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Surgery for Cushing's Disease
by Brooke Swearingen, M.D.

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The diagnosis of Cushing's syndrome is made on the basis of clinical assessment and dynamic hormone testing. The availability of new diagnostic and imaging techniques has improved the sensitivity of nricroadenoma detection. A positive MRI is useful, but MR images show no or equivocal evidence of tumor in 30% of pathologically proven cases.¹ The false positive rate is up to 28%; therefore radiologic investigation must be used with hormone testing for tumor localization. Inferior petrosal sinus sampling clearly improves the certainty of diagnosis, and such data are useful in planning surgical therapy. In a small number of cases, however, tumor is found at operation on the side opposite to that predicted by the catheterization; it is important, therefore that both sides of the gland be explored. Nonetheless, we believe that an adequate diagnostic evaluation requires high field strength MRI as well as inferior petrosal sinus sampling in all cases of suspected microadenomas.

Transsphenoidal microsurgery for Cushing's disease remains the single best therapy when compared with drug or radiation treatment. The current treatment algorithm has been recently reviewed.² Surgical therapy at large centers offers an initial remission rate for micro-adenomas of 85-90%,³ with an overall complication rate of 3%, (including hormone deficiencies).⁴ Our own data over the past five years show a remission rate of 89% for first time surgery in microadenomas. If no tumor is found on bilateral gland exploration, we perform a hemihypophysectomy on the side predicted by the inferior petrosal sinus catheterization, which correctly localizes tumor side in about 70% of cases.⁵ In those patients who fail the initial procedure, repeat surgery for total hypophysectomy has been shown to be of benefit, with remission rates of 50%⁶. If this is unsuccessful, bilateral adrenalectomy is the treatment of choice in most cases, or radiation therapy can be performed. Patients require careful monitoring in all cases, since relapse rates of 10-20% at five years are reported.

Pharmacologic and radiation therapy remain options in those patients who are not cured or are unable to undergo surgical therapy. Ketoconazole, metyrapone, mitotane, and aminoglutethimide are effective in achieving short-term chemical control. Side effects, expense, and escape from drug effects make medical therapy an impractical long-term solution. Mitotane therapy administered in conjunction with conventional fractionated radiation therapy (200 cGy fractions to a total of 4000 cGy) has been effective in controlling disease in 80% of patients in one series.⁷ Stereotactic radiosurgery at the Harvard Cyclotron has been effective, with a remission rate of 80%. Pituitary insufficiency remains a problem after radiation (15-50%), and there is a small risk of optic nerve or cavernous sinus injury.⁸ Careful monitoring is again essential, since the maximal benefit of radiation may require years to achieve.

References

1. Peck WW, Dillon WP, Norman TH, Wilson CB. High-resolution MR imaging of pituitary microadenomas at 1.5T experience with Cushing's disease. AJR. 1989; 152.145-51.
2. Klibanski A, Zervas NT Diagnosis and management of hormone secreting pituitary adenomas. N Engl J Med, 1991; 324:822-31.
3. Manipalam TJ, Tyrell JB, Wilson CB. Transsphenoidal rnicrosurgery for Cushing's disease: a report of 216 cases. Ann Int Med. 1988; 109:487-93.
4. Black P McL, Zervas NT, Candia GL. Incidence and management of complications of transsphenoidal operation for pituitary adenomas. J Neurosurg. 1987; 20:920-24.
5. Oldfield EH, Chrouso GP, Schulte HM, et al. Preoperative lateralization of ACTH-secreting pituitary microadenoma by bilateral and simultaneous inferior petrosal venous sinus sampling. N Engl J Med. 1985; 312:100-3.
6. Friedman RB, Oldfield EH, Nieinan LK, et al. Repeat transsphenoidal surgery for Cushing's disease. J Neurosurg. 1989; 71:520-27.
7. Schteingart DE, Tsao HS, Taylor CI, et al. Sustained remission of Cushing's disease with mitotane and pituitary irradiation. Ann Int Med. 1980; 92:613-19.
8. Kjellberg RN, Kliman B, Swisher B, Butler W. Proton beam therapy of Cushing's disease and Nelson's syndrome, in Secretory Tumors of the Pituitary Gland, Black P Mcl, ed. (New York, Raven Press, 1984) pp. 295-307.

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