Severity and management of hypercortisolism in patients with adrenocortical carcinoma and overt Cushing´s syndrome

OBJECTIVE: To analyze the association between the degree of hypercortisolism and survival outcomes of patients with Cushing´s syndrome (CS) due to adrenocortical carcinoma (ACC). METHODS: An international retrospective of patients with CS due to ACC. The primary outcomes were to evaluate the prognostic role of baseline hypercortisolism on survival outcomes, including progression-free survival (PFS), disease-free survival (DFS), and overall survival (OS). RESULTS: A total of 101 patients with ACC were included. The median urinary free cortisol (UFC) levels at the time of CS diagnosis were 6.4 times above the upper limit of normal (ULN) (IQR 2.9-14) and 53.5% (n = 54) of the cases had metastatic ACC. Maximum adrenal tumor size (OR 1.02, 95%CI 1.01-1.03) and UFC levels (1.62, 95%CI 1.03-2.57) were independent predictors of metastatic ACC. The median OS was 19.4 (range 1-176) months, the median DFS was 12.3 months (range 2.6-143), and PFS was 5.6 months (range 1.1-43.7). The risk of recurrence/progression increased as the severity of CS increased (21% in mild hypercortisolism (UFC <2xULN), 52% in moderate (2-5xULN) and 57% in severe CS (>5xULN), P = 0.035). UFC levels (HR 1.48; 95%CI 0.97-2.24, P = 0.057) tended to be associated with the risk of progression (metastatic ACC). When we considered a combined outcome (progression in metastatic ACC and recurrence in localized ACC), age, UFC, hypokalemia, R0 after surgery, and Ki-67 were independent predictors of recurrence/progression. CONCLUSION: Adrenal tumor size and the severity of cortisol excess are associated with a higher probability of metastatic disease at diagnosis. Our study suggests that the severity of cortisol excess appears to be associated with an increased risk of tumor recurrence/progression, suggesting that hypercortisolism intensity may serve as a marker of aggressive disease.

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Journal
The Journal of Clinical Endocrinology & Metabolism
Published
2026-09-10
DOI
https://doi.org/10.1210/clinem/dgag373
Primary Topic
Adrenal and Paraganglionic Tumors
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article
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article

Severity and management of hypercortisolism in patients with adrenocortical carcinoma and overt Cushing´s syndrome

Massimo Terzolo, Anna Casteràs, Markus Kroiss, Martín Reincke et al.
The Journal of Clinical Endocrinology & Metabolism
Adrenal and Paraganglionic Tumors
article

Severity and management of hypercortisolism in patients with adrenocortical carcinoma and overt Cushing´s syndrome

Massimo Terzolo, Anna Casteràs, Markus Kroiss, Martín Reincke, Irina Bancos, Mario Detomas, Paola Gracia Gimeno, Matthias Oettle, Marta Araujo‐Castro, Guillermo Serra, Stefania Cruz Calderón, Otilia Kimpel, Anja Barač Nekić, Marianna Torchio, Andrés Felipe García Ramos, Betina Biagetti, Francisco Gonzalez Tapia, Darko Kaštelan, B Rodríguez-Jiménez, Eider Pascual‐Corrales, Haibo Lu, Maria Teresa Rodrigo‐Calvo, María Dolores Moure Rodríguez, Rosario Oliva Rodríguez, José María Recio, María Bernarda Iriarte-Durán, María Pasarón, Néstor López Pompey, Andrés Cardona, Claudia Lozano Aida, Wilfredo Antonio Rivera-Martínez, Miguel Paja Fano, Edelmiro Menéndez, Johnayro Gutiérrez Restrepo, Melani Naglic, Rogelio García-Centeno, Felicia Alexandra Hanzu, Laura Gónzalez Fernández, Aura D Herrera-Martínez, Nuria Valdes, Pedro Iglesias, Carlos E Builes Montaño, Concepción Blanco Carrerra, Mauricio Alvarez, Fernando Guerrero-Pérez, Valentina Morreli
article en

