儿童和青少年垂体瘤的临床诊治分析

目的 探讨儿童和青少年垂体瘤患者的临床资料和诊治特点。方法 回顾性分析1989年至2010年收治的74例儿童和青少年垂体腺瘤患者的病历资料。结果 74例患者中46例（62.2％）发病于青春后期,平均发病年龄17.7岁;男女比例1∶1.85;肿瘤直径0.4～6.0cm;海绵窦侵袭性肿瘤24例（2.4％）;泌乳素瘤、无功能腺瘤、促肾上腺皮质激素腺瘤及生长激素腺瘤分别为43例（58.1％）、16例（21.6％）、10例（13.5％）和5例（6.8％）。24例海绵窦侵袭肿瘤患者中,男性14例,女性10例;43例泌乳素瘤患者男性9例,女性34例。74例患者最常见的临床表现为内分泌症状和视力障碍。所有患者均经手术治疗,术前仅9例患者曾接受多巴胺激动剂治疗,术后部分患者行多巴胺受体激动剂治疗和放疗,49例获随访,6例患者复发后再次手术治疗。32例视力障碍患者中有29例术后恢复正常或改善。结论 儿童和青少年垂体瘤患者好发于青春后期,各类型肿瘤中男女发病比例不同。在儿童和青少年垂体瘤患者中需普及多巴胺受体激动剂治疗,多巴胺受体激动剂、手术及必要时予以放疗可使患者达到良好的治疗效果。     

McCune–Albright syndrome: surgical and therapeutic challenges in GH-secreting pituitary adenomas

McCune–Albright syndrome (MAS) is a postzygotic (non-germline) disorder characterized by polyostotic fibrous dysplasia, cafe-au-lait macules and hypersecretory endocrinopathies. A significant percentage of MAS patients have pituitary adenomas that are either growth hormone (GH) or mixed GH/prolactin (PRL)-producing. Surgical excision may be challenging—or even impossible—due to the associated severe fibrous dysplasia of the skull base. Treatment relies on an interdisciplinary, multi-modal approach from endocrinologists, neurosurgeons and radiation oncologists. We present two cases of women with MAS and GH-secreting pituitary adenomas, encountered in our 30-year experience with pituitary diseases. The first patient successfully underwent transsphenoidal surgical resection for a pituitary microadenoma in 1997 (at age 18) and again in 2009 for recurrent disease, with a significant reduction in IGF-1 level. Immunohistochemistry (IHC) and electron microscopy (EM), performed on both specimens, showed a mammosomatotroph adenoma with GH, PRL, alpha subunit (+) IHC, with increased fibrous bodies developing over the 13-year interval. Focal hyperplasia could be discerned. EM in 1997 showed an admixture of mammosomatotrophs, mature lactotrophs and somatotrophs, with a bimodal population identified in 2009. The second MAS patient had long-standing polyostotic fibrous dysplasia, but was only recently diagnosed with GH excess and a pituitary adenoma, at the age of 29 years. Surgical resection was not advised in this patient because of the massive obstructive skull-base fibrous dysplasia. Medical therapy was initiated with somatostatin analogues, although responses in both patients have been suboptimal to date. We review the literature on GH excess in MAS to highlight its surgical and medical challenges.     

Pituitary adenomas in old Sprague-Dawley rats: a histologic, ultrastructural, and immunocytochemical study

Fifty-five adenomas were identified and characterized in the anterior pituitaries of 27 male and 39 female SD rats, over 24 months of age, by histology, ultrastructural morphology, and immunocytochemistry. Adenomas were found in 85% of male and 79% of female rats; all known adenohypophysial hormones were represented in various tumors. Prolactin (PRL)-containing adenomas were the most common (47.2%); luteinizing hormone-(LH)-containing adenomas (16.3%), immunonegative adenomas (12.7%), PRL- and growth hormone (GH)-containing adenomas (10.9%), thyroid-stimulating hormone (TSH)-containing adenomas (3.6%), adrenocorticotropin hormone (ACTH)-containing adenomas (3.6%), and GH-containing adenomas (1.8%) were also identified. Unexpected combinations were observed in 3 tumors (5.4%); a GH-LH-containing adenoma, a PRL-ACTH-containing adenoma, and a PRL-LH-TSH-containing adenoma were noted. One intermediate lobe adenoma and 1 metastatic plasmacytoma were diagnosed. It can be concluded that spontaneous pituitary adenomas in aging SD rats are potential models of the human disease because of diversity of hormone content and morphologic appearance.     

