Pituitary Adenomas

Abstract

Pituitary adenomas are by far the most common sellar tumor and magnetic resonance imaging is the modality of choice for their detection and characterization. However, most of these neoplasms are asymptomatic and frequently incidentally visualized. One also has to be aware of common other incidental findings and normal age-related changes in the appearance of the gland. By convention, 10 mm is used as the size threshold to separate macroadenomas from microadenomas. For microadenomas, imaging is primarily used for lesion detection and localization, whereas with macrodenomas, the goal is to establish whether the mass represents a pituitary tumor or some other lesion and to precisely delineate its extent.

Pituitary adenomas are by far the most common sellar tumor encountered on imaging, representing about 10% to 15% of all surgically treated intracranial neoplasms.^1,2 Recent reviews estimated an overall prevalence of these tumors at 10% to 16.7% in the general population.^3,4 However, most of these are asymptomatic, incidentally found in autopsy or radiological studies. Pituitary adenomas produce symptoms by secreting hormones, depressing the secretion of hormones, and/or by mass effect from compression of the adjacent structures. By convention, 10 mm is used as the size threshold to separate macroadenomas from microadenomas. Some authors also use the term picoadenoma for lesions smaller than 3 mm because they may be a particular diagnostic challenge.² Prolactinomas are primarily treated medically, with bromocriptine and analogues, which can lead to drastic and rapid decrease in tumor volume, frequently within days and even hours.^5,6 For other hormonally active pituitary tumors as well as for nonsecreting adenomas, surgical resection is the first-line modality of treatment. Significant reduction in growth hormone (GH)-secreting tumors may be achieved by somatostatin analogs, preoperatively or when surgery is contraindicated. Radiation therapy, including radiosurgery, is used after incomplete surgical resection, particulary for tumors that are invading the cavernous sinus and not in contact with the optic chiasm.⁵

The goals of pretreatment imaging studies are somewhat different for microadenomas and macroadenomas. Microadenomas are almost always intrasellar in location and without significant mass effect; therefore, imaging is primarily used for lesion detection and localization. Macrodenomas however generally present with symptoms caused by compression on the adjacent structures, most commonly the optic chiasm; and the role of magnetic resonance (MR) imaging is to establish whether the mass represents a pituitary tumor or some other lesion and to assess its extent.

MICROADENOMAS

Approximately 75% to 80% of pituitary adenomas are hormonally active, of which prolactinomas are by far the most common, and are usually located in lateral aspects of adenohypophysis (Fig. 1). Prolactinomas typically occur in young women presenting with amenorrhea and galactorrhea. These tumors are much less common in men, in whom impotence is the most common presenting symptom. A recent study indicated that the biology and clinical course may differ between sexes: in men, the prolactin levels are higher, the tumors are larger and more invasive, and the outcome is worse than in women, probably because of rapid tumor growth.⁷ There is a solid correlation between the prolactin blood levels and MR imaging: prolactin concentration greater than 200 ng/mL practically guarantees adenoma detection, whereas with concentration less than 50 ng/mL, positive imaging findings are found in less than 50% of cases. However, many macroadenomas are detected in women with prolactin levels less than 200 ng/mL, and some of the microadenomas are found in patients with prolactin concentration greater than 200 ng/mL.⁸

FIGURE 1: Pituitary microadenoma-prolactinoma. Coronal noncontrast T1-weighted image (A) shows only a slightly enlarged left aspect of the pituitary gland (arrow) without a defined signal abnormality. On a corresponding T2-weighted image (B), the adenoma is visualized as a hyperintense lesion. The tumor is very clearly depicted on dynamic contrast-enhanced T1-weighted image (C) as an area lacking contrast enhancement [the images are acquired every 15 seconds with a T1-weighted fast spin echo (FSE) pulse sequence]. On standard postcontrast T1-weighted image (D), the adenoma is far less conspicuous.

