垂体瘤处理

Pituitary Adenomas(Macroadenomas),浙医二院内分泌科 任跃忠,2010 12 11,Pituitary Macroadenomas,The sellar蝶鞍region is a site of various types of tumors. Pituitary adenomas are the most common and account for 10-15% of all intracranial tumors. Tumors exceeding 10 mm are defined as macroadenomas, and those smaller than 10 mm are termed microadenomas. Most pituitary adenomas are microadenomas.,Pathophysiology,Pituitary macroadenomas are benign epithelial neoplasms composed of adenohypophysial cells. Primary malignant tumors of the pituitary are extremely rare. Pituitary tumor development is a monoclonal process with several contributing factors. arise from a mutated pituitary cell. remain unknown.Some pituitary tumors may occur as part of a clinical syndrome. Inmultiple endocrine neoplasia type 1 (MEN 1).,Frequency,United StatesPituitary tumors are found on autopsy in as many as 25% of unselected cases. The annual incidence of pituitary neoplasms varies from 1-7 cases per 100,000 population based on neurosurgical series.Mortality/MorbidityMorbidity in pituitary macroadenomas varies from incidentally discovered nonfunctioning tumors to disabling macroadenomas. Morbidity results from mass effects (eg, bitemporal hemianopsia双颞侧偏盲), hormonal imbalance (pituitary hormone deficiency due to compression of the normal pituicytes or hormonal excess from the tumor), and patient comorbidities. Significant morbidity is also associated with treatment of these tumors.,RaceNo racial predilection exists for pituitary macroadenomas.SexAutopsy series show an equal distribution of pituitary tumors between men and women. Corticotropinomas . mainly in women, . 4:1. . Amenorrhea (or menstrual irregularities), which is a relatively common symptom in women with macroadenomas, raises the suspicion of a pituitary lesion.AgeTumors affect individuals of all ages, but incidence increases with age, peaking between the third and sixth decades of life.,Clinical,HistoryPatients with pituitary macroadenomas may be asymptomatic or may present with complaints due to hormonal imbalance or mass effects.Pituitary hormone effects depend on the hormones involved. Panhypopituitarism spared. The larger the tumor, the more likely it is to involve most hormones. . The most sensitive are the somatotrophs and the gonadotrophs, whereas corticotrophs and thyrotrophs tend to be more resistant. Hyperprolactinemia presents with hypogonadism, infertility不育, amenorrhea, and galactorrhea乳溢. Hyperprolactinemia can be due to increased hormone production by a prolactinoma, or it can be the result of stalk compression by the macroadenoma regardless of hormone activity. .,Corticotropin excess presents with Cushing disease. Corticotropinomas are rarely macroadenomas. Corticotropin suppression due to compression of the normal corticotrophs presents with glucocorticoid insufficiency. The clinical picture of secondary glucocorticoid deficiency is much milder than .Thyrotropin excess presents with secondary hyperthyroidism. Thyrotropinomas are very rare tumors. They present most frequently as macroadenomas. . naturally aggressive . presents with secondary hypothyroidism. Excess growth hormone presents with acromegaly as the result of a somatotropinoma (often a macroadenoma), while inadequate growth hormone presents with failure to thrive in children but often no complaints in adults.,Gonadotropinomas most often are asymptomatic and usually secrete inactive follicle-stimulating hormone (FSH) and luteinizing hormone (LH)-like glycoproteins and/or alpha subunit. They often are macroadenomas and usually result in hypopituitarism. Rarely, they can lead to testicular enlargement in men and ovarian hyperstimulation in women. Mass effects of the macroadenoma may present with visual deficits, headache, elevated intracranial pressure, or intracranial hemorrhage.,Pituitary apoplexy垂体卒中 as a medical emergency with a headache, sudden collapse暴脱, shock, and death if not treated emergently. This