in 20–70% (Supplementary Table 5). The response to dopamine agonists with regard to TSH secretion and tumour shrinkage has been variable, with best results in mixed thyrotroph/lactotroph tumours. 标准药物治疗抵抗 Resistance to standard medical treatment 多巴胺激动剂 Dopamine agonists 多巴胺受体激动剂的完全抵抗，定义为卡麦角林剂量增至3.5mg/周，催乳素仍不能正常化且肿瘤体积减低小于50%，约占泌乳素大腺瘤的10%。多巴胺耐药泌乳素瘤通常是侵袭性大腺瘤，根据一些研究提示这种大腺瘤有更多的血管生成和更显著的增殖。抵抗性肿瘤通常表达较少的多巴胺D2受体和ER受体;其他机制也已提出。 Complete resistance to dopamine agonists, defined as failure to normalise prolactin and a less than 50% decrease in size on doses of cabergoline up to 3.5 mg/week, represents less than 10% of macroprolactinomas. Dopamine-resistant lactotroph tumours often are invasive macroadenomas, and according to some studies are more angiogenic and more proliferative. The resistant tumours often express a lower number of dopamine D2 receptors and ER receptors; other mechanisms have been proposed. 此外，高剂量卡麦角林（高达11 mg /周）有报道可使大多数患者的催乳素正常化（补充表5）。建议侵袭性泌乳素瘤患者多巴胺激动剂可以使用到最高可耐受剂量。 Furthermore, high doses, up to 11 mg/week, have been shown to result in prolactin normalisation in most patients (Supplementary Table 5). It is proposed that the highest tolerated dose of dopamine agonist should be used in patients with aggressive prolactinomas. 生长抑素类似物 Somatostatin analogues 在肢端肥大症中，治疗抵抗（定义为完全缺乏生化和肿瘤反应）发生在少于10％的患者中。分子基础知之甚少。已经提出了几种机制，例如生长抑素受体（sst）的缺陷表达或遗传改变和信号转导受损。已经阐明了sst2 mRNA，蛋白表达和奥曲肽不能使GH降低之间的相关性。然而，个体差异较大，一些肿瘤高表达sst2，但对SSA治疗反应差....... In acromegaly, treatment resistance, defined as a complete lack of biochemical and tumour response, occurs in less than 10% of the patients. The molecular basis is poorly understood. Several mechanisms have been proposed, such as defective expression or genetic alterations of somatostatin receptors (sst) and impaired signal transduction. A correlation has been demonstrated among sst2 mRNA, protein expression and the GH-lowering response to octreotide. However, marked case-to-case variations among individual tumours have been found, and some tumours with high sst2 may show a poor response to SSA. Pituitary somatotroph adenomas from AIP mutation carriers are less responsive to sst2 analogues and recent data suggest that membranous sst2a are downregulated, whereas the expression of sst5 and the response to pasireotide are similar in AIP-sufficient and AIP-deficient tumours. Supplementary Table 5 补充表5 按照现行指南的建议，常规垂体靶向治疗功能垂体瘤的剂量。 Doses for conventional pituitary-directed treatment of functioning pituitary tumours, as suggested by current guidelines. 泌乳素瘤 Lactotroph tumours
生长激素瘤 Somatotroph tumours
垂体ACTH瘤 Corticotroph tumours
促甲状腺素瘤 Thyrotroph tumours
*在内分泌协会临床实践指南制定时可获得有限的数据，自获准用于肢端肥大症 * with limited data available at time of the development of the Endocrine Society Clinical Practice Guideline, but since being licensed for patients with acromegaly 3.4 侵袭性垂体瘤的药物治疗 3.4 Medical therapies in aggressive pituitary tumours 侵袭性垂体瘤通常对用于非侵袭性肿瘤的标准药物疗法反应不佳。然而，对于转移性疾病的单个患者，据报道非细胞毒性药物至少可以暂时降低肿瘤负荷，如两例泌乳素瘤应用溴隐亭和一例恶性转移瘤中应用高剂量的奥曲肽的报道。标准药物治疗不会阻止侵袭性促性腺激素/ NFPA肿瘤的生长。 