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Neuroradiology |
1 From the Department of Radiology, Kobe City General Hospital, Japan (A.H., T.T., T.M.); and Departments of Radiology (A.H., Y.I., T.T.) and Pathology (K.W., T.H.), Osaka City University Medical School, Japan. Received June 6, 2002; revision requested August 14; revision received September 17; accepted November 18. Address correspondence to A.H., Department of Radiology, Osaka City Juso Hospital, 2-12-27 Nonakakita, Yodogawa-ku, Osaka 532-0034, Japan (e-mail: y10509@zc5.so-net.ne.jp).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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MATERIALS AND METHODS: A total of 174 pathologically proven pituitary adenomas were evaluated retrospectively on magnetic resonance (MR) images to determine the signal intensity (on T2-weighted images), maximum diameter, and amount of suprasellar and infrasellar extension. For microadenomas, sellar depth was also measured. GH–producing adenomas were classified at histologic evaluation as densely or sparsely granulated. Specimens from 38 adenomas were stained to assess the amounts of fibrous tissue, iron, and amyloid they contained. Results were correlated with the size and hormonal activity of adenomas by using the 
2, unpaired t, and Mann-Whitney U tests.
RESULTS: Among 174 pituitary adenomas, 42 were GH–producing adenomas. Of these, 16 were densely granulated, and 24 were sparsely granulated (two histologic specimens were lost). Signal intensity was evaluated among 153 adenomas. On T2-weighted MR images, hypointensity was seen more commonly in adenomas that produced GH (16 of 40 cases [40%]; P < .001) than in those that did not; hypointensity was nearly exclusive to densely granulated GH–producing adenomas. The amounts of amyloid, fibrous tissue, and iron contained in adenomas demonstrated little relationship with signal intensity. Average suprasellar extension was significantly smaller in adenomas that produced GH (-0.8 mm) than in those that did not (5.3 mm) (P < .001). GH–producing adenomas tended to demonstrate infrasellar extension rather than suprasellar extension. Average sellar depth associated with GH–producing microadenomas (13.3 mm) was significantly greater than for non–GH-producing microadenomas (9.7 mm; P < .001).
CONCLUSION: Characteristic features regarding growth direction and T2 signal intensity can be identified for GH–producing adenomas.
© RSNA, 2003
Index terms: Hormones • Pituitary, MR, 145.1214 • Pituitary, neoplasms, 145.372
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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We have noted that growth hormone (GH)–producing adenomas are most likely to be hypointense on T2-weighted images and are relatively unlikely to demonstrate suprasellar extension. We also noted that GH-producing microadenomas appeared to be associated with sellar enlargement. In this retrospective study, we sought to identify characteristic features of GH-producing adenomas.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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Criteria for classifying GH-producing adenoma included histologic confirmation of the pituitary adenoma and serum GH concentrations exceeding normal limits (>5 µg/L). Patients with GH-producing adenomas had developed features of acromegaly. Criteria for classifying PRL-producing adenoma included histologic confirmation of the pituitary adenoma and serum PRL concentrations exceeding 200 µg/L (normal concentration, >20 µg/L). In patients with PRL concentrations between 50 and 200 µg/L, classification was made at immunohistochemical examination. In all patients with ACTH-producing adenoma, serum cortisol and ACTH concentrations were elevated, and surgical specimens were reactive for ACTH at immunohistochemical examination. In the two patients diagnosed with FSH-producing adenoma, respective serum FSH concentrations were 440 and 175 IU/L (normal concentration, 1.6–17.8 IU/L). All other adenomas were classified as nonfunctioning adenomas.
Imaging and Evaluation
MR imaging was performed with superconducting imagers operating at 1.0 or 1.5 T. As a minimum, coronal T1- and T2-weighted images and sagittal T1-weighted images were obtained. Contrast material–enhanced imaging was also performed in all cases. Section thickness was 3.0 mm with a 0.3–1.0-mm intersection gap. T1-weighted spin-echo images were obtained at 417–600/14–24 (repetition time msec/echo time msec) with two to four signals acquired. T2-weighted spin-echo or fast spin-echo images were obtained at 3,400–4,000/96–108 with two to four signals acquired. These images were evaluated by two neuroradiologists (A.H., Y.I.) who reached a consensus concerning the signal intensity on T2-weighted images, the maximum diameter, the extent of suprasellar and infrasellar extension, and cavernous sinus invasion of the adenomas. For microadenomas, sellar depth was also measured.
