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*Substance via MeSH
Medline Plus Health Information
*Cushing's Syndrome
The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 8 2912-2923
Copyright © 1999 by The Endocrine Society

Original Studies

Extrapituitary Parasellar Microadenoma in Cushing’s Disease

Ryszard M. Pluta, Lynnette Nieman, John L. Doppman, Joseph C. Watson, Nancy Tresser, David A. Katz1 and Edward H. Oldfield

Surgical Neurology Branch (R.M.P., J.C.W., E.H.O.), National Institute of Neurological Disorders and Stroke, and Developmental Endocrinology Branch (L.N.), National Institute of Child Health and Human Development, Radiology Department (J.L.D.), Clinical Center, Office of the Clinical Director (N.T., D.A.K.), NINDS, and Laboratory of Pathology, NCI, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Edward H. Oldfield, M.D., Chief, Surgical Neurology Branch, Building 10, Room 5D37, 10 Center Drive, Bethesda, Maryland 20892-1414.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 Conclusion
 References
 
Negative sellar exploration (despite the results of endocrine evaluation indicating Cushing’s disease), the high incidence of failure of total hypophysectomy, and remission of Cushing’s syndrome after unsuccessful hypophysectomy and sellar irradiation suggest that the etiology of refractory Cushing’s disease, in some patients, lies near the sella but not in the pituitary gland. We present 5 patients, out of 626 who received surgery for Cushing’s disease, in whom an ACTH-secreting extrapituitary parasellar adenoma was identified: 2 after unsuccessful total hypophysectomy for the treatment of refractory Cushing’s disease, 2 after unsuccessful hemihypophysectomy (the first, 2 yr before treatment at the NIH for Nelson’s syndrome; and the second, with recurrent Cushing’s disease 5 yr after negative transsphenoidal exploration), and 1 with a preoperative diagnosis of an intraclival microadenoma, which was cured by resection of the tumor. In all cases, an extrapituitary parasellar microadenoma was confirmed unequivocally as the cause of the disease, by negative pathology of the resected pituitary gland (patients 1, 2, 3, and 5), and/or the remission of the disease after selective resection of the extrasellar adenoma (patients 3, 4, and 5). Three of 5 patients had a partial empty sella. These patients support the thesis that ACTH-secreting tumors can arise exclusively from remnants of Rathke’s pouch, rather than from the adenohypophysis (anterior lobe or pars tuberalis of the pituitary gland) and can be a cause of Cushing’s disease. In the sixth presented case, an extrapituitary tumor was suspected at surgery after negative pituitary exploration, but serial sections of the hemihypophysectomy specimen revealed a microscopic focus of tumor at the margin of the resected gland. This case demonstrates the importance of negative pituitary histology to establish the presence of an extrapituitary parasellar tumor as an exclusive source of ACTH, and it supports the value of clinical outcome to establish the diagnosis with selective adenomectomy of an extrapituitary parasellar tumor. In patients with negative pituitary magnetic resonance imaging, especially in the presence of a partial empty sella, the diagnostic and surgical approach in Cushing’s disease should consider the identification and resection of extrapituitary parasellar adenoma, which can avoid total hypophysectomy, as was possible in 3 of our 5 patients.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 Conclusion
 References
 
ALGORITHMS have been established to diagnose an ACTH-secreting tumor as a cause of Cushing’s syndrome (1, 2, 3, 4, 5, 6). According to these algorithms, after confirmation of hypercortisolemia and inappropriately high plasma ACTH levels (6, 7), if the high-dose dexamethasone suppression test (8, 9) or a CRH-stimulation test confirms the presence of a pituitary adenoma, the diagnosis is Cushing’s disease (2, 5, 10). These endocrinological findings are followed by sellar magnetic resonance imaging (MRI) with gadolinium for anatomic localization of the tumor. A clearly positive MRI almost always correctly localizes the adenoma. If the results of the dexamethasone suppression test and the CRH test conflict, or are not definitive, or no tumor is evident on MRI, inferior petrosal sinus (IPS) sampling with CRH stimulation can unequivocally confirm the presence of a pituitary tumor (2). Despite such biochemical identification of pituitary cause of Cushing’s syndrome, no tumor is identified during transsphenoidal exploration of the sella turcica in as many as 25% of patients (4, 11, 12). Failure of intraoperative tumor identification may be explained by misdiagnosis, a very small pituitary tumor, lack of surgical experience (13), corticotroph hyperplasia (4, 12, 14), or an extrapituitary parasellar adenoma (13, 15, 16, 17, 18). If no tumor can be identified during surgery, some neurosurgeons advocate hemihypophysectomy (if IPS lateralizes) (19, 20) or partial or total hypophysectomy (4, 5, 14, 17, 21, 22). However, after total resection of the pituitary gland, when no tumor can be found, hypercortisolemia persists in as many as 42% of patients (5, 15, 17, 23, 24, 25) and is often cured only after sellar and parasellar irradiation (14, 25, 26, 27). Thus, in cases of intractable Cushing’s disease, especially when the biochemical tests exclude ectopic ACTH-secreting tumors, the presence of an extrapituitary parasellar adenoma, despite its rare occurrence, should be suspected as the cause of hypercortisolemia (13, 28, 29).