Immunohistochemical detection of human Natural Killer cell like immuno-reactivity in human pituitary adenomas,using monoclonal antibody NK-1

Natural killer (NK) cells are specialized lymphocytes which arecharacterized as non-T and non-B cells, as they lack classic T and B cellsurface markers. Recently, NK like immunoreactivity has been identified inendocrine and neuronal tissues as well as in the tumors derived from theneuroectoderm and neuroendocrine system. We examined the expression of NK-1like immunoreactivity in 6 normal pituitary glands and in 55 cases ofneoplastic pituitaries (16 growth hormone (GH) producing adenomas, 14prolactin (PRL) producing adenomas, 4 thyrotropin (TSH) producing adenomas,5 adrenocortocitropin (ACTH) producing adenomas and 16 non-functioningadenomas) immunohistochemically. The expression of the S-100 protein, whichis a marker for folliclo-stellate (FS) cells, which have been reported tosecrete cytokines as immuno-endocrine modulators, were also examined. Innormal pituitary glands, NK-1 was detected in all 6 tissues in the cytoplasmof about 5–10% of the anterior pituitary cells. By serialsectioning and double immunostaining, NK-1 immunopositivity was frequentlyfound to be localized in ACTH cells. The colocalization with other anteriorpituitary hormones such as GH, PRL, the beta-subunit of luteinizing hormone(LH), follicle stimulating hormone (FSH), TSH and-subunit of glycoprotein (SU) was not observed. The S-100immunopositive FS cells, which were scattered among hormone producing cells,were closely associated with NK-1 immunoreactive cells in the normalpituitaries. Among the 55 cases of pituitary adenomas, NK-1 was present inall the types of pituitary tumors, and a total of 33 (60.0%)contained NK-1 positive tumor cells. The frequency of NK-1 immunoreactivityin the individual adenoma types was; 14 of 16 GH producing adenomas(87.5%), 7 of 14 PRL producing adenomas (50%), 3 of 4 TSHproducing adenomas (75%), 3 of 5 ACTH producing adenomas(60%), and 5 of 16 nonfuctioning adenomas (31.3%). By doubleimmunostaining, NK-1 was found to be frequently colocalized with ACTH inACTH producing adenomas, and was colocalized with PRL in PRL producingadenomas, or with GH, PRL or the -subunit in GH producing adenomacells. NK-1 immunoreactive cells were observed in close association withS-100 immunopositive FS cells in the adenomas. Our results may indicate thatNK-1 positive cells may have functions as a paracrine modulators of theirneighboring cells, which includes S-100 positive FS cells.     

垂体腺瘤术后免疫组化分型与术前激素水平相关性研究

目的:回顾性分析垂体腺瘤手术患者病理免疫组化染色结果与术前相关激素水平的相关性。方法:收集自2011年1月至2016年12月在青岛大学附属医院行手术治疗的垂体腺瘤患者189例,术前行影像学检查、垂体相关激素测定,术后行病理免疫组化染色。采用SPSS 17.0软件进行统计学分析,采用双变量相关分析中的Spearman分析判断两种变量之间的关联性,通过Kappa值判断术前激素水平与病理诊断的一致性。P＜0.05差异有统计学意义。结果:189例垂体腺瘤患者,＞40~60岁组构成比明显高于≤20岁、＞20~40岁、＞60~80岁各组（60.8% vs 1.1%、22.8%、15.3%,均P＜0.05）;大腺瘤明显多于微腺瘤和巨大腺瘤（86.5% vs 4.7%、8.8%,P＜0.05）;PRL瘤血清PRL程度与肿瘤直径呈正相关（r=0.530,P＜0.05）。GH瘤血清GH水平与肿瘤直径呈正相关（r=0.629,P＜0.05）,与年龄呈负相关（r=-0.715,P＜0.05）;垂体PRL瘤、GH瘤血清学诊断与术后免疫组化染色诊断的符合率分别为85.5%、78.9%,Kappa系数分别为0.688、0.465,说明两种诊断的一致性好;以PRL＞100 ng/mL作为PRL瘤的血清学诊断标准时,其与免疫组化染色诊断的符合率和Kappa系数最高,为81.9%和0.517。结论:手术的垂体腺瘤中以大腺瘤为主,好发年龄＞40~60岁。血清PRL、GH水平均与肿瘤直径呈正相关;GH水平与年龄呈负相关。垂体腺瘤临床血清学诊断与病理免疫组化诊断有一致性,以PRL瘤、GH瘤的一致性为最高。PRL＞100 ng/mL可以作为诊断PRL瘤的血清学参考值。     