Signal intensity of the solid portion of the adenomas on T2-weighted MR images was classified as hypointense when equal to or lower than the signal intensity of white matter, isointense when higher than that for white matter and lower than that for gray matter, and hyperintense when equal to or higher than that for gray matter. To determine which portion of an adenoma was solid, gadolinium-enhanced images were often used.
In adenomas with suprasellar or infrasellar extension, the vertical extent of the suprasellar portion and the infrasellar portion of the adenoma was measured. When a large adenoma obscured the sella turcica, a posterior extension line of the planum sphenoidale was arbitrarily designated to be the upper margin of the sella; the sellar floor was designated as 10 mm below this line. The height of suprasellar extension minus the depth of infrasellar extension was termed the suprasellar extension value. Thus, the suprasellar extension value expressed the vertical direction in which the adenoma tended to extend (Fig 1).
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Cavernous sinus invasion was judged according to the criteria presented by Cottier et al (3). Cavernous sinus invasion was present when the percentage of encasement of the internal carotid artery by tumor was 67% or greater, when the venous component of the carotid sulcus was not depicted, or when a line joining the lateral wall of the intracavernous and supracavernous internal carotid artery was crossed by the tumor.
Histologic Evaluation
Of the 42 GH-producing adenomas, 40 were subclassified as either densely granulated or sparsely granulated by using hematoxylin-eosin, periodic acid–Schiff orange G, and anti-GH staining (A.H., K.W., T.H., by consensus). In two cases this subclassification was not carried out because specimens had been lost. Densely granulated adenomas had numerous secretory granules and strong immunoreactivity for GH throughout the cytoplasm, while sparsely granulated adenomas had few secretory granules and only weak immunoreactivity for GH.
In a limited number of surgical specimens, additional special stains were used: Congo red for amyloid, azan Mallory for fibrous tissue, and Prussian blue for iron (A.H., K.W., T.H., by consensus). When amyloid was detected in more than 25% of the interstitial space, the adenoma was considered to contain a moderate amount; when amyloid was detected in less than 25% of the interstitial space, the adenoma was considered to contain a small amount. Fibrous tissue that occupied more than 25% of the interstitial space was considered to be a moderate amount; fibrous tissue that occupied less than 25% of the interstitial space was considered to be a small amount. Adenomas were classified into those with iron and those without iron.
Statistical Evaluation
Results of imaging were correlated with the hormonal activity and size of adenomas. Statistical analysis was performed with the 2 test, unpaired t test, or Mann-Whitney U test as appropriate (A.H.). A P value less than .05 was considered to indicate statistical significance.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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On T2-weighted images, hypointensity was significantly more common among GH-producing adenomas than non–GH-producing adenomas (P < .001). Of the 40 GH-producing adenomas evaluated, 16 (40%) were hypointense, 13 (32%) were isointense, and 11 (28%) were hyperintense. Of 47 PRL-producing adenomas, one (2%) was hypointense, 17 (36%) were isointense, and 29 (62%) were hyperintense. Of 59 nonfunctioning adenomas, four (7%) were isointense and 55 (93%) were hyperintense; none were hypointense. No ACTH-producing adenomas or FSH-producing adenomas were hypointense. In other words, among all non–GH-producing adenomas only one, a PRL-producing adenoma, was hypointense. On T2-weighted images, hypointensity was significantly more common among GH-producing adenomas (P < .001), while hyperintensity was significantly more common among non–GH-producing adenomas (P < .001). No significant differences were noted between PRL-producing adenomas, ACTH-producing adenomas, and nonfunctioning adenomas.
Among GH-producing adenomas, all 15 densely granulated adenomas in which signal intensity could be judged demonstrated hypointensity on T2-weighted images (Fig 2). In contrast, only one of 24 sparsely granulated adenomas demonstrated hypointensity on T2-weighted images (Fig 3). A significant difference was noted between the two (P < .001).
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Suprasellar Extension Value
In the 144 adenomas (including 36 GH-producing adenomas) that had suprasellar or infrasellar extension (almost all macroadenomas, some microadenomas with infrasellar extension), suprasellar extension value was measured. The average suprasellar extension value was 3.8 mm among all adenomas: -0.8 mm in GH-producing adenomas, 4.1 mm in PRL-producing adenomas, and 5.7 mm in nonfunctioning adenomas. The average suprasellar extension value was significantly smaller for GH-producing adenomas than for other adenomas (P < .001) and was significantly larger for nonfunctioning adenomas than for other adenomas (P = .014) (Fig 4). The average suprasellar extension value was -3.6 mm for densely granulated adenomas and 0.2 mm for sparsely granulated adenomas (no significant difference, P = .063). No densely granulated adenomas demonstrated suprasellar extension.
