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The management of non-functioning pituitary adenomas
Correspondence Address:
Non-functioning pituitary adenomas most commonly present secondary to mass effect and are classified according to their size and immunohistochemical staining. Local intrasellar mass effect may cause varying degrees of hypopituitarism. With extrasellar growth, neurological signs and symptoms develop. Appropriate therapy for these tumors requires close interaction across multiple disciplines. Trans-sphenoidal surgery offers safe and effective treatment in the overwhelming majority of patients with relatively low risk of new neurological and endocrinologic deficits. The multidisciplinary management of non-functioning adenomas, their diagnosis and therapeutic outcomes, is discussed.
Pituitary adenomas are the third most frequently encountered primary intracranial neoplasm after gliomas and meningiomas.[1] These tumors present with an annual incidence of between 0.5 and 8.2 per 100,000.[1],[2],[3],[4],[5],[6] Most series estimate the prevalence to be approximately 10%, a figure supported by data from magnetic resonance imaging (MRI) series.[7],[8],[9],[10] Currently, a more detailed understanding of the classification, pathogenesis, diagnosis, and treatment of pituitary adenomas is available. In this article we will discuss the current concepts in the management of non-functioning adenomas.
Because of the variety of tumor types and clinical presentations, an assortment of classification systems has been proposed to codify these tumors. Clinically, our approach primarily distinguishes tumors based on size and functional status. Pituitary adenomas that are < 10 mm are termed microadenomas; those greater than 10 mm are identified as macroadenomas. Clinically non-functioning adenomas (NFA) are actually a diverse group of tumors that include glycoprotein adenomas (a-subunit, luteinizing hormone (LH), follicle-stimulating hormone (FSH)), the null cell adenoma and oncocytoma. Although the clinical and biochemical functional status generally correlates with the immunohistochemical findings, exceptions do exist. A notable exception is the silent corticotroph (ACTH) adenoma that clinically behaves as a non-functioning adenoma but stains positively for ACTH. The most comprehensive classification schema that accounts for virtually all the exceptions is that of the World Health Organization which codifies tumors based upon: 1) clinical presentation and biochemical secretory activity, 2) size and invasiveness (i.e. micro vs. macroadenoma), 3) histologic features (adenoma versus carcinoma), 4) immunohistochemical profile, and 5) ultrastructural features on electron microscopy.[11]
Authors have generally argued that pituitary tumors result from either an abnormal response to hypothalamic stimulation or from intrinsic abnormalities within the pituitary gland itself. These theories are not mutually exclusive as extrinsic factors can provide a permissive environment for molecular events to occur within the gland. At the beginning of the previous decade, it was recognized that pituitary tumors are monoclonal in origin.[12],[13] This phenomenon suggested that pituitary tumors result from genetic mutations in a single cell involving activation of oncogenes, inactivation of tumor suppressor genes, and alterations of transcription factors regulating cell growth and differentiation. Although the precise mechanisms of tumorigenesis are yet to be fully elucidated, the previous decade has provided some clues as to the origin and progression of pituitary adenomas.