Most microadenomas (approximately 75%) are seen on precontrast T1-weighted images as a round or oval, sometimes flattened or triangular, area of abnormal low signal (Fig. 2). Some microadenomas may be of hyperintense T1 signal, presumably because of internal hemorrhagic transformation (Fig. 3). T2 hyperintensity is found in more than 80% of microprolactinomas, although in some cases this represents only a portion of the tumor (Fig. 4). GH-secreting adenomas are, on the other hand, iso- to hypointense on T2-weighted images most cases.² Interestingly, relatively hypointense prolactinomas tend to have higher hormone secretion compared with their counterparts with bright T2 signal (Fig. 5).² Some microadenomas, especially very small ones, are depicted on T2-weighted images only (Fig. 6). About 5% to 10% of microadenomas are detected exclusively on postcontrast images, which are generally performed with a half dose of gadolinium agents.^1,2

FIGURE 2: Pituitary microadenoma-prolactinoma. A small mass is seen in the lateral aspect of the pituitary gland in a 29-year-old woman with amenorrhea and galactorrhea. Coronal precontrast T1-weighted image (A) shows a hypointense lesion in the left lateral aspect of the gland (arrow). The lesion is slightly more conspicuous on a more posterior image (B).

FIGURE 3: Pituitary microadenoma-prolactinoma. Coronal precontrast T1-weighted image (A) shows a slightly enlarged right side of the pituitary gland with a hyperintense area (arrow), indicating possible tumor. On corresponding postcontrast image (B), the tumor is better delineated because of relatively low enhancement.

FIGURE 4: Pituitary adenoma-prolactinoma. A hypointense mass (arrows) is seen on precontrast coronal T1-weighted image (A). A portion of the mass is hyperintense (arrow) on corresponding T2-weighted image. The tumor is well-defined on matching postcontrast T1-weighted image (C). The internal area of stronger enhancement approximately corresponds to T2 hyperintensity.

FIGURE 5: Pituitary microadenoma-microprolactinoma. Precontrast coronal T1-weighted image (A) in a patient with prolactin levels around 900 ng/mL shows an ill-defined small mass (arrow) in the left inferior aspect of the sella. Corresponding T2-weighted image (B) reveals that the mass is of relatively low T2 signal intensity. Dynamic postcontrast coronal image (C) clearly delineates the lesion. The tumor is immediately adjacent to the inferior aspect of the cavernous left internal carotid artery (ICA) (arrowhead), which could be indicative of cavernous sinus extension. The mass is slightly less conspicuous on corresponding postcontrast T1-weighted image (D).

FIGURE 6: Pituitary microadenoma-microprolactinoma. Precontrast coronal T1-weighted image (A) demonstrates subtle asymmetry of the pituitary gland; the right side shows minimal decrease in signal intensity. A small hyperintense lesion (arrow) is clearly visualized on corresponding T2-weighted image (B). Matching postcontrast T1-weighted image (C) fails to clearly visualize the tumor.

Dynamic postcontrast imaging further increases sensitivity, detecting an additional 10% of lesions (Fig. 7).^1,9,10 The adenohypophysis has a portal rather than a direct arterial blood supply, which enables dynamic MR [or computed tomography (CT)] imaging. This technique requires a bolus injection of contrast, which is then followed by rapid acquisition of a few slices (generally 3 to 5) covering the entire pituitary gland. The image acquisition lasts from 10 to 40 seconds and is immediately repeated 5 to 10 times. The normal gland enhances after the infundibulum and cavernous sinuses have already opacified, with a characteristic centrifugal enhancement pattern. The tumors typically show a different dynamic pattern, usually of delayed or complete lack of enhancement (Fig. 7). In few cases, adenomas accumulate contrast medium earlier than the normal glandular tissue, presumably reflecting a direct arterial dural supply, indicative of dural invasion. Delayed MR imaging 30 to 40 minutes after contrast injection may show late prominent enhancement of adenoma on relatively dark background of the normal gland.^1,2 The overall sensitivity of MR imaging for microadenoma detection using all the different techniques approaches 90%.^1,10

FIGURE 7: Pituitary microadenoma-microprolactinoma. There is a mild asymmetry of the pituitary gland on precontrast T1-weighted image (A), with mild fullness on the left. Note that the pituitary stalk is also deviated to the left. Corresponding T2-weighted image (B) offers no additional information. An area of clear delayed enhancement (arrows) is seen in the left lateral aspect of the gland on matching dynamic postcontrast image (C). This finding is consistent with microadenoma. The tumor is not detectable on corresponding postcontrast T1-weighted image (D). Deviation of the pituitary stalk is a relatively frequent normal variant and not a reliable sign of microadenoma detection.

