A Highly Sensitive and Specific ACTH-Based Predictor of Long-Term Remission after Surgery for Cushing’s Disease

Over 70% of cases of Cushing’s syndrome are caused by an ACTH-secreting pituitary tumor, known as Cushing’s disease.[1] An early predictor for long-term remission of Cushing’s disease after surgery has received substantial interest in the neurosurgical and endocrinological literatures.[2] While previous studies have examined the predictive value of early postoperative ACTH levels, intraoperative ACTH levels have not been evaluated. We examined intraoperative ACTH levels and describe a highly sensitive and specific predictor for long-term remission in a subset of Cushing’s patients.

The medical records of 46 consecutive patients who underwent surgery for Cushing’s disease from July 21, 2011 to June 14, 2018 were retrospectively reviewed. Peripheral blood ACTH levels were drawn preoperatively, intraoperatively, and on the first day after surgery (POD1). Intraoperative ACTH levels were drawn during exposure, during manipulation of the tumor, and during closure.

Patients’ demographics, pathology results, and long-term outcomes are described in Table 1. Preoperative, intraoperative, and postoperative ACTH levels are shown in [Fig. 1]. Confirming previous work, POD1 ACTH level was a sensitive and specific measure of long-term remission ([Fig. 2]; area under the curve = 0.765; mean follow-up = 3.048 years; range, 0.41–7.8 years).

Next, we compared ACTH levels in the patients who underwent purely extracapsular resection and those in whom the tumor was removed in piecemeal fashion. We saw a higher intraoperative maximum ACTH level in the piecemeal group (299.54 ± 304.62 pg/mL) compared with the extracapsular group (112.37 ± 96.72 pg/mL; p-value = 0.008). We reasoned that in the patients who underwent piecemeal resection, an intraoperative ACTH spike is associated with tumor identification and physical disruption, which could be related to long-term remission. Notably, in the piecemeal group of patients, the ratio of the intraoperative maximum divided by the intraoperative minimum ACTH level was higher in those with long-term remission (4.83 − 4.25 pg/mL) compared with those with recurrence (2.55 ± 0.52 pg/mL), suggesting that in this subset of patients, an intraoperative ACTH spike associated with a low ACTH level during closure could be predictive of long-term remission. Thus, we hypothesized that combining the intraoperative ACTH ratio with the POD1 postoperative ACTH level ([intraoperative ACTH maximum/intraoperative ACTH minimum]/POD1 ACTH) would be a sensitive and specific predictor of long-term remission. In fact, in the subset of patients who underwent piecemeal dissection, this showed to be highly specific and sensitive, with an area under the curve of 0.904 ([Fig. 3]).

Fig. 1 Preoperative, intraoperative, and postoperative ACTH levels.

Fig. 2 A sensitive and specific measure of long-term remission.

Fig. 3 The subset of patients.

Table 1 Patient demographics, pathology results, and long-term outcomes

No conflict of interest has been declared by the author(s).

• References

• Lonser RR, Nieman L, Oldfield EH. Cushing’s disease: pathobiology, diagnosis, and management. J Neurosurg 2017; 126 (02) 404-417
• Pendharkar AV, Sussman ES, Ho AL, Hayden Gephart MG, Katznelson L. Cushing’s disease: predicting long-term remission after surgical treatment. Neurosurg Focus 2015; 38 (02) E13