Oncocytic Pituicytoma in a Patient with Cushing’s Disease

Posted on February 20, 2025 by MaryO

The final, formatted version of the article will be published soon.

1) Background: Posterior pituitary tumors (PPTs) are extremely rare, with fewer than 400 cases reported to date. In 2022, the WHO classified four types of tumors originating from the posterior pituitary: traditional pituicytoma, oncocytic pituicytoma, granular pituicytoma, and ependymal pituicytoma. To our knowledge, only one subject with coexistence of Cushing’s disease and oncocytic pituicytoma (spindle cell oncocytoma) has been reported, but the clinical features of this patient were not described in detail.

2) Case presentation: We presented a case of a patient with Cushing’s syndrome and a pituitary mass. Transsphenoidal surgery was performed, and pathologic examination revealed two distinct tumors: a corticotroph adenoma with a diameter of less than 2mm and a larger oncocytic pituicytoma. Post-surgery serum cortisol was 51 nmol/L, indicating complete remission. Corticotroph adenoma or corticotroph hyperplasia were identified after surgery in less than half of the subjects with Cushing’s disease and PPT. (3)

Conclusions: Our study indicates that Cushing’s disease in patients with PPT may be caused by the existence of collision lesions, with corticotroph adenoma or hyperplasia being difficult to detect due to their small dimensions.

Keywords: Cushing’s disease, oncocytic pituicytoma, Spindle cell oncocytoma, pituitary adenoma, Posterior pituitary tumors

Received: 27 Aug 2024; Accepted: 17 Feb 2025.

Copyright: © 2025 Li, Chen, Tan, Yu, Tang, Cai and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Huiwen Tan, Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China
Ying Tang, Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
Bowen Cai, Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
Jianwei Li, Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, China

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

 

From https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2025.1487120/abstract

 

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Cushing Disease Clinical Phenotype and Tumor Behavior Vary With Age

Posted on January 24, 2025 by MaryO

Abstract

Context

Little is known about presenting clinical characteristics, tumor biology, and surgical morbidity of Cushing disease (CD) with aging.

Objective

Using a large multi-institutional data set, we assessed diagnostic and prognostic significance of age in CD through differences in presentation, laboratory results, tumor characteristics, and postoperative outcomes.

Methods

Data from the Registry of Adenomas of the Pituitary and Related Disorders (RAPID) were reviewed for patients with CD treated with transsphenoidal tumor resection at 11 centers between 2003 and 2023. Outcomes assessed included comorbidities, presenting features, preoperative endocrine evaluations, perioperative characteristics, postoperative endocrine laboratory values, and complications.

Results

Of the 608 patients evaluated, 496 (81.6%) were female; median age at surgery was 44 years (range, 10-78 years). Increasing age was associated with increasing comorbidities, frailty, rates of postoperative thromboembolic disease, Knosp grade, tumor size, and postoperative cortisol and adrenocorticotropin nadirs. Conversely, increasing age was associated with decreased hallmark CD features, preoperative 24-hour urinary free cortisol, Ki-67 indices, and arginine vasopressin deficiency. Younger patients presented more frequently with weight gain, facial rounding/plethora, abdominal striae, hirsutism, menstrual irregularities, dorsocervical fat pad, and acne. Obstructive sleep apnea and infections were more common with increasing age.

Conclusion

There are age-dependent differences in clinical presentation, tumor behavior, and postoperative outcomes in patients with CD. Compared to younger patients, older patients present with a less classic phenotype characterized by fewer hallmark features, more medical comorbidities, and larger tumors. Notably, age-related differences suggest a more indolent tumor behavior in older patients, potentially contributing to delayed diagnosis and increased perioperative risk. These findings underscore the need for tailored diagnostic and therapeutic approaches across age groups, with a focus on managing long-term comorbidities and optimizing surgical outcomes.

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Can We Predict the Risk of Venous Thromboembolism in Patients With Cushing’s Syndrome

Posted on January 22, 2025 by MaryO

Purpose

Patients with Cushing’s syndrome (CS) have an increased venous thromboembolism (VTE) risk with most studies focusing on the perioperative period. The purpose of this study was to assess the 5-year VTE risk and identify predictors of VTE at CS diagnosis.

Methods

A comparative nationwide retrospective cohort study of 609 patients (mean age 48.1 ± 17.2 years, 65.0% women) with CS, and 3018 age-, sex-, body mass index-, and socioeconomic status-individually matched controls. Ectopic CS and adrenal cancer were excluded. The time-to-event of pulmonary embolism (PE) or deep vein thrombosis (DVT) within 5 years of CS diagnosis was examined. VTE risk was calculated with death as competing event.

Results

VTE occurred in 16 cases (2.6%), compared to 17 (0.56%) controls (hazard ratio [HR] 4.71, 95% CI, 2.38–9.33). The 5-year HRs for PE and DVT were 7.47 (95% CI, 2.66–20.98) and 3.32 (95% CI, 1.36–8.12), respectively. After excluding patients and controls with current or prior malignancy the risk for VTE was 7.57 (95% CI, 2.98–19.20). Patients with CS ≥ 60 years at diagnosis (HR, 3.49; 95% CI, 1.30–9.35), with hypertension (HR, 5.53; 95% CI, 1.26–24.27), ischemic heart disease (HR, 3.60; 95% CI, 1.25–10.36), kidney disease (HR, 4.85; 95% CI, 1.39–16.90), or VTE event prior to CS diagnosis (HR, 33.65; 95% CI, 10.07–112.42) had an increased risk of VTE within five years.

Conclusions

In this large cohort of patients with CS, the 5-year VTE risk was 5 times higher compared with matched controls. Key baseline predictors included age ≥ 60, hypertension, heart/kidney disease, and prior VTE.

