New data on relacorilant (Corcept Therapeutics), a selective glucocorticoid receptor modulator, revealed several cardiometabolic benefits for patients with hypercortisolism.
Researchers presented results from the GRACE and GRADIENT trials, which assessed relacorilant in adults with hypercortisolism. GRACE was an open-label trial that enrolled adults with endogenous hypercortisolism, whereas GRADIENT included those with adrenal hypercortisolism and randomly assigned participants to relacorilant or placebo.
Both trials demonstrated similar reductions in body weight. The relacorilant group in GRADIENT had a 3.6 kg reduction in body weight, and adults in GRACE reduced their body weight by 3.3 kg at 22 weeks.
“Relacorilant may improve many of the common features of hypercortisolism, which may provide a holistic benefit to our patients,” Oksana Hamidi, DO, MSCS, study investigator and associate professor in the division of endocrinology at UT Southwestern Medical Center, told Healio | Endocrine Today. “An interesting observation was that relacorilant can lead to weight loss, and that weight loss is mostly fat mass, with lean mass being preserved or even increasing. The ability to maintain muscle is particularly important for our patients.”
In a cardiometabolic analysis, adults with hypertension receiving relacorilant had greater reductions in both systolic and diastolic blood pressure compared with placebo. For adults with hyperglycemia at baseline, the relacorilant group had greater declines in fasting glucose and glucose area under the curve.
Corin Badiu, MD, study investigator, professor of endocrinology and head of the department of endocrinology IV in the National Institute of Endocrinology and “C.Davila” University of Medicine and Pharmacy in Bucharest, Romania, and fellow of the Romanian Academy of Medical Sciences, said the benefits of relacorilant may extend into additional areas that could be studied in the future.
“Apart from metabolic and cardiovascular improvements, we expect long-term improvements in bone mass, liver steatosis, mood, sleep and other behavioral aspects [that] are disturbed in hypercortisolism,” Badiu told Healio | Endocrine Today.
Irina Bancos, MD, MSc, professor of medicine in the division of endocrinology, metabolism and nutrition at Mayo Clinic, said relacorilant could provide benefits similar to mifepristone (Korlym, Corcept Therapeutics) for patients with hypercortisolism, but with fewer adverse events related to progesterone health. Bancos was not involved with the trial.
“Why is there a need for another medication in the same class by the same company? The major reason is to achieve the same metabolic impact as far as weight loss and improvement of hyperglycemia … but also to decrease the side effects,” Bancos told Healio | Endocrine Today.
IntroductionCushing’s disease (CD) is the most common cause of endogenous Cushing’s syndrome. Adrenocorticotropic hormone (ACTH) has trophic and mitogenic effects on the adrenal cortex that may cause diffuse adrenal enlargement and nodular lesions.
AimTo evaluate the prevalence of adrenal structural abnormalities in patients with CD.
MethodsRetrospective cohort study. We conducted a computerized search in our medical centers databases for the diagnosis of CD recorded between the years 1995–2024. Out of 124 patients with ACTH dependent Cushing’s syndrome, we identified 68 patients with CD who underwent adrenal imaging. We analyzed the clinical, biochemical, and imaging data.
ResultsOur cohort included 68 patients (51 females, 75.0%; mean age at the time of adrenal imaging, 44.6 ± 14.9 years). Sixteen (23.5%) patients had an adrenal nodule ≥10 mm (median size, 27.5 mm, IQR 14.3–38.3), and 19 others (27.9%) had adrenal hyperplasia or nodules <10 mm. The prevalence of adrenal nodules increased with age from 16.7% in patients aged 26–35 years to 26.3% in those aged above 55. Patients with adrenal nodules were older compared to those with normal adrenal glands (mean age, 49.0 ± 12.4 vs 39.1 ± 14.9 years; p = 0.03), and had lower ACTH level (0.7 x ULN, IQR 0.5–1.2, vs 1.2 x ULN, IQR 0.9–1.8, p = 0.02).