tends to occur in macroadenomas. Administration of stimulatory agents, such as thyroid-stimulating hormone TSH, gonadotropin-releasing hormone (GnRH), and insulin-hypoglycemia, have been postulated to lead to increased metabolic needs by the macroadenoma (which has deficient blood supply), leading to necrosis. Nelson syndrome results from treatment of Cushing disease with bilateral adrenalectomy. The lack of negative glucocorticoid feedback is postulated to lead to excessive tumor growth. Such tumors are much more aggressive and locally invasive compared to the usual corticotroph adenomas,PhysicalMost patients do not have physical findings associated with macroadenomas. Physical findings may be attributable to the mass effects or hormonal disruption. When the tumor extends onto the optic chiasm视交叉, visual field deficits may be demonstrable. Sudden increase in tumor size, such as can occur with hemorrhage, may lead to elevated intracranial pressure. Hormonally active tumors might present with symptoms due to target organ stimulation, such as hyperthyroidism, Cushing syndrome, or hyperprolactinemia.CausesThe cause of pituitary macroadenomas is unknown. The most favored theory attributes monoclonal neoplastic transformation of pituitary cells as the cause of tumor initiation and growth.,Differential Diagnoses,TuberculosisOther Problems to Be Considered Lymphocytic hypophysitis淋巴细胞性垂体炎Pituitary hyperplasia (as in pregnancy, longstanding hypothyroidism, and ectopic hypothalamic factor production, such as corticotropin-releasing hormone CRH or growth hormonereleasing hormone GHRH)Metastatic tumorsGerminomas生殖细胞瘤Granulomatous disease肉芽肿病 (eg, tuberculosis, syphilitic gumma梅毒性树胶肿, sarcoidosis肉状瘤病)Vascular aneurysms动脉瘤Craniopharyngiomas颅咽管瘤Histiocytosis-x组织细胞增多病 Tumors of the clivus斜坡 (eg, chordomas脊索瘤),Workup-Laboratory Studies,Laboratory tests include basal hormone levels and dynamic hormone measurements depending on the tumor studied. All tumors should have screening basal hormone measurements, which may include prolactin, thyrotropin, thyroxine, adrenocorticotropin, cortisol, LH, FSH, estradiol, testosterone, growth hormone, insulinlike growth factor-1 (IGF-1), and alpha subunit glycoprotein. Dynamic hormone tests are performed to assess the functionality of a tumor and assist in differential diagnosis. They also can be used to assess anterior pituitary reserve. Thyrotropin-releasing hormone (TRH) causes elevation of serum prolactin and thyrotropin. Prolactinomas, hyperprolactinemic states, hyperthyroidism, and panhypopituitarism exhibit a blunted response.,GHRH produces an elevation in growth hormone. This response is blunted in growth hormone deficiency, Cushing disease, and hypothyroidism. . Acromegaly may produce a paradoxical反常的reduction in growth hormone. Hyperglycemia suppresses serum growth hormone. This suppression does not occur in pituitary tumors secreting growth hormone, ectopic growth hormonereleasing tumors, Cushing syndrome, and anorexia厌食症nervosa. A paradoxical rise in growth hormone may be observed in acromegaly, acute illness, and chronic renal failure. .CRH causes a rise in corticotropin. This response is exaggerated in Cushing disease but blunted in other causes of Cushing syndrome. When combined with inferior petrosal sinus sampling岩下窦取血法, this test may assist in differentiating Cushing disease from benign ectopic adrenocorticotropic hormone (ACTH) syndrome.,Insulin-induced hypoglycemia causes a rise in corticotropin, cortisol, and growth hormone. A blunted response is observed in Cushing syndrome, growth hormone deficiency, hypothyroidism, and hyperthyroidism. Metyrapone美替拉酮causes a rise in morning serum 11-deoxycortisol and urinary 17-hydrocorticosteroids (17-OH steroids). An exaggerated response occurs in Cushing disease, but no response is observed in other causes of Cushing syndrome. Dexamethasone suppression testing is used in Cushing syndrome evaluation. An overnight 1-mg