Abstract

OBJECTIVE: To analyze the association between the degree of hypercortisolism and survival outcomes of patients with Cushing´s syndrome (CS) due to adrenocortical carcinoma (ACC). METHODS: An international retrospective of patients with CS due to ACC. The primary outcomes were to evaluate the prognostic role of baseline hypercortisolism on survival outcomes, including progression-free survival (PFS), disease-free survival (DFS), and overall survival (OS). RESULTS: A total of 101 patients with ACC were included. The median urinary free cortisol (UFC) levels at the time of CS diagnosis were 6.4 times above the upper limit of normal (ULN) (IQR 2.9-14) and 53.5% (n = 54) of the cases had metastatic ACC. Maximum adrenal tumor size (OR 1.02, 95%CI 1.01-1.03) and UFC levels (1.62, 95%CI 1.03-2.57) were independent predictors of metastatic ACC. The median OS was 19.4 (range 1-176) months, the median DFS was 12.3 months (range 2.6-143), and PFS was 5.6 months (range 1.1-43.7). The risk of recurrence/progression increased as the severity of CS increased (21% in mild hypercortisolism (UFC <2xULN), 52% in moderate (2-5xULN) and 57% in severe CS (>5xULN), P = 0.035). UFC levels (HR 1.48; 95%CI 0.97-2.24, P = 0.057) tended to be associated with the risk of progression (metastatic ACC). When we considered a combined outcome (progression in metastatic ACC and recurrence in localized ACC), age, UFC, hypokalemia, R0 after surgery, and Ki-67 were independent predictors of recurrence/progression. CONCLUSION: Adrenal tumor size and the severity of cortisol excess are associated with a higher probability of metastatic disease at diagnosis. Our study suggests that the severity of cortisol excess appears to be associated with an increased risk of tumor recurrence/progression, suggesting that hypercortisolism intensity may serve as a marker of aggressive disease.

The Journal of Clinical Endocrinology & Metabolism
Mayo Clinic (US), University Hospital Centre Zagreb (HR), Henan University of Science and Technology (CN), Instituto Cajal (ES), University of Würzburg (DE), Bellvitge University Hospital (ES), Hospital General Universitario Gregorio Marañón (ES), LMU Klinikum (DE), Institut d'Investigació Biomédica de Bellvitge (ES), BioCruces Health research Institute (ES), Hospital Universitario Virgen Macarena (ES), Hospital de Basurto (ES), Fundación Valle del Lili (CO), Complejo Hospitalario de Salamanca (ES), Hospital Royo Villanova (ES), Hospital Universitario Puerta de Hierro Majadahonda (ES), Hospital Universitario Príncipe de Asturias (ES), Clínica Somer (CO), Hospital Militar Central (CO), Hospital Pablo Tobon Uribe (CO), Hospital Clínic de Barcelona (ES), Clínica Santa María (CO), Hospital Universitario Reina Sofía (ES), Mayo Clinic in Arizona (US), Universitätsklinikum Würzburg (DE), Instituto Ramón y Cajal de Investigación Sanitaria (ES), Vall d'Hebron Hospital Universitari (ES), Universidad de Medellín (CO), IRCCS Istituto Auxologico Italiano (IT), First Affiliated Hospital of Henan University of Science and Technology (CN), Mayo Clinic in Florida (US), Clínica CES (CO), Hospital Universitario De Cabueñes (ES), Hospital Universitario Son Espases (ES), Ospedale San Luigi Gonzaga (IT), Hospital Universitario Ramón y Cajal (ES), Instituto de Investigación Sanitaria del Principado de Asturias (ES), Universitat de Barcelona (ES), Ludwig-Maximilians-Universität München (DE), Universidad del Valle (CO)
Good health and well-being
Openalex Percentile: Top 8%
Adrenal and Paraganglionic Tumors
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