Several oncogenes have been implicated in the development of non-functioning pituitary adenomas. These oncogenes include the stimulatory guanine nucleotide-binding protein (gsp) gene that produces an independently active adenyl cyclase signaling system that increases cyclic AMP, leading to cell cycle progression and GH hypersecretion.[14],[15] Mutations of the gsp gene have been noted in about 40% of GH adenomas but also in 10% of NFAs.[16],[17],[18],[19],[20],[21],[22],[23] The c-myc oncogene, located on chromosome 8q24, has been reported in nearly one-third of all pituitary adenomas including NFAs, and also in prolactinomas, GH adenomas and ACTH adenomas.[24],[25],[26] The pituitary tumor transforming gene (PTTG) appears to induce basic fibroblast growth factor (bFGF) expression and secretion and may foster genetic instability.[27],[28] PTTG gene expression is increased in a majority of NFAs.[27],[28] Other oncogenes have been noted in more clinically aggressive tumors. These include the Cyclin D1 (CCND1) and the H-ras oncogene, both of which have been reported in pituitary carcinomas and invasive tumors.[29],[30],[31],[32],[33] The absence of these oncogenes in clinically benign tumors indicates that their activation may be a late event causing progression to a more aggressive type and is evidence against them having a major role in initiating tumor formation.[18]
Tumor suppressor gene inactivation has also been implicated in the development of pituitary adenomas. Among the earliest recognized tumor suppressor genes associated with pituitary adenomas is the MEN-1 gene located on chromosome 11q13.[34],[35] Twenty-five per cent of patients with the autosomal dominant inherited germline mutation (MEN-1 syndrome) develop pituitary tumors.[13],[15],[16],[35],[36],[37] Several other tumor suppressor genes have been implicated in the progression to invasive tumor types. These include the mutated p53 gene, located on chromosome 17p13, a yet uncharacterized deletion in a locus near the retinoblasoma (Rb) gene (on the long arm of chromosome 13), and loss of heterozygosity (LOH) on chromosomes 11q13, 13q12-14, and 10q26.[31],[38],[39],[40],[41],[42]
Clinical presentation and diagnosis Clinically, NFAs account for approximately 25 to 35% of tumors resected surgically.[43],[44] Because of the increased availability and use of MRI, an increasing numbers of patients present with incidentally diagnosed pituitary adenomas. On further evaluation, approximately 5% will have evidence of visual deficits and around 15% will have some degree of pituitary dysfunction.[45] About two-thirds are microadenomas at diagnosis and although these can often be followed conservatively, more than one-third of incidental macroadenomas will show significant growth on serial imaging.[8],[45],[46],[47],[48] NFAs are actually a diverse group of tumors including gonadotroph adenomas and null-cell adenomas. Gonadotroph adenomas occur at approximately twice the frequency as the true non-secreting adenomas.[49] Despite this diversity, the tumor subtypes appear to behave in a uniform manner clinically.[50],[51] Patients generally present with signs and symptoms relating to local (sellar) and extrasellar mass effect. Local intrasellar growth may cause varying degrees of pituitary dysfunction. The cell populations that appear most susceptible are the gonadotrophs (luteinizing hormone (LH) and follicle-stimulating hormone (FSH)), followed by the thyrotrophs (TSH), somatotrophs, and corticotrophs. Hypogonadism in men causes diminished libido and erectile dysfunction. Female hypogonadism causes amenorrhea and diminished libido. Hypothyroidism can cause an array of symptoms including headache, weight gain, constipation, cold intolerance, depression, and diminished mental acuity. Growth hormone deficiency is characterized by decreased exercise tolerance, increased central adiposity, anxiety, and mood changes. Relative adrenal insufficiency manifests with proximal weakness, fatigue, anorexia, myalgias, arthralgias, gastrointestinal symptoms, and orthostasis. Sudden pituitary insufficiency may occur in the setting of pituitary apoplexy. When acute, cortisol deficiency, or Addisonian crisis, may cause headaches, visual disturbance, hyponatremia, mental status changes, and cardiovascular collapse. As the tumor expands beyond the confines of the sella, neurological signs begin to manifest. Headache, a common complaint, occurs as the expanding tumor stretches the sellar dura and diaphragma sellae. Suprasellar growth and resultant chiasmal compression commonly causes varying degrees of visual disturbance and bitemporal hemianopsia. Massive suprasellar growth may, less commonly, cause obstructive hydrocephalus. Lateral growth into the cavernous sinus may cause diplopia and facial pain or numbness. Further lateral growth into the mesial temporal lobe may also provoke seizures. An expanding tumor often compresses the pituitary stalk and disrupts the tonic hypothalamic inhibition of prolactin secretion. This “stalk effect” causes increased prolactin levels mimicking those seen in prolactinomas, however, prolactin levels secondary to stalk effect should be mild and generally do not exceed 150 ng/ml. Although two-thirds of the NFAs are glycoprotein adenomas, these tumors do not efficiently secrete ±-subunit (±SU), FSH, or LH. Only about one-third of these have biochemical elevations in one of these markers.