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Advances in pituitary imaging technology and future prospects
Best Practice & Research Clinical Endocrinology & Metabolism 26 (2012) 35–46
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Advances in pituitary imaging technology and future prospects Sachit Shah, MRCP, FRCR, Specialist Registrar in Neuroradiology, Adam D. Waldman, PhD, MRCP, FRCR, Consultant Neuroradiologist *, Amrish Mehta, FRCR, Consultant Neuroradiologist Department of Imaging, Imperial College Healthcare NHS Trust & Imperial College, London, UK
Keywords: pituitary gland magnetic resonance imaging incidental findings
There have been substantial advances in pituitary imaging in the last half-century. In particular, magnetic resonance imaging is now established as the imaging modality of choice, providing high quality images of the hypothalamic–pituitary axis and adjacent structures. More recent technological advances, such as the emergence of 3 Tesla MRI, are already being widely incorporated into imaging practice. However, other advanced techniques, including a variety of potential imaging biomarkers, still require further research to evaluate their potential and define their precise role. The recent development of intraoperative MRI appears promising and may have the potential to improve the outcome of pituitary surgery. Modern high quality imaging inevitably leads to the discovery of incidental lesions, including those within the pituitary gland, although it also plays a central role in their subsequent evaluation and management. Ó 2011 Elsevier Ltd. All rights reserved.
Introduction Pituitary imaging has progressed significantly since DiChiro and Nelson published their landmark article on normal measurements of the sella turcica some fifty years ago1 (Fig. 1). The use of computed
* Corresponding author. Department of Imaging, Imperial College Healthcare NHS Trust, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, UK. Tel.: þ44 20 3311 1234; Fax: þ44 20 3311 1885. E-mail address: [email protected] (A.D. Waldman). 1521-690X/$ – see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.beem.2011.08.003
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tomography (CT) in the evaluation of sellar and parasellar masses was first described in the 1970s,2 followed approximately a decade later by the discovery of magnetic resonance imaging (MRI) of the pituitary gland.3 Since then, technological developments in CT and MR, including the addition of thinner sections and newer contrast enhancement methods have further refined pituitary imaging. Here, we provide an overview of currently available and commonly utilised imaging techniques, and an assessment of the potential clinical utility of emerging methods. The role of imaging in the discovery, and subsequent evaluation and management of the incidental pituitary lesion will also be addressed. Anatomy, embryology and imaging characteristics of the pituitary gland The pituitary gland is located within the sella turcica, a cup shaped depression in the sphenoid bone, which is bordered inferiorly and anteriorly by the sphenoid sinus. Above the pituitary gland is the suprasellar cistern, which contains the optic chiasm. The lateral walls of the pituitary fossa are formed by the cavernous sinuses, which contain the internal carotid arteries and 6th cranial nerves and, more
Fig. 1. The evolution of pituitary imaging. Lateral plain radiograph (a) demonstrating expansion of the sella turcica. Coronal reformatted post-contrast CT image (b) showing a large enhancing sellar and suprasellar mass. Coronal pre- (c) and post-contrast (d) T1-weighted MR images, revealing a large enhancing sellar mass with suprasellar extension consistent with a macroadenoma, with elevation and compression of the optic chiasm (arrowheads).
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laterally the 3rd, 4th, first and second divisions of the 5th cranial nerves in its walls. The pituitary gland is connected to the hypothalamus via the infundibulum. Embryologically, the anterior and posterior pituitary lobes are distinct.4 The anterior lobe is derived from an invagination of the oral ectoderm known as Rathke’s Pouch. The posterior pituitary forms from a protrusion of the neural ectoderm of the diencephalon. Between the anterior and posterior lobes lies a vestigial intermediate lobe, known as the pars intermedia. This is a potential site for non-functioning Rathke’s cleft cysts. The average pituitary gland measures between 3 and 8 mm in height, and is generally larger in females than males. Variations in the size of the gland are demonstrated at birth, when it is typically globular in shape, and during adolescence, due to physiological hypertrophy.4 However, the most striking physiological changes occur during pregnancy, when the gland progressively enlarges, reaching a height of up to 10 mm immediately after delivery.5 A slight increase in size also occurs during the sixth decade in females. The MR signal characteristics of the pituitary gland also change during life. At birth it returns high signal on T1-weighted images.6 By approximately 6 weeks of age this high signal diminishes anteriorly and becomes isointense to grey matter. The posterior pituitary tissue, however, retains bright signal, thought to be due to the presence of high neurophysin content not present in anterior pituitary tissue.7 Magnetic resonance imaging MRI is now established as the modality of choice for assessment of the hypothalamic–pituitary axis on the basis of excellent anatomical tissue discrimination even without pharmaceutical contrast agents, the ability to perform direct multiplanar scanning and the absence of ionising radiation in a patient group that often require multiple follow-up examinations.8 There are a number of potentially useful MRI sequences for imaging the pituitary gland and hypothalamus. However, T1-weighted sequences are most commonly used in clinical practice, as they provide excellent contrast between the pituitary gland and adjacent cerebrospinal fluid, bone marrow fat, blood vessel flow voids and paranasal sinus air (Fig. 1c). T2-weighted sequences are also typically used, as their sensitivity to changes in water content can be useful in the detection and evaluation of pituitary lesions as well as in the assessment of adjacent neurologic structures such as the hypothalamus and optic chiasm. High-resolution images are acquired most often in sagittal and coronal planes, as these provide clear anatomic information on the relationship of the gland to adjacent structures, as well as providing the best views of the pituitary stalk. The administration of intravenous paramagnetic contrast agents, typically gadolinium chelates, is common practice and results in enhancement of the pituitary gland and stalk on T1-weighted images. However, many tumours and inflammatory lesions also enhance, and therefore this commonly does not result in improved conspicuity of these lesions.8 Moreover, as the adjacent blood vessels, paranasal sinus mucosa and meninges also enhance, detection of local invasion may also not be improved. These agents do not cross the intact blood–brain barrier and therefore the hypothalamus and optic chiasm do not normally enhance. In current imaging practice, T1-weighted spin echo sequences are acquired, with repetition times (TR) of 500–600 ms, echo times (TE) of 15 ms and with two or more excitations, in coronal and sagittal planes using a matrix size of 256 256, to give 3 mm thick contiguous slices. On average, each sequence takes 5–10 min. In some centres, a 3D volumetric MPRAGE is also acquired, which provides higher out of plane resolution and enables post-processing of images in different planes, but can add to the overall acquisition time. Advanced MRI techniques Dynamic contrast enhanced MR imaging Dynamic contrast enhanced (DCE) MRI involves rapid sequential imaging of the pituitary gland during the first 60 s following iv injection of contrast media. The technique emerged in the 1990s as a promising tool in the evaluation of pituitary adenomas, on the basis of temporal differences in