ConclusionsWe identified abnormal adrenal imaging in 51.5% of patients with CD. The prevalence of adrenal nodules in our study was 10-fold higher than in the normal population, for all age groups. This suggests that chronic ACTH secretion in CD is associated with adrenal nodules appearance.
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Cushing’s disease (CD) is the most common etiology (70%) of endogenous Cushing’s syndrome [1]. CD is caused by a pituitary adenoma that autonomously secretes adrenocorticotropic hormone (ACTH), leading to cortisol overproduction and secretion from the adrenal cortex [2].
ACTH is a predominant trophic factor of the adrenal cortex. Several animal models, in which ACTH or its receptor (melanocortin 2 receptor, MC2R) were eliminated, have confirmed the central role of ACTH in maintaining normal growth of the adrenal cortex [3, 4]. While ACTH also exerts a mitogenic effect, the precise mechanism by which it promotes adrenocortical growth and proliferation is complex and only partially understood [5]. Due to the effects of ACTH on the adrenal cortex, patients with ACTH-dependent Cushing’s syndrome have high prevalence of adrenal hyperplasia, reaching up to 60% [6, 7].
Adrenal incidentaloma (AI) is an adrenal mass (≥1 cm) detected on imaging not performed for a suspected adrenal disease [8]. Autopsy studies suggest that the overall prevalence of adrenal masses ranges from 1.1–8.7%, which increases with age [9]. In recent decades, with advancement in imaging technologies, radiological studies have become more common and accurate, with the prevalence of AI’s in imaging studies approaching values similar to those found in autopsy studies [8, 10,11,12,13,14].
In contrast to adrenal hyperplasia, there are limited studies examining the prevalence of adrenal nodules in CD. These studies, which included small cohorts of up to 40 patients with CD, found a significantly higher prevalence of adrenal nodules, with rates ranging from 4% to nearly 40% among studied individuals [6, 7, 15].
Our aim was to study the morphology of the adrenal glands and assess the prevalence of abnormal adrenal findings, including hyperplasia and adrenal nodules, in a large cohort of patients with CD.
Materials and methods
We conducted a computerized search in Rabin and Shamir Medical Centers databases for the diagnosis of Cushing’s syndrome and screened for patients with ACTH-dependent Cushing’s syndrome. Cushing’s syndrome was diagnosed in patients with characteristic symptoms and signs and hypercortisolemia. Hypercortisolemia was confirmed according to laboratory findings including high 24 h urinary free cortisol (UFC), elevated midnight salivary cortisol, and abnormal 1 mg dexamethasone suppression test. We further classified these patients to ACTH-dependent Cushing’s syndrome, based on ACTH level in the normal or above the normal range.
A diagnosis of CD was confirmed by a pituitary adenoma of ≥6 mm depicted by seller MRI, an inferior petrosal sinus sampling (IPSS) supporting a pituitary source of ACTH secretion, immunostaining for ACTH and/or T-PIT in resected tumor specimens, and/or hormonal remission following successful trans-sphenoidal adenoma resection.
After identifying all patients with CD, our cohort included only patients with CD who have undergone abdominal computed tomography (CT) or abdominal magnetic resonance imaging (MRI), during the active phase of their disease.
In addition, we assembled a cohort of patients with ACTH-dependent Cushing’s syndrome in whom the source of ACTH secretion was not identified, that is, patients with ACTH-dependent Cushing’s syndrome without tumor localization.
Patients with malignant pituitary tumor and those with confirmed ectopic ACTH secretion were excluded. Patients that were treated with glucocorticoids were also excluded.
Based on an imaging report from an expert radiologist, all adrenal images were classified into three categories: normal, hyperplastic, or nodular adrenal glands. All adrenal nodules were classified according to nodule size: maximal nodule diameter below 10 mm, or ≥10 mm.
The study was approved by the Rabin Medical Center and Shamir Medical Center institutional review boards with waiver of patient consent, as complied with the Helsinki Declaration.
The authors received no funding for performing this study.
