Pituitary tumors

Opinion statement  Pituitary adenomas are the most common intrasellar tumors. With the exception of prolactinomas, first-line treatment is almost always surgical. Prolactinomas are usually treated with dopamine agonists such as cabergoline or bromocriptine. Somatostatin analogues, such as octreotide and lanreotide, can be adjunctive to surgical therapy in acromegaly, although they can be used as primary therapy in selected cases. Pegvisomant, a growth hormone receptor antagonist, is reserved for acromegalic patients who are resistant to treatment with somatostatin analogues. No effective medical therapy is available for adenomas that secrete adrenocorticotropic hormone, and occasionally bilateral adrenalectomy is required to resolve severe hypercortisolemia. Radiation therapy (fractionated or radiosurgery) can be used for residual or recurrent pituitary tumors. Asymptomatic, nonfunctioning pituitary adenomas may be followed without any intervention, but surgery is typically indicated if there are symptoms of mass effect on the optic chiasm or endocrine dysfunction. In the hands of an experienced pituitary neurosurgeon, the prognosis for endocrinologic recovery and visual improvement is good.     

Clinically non functioning pituitary adenomas and gonadotroph-cell adenomas

Clinically non-functioning pituitary adenomas and gonadotroph-cell adenomas are relatively common: microadenomas (< 1cm) are usually pituitary incidentalomas while most macroadenomas are revealed by mass effect and/or hypopituitarism. They are rarely associated with high gonadotropin (Luteinizing hormone, LH; Follicle-stimulating hormone FSH) levels while increased alpha-subunit levels are more frequent. Immunocytochemistry of pituitary tumor confirms the diagnosis of clinically non-functioning or gonadotroph-cell adenoma. Pituitary MRI follow-up seems to be indicated for microadenoma. Treatment of macroadenoma with visual field defect or hypopituitarism is transphenoidal surgery, but cure is rarely obtained and tumor recurrence is significant during follow-up. Therefore postoperative treatment (pituitary radiotherapy or medical treatment with dopamine agonists or somatostatin analogs) should be discussed against close follow-up with repeated MRI scans.     

Should silent corticotroph-cell adenoma be classified as a non-functional pituitary adenoma?

A 45-year-old man underwent surgery for a silent corticotroph-cell pituitary adenoma which developed in 9 months. The tumor was termed silent because it exhibited increased corticotropic secretion without clinical signs of hypercorticism. This classes it as a non-functional adenoma. The non-functional group includes different types of adenomas such as gonadotroph and other silent thyreotroph and somatotroph adenomas with variable proliferative potential. Silent corticotroph-cell adenoma is considered as an aggressive tumor. In contrast, gonadotroph adenomas usually grow slowly and postoperative tumor remnants can remain stable for years. Because of this variability in tumor growth, the therapeutic decision is difficult if there is a postoperative remnant. No precise guidelines can be established. We suggest that non-functional pituitary adenomas should be considered separately, according to the histological type. This classification is essential for improving knowledge and specifying indications for radiotherapy.     

Imaging of pituitary adenomas

In cases of pituitary hormone hypersecretion, magnetic resonance imaging (MRI) can demonstrate the causal lesion, which is often small (microadenoma). In pituitary adenomas with suprasellar extension, MRI shows the tumor's relation to the surrounding structures: the optic chiasm, the internal carotid artery, the sphenoidal sinus, etc. MRI usually makes it possible confirm or rule out any cavernous sinus invasion by the pituitary adenoma, a determination essential for planning treatment. After pituitary surgery, MR imaging is again essential for visualizing any residual tumor tissue and - if the MRI is carefully performed to be reproducible - for assessing its development over time.     