[51],[52],[53] For this reason, the diagnosis of NFA preoperatively entails ruling out the secretory syndromes and confirming a pituitary mass on MRI. Despite our individualized approach, certain protocols are universal. A careful neurological and endocrinological history is essential in all patients. The subsequent biochemical diagnosis should be followed by a careful screening of the pituitary axis to establish any preoperative endocrine insufficiency. Reasonable laboratory evaluation should include baseline PRL, GH, insulin-like growth factor type 1 (IGF-1), ACTH, cortisol, LH, FSH, TSH, thyroxine, testosterone, and estradiol. Of particular importance is the detection of cortisol and thyroid deficiency because failure to establish this preoperatively can have dire consequences. All patients will also need pretreatment high-resolution MRI using specific pituitary protocols. The gadolinium enhanced sagittal and coronal planes are most helpful in surgical planning, but serial volumetric analysis is also essential in gauging the efficacy of therapy. Also, prior to medical or surgical therapy, patients should have neuro-ophthalmologic testing including fundoscopy, formal visual field testing (automated perimetry), and quantified visual acuity. The goals of therapy are improved quality of life and survival, relief of mass effect and reversal of its associated signs and symptoms, normalization of hormonal hypersecretion, preservation or recovery of normal pituitary function, and prevention of recurrence. This effort requires a multidisciplinary team approach that includes endocrinologists, neurosurgeons, neuroophthalmologists, radiation therapists, and neuroradiologists. Therapy The primary treatment of NFAs is transsphenoidal surgery. The standard technique involves either an endonasal or sublabial approach to the sellae with a microsurgical resection of the tumor. Pediatric patients, adults with small nares, and patients with very large tumors are often approached via a sublabial incision. In the vast majority of patients, however, the endonasal corridor provides adequate exposure. More recently, endoscopic techniques have been developed that have added to the surgical armamentarium.[54],[55],[56] The endoscope allows for a relatively atraumatic approach to the sellae and provides an excellent panoramic view of the regional anatomy and its relationship to the tumor. The angled views allow inspection of suprasellar regions that are simply not possible with the microscope. In our hands, we have found it most useful as an adjunct in verifying the adequacy of microsurgical resection. Studies confirming improved outcomes using the endoscope, however, are not yet available. Those patients undergoing surgery are administered perioperative hydrocortisone for the first 24 hours following surgery. Morning cortisol levels are measured on postoperative days 2 and 3. Patients with serum cortisol levels< 8¼g/dl (225 nmol/L) are given steroid replacement. Those with preoperative cortisol deficiency are tapered postoperatively to their preoperative regimen. Patients are also monitored closely for diabetes insipidus by monitoring daily weight, urine specific gravity every 4 hours, fluid intake and output, and serum sodium. Visual field deficits improve in 70 to 87% of patients with preoperative deficits.[44],[57],[58] Normalization of vision is reported in approximately 25%.[57] Improvement in pituitary deficiency is seen in up to 27% and normalized endocrine function in nearly 15%.[57],[58],[59] Normal pituitary function is preserved in approximately 70%.[60] Nevertheless, 90% of premenopausal women with preoperative preserved menstruation retain normal menstruation postoperatively.[61] Regular menstruation is restored in those with preoperative amenorrhea in 56%.[61] New endocrine deficits, seen more frequently in macroadenomas, have been reported in up to 40%.[57],[58],[60] However, our results indicate that only 3% of patients with microadenomas and 5% of patients with macroadenomas with preoperative normal pituitary function experienced new hormonal deficits.