Statistical analysis and plan
Statistical analysis was performed using IBM SPSS version 29.0 (IBM Corp., Armonk, NY).
Continuous variables were presented by Mean (SD) or Median (IQR) as appropriate. Dichotomous variables were presented by N (%).
T-test and Mann–Whitney tests were used to compare values of normally and non-normally distributed continuous variables, with Chi-Square test used for comparison of categorical variables.
Two-sided P-values less than 0.05 were considered statistically significant.
Results
From March 1995 to December 2024, a total of 124 patients with ACTH-dependent Cushing’s syndrome were identified. There were 103 patients with the diagnosis of CD, and 21 patients with ACTH-dependent Cushing’s syndrome without tumor localization. After carefully reviewing each case, we excluded 35 patients without reported adrenal imaging (Fig. 1).
Fig. 1
Patient selection flowchart. ACTH adrenocorticotropic hormone, CD Cushing’s disease, CT computed tomography, MRI magnetic resonance imaging
The main cohort included 68 patients with CD and available adrenal imaging (51 females, 75.0%; mean age at the time of adrenal imaging, 44.6 ± 14.9 years). The median pituitary adenoma size (i.e. largest adenoma diameter) was 6 mm (IQR 4.75–10.25). The median ACTH level was 1.2 x ULN (IQR 0.8–1.9), and the median UFC level was 3.5 x ULN (IQR 2.0–6.0) (Table 1).
Table 1 Baseline characteristics of 68 patients with Cushing’s disease and 10 subjects with ACTH dependent Cushing’s syndrome without tumor localization
Sixty-five (95.6%) patients underwent trans-sphenoidal surgery (TSS), 44 of them (67.7%) had a resected adenoma expressing ACTH and/or T-PIT, 7 (10.8%) had no pituitary adenoma in pathology, and for 14 (21.5%) patients we did not have available pathology reports. Forty-six of the 65 (70.8%) patients experienced hormonal remission following surgery (Table 1).
During follow-up, 17 (26.2%) patients underwent repeated pituitary surgery, 8 of them due to persistent disease, and 9 due to recurrent elevated cortisol. Fifteen (22.1%) patients underwent radiation therapy. Thirty-nine (57.4%) patients received medical therapy for CD with adrenal steroidogenesis inhibitors and medications targeting pituitary somatostatin or dopamine receptors. Of these, seven (17.9%) patients were treated medically before TSS, 31 (79.5%) after TSS, and one (2.6%) patient received medical therapy both before and after TSS (Table 1).
Abdominal imaging findings in patients with CD
Sixty-three patients had abdominal CT, including five who had Ga68 positron emission tomography (PET) CT without pathologic adrenal Ga68 uptake on functional imaging. Five additional patients had abdominal MRI.
Twenty-three (33.8%) patients underwent adrenal imaging as part of their medical evaluation following the diagnosis of Cushing’s syndrome. Five (7.4%) patients underwent adrenal imaging due to persistent or recurrent disease following surgery. Eleven (16.2%) patients had adrenal imaging because of abdominal pain, thirteen (19.1%) patients for other reasons not related to Cushing’s syndrome (e.g. following abnormal finding in ultrasonography (US), or before abdominal/gynecological surgery) and sixteen patients (23.5%) for unknown reasons.
A total of 16 (23.5%) patients had an adrenal nodule ≥10 mm (median size, 27.5 mm, IQR 14.3–38.3) (Table 1). All of the nodules were radiologically defined as compatible with adenomas, based on low Hounsfield Units (HU) on non-contrast CT or signal drop on out-of-phase MRI sequences. Five patients had nodules in the right adrenal gland, six others had nodules in the left adrenal gland, and five patients had adrenal nodules ≥10 mm in both adrenal glands – one nodule in each side. There was only one patient with adrenal imaging consistent with bilateral multinodular adrenal hyperplasia, that was classified into the group of patients with adrenal nodule ≥10 mm. Nine (13.2%) patients had an adrenal nodule ≥20 mm (Fig. 2).