Technical considerations of transsphenoidal removal of fibrous pituitary adenomas and evaluation of collagen content and subtype in the adenomas

Pituitary adenomas are usually soft, but 5-13.5% are fibrous adenomas which are difficult to remove. Magnetic resonance (MR) imaging and operative findings were evaluated in eight patients (12.1%) with fibrous pituitary adenoma among 66 patients. Tumor specimens were examined histologically and immunohistochemically for collagen content and subtypes. Seven patients had clinically inactive non-functioning pituitary adenomas and one patient growth hormone-secreting adenoma. All patients underwent transsphenoidal surgery. Four cases were giant adenomas with suprasellar extension of more than 2 cm. T1- and T2-weighted MR imaging showed the tumors as nearly isointense to the surrounding brain, except in one case where the tumor was high intense on T2-weighted MR imaging. All tumors required piecemeal resection using a micro-dissector and tumor forceps. Four tumors of maximum size more than 3 cm needed a second operation. The interface between the thinned normal pituitary gland and fibrous adenoma was intended to identify at the anterior-superior portion in recent four cases, which was helpful to remove the tumors and preserve pituitary functions. Histological examination revealed prominent deposition of collagen in the perivascular area. The percentage of collagen content in fibrous adenomas was more than 5% and significantly higher than that in soft adenomas and normal pituitary glands. Immunohistochemical examination showed positive staining for collagen types I and III in the fibrous adenomas, but only for type V collagen in the normal pituitary glands. Large fibrous adenomas can be resected by transsphenoidal surgery which may require two-stage operations. Identification of the interface between the normal pituitary gland and adenoma is helpful to remove fibrous adenomas and to preserve pituitary functions. We propose that firm adenomas containing more than 5% collagen are "fibrous" adenomas.     

Clinically non-functioning pituitary adenomas

Clinically non functioning pituitary adenomas (NFPAs) include all pituitary adenomas that are not hormonally active. They are not associated with clinical syndromes such as amenorrhea-galactorrhea (prolactinomas), acromegaly, Cushing's disease or hyperthyroidism (TSH-secreting adenomas) and are therefore usually diagnosed by signs and symptoms related to a mass effect (headache, visual impairment, sometimes pituitary apoplexy), but also incidentally. Biochemical work up often documents several pituitary insufficiencies. In histopathology, the majority of NFPAs are gonadotroph. In the absence of an established medical therapy, surgery is the mainstay of treatment, unless contraindicated or in particular situations (e.g. small incidentalomas, distance from optic pathways). Resection, generally via a trans-sphenoidal approach (with the help of an endoscope), should be performed by a neurosurgeon with extensive experience in pituitary surgery, in order to maximize the chances of complete resection and to minimize complications. If a tumor remnant persists, watchful waiting is preferred to routine radiotherapy, as long as the tumor residue does not grow and is distant from the optic pathways. NFPA can sometimes recur even after complete resection, but predicting the individual risk of tumor remnant progression is difficult. Postoperative irradiation is only considered in case of residual tumor growth or relapse, due to its potential side effects.     

Neurosurgery and pituitary tumors: surgical indications and outcome

TWO MAIN FEATURE: Indication for surgery in patients with pituitary tumors depends first on the anatomical situation: the enclosed or invasive nature of the tumor. Total resection of an enclosed tumor, even if it is a huge one, can be expected to be successful. For invasive tumors, surgery will be subtotal unless the invasion is very limited. The second consideration is the efficacy and limitations of medical treatment. At present, only secreting pituitary adenomas are accessible to medical therapy. Other pituitary tumors, and non-functioning pituitary adenomas are not suitable for valid medical treatment and may warrant a surgical strategy. CHOICE OF THE OPERATIVE APPROACH: Anatomical and radiological considerations are determining. For secreting pituitary adenomas, first intention surgery via a transphenoidal access is advocated when surgery can be expected to achieve complete tumor resection without damaging the normal gland. For other cases, medical treatment has to be instituted prior to surgery which will be discussed in case of failure, intolerance or for tumor reduction. Transphenoidal surgery is strongly advocated in case of a pituitary incidentaloma with a visual danger, even in old patients. OUTCOME: Visual symptoms are often improved after neurosurgery for pituitary tumors. Hormone cure is frequent in microsecreting pituitary adenomas, rarely in invasive tumors.     