The tumors that are iso- to hypointense to the normal gland on T2-weighted sequences tend to be fibrotic and indurated (especially if not associated with very high prolactin levels), which indicates increased difficulty of surgical resection.¹ Although unilateral focal fullness of the gland may help in microadenoma detection, deviation of the infundibulum is a very nonspecific sign and a frequent normal finding.¹¹ In some cases, the deviation of the stalk may in fact be toward the side of the tumor (Fig. 7).

It should be noted that dedicated pituitary gland CT study (Fig. 8) is probably only slightly inferior to MR imaging and should be performed in cases when MR imaging is contraindicated.^9,12 Furthermore, modifications of the sellar floor may be difficult to visualize on MR imaging, especially cortical bone thinning, which may be better evaluated with a CT scan. Feasibility and utility of high-quality dynamic CT imaging with modern multislice scanners have been clearly demonstrated.¹²

FIGURE 8: Pituitary microadenoma-prolactinoma. Coronal reformatted postcontrast dynamic CT image in a patient with cardiac pacemaker and hyperprolactinemia shows a pituitary mass with delayed enhancement (arrow), consistent with adenoma.

Imaging studies have not been very reliable for detection of the second most common microadenoma, corticotropin-secreting tumor in patients with Cushing disease. These lesions are usually very small, located in the more central portions of the adenohypophysis, and often with signal intensity and enhancement characteristics similar to the normal pituitary parenchyma (Fig. 9). The sensitivity of MR imaging for these tumors is therefore generally only around 50% to 60%.^1,2,10 It seems that this low sensitivity may be somewhat improved using a high spatial resolution 3D gradient-echo MR pulse sequence, up to 80%; however, it is at the expense of a slightly higher false-positive rate.¹³ Inferior petrosal and/or cavernous sinus sampling, especially if performed before and after administration of corticotropin-releasing hormone, is a more reliable technique and a powerful tool for differentiating Cushing disease from ectopic corticotropin-secreting tumors, with reported sensitivity and specificity of more than 90%.^14,15 The accuracy of this invasive procedure is however not as high for correct lesion localization.¹⁵

FIGURE 9: Pituitary microadenoma-corticotropin-secreting. Precontrast coronal T1-weighted image (A) in a 30-year-old patient with Cushing disease shows an ill-defined subtle hypodensity (arrow) in the inferior aspect of the sella, close to the midline and extending into the sphenoid sinus. The lesion is hyperintense (arrow) and better visualized on corresponding T2-weighted image (B). Postcontrast T1-weighted image at a similar level (C) shows relatively low enhancement within the lesion. The findings are suspicious for dural invasion, which was confirmed on histology. Also note that the subarachnoid spaces are somewhat diffusely dilated for the age of the patient, which is a common finding in Cushing disease because of high levels of endogenous corticosteroid hormones.

To competently evaluate the pituitary gland on imaging studies, one also has to be aware of common incidental findings and normal age-related changes in the appearance. It is considered that a focal 2- to 3-mm pituitary lesion seen on MR imaging has an approximately 50% chance of representing just incidental insignificant finding.¹⁶ A recent survey of unsuspected endocrinologically silent pituitary masses (pituitary "incidentalomas";) found that only 12% of these lesions showed increase in size on follow-up MR imaging, and most of these were presumed to represent nonfunctioning adenomas.¹⁷ Surgical treatment may be indicated for incidentalomas that are adjacent to the optic chiasm.