206例垂体腺瘤的免疫组化,电镜及内分泌特征的研究

本文采用免疫组化及电镜观测分析了206例垂体腺瘤,根据激素分泌及超微结构特征将肿瘤分为11类.其中泌乳素腺瘤最常见(35.92%);其次是生长激素腺瘤(19.42%);零细胞腺瘤(16.50%)等.本文借助流式细胞术DNA分析研究了38例术后复发的垂体腺瘤后认为:嗜酸性干细胞腺瘤和伴Nelson综合征的促肾上腺皮质激素腺瘤有术后复发的倾向;此外,侵袭性生长的腺瘤和流式细胞术测定时DNA含量较高的DNA异倍体腺瘤的恶性度相对较高,术后易于复发.     

侵袭性垂体腺瘤的组织学与临床预后的关系

目的分析经蝶窦入路切除的侵袭性垂体腺瘤的组织学侵袭性与临床预后的关系。方法我科自2000年1月-2003年5月行经蝶手术切除的具有完整影像学、病理学和随访资料的侵袭性垂体腺瘤82例,其中PRL 腺瘤39例,GH腺瘤13例,ACTH腺瘤6例,无功能腺瘤24例,随访时间5-30个月。结果侵袭性垂体腺瘤MRI影像学特点为鞍底受侵下陷,部分肿瘤突入蝶窦;颈内动脉包绕;海绵窦受累,鞍隔突破等,病理检查以鞍底硬膜浸润的发生率最高,并有20例(24.4%)发现有肿瘤内卒中或出血。PRL腺瘤的全切率明显低于无功能腺瘤(P<0.01), 而无功能腺瘤、GH腺瘤与AcTH腺瘤之间相差不明显。PRL腺瘤的复发率较无功能腺瘤和GH腺瘤高(P<0.05)。结论侵袭性垂体腺瘤中,无功能腺瘤与GH腺瘤的治疗效果优于PRL腺瘤,垂体腺瘤的侵袭性生物学行为导致手术全切机率下降,是术后复发的丰要原因。     

醋酸兰瑞肽辅助伽玛刀治疗生长激素型垂体腺瘤的临床疗效及对生长激素和胰岛素样生长因子1水平的影响

目的探讨醋酸兰瑞肽辅助伽玛刀治疗生长激素(GH)型垂体腺瘤的临床疗效及对GH和胰岛素样生长因子1(IGF1)水平的影响。方法依据治疗方案的不同将65例GH型垂体腺瘤患者分为对照组(n=32)和观察组(n=33),对照组患者采用伽玛刀进行治疗,观察组患者在对照组的基础上联合使用醋酸兰瑞肽辅助治疗。比较两组患者治疗后的临床疗效和内分泌学疗效,比较治疗前及治疗后两组患者的血清GH和IGF1水平,并记录两组患者的不良反应发生情况。结果治疗后,观察组患者的临床疗效和内分泌学疗效均明显优于对照组,差异均有统计学意义(P﹤0.01)。治疗后,两组患者的血清GH和IGF1水平均低于本组治疗前,且观察组患者的血清GH和IGF1水平均低于对照组,差异均有统计学意义(P﹤0.05)。两组患者的不良反应发生率比较,差异无统计学意义(P﹥0.05)。结论与单独应用伽玛刀治疗相比,醋酸兰瑞肽辅助伽玛刀治疗GH型垂体腺瘤的临床疗效较好,且可降低患者的血清GH和IGF1水平。     