[62] Immediate postoperative polyuria occurs in about 30% of patients, but in only 3 to 10% does this polyuria persist beyond the first week of surgery.[62],[63] Delayed hyponatremia, occurring most often 7 to 10 days after surgery, is evident in 1 to 2.4%.[62],[63] Worsening in preoperative vision can be seen in 1 to 4%.[59],[64] Anatomic complications include nasal septal perforations in 7% and fat graft hematomas in 4%.[60],[64] Postoperative cerebrospinal fluid leaks and meningitis are reported in 0.5 to 3.9%.[64],[65] Recurrence does develop over time and in our series, at 10 years, 16% experienced recurrent disease.[44] However, recurrence requiring repeat surgery occurs in only 6% of patients. Completeness of resection as judged on postoperative MRI can predict recurrence. Although one-third of patients with residual tumor have recurrent tumor growth, less than 3% with complete resection experience recurrent disease within a mean of 3.3 years.[66] For tumors with incomplete resection, medical and radiation therapy can be considered. However, neither medical therapy nor radiation therapy is recommended as primary treatment. Although dopamine agonists, GnRH agonists, and octreotide therapy have been employed, their efficacy has not been proven. Postoperative adjuvant radiation therapy has been advocated for incompletely removed tumors and tumors with cavernous sinus invasion.[67],[68] Our practice has been to delay radiation therapy until there is evidence of progressive regrowth of the tumor. In many such cases, repeat trans-sphenoidal surgery for debulking is recommended prior to radiation therapy. External beam radiotherapy has long been applied to treat patients with tumor recurrence and residual disease. Although this therapy effectively reduces the risk of recurrent disease, there are several distinct disadvantages.[69],[70] These include the inconvenience of repeated treatments over time, the high incidence of progressive pituitary dysfunction, the albeit small risk of late secondary tumors, delayed cognitive deficits, and slow regression response.[71],[72] A growing literature is available that has investigated the efficacy of Gamma Knife radiosurgery.[73],[74],[75],[76] Control of tumor growth is reported in up to 100% of microadenomas and 90% of macroadenomas. Volume reduction of greater than 50% has been reported in nearly 30% of patients.[76] New cranial nerve deficits are rare and appear to occur in less than 5%. New hormonal deficits are, in some series, reported to be quite rare, occurring in less than 5%.[73],[76] However, this is likely a function of the generally short follow-up in each study. In studies with longer follow-up (4.6 years), new hormonal deficits are seen most commonly in thyroid function (24%) and least commonly in cortisol levels (9%).[74] With even longer follow-up, a higher rate of endocrinopathy will likely be evident. Gamma knife radiosurgery has a limited role in tumors that have continued optic nerve or chiasmal compression. Tumors that are less than 3 mm from the visual pathways are not amenable to radiosurgery and these patients require either repeated surgery to create the required distance or conventional external beam radiotherapy.
Gene therapy may play a role in the future treatment of pituitary adenomas. Rats harboring estrogen-induced prolactinomas were treated with a tetracycline-regulated adenovirus carrying the gene for tyrosine hydroxylase (the rate limiting enzyme in dopamine synthesis). Researchers found a significant reduction in both tumor growth and plasma prolactin levels.[77] Tissue-specific promoters may also play a role in directing gene therapy. Researchers have shown that stereotactically injected recombinant adenoviruses containing the human growth hormone and the human glycoprotein hormone alpha-subunit promoter can selectively drive the expression of the beta-galactosidase gene in cells expressing those hormones.[78],[79] Tissue culture experiments have also indicated that these tissue-specific promoters can selectively drive the expression of toxic gene therapy with excellent cytotoxicity to specific pituitary cell lines. Future in vivo studies evaluating the efficacy of tissue-specific promoters that drive the expression of toxic gene therapy agents are anticipated.
Although NFAs present most commonly with visual field deficits, careful screening for pituitary insufficiency is mandatory. Transsphenoidal surgery effectively relieves mass effect and preserves normal endocrine function in the majority of patients. Medical therapy and radiation therapy are reserved for refractory tumors. With improved understanding of the molecular pathogenesis, future therapy should treat these tumors more effectively.
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