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gadolinium uptake between adenoma and normal gland.9 Initial studies demonstrated that DCE-MRI was particularly useful in the detection and accurate delineation of microadenomas with no contour abnormality.10,11 More recent research has again demonstrated the value of this technique in the detection of microadenomas in patients with Cushing’s disease, with sensitivities of 67–95% compared to 50–60% using conventional contrast enhanced MRI.12,13 In addition, dynamic MRI has a greater negative predictive value for Cushing’s disease than laboratory testing in patients with mild or episodic hypercortisolism. However, this is achieved at the expense of specificity, with a relatively high rate of false-positive results (up to 30%).12,14 Moreover, whilst most modern MRI systems can run dynamic sequences, experience in acquiring and post-processing the images is not available at all centres. For these reasons, there has not been widespread incorporation of this technique into routine clinical practice, and its future role in the evaluation of microadenomas remains uncertain. 3 Tesla MRI The ability of MRI to resolve adjacent structures, i.e. spatial resolution, is clearly vitally important in the assessment of the pituitary gland. Spatial resolution depends in part on the signal-to-noise ratio of the acquired signal, which can be increased by two primary methods. One is by acquiring more data and signal averaging, which lengthens the acquisition time, and may lead to problems with motion artefact and impact on patient throughput in imaging practice. Another approach is to increase the strength of the main magnetic field, measured in Teslas (1 T ¼ 10,000 times the Earth’s magnetic field). Although 1.5T MRI systems remain the industry standard, 3T MRI is increasingly available worldwide. Recent studies have evaluated the role of higher field strength magnets in the assessment of the hypothalamic–pituitary axis, and appear to demonstrate clear advantages in the assessment of pituitary macroadenomas.15 In particular, imaging at 3T is superior to 1.5T for the prediction of cavernous sinus invasion, with reported sensitivities of 83% compared to 67%, specificities of 84% compared to 58%, and improved correlation with surgical findings.16 Better delineation of parasellar anatomy is also reported, with improved identification of nerves within the cavernous sinus (Fig. 2a). In addition, recent research has also demonstrated that the improved signal-to-noise ratio and spatial resolution of a 3T system allows better localisation of microadenomas in patients with Cushing’s disease17 (Fig. 2b). These studies suggest that the introduction of 3T MRI into routine clinical practice is likely to benefit pituitary imaging, with improved pre-operative assessment of sellar lesions. However, it should be noted that in comparison with 1.5T, imaging at 3T is prone to increased susceptibility artefacts and magnetic field inhomogeneities, which are particularly marked around the pituitary fossa due to the proximity of bone and air interfaces, and may limit image quality. Moreover, prolonged T1 and reduced intensity of contrast enhancement at 3T may affect the delineation of pituitary lesions from surrounding structures. It is therefore clearly necessary to optimise the imaging parameters to achieve the improvements in diagnostic quality described above. It has been postulated that at 3T, post-contrast T1-weighted 3D gradient echo sequences are more useful for evaluating sellar lesions than conventional 2D spin echo sequences. This is thought to be due a short TE, which reduces pulsation artefacts, and thin-slice imaging, which reduces partial volume effects. Furthermore, such sequences are less prone to magnetic field inhomogeneities, although they are affected by hyperintensity of blood vessels, and increased susceptibility effects.18 There is indeed recent evidence that 3D gradient echo sequences provided significantly better images than spin echo sequences in terms of the border of sellar lesions, delineation of cranial nerves, and overall image quality.19 Perfusion MRI Perfusion MRI provides potential imaging biomarkers of cerebral microvascularity, and has an established role in the evaluation of acute stroke and intrinsic brain tumours. The application of this technique in the evaluation of pituitary lesions has been limited, but may have significant future
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potential, as demonstrated by research evaluating the effects of dopamine agonists on the vascularity of prolactinomas compared with the normal pituitary gland.20 In a relatively small study, functional microadenomas were found to have greater vascularity than the normal pituitary, whereas macroadenomas were indistinguishable from normal gland. Importantly, following treatment with a dopamine agonist, there were significant decreases in vascular parameters in both macroadenomas and microadenomas, but not in normal pituitary glands, and this preceded a reduction the size of the lesions. Interestingly in one patient with a macroadenoma where there was no decrease in vascularity, no subsequent decrease in the size of the lesion was shown. Although further studies with larger patient numbers are clearly needed, these findings do suggest a potential role for perfusion MR as an imaging biomarker in the evaluation of pituitary adenomas, and
Fig. 2. High-resolution pituitary MR imaging at 3T. Coronal post-contrast T1-weighted 3T MR images demonstrating (a) clear anatomic delineation of cranial nerves III, V1, V2 and VI (labelled) within the cavernous sinus and its lateral walls, and (b) a focal round hypointense lesion within the left side of the pituitary gland consistent with a microadenoma (arrow).
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in particular to identify lesions that are unlikely to respond to medical therapy and therefore require surgery. Diffusion weighted imaging (DWI) One of the considerations in the surgical approach to macroadenomas is tumour consistency.21 Whilst most macroadenomas are soft and easily resectable, about 10% of large pituitary tumours may be fibrous. These harder components cannot be successfully removed with endoscopic techniques and may require a more extensive transsphenoidal approach.22 The role of conventional MRI in the prediction of the consistency of macroadenomas is controversial. Although in theory the relatively high collagen content in fibrous tumours should account for lower signal intensity on T2-weighted images, this correlation has not been consistently demonstrated in practice.21,23 A potential role for diffusion weighted imaging in improving the pre-operative characterisation of tumour components has therefore been proposed, based on differences in water diffusion. A recent prospective study of twenty-two patients with macroadenomas demonstrated a significant correlation between diffusion parameters and tumour consistency.22 Adenomas with higher apparent diffusion coefficient (ADC) values on pre-operative imaging were found to have a hard consistency at surgery and high collagen content (and reduced cellularity) on histology (Fig. 3). No such correlation was found comparing signal intensities on conventional T1 and T2-weighted sequences. Although these initial findings suggested that DWI could provide useful information about the consistency of macroadenomas, and therefore help avoid multistage surgical procedures, subsequent similar DWI studies have found no such correlation between ADC values and tumour consistency or collagen content.24,25 Therefore, at present, the role of DWI in the prediction of pituitary tumour consistency remains uncertain. Diffusion tensor imaging (DTI) The freedom of motion of water molecules in nerve fibre tracts is anisotropic, i.e. their movement is less restricted along the fibre tract rather than orthogonal to it. This difference can be exploited by DTI, which measures the magnitude and direction of this difference in motion to provide maps of nerve fibre tracts in the brain. As we have already seen, a critical issue in imaging pituitary macroadenomas is the presence of cavernous sinus invasion, which can significantly affect the surgical management. Traditionally, radiological evaluation of cavernous sinus invasion has relied largely on the anatomic relationship of tumour to the internal carotid arteries and cavernous sinus venous compartments.26 However, it has been hypothesised that cavernous sinus invasion may be better assessed by utilising anisotropic imaging techniques to detect interference of the uniformity of nerve fibres within the cavernous sinus.27 Using this technique, the oculomotor, and ophthalmic and maxillary divisions of the trigeminal nerve were identified in all 116 imaged cavernous sinuses. Moreover, in patients with pituitary macroadenomas with cavernous sinus invasion, there was excellent concordance between imaging and surgical findings, with a sensitivity and specificity of 100% for oculomotor nerve involvement. This early study highlights the potential future use of this technique in the assessment of cavernous sinus invasion by pituitary macroadenomas. MR spectroscopy Proton MR spectroscopy (MRS) has emerged as a useful technique to assess metabolic features noninvasively in a variety of cerebral disorders. In particular, it is increasingly utilised in the assessment and follow-up of intracranial gliomas, where it can provide information on tumour grade and posttreatment recurrence.28 As some pituitary adenomas behave more aggressively than others, with rapid increases in size and a propensity for recurrence, MRS could potentially be applied to predict the behaviour of these tumours, and provide information on the likely success of treatment and prognosis. Indeed, a recent small study found a strongly positive correlation between the level of choline metabolites on MRS, and histological indices of proliferation in patients with pituitary
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macroadenomas.29 However, at present this technique only provides reliable spectroscopic data in adenomas larger than 2 cm, and is unreliable in the presence of intratumoral haemorrhage due to susceptibility effects. MRS therefore clearly remains an experimental technique in pituitary imaging, but has potential applications in stratifying tumour behaviour non-invasively in selected cases where metabolite data can be acquired. Intraoperative MRI (iMRI) The development of low field strength open MR systems in the mid-1990s made intraoperative MRI possible for the first time, and it has since been shown to be safe and reliable in the surgical environment.30,31 In recent years, iMRI has attracted increasing interest in the surgical management of pituitary lesions, with particular reference to guiding the surgeon to tumour remnants concealed from the operating microscope during transsphenoidal surgery.