dexamethasone dose fails to suppress morning serum cortisol in Cushing syndrome but is only a screening test. Low-dose and high-dose . Cosyntropin 1-24促肾上腺皮质激素testing and corticotropin infusion testing assist in assessing the hypothalamic-pituitary-adrenal axis for adrenocortical insufficiency. GnRH causes an increase in LH and FSH levels. This response is blunted in pituitary hypogonadism but exaggerated in primary hypogonadism. Test results, however, are not very dependable.,Workup-Imaging Studies,Pituitary imaging Plain skullradiographs are poor at delineating soft tissues. CT scanning is better at depicting bony structures and calcifications within soft tissues than either plainradiography or MRI. . such as germinomas生殖细胞瘤, craniopharyngiomas, and meningiomas脑(脊)膜瘤, are better determined with CT scanning MRI is more expensive than CT scans but is the preferred imaging study for the pituitary because it provides better visualization of soft tissues and vascular structures. No exposure to ionizing radiation occurs, T1-weighted images, fat produces highsignal intensity images. . T2-weighted images of structures with high water content, such as cerebrospinal fluid and cystic lesions, produce high-intensity signals, while structures with high fat content present with low-intensity signals.,Other TestsVisual field testing should be performed, especially in tumors involving the optic chiasm. The severity of visual defects may dictate a more aggressive treatment course.Histologic FindingsThe histology of pituitary macroadenomas shows varying levels of neoplastic activity. Frozen sections are usually not dependable for definitive diagnosis. Hormonal immunohistochemical stains for neuroendocrine markers are useful, especially in the nonfunctioning tumors.,Treatment Medical Care,The goal of treatment is complete cure. When this is not attainable, reducing tumor mass, restoring hormone function, and restoring normal vision are attempted using medications, surgery, and radiation. Pituitary macroadenomas often require surgical intervention for cure. The exceptions to this rule are the macroprolactinomas, .Prolactin-secreting macroadenomas respond to dopaminergic agonists. The most frequently employed medications include bromocriptine, cabergoline卡麦角林. Quinagolide喹高利特is an alternative with fewer adverse effects than bromocriptine. . (For prolactin-secreting microadenomas, surgical removal is followed by recurrence in about 50% of patients. Therefore, medical therapy is preferred. ),Growth hormone-secreting tumors should be treated surgically, often followed by radiation therapy. . Radiation therapy results in 50% reduction in growth hormone levels within 2 years, followed by an additional 25% in the following 2 years. . Medical treatment is used after surgery to suppress growth hormone secretion, awaiting the occurrence of the effects of radiotherapy. Octreotide善得定is the treatment of choice. . . Growth hormone receptor antagonists have been another addition to the treatment of acromegaly. Dopamine agonists also may be used but are not as effective as octreotideCorticotropin-secreting pituitary tumors are treated using surgery and radiation therapy (however, they are rather radioresistant). Medical therapy is reserved for patients whose therapy fails,. . Centrally acting medications . include bromocriptine, valproic acid丙戊酸, and cyproheptadine丙戊酸. Peripherally acting agents include ketoconazole, mitotane米托坦, and metyrapone美替拉酮.,Gonadotropin-secreting macroadenomas are treated surgically, followed by radiation. . Bromocriptine or octreotide may be used. . Nonsecretory macroadenomas are treated surgically. If surgery is contraindicated, octreotide or bromocriptine may be tried; however, the results are often disappointing. Thyrotropin-secreting tumors are treated surgically, followed by radiation therapy. Octreotide is quite effective in such tumors . Traditional radiotherapy using external beam radiation is used