Nineteen (27.9%) patients had adrenal hyperplasia and/or nodules smaller than 10 mm (Table 1).
Patients with adrenal nodules ≥10 mm, as well as those with adrenal hyperplasia and/or nodules <10 mm, were significantly older compared to individuals with normal adrenal glands (mean age at imaging: 49.0 ± 12.4 and 50.4 ± 13.7 vs 39.1 ± 14.9 years, respectively; p = 0.03 and p = 0.01). Only patients with adrenal nodules ≥10 mm had significantly lower ACTH levels compared to patients with normal adrenal glands (0.7 x ULN, IQR 0.5–1.2, vs 1.2 x ULN, IQR 0.9–1.8; p = 0.02) (Table 2).
Table 2 Clinical characteristics of CD patients with adrenal nodules ≥10 mm, adrenal hyperplasia and/or nodule <10mm and with normal adrenal glands
The prevalence of adrenal nodules increased with age from 16.7% in patients aged 26–35 years to 27.8, 30.8 and 26.3% in those aged 36–45, 46–55, and above 55 years, respectively (Fig. 3).
Fig. 3
Prevalence of adrenal nodules ≥10 mm in CD patients (current study) and in the general population (Jing et al.), stratified by age group
Urinary free cortisol (UFC) levels did not differ significantly among the three groups. Patients with adrenal nodules ≥10 mm had a median UFC level of 4.0 x ULN (IQR 1.7–6.3), those with adrenal hyperplasia and/or nodules <10 mm had a median of 3.8 x ULN (IQR 3.0–6.0), and patients with normal adrenal glands had a median of 3.5 x ULN (IQR 2.0–6.0) (p = 0.77 and p = 0.63, respectively vs. normal adrenal glands) (Table 2).
A pituitary adenoma was depicted by sellar MRI in 54 (79.4%) patients. Patients with adrenal nodules ≥10 mm tended to harbor a larger pituitary adenoma compared to patients with normal adrenals (median adenoma size, 7.0 mm (IQR 6.0–11.5) vs 6.0 mm (IQR 4.0–8.0) respectively; p = 0.11). Patients with adrenal hyperplasia and/or nodules <10 mm had a median adenoma size of 5.5 mm (IQR 3.0–13.0), which was not significantly different compared to patients with normal adrenal glands (p = 0.63) (Table 2).
Remission rates after TSS were not significantly different among the groups. Among patients with adrenal nodules ≥10 mm, 12 (80%) patients achieved remission, compared to 23 (71.9%) patients with normal adrenal glands (p = 0.73). Similarly, 11 patients (61.1%) with adrenal hyperplasia and/or nodules <10 mm achieved remission, with no significant difference compared to patients with normal adrenal glands (p = 0.53) (Table 2).
Clinical characteristics of four patients with CD who underwent unilateral adrenalectomy
Four patients (all females; mean age at the time of adrenal imaging, 46.3 ± 6.8 years) underwent unilateral adrenalectomy for a benign adrenocortical adenoma (adrenal adenoma size between 2.8–6.4 cm). One patient underwent adrenalectomy prior to TSS, with persistent hypercortisolism following adrenal surgery but achieved remission after TSS (Table 3).
Table 3 Clinical characteristics of four patients with CD who underwent unilateral adrenalectomy
Three patients underwent adrenalectomy after TSS. All three patients exhibited persistent hypercortisolism prior to adrenalectomy, with a median UFC level of 3.0 x ULN (IQR 1.9–6.1). The median ACTH level was 0.6 x ULN (IQR 0.3–1.1). One of them experienced transient postoperative cortisol normalization, while the other two achieved remission following adrenalectomy (Table 3).
Abdominal imaging findings in patients with ACTH-dependent Cushing’s syndrome without tumor localization
Ten patients (including 7 females) with ACTH-dependent Cushing’s syndrome without tumor localization had adrenal imaging. Compared to patients with CD, these patients were older (mean age at the time of adrenal imaging, 58.4 ± 15.1 vs 44.7 ± 14.9 years, p < 0.01). Three of these patients (30.0%) had adrenal nodule ≥10 mm (median size, 14 mm, IQR 11.7–18), and 6 (60.0%) had adrenal hyperplasia or small nodules <10 mm (Table 1).
