Abstract
Context: GH-secreting pituitary adenomas are nearly always visible on conventional magnetic resonance (MR) imaging. However, management and outcome of acromegalic patients lacking imaging evidence of GH-secreting pituitary adenomas are undefined.
Objective: The aim was to evaluate surgical exploration for MR-invisible GH-secreting pituitary adenomas.
Design and Setting: We conducted a retrospective review at two tertiary care centers.
Patients or Other Participants: Consecutive acromegalic patients without imaging evidence of a pituitary adenoma on pre- and postcontrast, spin echo T1-weighted MR imaging and who lacked evidence of an ectopic (nonpituitary) source causing GH excess were included.
Interventions: Surgical exploration with identification and resection of a pituitary adenoma was performed.
Main Outcome Measures: Laboratory values (GH, IGF-I), surgical findings, and clinical outcome were analyzed.
Results: Six patients (three males, three females; 3% of all patients) with suspected GH-secreting adenomas did not demonstrate imaging evidence of pituitary adenoma on conventional MR imaging. Three patients underwent a postcontrast, volumetric interpolated breath-hold examination MR-imaging sequence (1.2-mm slice thickness), which revealed a 4-mm pituitary adenoma not seen on the spin echo T1-weighted MR imaging in one patient. A pituitary adenoma was identified and removed in all patients (mean diameter, 5.6 mm; range, 5 to 6.7 mm). Histological analysis confirmed that the lesions were GH-secreting adenomas. All patients achieved biochemical remission after surgical resection.
Conclusion: Acromegaly can be caused by GH-secreting pituitary adenomas that are not evident on conventional MR imaging. Adenomas in some of these patients become evident using volumetric interpolated breath-hold examination MR imaging. Surgical exploration of the pituitary gland in acromegalic patients with endocrine findings consistent with a GH-secreting adenoma but negative MR imaging can lead to identification and removal of an adenoma.
Acromegalic patients with a suspected GH-secreting pituitary adenoma but negative magnetic resonance imaging should undergo surgical exploration, which can lead to tumor removal with biochemical remission.
Acromegaly is caused by abnormally elevated levels of GH and secondary increases in IGF-I. Acromegaly has an incidence of three to four cases per million people (1). Signs and symptoms include facial and extremity disfigurement along with rheumatological, cardiovascular, respiratory, and metabolic complications. Diagnosis of acromegaly is based on a GH nadir greater than 1 ng/ml after administration of an oral glucose tolerance test and the detection of elevated levels of IGF-I based on age and gender (2). Greater than 95% of acromegaly cases are caused by a benign GH-secreting pituitary adenoma (involving somatotroph cells) (3). Less than 5% of acromegaly cases will be caused by an ectopic source, including ectopic secretion by an ectopic GHRH tumor, a hypothalamic secreting GHRH tumor, or an ectopic GH-secreting tumor.
Because the time from onset of signs/symptoms to diagnosis of acromegaly is long (symptom onset to diagnosis is often 4 to 10 yr) (4,5), pituitary adenomas that cause GH excess are often large (greater than 10 mm) and are easily identified on routine magnetic resonance (MR)-imaging sequences. Consequently, after laboratory confirmation of GH and IGF-I excess, the diagnosis of GH-secreting pituitary adenomas in acromegaly patients is confirmed by conventional spin echo (SE) T1-weighted MR imaging (6,7). Typically, after MR imaging confirms the presence of a pituitary adenoma in acromegalic patients, surgical resection is performed. Although surgical resection frequently results in biochemical remission after complete removal of GH-secreting microadenomas (approximately 75% rate of remission), remission after surgery for GH-secreting macroadenomas is lower (approximately 50%) due to the inability to completely remove larger, more extensive lesions (8).
Despite the often routine confirmation of GH-secreting tumor on MR imaging, in rare circumstances, acromegalic patients without an ectopic source will not have imaging evidence of a pituitary adenoma. Based on the lack of imaging to confirm a pituitary tumor in these patients, the management (medical vs. surgical exploration) and expected outcome has not been defined. To better understand the frequency of this circumstance and to better define the optimal treatment for this subset of patients, we reviewed the findings in acromegalic patients without endocrine evidence of an ectopic etiology or imaging evidence of a pituitary adenoma (on standard MR imaging).
Patients and Methods
Patients and testing
Acromegalic patients from the National Institutes of Health and the University of Virginia without evidence of an ectopic source for GH excess and without imaging evidence of a pituitary adenoma on standard SE T1-weighted or T2 MR imaging were included. Clinical data from one patient that was described previously are included (9). Preoperative and postoperative laboratory testing were consistent with GH excess in all patients (Table 1). Informed consent was obtained from all patients to participate in respective clinical research protocols at the National Institutes of Health and the University of Virginia.
