Usefulness of inferior petrosal sinus venous endocrine markers in Cushing's disease

✓ Bilateral and simultaneous sampling of the inferior petrosal sinuses in patients with Cushing's disease has been used to establish the presence and laterality of adrenocorticotropic hormone (ACTH)-producing microad-enomas prior to transsphenoidal surgery. Successful preoperative lateralization depends upon equivalent dilution of pituitary venous blood on the two sides since samples which are diluted by unequal amounts of non-pituitary blood may lead to erroneous results. To assure valid sampling results, the use of other pituitary hormones, measured simultaneously, has been proposed to correct the ACTH concentrations from the inferior petrosal sinuses against unequal dilution by non-pituitary venous blood. This proposal presumes that ACTH-secreting microadenomas will not cause unequal delivery of the other pituitary hormones into the two inferior petrosal sinuses. The inferior petrosal sinus concentrations of prolactin (PRL), thyrotropin (TSH), and the alpha subunit of human chorionic gonadotropin (α-HCG) were evaluated as indicators of pituitary venous blood dilution in 11 patients with Cushing's disease. Four patients with ectopic ACTH syndrome served as controls. Blood was withdrawn simultaneously from catheters in both inferior petrosal sinuses and from a peripheral vein for measurement of ACTH, PRL, TSH, and α-HCG. The ACTH concentrations were then corrected for dilution by non-pituitary blood by dividing the ACTH concentration from each side by the ratio of the inferior petrosal sinus to peripheral blood concentrations of PRL, TSH, and α-HCG for that side. At surgery, all 11 patients had ACTH-secreting microadenomas on the side predicted by the uncorrected ACTH concentrations. However, in three patients the corrected ACTH values would have led to erroneous results. Among the 18 sets of corrected inferior petrosal sinus measurements in these three patients, the corrected ACTH values failed to show an inferior petrosal sinus gradient in six and localized the tumor to the side opposite the adenoma in four. Incorrect lateralization was obtained with each of the hormones (PRL, TSH, and α-HCG) used for correction. Furthermore, the ipsilateral (side of tumor)-to-contralateral inferior petrosal sinus gradient of ACTH in patients with Cushing's disease was generally paralleled by a significant inferior petrosal sinus gradient of PRL, TSH, and α-HCG to the side of the tumor, whereas patients with the ectopic ACTH syndrome tended not to exhibit lateralizing (side-to-side) gradients. These findings indicate that the simultaneous measurement of inferior petrosal sinus concentrations of PRL or TSH or of the glycoprotein hormone α subunit does not improve preoperative localization of ACTH-secreting microadenomas and may lead to incorrect lateralization of the tumor. The results also suggest that ACTH-secreting microadenomas cause enhanced delivery of PRL, TSH, and α subunit into the inferior petrosal sinus ipsilateral to the tumor which, in turn, may reflect paracrine stimulation of hormone secretion in the anterior pituitary gland surrounding ACTH-secreting microadenomas.

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Surgical treatment of Cushing's disease

Journal of Neurosurgery ◽

10.3171/jns.1987.66.2.0204 ◽

1987 ◽

Vol 66 (2) ◽

pp. 204-212 ◽

Cited By ~ 101

Author(s):

William F. Chandler ◽

David E. Schteingart ◽

Ricardo V. Lloyd ◽

Paul E. McKeever ◽

Gloria Ibarra-Perez

Keyword(s):

Cushing’S Disease ◽

Immunohistochemical Staining ◽

Adrenocorticotropic Hormone ◽

Cushing's Disease ◽

Content Type ◽

Acth Secreting ◽

Endocrine Symptoms ◽

Lung Carcinoid ◽

Fine Print ◽

Pharyngeal Pituitary

✓ The endocrinological, radiological, surgical, and pathological experience with 34 consecutive patients operated on for Cushing's disease is presented. Preoperative endocrine evaluation demonstrated that 19 patients had “typical” endocrine patterns for pituitary adrenocorticotropic hormone (ACTH)-dependent hypercortisolism and 11 had “atypical” testing. Pituitary pathology was found in 95% of the patients with typical preoperative endocrine testing but in only 55% of those with atypical testing. Eight of 34 preoperative computerized tomography scans demonstrated tumors, which correlated in all instances with the surgical findings. Microadenomas were removed from 25 patients, 22 of whom achieved postoperative remission of endocrine symptoms. Macroadenomas were found in three patients, only one of whom achieved remission after surgery. One patient had removal of an adenoma in the pharyngeal pituitary, and in another an ectopic lung carcinoid was excised; both of these patients were in postoperative remission. Four patients underwent transsphenoidal exploration but no definitive explanation was found for their hypercortisolism; these patients were not in remission. Immunohistochemical staining was performed on every specimen and all tumors showed excessive ACTH-secreting cells. A new rapid stain of the fibrovascular stroma is described.