We present 5 patients, out of 626 who received surgery for Cushing’s disease, with ACTH-secreting extrapituitary parasellar microadenomas causing Cushing’s disease. In 3 patients, in whom total hypophysectomy (patients 1 and 2) or hemihypophysectomy (patient 3) failed to cure Cushing’s disease, the microadenomas originated in the parasellar dura mater. In patient 4, an intraclival microadenoma was diagnosed and resected, and hypophysectomy was not performed. In patient 5, an ACTH-secreting adenoma was resected from the roof of the left sphenoid sinus. A sixth presented case is included, in which an entirely extrapituitary parasellar tumor was suspected at surgery after negative pituitary exploration, but serial sections of the hemihypophysectomy specimen revealed a microscopic focus of the tumor at the surface of the gland. This later case demonstrates the possibility of the majority of the tumor mass lying outside the pituitary gland despite a small focus of tumor within the gland, a circumstance that may be overlooked without careful pathological analysis of the adjacent gland. This finding also underscores the value of the clinical outcome as a decisive modality for diagnosis of a parasellar extrapituitary adenoma.

The preoperative diagnosis of Cushing’s disease in our patients was established on the basis of endocrine and radiological findings, including the low- and high-dose dexamethasone suppression tests (8, 30), the CRH stimulation tests (31, 32), and (when appropriate) bilateral IPS ACTH sampling before and after ovine-CRH stimulation (2, 33, 34). MRI and computed tomography (CT) of the sellar region and adrenal glands, respectively, were obtained preoperatively.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 Conclusion
 References
 
Patient 1

A 61-yr-old Chilean woman was admitted with symptoms typical of Cushing’s syndrome for 36 yr. The plasma ACTH level was detectable (26 pg/mL) despite urine cortisol levels (urinary free cortisol) of 1100 µg/24 h (normal, 20–90 µg/24 h). The ACTH (87%) and cortisol (45%) increases during ovine-CRH (Bachem, Inc., Torrance, CA) (35) stimulation were consistent with a diagnosis of Cushing’s disease, as was the suppression of urinary free cortisol, during the high-dose dexamethasone test, to 3% of basal values (urine cortisol excretion declined from mean basal levels of 744 to 18 mcg/24 h during dexamethasone, 2 mg every 6 h) (8). MRI revealed an empty sella with a rim of enhancing pituitary tissue along the sides and the floor of the sella (Fig. 1AGo). IPS sampling revealed baseline ACTH levels of 167 pg/mL from the right IPS and 238 pg/mL from the left IPS. The ratio of central-to-peripheral ACTH levels was 6.3 on the right and 9 on the left IPS, and the ratio increased to 70 on the right and 74 on the left after ovine-CRH stimulation, when ACTH levels were 1260 pg/mL and 1330 pg/mL from the right and left IPS, respectively.



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  		Figure 1. Patient 1. This 61-yr-old woman had had Cushing’s syndrome for 36 yr. A, Preoperative MRI revealed an empty sella. After pituitary exploration did not reveal a tumor, total hypophysectomy was performed. Serial microscopic sections of the gland were negative for tumor. She died of pancreatitis and sepsis 2 months later. B and C, Postmortem study revealed an ACTH-secreting tumor, which was contained within the dura (arrowheads) of the floor of the sella (B, Reticulin staining, magnification = 11.5x; C, ACTH-immunostaining, magnification = 11.5x).

 
The patient underwent transsphenoidal surgery. No tumor was found despite extensive exploration of the pituitary gland; because of the patient’s age and the severity of Cushing’s syndrome, a total hypophysectomy was performed. Diabetes insipidus and hypothyroidism developed postoperatively. However, urine 17-hydroxycorticosteroid excretion remained high (16.4 mg/24 h). Serial microscopic sections of the pituitary revealed no tumor. Persistent cerebrospinal fluid leakage necessitated reoperation 16 days later, at which no residual pituitary tissue or adenoma was identified. The patient died of complications of pancreatitis and intraabdominal sepsis, 2 months after surgery. Postmortem examination disclosed no residual pituitary tissue, but a 2-mm ACTH-positive adenoma was found contained within the dura of the floor of the sella turcica (Fig. 1Go, B and C).