From https://link.springer.com/article/10.1007/s11102-024-01482-0

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Ectopic Adrenocorticotrophic Hormone Syndrome in a 10-Year-Old Girl With a Thymic Neuroendocrine Tumor

Posted on November 29, 2024 by MaryO

Abstract

Background

Thymic neuroendocrine tumor as a cause of Cushing syndrome is extremely rare in children.

Case presentation

We report a case of a 10-year-old girl who presented with typical symptoms and signs of hypercortisolemia, including bone fractures, growth retardation, and kidney stones. The patient was managed with oral ketoconazole, during which she experienced adrenal insufficiency, possibly due to either cyclic adrenocorticotropic hormone (ACTH) secretion or concurrent COVID-19 infection. The patient underwent a diagnostic work-up which indicated the possibility of an ACTH-secreting pituitary neuroendocrine tumor. However, after a transsphenoidal surgery, the diagnosis was not confirmed on histopathological examination. Subsequent bilateral inferior petrosal sinus sampling showed strong indications of the presence of ectopic ACTH syndrome. Detailed rereading of functional imaging studies, including 18F-FDG PET/MRI and 68Ga DOTATOC PET/CT, ultimately identified a small lesion in the thymus. The patient underwent videothoracoscopic thymectomy that confirmed a neuroendocrine tumor with ACTH positivity on histopathological examination.

Conclusion

This case presents some unique challenges related to the diagnosis, management, and treatment of thymic neuroendocrine tumor in a child. We can conclude that ketoconazole treatment was effective in managing hypercortisolemia in our patient. Further, a combination of functional imaging studies can be a useful tool in locating the source of ectopic ACTH secretion. Lastly, in cases of discrepancy in the results of stimulation tests, bilateral inferior petrosal sinus sampling is highly recommended to differentiate between Cushing disease and ectopic ACTH syndrome.

Peer Review reports

Background

In children above seven years of age, the majority of pediatric Cushing syndrome (CS) cases are caused by a pituitary neuroendocrine tumors (PitNET). However, a differential diagnosis of hypercortisolemia in children is often challenging concerning the interpretation of stimulation tests and the fact that up to 50% of PitNET may not be detected on magnetic resonance imaging (MRI) [1]. An ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is extremely rare in children. Its diagnosis is often missed or confused with Cushing disease (CD) [2]. Most ACTH-secreting tumors originate from bronchial or thymic neuroendocrine tumors (NETs), or less commonly, from NETs in other locations. To diagnose EAS, specific functional imaging studies are often indicated to elucidate the source of ACTH production.

Pharmacotherapy may be used before surgery to control hypercortisolemia and its symptoms/signs, or in patients in whom the source of hypercortisolism has not been found (e.g., EAS), or surgery failed. Ketoconazole or metyrapone, as adrenal steroidogenesis blockers, were found to be very efficient, although they exhibit side effects [3].

Furthermore, cyclic secretion of ACTH followed by fluctuating plasma cortisol levels is extremely rare in children, including those with EAS [4, 5]. Therefore, in cyclic EAS, the use of steroid inhibitors or acute illness or trauma can be associated with adrenal insufficiency, which can be life-threatening. Here we describe the clinical features, laboratory and radiological investigations, results, management, and clinical outcome of a 10-year-old girl with a thymic NET presenting with ACTH secretion.

Case presentation

A 10-year-old girl was acutely admitted to our university hospital for evaluation of facial edema and macroscopic hematuria in May 2021. A day before admission, she presented to the emergency room for dysuria, pollakiuria, nausea, and pain in her right lower back. Over the past year she had experienced excessive weight gain with increased appetite and growth retardation (Fig. 1). Her height over three years had shifted from the 34th to the 13th centile (Fig. 1). Her parents noticed facial changes, pubic hair development, increased irritability, and moodiness.

Fig. 1

figure 1

Body weight, body height, and body mass index development of the case patient. The black arrow indicates the first presentation, the blue arrow indicates the start of ketoconazole treatment and the yellow arrow indicates the time of thymectomy. Mid-parental height is indicated by the green line

At admission, she was found to have a moon face with a plethora, few acne spots on forehead, as well as facial puffiness. In contrast to slim extremities, an abnormal fat accumulation was observed in the abdomen. Purple striae were present on abdomen and thighs. She did not present with any bruising, proximal myopathy, or edema. On physical examination, she was prepubertal, height was 135 cm (13th centile), and weight was 37 kg (69th centile) with a BMI of 20.4 kg/m2 (90th centile). She developed persistent hypertension. Her past medical history was uneventful except for two fractures of her upper left extremity after minimal trips one and three years ago, both treated with a caste. Apart from hypothyroidism on the maternal side, there was no history of endocrine abnormalities or tumors in the family.

In the emergency room, the patient was started on sulfonamide, pain medication, and intravenous (IV) fluids. Her hypertensive crises were treated orally with angiotensin-converting enzyme inhibitor or with a combination of adrenergic antagonists and serotonin agonists administered IV. Hypokalemia had initially been treated with IV infusion and then with oral potassium supplements. A low serum phosphate concentration required IV management. The initial investigation carried out in the emergency room found hematuria with trace proteinuria. Kidney ultrasound showed a 5 mm stone in her right ureter with a 20 mm hydronephrosis. She did not pass any kidney stones, however, fine white sand urine analysis reported 100% brushite stone.

Hypercortisolemia was confirmed by repeatedly increased 24-hour urinary free cortisol (UFC), (5011.9 nmol/day, normal range 79.0-590.0 nmol/day). Her midnight cortisol levels were elevated (961 nmol/l, normal range 68.2–537 nmol/l). There was no suppression of serum cortisol after 1 mg overnight dexamethasone suppression test (DST) or after low-dose DST (LDDST). An increased morning plasma ACTH (30.9 pmol/l, normal range 1.6–13.9 pmol/) suggested ACTH-dependent hypercortisolemia. There was no evidence of a PitNET on a 1T contrast-enhanced MRI. The high-dose DST (HDDST) did not induce cortisol suppression (cortisol 1112 nmol/l at 23:00, cortisol 1338 nmol/l at 8:00). Apart from the kidney stone, a contrast-enhanced computed tomography (CT) of her neck, chest, and abdomen/pelvis did not detect any lesion. Various tumor markers were negative and the concentration of chromogranin A was also normal.

