Somatotroph Pituitary Adenomas (Acromegaly) The Diagnostic Pathway (11-2K-234) Common presenting symptoms/clinical assessment: Pituitary adenomas are benign neoplasms of the pituitary gland. In patients with somatotroph adenomas, the elevated GH and IGF-I levels lead to a wide range of cardiovascular, respiratory, endocrine and metabolic morbidities. These can range in severity from subtle signs of acral enlargement or soft-tissue swelling to diabetes mellitus and cardiac failure (Table 1). Symptoms from an expanding tumour, such as visual-field defects and headache, might accompany the clinical presentation of acromegaly. Table 1-Systemic manifestations of elevated GH and IGF1 levels System Soft Tissue and Skin Bone and Joints Cardiovascular Respiratory Metabolic Endocrine Gastrointestinal Clinical Features Acral enlargement Soft tissue hyperplasia Increased sweating Increased cartilage thickness Arthropathy Carpal tunnel syndrome Hypertension Dilated Cardiomyopathy Heart failure Arrhythmias Sleep apnoea Macroglossia Upper airway obstruction Diabetes mellitus Insulin resistance Impaired glucose tolerance Dyslipidaemia Thyrotoxicosis Hyperparathyroidism Hypercalciuria Colonic polyps and increased risk of colon cancer Page 1 of 7
Biochemical assessment: Biochemical assessment is the best way to diagnose new cases of acromegaly or monitor residual/ recurrent disease. This includes: -serum levels of IGF-1 and GH -measurement of GH suppression (nadir) after an oral glucose challenge (2h-OGTT) -in selected cases with florid symptoms and signs of acromegaly, positive neuro-imaging and where random GH and IGF-1 levels are clearly raised an OGTT for suppression of GH may not be required Radiological assessment: All patients with a suspected somatotroph adenoma should have a MRI scan as per current WCFT imaging protocol for pituitary tumours which includes the following sequences: -T2 axial brain images -T1 sagittal and coronal images of pituitary -Post gadolinium T1 sagittal and coronal images of pituitary Ophthalmological assessment: In patients with macroadenomas where optic apparatus involvement is seen on imaging, formal visual field testing should be performed. The Treatment Pathway (11-2K-235) Surgery: Transsphenoidal surgery is the treatment of choice for GH-secreting pituitary adenomas and should be considered as first-line therapy and should be performed by an experienced, dedicated pituitary neurosurgeon. A proportion of somatotroph macroadenomas (i.e. tumours with cavernous sinus invasion lateral to the carotid artery or those with bone invasion or transcapsular intra-arachnoid invasion) are less likely to be controlled with surgery alone. Recent studies suggest that good primary surgical debulking followed by medical therapy for hormonal control and/or radiation therapy for treatment of residual tumour, may increase the proportion of patients that subsequently achieve GH control and normalized IGF-I levels, especially when more than 75% of the tumour is removed (Melmed et al. Guidelines for Acromegaly Management J Clin Endocrinol Metab, May 2009, 94(5):1509 1517). Page 2 of 7
Anatomical location and size of the tumour influence the post-surgery biochemical control rates.in patients with intrasellar microadenomas, surgical removal provides biochemical control with normalization of IGF-I in 75 95% of patients. Control rates are lower in patients with non-invasive macroadenomas, but even in these cases surgical removal provides biochemical control with normalization of IGF-I in 40 68% of patients. Contraindications to surgery include patient refusal, severe cardiomyopathy or respiratory disease, or the lack of an available skilled surgeon. Pre-surgical treatment with somatostatin analogues (SSA) Medical treatment with a SSA before surgery is certainly not contraindicated, but there is currently insufficient evidence to recommend it routinely for improved surgical outcome or reduced postoperative complications. Medical Therapy: Long-acting somatostatin analogues (SSAs): To provide disease control, or partial control, in the time between administration of radiotherapy and the onset of maximum benefit attained from radiation therapy (this can take several years to produce disease control) After surgery has failed to achieve biochemical control As first-line therapy when there is a low probability of a surgical cure (for example, large extrasellar tumors with no evidence of central compressive effects) and patients are at high surgical risk and/or who decline surgery Dopamine agonists (DAs): Cabergoline has limited efficacy in acromegaly. As mono-therapy it is effective in less than 10% of patients May be useful: after surgery in selected patients, such as those with markedly elevated prolactin and/or modestly elevated GH and IGF-I levels as combination therapy to SSA therapy in patients partially responsive to a maximum SSA dose Page 3 of 7
