Surgery advised in face of uncertain sinus sampling result in Cushing patients

By Eleanor McDermid

Surgeons should consider transsphenoidal surgery (TSS) in patients with Cushing disease (CD) caused by adrenocorticotropic hormone (ACTH) overproduction, almost irrespective of the results of inferior petrosal sinus sampling (IPSS), say US researchers.

Sameer Sheth (Massachusetts General Hospital, Boston, USA) and colleagues found a pituitary source of ACTH overproduction in almost all patients in whom IPSS predicted an ectopic tumor but none was found on imaging.

"Recognition of this issue should help reduce deleterious delays in the treatment of patients with CD," they write in Neurosurgery.

Of 283 patients who underwent IPSS at the team's institution, 21 were predicted to have an ectopic source of ACTH, because they had an IPS:peripheral ACTH ratio below 2 at baseline or below 3 after administration of corticotrophin-releasing hormone (CRH). Five of these patients had ectopic tumors identified on imaging and four underwent adrenalectomy, but no ACTH source was found in 12 patients, despite "extensive investigation."

All 12 patients underwent exploratory TSS, confirming a pituitary source in 11.

Bilateral IPSS proved impossible in a further 32 patients. Available samples supported a central source in 21 patients, of whom 20 had a pituitary source when investigated surgically. Samples in the other 11 patients supported an ectopic source, but none could be found on imaging, and all of these patients proved to have a pituitary source when they underwent exploratory TSS.

In view these findings, "the utility of performing [IPSS] at all may be reasonably questioned," say Sheth et al.

"We continue to perform IPSS because a positive study has a very high predictive value (98%), which legitimizes an aggressive surgical approach and confirms the need for pituitary-directed therapy if surgery is unsuccessful."

They add: "Given the high positive predictive value of the IPSS and the morbidity of untreated [Cushing syndrome], a centralized result provides the rationale for persistence and thoroughness during TSS."

The team's data also show that use of a post-CRH IPSS threshold of about 1.8 would have reduced the number of false-negative results (where a pituitary source is diagnosed as an ectopic source). Using this cutoff for patients in the current study, six false-negative results would have become true negatives, but the number of false positives would not have increased.

"It would be worthwhile to validate alternative thresholds in other data sets, particularly because the composition of our patient population reflects referral bias to our institution, possibly accounting for the relatively small number of ectopic ACTH-producing tumors identified," say the researchers.

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