Table 1.
Clinical features, endocrine and MR imaging results
| Patient no. | Sex | Age (yr) | Adenoma size at surgery (mm) | Preoperative GH (ng/ml) | Preoperative IGF-I (ng/ml) | Postoperative basal GH (ng/ml) | Postoperative GH after GTT (ng/ml) | Postoperative IGF-I (ng/ml) | VIBE visible |
|---|---|---|---|---|---|---|---|---|---|
| 1 | M | 28 | 6 | 7 | 270 | 1 | <0.4 | 77 | N/A |
| 2 | M | 63 | 5 | 6.6 | 372 | 2 | <1 | 174 | N/A |
| 3 | M | 67 | 5 | 2.4 | 446 | 0.4 | <0.02 | 204 | N/A |
| 4 | F | 51 | 5 | 1.5 | 410 | 0.2 | 0.07 | 163 | No |
| 5 | F | 62 | 6.7 | 0.8 | 702 | <0.05 | <0.05 | 184 | Yes |
| 6 | F | 63 | 6 | 3 | 109 | <1 | <1 | 148 | No |
GTT, Glucose tolerance test; M, male; F, female; NA, not available.
Imaging
Patients underwent pre- and postcontrast, SE, T1-weighted, and T2-weighted MR imaging of the pituitary. To determine whether volumetric interpolated breath-hold examination (VIBE) MR imaging with thin slices (1.2 mm) could be used to detect an adenoma when standard MR imaging routines were negative, three patients included in this series also underwent postcontrast VIBE MR imaging (10,11,12).
Surgery
All patients underwent surgical exploration of the pituitary gland via a transsphenoidal approach. The sphenoid sinus was accessed either by a microscopic, sublabial approach or by an endoscopic, endonasal approach, depending on surgeon preference and expertise. Once an adenoma was identified, it was resected using the pseudocapsular technique described previously (13).
Results
Patients
A total of 190 patients with contrast-enhanced MR imaging of the pituitary underwent surgery for suspected GH-secreting adenomas. Six of these acromegalic patients (3.2%; three males, three females) without MR-imaging evidence of a pituitary adenoma on standard MR sequences were identified. All patients had an endocrinological evaluation consistent with excess GH and IGF-I (Table 1). All six patients underwent surgical exploration of the pituitary gland at either the National Institutes of Health or the University of Virginia. Mean age at surgery was 56 yr (range, 28 to 67 yr).
Imaging findings
None of the patients showed evidence of pituitary adenoma on standard SE T1-weighted MR imaging (with and without contrast) before surgery. Three patients also underwent a postcontrast VIBE MR imaging (Fig. 1). Although VIBE imaging in one patient revealed a 4-mm hypointense region that corresponded with a microadenoma discovered at surgery (Fig. 2), it did not reveal evidence of an adenoma in the other two patients.
Figure 1.
Coronal MR imaging of the pituitary gland in patient 6 (Table 1). Left, Postcontrast T1-weighted imaging lack of evidence of a pituitary adenoma. Right, Postcontrast, VIBE on MR imaging did not reveal a lesion, although a 6-mm adenoma was found on the far left side of the anterior lobe at surgery.
Figure 2.
Coronal MR imaging of the pituitary gland in patient 5 (Table 1). Left, Postcontrast T1-weighted imaging lack of evidence of a pituitary adenoma. Right, Postcontrast, VIBE on MR imaging demonstrating a hypointense lesion (arrows) that was confirmed to be an adenoma at surgery.
Surgical and pathological findings
The pituitary gland was approached using a microscopic, sublabial-transsphenoidal approach in three patients and an endoscopic, endonasal-transsphenoidal approach in three patients. At surgery, a microadenoma was discovered in all patients. All adenomas had a defined pseudocapsule that permitted the removal of the lesion via an extracapsular approach. Mean size of the resected adenomas was 5.6 mm (range, 5 to 6.7 mm) (Table 1). Histological analysis of the resected lesions confirmed that they were GH-secreting adenomas in every case.
Clinical findings
After surgery, all patients achieved biochemical remission. All patients had basal GH less than 2.5 ng/ml, suppression of GH to a nadir of 1 ng/liter or less during an oral glucose tolerance test, and normal IGF-I levels (Table 1), and all patients retained normal pituitary function.