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Surgical management of adrenocorticotropic hormone—secreting macroadenomas: outcome and challenges in patients with Cushing's disease or Nelson's syndrome

Journal of Neurosurgery ◽

10.3171/jns.2005.103.5.0825 ◽

2005 ◽

Vol 103 (5) ◽

pp. 825-830 ◽

Cited By ~ 60

Author(s):

Claudio De Tommasi ◽

Mary Lee Vance ◽

David O. Okonkwo ◽

Alfa Diallo ◽

Edward R. Laws

Keyword(s):

Cushing’S Disease ◽

Adrenocorticotropic Hormone ◽

Signs And Symptoms ◽

Disease Recurrence ◽

Cushing's Disease ◽

Nelson’S Syndrome ◽

Content Type ◽

Nelson's Syndrome ◽

Acth Secreting ◽

Fine Print

Object. Adrenocorticotropic hormone (ACTH)—secreting pituitary macroadenomas are an uncommon cause of Cushing's disease (CD) and, subsequently, Nelson's syndrome (NS). They have been associated with low postoperative remission rates. The outcome of modern surgical treatment is unclear and thus was assessed in a series of 43 patients, with the goal of improving therapeutic results in patients with ACTH-secreting macroadenomas. Methods. Thirty-seven patients presented with CD and six with NS. They represented 15% of the patients surgically treated at the authors' institution for ACTH-secreting adenomas. The median patient age was 38 years (range 14–71 years), and the mean duration of follow up was 37 months (range 1–108 months). Remission occurred in 25 (67.6%) of 37 patients with CD, whereas the disease persisted in 12 (32.4%) of 37 patients. After an initial remission, three (12%) of 25 patients demonstrated signs and symptoms indicative of disease recurrence. Among patients with NS, only one (16.6%) displayed remission. Invasion of the dura mater by tumor was histologically demonstrated in 10 patients with CD and in two patients with NS. Conclusions. Comprehensive management of CD caused by ACTH-secreting macroadenomas through the appropriate use of combination therapy, including surgery, radiotherapy, radiosurgery, and adrenalectomy, can lead to outcomes similar to those for microadenomas. Disease recurrence and persistence rates are higher, often because of the invasiveness associated with macroadenomas. Remission of NS-associated macroadenomas is difficult to achieve. Strategies for the characterization and treatment of invasive macroadenomas are needed.

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Outcome of Petrosal Venous Sampling in Consecutive 68 Patients From a Major Neurosurgical Center in the United Kingdom

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1066 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A523-A523

Author(s):

Ziad Hussein ◽

Hani J Marcus ◽

Joan Greive ◽

Neil Dorward ◽

Pierre M Bouloux ◽

...

Keyword(s):

