Crooke Cell Adenomas versus Corticotroph Adenomas: Radiographic Features and Remission Rates Following Surgery for Cushing's Disease

Background: Crooke cell adenomas (CCA) are an uncommon morphologic variant of ACTH-secreting pituitary adenoma characterized by a large population of neoplastic cells with Crooke's hyaline change, a ring-like deposition of cytokeratin that occurs in response to systemic hypercortisolemia. Due to their rarity, only small series describing these tumors have been published. Previous reports suggest that CCAs are more aggressive and locally invasive compared with their corticotroph counterparts, and surgical remission rates are lower. Much of these data come from small series and meta-analyses, and no large study has directly compared the outcomes of CCAs versus corticotroph adenomas after surgery. The goal of this study was to describe the radiographic features of CCAs in comparison to corticotroph adenomas and describe their short- and long-term remission rates after surgery.

Methods: Patients with Cushing's disease from a single institution retrospective registry from 2015 to 2021 were identified. Demographic, radiographic, histopathologic, and laboratory data were collected. Early remission was defined as inpatient postoperative cortisol nadir less than 2.0 µg/dL, and long-term remission was defined as normalization of hypercortisolemia on routine testing (i.e., 24-hour urine free cortisol, late night saliva testing, and low-dose dexamethasone suppression test).

Results: A total of 97 patients with Cushing's disease were identified, of which 17 (17.5%) patients had CCAs and 53 (54.6%) had corticotroph adenomas. 27 (27.8%) patients did not have an adenoma found during surgery. Patients with CCAs were more likely to be male (9/17 (52.9%) vs 9/53 (17.0%), p=.0083), had larger mean tumor volume (3.60 ± 4.5 cm³ vs. 0.46 ± 1.1 cm³, p = 0.00001) and were more likely to be radiographically invasive by Knosp classification (4/14 [28.6%] vs. 1/51 [2.0%], p = 0.0064). Similar proportions of patients in each cohort underwent resection via an endoscopic approach (11/17 [64.7%] vs. 37/53 [69.8%], p = 0.7671) and had similar MIB-1 proliferative activity (5/17 [29.4%] CCA vs. 7/48 [14.6%] corticotroph MIB-1 >3%, p = 0.273). CCAs had a higher mean postoperative cortisol nadir (16.2 ± 19.0 µg/dL vs. 4.3 ± 8.6 µg/dL, p = 0.0016; range: 1.1–49.1 µg/dL for CCA vs. 0.5–58.0 µg/dL for corticotroph), lower rates of perioperative remission (2/11 [18.1%] vs. 31/53 [58.4%], p = 0.0205), and lower rates of long-term remission (8/16 [50.0%] vs. 42/53 [79.2%], p = 0.0295). Mean follow-up was similar between the cohorts (30.8 ± 40.3 months CCA vs. 24.3 ± 20.9 months corticotroph, p = 0.3965), and ranged from 1 to 156 months in the CCA group versus 1 to 79 months in the corticotroph group.

Conclusions: CCAs are often larger, more invasive, and more clinically aggressive with lower surgical remission rates compared with standard ACTH-secreting corticotroph adenomas. Patients with Cushing's disease of Crooke cell origin must be counseled about the higher likelihood of needing adjuvant therapy to achieve remission, and vigilance should remain high for biochemical recurrence. This is the largest series of CCAs in the modern era from a single institution, and the only study to directly compare remission rates between CCAs and corticotroph adenomas.

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

Publication History

Article published online:
01 February 2023