Fig. 3. Macroadenoma with hard consistency at surgery. Coronal T2-weighted MR image (a) demonstrates a large heterogeneous sellar and suprasellar mass (arrows). The coronal DW MR image (b) demonstrates that the mass is relatively hypointense, and the corresponding ADC map (c) reveals an increase in the diffusion coefficient compared to brain parenchyma. The histologic specimen (d) demonstrates abundant fibrous stroma and low cellularity. (Images kindly provided by: Pierallini A et al. Radiology 2006; 239: 223–231)
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Several studies have evaluated the use of low field strength iMRI in this setting and have found that its use frequently reveals residual tumour, and enables more complete primary resections, particularly for tumours with suprasellar components, leading to a decreased likelihood of repeat surgery.32–34 In addition, the constantly updated images allow real-time intraoperative visualisation of key anatomical landmarks such as the optic chiasm and carotid arteries, enabling the surgeon to visualise changes in the position of these structures because of brain shift or other operative changes.35 In theory, this provides an advantage over frame-based and frameless stereotactic surgical techniques, and would therefore be expected to lead to improved patient safety and lower morbidity. At present, however, few studies including discussions of complication rates are available for evaluation. The relatively poor image quality of low field strength MRI appears to only reliably allow the evaluation of suprasellar tumour parts, with limited accuracy for infrasellar and cavernous sinus extension.34,36 There has therefore been increasing interest in the potential role of high field strength iMRI, and recent studies using 1.5T iMRI in transsphenoidal surgery have shown that, in addition to the suprasellar compartment, the intra- and parasellar structures are visualised in great detail, with no difference in image quality compared to standard pre-operative MRI.37 The use of 1.5T iMRI in this scenario again results in more extensive resections, with an increase in the percentage of complete tumour removals from 57% to 87%. Moreover, in those cases where complete resection is not possible, the high quality images acquired from 1.5T iMRI allow immediate planning of further post-operative treatment options, such as radiation therapy or transcranial surgery.38 Without good quality intraoperative imaging, such planning would not be possible until 2–3 months after surgery, due to artefacts and other limitations of early post-operative imaging. In summary, intraoperative MR imaging may have a role in the resection of pituitary lesion remnants that are poorly visualised under the operating microscope, enabling more complete resections and in theory improving patient safety and post-operative treatment planning. Prospective studies of the impact of iMRI on recurrence rates and long-term outcomes have, however, yet to be performed. Computed tomography CT of the pituitary region remains the primary imaging modality for patients who are unable to undergo MRI, for example due to cardiac pacemaker devices or claustrophobia. Modern multidetector CT scanners can quickly acquire high-resolution images of excellent quality in the axial plane. These images can then be post-processed to provide coronal and sagittal views. Although sellar anatomy is well depicted on unenhanced images, intravenous injection of iodinated contrast media is also commonly used to improve the tissue contrast between normal gland and pathological lesions (Fig. 1b). Despite the inferior soft tissue discrimination of CT compared to MRI, it provides better imaging of bone, and remains useful for identifying the presence of calcification, or demonstrating bony erosion of the sellar floor.39,40 In addition, CT provides important pre-operative data for transsphenoidal hypophysectomy, including the bony structure of the ethmoid and sphenoid sinuses.8 However, the technique necessitates exposure to ionising radiation, and in a patient group that often require multiple follow-up imaging examinations, this is clearly not ideal. Nuclear isotope (radionuclide) imaging Radionuclide techniques play a relatively limited role in pituitary evaluation. Sellar masses may be detected with single photon emission tomography (SPECT), using pharmaceuticals that specifically bind to pituitary receptors. One such example is the use of 111indium labelled octreotide for investigating non-functioning adenomas.41 However, its usefulness is limited by the fact that other parasellar tumours such as meningiomas may express somatostatin receptors and therefore also take up octreotide.42 There is also a limited role for positron emission tomography (PET) using 18F-fluoro-deoxy-Dglucose (FDG) in assessing biological activity of pituitary tumours, as the majority of pituitary lesions are slow growing, and therefore not metabolically active. Tracers such as 11C-methionine have shown some promise, although the short half-life and high cost of production of this pharmaceutical currently restricts its use to research purposes.43
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Pituitary incidentalomas An inevitable consequence of high quality modern imaging is the incidentally discovered lesion. Pituitary ‘incidentalomas’ are, by definition, lesions that are revealed, usually by CT or MRI, in the investigation of unrelated disorders. Clearly, the converse also occurs: incidental abnormalities elsewhere in the brain are often uncovered as a consequence of pituitary imaging. In population studies, the prevalence of incidental pituitary adenomas has been estimated to be in the region of 0.7/1000 (0.07%).44 However, this has been reported to be even higher in adults undergoing imaging studies for other reasons, with incidental macroadenomas shown in up to 0.2% of cases.45,46 This suggests that these patients may in fact have a potentially relevant symptom that was not readily apparent or reported but that led to the imaging examination. Indeed, the most common reason for the imaging study leading to the discovery of the pituitary incidentaloma is headache.47
Fig. 4. Incidental pituitary lesion in a patient being investigated for headache. Dedicated pituitary imaging was performed following the initial imaging study: coronal T2-weighted (a) and sagittal post-contrast T1-weighted (b) MR images demonstrate a small triangular lesion located at the junction of the anterior and posterior pituitary (arrows), consistent with an incidental pars intermedia cyst.