Ectopic pituitary adenoma of the third ventricle. Case report

Ectopic pituitary adenomas without associated intrasellar adenomas are rare and are usually located in the sphenoid sinus. Most have been reported without modern radiological, endocrinological, or electron microscopic (EM) documentation. The case of a 47-year-old man with a third ventricular, ectopic, clinically nonsecretory pituitary adenoma, which was shown to be a gonadotrophic adenoma by immunohistochemical and EM study, is reported. Neurological examination, extensive neurodiagnostic imaging, surgical anatomical observation, and endocrinological evaluation showed no evidence of neoplasia outside the third ventricle.     

Anaesthesia for pituitary surgery

Surgical lesions of the pituitary gland, the majority of which are benign adenomas of the anterior lobe, present a varied and challenging spectrum of peri-operative anaesthetic problems. Successful management is based on a comprehensive understanding of the applied anatomy and physiology of the pituitary gland, the endocrine and neurosurgical consequences of pituitary adenomas and the specific implications of the chosen neurosurgical approach. The majority of pituitary adenomas can be resected adequately by an extracranial trans-sphenoidal approach, although transcranial resection may be necessary if the tumour has a significant suprasellar extension or if the diagnosis is in doubt. In general terms, pituitary surgery demands the same levels of peri-operative care as those required by intracranial surgery.     

Morphological study of clinically nonsecreting pituitary adenomas in patients under 40 years of age

Clinically nonsecreting pituitary adenomas removed at surgery from 69 patients under 40 years of age were studied by histological, immunocytochemical, and transmission electron microscopic examination. By morphological analysis, 19 tumors were found to be null-cell adenomas, 17 silent gonadotroph adenomas, 14 silent subtype 3 adenomas of unknown cellular origin, 13 silent subtype 1 or subtype 2 corticotroph adenomas, three oncocytomas, and three silent thyrotroph adenomas. These results indicate that the incidence of null-cell adenomas and oncocytomas, which are known to be the most common types of nonsecreting pituitary adenomas in patients over 40 years of age, is relatively low in younger patients. This trend is even more obvious in patients younger than 30 years of age. It can be concluded that clinically nonsecreting pituitary adenomas represent a heterogeneous group morphologically, and that the incidence of the different tumor types varies depending on the patient's age. These findings underline the importance of careful morphological studies. It is proposed that, in order for the correct morphological diagnosis to be made, tumors removed surgically from patients with clinically nonsecreting pituitary adenomas (especially younger patients) should be investigated not only by histological means but also by immunocytochemical and electron microscopic examination. The information obtained from such analysis may be useful in assessing prognosis and deciding on the appropriate treatment.     

Corticotroph microadenomas of the pituitary stalk. Diagnostic and therapeutic difficulties

Thirteen percent of the pituitary adenomas in our series have been corticotroph adenomas. Most have been microadenomas located in the adenohypophysis, more often laterally than posteromedially. In a few rare cases, the corticotroph cells of the pars tuberalis gave rise to an adenoma. Only 16 cases of pituitary stalk adenomas have been published to date. We report here three new cases among a series of 150 patients who underwent surgery for corticotroph adenomas (2% incidence as in the literature). There was no difference in the clinical or biological presentation of intrasellar and pituitary stalk adenomas. This location must be systematically searched on the MRI, but a negative exploration cannot excluded the diagnosis of pituitary stalk adenoma like in intrasellar ones. Two anatomical entities seems to be separated. Some stalk adenomas developed preferentially in the supradiaphragmatic space (one in our series) and are accessible for selective resection. Others develop within the pituitary stalk itself and sometimes in the pars distalis (two patients in our series) which requires section of the pituitary stalk with hypophysectomy if the lower limit is not clearly seen during surgery. The subfrontal or pterional access is the approach of choice for suprasellar tumors. These approaches remain controversial for pituitary stalk adenomas because of the poor visibility of the pituitary stalk and the floor of the third ventricle. The transnasosphenoidal approach with extension to the sphenoidal planum and opening of the optochiasmatic cisterna appears to be the best alternative for surgical removal of these adenomas.     