Immunohistochemistry as a predictor of clinical outcome in patients given postoperative radiation for subtotally resected pituitary adenomas

Summary There is general agreement that postoperative radiation therapy is beneficial for patients with subtotally resected pituitary adenomas. We have identified 41 such patients treated during a 20-year period who received postoperative irradiation for a pituitary adenoma. The usual dose was 5040 cGy in 28 fractions. The mean follow-up time was 10.3 years. On routine hematoxylin and eosin (H&E) staining, there were thirty-three chromophobe, seven eosinophilic, and one basophilic adenoma. Tissue blocks were stained for growth hormone (GH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH), prolactin (PRL), and/or adrenocorticotropin ACTH) using the peroxidase-antiperoxidase immunohistochemistry (IHC) method. Routine H&E staining was a poor predictor of the IHC stain. While most patients with a known clinical endocrine syndrome stained positive on IHC for the suspected offending hormone, many patients without a clinical syndrome also stained positive indicating the presence of hormonally occult adenomas in this locally invasive group. The IHC stain results were compared to clinical outcome. The presence of positive GH IHC staining decreased the 15-year progression-free survival (PFS) from 100% to 64% compared to GH negative adenomas (p=0.06). There was a trend toward decreased 15-year PFS in patients who did not stain for LH. Positive staining for prolactin, ACTH, or TSH had no influence on the progression-free survival. We conclude that additional prognostic information can be obtained in this subset of patients (by performing IHC analysis) that is not known by the clinical presentation or appearance on H&E stain.Supported by the American Cancer Society Clinical Oncology Career Development Award.     

Stereotactic conformal radiotherapy in patients with growth hormone-secreting pituitary adenoma

PURPOSE: To evaluate the reduction of hormonal overproduction and side effects as well as survival rates after fractionated stereotactic conformal radiotherapy (FSRT) and radiosurgery in patients with growth hormone (GH)-secreting pituitary adenoma. METHODS AND MATERIALS: Between January 1989 and May 2001, 25 consecutive patients were treated with FSRT (n = 20) or radiosurgery (n = 5) for GH-secreting pituitary adenoma. Nine patients were treated for recurrent disease after primary surgery. One patient had primary radiotherapy because of inoperability, and 15 patients received radiotherapy after subtotal resection due to increased GH level. Median total dose was 52.2 Gy for FSRT and 15 Gy for radiosurgery. RESULTS: Radiologic local tumor control was 100% after a median follow-up of 59.8 months (range, 20.3-168.2 months). Seventeen patients had stable disease on CT/MRI, and eight showed a reduction of tumor volume on MRI scans. Endocrinologic control was 92% (23 of 25 patients). Two patients had an endocrinologic recurrence 21 and 54 months after FSRT. A normalization of preexisting acromegalic symptoms was seen in 1 patient, 4.5 years after FSRT. GH level normalized in 21 of 25 patients after 26 months median. Five of these patients underwent concurrent Octreotid therapy because of increased insulin-like growth factor I levels. Improvement of visual acuity was seen in 1 patient. New onset of clinically evident hypopituitarism as an adverse reaction of stereotactic radiotherapy was only infrequently observed in this series. CONCLUSION: Stereotactic conformal radiotherapy is effective and safe in the treatment of GH-secreting pituitary adenoma to reduce hormonal overproduction and to improve local control. It is an alternative option to surgery especially for patients at high risk of surgical complications due to comorbidity.     

Radiation Therapy Alone for Growth Hormone-Producing Pituitary Adenomas

We present our experience in the treatment of growth hormone (GH)-producing pituitary adenomas using irradiation alone. Between 1983 and 1991, 21 patients suffering from GH-secreting pituitary adenomas were treated with radiotherapy alone. Two bilateral opposing coaxial fields were used in 10 patients and in the remaining 11 a third frontovertex field was added. Treatment was given in 1.8-2 Gy daily fractions and total dose ranged between 45 and 54 Gy. Treatment was given using a cobalt unit. Four patients treated with somatostatin prior to and 14 patients treated after the end of radiotherapy experienced symptom relief for 6-28 weeks. The 5-year actuarial rate of disease control was 72%. Five out of six failed patients had macroadenomas. Hypopituitarism was observed in 5/21 (24%) patients. Whereas RT alone is effective in the treatment of microadenomas, this is not true for large infiltrative macroadenomas.     