GH receptor antagonist (GHRA): Only one GHRA is available, pegvisomant. Main indication is in patients that have persistently elevated IGF-I levels despite maximal therapy with other treatment modalities (surgery, radiotherapy and medical therapy). Tumour growth is infrequent (<2%) and approximately 25% of patients may have liver function abnormalities but these appear to be transient in most patients without changing the GHRA dose Radiotherapy: Should be considered in the following patients: those who do not attain normalization of GH/IGF-1 levels with surgery and/or medical therapy and residual tumour is not amenable to further surgical resection radiotherapy can be considered in patients controlled on drug therapy to allow for potential termination of such therapy, which would otherwise be lifelong Conventional radiotherapy (conformal fractionated radiotherapy) can lower GH levels and normalize IGF-I in over 60% of patients, but maximum response is achieved 10 15 yr after radiotherapy is administered. Medical therapy with a SSA is usually required during this latency period. An alternative to conventional radiotherapy is single-dose, focused radiotherapy such as that achieved with the Gamma Knife or Linear Accelerator. Five-year remission rates with gamma knife radiotherapy in patients with acromegaly (after surgical debulking) range from 29 to 60%. However, studies of gamma knife radiotherapy suffer from selection bias because only patients with a smaller tumour size are included. Stereotactic radiotherapy may produce beneficial effects on GH and IGF-I sooner than conventional radiotherapy, but this may be due to selection bias in trials. If radiation therapy is deemed necessary, the choice of technique is dependent upon the tumour characteristics; conventional radiotherapy is preferred for large tumour remnants or tumours that are too close to optic pathways, whereas stereotactic radiotherapy is preferred when there is a smaller tumour size. Page 4 of 7
The Follow Up Pathway (11-2K-236) To minimise duplication of clinic appointments and MRI scans the following is proposed: A joint neurosurgery / neuro-endocrinology clinic appointment is desirable this minimises clinic appointments and avoids duplication of follow-up imaging and follow up pituitary function testing MRI is the modality of choice for follow up and should be performed as per current WCFT imaging protocol for pituitary tumours Once tumour growth control and biochemical control of the disease have been established following the appropriate treatment modalities, follow-up could be transferred and / or shared with the patient s local hospital-based Endocrinology team Referral back to the joint neurosurgery / neuro-endocrinology clinic and the regional Pituitary MDT can take place at any time during the follow-up pathway when evidence of tumour growth or loss of biochemical control of the disease become evident Biochemical assessment of disease control: - Nadir GH during an OGTT. This test should be performed 3 6 months after surgery - IGF-I, a random GH or GH during an OGTT should be measured at subsequent follow-up visits - OGTT is not helpful in monitoring therapeutic responses while patients are receiving medical therapy with an SSA According to the recent Consensus on criteria for cure of Acromegaly biochemical control is generally defined as: - normal IGF-1 for age and gender and - GH less < 0.4 mcg/l during an OGTT If IGF-I and GH are elevated, additional therapy should be considered. If IGF-I and GH measurements are discrepant, clinical judgment should be used. Patients with random serum GH level below 2.5 mcg/l after treatment had mortality close to expected levels [SMR, 1.1 (95% CI, 0.9 1.4), compared with a SMR of 1.9 (95% CI, 1.5 2.4) for those with a final GH level >2.5 mcg/l]. Similarly, a normal serum IGF-I level for age and sex at last follow-up after treatment was associated with an SMR of 1.1 (95% CI, 0.9 1.4) compared with an SMR of 2.5 (95% CI, 1.6 4.0) for those with elevated IGF-I levels. The appropriate use of modern management modalities reduces mortality from acromegaly to the level in the general population. Thus, normalizing mortality in patients with acromegaly is a key aim of disease management and long-term follow up. Page 5 of 7
Radiological follow up: - Postoperative MRI 3 4 months after surgery to establish a baseline for future follow-up - Patients receiving medical therapy (primary or secondary therapy after surgery and/or radiotherapy) should be assessed by MRI 3 6 months after starting therapy - Subsequent intervals of MRI scanning in patients with acromegaly after surgery and/or during medical therapy, depends on disease control and clinical judgement Pituitary function: - Pituitary function (dynamic testing) should be assessed 3 months after surgery - If this test gives normal results, there is no need for repeat dynamic pituitary function testing provided that no additional treatment modalities are required for tumour growth control or hormonal control - After radiation therapy, repeated assessment of pituitary function over the years is needed because hypopituitarism can take 10 or more years to develop - In patients receiving medical therapy, pituitary function should be assessed as clinically required Colonoscopy: The incidence of premalignant colonic lesions may be increased in acromegaly. At least one baseline colonoscopy assessment is required in all patients with acromegaly regardless of age at presentation and disease duration. Patients with colonic polyps should be followed according to the international guidelines for colon cancer. Echocardiography: - Echocardiography should be performed at baseline - In the presence of cardiomyopathy cardiology referral is appropriate Sleep disturbance: Sleep quality and disturbances such as obstructive sleep apnoea in patients with acromegaly require detailed assessment and appropriate referral for diagnosis and management. REFERENCES Page 6 of 7
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