Pituitary Adenoma ◽

Cushing’S Disease ◽

Tumor Resection ◽

Cushing's Disease ◽

Ectopic Acth Syndrome ◽

Venous Sampling ◽

Ectopic Acth ◽

Gradient Ratio ◽

Acth Secreting ◽

Two Sides

Abstract Background: Cushing’s disease is a challenging endocrine disorder caused by non-physiological cortisol excess from adrenocorticotropic hormone (ACTH) secreting pituitary adenoma. Inferior petrosal venous sampling (IPSS) is considered the gold standard investigation to differentiate Cushing’s disease from ectopic ACTH syndrome. Methods: This retrospective study included all patients who underwent IPSS between January 2011 and October 2020 at The National Hospital for Neurology and Neurosurgery in London. Patients demographics, radiological, surgical, endocrinological and, histological data were retrieved. We assessed the accuracy of IPSS in localizing ACTH secreting pituitary adenoma and its concordance with neuroimaging and surgical findings at the time of tumor resection. Results: In total 68 patients underwent IPSS, 22 males and 46 females. The median age was 42 years. IPSS was performed prior to primary surgery in 61 patients (90%) and before secondary surgery in 4 patients (6%). Three patients (4%) are awaiting surgery at the time of our study. Fifty-two patients (80%) had positive histology of ACTH expressing adenoma. Four patients (8%) had ectopic ACTH syndrome. The sensitivity of IPSS in predicting Cushing’s disease prior to corticotropin-releasing hormone (CRH) stimulation was 91% (95% CI [83% to 97%]) and accuracy of 88% (95% CI [77% to 95%]). The sensitivity of IPSS post CRH administration was 96% (95% CI [87% to 100%]) with accuracy of 86% (95% CI [75% to 93%]). Data on lateralization of pituitary adenoma were available for 63 patients. Prior to CRH stimulation, lateralization was right sided in 35 patients (56%), left sided in 15 (24%), and 13 patients (20%) did not have adequate interpetrosal sinus ACTH ratio. Lateralization post CRH stimulation was right sided in 40 patients (64%), left sided in 20 (32%), and 3 patients (4%) did not achieve adequate ACTH gradient ratio between two sides. Eighteen patients (30%) switched adenoma lateralization between pre and post CRH stimulation. Post CRH IPSS was consistent with neuroradiology in localizing pituitary adenomas in 59% (29 out of 49 patients) and concordant with surgical findings in 41% (25 out of 61 patients). Patients with ectopic ACTH syndrome had negative IPSS at all stages. IPSS procedure failed in 2 patients (3%). No post procedure complications were reported. Conclusion: IPSS has high sensitivity in diagnosing pituitary driven Cushing’s disease with good safety profile. However, the reliability in lateralizing pituitary adenoma is debated. One third of patients in this cohort switched lateralization before and after CRH administration. Studies on monkeys and rats showed that CRH induces coronary vasodilation and reduction in systemic vascular resistance. This suggest that CRH might have vasoactive effect on pituitary blood vessels with subsequent influence on IPS:P ACTH gradient ratio between the two sides.

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False-positive inferior petrosal sinus sampling in the diagnosis of Cushing's disease

Journal of Neurosurgery ◽

10.3171/jns.1995.83.6.1087 ◽

1995 ◽

Vol 83 (6) ◽

pp. 1087-1091 ◽

Cited By ~ 59

Author(s):

Yoshihiro Yamamoto ◽

Dudley H. Davis ◽

Todd B. Nippoldt ◽

William F. Young ◽

John Huston ◽

...

Keyword(s):

Cushing’S Disease ◽

False Positive ◽

Adrenocorticotropic Hormone ◽

Pituitary Tumors ◽

Cushing's Disease ◽

Inferior Petrosal Sinus ◽

Acth Secretion ◽

Content Type ◽

Inferior Petrosal Sinus Sampling ◽

Acth Secreting

✓ Inferior petrosal sinus sampling (IPSS) for adrenocorticotropic hormone (ACTH) levels in patients with Cushing's syndrome has become a useful method to distinguish ACTH-secreting pituitary tumors (Cushing's disease) from other causes of the syndrome, principally ectopic adrenocorticotropin secretion by an occult tumor. Although the test is generally regarded as highly specific, the authors recently encountered two patients whose IPSS measurements were false-positive for Cushing's disease. The results of IPSS suggested a pituitary origin of ACTH secretion in both patients, but transsphenoidal surgery failed to disclose a pituitary adenoma or to improve postoperative plasma cortisol levels. Both patients subsequently were found to have an ACTH-secreting carcinoid tumor of the lung. The false-positive IPSS studies were due to periodic hormonogenesis. The patients must be hypercortisolemic at the time IPSS is performed for the study to be valid.

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Selective Venous Sampling for ACTH in Cushing’s Syndrome: Differentiation Between Cushing’s Disease and the Ectopic ACTH Syndrome

The Journal of Urology ◽

10.1016/s0022-5347(17)53960-9 ◽

1982 ◽

Vol 127 (3) ◽

pp. 618-619

Author(s):

J.W. Findling ◽

D.C. Aron ◽

J.B. Tyrrell ◽

J.H. Shinsako ◽

P.A. Fitzgerald ◽

...