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Because incidentalomas infrequently come to surgery, the underlying pathological diagnosis generally remains unknown. However, the available evidence suggests that the pathology of incidentalomas reflects the general data on sellar masses, with adenomas accounting for approximately 90%, and most of the remainder being Rathke’s cleft cysts or craniopharyngiomas.48,49 The initial approach to a patient discovered to have a pituitary incidentaloma depends on whether there is hormone hypersecretion, or evidence of mass effect with pressure on adjacent structures from clinical, laboratory or imaging studies.50 MRI plays a central role in this initial evaluation, and all patients should undergo a specific pituitary protocol examination to better delineate its nature and extent (Fig. 4). Referral for surgical treatment is required at this stage if the lesion abuts or compresses the optic nerves or chiasm on imaging. Patients with incidentalomas not meeting criteria for surgical removal should be followed-up with serial MRI, as it has been demonstrated that although these lesions are generally slow growing, the true proliferative nature of the incidentaloma is unknown. In data combined from a number of studies, 8.2% of ‘macroincidentalomas’ enlarged per year, compared to 1.7% of ‘microincidentalomas’.51 It is therefore generally accepted that follow-up MRI should be performed after 6 months for macroincidentalomas and after 1 year for microincidentalomas. The optimal interval and duration of long-term follow-up imaging is more uncertain, but in general this should take into account an assessment of the risk of progression of the lesion versus the burden to the patient of repeated surveillance testing. Clearly, a significant increase in the size of the lesion should be an indication for more frequent or detailed evaluations, as guided clinically. The Endocrine Society has recently published guidelines on the evaluation and treatment of pituitary incidentalomas, summarising the above.52 They recommend that patients with incidentalomas not meeting criteria for surgical removal be followed-up with MRI at 6 months for macroincidentalomas and 1 year for microincidentalomas, and thereafter progressively less frequently if unchanged in size. They also recommend that patients be referred for surgery if there is clinical, laboratory or imaging evidence of compressive mass effect from the tumour, or if the incidentaloma is a hypersecreting tumour other than a prolactinoma.
Summary Multiple advances in pituitary imaging technology have been made in the past half-century. MRI is now established as the imaging modality of choice, and produces high quality images of the gland and adjacent structures, especially at 3T. Modern multislice CT provides a viable alternative and additional imaging modality. Intraoperative MRI may lead to improvements in the surgical treatment of pituitary lesions, but further prospective study of the impact of this technology on morbidity and long-term outcome is required. Physiological and molecular imaging with MRI and PET can provide biomarkers of tumour behaviour and treatment response, although their precise role in clinical practice and therapeutic trials is yet to be established. Modern brain imaging results in the discovery of unsuspected or incidental pituitary lesions, but also plays a central role in their evaluation and management. Practice points Unenhanced high-resolution T1-weighted MRI sequences are most commonly used in clinical practice due to the excellent contrast between the pituitary gland and adjacent structures 3T MRI provides better delineation of parasellar anatomy, improved prediction of cavernous sinus invasion, and more accurate localisation of microadenomas Although dynamic contrast enhanced MRI improves detection rates of microadenomas, it occurs at the expense of a reduction in specificity, and has therefore not been widely incorporated into routine imaging practice Patients with incidental pituitary lesions not meeting criteria for surgical removal should be followed-up with MRI at 6 months for ‘macroincidentalomas’ and at 1 year for ‘microincidentalomas’
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Research agenda Physiological (perfusion MRI, diffusion weighted imaging, diffusion tensor imaging and MR spectroscopy) and molecular (PET/SPECT) imaging may provide potential biomarkers of the behaviour of pituitary masses, although further studies are needed to evaluate their potential and define their precise role Investigations into the long-term outcomes of intraoperative MRI, particularly with respect to tumour recurrence compared to standard pituitary surgery, are required
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27. Yoneoka Y, Watanabe N, Matsuzawa H et al. Preoperative depiction of cavernous sinus invasion by pituitary macroadenoma using three-dimensional anisotropy contrast periodically rotated overlapping parallel lines with enhanced reconstruction imaging on a 3-tesla system. Journal of Neurosurgery 2008; 108: 37–41. 28. Sibtain NA, Howe FA & Saunders DE. The clinical value of proton magnetic resonance spectroscopy in adult brain tumours. Clinical Radiology 2007; 62: 109–119. 29. Stadlbauer A, Buchfelder M, Nimsky C et al. Proton magnetic resonance spectroscopy in pituitary macroadenomas: preliminary results. Journal of Neurosurgery 2008; 109: 306–312. *30. Black PM, Moriarty T, Alexander 3rd E et al. Development and implementation of intraoperative magnetic resonance imaging and its neurosurgical applications. Neurosurgery 1997; 41: 831–842. 31. Schwartz RB, Hsu L, Wong TZ et al. Intraoperative MR imaging guidance for intracranial neurosurgery: experience with the first 200 cases. Radiology 1999; 211: 477–488. 32. Bohinski RJ, Warnick RE, Gaskill-Shipley MF et al. Intraoperative magnetic resonance imaging to determine the extent of resection of pituitary macroadenomas during transsphenoidal microsurgery. Neurosurgery 2001; 49: 1133–1143. 33. Nimsky C, Ganslandt O, Tomandl B et al. Low-field magnetic resonance imaging for intraoperative use in neurosurgery: a 5-year experience. European Radiology 2002; 12: 2690–2703. 34. Wu JS, Shou XF, Yao CJ et al. Transsphenoidal pituitary macroadenomas resection guided by PoleStar N20 low-field intraoperative magnetic resonance imaging: comparison with early post-operative high-field magnetic resonance imaging. Neurosurgery 2009; 65: 63–70. 35. Jones J & Ruge J. Intraoperative magnetic resonance imaging in pituitary macroadenoma surgery: an assessment of visual outcome. Neurosurgical Focus 2007; 23: E12. 