A corticotropin-releasing hormone (CRH) stimulation test induced an increase in serum cortisol by 32% at 30 min and ACTH concentration by 67% at 15 min (Table 1). A 3T contrast-enhanced MRI scan of the brain identified a 3 × 2 mm lesion in the lateral right side of the pituitary gland (Fig. 2). An investigation of other pituitary hormones was unremarkable. Apart from low serum potassium (minimal level of 2.8 mmol/l; normal range 3.3–4.7 mmol/l) and phosphate (0.94 mmol/l; normal range 1.28–1.82 mmol/l) concentrations, electrolytes were normal. The bone mineral density assessed by whole dual-energy X-ray absorptiometry was normal.

Fig. 2

figure 2

Coronal and sagittal 3T contrast-enhanced brain MRI scans. A suspected 3 × 2 mm lesion in the lateral right side of the pituitary gland (yellow arrows)

The patient was presented at the multidisciplinary tumor board and it was decided that she undergoes transsphenoidal surgery for the pituitary lesion. No PitNET was detected on histopathological examination and no favorable biochemical changes were noted after surgery. After the patient recovered from surgery, subsequent bilateral inferior petrosal sinus sampling (BIPSS) confirmed EAS as the maximum ratio of central to peripheral ACTH concentrations was only 1.7. During the investigation for tumor localization, she was started on ketoconazole treatment (300 mg/day) to alleviate symptoms and signs of hypercortisolism. Treatment with ketoconazole had a beneficial effect on patient health (Fig. 1). There was a weight loss of 2 kg in a month, a disappearance of facial plethora, and a decrease in vigorous appetite. Her liver function tests remained within the normal range.

Table 1 Result of corticotropin-releasing hormone stimulation test

The 24-hour UFC excretion normalized three weeks after ketoconazole initiation. However, six weeks after continuing ketoconazole therapy (400 mg/day), the patient complained of nausea, vomiting, and diarrhea. She was found to have adrenal insufficiency with a low morning serum cortisol of 10.70 nmol/l (normal range 68.2–537 nmol/l) and salivary cortisol concentrations < 1.5 nmol/l (normal range 1.7–29 nmol/l). She was also found to be positive for COVID-19 infection. Ketoconazole treatment was stopped and our patient was educated to take stress steroids in case of persisting or worsening symptoms. Her clinical status gradually improved and steroids were not required.

Meanwhile, whole-body fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET)/MRI was performed with no obvious hypermetabolic lesion suspicious of a tumor. No obvious accumulation was detected on 68Ga-DOTATOC PET/CT images (Fig. 3). However, a subsequent careful and detailed re-review of the images detected a discrete lesion on 18F-FDG PET/MRI and 68Ga-DOTATOC PET/CT scans in the left anterior mediastinum, in the thymus (Fig. 4).

Fig. 3

figure 3

18F-FDG PET/MRI (A) and 68Ga-DOTATOC (B) PET/CT scans. Whole body MIP reconstructions. Subtle correspondent focal hyperactivity in the left mediastinum (black arrow). The 18F-FDG PET/MRI image courtesy of Prof. Jiri Ferda, MD, PhD, Clinic of the Imaging Methods, University Hospital Plzen, Czech Republic

Fig. 4

figure 4

Axial slices of PET/MRI (A–C) and 68Ga-DOTATOC (D–F) PET/CT scans. Subtle correspondent focal hyperactivity in the left mediastinum (white arrow). No obvious finding on MRI (C) and CT (F) scans. The FDG PET/MRI image courtesy of Prof. Jiri Ferda, MD, PhD, Clinic of the Imaging Methods, University Hospital Plzen, Czech Republic

Three weeks after the episode of adrenal insufficiency and being off ketoconazole treatment, our patient´s pre-surgery laboratory tests showed slightly low morning cortisol 132 nmol/l with surprisingly normal ACTH 2.96 pmol/l (normal range 1.6–13.9 pmol/). Given the upcoming surgery, she was initiated on a maintenance dose of hydrocortisone (15 mg daily = 12.5 mg/m2/day). Further improvement of cushingoid characteristics (improvement of facial plethora and moon face, weight loss) was noticed. Our patient underwent videothoracoscopic surgery, and a hyperplastic thymus of 80 × 70 × 15 mm with a 4 mm nodule was successfully removed. Tumor immunohistochemistry was positive for ACTH, chromogranin A, CD56, and synaptophysin. Histopathological findings were consistent with a well-differentiated NET grade 1. A subsequent genetic screening did not detect any pathogenic variant in the MEN1 gene.

After surgery, hydrocortisone was switched to a stress dose and gradually decreased to a maintenance dose. Antihypertensive medication was stopped and further weight loss was observed after thymectomy. Within a few weeks after the thoracic surgery, the patient entered puberty, her mood improved significantly, and potassium supplements were stopped. Finally, hydrocortisone treatment was stopped ten months after thymectomy.