Patient 2

A 36-yr-old woman had symptoms of Cushing’s syndrome that began 5 yr previously. Plasma ACTH levels ranged from 24–115 pg/mL (normal, 30–60 pg/mL), urine cortisol excretion ranged from 155–171 µg/24 h. Basal urine 17-hydroxycorticosteroid excretion was elevated (23.8 mg/24 h), without significant change after low-dose dexamethasone (17.0 mg/24 h), but a decrease after high-dose dexamethasone (4.6 mg/24 h) (8). Both ACTH and cortisol values increased by 36% and 50% after ovine-CRH (1 µg/kg, iv). MRI revealed an empty sella (Fig. 2AGo). IPS sampling revealed baseline ACTH levels of 52.5 pg/mL on the right and 44.2 pg/mL on the left. The ratio of central-to-peripheral ACTH levels was 1.1 and 0.9, respectively, but the ratio increased to 7.8 on the right and 1.6 on the left after CRH stimulation.



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  		Figure 2. Patient 2. This 36-yr-old women had had Cushing’s syndrome for 5 yr. A, Preoperative MRI revealed an empty sella without an adenoma. At surgery, 85% of an extremely small pituitary gland was removed, leaving a small pituitary remnant attached to the stalk. Serial microscopic sections of the gland were negative for tumor. Hypercortisolemia persisted postoperatively, and she received bilateral adrenalectomy. B, One year later, the MRI revealed an intracavernous tumor on the right (arrows). C, The tumor was irradiated, and follow-up MRI (7 yr after irradiation) confirmed reduction of tumor size.

 
At transsphenoidal exploration an empty sella was confirmed, and no tumor was found, despite extensive exploration of the pituitary gland. At least 85% of the pituitary gland, which was compressed against the wall of the left cavernous sinus, was then removed. Hypothyroidism and diabetes insipidus developed postoperatively, but hypercortisolemia persisted (urine free cortisol, 251- 480 µg/24 h). Serial microscopic sections of the resected pituitary revealed no adenoma. Because it seemed unlikely that further pituitary surgery would be of benefit, the patient received bilateral adrenalectomy and hormonal replacement therapy.

One year later, Nelson’s syndrome developed (plasma ACTH level, 4,740 pg/mL). CT and MRIs during the next 2 yr revealed progressive enlargement of a mass in the right cavernous sinus consistent with an intracavernous adenoma (Fig. 2BGo). The plasma ACTH level increased to 317,000 pg/mL. Subsequently, the patient underwent radiation therapy to the sella and cavernous sinus (5,000 rad) that successfully halted tumor progression. Plasma ACTH levels decreased to 1,760–6,960 pg/mL, and the tumor diminished in size during 7 yr of follow-up (Fig. 2CGo).

Patient 3

A 31-yr-old man had Cushing’s syndrome for 3 yr. The plasma ACTH level was 74 pg/mL, and plasma cortisol was 28 µg/dL. Urine cortisol excretion was 695 µg/24 h, and basal urine 17-hydroxycorticosteroids excretion was 21 mg/24 h. The urine cortisol excretion declined in response to a 8-mg high-dose dexamethasone test (from 600 to 90 µg/24 h). IPS sampling revealed baseline ACTH levels of 84 pg/mL on the right and 303 pg/mL on the left. The ratio of central-to-peripheral ACTH levels was 7 and 25 on the right and left, respectively, and the ratio increased to 11 on the right and 16 on the left after CRH stimulation. MRI revealed a shift of the pituitary stalk to the left. However, two transsphenoidal explorations of the pituitary gland, performed at another institution, 2 yr before admission to the NIH, were negative for tumor. During the second operation, a right-sided hemihypophysectomy was performed. The serial microscopic sections of the tissue were negative for tumor. Postoperatively, he developed chronic diabetes insipidus that was treated with desmopressin, but hypercortisolism persisted (urine cortisol, 304 µg/24 h), and the patient was advised to have a bilateral adrenalectomy. Postoperative MRI revealed a partial empty sella, but no tumor was evident. One year before admission to our service, bilateral adrenalectomy was performed; and 6 months later, sellar MRI revealed the presence of a rapidly growing adenoma in the right side of the sella (Nelson’s syndrome; Fig. 3AGo) that produced a right-sided temporal visual field deficit.