侵袭性垂体腺瘤的组织学与临床预后的关系(英文)

目的分析经蝶窦入路切除的侵袭性垂体腺瘤的组织学侵袭性与临床预后的关系。方法我科自2000年1月～2003年5月行经蝶手术切除的具有完整影像学、病理学和随访资料的侵袭性垂体腺瘤82例,其中 PRL腺瘤39例,GH 腺瘤13例,ACTH 腺瘤6例,无功能腺瘤24例,随访时间5～30个月。结果侵袭性垂体腺瘤 MRI 影像学特点为鞍底受侵下陷,部分肿瘤突入蝶窦;颈内动脉包绕;海绵窦受累,鞍隔突破等,病理检查以鞍底硬膜浸润的发生率最高,并有20例(24.4%)发现有肿瘤内卒中或出血。PRL 腺瘤的全切率明显低于无功能腺瘤(P<0.01),而无功能腺瘤、GH 腺瘤与 ACTH 腺瘤之间相差不明显。PRL 腺瘤的复发率较无功能腺瘤和 GH 腺瘤高(P<0.05)。结论侵袭性垂体腺瘤中,无功能腺瘤与 GH 腺瘤的治疗效果优于 PRL 腺瘤,垂体腺瘤的侵袭性生物学行为导致手术全切机率下降,是术后复发的主要原因。     

高风险垂体腺瘤的临床病理特征

  目的  探讨高风险垂体腺瘤的临床病理特征及诊断要点。  方法  选取2017年6月至2020年9月北京大学国际医院收治的24例高风险垂体腺瘤患者,进行形态学观察、免疫组织化学染色及基因检测,同时收集患者的临床资料并进行随访,综合分析病理特点与临床特征的相互关系。  结果  24例高风险垂体腺瘤中男性14例,女性10例,发病年龄28～68岁,平均年龄45.4岁,临床表现为鞍区占位或激素分泌异常的症状。肿瘤最大径0.7～4.8 cm,影像学提示侵袭性腺瘤12例。根据固有激素、转录因子和低分子量角蛋白的免疫组织化学染色特点,结合临床症状及血清激素水平进行诊断,其中稀疏颗粒型生长激素细胞腺瘤4例,沉默性促肾上腺皮质激素细胞腺瘤12例,男性泌乳激素细胞大腺瘤6例,多激素PIT-1阳性腺瘤2例。基因检测1例存在GNAS基因突变。14例获得随访资料,2例复发（其中1例因肿瘤复发死亡）。  结论  高风险垂体腺瘤的诊断应该结合免疫组织化学、血清激素水平及临床症状综合分析,并且需要提示临床复发和进展的风险。      

应用神经导航辅助技术在内镜下切除伴有甲介、鞍前型蝶窦的垂体腺瘤

背景与目的：多数学者认为伴有甲介、鞍前型蝶窦的垂体腺瘤不适合内镜下切除．但应用神经导航辅助技术可以克服其在内镜下手术的缺陷。本文着重探讨应用神经导航辅助技术在内镜下切除伴有甲介、鞍前型蝶蜜的垂体腺瘤。方法：回顾性分析我院自2004年10月至2008年10月应用神经导航技术对伴有甲介、鞍前型蝶窦变异的垂体瘤进行内镜下单鼻孔手术21例。其中生长激素腺瘤4例．高泌乳素腺瘤6例,促肾上腺皮质激素腺瘤7例,无功能性腺瘤4例。蝶窦冠状CT及蝶窦X线平片提示蝶窦形态,甲介型9例。鞍前型12例。术前行头部CT、MRI扫描,术中神经导航定位,在内镜下经单鼻孔切除肿瘤。结果：术后随访6．24个月,术前症状（视力受损、尿崩症）均在术后消失,血液、内分泌指标均在正常范围内。术后随访1年以上的病例（17例）复查MRI均提示未见肿瘤残留或复发。术后所有病例均未出现颅内出血、视力、视野障碍、尿崩、脑脊液漏、颅内感染等并发症。结论：对于伴有甲介、鞍前型蝶窦变异的垂体瘤手术．应用神经导航辅助内镜能确保术中定位准确,术野大且直观。有利于切除肿瘤．并保护周围重要结构．     

Cytocidal effects of bromocriptine, somatostatin analog, and heat on growth hormone-secreting pituitary adenoma in vitro.