Discussion and conclusions

The case presented here demonstrates a particularly challenging work-up of the pediatric patient with the diagnosis of CS caused by EAS due to thymic NET. Differentiating CD and EAS can sometimes be difficult, including the use of various laboratory and stimulation tests and their interpretation, as well as proper, often challenging, reading of functional imaging modalities, especially if a discrete lesion is present at an unusual location [1]. When using established criteria for Cushing disease (for the CRH test an increase of cortisol and/or ACTH by ≥ 20% or ≥ 35%, respectively, and a ≥ 50% suppression of cortisol for the HDDST) our patient presented discordant results. The CRH stimulation test induced an increase in cortisol by 32% and ACTH by 67% and the 3T MRI pointed to the right-side pituitary lesion, both to yield false positive results. The HDDST, on the other hand, did not induce cortisol suppression and was against characteristic findings for CD. We did not proceed with desmopressin testing, which also induces an excess ACTH and cortisol response in CD patients and has rarely been used in pediatric patients, except in those with extremely difficult venous access [6]. Recently published articles investigated the reliability of CRH stimulation tests and HDDST and both concluded that the CRH test has greater specificity than HDDST [7, 8]. Elenius et al. suggested optimal response criteria as a ≥ 40% increase of ACTH and/or cortisol (cortisol as the most specific measure of CD) during the CRH test and a ≥ 69% suppression of serum cortisol during HDDST [7]. Using these criteria, the CD would be excluded in our patient. To demonstrate that the proposed thresholds for the test interpretation widely differ, Detomas et al. proposed a ≥ 12% cortisol increase and ≥ 31% ACTH increase during the CRH test to confirm CD [8].

The fact that up to 50% of PitNET may not be detected on MRI [1] and that more than 20% of patients with EAS are reported to have pituitary incidentalomas [9] makes MRI somewhat unreliable in differentiating CD and EAS. However, finally, well-established and generally reliable BIPSS in our patient supported the diagnosis of EAS. Thus, BIPSS is considered a gold standard to differentiate between CD and EAS; however, it can still provide false negative results in cyclic CS if performed in the trough phase [10] or in vascular anomalies or false positive results as in a recent case of orbital EAS [11].

In children, the presence of thymus tissue may be misinterpreted as normal. Among other reports of thymic NET [12], Hanson et al. reported a case of a prepubertal boy in whom a small thymic NET was initially treated as normal thymus tissue on CT [13]. In our case, initially, the lesion was not detected on the 18F-FDG and 68Ga-DOTATOC PET scans. A small thymic NET was visible only after a detailed and careful re-reading of both PET scans. Although somatostatin receptor (SSR) PET imaging may be helpful in identifying ectopic CRH- or ACTH-producing tumors, there are still some limitations [13]. For example, in the study by Wannachalee et al., 68Ga-DOTATATE identified suspected primary lesions causing ECS in 65% of patients with previously occult tumors and was therefore concluded as a sensitive method for primary as well as metastatic tumors [14]. In our patient, the final correct diagnosis was based on the results of both PET scans. This is in full support of the article published by Liu et al. who concluded that 18F-FDG and SSR PET scans are complementary in determining the proper localization of ectopic ACTH production [15]. Additionally, it is worth noting that not all NETs stain positively for ACTH which may present a burden in its identification.

To control hypercortisolemia, both ketoconazole and metyrapone were considered in our patient. Due to the side effects of metyrapone on blood pressure, ketoconazole was started as a preferred option in our pediatric patient. A retrospective multicenter study concluded that ketoconazole treatment is effective with acceptable side effects, with no fatal hepatitis and adrenal insufficiency in 5.4% of patients [3]. During ketoconazole treatment, our patient developed adrenal insufficiency; however, it is impossible to conclude whether this was solely due to ketoconazole treatment or whether an ongoing COVID-19 infection contributed to the adrenal insufficiency or whether this was caused by a phase of lower or no ACTH secretion from the tumor often seen in patients with cyclic ACTH secretion. The patient’s cyclic ACTH secretion is highly probable since her morning cortisol was slightly lower and ACTH was normal, even after being off ketoconazole treatment for 3 weeks.

When retrospectively and carefully reviewing all approaches to the diagnostic and management care of our pediatric patient, it would be essential to proceed to BIPSS before any pituitary surgery, especially when obtaining discrepant results from stimulation tests, as well as detecting a discrete pituitary lesion (≤ 6 mm) as recommended by the current guidelines [16]. This was our first experience using ketoconazole in a young child, and although this treatment was associated with very good outcomes in treating hypercortisolemia, close monitoring, and family education on signs and symptoms of adrenal insufficiency are essential to recognizing adrenal insufficiency promptly in any patient with EAS, especially those presenting also with some other comorbidities or stress, here COVID-19 infection.

In conclusion, the pediatric patient here presenting with EAS caused by thymic NET needs very careful assessment including whether cyclic CS is present, the outline of a good management plan to use all tests appropriately and in the correct sequence, monitoring carefully for any signs or symptoms of adrenal insufficiency, and apply appropriate imaging studies, with experienced radiologists providing accurate readings. Furthermore, ketoconazole treatment was found to be effective in reducing the symptoms and signs of CS in this pediatric patient. Finally, due to the rarity of this disease and the challenging work-up, we suggest that a multidisciplinary team of experienced physicians in CS management is highly recommended.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

ACTH:
Adrenocorticotrophic hormone
BIPSS:
Bilateral inferior petrosal sinus sampling
CD:
Cushing disease
CRH:
Corticotropin-releasing hormone
CS:
Cushing syndrome
CT:
Computed tomography
DST:
Dexamethasone suppression test
EAS:
Ectopic adrenocorticotropic hormone syndrome
18F-FDG PET:
Fluorine-18 fluorodeoxyglucose positron emission tomography
HDDST:
High-dose dexamethasone suppression test
IV:
Intravenous
LDDST:
Low-dose dexamethasone suppression test
NET:
Neuroendocrine tumor
PitNET:
Pituitary neuroendocrine tumor
UFC:
Urinary free cortisol

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Acknowledgements

The authors thank all the colleagues from the Thomayer University Hospital and Military University Hospital who were involved in the inpatient care of this patient.

Funding

This work was supported by the Charles University research program Cooperatio Pediatrics, Charles University, Third Faculty of Medicine, Prague.

