Evidence map›Paper›PMID 41785910›Full record

ArticleThe lancet. Diabetes & endocrinology2026

Risk of recurrence after successful surgery for Cushing's disease and association with USP8 genotype and tumour size: an international, retrospective, longitudinal cohort study.

Qilin Zhang, Yixin Cai, Yuyu Liu, Boyuan Yao, Prajina Sharma, Elisabeth Ruoff, Zengyi Ma, Stephanie Zopp, Yue Wu, Ana Paula Abreu and 25 more

Abstract readMulticenter Study
PubMed Full text at PMC Publisher
In one paragraph

Article in The lancet. Diabetes & endocrinology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

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1citing papers in PubMed
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1 · What the graph read from it

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3 · Its place in the literature

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1 citing paper in PubMed.

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4 · The record

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5 · Who and what money

Authors and funding

35 authors.

Qilin ZhangDepartment of Neurosurgery and National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China; Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Neuroendocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Yixin CaiDepartment of Neurosurgery and National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Yuyu LiuDepartment of Neurosurgery and National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Boyuan YaoDepartment of Neurosurgery and National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Prajina SharmaMedizinische Klinik und Poliklinik IV, LMU Klinikum, LMU München, Munich, Germany.
Elisabeth RuoffMedizinische Klinik und Poliklinik IV, LMU Klinikum, LMU München, Munich, Germany.
Zengyi MaDepartment of Neurosurgery and National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Stephanie ZoppMedizinische Klinik und Poliklinik IV, LMU Klinikum, LMU München, Munich, Germany.
Yue WuDepartment of Radiology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Ana Paula AbreuDivision of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Shuo ZhangDepartment of Endocrinology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Maria A TichomirowaService d'Endocrinologie, Centre Hospitalier du Nord, Ettelbruck, Luxembourg.
Yi WangDepartment of Neurosurgery and National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Günter StallaMedicover Neuroendocrinology, Munich, Germany.
Nidan QiaoDepartment of Neurosurgery and National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Zhao YeDepartment of Neurosurgery and National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Felicia A HanzuEndocrinology & Nutrition Department, Hospital Clinic, University of Barcelona, IDIBAPS, Barcelona, Spain.
Hong ChenDepartment of Pathology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Michael BuchfelderDepartment of Neurosurgery, University of Erlangen-Nurnberg, Erlangen, Germany.
Zhenwei YaoDepartment of Radiology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Jörg FlitschDepartment of Neurosurgery, Universitätskrankenhaus Hamburg-Eppendorf, Hamburg, Germany.
Yiming LiDepartment of Endocrinology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Jun ThorsteinsdottirDepartment of Neurosurgery, LMU University Hospital, LMU Munich, Germany.
Yongfei WangDepartment of Endocrinology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Isabella Nasi-KordhishtiDepartment of Neurosurgery, University of Tübingen, Tübingen, Germany.
Hongying YeDepartment of Endocrinology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Jürgen HoneggerDepartment of Neurosurgery, University of Tübingen, Tübingen, Germany.
Silviu SbieraDepartment of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, Würzburg, Germany.
Ursula B KaiserDivision of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Martin FassnachtDepartment of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, Würzburg, Germany.
Zhaoyun ZhangDepartment of Endocrinology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Martin ReinckeMedizinische Klinik und Poliklinik IV, LMU Klinikum, LMU München, Munich, Germany. Electronic address: martin.reincke@med.uni-muenchen.de.
Marily TheodoropoulouMedizinische Klinik und Poliklinik IV, LMU Klinikum, LMU München, Munich, Germany. Electronic address: marily.theodoropoulou@med.uni-muenchen.de.
Yao ZhaoDepartment of Neurosurgery and National Center for Neurological Disorders, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Key Laboratory of Brain Function Restoration and Neural Regeneration, Shanghai, China; Neurosurgical Institute of Fudan University, Shanghai, China; National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China; Shanghai Clinical Medical Center of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China. Electronic address: zhaoyao@huashan.org.cn.
Luis Gustavo Perez-RivasMedizinische Klinik und Poliklinik IV, LMU Klinikum, LMU München, Munich, Germany.

Funding

Reproductive physiology of gonadotropin synthesisR37HD019938 · NICHD · BRIGHAM AND WOMEN'S HOSPITAL · PI Ursula B. Kaiser · 2019 to 2026
$4.3M
NICHD NIH HHS R37 HD019938
6 · The paper itself

Abstract

backgroundRecurrence after successful pituitary surgery remains a challenge in the management of patients with Cushing's disease, with no reliable predictors of long-term outcome. Pathogenic somatic USP8 variants are found in one third of cases and their association with recurrence is unclear. The aim of this study was to determine the association between USP8 status and postoperative outcome.

methodsThis international, retrospective, longitudinal study was done in eight tertiary centres in east Asia, Europe, and North America. We reviewed clinical records and genetic information of patients with clinically diagnosed and pathologically confirmed Cushing's disease who underwent first pituitary surgery in any of the participating centres between Jan 1, 1989, and April 1, 2024. Inclusion criteria were postoperative follow-up of at least 3 months after first pituitary surgery, known postsurgical outcome, and tissue availability or known USP8 status. The primary outcomes were recurrence and time to recurrence after first surgery. We assessed recurrence-free intervals and recurrence risk using survival analysis, multivariate logistic regression, and Cox proportional hazards models.

findingsWe retrospectively retrieved and examined clinical records from 558 patients, 123 of whom were excluded. 360 (83%) of 435 patients were female and 75 (17%) were male. We detected USP8 variants in 195 (45%) cases. Recurrence was recorded in 66 (18%) of 371 patients in immediate remission. Risk of recurrence depended on USP8 status and tumour size. Patients with USP8-variant microadenomas and USP8-variant macroadenomas had similar cumulative hazards for recurrence, so they were considered as a single risk group. 10-year recurrence rate was higher for USP8-variant tumours (36·8%, 95% CI 23·7-47·7) than for wildtype microadenomas (15·0%, 4·9-24·0; adjusted p=0·016) but was lower than for wildtype macroadenomas (44·5%, 26·2-58·2; adjusted p=0·025). Patients with USP8-variant tumours (hazard ratio 2·41, 95% CI 1·19-4·87; p=0·014) or wildtype macroadenomas (4·48, 2·11-9·52; p<0·0001) had significantly higher risk of recurrence than patients with wildtype microadenomas, even after adjusting for age, postoperative nadir serum cortisol, tumour invasion, and ethnicity or centre.

interpretationCombined USP8 genotype-tumour size identified patients at increased risk of recurrence, particularly in largely heterogeneous groups of patients with non-invasive tumours or low postoperative serum cortisol not considered high risk in standard care. Implementing this combined genetic-clinical stratification could provide more accurate risk assessment, indicate those at higher risk of recurrence, and ultimately personalise long-term follow-up in patients with Cushing's disease.

fundingDeutsche Forschungsgemeinschaft, National Natural Science Funds of China, and CAMS Innovation Fund for Medical Sciences.

Indexed as

AdenomaEndopeptidasesEndosomal Sorting Complexes Required for TransportNeoplasm Recurrence, LocalPituitary ACTH HypersecretionUbiquitin ThiolesteraseAdultFemaleGenotypeHumansLongitudinal StudiesMaleMiddle AgedRetrospective StudiesRisk FactorsTumor BurdenEndopeptidasesEndosomal Sorting Complexes Required for TransportUbiquitin ThiolesteraseUSP8 protein, human

Identifiers

PMID41785910
PMCPMC13179832

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