Aggressive pituitary tumours usually respond poorly to the standard medical treatments used for non-aggressive tumours. However, in single patients with metastatic disease, non-cytotoxic drugs have been reported to, at least temporarily, reduce tumour burden, bromocriptine in two lactotroph tumours (92) and a high dose of octreotide in a malignant thyrotroph tumour (93). Standard medical treatments do not arrest growth of aggressive gonadotroph/NFPA tumours. 侵袭性皮质垂体ACTH瘤患者的发病率和死亡率主要与皮质醇过量有关。减少肾上腺糖皮质激素合成的药物的剂量应旨在实现皮质醇正常分泌。帕瑞肽在侵袭性ACTH瘤的应用中缺乏经验。有一例报道垂体ACTH大腺瘤双侧肾上腺切除术后患者ACTH降低并且鞍上肿瘤持续减小。在另外8例Nelson综合征患者中，尽管帕瑞肽可使大多数患者ACTH水平降低，但帕对肿瘤体积的影响很小（Daniel et al。，Abstract Endo 2016，OR 18-5）。在最近一份关于3例（其中1例癌）侵袭性非典型ACTH大腺瘤患者的报道中帕瑞肽无临床效果；而另一个报道，3例停用TMZ后复发的垂体ACTH瘤患者应用帕瑞肽无效。在双侧肾上腺切除术后，以及类固醇生成抑制剂治疗恢复正常皮质醇水平后，还有一些关于垂体ACTH瘤生长的报道。大腺瘤和侵袭性ACTH瘤患者的这种风险似乎更高。双侧肾上腺切除术在多大程度上可能引发侵略性行为仍然不得而知。垂体ACTH瘤本身的生物学特征可能是继续增长的主要决定因素。没有足够的证据推荐或反对以下情况：药物治疗、手术或放疗不能控制的皮质醇分泌过量的侵袭性垂体ACTH瘤患者进行双侧肾上腺切除术。 Morbidity and mortality in patients with aggressive corticotroph tumours are mostly related to cortisol excess. Drugs reducing adrenal glucocorticoid synthesis should be given in doses aiming at achieving eucortisolism. There is little experience with pasireotide in aggressive corticotroph tumours. A single patient with a large corticotroph tumour following bilateral adrenalectomy had a lowering of ACTH and sustained reduction of the suprasellar tumour (94). In another eight patients with Nelson’s syndrome, pasireotide had minimal effects on tumour volume, in spite of reductions in ACTH levels in most patients (Daniel et al., abstract Endo 2016, OR 18-5). In a recent report on three patients with aggressive atypical corticotroph macroadenomas, of which one was a carcinoma, pasireotide was not clinically useful (95), and in three patients with recurrent corticotroph tumour after discontinuation of TMZ, pasireotide had no effect (12). There are several reports of corticotroph tumour growth after bilateral adrenalectomy, as well after achieving eucortisolism after treatment with steroidogenic inhibitors (96). This risk seems higher in patients with macroadenomas and aggressive corticotroph tumours (97, 98). To what extent bilateral adrenalectomy might trigger aggressive behaviour remains unknown. The biology of the corticotroph tumour per se might be the major determinant of continued progressive growth. There is not sufficient evidence to recommend or recommend against bilateral adrenalectomy in patients with aggressive corticotroph tumours in whom cortisol excess cannot be controlled by pharmacotherapy, surgery and radiotherapy. R 3.4.1 推荐使用替莫唑胺（TMZ）单一疗法作为侵袭性垂体肿瘤和垂体瘤的一线化疗，追踪记录的肿瘤生长（++ 00）。 R 3.4.1 We recommend use of temozolomide monotherapy as first-line chemotherapy for aggressive pituitary tumours and pituitary carcinomas, following documented tumour growth (++00). R 3.4.2 我们建议在3个周期后首先评估治疗反应。如果证明有放射学进展，应停止替莫唑胺治疗（++ 00）。 R 3.4.2 We recommend first evaluation of treatment response after 3 cycles. If radiological progression is demonstrated, temozolomide treatment should be ceased (++00). R 3.4.3 我们推荐使用标准剂量方案：每28天连续5天使用150-200 mg / m2（+000）。 R 3.4.3 We recommend use of the standard dosing regimen: 150–200 mg/m2 for 5 consecutive days every 28 days (+000). R 3.4.4 我们建议监测血液学参数，肝功能检查和治疗期间潜在不良反应的仔细临床观察（+++ 0）。 