Author information

Authors and Affiliations

  1. Department of Children and Adolescents, Third Faculty of Medicine, Charles University, University Hospital Kralovske Vinohrady, Šrobárova 50, Prague, 100 34, Czech Republic

    Irena Aldhoon-Hainerová

  2. Department of Pediatrics, Thomayer University Hospital, Prague, Czech Republic

    Irena Aldhoon-Hainerová

  3. Department of Medicine, Military University Hospital, Prague, Czech Republic

    Mikuláš Kosák

  4. Third Department of Medicine, First Faculty of Medicine, Charles University, Prague, Czech Republic

    Michal Kršek

  5. Institute of Nuclear Medicine, First Faculty of Medicine, Charles University, General University Hospital, Prague, Czech Republic

    David Zogala

  6. Developmental Endocrinology, Metabolism, Genetics and Endocrine Oncology Affinity Group, Eunice Kennedy Shriver NICHD, NIH, Bethesda, MD, USA

    Karel Pacak

Contributions

All authors made individual contributions to the authorship. IAH, MK, MK, and DZ were involved in the diagnosis and management of this patient. DZ was responsible for the patient´s imaging studies. IAH wrote the first draft of the manuscript. KP revised the manuscript critically. All authors reviewed and approved the final draft.

Corresponding author

Correspondence to Irena Aldhoon-Hainerová.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Signed informed consent was obtained from the patient and the patient´s parents for the publication of this case report and accompanying images.

Competing interests

The authors declare no competing interests.

Additional information

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https://bmcendocrdisord.biomedcentral.com/articles/10.1186/s12902-024-01756-5

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Higher Risk and Earlier Onset Glaucoma in Cushing’s Syndrome

Posted on November 27, 2024 by MaryO

Abstract

Purpose

Glaucoma incidence in patients with endogenous Cushing’s syndrome (CS) has never been established. We aim to assess the risk for glaucoma among CS patients compared to controls and determine the age of disease onset.

Methods

A nationwide retrospective matched-cohort study of patients with endogenous CS diagnosed between 2000 and 2023. Patients with CS were matched in a 1:5 ratio, with a control group individually matched for age, sex, socioeconomic status and body mass index. Main outcomes were the incidence of glaucoma and disease onset.

Results

A total of 609 patients [396 women (65%); mean age 48.1 ± 17 years] were included in the CS group and 3018 controls. Follow-up duration was 14.6 years (IQR 9.8–20.2) for the study group. The aetiology of hypercortisolism was divided into pituitary (259, 42.6%), adrenal (206, 33.8%) and unconfirmed aetiology (144, 23.6%) patients. At baseline, 44 (7.2%) CS patients had a diagnosis of glaucoma, compared with 151 (5%) controls. The overall risk for glaucoma was 74% higher in patients with CS compared with matched controls (hazard ratio = 1.74, p = 0.002). Patients with CS who developed glaucoma were younger (mean age of 62 ± 14.7 years) than controls (mean ± SD age, 62 ± 14.7 years), (p = 0.02). The overall risk for glaucoma in CS was high for both patients in remission and patients with persistent hypercortisolism (p = 0.048). Patients with active hypercortisolism experienced an earlier glaucoma onset (82.1 ± 88.0 months).

Conclusions

Endogenous CS is associated with increased risk for glaucoma regardless of remission status and develops at a younger age compared with the general population.

1 INTRODUCTION

Glaucoma is a chronic, irreversible vision-threatening disease affecting more than 80 million people worldwide (Quigley & Broman, 2006). It is the leading cause of irreversible blindness and the second cause of overall global blindness after cataracts (Tham et al., 2014).

Steroid-induced glaucoma, categorized as secondary open-angle glaucoma, is commonly associated with exogenous topical steroid administration rather than endogenous glucocorticoid overproduction (Phulke et al., 2017). Approximately, 30% of the general population are classified as steroid responders, experiencing elevated intraocular pressure (IOP) following corticosteroid administration (Becker, 1965).

Cushing syndrome (CS) is an endocrine disorder which results from excess cortisol production. The most common cause of CS is exogenous steroid use, followed by endogenous cortisol overproduction (Gadelha et al., 2023). In most cases (60%–70%), the corticotropin excess is produced by an adrenocorticotropic-hormone (ACTH)-secreting pituitary adenoma, followed by adrenal aetiologies (20%–30%) and ectopic ACTH-producing neuroendocrine tumours (Gadelha et al., 2023; Reincke & Fleseriu, 2023).

The treatment of CS typically commences with surgical intervention to remove the source responsible for excessive cortisol production, followed by medical therapies (Fleseriu et al., 2021).

There is a known higher risk of glaucoma in patients treated with glucocorticoids; however, data concerning the risk for developing high IOP and glaucoma in patients with CS are limited to case reports and small studies (Blumenthal et al., 1999; Gupta et al., 2015; Haas & Nootens, 1974; Khaw et al., 2010; Tsushima et al., 2019; Virevialle et al., 2014).

In this retrospective matched-cohort study, we aim to assess the risk for glaucoma in patients with CS, as compared with age, sex, socioeconomic status and body mass index (BMI)-matched controls. Furthermore, we assess the glaucoma risk according to the CS aetiology, degree of UFC elevation and remission status.

2 MATERIALS AND METHODS

A retrospective matched-cohort study compared patients with CS to controls without hypercortisolism. Data were sourced from Clalit Health Services (CHS), serving over 4.8 million members. Institutional ethics committee approval was obtained from Rabin Medical Center, adhering to the Declaration of Helsinki and good clinical practice (RMC-0779-22, 11.12.2022). As data were anonymized, written consent was deemed unnecessary.

Using International Classification of Diseases (ICD-10) codes, clinical diagnoses with matching dates were identified. Data were extracted from the electronic health record database via the CHS research data-sharing platform, operated by MDClone. Collected information for potential cases included patient demographics and clinical features at CS diagnosis, along with diagnoses of various comorbidities, including glaucoma.