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Histologic Evaluation
Among GH-producing adenomas, there were 16 densely granulated and 24 sparsely granulated adenomas.
Special stains were used for 22 GH-producing adenomas, six PRL-producing adenomas, three ACTH-producing adenomas, and seven nonfunctioning adenomas. Eight adenomas were hypointense, 13 were isointense, and 17 were hyperintense on T2-weighted images. Table 2 summarizes the histologic findings for amyloid, fibrous tissue, and iron in the adenomas. The levels of amyloid, fibrous tissue, and iron had little relation to signal intensity. A moderate amount of amyloid was noted in three (38%) of eight adenomas with hypointensity on T2-weighted images and in eight (27%) of 30 adenomas without hypointensity. Iron-containing cells were noted in one adenoma with hypointensity on T2-weighted images and were also found in several adenomas without hypointensity. A moderate amount of fibrous tissue was present in two (25%) of eight adenomas with hypointensity on T2-weighted images and also in 10 (33%) of 30 adenomas without hypointensity. Therefore, the amounts of amyloid, fibrous tissue, and iron contained in adenomas had little apparent influence on signal intensity.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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GH-producing Adenomas
GH-producing adenomas, which account for 20% of pituitary adenomas, can be divided according to histologic findings into densely granulated adenomas, sparsely granulated adenomas, and bihormonal adenomas producing GH and PRL (4). Densely granulated adenomas compose approximately 7% of pituitary adenomas, and they have numerous secretory granules in the cytoplasm and display cytoplasmic acidophilia, as well as strong immunoreactivity for GH throughout the cytoplasm. This subgroup is known to be slow growing and relatively noninvasive. Nuclear and cellular pleomorphisms are sometimes seen in densely granulated adenomas, but they are not so severe (4). In contrast, sparsely granulated adenomas represent approximately 6% of pituitary adenomas and have relatively few secretory granules. The cells are chromophobic, and immunoreactivity for GH is weak. These adenomas are aggressive, and varying degrees of nuclear and cellular pleomorphism are seen (4). As previously described, in our study densely granulated adenomas demonstrated less invasiveness (cavernous sinus invasion was not seen) and smaller size than did sparsely granulated adenomas (Figs 2, 3).
Bihormonal adenomas that produce GH and PRL represent 6% of all pituitary adenomas. They are further classified into mixed GH cell (densely or sparsely granulated) and PRL cell adenoma, mammosomatotroph cell adenoma, and acidophil stem cell adenoma (4). In this study, some GH- and PRL-producing adenomas were immunohistologically evident, but none showed symptomatic hyperprolactinemia or elevation of serum PRL levels exceeding 100 µg/L. We therefore regarded them as GH-producing adenomas. Mammosomatotroph cell adenomas resemble densely granulated adenomas at both clinical and pathologic examination, and they are distinguishable only at electron microscopy. Therefore, we regarded them as densely granulated GH-producing adenomas in our study. Acidophil stem cell adenoma resembles sparsely granulated adenoma, and any such case was regarded as a sparsely granulated GH-producing adenoma in our study. Similarly, mixed GH cell and PRL cell adenomas were regarded here as densely or sparsely granulated GH-producing adenomas.
We sought to determine which histologic features correspond to hypointensity on T2-weighted images. In our study, 17 adenomas were hypointense, while other pituitary adenomas were either isointense or hyperintense. Hypointensity on T2-weighted images can be caused by intratumoral hematoma, fibrous tissue, amyloid, iron, calcification, melanin, or protein-rich fluid.
Our histologic findings demonstrated moderate amounts of fibrous tissue, amyloid, or sometimes iron in some adenomas; however, the amount of amyloid, fibrous tissue, or iron contained did not appear to be related to hypointensity on T2-weighted images in these cases (Table 2). Amyloid is well known to cause hypointensity on T2-weighted images; in one study, a T2-hypointense nonfunctioning pituitary adenoma with amyloid deposition has been reported (5). In our study, however, moderate amounts of amyloid were found in only 38% of T2-hypointense adenomas, in comparison with 27% of adenomas without hypointensity on T2-weighted images.
Interestingly, 16 of the 17 hypointense adenomas were GH-producing adenomas, and 15 of these 16 were densely granulated. All densely granulated adenomas were hypointense on T2-weighted images. Densely granulated adenomas have numerous secretory granules and strong cytoplasmic immunoreactivity for GH, while most other pituitary adenomas have few or no secretory granules. We therefore suspect that secretory granules may influence signal intensity on T2-weighted images. High intragranular protein concentrations might account for the T2 hypointensity. Like densely granulated GH-producing adenomas, densely granulated PRL-producing adenomas and ACTH-producing adenomas also have numerous secretory granules. However, almost all PRL-producing adenomas are sparsely granulated; densely granulated PRL-producing adenomas are very rare. No ACTH-producing adenomas demonstrated hypointensity on T2-weighted images in our study. The secretory granules of ACTH-producing adenomas are basophilic, while those of GH-producing adenomas are acidophilic (4). This chemical difference might explain why ACTH-producing adenomas lack T2 hypointensity despite having numerous granules.