Pituitary cysts may generally be distinguished from neoplasms by their characteristic signal intensity patterns due to high water content (very low T1 and high T2 signal) and complete absence of contrast enhancement.¹ Rathke cleft cysts are commonly encountered; they are located in the center of the gland and may contain characteristic nodules of low T2 signal or be completely hypointense on T2-weighted images.¹⁸ Presence of a fluid-fluid level on sagittal or axial images is highly indicative of adenomas, representing intratumoral degeneration and hemorrhage, which almost never occur in cysts (Fig. 10).

FIGURE 10: Pituitary adenoma with hemorrhage. Axial FSE T2-weighted image through the sella (A) demonstrates a round mass with a fluid-fluid level appearance (arrow). The anterior aspect of the lesion is hyperintense, whereas the posterior portion is iso- to hypointense. Gradient echo T2*-weighted image at a similar level (B) reveals signal dropout within the mass. The findings are consistent with blood products from hemorrhage within a pituitary adenoma, which is not uncommon. Fluid levels and hemorrhage are exceedingly rare in pituitary cysts.

The gland enlarges during puberty, especially in girls, when it may have a convex superior contour and reach 10 mm in height (Fig. 11). Such appearance is also common during midmenstrual cycle in fertile women and during pregnancy, although in the first postpartum week, the gland may reach 12 mm in height.¹ These normal findings should not be confused with pituitary lesions.

FIGURE 11: Normal pituitary gland in a 13-year-old girl. Midsagittal precontrast T1-weighted image (A) shows that the anterior pituitary lobe is isointense with the brain, of convex superior contour, and about 9 mm in height. The optic chiasm, clivus, sphenoid sinus, and basilar cisterns are normal. The hyperintense posterior lobe ("the pituitary bright spot";) is well seen. Coronal T1-weighted image (B) shows convex superior contour of the hypophysis, which is of homogenous appearance. Corresponding T2-weighted image (C) also demonstrates homogenous appearance of the pituitary gland. On dynamic postcontrast image (D), normal enhancement pattern is seen with prominent contrast accumulation in the cavernous sinuses, followed by the infundibulum and adjacent superior medial aspect of the hypophysis (called pituitary tuft). Later dynamic images demonstrated progressive symmetric enhancement of the adenohypophysis in a centrifugal fashion.

MACROADENOMAS

Nonfunctional pituitary adenomas present with symptoms associated with compression on the adjacent structures, most notably bitemporal hemianopsia, and are usually diagnosed late when they have reached macroadenoma size (Fig. 12). However, hormonally active adenomas may also present as large masses, which is almost a rule for GH-secreting and thyrotropin-secreting tumors that are usually more than 10 mm in diameter at the time of diagnosis.^1,2,19-21 Rapid hormonal evaluation is therefore mandatory even in patients presenting with large sellar masses and neurological symptoms. With macroadenomas, detection is generally not problematic, and precise delineation of tumor extension is the main imaging goal. Tumor progression is resistant to therapy in a minority (less than 10%) of patients with acromegaly, regardless of treatment modality. The best predictors of such an unfavorable outcome are young age and high pretreatment GH levels, as well as tumors more than 15 mm and signs of cavernous sinus invasion on MR imaging.^19,20

FIGURE 12: Nonsecreting pituitary macroadenoma. Midsagittal T1-weighted image (A) shows a large intrasellar and suprasellar mass (arrow), around 4 cm in largest diameter. The pituitary bright spot of the posterior lobe is seen displaced superiorly (arrowhead). Coronal T1-weighted image again shows the tumor, of a "snowman"; appearance. The posterior lobe is displaced to the left superior aspect of the mass (arrowhead).

Macroadenomas are frequently of heterogenous appearance, particularly on T2-weighted images, with hyperintense areas reflecting cystic, necrotic, or hemorrhagic portions of the neoplasm. Similar to microadenomas, contrast enhancement of the tumors is usually not very prominent; the postcontrast images are primarily used to visualize the normal pituitary tissue, which demonstrates strong enhancement and is seen displaced along the edges of the adenoma^1,2,21 (Fig. 13). The location of the bright posterior lobe should also be established on precontrast T1-weighted images to minimize chances of permanent postoperative diabetes insipidus (Figs. 12,14). The frequent route of suprasellar spread in macroadenomas leads to the characteristic "figure of 8"; appearance because of tumor narrowing at the sellar diaphragm (Fig. 15). The relationship of the suprasellar mass and optic chiasm is best evaluated on coronal T2-weighted images because the chiasm (composed of white matter tracts) is clearly hypointense (Fig. 13).