Diagnosis time was defined as the first occurrence of elevated UFC, CS diagnosis or pituitary/adrenal surgery. Glaucoma diagnoses for both the patients with CS and control groups were acquired through ICD-10 coding. Patients with a diagnosis of glaucoma were identified by the appropriate ICD-10 coding, given by the treating ophthalmologist and incorporated to the patient’s medical record. Each patient with CS was matched 1:5 with controls by age, sex, socioeconomic status and BMI; notably, these controls have never had testing for hypercortisolism.

The follow-up duration commenced from the diagnosis date for both patients with CS and their matched controls, extending until death, CHS membership cessation or the data collection cut-off of 30 September 2023. Early biochemical remission was established as of 24-h UFC levels normalization without requiring medical intervention for hypercortisolism or necessitating glucocorticoid replacement therapy following pituitary or adrenal surgery, occurring within 26 months from the initial diagnosis of CS. The main outcome was defined as the timing of glaucoma diagnosis following the diagnosis of CS in the study group.

In secondary analyses, the occurrence of glaucoma was compared between patients who achieved biochemical remission and those who did not as well as by aetiology of CS and degree of maximal UFC elevation.

2.1 Statistical analysis

Statistical analysis was generated using SAS Software, Version 9·4, SAS Institute Inc., Cary, NC, USA. Continuous variables were presented by mean ± standard deviation or median and interquartile range [IQR]. Categorical variables were presented by (N, %). The t-test, the Mann–Whitney U-test, and the Chi-squared test were used for comparison, between cases and controls, of normally distributed, non-normal and categorical variables, respectively. Cumulative incidence plots, for glaucoma after CS, where death without glaucoma was treated as a competing risk, were created. The Cox proportional hazard model, with death without glaucoma treated as a competing risk, was used to calculate hazard ratios (HR). The appropriateness of the proportional hazard assumption was assessed visually. Two-sided p-values less than 0.05 were considered statistically significant.

3 RESULTS

3.1 Study cohort and patient characteristics

Between 1 January 2000 and 30 September 2023, a cohort of 609 patients (65% women) with CS was included, with a mean age of 48.1 ± 17 years. Each patient was matched with up to five controls based on age, sex, socioeconomic status and BMI, resulting in a control group comprising 3018 patients. (Table 1).

TABLE 1. Demographics and Clinical Characteristics of Study Patients.
CS patients/controls All
CS patients Controls
Patients, n 609 3018 3627
Age at diagnosis, Mean ± SD 48 ± 17.17 47.97 ± 17.19 47.99 ± 17.18
Gender
Male 213 (35%) 1043 (35%) 1256 (35%)
Female 396 (65%) 1975 (65%) 2371 (65%)
Glaucoma 44 (23%) 151 (77%) 195 (5%)
Socioeconomic statusa
Low 74 (13%) 371 (13%) 445 (13%)
Middle 349 (60%) 1719 (60%) 2068 (60%)
High 153 (27%) 760 (27%) 913 (27%)
Smoking statusa
Never 198 (60%) 910 (63%) 1108 (62%)
Current/Past smoker 133 (40%) 544 (37%) 677 (38%)
BMI at diagnosis, Mean ± SDb 30.9 ± 7.6 30 ± 6.9 30.2 ± 7.01
Diabetes mellitus at diagnosis 140 (23%) 396 (13%) 536 (15%)
HTN at diagnosis 343 (56%) 957 (32%) 1300 (36%)
Dyslipidaemia at diagnosis 258 (42%) 874 (29%) 1132 (31%)
CAD at diagnosis 70 (11%) 191 (6%) 261 (7%)
History of stroke 27 (4%) 82 (3%) 109 (3%)
  • Abbreviations: BMI, body mass index; CAD, coronary artery disease; CS, Cushing’s syndrome; HTN, hypertension; N, number; SD, standard deviation.
  • a Data were not available for all patients.
  • b Number of patients were: 363 (60%) cases, 1549 (51%) controls and 1912 (53%) total.

Follow-up duration was 14.6 years (IQR 9.8–20.2) for the study group and 14.8 (IQR 9.9–20.2) for the matched controls.

Diabetes mellitus, hypertension, coronary artery disease, dyslipidaemia and stroke exhibited higher prevalence among CS patients compared to their matched controls (p < 0.01) (See Table 1).

The aetiology of hypercortisolism was divided into pituitary CS (pCS) in 259 (42.6%) patients and adrenal CS (aCS) in 206 (33.8%) patients. Disease aetiology could not be ascertained from the available data in 144 (23.6%) patients.

3.2 Risk factors for glaucoma in Cushing’s syndrome

Overall, 78 (78/609, 12.8%) patients with CS and 250 (250/3018, 8.3%) patients without CS developed glaucoma up to the last follow-up. When stratified by age group at the time of glaucoma diagnosis, patients with CS had the following distribution: 1.5% (nine patients) were diagnosed before the age of 40; 6.2% (38 patients) between the ages of 40 and 65; and 5% (31 patients) at the age of 65 and older. In comparison, among controls, the proportions were 0.3% (eight patients), 3.7% (113 patients) and 4.3% (129 patients) for the respective age groups.

These groups were further divided into patients with a history of glaucoma before and after the study baseline (CS diagnosis).

Reported prior history of glaucoma before CS diagnosis was noted in 34 patients with CS (5.58%), whereas among the controls, 99 patients (3.28%) had a history of glaucoma before the study baseline (p < 0.0089).

Following the diagnosis of CS, 44 (7.2%) patients with CS developed glaucoma, compared with 151 (5%) controls. (Table 1) The difference between groups was statistically significant (HR 1.74, 95% CI 1.17–2.60, p = 0.002).

The risk assessment for glaucoma, with death considered as a competing risk, revealed that by the end of the follow-up period, CS patients had a 74% higher overall risk for glaucoma compared to their matched controls (p = 0.002), (Figure 1).