Plurihormonal pituitary adenoma with concomitant adrenocorticotropic hormone (ACTH) and growth hormone (GH) secretion: a report of two cases and review of the literature

Plurihormonal pituitary adenomas are tumours that show immunoreactivity for more than one hormone that cannot be explained by normal adenohypophysial cytodifferentiation. The most common combinations in these adenomas include growth hormone (GH), prolactin (PRL) and one or more glycoprotein hormone sub-units (β-TSH, β-FSH, β-LH and αSU). The authors report two cases of a plurihormonal pituitary adenoma expressing the rare combination of ACTH and GH. They both underwent successful transphenoidal hypophysectomy (TSH). Long-term post-operative follow-up revealed no evidence of tumour recurrence. Due to the multiple secretions and plurihormonal characteristics clinical diagnosis of composite pituitary adenomas can be difficult. The authors discuss the diagnosis and management of composite pituitary adenomas and review the literature regarding this rare phenomenon.     

Return of gonadal function with resection of nonfunctioning pituitary adenoma

A 42-year-old man with severe testicular failure (testosterone 24 ng/dl, normal 300-1100) was found to have a nonfunctioning chromophobe pituitary adenoma. Resection of the pituitary tumor resulted in recovery of gonadal function (testosterone 359 ng/dl). Hypogonadism caused by pituitary adenomas is usually attributed to either hyperprolactinemia or irreversible destruction of normal pituitary tissue, neither of which is applicable to this patient. The recovery of our patient's gonadal function after operation suggests that a reversible compression of viable tissue or impairment of hypothalamic-pituitary communications was responsible for his endocrine deficiency.     

扩大额下硬膜内入路显微切除大型垂体腺瘤

目的 探讨扩大额下硬膜内入路显微手术切除大型和巨大型垂体腺瘤的手术方式和临床疗效。方法 采用扩大额下硬膜内入路切除体腺瘤,对生长入蝶窦内的肿瘤则磨除蝶骨平板切除窦内肿瘤,显微切除鞍上肿瘤时应解剖出垂体柄和受挤压的垂体组织并加以保护,以免术中损伤。结果 16例大型和巨大型垂体瘤全切除13例（81.25％）,次全切除3例,无重残及死亡病例。结论 该手术入路的显微手术能有效地提高大型和巨大型垂体腺瘤的全切除率,亦适用于鞍区的肿瘤的显微手术。     

The Role of Genetic and Epigenetic Changes in Pituitary Tumorigenesis

Pituitary adenomas are one of the most common intracranial tumors. Despite their benign nature, dys-regulation of hormone secretion causes systemic metabolic deterioration, resulting in high mortality and an impaired quality of life. Tumorigenic pathogenesis of pituitary adenomas is mainly investigated by performing genetic analyses of somatic mutations in the tumor or germline mutations in patients. Genetically modified mouse models, which develop pituitary adenomas, are also used. Genetic analysis in rare familial pituitary adenomas, including multiple endocrine neoplasia type 1 and type 4, Carney complex, familial isolated pituitary adenomas, and succinate dehydrogenases (SDHs)-mediated paraganglioma syndrome, revealed several causal germline mutations and sporadic somatic mutations in these genes. The analysis of genetically modified mouse models exhibiting pituitary adenomas has revealed the underlying mechanisms, where cell cycle regulatory molecules, tumor suppressors, and growth factor signaling are involved in pituitary tumorigenesis. Furthermore, accumulating evidence suggests that epigenetic changes, including deoxyribonucleic acid (DNA) methylation, histone modification, micro ribonucleic acids (RNAs), and long noncoding RNAs play a pivotal role. The elucidation of precise mechanisms of pituitary tumori-genesis can contribute to the development of novel targeted therapy for pituitary adenomas.     