FIGURE 13: Nonsecreting pituitary macroadenoma. An intrasellar homogenous mass (arrow) with suprasellar extension is depicted on precontrast coronal T1-weighted image (A). The optic chiasm cannot be clearly distinguished from the lesion. Corresponding T2-weighted image (B) again shows the homogenous mass, although the displaced and compressed optic chiasm (arrowheads) is also clearly visualized. Matching postcontrast T1-weighted image reveals that the tumor (arrow) enhances to a lesser degree compared with the normal glandular tissue (arrowhead), which is compressed and displaced to the right. Postcontrast images enable preoperative localization of the normal adenohypophysis.

FIGURE 14: GH-secreting pituitary macroadenoma. Coronal T1-weighted image reveals an intrasellar and suprasellar mass with associated displacement of the posterior pituitary lobe to the left (arrowhead). The tumor is spreading to the right, crossing the lateral intercarotid line (arrow), which is highly suggestive of cavernous sinus invasion.

FIGURE 15: GH-secreting pituitary macroadenoma. Coronal T1-weighted image (A) shows a characteristic figure of 8 appearance of this macroadenoma with suprasellar extension caused by tumor "waist"; narrowing at the sellar diaphragm. There is a hyperintense area (arrowhead) within the tumor, suggestive of hemorrhage. Corresponding T2-weighted image (B) demonstrates areas of high (arrowhead) and low (arrow) signal intensity within the tumor, confirming the presence of blood products.

Cavernous sinus invasion is a poor prognostic sign, indicating an aggressive and generally nonresectable tumor. Clinical symptoms and signs of cavernous sinus invasion occur relatively late and correlate with very high hormone levels, which are helpful only in secreting adenomas.¹ Evaluation of coronal MR images using a number of criteria therefore plays an important role in diagnosis, and detailed analysis provides reliable assessment in most cases.²² The intercarotid lines may be drawn on coronal images at the pituitary gland level, where they connect the cavernous and supracavernous ICA segments. The lateral and medial intercarotid lines connect the respective aspects of the vessel. Very sensitive signs of cavernous sinus invasion are tumor surrounding more than 66% of the cavernous ICA circumference (Fig. 16), tumor crossing the lateral intercarotid line (Figs. 14,17), and extension into the carotid sulcus venous compartment (Fig. 18). The carotid sulcus or medial venous compartment is the portion of the cavernous sinus that is found immediately inferior to the ICA, and it is considered invaded if the tumor is found crossing the inferiormost aspect of the cavernous ICA (Fig. 18).^22,23

FIGURE 16: Nonsecreting pituitary macroadenoma with cavernous sinus invasion. Axial FSE T2-weighted image shows a sellar mass (arrows), which is present on both sides of the right ICA. Coronal T1-weighted image (B) reveals that the tumor (arrows) completely surrounds the right cavernous ICA (arrowhead), which is a definite sign of cavernous sinus invasion.

FIGURE 17: GH-secreting pituitary macroadenoma with cavernous sinus invasion. Postcontrast coronal T1-weighted image reveals a large homogenous sellar mass with suprasellar and sphenoid sinus extension (large arrows). The tumor also crosses the left lateral intercarotid line (arrowhead), which is highly indicative of cavernous sinus invasion. The lateral intercarotid line is drawn on the right (small arrows), connecting the lateral aspects of the vessel segments. The normal pituitary tissue is displaced to the right.

FIGURE 18: Pituitary adenoma with cavernous sinus invasion. Coronal postcontrast dynamic image demonstrates the hypoenhancing tumor (arrow) immediately adjacent to the inferior aspect of the right cavernous ICA, in the region of the carotid sulcus (median) venous compartment. The normal avidly enhancing carotid sulcus of the cavernous sinus is shown on the left (arrowhead).