R 3.4.4 We recommend monitoring of haematological parameters, liver function tests and careful clinical observation for potential adverse effects during treatment (+++0). R 3.4.5 我们建议，在尚未达到最大剂量放疗的肿瘤生长迅速的患者中，将替莫唑胺与放疗（Stupp方案）联合应用（+000）。 R 3.4.5 We suggest, in patients with rapid tumour growth in whom maximal doses of radiotherapy have not been reached, combining temozolomide with radiotherapy (Stupp protocol) (+000). R 3.4.6 我们建议应该由神经病理学专家通过免疫组织化学评估MGMT状态。高MGMT表达暗示缺乏反应; 但是，仍可能有例外（++ 00）。 R 3.4.6 We suggest that evaluation of MGMT status by immunohistochemistry by an expert neuropathologist should be performed. High MGMT expression is suggestive of a lack of response; however, there may be exceptions (++00). R 3.4.7 在一线替莫唑胺治疗的患者中，如在3个周期后评估有反应，我们建议治疗至少持续6个月，如果持续治疗有益，考虑更长的持续时间（+000）。 R 3.4.7 In patients responding to first-line temozolomide, as assessed after 3 cycles, we suggest treatment to be continued for at least 6 months in total, with consideration for longer duration if continued therapeutic benefit is observed (+000). R 3.4.8 在替莫唑胺治疗中肿瘤进展迅速的患者中，我们建议使用其他系统性细胞毒治疗进行试验。鉴于已报道多种化学治疗药物，我们不能建议特定的治疗方案（+000）。 R 3.4.8 In patients with rapid tumour progression on temozolomide treatment, we suggest a trial with other systemic cytotoxic therapy. Given the variety of chemotherapeutic agents that have been reported, we cannot suggest a particular regimen (+000). R 3.4.9 对于替莫唑胺治疗有反应，后出现复发的患者，我们建议进行3个替莫唑胺周期的第二次试验（+000）。 R 3.4.9 In patients who develop a recurrence following response to temozolomide treatment, we suggest a second trial of 3 cycles of temozolomide (+000). 2006年，有三个研究报道了4例提莫唑胺治疗有效的难治性垂体腺瘤。2010-2016年相继有11个报道至少3例以上的提莫唑胺治疗研究（图1）。总病例数达到106例。其中34例为垂体癌，其他侵袭性垂体瘤。 图1 Figure 1 Meta-analysis of treatment effect in aggressive pituitary tumours and carcinomas. 替莫唑胺治疗方法为150-200mg/m2，连用5天，休息23天（共4周）。尽管上述肿瘤类型、治疗和随访时间计划不同，但整体有效（肿瘤体积缩小甚至消失）率47%（95%CI 36-58）。上述病例中，提莫唑胺最常见的并发症是乏力（60%）、恶心呕吐（33%）及骨髓抑制（31%）。一般通过降低剂量或延迟治疗周期，患者可以缓解而继续治疗。最严重的并发症是骨髓抑制和肝功能损害。因此应用经典方案需要在没疗程第22天查血常规，如果中性粒低于1.5x10￥9/L或血小板低于100 X 10$9/L需要停药。直到中性粒细胞核血小板恢复到上述标准之上，才能重新开始新的治疗周期。因此建议，次药物治疗的患者2周需复查血常规。 3.5 转移性疾病的局部治疗 3.5 Local treatment of metastatic disease R 3.5.1 对于孤立转移患者，我们建议考虑局部区域治疗，不影响（独立于）是否需要全身治疗的决定（+000）。 R 3.5.1 In patients with isolated metastases, we suggest consideration of loco-regional therapies, independent of decisions regarding the need for systemic treatment (+000). 4.侵袭性垂体瘤随访 4. Follow-up of an aggressive pituitary tumour R 4.1 我们建议根据之前的肿瘤生长速度和/或肿瘤位置（接近重要结构），每3-12个月进行一次影像检查（在大多数情况下用MRI）（+000）。 R 4.1 We recommend that imaging (MRI in most instances) is performed every 3–12 months as guided by prior tumour growth rate and/or location of tumour (proximity to vital structures) (+000). R 4.2 建议根据临床情况每3-12个月进行一次全内分泌评估（+000）。 R 4.2 We recommend that full endocrine evaluation should be performed every 3–12 months as guided by the clinical context (+000). R 4.3 我们建议对侵袭性垂体瘤患者进行终生随访（++ 00）。 R 4.3 We recommend lifelong follow-up of patients with aggressive pituitary tumours (++00). CK认证规范 @CK医学科普 权威规范 @CK医学科普 内分泌代谢病规范化诊治 @CK医学科普 欢迎个人转发，如转载请注明出处及二维码 下丘脑垂体相关 l 系列
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CK医学科普