36. Kreutzer J & Fahlbusch R. Diagnosis and treatment of pituitary tumors. Current Opinion in Neurology 2004; 17: 693–703. 37. Nimsky C, von Keller B, Ganslandt O et al. Intraoperative high-field magnetic resonance imaging in transsphenoidal surgery of hormonally inactive pituitary macroadenomas. Neurosurgery 2006; 59: 105–114. 38. Nimsky C, Ganslandt O, Von Keller B et al. Intraoperative high-field-strength MR imaging: implementation and experience in 200 patients. Radiology 2004; 233: 67–78. 39. Lundin P, Bergstrom K, Thuomas KA et al. Comparison of MR imaging and CT in pituitary macroadenomas. Acta Radiologica 1991; 32: 189–196. 40. Miki Y, Kanagaki M, Takahashi JA et al. Evaluation of pituitary macroadenomas with multidetector-row CT (MDCT): comparison with MR imaging. Neuroradiology 2007; 49: 327–333. 41. Krenning EP, Kwekkeboom DJ, Bakker WH et al. Somatostatin receptor scintigraphy with 111In-DTPA-D-Pne and 123ITyr3-octeotride: the Rotterdam experience in more than 1000 patients. European Journal of Nuclear Medicine 1993; 20: 716–721. 42. Lamberts SW, Krenning EP & Renbi JC. The role of somatostatin and its analogs in the diagnosis and treatment of tumours. Endocrine Reviews 1991; 12: 450–482. 43. Khan S, Lloyd C, Szyszko T et al. PET imaging in endocrine tumours. Minerva Endocrinologica 2008; 33: 41–52. 44. Fernandez A, Karavitaki N & Wass JA. Prevalence of pituitary adenomas: a community-based cross-sectional study in Banbury (Oxfordshire, UK). Clinical Endocrinology 2010; 72: 377–382. 45. Yue NC, Longstreth Jr. WT, Elster AD et al. Clinically serious abnormalities found incidentally at MR imaging of the brain: data from the Cardiovascular Health Study. Radiology 1997; 202: 41–46. 46. Nammour GM, Ybarra J, Naheedy MH et al. Incidental pituitary macroadenoma: a population-based study. American Journal of Medical Sciences 1997; 314: 287–291. 47. Sanno N, Oyama K, Tahara S et al. A survey of pituitary incidentaloma in Japan. European Journal of Endocrinology 2003; 149: 123–127. 48. Freda PU & Post KD. Differential diagnosis of sellar masses. Endocrinology and Metabolism Clinics of North America 1999; 28: 81–117. 49. Fainstein Day P, Guitelman M, Artese R et al. Retrospective multicentric study of pituitary incidentalomas. Pituitary 2004; 7: 145–148. 50. Serhal D, Weil RJ & Hamrahian AH. Evaluation and management of pituitary incidentalomas. Cleveland Clinic Journal of Medicine 2008; 75: 793–801. 51. Fernandez-Balsells MM, Murad MH, Barwise A et al. Natural history of nonfunctioning pituitary adenomas and incidentalomas: a systematic review and metaanalysis. Journal of Clinical Endocrinology and Metabolism 2011; 96: 905–912. *52. Freda PU, Beckers AM, Katznelson L et al. Pituitary incidentaloma: an endocrine society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 2011; 96: 894–904.
Contents lists available at ScienceDirect
Best Practice & Research Clinical Endocrinology & Metabolism journal homepage: www.elsevier.com/locate/beem
4
Advances in pituitary imaging technology and future prospects Sachit Shah, MRCP, FRCR, Specialist Registrar in Neuroradiology, Adam D. Waldman, PhD, MRCP, FRCR, Consultant Neuroradiologist *, Amrish Mehta, FRCR, Consultant Neuroradiologist Department of Imaging, Imperial College Healthcare NHS Trust & Imperial College, London, UK
Keywords: pituitary gland magnetic resonance imaging incidental findings
There have been substantial advances in pituitary imaging in the last half-century. In particular, magnetic resonance imaging is now established as the imaging modality of choice, providing high quality images of the hypothalamic–pituitary axis and adjacent structures. More recent technological advances, such as the emergence of 3 Tesla MRI, are already being widely incorporated into imaging practice. However, other advanced techniques, including a variety of potential imaging biomarkers, still require further research to evaluate their potential and define their precise role. The recent development of intraoperative MRI appears promising and may have the potential to improve the outcome of pituitary surgery. Modern high quality imaging inevitably leads to the discovery of incidental lesions, including those within the pituitary gland, although it also plays a central role in their subsequent evaluation and management. Ó 2011 Elsevier Ltd. All rights reserved.
Introduction Pituitary imaging has progressed significantly since DiChiro and Nelson published their landmark article on normal measurements of the sella turcica some fifty years ago1 (Fig. 1). The use of computed
* Corresponding author. Department of Imaging, Imperial College Healthcare NHS Trust, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, UK. Tel.: þ44 20 3311 1234; Fax: þ44 20 3311 1885. E-mail address: [email protected] (A.D. Waldman). 1521-690X/$ – see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.beem.2011.08.003
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tomography (CT) in the evaluation of sellar and parasellar masses was first described in the 1970s,2 followed approximately a decade later by the discovery of magnetic resonance imaging (MRI) of the pituitary gland.3 Since then, technological developments in CT and MR, including the addition of thinner sections and newer contrast enhancement methods have further refined pituitary imaging. Here, we provide an overview of currently available and commonly utilised imaging techniques, and an assessment of the potential clinical utility of emerging methods. The role of imaging in the discovery, and subsequent evaluation and management of the incidental pituitary lesion will also be addressed. Anatomy, embryology and imaging characteristics of the pituitary gland The pituitary gland is located within the sella turcica, a cup shaped depression in the sphenoid bone, which is bordered inferiorly and anteriorly by the sphenoid sinus. Above the pituitary gland is the suprasellar cistern, which contains the optic chiasm. The lateral walls of the pituitary fossa are formed by the cavernous sinuses, which contain the internal carotid arteries and 6th cranial nerves and, more
Fig. 1. The evolution of pituitary imaging. Lateral plain radiograph (a) demonstrating expansion of the sella turcica. Coronal reformatted post-contrast CT image (b) showing a large enhancing sellar and suprasellar mass. Coronal pre- (c) and post-contrast (d) T1-weighted MR images, revealing a large enhancing sellar mass with suprasellar extension consistent with a macroadenoma, with elevation and compression of the optic chiasm (arrowheads).