Details are in the caption following the image

Overall risk for glaucoma with death as a competing event. CS = Cushing’s syndrome.

Patients with CS experienced glaucoma onset at a notably younger age than controls. The mean age of glaucoma onset among those with a history of glaucoma before CS diagnosis was 56.6 ± 12.9 years, in contrast to controls with a mean age of 61.6 ± 10.1 years (p = 0.005). After CS diagnosis, the age of glaucoma onset remained significantly younger in CS patients compared to their matched controls (mean age of 62 ± 14.7 years vs. 66 ± 11.3 years, respectively; p = 0.02).

We performed a subgroup analysis of patients with CS and glaucoma by the source of the excessive production of cortisol, including pituitary, adrenal and unknown-origin CS. No difference was observed in the risk for glaucoma in patients with either pituitary, adrenal or unknown-origin CS, compared to their matched controls. In the CD group, 15 patients (7%) were diagnosed with glaucoma, whereas in the control group, 47 patients (4%) developed glaucoma. Similarly, among patients with adrenal CS, 12 patients (7%) were diagnosed with glaucoma, compared with 45 (5%) individually-matched controls.

A univariate analysis to examine the effect of specific variables, including diabetes mellitus, BMI, smoking history, ischemic heart disease, hypertension, dyslipidaemia, history of stroke, socio-economic status and gender in CS patients with and without glaucoma was performed.

Severity of CS disease was evaluated by the maximal UFC levels that were ≥5 times higher in 8.1% (14/172) of patients with glaucoma, and ≤5 times higher in 8.8% (15/170). There was no correlation between maximal UFC levels and the risk for glaucoma (p = 0.19).

Of the 44 patients with CS diagnosed with glaucoma following a CS diagnosis, 13 cases (29%) had comorbid diabetes mellitus, compared to 85 of 441 (19.3%) patients without glaucoma. This suggests a trend towards an 82% higher risk of glaucoma in patients with diabetes mellitus compared to those without it (p = 0.06).

Additionally, a history of stroke was found to be more prevalent among patients with CS with glaucoma (three cases, 6.8%) compared to those without glaucoma (17 cases, 3.8%); however, the difference did not reach statistical significance. Gender did not emerge as a risk factor for glaucoma as the female-to-male ratio was consistent among patients with and without glaucoma.

3.3 Risk for glaucoma following remission of Cushing’s syndrome

Data on early biochemical remission status following a CS diagnosis were available for 471 patients; 312 (66%) achieved early biochemical remission, while 159 (34%) had persistent hypercortisolaemia. Overall, 62 (13%) patients CS, either with or without remission, had glaucoma in this study group. To assess the risk for glaucoma following a CS diagnosis, we excluded 28 patients who developed glaucoma before the CS diagnosis. Among the remaining 34 glaucoma patients diagnosed after a CS diagnosis, 22 (7.5%) achieved early biochemical remission, while 12 (7.9%) did not. The overall risk of glaucoma in Cushing’s syndrome was elevated for both individuals experiencing remission and those with persistent hypercortisolism (p = 0.048) (Figure 2). However, the difference between those who achieved remission and those who did not was not statistically significant (Table 2). Compared to their matched controls, patients with CS without early biochemical remission did not exhibit a statistically significant higher risk for glaucoma (p = 0.18). However, while the time span between CS diagnosis and glaucoma diagnosis was comparable between CS patients in remission and controls (88.6 ± 73.06 and 88.9 ± 88.4 months, respectively), CS patients not in remission experienced an earlier onset of glaucoma (82.1 ± 88.0 months).

Details are in the caption following the image

Risk for glaucoma in patients with and without early biochemical remission with death as a competing event.
TABLE 2. Patients with glaucoma and Cushing’s syndrome, with and without disease remission.
CS Glaucoma Glaucoma prior to CS
Total N. 471 34 28
Remission (n, %)a 312 (66%) 22 (65%) 20 (71%)
No remission (n, %) 159 (34%) 12 (35%) 8 (29%)
  • Abbreviations: CS, Cushing’s syndrome; N, number.
  • a Remission is defined as a normal 24-h UFC level without treatment for hypercortisolism, or hypocortisolism necessitating glucocorticoid replacement after pituitary or adrenal surgery, within 24 months following diagnosis of CS.

4 DISCUSSION

While data on glucocorticoid treatment and glaucoma are more established, the incidence of glaucoma in patients with CS is not known. In this nationwide retrospective matched-cohort study, the first of its kind to assess the risk for glaucoma in patients with CS, we demonstrated that individuals with endogenous CS exhibit a heightened risk of early-onset glaucoma. Additionally, patients with CS tended to develop glaucoma at a significantly younger age compared to matched controls from the general population. Importantly, this difference persisted even after excluding both cases and controls with a prior diagnosis of glaucoma.

The mechanism of steroid-induced glaucoma is not well understood; decreased trabecular meshwork outflow due to increased resistance is suspected to be the main cause of IOP elevation (Kersey & Broadway, 2005).

The overall prevalence of glaucoma in the general population increases with age and ranges from 1.5% to 1.9% in ages 40 to 65 years, increasing to 2% to 7% in patients 65 and older (Friedman, 2004). In our cohort, we observed that while the incidence of glaucoma in the control group increased with age, among patients with CS, the highest incidence of glaucoma was observed among those aged between 40 and 65 years. Additionally, the incidence of glaucoma before the age of 40 was five times higher among patients with CS compared to controls, highlighting a significantly elevated risk of early-onset glaucoma among individuals with hypercortisolism. Glaucoma prevalence in Israel is similar to worldwide reported rates (Levkovitch-Verbin et al., 2014). The higher incidence of glaucoma observed in both the study and control groups in our study as compared to the literature may be attributed to the study’s definition of glaucoma, which is based on ICD-10 codes in patients’ medical records. Furthermore, patients receiving medications potentially increasing IOP were not excluded. Thus, despite the overall higher glaucoma rates observed here, since both the study and control groups rely on the same diagnostic criteria, the increased incidence of glaucoma in patients with CS as compared to matched controls in our study is significant and warrants attention.