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  		Figure 3. Patient 3. This 31-yr-old man previously had an unsuccessful exploration of the pituitary gland for Cushing’s disease of 3 yr duration. Subsequently, he had a right hemihypophysectomy. Serial microscopic sections of the tissue were negative for tumor, the patient had persistent hypercortisolemia, and he received a bilateral adrenalectomy. A, Six months after adrenalectomy, MRI revealed a rapidly growing tumor on the right sellar and parasellar regions (arrows). At surgery, the macroadenoma of the right cavernous sinus (which was noted to be separate from the remaining pituitary gland and completely contained medially, anteriorly, and posteriorly by a layer of dura) was resected. B, C, and D, Photomicrographs present the ACTH-secreting tumor (arrows) that was seen in multiple specimens of the medial wall of the right cavernous sinus (the interior of the sinus was filled with gelfoam for hemostasis during surgery). Higher magnification (D) shows the tumor encased in the dura (white arrowheads; B, reticulin staining, magnification = 6.5x; C, ACTH-immunostaining, magnification = 6.5x; D, ACTH-immunostaining, magnification = 25x). The ACTH remained low during 3 yr of follow-up.

 
On admission, the plasma ACTH level was 7,250 pg/mL. At transsphenoidal surgery, the pituitary macroadenoma, which was noted to be entirely separate from the pituitary gland, was completely contained by a thin layer of dura on its anterior and medial surfaces. After entering the anterior wall of the cavernous sinus and dissection of the lateral aspect of the tumor from the medial wall of the internal carotid artery, the remaining tumor was removed with the surrounding dura. The patient’s postoperative course was uneventful. Histopathologic examination revealed an ACTH-positive tumor contained within the dura mater of the medial wall of the right cavernous sinus (Fig. 3Go; B, C, and D). After surgery, ACTH levels dropped to 8.9 pg/mL on postoperative day 8, and visual field examination indicated resolution of the preoperative deficit. The ACTH remained low (<7–29 pg/mL) during 3 yr of follow-up.

Patient 4

A 20-yr-old woman had Cushing’s syndrome for 8 yr. MRI, performed at another institution (4 yr before the admission to the NIH), revealed a partial empty sella with a shift of the pituitary stalk to the left. Transsphenoidal exploration of the pituitary gland was performed, and the suspected tumor was resected but proved histologically to be a region of fibrosis without ACTH-secreting tumor. Postoperatively, hypercortisolemia persisted, and the patient was advised to have bilateral adrenalectomy. She declined this recommendation and ketoconazole therapy was started, which produced clinical improvement. Repeated MRIs of the sella showed no evidence of a tumor. An octreotide radioisotope scan was also unrevealing.

At admission (6 weeks after stopping ketoconazole), the plasma ACTH level was 130 pg/mL, and urine cortisol excretion was 213 µg/24 h. The patient had a cortisol and ACTH response to ovine-CRH but did not show significant suppression of plasma cortisol levels after dexamethasone (8 mg at midnight). MRI revealed a partial empty sella with postoperative changes in the sella and a hypodense (before gadolinium infusion) contrast-enhancing lesion in the right half of the clivus (Fig. 4AGo). IPS sampling revealed baseline ACTH levels of 77 pg/mL on the right and 177 pg/mL on the left. The ratio of central-to-peripheral ACTH levels was 1.3 and 2.9, respectively; the ratio increased to 17.2 on the right and 8.4 on the left after CRH stimulation.



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  		Figure 4. Patient 4. This 20-yr-old woman had had Cushing’s syndrome for 8 yr. A preoperative CT scan revealed a partially empty sella with a shift of the pituitary stalk to the left. After a negative transsphenoidal exploration, she declined bilateral adrenalectomy. A, Four yr later, on admission to NIH, MRI revealed a suspicious lesion in the upper part of the clivus (T1-weighted sagittal view of the noncontrast MRI; arrow points toward the tumor; arrowhead points to the stalk of the small pituitary gland). The patient had a second transsphenoidal exploration with resection of an adenoma contained within the medial wall of the right cavernous sinus and from the upper portion of the right half of the clivus. B and C, Photomicrographs of the tumor removed from the medial wall of the cavernous sinus show that the ACTH-positive tumor was encapsulated by the dura (arrowheads; B, Reticulin staining, magnification = 16x; C, ACTH-immunostaining, magnification = 16x). D and E, Photomicrograph presents an additional tumor that was removed from the clivus. Small foci of the ACTH-positive tissue (arrows) are present inside the bone (arrowheads; D, Reticulin staining, magnification = 8.5x; E, ACTH-immunostaining, magnification = 8.5x). The patient was cured.