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laterally the 3rd, 4th, first and second divisions of the 5th cranial nerves in its walls. The pituitary gland is connected to the hypothalamus via the infundibulum. Embryologically, the anterior and posterior pituitary lobes are distinct.4 The anterior lobe is derived from an invagination of the oral ectoderm known as Rathke’s Pouch. The posterior pituitary forms from a protrusion of the neural ectoderm of the diencephalon. Between the anterior and posterior lobes lies a vestigial intermediate lobe, known as the pars intermedia. This is a potential site for non-functioning Rathke’s cleft cysts. The average pituitary gland measures between 3 and 8 mm in height, and is generally larger in females than males. Variations in the size of the gland are demonstrated at birth, when it is typically globular in shape, and during adolescence, due to physiological hypertrophy.4 However, the most striking physiological changes occur during pregnancy, when the gland progressively enlarges, reaching a height of up to 10 mm immediately after delivery.5 A slight increase in size also occurs during the sixth decade in females. The MR signal characteristics of the pituitary gland also change during life. At birth it returns high signal on T1-weighted images.6 By approximately 6 weeks of age this high signal diminishes anteriorly and becomes isointense to grey matter. The posterior pituitary tissue, however, retains bright signal, thought to be due to the presence of high neurophysin content not present in anterior pituitary tissue.7 Magnetic resonance imaging MRI is now established as the modality of choice for assessment of the hypothalamic–pituitary axis on the basis of excellent anatomical tissue discrimination even without pharmaceutical contrast agents, the ability to perform direct multiplanar scanning and the absence of ionising radiation in a patient group that often require multiple follow-up examinations.8 There are a number of potentially useful MRI sequences for imaging the pituitary gland and hypothalamus. However, T1-weighted sequences are most commonly used in clinical practice, as they provide excellent contrast between the pituitary gland and adjacent cerebrospinal fluid, bone marrow fat, blood vessel flow voids and paranasal sinus air (Fig. 1c). T2-weighted sequences are also typically used, as their sensitivity to changes in water content can be useful in the detection and evaluation of pituitary lesions as well as in the assessment of adjacent neurologic structures such as the hypothalamus and optic chiasm. High-resolution images are acquired most often in sagittal and coronal planes, as these provide clear anatomic information on the relationship of the gland to adjacent structures, as well as providing the best views of the pituitary stalk. The administration of intravenous paramagnetic contrast agents, typically gadolinium chelates, is common practice and results in enhancement of the pituitary gland and stalk on T1-weighted images. However, many tumours and inflammatory lesions also enhance, and therefore this commonly does not result in improved conspicuity of these lesions.8 Moreover, as the adjacent blood vessels, paranasal sinus mucosa and meninges also enhance, detection of local invasion may also not be improved. These agents do not cross the intact blood–brain barrier and therefore the hypothalamus and optic chiasm do not normally enhance. In current imaging practice, T1-weighted spin echo sequences are acquired, with repetition times (TR) of 500–600 ms, echo times (TE) of 15 ms and with two or more excitations, in coronal and sagittal planes using a matrix size of 256 256, to give 3 mm thick contiguous slices. On average, each sequence takes 5–10 min. In some centres, a 3D volumetric MPRAGE is also acquired, which provides higher out of plane resolution and enables post-processing of images in different planes, but can add to the overall acquisition time. Advanced MRI techniques Dynamic contrast enhanced MR imaging Dynamic contrast enhanced (DCE) MRI involves rapid sequential imaging of the pituitary gland during the first 60 s following iv injection of contrast media. The technique emerged in the 1990s as a promising tool in the evaluation of pituitary adenomas, on the basis of temporal differences in
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gadolinium uptake between adenoma and normal gland.9 Initial studies demonstrated that DCE-MRI was particularly useful in the detection and accurate delineation of microadenomas with no contour abnormality.10,11 More recent research has again demonstrated the value of this technique in the detection of microadenomas in patients with Cushing’s disease, with sensitivities of 67–95% compared to 50–60% using conventional contrast enhanced MRI.12,13 In addition, dynamic MRI has a greater negative predictive value for Cushing’s disease than laboratory testing in patients with mild or episodic hypercortisolism. However, this is achieved at the expense of specificity, with a relatively high rate of false-positive results (up to 30%).12,14 Moreover, whilst most modern MRI systems can run dynamic sequences, experience in acquiring and post-processing the images is not available at all centres. For these reasons, there has not been widespread incorporation of this technique into routine clinical practice, and its future role in the evaluation of microadenomas remains uncertain. 3 Tesla MRI The ability of MRI to resolve adjacent structures, i.e. spatial resolution, is clearly vitally important in the assessment of the pituitary gland. Spatial resolution depends in part on the signal-to-noise ratio of the acquired signal, which can be increased by two primary methods. One is by acquiring more data and signal averaging, which lengthens the acquisition time, and may lead to problems with motion artefact and impact on patient throughput in imaging practice. Another approach is to increase the strength of the main magnetic field, measured in Teslas (1 T ¼ 10,000 times the Earth’s magnetic field). Although 1.5T MRI systems remain the industry standard, 3T MRI is increasingly available worldwide. Recent studies have evaluated the role of higher field strength magnets in the assessment of the hypothalamic–pituitary axis, and appear to demonstrate clear advantages in the assessment of pituitary macroadenomas.15 In particular, imaging at 3T is superior to 1.5T for the prediction of cavernous sinus invasion, with reported sensitivities of 83% compared to 67%, specificities of 84% compared to 58%, and improved correlation with surgical findings.16 Better delineation of parasellar anatomy is also reported, with improved identification of nerves within the cavernous sinus (Fig. 2a). In addition, recent research has also demonstrated that the improved signal-to-noise ratio and spatial resolution of a 3T system allows better localisation of microadenomas in patients with Cushing’s disease17 (Fig. 2b). These studies suggest that the introduction of 3T MRI into routine clinical practice is likely to benefit pituitary imaging, with improved pre-operative assessment of sellar lesions. However, it should be noted that in comparison with 1.5T, imaging at 3T is prone to increased susceptibility artefacts and magnetic field inhomogeneities, which are particularly marked around the pituitary fossa due to the proximity of bone and air interfaces, and may limit image quality. Moreover, prolonged T1 and reduced intensity of contrast enhancement at 3T may affect the delineation of pituitary lesions from surrounding structures. It is therefore clearly necessary to optimise the imaging parameters to achieve the improvements in diagnostic quality described above. It has been postulated that at 3T, post-contrast T1-weighted 3D gradient echo sequences are more useful for evaluating sellar lesions than conventional 2D spin echo sequences. This is thought to be due a short TE, which reduces pulsation artefacts, and thin-slice imaging, which reduces partial volume effects. Furthermore, such sequences are less prone to magnetic field inhomogeneities, although they are affected by hyperintensity of blood vessels, and increased susceptibility effects.18 There is indeed recent evidence that 3D gradient echo sequences provided significantly better images than spin echo sequences in terms of the border of sellar lesions, delineation of cranial nerves, and overall image quality.19 Perfusion MRI Perfusion MRI provides potential imaging biomarkers of cerebral microvascularity, and has an established role in the evaluation of acute stroke and intrinsic brain tumours. The application of this technique in the evaluation of pituitary lesions has been limited, but may have significant future
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potential, as demonstrated by research evaluating the effects of dopamine agonists on the vascularity of prolactinomas compared with the normal pituitary gland.20 In a relatively small study, functional microadenomas were found to have greater vascularity than the normal pituitary, whereas macroadenomas were indistinguishable from normal gland. Importantly, following treatment with a dopamine agonist, there were significant decreases in vascular parameters in both macroadenomas and microadenomas, but not in normal pituitary glands, and this preceded a reduction the size of the lesions. Interestingly in one patient with a macroadenoma where there was no decrease in vascularity, no subsequent decrease in the size of the lesion was shown. Although further studies with larger patient numbers are clearly needed, these findings do suggest a potential role for perfusion MR as an imaging biomarker in the evaluation of pituitary adenomas, and
Fig. 2. High-resolution pituitary MR imaging at 3T. Coronal post-contrast T1-weighted 3T MR images demonstrating (a) clear anatomic delineation of cranial nerves III, V1, V2 and VI (labelled) within the cavernous sinus and its lateral walls, and (b) a focal round hypointense lesion within the left side of the pituitary gland consistent with a microadenoma (arrow).