Keyword(s):

Cushing’S Syndrome ◽

Cushing’S Disease ◽

Cushing's Syndrome ◽

Cushing's Disease ◽

Ectopic Acth Syndrome ◽

Syndrome Differentiation ◽

Venous Sampling ◽

Ectopic Acth ◽

Selective Venous Sampling

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Radiosurgery for Cushing's disease after failed transsphenoidal surgery

Journal of Neurosurgery ◽

10.3171/jns.2000.93.5.0738 ◽

2000 ◽

Vol 93 (5) ◽

pp. 738-742 ◽

Cited By ~ 175

Author(s):

Jonas M. Sheehan ◽

Mary L. Vance ◽

Jason P. Sheehan ◽

Dilantha B. Ellegala ◽

Edward R. Laws

Keyword(s):

Gamma Knife ◽

Cushing’S Disease ◽

Tumor Size ◽

Transsphenoidal Surgery ◽

Gamma Knife Radiosurgery ◽

Magnetic Resonance Images ◽

Cushing's Disease ◽

Content Type ◽

Fine Print

Object. Although transsphenoidal surgery has become the standard of care for Cushing's disease, it is often unsuccessful in normalizing cortisol production. In this study the authors investigate the safety and efficacy of gamma knife radiosurgery (GKRS) for Cushing's disease after failed transsphenoidal surgery.Methods. The records of all patients who underwent GKRS at the authors' institution after unsuccessful transsphenoidal surgery for Cushing's disease were retrospectively reviewed. Successful treatment was considered a normal or below-normal 24-hour urinary free cortisol (UFC) level. Records were also evaluated for relapse, new-onset endocrine deficiencies, interval change in tumor size, and visual complications.Forty-three patients underwent 44 gamma knife procedures with follow up ranging from 18 to 113 months (mean 39.1, median 44 months). Normal 24-hour UFC levels were achieved in 27 patients (63%) at an average time from treatment of 12.1 months (range 3–48 months). Three patients had a recurrence of Cushing's disease at 19, 37, and 38 months, respectively, after radiosurgery. New endocrine deficiencies were noted in seven patients (16%). Follow-up magnetic resonance images obtained in 33 patients revealed a decrease in tumor size in 24, no change in nine, and an increase in size in none of the patients. One patient developed a quadrantanopsia 14 months after radiosurgery despite having received a dose of only 0.7 Gy to the optic tract.Conclusions. Gamma knife radiosurgery appears to be safe and effective for the treatment of Cushing's disease refractory to pituitary surgery. Delayed recurrences and new hormone deficiencies may occur, indicating the necessity for regular long-term follow up.

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Multiple pituitary adenomas in Cushing's disease

Journal of Neurosurgery ◽

10.3171/jns.2000.93.5.0753 ◽

2000 ◽

Vol 93 (5) ◽

pp. 753-761 ◽

Cited By ~ 45

Author(s):

John K. Ratliff ◽

Edward H. Oldfield

Keyword(s):

Cushing’S Disease ◽

Medical Records ◽

Pituitary Adenomas ◽

Cushing's Disease ◽

Clinical Database ◽

Null Cell ◽

Content Type ◽

Initial Surgery ◽

Repeated Surgery ◽

Fine Print

Object. Clinically evident multiple pituitary adenomas rarely occur. The authors assess the incidence and clinical relevance of multiple adenomas in Cushing's disease.Methods. A prospective clinical database of 660 pituitary surgeries was analyzed to assess the incidence of multiple pituitary adenomas in Cushing's disease. Relevant radiographic scans, medical records, and histopathological reports were reviewed.Thirteen patients with at least two separate histopathologically confirmed pituitary adenomas were identified. Prolactinomas (nine patients) were the most common incidental tumors. Other incidental tumors included secretors of growth hormone ([GH], one patient) and GH and prolactin (two patients), and a null-cell tumor (one patient). In two patients, early repeated surgery was performed because the initial operation failed to correct hypercortisolism, in one instance because the tumor excised at the initial surgery was a prolactinoma, not an adrenocorticotropic hormone—secreting tumor. One patient had three distinct tumors.Conclusions. Multiple pituitary adenomas are rare, but may complicate management of patients with pituitary disease.