Differentiation of pituitary adenomas from other sellar and parasellar tumors by 99mTc(V)-DMSA scintigraphy

Pentavalent technetium-99m dimercaptosuccinic acid [99mTc(V)-DMSA] scintigraphy was evaluated for the differentiation of pituitary adenomas, especially non-functioning adenomas, from other sellar and parasellar lesions. Diffuse 99mTc(V)-DMSA accumulation within the tumor was found in seven of seven non-functioning, three of four growth hormone-secreting, and seven of eight prolactin-secreting adenomas, but only partial accumulation in only two of 16 non-pituitary adenomas and normal pituitary glands. There were no significant relationship between tumor-to-background ratios and tumor size or serum hormone level. 99mTc(V)-DMSA scintigraphy showed overall sensitivity of 81% (17/21 cases) for detecting pituitary adenomas, in particular 100% for non-functioning adenomas. 99mTc(V)-DMSA may be useful for detecting pituitary adenomas, especially non-functioning adenomas, and for the differentiation of non-functioning pituitary adenomas from other sellar and parasellar lesions.     

神经导航在经蝶垂体腺瘤手术中的应用

目的 总结神经导航下经蝶手术治疗垂体腺瘤的经验,并讨论其适应证.方法 对2006年1月至2010年12月138例神经导航下经蝶垂体腺瘤手术病例进行回顾性分析.手术适应证包括:既往经蝶手术后复发性垂体腺瘤36例,侵袭型垂体腺瘤45例,位于垂体侧方或深部的微腺瘤45例,蝶窦气化不良4例,颅底异常增厚3例,双侧颈内动脉间距狭窄4例,鼻中隔偏曲1例.结果 复发性垂体腺瘤全切除12例,次全切除9例,术后出现瘤腔血肿2例,脑脊液漏4例,其中3例合并颅内感染,2例合并交通性脑积水,永久性动眼神经麻痹1例,垂体功能低下者3例;治愈9例,缓解8例.侵袭型垂体腺瘤全切除5例,次全切除27例,术后出现脑脊液漏并颅内感染1例,瘤腔血肿1例;治愈2例,缓解22例;侵袭型激素分泌型垂体腺瘤30例均未治愈缓解.微腺瘤45例均为激素分泌型,均全部切除,治愈38例.颈动脉间距狭窄4例和鼻中隔偏曲1例均全切除和治愈.蝶窦气化不良肿瘤全切除2例,次全切除2例,治愈1例.颅底异常增厚肿瘤全切除2例,次全切除1例,治愈1例.结论 神经导航可以使部分经蝶垂体腺瘤切除手术更加准确、安全、有效,在一定程度上扩大了经蝶手术的适应证.

Abstract：

Objectives To summarize the experiences in clinical application of neuronavigation in transsphenoidal microsurgery of specific pituitary adenomas, and to discuss its indications. Methods From January 2006 to December 2010,138 cases of transsphenoidal microsurgery for specific pituitary adenomas under neuronavigation were reviewed. The indications for neuronavigation in transsphenoidal microsurgery includes: recurrent or regrowth of residual pituitary adenomas after former transsphenoidal surgery in 36 cases, invasive pituitary adenomas in 45 cases, extremely laterally or deeply situated microadenomas in 45 cases, poor pneumatization of the sphenoid in 4 cases, skull base anomalies due to osteodysplasia fibrosa in 3 cases, narrow space between bilateral internal carotid arteries in 4 cases, distortion of nasal septum in 1 case. Results In the recurrence group, 12 were totally removed, 9 subtotally removed;postoperative complications included hematoma within the tumor cavity in 2 cases, cerebrospinal fluid (CSF) leakage in 4 cases among which 3 developed intracranial infection and 2 communicating hydrocephalus, oculomotor paralysis in 1 case and hypopituitarysm in 3 cases;9 were cured and 8 remission. In the invasive group, 5 were totally removed, 27 subtotally removed;postoperative complications included hematoma within the tumor cavity in 1 case, CSF leakage and intracranial infection in 1 case;2 were cured and 22 remission. None of the 30 invasive hormone-secreting adenomas were cured or remission. The 45 cases of hormone-secreting microadenomas were all totally removed, among which 38 were cured. Among the poor sphenoid pneumatization group, total and subtotal tumor removal were achieved in 2 cases respectively with only one cured. In the skull base anomaly group, 2 were totally removed and 1 subtotally removed, with only one cured. For the cases with narrow space between bilateral internal carotid arteries and distortion of nasal septum, all were totally removed and cured. Conclusions Transsphenoidal microsurgery under neuronavigation can be applied for pituitary adenomas in above specific indications. It is an accurate, safe and effective approach for specific pituitary adenomas, which can not only expand the indication of transsphenoidal microsurgery for pituitary adenomas, but also reduce the harmful exposure of X-rays for the operating staff.     