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in particular to identify lesions that are unlikely to respond to medical therapy and therefore require surgery. Diffusion weighted imaging (DWI) One of the considerations in the surgical approach to macroadenomas is tumour consistency.21 Whilst most macroadenomas are soft and easily resectable, about 10% of large pituitary tumours may be fibrous. These harder components cannot be successfully removed with endoscopic techniques and may require a more extensive transsphenoidal approach.22 The role of conventional MRI in the prediction of the consistency of macroadenomas is controversial. Although in theory the relatively high collagen content in fibrous tumours should account for lower signal intensity on T2-weighted images, this correlation has not been consistently demonstrated in practice.21,23 A potential role for diffusion weighted imaging in improving the pre-operative characterisation of tumour components has therefore been proposed, based on differences in water diffusion. A recent prospective study of twenty-two patients with macroadenomas demonstrated a significant correlation between diffusion parameters and tumour consistency.22 Adenomas with higher apparent diffusion coefficient (ADC) values on pre-operative imaging were found to have a hard consistency at surgery and high collagen content (and reduced cellularity) on histology (Fig. 3). No such correlation was found comparing signal intensities on conventional T1 and T2-weighted sequences. Although these initial findings suggested that DWI could provide useful information about the consistency of macroadenomas, and therefore help avoid multistage surgical procedures, subsequent similar DWI studies have found no such correlation between ADC values and tumour consistency or collagen content.24,25 Therefore, at present, the role of DWI in the prediction of pituitary tumour consistency remains uncertain. Diffusion tensor imaging (DTI) The freedom of motion of water molecules in nerve fibre tracts is anisotropic, i.e. their movement is less restricted along the fibre tract rather than orthogonal to it. This difference can be exploited by DTI, which measures the magnitude and direction of this difference in motion to provide maps of nerve fibre tracts in the brain. As we have already seen, a critical issue in imaging pituitary macroadenomas is the presence of cavernous sinus invasion, which can significantly affect the surgical management. Traditionally, radiological evaluation of cavernous sinus invasion has relied largely on the anatomic relationship of tumour to the internal carotid arteries and cavernous sinus venous compartments.26 However, it has been hypothesised that cavernous sinus invasion may be better assessed by utilising anisotropic imaging techniques to detect interference of the uniformity of nerve fibres within the cavernous sinus.27 Using this technique, the oculomotor, and ophthalmic and maxillary divisions of the trigeminal nerve were identified in all 116 imaged cavernous sinuses. Moreover, in patients with pituitary macroadenomas with cavernous sinus invasion, there was excellent concordance between imaging and surgical findings, with a sensitivity and specificity of 100% for oculomotor nerve involvement. This early study highlights the potential future use of this technique in the assessment of cavernous sinus invasion by pituitary macroadenomas. MR spectroscopy Proton MR spectroscopy (MRS) has emerged as a useful technique to assess metabolic features noninvasively in a variety of cerebral disorders. In particular, it is increasingly utilised in the assessment and follow-up of intracranial gliomas, where it can provide information on tumour grade and posttreatment recurrence.28 As some pituitary adenomas behave more aggressively than others, with rapid increases in size and a propensity for recurrence, MRS could potentially be applied to predict the behaviour of these tumours, and provide information on the likely success of treatment and prognosis. Indeed, a recent small study found a strongly positive correlation between the level of choline metabolites on MRS, and histological indices of proliferation in patients with pituitary
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macroadenomas.29 However, at present this technique only provides reliable spectroscopic data in adenomas larger than 2 cm, and is unreliable in the presence of intratumoral haemorrhage due to susceptibility effects. MRS therefore clearly remains an experimental technique in pituitary imaging, but has potential applications in stratifying tumour behaviour non-invasively in selected cases where metabolite data can be acquired. Intraoperative MRI (iMRI) The development of low field strength open MR systems in the mid-1990s made intraoperative MRI possible for the first time, and it has since been shown to be safe and reliable in the surgical environment.30,31 In recent years, iMRI has attracted increasing interest in the surgical management of pituitary lesions, with particular reference to guiding the surgeon to tumour remnants concealed from the operating microscope during transsphenoidal surgery.
Fig. 3. Macroadenoma with hard consistency at surgery. Coronal T2-weighted MR image (a) demonstrates a large heterogeneous sellar and suprasellar mass (arrows). The coronal DW MR image (b) demonstrates that the mass is relatively hypointense, and the corresponding ADC map (c) reveals an increase in the diffusion coefficient compared to brain parenchyma. The histologic specimen (d) demonstrates abundant fibrous stroma and low cellularity. (Images kindly provided by: Pierallini A et al. Radiology 2006; 239: 223–231)
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Several studies have evaluated the use of low field strength iMRI in this setting and have found that its use frequently reveals residual tumour, and enables more complete primary resections, particularly for tumours with suprasellar components, leading to a decreased likelihood of repeat surgery.32–34 In addition, the constantly updated images allow real-time intraoperative visualisation of key anatomical landmarks such as the optic chiasm and carotid arteries, enabling the surgeon to visualise changes in the position of these structures because of brain shift or other operative changes.35 In theory, this provides an advantage over frame-based and frameless stereotactic surgical techniques, and would therefore be expected to lead to improved patient safety and lower morbidity. At present, however, few studies including discussions of complication rates are available for evaluation. The relatively poor image quality of low field strength MRI appears to only reliably allow the evaluation of suprasellar tumour parts, with limited accuracy for infrasellar and cavernous sinus extension.34,36 There has therefore been increasing interest in the potential role of high field strength iMRI, and recent studies using 1.5T iMRI in transsphenoidal surgery have shown that, in addition to the suprasellar compartment, the intra- and parasellar structures are visualised in great detail, with no difference in image quality compared to standard pre-operative MRI.37 The use of 1.5T iMRI in this scenario again results in more extensive resections, with an increase in the percentage of complete tumour removals from 57% to 87%. Moreover, in those cases where complete resection is not possible, the high quality images acquired from 1.5T iMRI allow immediate planning of further post-operative treatment options, such as radiation therapy or transcranial surgery.38 Without good quality intraoperative imaging, such planning would not be possible until 2–3 months after surgery, due to artefacts and other limitations of early post-operative imaging. In summary, intraoperative MR imaging may have a role in the resection of pituitary lesion remnants that are poorly visualised under the operating microscope, enabling more complete resections and in theory improving patient safety and post-operative treatment planning. Prospective studies of the impact of iMRI on recurrence rates and long-term outcomes have, however, yet to be performed. Computed tomography CT of the pituitary region remains the primary imaging modality for patients who