 
At transsphenoidal surgery, a pituitary tumor was removed from the medial wall of the right cavernous sinus (Fig. 4Go, B and C) and from the upper portion of the right half of the clivus (Fig. 4Go, D and E). There was no connection between either of the two tumor sites and the pituitary gland, and no communication was evident between the two tumor sites. There was no evidence of intrasellar tumor or of tumor reaching the inner layer of dura from the extradural sites. The patient’s postoperative course was uneventful. After surgery, morning plasma cortisol levels ranged from 1.8–2.6 µg/dL, and urine cortisol excretion was less than 10 µg/24 h. Histopathologic examination revealed ACTH-positive tumor in the medial wall of the right cavernous sinus and in the clivus, without invasion of medial surface of the dura mater (Fig. 4Go, B and D). Two months later, the patient regained regular menstruation; and 1 yr after surgery, her urine free cortisol level remained low (9 µg/24 h). She discontinued cortisone treatment, after ACTH stimulation test, was normal, and she had a normal pregnancy, with delivery about 18 months after surgery.

Patient 5

A 27-yr-old man was admitted for treatment of recurrent Cushing’s syndrome, 7 yr after a transient remission was achieved by sellar exploration and left hemihypophysectomy. During the first evaluation for Cushing’s syndrome, the plasma ACTH level was 16.5 pg/mL, and plasma cortisol was 32 µg/dL. Urine cortisol excretion ranged from 600-2900 µg/24 h. Basal urine 17-hydroxycorticosteroid excretion was not measured, because of assay interference by Tegretol. The urine cortisol excretion declined, in response to an 8-mg high-dose dexamethasone test (from 1,760 to 604 µg/24 h). IPS sampling revealed baseline ACTH levels of 152 pg/mL on the right and 839 pg/mL on the left. The basal ratio of central-to-peripheral ACTH levels was 1.4 and 8 on the right and left, respectively, and the ratio increased to 1.7 on the right and 13 on the left after ovine-CRH stimulation. MRI revealed a soft tissue density in the medial wall of the left sphenoid sinus (Fig. 5Go, A and B). Transsphenoidal exploration of the pituitary gland was negative for tumor, and a left hemihypophysectomy was performed. Serial microscopic sections of the tissue were negative for tumor. Postoperative ovine-CRH stimulation demonstrated a peak cortisol response of 1.9 µg/dL, with all cortisol values less than 1 µg/dL, but ACTH levels peaked at 19.9 pg/mL. Urine cortisol excretion remained in the normal range for 2 yr after surgery. Five years after surgery, he was readmitted for evaluation of possible recurrent Cushing’s syndrome. At that time, the plasma ACTH level was 119 pg/mL, and plasma cortisol was 34 µg/dL. Urine cortisol excretion ranged from 324–755 µg/24 h. Plasma cortisol levels declined in response to the overnight 8-mg high-dose dexamethasone test (from 28.8 to 4.8 µg/dL) (36). MRI revealed an empty sella with abnormal signal density in the floor of the sella, consistent with postoperative changes, and a soft tissue nodule in the roof of the left sphenoid sinus (Fig. 5Go, C and D). The patient refused treatment and left the hospital against medical advice.



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  		Figure 5. Patient 5. A 27-yr-old man was admitted for treatment of recurrent Cushing’s syndrome after remission of hypercortisolism was probably induced by incidental resection of an ACTH-secreting adenoma from the mucosa of the sphenoid sinus during sellar exploration performed 7 yr earlier. At the initial evaluation, MRI revealed a soft tissue nodule (white arrow) in the medial wall of the left sphenoid sinus (A, T1-weighted coronal MRI with contrast; B, T1-weighted sagittal MRI with contrast). Transsphenoidal exploration of the pituitary gland was negative for tumor, and a left hemihypophysectomy was performed. Serial microscopic sections of the tissue were negative for tumor. Despite these negative findings, a biochemical and clinical remission of Cushing’s disease was achieved for 5 yr. Seven years after the initial transsphenoidal surgery, he was readmitted for the treatment of recurrent Cushing’s syndrome. Before the second surgery, MRI revealed a partial empty sella with abnormal signal density in the floor of the sella consistent with postoperative changes and a nodule of soft tissue (white arrow) in the roof of the left sphenoid sinus (C, T1-weighted coronal MRI with contrast; D, T1-weighted sagittal MRI with contrast). At transsphenoidal surgery, the nasal polyp was removed from the wall of the left sphenoid sinus. E and F, Photomicrographs of the tumor removed from the roof of the sphenoid sinus show that the ACTH-positive tumor (arrows) was encapsulated by nasal mucosa (arrowheads; E, Hematoxylin and eosin staining, magnification = 16x; F, ACTH-immunostaining, magnification = 16x). Higher magnification (G) shows the tumor (arrows) encased in the nasal epithelium (arrowheads; G, ACTH-immunostaining, magnification = 100x). Biochemical remission occurred postoperatively.