The effects of bromocriptine (BC), a somatostatin analog (SMS), and heat on the secretion of growth hormone (GH) and prolactin (PRL), and on the morphologic features of human GH-secreting pituitary adenoma were studied in vitro. The treatment with BC, SMS, or heat (41.5 degrees C and 42.5 degrees C) markedly suppressed the secretion of GH and PRL from the adenoma cells and reduced the number of cells immunoreactive with GH or PRL. The combined treatment with BC and heat induced a marked reduction in the number of GH and PRL cells consistent with the effect on the secretion of GH and PRL. These results suggest that BC, SMS, and heat treatments produced the cytotoxic effects on pituitary adenoma cells, and that the simultaneous treatment of BC and heat enhanced this effect.     

垂体腺瘤的手术治疗：单中心508例临床总结

目的总结垂体腺瘤I临床特征、手术策略及术后并发症。方法回顾性分析2010年1月至2012年12月期间南京医科大学第一附属医院收治的508例垂体腺瘤的临床特征,比较经蝶窦人路与开颅手术的治疗效果及相关并发症。结果垂体腺瘤男女发病比为1：1．32,发病高峰年龄为31～60岁,占70．5％。垂体腺瘤激素类型以泌乳素腺瘤、生长激素腺瘤及无内分泌功能腺瘤居多。93．5％的术式为经蝶窦入路。经蝶窦入路垂体腺瘤手术全切率为85．2％,术后7天症状缓解率88．8％,术后5天激素水平明显好转率87．0％。结论经蝶窦人路手术已取代开颅手术成为垂体腺瘤切除术的首选方法。     

51例垂体腺瘤体外培养和免疫组化的研究

对51例垂体腺瘤手术标本进行体外培养和免疫组化研究。结果显示垂体腺瘤细胞体外培养有分泌功能.成活率达88％。血清激素水平高,免疫组化呈阳性的腺瘤细胞分泌激素一般也多。部分无功能腺瘤细胞也具有分泌功能,与免疫组化阳性程度不成正比。除催乳素腺瘤外,大多数腺瘤可同时分泌两种激素。实验结果提示细胞培养结合免疫组化、血清激素水平和临床症状,可以对垂体腺瘤作出形态与功能统一的、较完善的分类,有助于临床诊断和治疗。     

Neural cell adhesion molecule expression in human pituitary adenomas

Neural cell adhesion molecule (NCAM) is a cell surface glycoprotein whose expression may be important in metastatic or local growth of neoplasms. Expression of NCAM in human pituitary adenomas was assessed on snap-frozen and Bouin's and/or formalin-fixed, paraffin-embedded archival tissue using a sensitive alkaline phosphatase-antialkaline phosphatase method of immunostaining with the monoclonal antibody, NKH-1.The 20 pituitary adenoma patients consisted of 13 males and 7 females, ages 19–78 years, with null cell macroadenomas (3), plurihormonal macroadenomas (4), weak gonadotropic macroadenomas (5), growth hormone-prolactin adenomas (2), and prolactinomas (6). Eight of the adenomas were clinically invasive. The snap-frozen material from 14 pituitary tumors showed immunostaining for NCAM in either a cytoplasmic, peripheral membranous, or mixed pattern; 2 of 3 prolactinomas showed patchy immunostaining. The Bouin's and/or formalin-fixed pituitary adenoma specimens from 6 clinically invasive cases showed less distinct NCAM localization but 4 out of 6 showed diffusely positive NCAM immunostaining, with greatest intensity appreciated on the Bouin's-fixed tissue. There was no correlation between NCAM staining pattern and invasive characteristics of the tumors. These results suggest that NCAM expressivity is not a useful marker for assessing pituitary adenoma tumor invasiveness.