are unable to undergo MRI, for example due to cardiac pacemaker devices or claustrophobia. Modern multidetector CT scanners can quickly acquire high-resolution images of excellent quality in the axial plane. These images can then be post-processed to provide coronal and sagittal views. Although sellar anatomy is well depicted on unenhanced images, intravenous injection of iodinated contrast media is also commonly used to improve the tissue contrast between normal gland and pathological lesions (Fig. 1b). Despite the inferior soft tissue discrimination of CT compared to MRI, it provides better imaging of bone, and remains useful for identifying the presence of calcification, or demonstrating bony erosion of the sellar floor.39,40 In addition, CT provides important pre-operative data for transsphenoidal hypophysectomy, including the bony structure of the ethmoid and sphenoid sinuses.8 However, the technique necessitates exposure to ionising radiation, and in a patient group that often require multiple follow-up imaging examinations, this is clearly not ideal. Nuclear isotope (radionuclide) imaging Radionuclide techniques play a relatively limited role in pituitary evaluation. Sellar masses may be detected with single photon emission tomography (SPECT), using pharmaceuticals that specifically bind to pituitary receptors. One such example is the use of 111indium labelled octreotide for investigating non-functioning adenomas.41 However, its usefulness is limited by the fact that other parasellar tumours such as meningiomas may express somatostatin receptors and therefore also take up octreotide.42 There is also a limited role for positron emission tomography (PET) using 18F-fluoro-deoxy-Dglucose (FDG) in assessing biological activity of pituitary tumours, as the majority of pituitary lesions are slow growing, and therefore not metabolically active. Tracers such as 11C-methionine have shown some promise, although the short half-life and high cost of production of this pharmaceutical currently restricts its use to research purposes.43
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Pituitary incidentalomas An inevitable consequence of high quality modern imaging is the incidentally discovered lesion. Pituitary ‘incidentalomas’ are, by definition, lesions that are revealed, usually by CT or MRI, in the investigation of unrelated disorders. Clearly, the converse also occurs: incidental abnormalities elsewhere in the brain are often uncovered as a consequence of pituitary imaging. In population studies, the prevalence of incidental pituitary adenomas has been estimated to be in the region of 0.7/1000 (0.07%).44 However, this has been reported to be even higher in adults undergoing imaging studies for other reasons, with incidental macroadenomas shown in up to 0.2% of cases.45,46 This suggests that these patients may in fact have a potentially relevant symptom that was not readily apparent or reported but that led to the imaging examination. Indeed, the most common reason for the imaging study leading to the discovery of the pituitary incidentaloma is headache.47
Fig. 4. Incidental pituitary lesion in a patient being investigated for headache. Dedicated pituitary imaging was performed following the initial imaging study: coronal T2-weighted (a) and sagittal post-contrast T1-weighted (b) MR images demonstrate a small triangular lesion located at the junction of the anterior and posterior pituitary (arrows), consistent with an incidental pars intermedia cyst.
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Because incidentalomas infrequently come to surgery, the underlying pathological diagnosis generally remains unknown. However, the available evidence suggests that the pathology of incidentalomas reflects the general data on sellar masses, with adenomas accounting for approximately 90%, and most of the remainder being Rathke’s cleft cysts or craniopharyngiomas.48,49 The initial approach to a patient discovered to have a pituitary incidentaloma depends on whether there is hormone hypersecretion, or evidence of mass effect with pressure on adjacent structures from clinical, laboratory or imaging studies.50 MRI plays a central role in this initial evaluation, and all patients should undergo a specific pituitary protocol examination to better delineate its nature and extent (Fig. 4). Referral for surgical treatment is required at this stage if the lesion abuts or compresses the optic nerves or chiasm on imaging. Patients with incidentalomas not meeting criteria for surgical removal should be followed-up with serial MRI, as it has been demonstrated that although these lesions are generally slow growing, the true proliferative nature of the incidentaloma is unknown. In data combined from a number of studies, 8.2% of ‘macroincidentalomas’ enlarged per year, compared to 1.7% of ‘microincidentalomas’.51 It is therefore generally accepted that follow-up MRI should be performed after 6 months for macroincidentalomas and after 1 year for microincidentalomas. The optimal interval and duration of long-term follow-up imaging is more uncertain, but in general this should take into account an assessment of the risk of progression of the lesion versus the burden to the patient of repeated surveillance testing. Clearly, a significant increase in the size of the lesion should be an indication for more frequent or detailed evaluations, as guided clinically. The Endocrine Society has recently published guidelines on the evaluation and treatment of pituitary incidentalomas, summarising the above.52 They recommend that patients with incidentalomas not meeting criteria for surgical removal be followed-up with MRI at 6 months for macroincidentalomas and 1 year for microincidentalomas, and thereafter progressively less frequently if unchanged in size. They also recommend that patients be referred for surgery if there is clinical, laboratory or imaging evidence of compressive mass effect from the tumour, or if the incidentaloma is a hypersecreting tumour other than a prolactinoma.
Summary Multiple advances in pituitary imaging technology have been made in the past half-century. MRI is now established as the imaging modality of choice, and produces high quality images of the gland and adjacent structures, especially at 3T. Modern multislice CT provides a viable alternative and additional imaging modality. Intraoperative MRI may lead to improvements in the surgical treatment of pituitary lesions, but further prospective study of the impact of this technology on morbidity and long-term outcome is required. Physiological and molecular imaging with MRI and PET can provide biomarkers of tumour behaviour and treatment response, although their precise role in clinical practice and therapeutic trials is yet to be established. Modern brain imaging results in the discovery of unsuspected or incidental pituitary lesions, but also plays a central role in their evaluation and management. Practice points Unenhanced high-resolution T1-weighted MRI sequences are most commonly used in clinical practice due to the excellent contrast between the pituitary gland and adjacent structures 3T MRI provides better delineation of parasellar anatomy, improved prediction of cavernous sinus invasion, and more accurate localisation of microadenomas Although dynamic contrast enhanced MRI improves detection rates of microadenomas, it occurs at the expense of a reduction in specificity, and has therefore not been widely incorporated into routine imaging practice Patients with incidental pituitary lesions not meeting criteria for surgical removal should be followed-up with MRI at 6 months for ‘macroincidentalomas’ and at 1 year for ‘microincidentalomas’
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Research agenda Physiological (perfusion MRI, diffusion weighted imaging, diffusion tensor imaging and MR spectroscopy) and molecular (PET/SPECT) imaging may provide potential biomarkers of the behaviour of pituitary masses, although further studies are needed to evaluate their potential and define their precise role Investigations into the long-term outcomes of intraoperative MRI, particularly with respect to tumour recurrence compared to standard pituitary surgery, are required
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