 
The patient returned 2 yr later for transsphenoidal surgery. Preoperative midnight plasma cortisol was elevated, and urine cortisol excretion was 291 µg/24 h. At transsphenoidal surgery a nasal polyp was removed from the roof of the sphenoid sinus and was sent for histopathology. Exploration of the left cavernous sinus, residual pituitary gland, and the right cavernous sinus were negative. The patient’s postoperative course was uneventful. Histopathologic examination of the nasal polyp revealed an ACTH-positive tumor contained within the nasal mucosa (Fig. 5Go, E and F). After surgery, plasma cortisol levels were below 1 µg/dL before and after stimulation with ovine CRH.

Patient 6

A 41-yr-old woman had Cushing’s syndrome for 5 yr but was only diagnosed 6 months before admission, when a high urine cortisol excretion was confirmed. MRI performed at another institution did not reveal an adenoma of the pituitary gland.

At admission, the plasma ACTH level was 6 pg/mL but rose to 36.9 pg/mL after ovine-CRH stimulation, consistent with a pituitary source of ACTH. Urine cortisol excretion ranged from 298–789 µg/24 h. The patient had a cortisol response to ovine-CRH, but she did show significant suppression of plasma cortisol levels after dexamethasone (8 mg at midnight). IPS sampling revealed baseline ACTH levels of 35 pg/mL on the right and 8.2 pg/mL on the left. The ratio of central-to-peripheral ACTH levels was 3.9 and 0.9, respectively.

At transsphenoidal surgery, after negative exploration of the pituitary gland, a right hemihypophysectomy was performed. Upon removal of the right half of the gland, it was noted that there was a tumor in the posterior aspect of the right cavernous sinus. This tumor was removed. There was no obvious connection between the tumor and the pituitary gland. There was no evidence of intrasellar tumor or of tumor reaching the inner surface of the dura from the extradural site. The patient’s postoperative course was uneventful, except for diabetes insipidus. After surgery, morning plasma cortisol levels were less than 1 µg/dL, and urine cortisol excretion was less than 10 µg/24 h. The ovine-CRH test demonstrated a peak cortisol level of 1.8 µg after 3 h (the 1-h level was below 1 µg). Histopathologic examination revealed an ACTH-positive tumor in the posterior wall of the right cavernous sinus without invasion of the medial surface of the dura mater (Fig. 6Go, A and B). Serial sections of the right half of the pituitary gland revealed a microscopic focus of ACTH-positive tumor at the surface of the pituitary gland in the lower part of the resected half of the gland (Fig. 6Go, C and D).



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  		Figure 6. Patient 6. This 41-yr-old woman was diagnosed with Cushing’s disease for 5 yr. Preoperative MRI did not reveal an adenoma. After no tumor was identified within the pituitary gland, a right-sided hemihypophysectomy was performed, and a tumor was resected from the right cavernous sinus. A and B, Photomicrographs present the ACTH-positive tissue comprising the posterior aspect of the medial wall of the right cavernous sinus. The tumor was contained within the dural layers (arrowheads; A, reticulin staining, magnification = 16x; B, ACTH-immunostaining, magnification = 16x). C and D, Photomicrographs of the right hemihypophysectomy specimen reveal a microscopic focus of ACTH-positive adenoma on the surface of the posterior aspect of the resected gland (arrow; C, Reticulin staining, magnification = 100x; D, ACTH-immunostaining, magnification = 100x). Biochemical remission was achieved by the resection of both ACTH-positive foci.