Discussion
Diagnosis and management of acromegaly
Regardless of the underlying cause, untreated acromegaly is associated with significant morbidity and shortened life span (14). Subsequently, once a patient presents with acromegaly, diagnostic studies are performed to determine the source of GH excess and direct treatment. Because GH-secreting pituitary adenomas are the most common underlying cause of acromegaly (over 95% of cases), after serum IGF-I and GH levels are shown to be elevated, conventional T1-weighted MR imaging (with and without contrast) is performed and nearly always demonstrates a pituitary adenoma if it is present (3). When pituitary MR imaging does not reveal an adenoma, computed tomography (with and without contrast) of chest, abdominal, and pelvis is performed to determine whether an ectopic source of GHRH or GH exists.
Because surgical resection of pituitary GH-secreting adenomas can usually be performed safely with preservation of pituitary function and can be curative, it is generally considered the primary treatment for GH excess caused by pituitary adenomas. Other treatment options include medical or radiation therapy (15). Although medical therapy can reduce tumor size and normalize GH and IGF-I levels, it requires lifelong treatment, is ineffective in producing a clinically significant reduction in tumor size in most patients, often does not result in normal levels of serum IGF-I, and can be associated with side effects. Radiation therapy (either fractionated or stereotactic radiosurgery) for GH-secreting pituitary adenomas is effective in achieving biochemical remission in approximately 50% of patients but results in pituitary hormone deficiency in 25 to 50% of patients, depending on the duration of follow-up (3). Furthermore, the effectiveness of radiation therapy in normalizing GH levels occurs over years, and adjuvant medical therapy is necessary to maintain biochemical control during that period of time. For these reasons, surgery is considered the initial therapy of choice in almost all patients.
Previous reports of patients with GH-secreting pituitary adenomas and negative MR imaging
Since the introduction of MR imaging, there have been two reports of acromegalic patients without MR-imaging evidence of pituitary adenomas that were discovered to have a pituitary adenoma during surgical exploration of the pituitary gland. In 1990, Doppman et al. (9) described three acromegalic patients in whom MR imaging failed to detect a pituitary adenoma that was later discovered at surgery (resected adenoma sizes, 6, 7, and 10 mm). Only one patient in that series underwent a contrast-enhanced MR study and is included in the present results (patient 1; Table 1). The other two patients in that series were evaluated with only precontrast MR imaging, which may have led to the lack of MR evidence of pituitary adenoma. Nevertheless, complete resection and remission were attained in these three patients. In 2009, Daud et al. (16) described an acromegalic patient that did not have imaging evidence of a pituitary adenoma despite MR imaging with and without contrast, including thin-cut spoiled-gradient recalled (SPGR) imaging. Surgical exploration was performed in the patient, and a 9-mm adenoma was discovered and resected, leading to biochemical remission.
Clinical implications
Although the underlying cause of GH excess can be determined in the vast majority of acromegaly cases, occasionally patients will not have imaging evidence of a pituitary adenoma or endocrine evidence of an ectopic source for GH excess. In the present results, the frequency of tumors with negative MR imaging was 3.2% (six of 190 patients). Similar to ACTH-secreting microadenomas in Cushing’s disease, the cases described in this study demonstrate that acromegaly can be caused by GH-secreting microadenomas (all equal to or less than 6.7 mm) in acromegalic patients that are not detectable by conventional pituitary MR imaging and that imaging sequences that have higher soft tissue sensitivity may be useful in detecting adenomas not visible using conventional techniques (11). Because contrast-enhanced VIBE MR imaging, which is similar to the SPGR technique (10,12), can provide superior soft tissue imaging, it was used in three patients after conventional T1-weighted imaging did not provide evidence of an adenoma. One of the three cases evaluated with contrast-enhanced VIBE MR imaging demonstrated a tumor that was not detected on conventional SE MR imaging (Fig. 2). These findings indicate that in some cases VIBE MR imaging can be more sensitive in detecting a GH adenoma than conventional T1-weighted MR imaging, as occurs with SPGR MR imaging in Cushing’s disease (11).
Conclusions
Although the small size of the tumors in this series contributed to the inability to detect them on MR imaging, GH-secreting tumors of this size are the most amenable to surgical cure, which underscores the importance of pituitary exploration. Furthermore, because the morbidity and mortality associated with resection of microadenomas is low and the possibility of immediate biochemical remission is excellent, surgical exploration in cases of MR-invisible GH-secreting pituitary adenomas is a reasonable approach in the management of acromegalic patients without evidence of an ectopic etiology of acromegaly.
Footnotes
This work was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health.
Disclosure Summary: The authors have nothing to declare.
First Published Online July 7, 2010
Abbreviations: MR, Magnetic resonance; SE, spin echo; SPGR, spoiled-gradient recalled; VIBE, volumetric interpolated breath-hold examination.
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