In addition to the densely granulated GH-producing adenomas, two other adenomas were hypointense on T2-weighted images. One was a sparsely granulated GH-producing adenoma, and the other was a PRL-producing adenoma. We could not explain why the sparsely granulated adenoma was hypointense; it included no amyloid, no iron, and little fibrous tissue. Unfortunately, no sample of the PRL-producing adenoma was available for further study; it might have been a densely granulated PRL-producing adenoma.
Another characteristic finding in GH-producing adenomas is a tendency to extend in an infrasellar rather than a suprasellar direction (Fig 4). As a result, optic chiasm compression is less common in GH-producing adenomas than in other adenomas. We can suggest three possible explanations of why GH-producing adenomas tend to extend in an infrasellar direction. The first is that since GH thickens soft tissue, the diaphragm of sella may be thickened or hardened, therefore favoring extension in the infrasellar direction. A second possible explanation is that GH decreases the bone density, so the sellar floor is easily eroded by the tumor. A third possible explanation is that GH itself, and not merely the tumor growth, enlarges the sella.
Sellar depth in GH-producing microadenomas was significantly greater than that in non–GH-producing microadenomas. With GH-producing microadenomas, cerebrospinal fluid could frequently be seen within enlarged sellas (Fig 5). Two reasons might account for the increased sellar depth found with GH-producing microadenomas: (a) spontaneous regression of a large adenoma and (b) enlargement of the sella by GH. In some reports, necrosis occurred in large adenomas and was absorbed, which resulted in a large sella that contained a microadenoma and cerebrospinal fluid (6,7). However, necrosis is an unlikely explanation in cases of large sellas with GH-producing microadenomas; most previously published reports indicated that necrosis or hemorrhage in adenomas had little relation to hormonal activity (8–10).
Characteristic features of GH-producing adenomas that are evident from this study can help to explain GH-associated sellar enlargement. GH is already known to enlarge the frontal sinus and mastoid air cells, so excessive GH might also enlarge the sella. GH accelerates the apposition of bone along the outer surface of the frontal sinus and the mastoid air cells associated with internal resorption; this increases the size of the sinus cavity (11). The sella is fairly similar in shape to the frontal sinus and the mastoid air cells, so GH may act similarly on the sella. In contrast, patients with pituitary dwarfism are known to have poorly developed sellas (12). Since deficiency of GH may inhibit sellar growth, excessive GH may cause sellar enlargement.
Cavernous Sinus Invasion
Larger adenomas are reportedly more likely to invade the cavernous sinus than are smaller adenomas (13,14), and our results agree. Invasion was more common in PRL-producing adenomas and less common in nonfunctioning adenomas. Scotti et al (15) found that invasion was more common in GH-producing adenomas and PRL-producing adenomas and less common in nonfunctioning adenomas. Our result partially agrees, but no significant difference was seen in the frequency of invasion between GH-producing adenomas and other adenomas. In our study, cavernous sinus invasion by GH-producing adenomas differed with respect to the pathologic subtype; sparsely granulated adenomas were significantly more likely to invade than were densely granulated adenomas.
In conclusion, we found that GH-producing adenomas are often hypointense on T2-weighted images, a feature that is almost exclusive to densely granulated GH-producing adenomas. Also, GH-producing adenomas show infrasellar extension more frequently than non–GH-producing adenomas do. Finally, GH-producing microadenomas are associated with a relatively large sella. The latter two findings suggest that excessive GH may cause sellar enlargement.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Author contributions: Guarantors of integrity of entire study, A.H., Y.I.; study concepts and design, A.H., Y.I.; literature research, A.H., Y.I., K.W.; clinical studies, A.H., Y.I., T.T.; data acquisition, A.H., Y.I., T.T.; data analysis/interpretation, A.H., Y.I., K.W., T.H.; statistical analysis, A.H.; manuscript preparation, A.H.; manuscript definition of intellectual content, A.H., Y.I.; manuscript revision/review, A.H., Y.I., T.T., T.M.; manuscript editing and final version approval, A.H., Y.I., T.M.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTSDISCUSSIONREFERENCES |
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