 

   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 Conclusion
 References
 
Despite sophisticated diagnostic techniques, including the dexamethasone suppression test, the ovine-CRH stimulation test, IPS sampling, MRI and CT, and aggressive surgical exploration of the pituitary gland, surgery often fails to cure endocrinologically-confirmed Cushing’s disease, even when total hypophysectomy is performed (5, 14, 15, 17, 24, 25). The presence of extrapituitary adenomas in and around the sella turcica represents one cause of surgical failure (13, 20, 21, 29, 37, 38, 39, 40, 41, 42). However, an unequivocal diagnosis of extrapituitary parasellar microadenoma is difficult and can be achieved only if a selective excision of the extrapituitary tumor cures the Cushing’s disease or if careful and complete histological analysis does not confirm the presence of a tumor in the pituitary gland after hypophysectomy. We present five patients with Cushing’s disease caused by ACTH-secreting extrapituitary parasellar microadenomas and one patient in whom the tumor initially seemed to be extrapituitary, but a microscopic focus of ACTH-positive adenoma was present in the hemihypophysectomy specimen. In the first patient, hypercortisolemia persisted after total hypophysectomy because of an extrapituitary microadenoma lying between the inner and outer layers of the dura (intradural) next to a normal pituitary gland, as confirmed at autopsy. In the second patient, hypercortisolemia persisted after total hypophysectomy that was negative for tumor; the patient then had bilateral adrenalectomy, which led to Nelson’s syndrome, a year after initial transsphenoidal surgery, when an adenoma appeared in the right cavernous sinus. In these two patients, histopathological studies of the pituitary gland unequivocally indicated that there was no tumor in the anterior lobe. In the third patient, a hemihypophysectomy contained no tumor and did not cure hypercortisolemia, and the patient had bilateral adrenalectomy, which may have contributed to rapid growth of an intracavernous adenoma (Nelson’s syndrome). In the fourth patient, cure was achieved by removal of a tumor from the clivus and the cavernous sinus, avoiding noncurative hypophysectomy and adrenalectomy. In the fifth patient, 5 yr of remission was achieved, most probably by accidental devascularization and/or partial removal of the ACTH-secreting adenoma in the mucosa of the sphenoid sinus during surgical exposure of the sella. Seven years later, the patient was cured by selective resection of a recurrent adenoma in the mucosa of the roof of the left sphenoid sinus. In the sixth patient, remission was achieved after hemihypophysectomy, containing a microscopic tumor and resection of tumor from the right cavernous sinus. In three of five patients, bilateral simultaneous IPS sampling indicated the correct diagnosis despite the extrapituitary site of the tumor.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
Conclusion
 References
 
Incidence of ACTH-secreting extrapituitary parasellar adenomas

Based on the number of patients in whom hypercortisolemia persists after total resection of the pituitary gland (5, 14, 15, 17, 24, 25) who are cured by sellar and parasellar irradiation (14, 25, 27), as many as 1% of patients with Cushing’s disease may harbor extrapituitary parasellar adenomas (5). The true incidence of this condition is obscured by a number of reports that mistakenly describe pituitary adenomas arising from the pituitary stalk (the pars tuberalis of adenohypophysis) (28, 43, 44, 45, 46, 47, 48) as being ectopic (13, 16, 49, 50). Because the pituitary stalk is normally enfolded by a superior extension of the anterior lobe, we propose the designation of extrapituitary parasellar adenoma for tumors without connection to intrasellar gland or the stalk. Using such a criteria, we have found only 11 previously reported cases of ACTH-secreting extrapituitary parasellar adenomas, which includes 4 patients with microadenomas (Table 1Go) (13, 20, 21, 29, 37, 38, 39, 40, 41, 42, 51). This is a surprisingly small number of cases, when one considers the well-established predominance of ACTH-secreting adenomas among extrapituitary parasellar adenomas (20, 41, 52, 53). However, because an extrapituitary parasellar adenoma (15, 43, 50) is one of several reasons for failed pituitary surgery (13, 16, 21, 29, 37, 38) and usually is cured by sellar and parasellar irradiation (14, 25, 26, 27), it is possible that many extrapituitary parasellar tumors are not diagnosed because the Cushing’s disease is cured by sellar radiation (14, 25, 26, 27).


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  		Table 1. Summary of reported cases of ACTH-secreting ectopic parasellar adenomas

 
Location of ACTH-secreting extrapituitary parasellar adenomas

Ectopic pituitary tissue is found commonly at autopsy (23, 54). The existence of ectopic hypophysis, developed during migration of Rathke’s pouch (54), could lead to growth of an adenoma (16) close to the midline between the pharyngeal mucosa (37, 55, 56) and the sella (13, 48). Usually, such adenomas develop in the pharyngeal mucosa (55, 56), sphenoid sinus (15, 20, 37, 38, 41, 51), sphenoid bone (57), clivus (18, 43, 58), or sella (13, 48). ACTH-secreting extrapituitary parasellar adenomas usually are found in the sphenoid sinus (Table 1Go; patient 5) (20, 21, 29, 38, 41, 51) but may also occur in the interpeduncular cistern (42), suprasellar space (39, 40), and inside the cavernous sinus (patients 2, 3, and 4 here; Table 1Go) (17). The presence of an extrapituitary microadenoma in the clivus (patient 4) is rare (18, 43, 58, 59).