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Cushing's disease with pituitary apoplexy leading to hypopituitarism, empty sella, and spontaneous fracture of the dorsum sellae

Journal of Neurosurgery ◽

10.3171/jns.1979.51.6.0866 ◽

1979 ◽

Vol 51 (6) ◽

pp. 866-869 ◽

Cited By ~ 19

Author(s):

Philip H. Gutin ◽

William G. Cushard ◽

Charles B. Wilson

Keyword(s):

Pituitary Adenoma ◽

Cushing’S Disease ◽

Plasma Cortisol ◽

Pituitary Apoplexy ◽

Empty Sella ◽

Cushing's Disease ◽

Content Type ◽

Urinary Levels ◽

Fine Print ◽

Transsphenoidal Resection

✓ A patient with a pituitary adenoma secreting adrenocorticotropin hormone manifested panhypopituitarism after an episode of pituitary apoplexy. The previously elevated urinary levels of 17-ketogenic steroids dropped sharply, and plasma cortisol became undetectable. The apoplexy also resulted in a partially empty sella on which the dorsum sellae collapsed. Recurrent Cushing's disease developed and was cured by transsphenoidal resection of a microadenoma.

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Localization of pituitary adenomas by using intraoperative ultrasoound pituitary in patients with Cushing's disease and no demonstrable tumor on magnetic resonance imaging

Journal of Neurosurgery ◽

10.3171/jns.1998.89.6.0927 ◽

1998 ◽

Vol 89 (6) ◽

pp. 927-932 ◽

Cited By ~ 67

Author(s):

Joe C. Watson ◽

Thomas H. Shawker ◽

Lynnette K. Nieman ◽

Hetty L. DeVroom ◽

John L. Doppman ◽

...

Keyword(s):

Magnetic Resonance ◽

Mr Imaging ◽

Cushing’S Disease ◽

Pituitary Adenomas ◽

Pituitary Surgery ◽

Intraoperative Ultrasonography ◽

Cushing's Disease ◽

Content Type ◽

Negative Findings ◽

Fine Print

Object. Pituitary surgery has been reported to produce remission of Cushing's disease with preservation of pituitary function in only 60 to 70% of patients. The inability to identify an adenoma accounts for most failed sellar explorations. Most negative surgical explorations occur in patients in whom magnetic resonance (MR) imaging of the pituitary demonstrates normal findings, which happens in at least 35 to 45% of patients with Cushing's disease. Methods. To examine the usefulness of intraoperative ultrasonography (IOUS) for identifying an adenoma in patients with no demonstrable tumor (negative findings) on pituitary MR imaging, we prospectively assessed the results of IOUS in 68 patients with a negative (59 patients) or equivocal (nine patients) MR image from a consecutive series of 107 patients with Cushing's disease (64%). We compared surgical findings and outcomes in these 68 patients with a group of 68 patients with Cushing's disease and negative findings on MR imaging in whom IOUS was not available. Intraoperative ultrasonography localized a tumor in 47 (69%) of 68 patients with negative findings on MR imaging. Surprisingly, the size of the adenomas that were detected with IOUS compared with the size of those not detected did not differ (6.8 ± 3.4 mm compared with 6.1 ± 2.8 mm [mean ± standard deviation], respectively [p = 0.5]). In four patients, no adenoma was found at surgery or in the pathological specimen (“true negative”). In eight patients, nine abnormalities detected by IOUS that were suspected adenomas were negative on exploration (“false positive”). Thus, IOUS has a sensitivity of 73% and a positive predictive value of 84% for detecting pituitary adenomas in patients with Cushing's disease and negative findings on MR imaging. Compared with the 68 patients who did not undergo IOUS, remission after surgery was improved (61 patients [90%] compared with 57 patients [84%]), the number of tumors found on exploration was increased (61 tumors compared with 51 tumors; p = 0.02), and the number of hemihypophysectomies was decreased (five compared with 15; p = 0.02) with IOUS. When the groups were compared after excluding patients with prior pituitary surgery, tumors were found in 91% versus 72% (p = 0.008), and remission occurred in 95% versus 87% of patients, respectively, in the groups that had or did not have IOUS. Conclusions. The IOUS is a sensitive imaging modality when used in patients with Cushing's disease in whom findings on pituitary MR imaging are negative. The improved ability to detect and localize these tumors by using IOUS positively affects surgical outcome.

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