Outcome of surgical treatment of 200 children with Cushing's disease

Abstract

Context: Factors influencing the outcome of surgical treatment of pediatric Cushing's disease (CD) have not been fully established.

Objective: The aim of this study was to examine features influencing the outcome of surgery for pediatric CD.

Design: In this prospective observational study, the clinical, imaging, endocrinological, and operative outcomes were analyzed in consecutive patients treated at the National Institutes of Health (NIH) from 1982 through 2010.

Setting: The study was conducted in a tertiary referral center.

Results: Two hundred CD patients (106 females, 94 males) were included. Mean age at symptom development was 10.6 ± 3.6 years (range, 4.0 to 19.0 y). Mean age at NIH operation was 13.7 ± 3.7 years. Twenty-seven patients (13%) had prior surgery at another institution. Magnetic resonance imaging identified adenomas in 97 patients (50%). When positive, magnetic resonance imaging accurately defined a discrete adenoma in 96 of the 97 patients (99%), which was more accurate than the use of ACTH ratios during inferior petrosal sinus sampling to determine adenoma lateralization (accurate in 72% of patients without prior surgery). A total of 195 of the 200 patients (98%) achieved remission after surgery (189 [97%] were hypocortisolemic; 6 [3%] were eucortisolemic postoperatively). Factors associated with initial remission (P < .05) included identification of an adenoma at surgery, immunohistochemical ACTH-producing adenoma, and noninvasive ACTH adenoma. Younger age, smaller adenoma, and absence of cavernous sinus wall or other dural invasion were associated with long-term remission (P < .05). A minimum morning serum cortisol of less than 1 μg/dl after surgery had a positive predictive value for lasting remission of 96%.

Conclusions: With rare disorders, such as pediatric CD, enhanced outcomes are obtained by evaluation and treatment at centers with substantial experience. Resection of pituitary adenomas in pediatric CD in that setting can be safe, effective, and durable. Early postoperative endocrine testing predicts lasting remission. Because lasting remission is associated with younger age at surgery, smaller adenomas, and lack of dural invasion, early diagnosis should improve surgical outcome.

Figure 1.

Gender ratio vs age at surgery.

Figure 2.

Pituitary MRI obtained after contrast with standard spin echo (left panel) and SPGR (right panel) techniques. Note microadenoma on the right side of the gland at the top of the anterior lobe seen with the SPGR, but not with the spin echo scan.

Figure 3.

Size of adenomas, as measured at surgery, in patients with positive and negative MRI. Although adenomas detected on MRI were larger than adenomas with negative MRI (independent 2-sided t test; P = .0004), there was considerable overlap in the size of the adenomas in the two groups, which suggests that factors other than size, such as tissue consistency of other unknown factors, account for a negative MRI in many patients. The bars represent the mean diameter.

Figure 4.

A, Kaplan-Meier plot of recurrence-free survival in patients with remission of CD after surgery. B, Comparison of recurrence-free survival between patients ≤ 13 years old and patients > 13 years old. Below the abscissa, 80/94 indicates the number of patients at risk ≤ 13 years/>13 years old at each interval.

Figure 5.

Correlation of measures of cortisol production on days 3–5 after surgery and recurrence or sustained remission during follow-up is shown for various categories of patients. The minimum values of AM cortisol (A) and 24-hour UFC (B) from days 3–5 after surgery are shown for each patient on the ordinate, and the duration of follow-up for that patient after surgery is presented on the abscissa. The 5 patients who failed surgery and patients with no follow-up are not included. Red markers indicate recurrence. A, Minimum AM cortisol on days 3–5 after surgery. B, Minimum 24-hour UFC on days 3–5 after surgery presented as a fraction of the lower limit of the normal range at the assay contemporary with the surgery (the range of normal changed with the use of different assays during the study; see “Patients and Methods”) and the patient age. The numbers in parentheses in panel B are the minimum AM cortisol for that patient. The limited number of patients with values exceeding very low levels in panels A and B limits the capacity to compare the use of those values to predict recurrence. Note also the limited duration of follow-up in most of the patients with measures of cortisol production in the normal range (eucortisolism). Measurements below the detection limit of the assay are assigned a value equal to the lower limit in panels A and B.