Diagnosis of ACTH-secreting extrapituitary parasellar adenoma

Extrapituitary parasellar macroadenomas are diagnosed from obvious radiographic abnormalities (patients 2, 3, and 5) (21, 40, 41, 42, 43, 58). On the other hand, there have been no instances in which the parasellar microadenoma has been diagnosed preoperatively, and all reported extrapituitary microadenomas have been an intraoperative surprise, especially when tissue incidentally found in the sphenoid sinus, revealed the presence of ACTH-secreting tumor at histology (Table 1Go, patient 5) (20, 29, 37).

In most patients with Cushing’s disease, tumor removal produces immediate remission of the disease. On the other hand, when hypercortisolemia persists and the patients are treated with total hypophysectomy (4, 12, 13, 14, 17, 22), about 40% continue to be hypercortisolemic (14, 17, 27). In this group, the microadenomas responsible for persistent disease were localized later because of tumor growth in the vicinity of the sella (4, 12, 21, 51, 60). Very rarely, in only five patients (including our patients 2 and 3) (21, 51), an ACTH-secreting extrapituitary parasellar adenoma progressed to Nelson’s syndrome after adrenalectomy. Perhaps more likely is the circumstance in which an extrapituitary parasellar tumor is not diagnosed because remission is achieved by parasellar irradiation (14, 25), the patient remains symptom-free after bilateral adrenalectomy (17), or the adenoma is removed accidentally (patient 5).

The presence of an empty sella at initial presentation in three of our five patients, as well as in several of the previously reported cases of extrapituitary parasellar adenomas (Table 1Go) (20, 39, 40, 41, 51, 58, 61), suggests that the presence of an extrapituitary parasellar tumor is more likely when an empty sella is found with Cushing’s disease. Because extrapituitary parasellar adenomas probably develop from a remnant of Rathke’s pouch, the absence of a completely developed pituitary gland may be a result of an incomplete migration of Rathke’s pouch and incomplete adenohypophyseal development. However, it should be also noted that Yamamoto et al. (6) reported two patients with an empty sella coexisting with an ectopic ACTH-secreting bronchial carcinoid in the lung.

Passage of time also can be an important factor in establishing the presence of extrapituitary parasellar adenoma. In 5–10% of cases of ectopic adenomas, the tumor is discovered only after total hypophysectomy (4, 12, 22), which may have been avoided by continued observation of the patient and radiographic reassessment of the sella at intervals. In our patients, a prolonged course (36 yr, patient 1), the development of Nelson’s syndrome (seventh year of the disease and 1 yr after bilateral adrenalectomy in patient 2, third year of disease and 6 months after adrenalectomy in patient 3) and prolonged observation because of partially successful medical treatment (8 yr after onset of disease and 4 yr after negative transsphenoidal exploration in patient 4) or the recurrence of Cushing’s disease (5 yr after initial surgery in patient 5) allowed growth of the tumor to a detectable size.

The sixth patient demonstrates another difficulty with establishing the diagnosis of extrapituitary parasellar adenoma. In this patient, the tumor was discovered inside the posterior part of the right cavernous sinus after hemihypophysectomy. However, careful histological examination of the resected part of the pituitary gland revealed the presence of a microscopic tumor in the gland. Such a small (<1 mm) tumor can be easily missed during surgical exploration of the gland; and the circumstance may, misleadingly, mimic an extrapituitary parasellar tumor. Therefore, with surgery limited to selective excision of a parasellar tumor, only sustained remission of hypercortisolism can indicate that the resected extrapituitary parasellar tumor was the cause of Cushing’s disease.


   Conclusion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 Conclusion
References
 
Negative sellar exploration, despite the results of endocrine evaluation indicating Cushing’s disease, the high incidence of failure of total hypophysectomy, and remission of Cushing’s syndrome after sellar irradiation, suggest that the etiology of refractory Cushing’s disease in many patients lies near the sella but is not in the pituitary gland. In such patients, the diagnostic and surgical effort should consider the identification and selective resection of an extrapituitary parasellar adenoma and the avoidance of total hypophysectomy and adrenalectomy, which necessitate life-long hormonal replacement therapy and risk development of Nelson’s syndrome (21, 27).


   Footnotes
 
1 Current address: Department of Pathology, Hartford Hospital, Hartford, Connecticut 06102. Back

Received February 24, 1999.

Revised April 26, 1999.

Accepted May 4, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 Conclusion
 References
 

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