Discussion
In the current study, we assessed the prevalence of adrenal nodular lesions and hyperplasia in patients with CD. We found that among 68 patients with CD who underwent adrenal imaging, 16 (23.5%) patients had an adrenal nodule ≥10 mm and 19 (27.9%) patients had adrenal hyperplasia or a nodule <10 mm. Additionally, we studied 10 patients with ACTH-dependent Cushing’s syndrome without tumor localization. Among these patients, 3 (30.0%) patients had an adrenal nodule ≥10 mm.
ACTH has trophic and mitogenic effects on the adrenal cortex [5], and chronic ACTH secretion may lead to adrenal hyperplasia. However, most of the literature on the co-existence of CD and adrenal nodules is based on case reports [16,17,18], with only a few studies focusing on the prevalence of adrenal nodules in cohorts of patients with CD [6, 7, 15].
Sohaib et al. reported that among 40 patients with CD, 25 (62.5%) had enlarged adrenal glands by CT, and seven patients (17.5% of the CD cohort) had an adrenal nodule ≥10 mm [7]. Imaki et al. found that among 24 patients with CD, 12 (50.0%) had adrenal hyperplasia, and only one (4.2%) had an adrenal nodule ≥10 mm [6]. Albiger et al. also studied the prevalence of adrenal nodules in CD, but defined a nodule as ≥5 mm. In their study, 15 out of 41 patients (36.6%) had adrenal nodules of this size [15] (Table 4). To the best of our knowledge, our study represents the largest investigation to date on the prevalence of adrenal abnormalities in CD patients (Table 4).
Table 4 Adrenal morphology in CD patients in the current study and three other main cohorts
In our study all patients underwent adrenal imaging during the active phase of their disease. Notably, 28 (41.2%) patients underwent adrenal imaging as part of their medical evaluation following the diagnosis of Cushing’s syndrome or due to persistent or recurrent disease. Shoaib et al. included CD patients who underwent CT imaging as part of their radiological assessment [7]. Albiger et al. included CD patients who had undergone abdominal CT scan as part of their initial evaluation or the assessment for persistent or recurrent disease [15].
With the increased use of abdominal imaging in recent decades, incidental findings of abnormal adrenal lesions have become more common [8]. The prevalence of AIs in the general poppulation has been reported to range from 1.2–5.0% in various studies [8, 10,11,12,13,14, 19], which is significantly lower than the prevalence observed in our CD patients.
A large retrospective cohort from the United Kingdom, including 479,975 outpatients that underwent in-hospital CT or MRI scans (excluding patients with known adrenal lesion), found that 1.2% of individuals had AI [19]. The prevalence of AI was higher in patients who underwent abdominal CT imaging, reaching to 3.0%. The authors found a correlation between age and the prevalence of AI, ranging from 0.2% in the youngest group (21–30 years) to 4.1% in the oldest group (age ≥91 years) [19]. Consistent with findings from previous studies [7, 15], our study also demonstrates that patients with adrenal nodules were significantly older compared to those with normal adrenal glands.
A recent study from China, which examined 25,356 healthy individuals (unselected population) who underwent abdominal CT imaging, found that 351 (1.4%) had an adrenal tumor [13]. Compared to the results of this study, we observed that in each age group, CD patients had a much higher prevalence of adrenal nodules: between 26–35 years 16.7% in our cohort vs 0.3% in the Chinese population, between 36–45 years 27.8% vs 0.7%, for subjects 46–55 years 30.8% vs 1.6%, and above the age of 55 years 26.3% vs 2.5% (Fig. 3).