Neurosurgery and pituitary tumors: etio-pathogenic considerations

PITUITARY ADENOMA: Based on the experience of nearly 5000 cases of surgically treated pituitary tumors at the neurosurgery department of the Foch Hospital, the pituitary adenoma is the most frequent pituitary tumor. Secreting tumors lead to a clinical syndrome depending on the level of hormone overproduction. Gonadotrop or non-functioning pituitary adenomas are mainly macroadenomas presenting with visual symptoms, hypopituitarism or as an incidentaloma. Anatomical features dictate the surgical approach. OTHER TUMORS: The other types of hypophyseal tumors, such as craniopharyngioma, Rathke's cleft cyst or others are usually surgical tumors because medical treatment is ineffective. Malignant pituitary tumors are unusual.     

Treatment of Pituitary Carcinomas and Atypical Pituitary Adenomas: A Review

Atypical pituitary adenomas (APAs) are aggressive tumors, harboring a Ki-67 (MIB-1) staining index of 3% or more, and positive immunohistochemical staining for p53 protein, according to the World Health Organization (WHO) classification in 2004. Pituitary carcinomas (PC) usually develop from progressive APAs and predominantly consist of hormone-generating tumors, defined by the presence of disseminations in the cerebrospinal system or systemic metastases. Most of the cases with these malignant pituitary adenomas underwent surgeries, irradiations and adjuvant medical treatments, nevertheless, the therapies are mainly palliative. Recently, the efficacy of temozolomide (TMZ), an orally administered alkylating agent, has been reported as an alternative medical treatment. However, some recent studies have demonstrated a significant recurrence rate after effective response to TMZ. Further clinical and pathological researches of malignant pituitary adenomas will be required to improve the outcome of patients with these tumors.     

Medical treatment of functional pituitary tumors

Medical therapy with a dopamine agonist is the most effective for treatment of a prolactin-producing adenoma and is considered as primary treatment. Surgery and pituitary radiation are reserved for patients who either do not tolerate or do not respond to a dopamine agonist drug. A somatostatin analogue is effective medical therapy for patients with acromegaly, and this is usually administered if there is persistent GH hypersecretion after surgical resection. Medical treatment for patients with Cushing's disease is directed at the adrenal glands to reduce cortisol hypersecretion. Unfortunately, there is no effective medical therapy to reduce pituitary corticotropin production. Medical therapy for a gonadotrope adenoma with a dopamine agonist or somatostatin analogue has limited utility but is employed in patients who are unable to undergo surgery and may delay or prevent additional tumor growth. Many patients with a pituitary adenoma can be successfully treated with one treatment, either a dopamine agonist for a prolactinoma or surgery for other types of tumors. A substantial number of patients require multimodality therapy, however, including medical therapy, surgery, and pituitary radiation. Because the biologic behavior of pituitary adenomas varies considerably, a patient with a pituitary adenoma requires lifelong regular monitoring for hormone hypersecretion, tumor recurrence, and development of new pituitary hormone deficiency. A coordinated plan of care among endocrinologists, neurosurgeons, neuroophthalmologists, and radiation therapists is necessary to provide optimal care for these patients.