In addition, patients with CS experienced the onset of glaucoma at a notably younger age compared to controls, with CS patients exhibiting glaucoma onset 4 years earlier than controls. When examining the ages of patients before their CS diagnosis, those diagnosed with glaucoma were statistically significantly younger than controls, with mean ages of 56 and 61 years, respectively. This observation, coupled with the well-documented diagnostic delay of CS (Rubinstein et al., 2020), suggests that the hypercortisolism before the formal diagnosis of CS did put them at a heightened risk of developing glaucoma at a younger age.

Notably, we did not find any correlation between maximum elevation of UFC and the risk of developing glaucoma. We postulate that extended hypercortisolism exposure could exert a more significant influence than the maximum UFC levels measured in the urine, which has known significant variability also.

The association between diabetes mellitus and glaucoma remains inconclusive due to conflicting findings in cohort and epidemiological studies (de Voogd et al., 2006; Hennis et al., 2003). However, a comprehensive meta-analysis published in 2014 suggested that individuals with diabetes mellitus face an elevated risk of developing glaucoma (Zhou et al., 2014). In our study, we observed that patients with CS and diabetes mellitus were more likely to develop glaucoma compared to those without diabetes mellitus. Another significant risk factor for developing high IOP and consequently glaucoma is chronic corticosteroids use, specifically topical steroids. When the IOP remains high for a prolonged duration, damage to the optic nerve (steroid-induced secondary glaucoma) may occur (Kersey & Broadway, 2005).

Though it seems intuitive that endogenous CS could match the exogenous CS numbers, there are no large population studies examining the association between CS and glaucoma. Several studies suggested a role for endogenous cortisol in the development of ocular hypertension and glaucoma, noting increased plasma and aqueous humour cortisol levels in glaucoma patients (Patel et al., 2023). However, only a few small cohort clinical studies have been performed on endogenous hypercortisolism in patients with CS causing increased IOP and glaucoma (Jonas et al., 1990; Ma et al., 2022), while another study showed no correlation between endogenous hypercortisolism and increased IOP (Mishra et al., 2017). There are several published case reports on endogenous hypercortisolism as a cause for secondary glaucoma; Virevialle et al. reported a case of a young female with painless loss of vision who had severe open-angle glaucoma with uncontrolled high IOP, requiring glaucoma surgery, which later was found to be secondary to CS related to an adrenal adenoma (Virevialle et al., 2014). Another case report published by Blumenthal et al. described a 33-year-old man with increased IOP represented as a manifestation of hypercortisolism caused by ectopic CS. Importantly, after surgical removal of the tumour, the high IOP resolved (Blumenthal et al., 1999). CD has also led to ocular hypertension and glaucoma in two cases, with IOP returning to normal levels in all four eyes after transsphenoidal tumour resection (Gupta et al., 2015). Noteworthy, in some of the reports, ocular hypertension and glaucoma were the presenting manifestations for CS diagnosis (Jonas et al., 1990; Ma et al., 2022; Mishra et al., 2017).

The overall risk for glaucoma was high for both patients with early biochemical remission and patients with no remission, which can be due to the limited number of patients in each group. However, patients with persistent hypercortisolaemia were diagnosed with glaucoma approximately 6 months earlier compared to both patients with CS in remission and controls. This observation could be attributed to the prolonged hypercortisolaemia in patients with CS without remission, leading to elevated IOP and subsequent development of glaucoma.

This study has several strengths, including a sufficiently large sample size for the primary analysis, long-term follow-up, and strict criteria for diagnosing CS, along with consideration of disease aetiology and remission status. The control group was carefully matched to minimize the influence of factors like age, sex, socioeconomic status and BMI on cancer risk. Additionally, the database encompasses the entire population, eliminating the risk of selection bias. Given the increased mortality associated with CS, we accounted for death as a competing risk in all analyses. Lastly, we performed necessary sensitivity analyses to ensure the robustness of our results.

The limitations of this study include the potential for missing data, which, due to its retrospective design, may have affected our ability to identify patients with CS and glaucoma, as well as to determine disease aetiology or remission status in some cases. Additionally, ascertainment bias cannot be excluded, as patients with CS may have been diagnosed with glaucoma more frequently due to more regular ophthalmologic examinations. Surveillance bias, where patients with more frequent healthcare visits or monitoring are more likely to be diagnosed with additional conditions due to being examined more often than others, could also result in an overestimation of the association between CS and glaucoma.

In this large nationwide retrospective matched-cohort study, we have shown for the first time that endogenous CS, whether caused by a pituitary or adrenal adenoma, is associated with an increased risk for glaucoma and a clinical manifestation at an earlier age versus general population, regardless of remission status or degree of UFC elevation. A delay in diagnosing both CS and glaucoma can result in significant ocular and systemic morbidities. Guidelines should also incorporate recommendations for periodic monitoring for intraocular pressure and/or glaucoma development to be routinely performed for patients with CS, especially if they also have concomitant comorbidities. Further research using larger multinational databases is warranted to validate our findings and uncover additional insights.

FUNDING INFORMATION

This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

CONFLICT OF INTEREST STATEMENT

Y.S., A.Z., Y.R., S.K., I.S. and T.S. do not have any financial or personal relationships with other people or organizations to disclose. A.A. has received occasional scientific fee for scientific consulting and advisory boards from Medison, C.T.S. pharma and Neopharm. M.F. has received research support from Oregon Health & Science University as a principal investigator from Recordati, Sparrow and Xeris and has performed occasional scientific consultancy for Recordati, Sparrow and Xeris.

From https://onlinelibrary.wiley.com/doi/10.1111/aos.16787

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