to complement surgery in inoperable cases or in patients declining surgery. . panhypopituitarism. Radiosurgery using a Gamma knife employs a computer-assisted stereotactic mapping followed by several discrete radiation treatment fields to the tumor. . Incidence of hypopituitarism is less. However, long-term studies are not available yet.,Treatment Surgical Care,Pituitary macroadenomas often require surgical extirpation for cure. Transsphenoidal经蝶骨的surgery is the approach of choice. Only about 1% a transcranial approach. Compared with remission rates of 90% in microadenomas, macroadenomas . 15-37% when treated with surgery alone. Radiation therapy and medical treatment often complement surgery. .ConsultationsWhen a pituitary macroadenoma is diagnosed, consultations with an endocrinologist, neurosurgeon, neuroradiologist, and neurophthalmologist神经眼科学shouldbe considered.,以GH瘤为例,中国肢端肥大症诊治规范：治疗目标是随机血清GH2.5ug/L；口服葡萄糖负荷血清GH水平1.0ug/L；血清IGF水平下降；肿瘤消除或缩小；临床症状消除或减轻；尽可能保留内分泌功能或进行激素替代。SSA治疗适应症：术前，缩小肿瘤体积；肿瘤切除后残余肿瘤的辅助治疗；放射治疗后的过渡治疗；并发症治疗。,GH瘤的治疗流程,多学科合作的个体化治疗方案:治疗前：定性诊断-定位诊断-垂体功能的全面评估-并发症评估,血压、血糖、心肺功能评估：血压、血糖术前应达到安全水平所有垂体、靶腺内分泌功能评估：甲状腺功能纠正与皮质功能替代之间的关系术前使用缩小肿瘤的药物（溴隐停、生长抑素）,尹剑 等。 中华神经外科杂志 2006年 22卷 6期 343-344,2.治疗后：定期评估，长期随诊(推荐1年1次）,纠正电解质紊乱垂体激素替代注意垂体周围组织损伤下丘脑综合征尿崩症SIADH脑耗盐综合征,3.并发症管理：血糖、血压、骨代谢、心功能、肾功能(专家小组包括：内分泌专家、神经外科专家、放射治疗专家、放射诊断学专家、病理学专家。),内分泌激素替代： 最好的方法是将病人移交给内分泌专科 没有内分泌专科的医院应注意以下问题： 靶腺激素替代：甲状腺素、皮质激素、性 激素、保持骨代谢正常三个月随访有应激情况要增加替代剂量,MedicationMedications are used to control excess hormone secretion or to replace deficient hormones.Dopaminergic agentsThese agents directly stimulate postsynaptic突触后的dopamine receptors. The dopaminergic neurons in the tuberoinfundibular结节漏斗部的process modulate the secretion of hormones from the anterior pituitary by secreting an inhibitory factor, believed to be dopamine.Bromocriptine (Parlodel)Dopamine agonist used to normalize serum prolactin levels. Semisynthetic, ergot alkaloid derivative. Strong dopamine D2-receptor agonist. Partial dopamine D1-receptor agonist.,Cabergoline (Dostinex)卡麦角林Dopamine agonist used to normalize serum prolactin levels. Long-acting dopamine receptor agonist with high affinity for D2 receptors. 0.25-1 mg PO twice qwkGrowth hormone receptor antagonistsUsed for the treatment of acromegaly.Pegvisomant (Somavert)培维索孟Genetically engineered growth hormone receptor antagonist used to treat acromegaly. Useful in patients not responding to somatostatin analogues. May be used concurrently with somatostatin analogues after surgery and radiation.,Somatostatin analogues生长抑素类似剂Used to control symptoms resulting from excess hormone secretion.Octreotide (Sandostatin)Somatostatin analogue used to normalize growth hormone levels. Acts primarily on somatostatin receptor subtypes II and V. Inhibits growth hormone secretion and has multiple other endocrine and nonendocrine effects, including inhibition of glucagon, VIP, and GI peptides.,Follow-up,Further Inpatient Care Correction of hormone imbalances should be attempted preoperatively. Adrenocortical insufficiency should be sought and corrected. Transient diabetes insipidus is common following surgery for macroadenomas. A triphasic response where diabetes insipidus is followed by hyponatremia and, later, diabetes insipidus again is more frequent following surgery for macroadenomas than microadenomas. Vasopressin may be required transiently. Permanent diabetes insipidus, however, is not frequent.Further Outpatient Care Monitor for remission by hormone assays and tumor size. Monitor for development of hypopituitarism. Radiation therapy may cause hypopituitarism months to years later.,Inpatient & Outpatient MedicationsMedications are based on hormonal abnormalities. For instance, dopaminergic agents are used for hyperprolactinemia, and somatostatin analogues are used for acromegaly.ComplicationsComplications result from mass effects and abnormal hormone function. Pituitary apoplexy垂体卒中, which is an acute hemorrhagic infarction of a pi