On the other hand, absence of tumor lateral to the medial intercarotid line and tumor surrounding less than 25% of the ICA circumference virtually exclude cavernous sinus invasion.^22,23 It should be mentioned that even small microadenomas, especially corticotropin-secreting ones, may be aggressive and invasive (Figs. 5,9), and in rare cases may even metastasize.

Enhancement and thickening of the adjacent dura are frequently seen with large pituitary adenomas, and this "dural tail"; is not a specific sign of sellar meningiomas.² In fact, this asymmetric tentorial enhancement is a helpful sign of aggressive adenomas, thought to be caused by venous congestion due to compression or invasion of the ipsilateral cavernous sinus.²⁴

Pituitary adenomas are prone to infarcts and hemorrhages, which are generally subclinical rather than giving rise to life-threatening pituitary apoplexy, presenting with headache, visual impairment, and ophthalmoplegia. In one study, around 20% of all adenomas (including microadenomas) showed evidence of hemorrhage, although only a quarter of these patients had clinical apoplexy.²⁵ Spontaneous infarcts and hemorrhages are in fact relatively frequently encountered with large GH-secreting adenomas (Fig. 15).² Furthermore, more than half of medically treated tumors show evidence of blood products on MRI (Fig. 19), along with volume reduction and cystic and fibrotic changes. On the other hand, diffusion-weighted imaging may have yet another useful application in detection of acute pituitary apoplexy. Similar to brain parenchyma, high signal intensity due to decreased diffusion of water molecules is detected in pituitary infarcts and acute hemorrhages.²⁶ Thickening of the sphenoid sinus mucosa has also been described as another feature suggestive of early pituitary apoplexy.²⁷ Intratumoral hemorrhage may occasionally be beneficial, and rare cases of spontaneous resolution of both functioning and nonfunctioning pituitary adenomas, presumably due to infracts and hemorrhage, have been described.^28,29

FIGURE 19: Prolactinoma with internal hemorrhage. Coronal precontrast T1-weighted image shows a large hyperintense area within the pituitary tumor. This finding is caused by the presence of methemoglobin and is common in medically treated adenomas. The patients with these findings indicative of tumor necrosis and hemorrhage are usually asymptomatic.

Pituitary carcinomas are rare, with fewer than 100 cases reported in the English language literature, and diagnosis requires the demonstration of metastatic lesions. The tumors present as invasive macroadenomas and almost always are hormonally active, usually corticotropin-secreting or prolactinomas. These tumors are associated with poor prognosis, and it seems that they show a greater tendency toward systemic than cerebrospinal metastases.^30,31 Neither MR imaging features nor histological examinations enable distinction from benign pituitary adenomas at the present time.

Pituitary adenomas may rarely be ectopic and arise outside the sella, such as neoplasms that are confined to the sphenoid sinus.³² Conversely, a number of less common intrasellar tumors may simulate very frequent pituitary adenomas and they can only sometimes be distinguished on MR imaging.³³ Loss of normal high T1 signal in the adjacent clivus and the thickened optic chiasm that appears contiguous with the mass are findings highly suspicious for metastatic tumors, which usually involve the posterior lobe. Breast cancer has relatively high propensity for pituitary metastases, which remain asymptomatic in most cases.³⁴ Whenever prominent flow voids are visualized within the tumor, the surgeons should be warned of possible life-threatening intraoperative blood loss; and diagnoses of hemangioblastoma, paraganglioma, or a very vascularized metastatic tumor should be entertained.³⁵

Intraoperative MR imaging of the sella has been extensively performed in a number of institutions over the past few years with the primary goal of more precise and complete resection of tumors, primarily via transsphenoidal microsurgical approach.³⁶ This promising technique could be especially advantageous for management of GH-secreting macroadenomas because postoperative tumor remnants and persistent elevated hormone levels are frequently encountered. A recent study has found that intraoperative MRI with a 1.5 T scanner did indeed allow better visualization of tumors and an increase in the rate of endocrine normalization (from 33% to 44%); however, cure could still not be achieved in about half of the patients.³⁷