We found that patients with adrenal nodules≥10 mm had a significantly lower ACTH level. Albiger et al. also found that ACTH levels were significantly lower in patients with adrenal nodules. Their hypothesis was that a gradual transition from pituitary to adrenal autonomy might suppress ACTH production [15]. Previous reports have suggested that, in a subgroup of patients with prolonged ACTH stimulation, there might be a transition from pituitary dependent to adrenal dependent Cushing’s syndrome [20, 21]. Tabarin et al., found that dexamethasone suppressibility and the stimulatory effect of metyrapone on ACTH secretion were less in CD patients with hyperplasia and adrenal nodules than in those with diffuse adrenal hyperplasia, suggesting a greater degree of adrenal autonomy in the former [22]. Dalmazi et al., found somatic mutations in the gene encoding the catalytic α (Cα) subunit of protein kinase A (PKA; PRKACA) in adrenal nodules of two patients with long-standing CD [23]. PRKACA somatic mutations are the most common genetic finding in adrenal adenomas associated with ACTH-independent Cushing syndrome [24], therefore these genetic alterations could represent a possible mechanism underlying adrenal nodule formation and autonomous cortisol hyperproduction in a subgroup of patients with long-standing CD.
In our study, 4 patients with adrenal nodules underwent unilateral adrenalectomy, two of them achieved full remission after the surgery. Interestingly, Dalmazi et al., described also that a patient who underwent unilateral adrenalectomy of a 35 mm adrenal nodule, achieved clinical and biochemical remission [23]. It may be worthwhile to consider unilateral adrenalectomy in selected CD patients with persistent hypercortisolemia after TSS, who have a large unilateral adrenal nodule.
There are several limitations to this study, primarily due to its retrospective design. The study cohort consists of patients who were referred for follow-up at endocrinology departments within tertiary hospitals. This setting likely leads to a higher frequency of imaging studies compared to the general population, potentially leading to a higher rate of incidental adrenal findings. Most of the patients did not have repeated adrenal imaging during their follow-up, so it is not possible to assess whether there was a change in the appearance of the adrenal glands following disease remission.
Moreover, there were instances where sufficient clinical data was unavailable to definitively confirm a diagnosis of CD in some patients. Thus, 10 patients were excluded from the main cohort analysis.
Another limitation is the relatively small sample size of the study population, which resulted in some findings not reaching statistical significance.
In conclusion, our study found that abnormal adrenal imaging was present in 51.5% of patients with CD. Notably, the prevalence of adrenal nodules in our cohort is 10 times higher than in the general population across all age groups, emphasizing a marked difference of adrenal morphology between CD patients and healthy individuals and suggesting that chronic ACTH stimulation leads to adrenal nodule development. The relative low levels of ACTH in patients with adrenal nodules may reflect partial autonomous cortisol secretion in some adrenal nodules. In light of this, adrenal nodules in patients with CD appear to be a relatively common finding, highlighting the importance of thorough laboratory and imaging diagnosis to identify the cause of hypercortisolism.
Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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Authors and Affiliations
Endocrine and Diabetes Institute, Shamir Medical Center, Zerifin, Be’er Ya’akov, Israel
Efrat Markus & Shlomit Koren
Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv, Israel
Efrat Markus, Yaron Rudman, Shlomit Koren & Ilan Shimon
Institute of Endocrinology, Beilinson Hospital, Rabin Medical Center, Petah Tikva, Israel
Yaron Rudman & Ilan Shimon
Contributions
All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Efrat Markus, Yaron Rudman, and Ilan Shimon. The first draft of the manuscript was written by Efrat Markus and Ilan Shimon and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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Ectopic adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome is a rare paraneoplastic disorder caused by excessive cortisol production from nonpituitary tumors. Olfactory neuroblastoma (ONB), a rare neuroendocrine malignancy of the sinonasal cavity, is an exceedingly uncommon source of ectopic ACTH production, with fewer than 25 cases reported worldwide. This report presents a case of ACTH-dependent Cushing syndrome due to ONB, emphasizing the diagnostic complexity, multidisciplinary management, and favorable clinical outcomes.
Case Presentation
A 70-year-old male presented with progressive muscle weakness, facial rounding, weight gain, hypertension, hypokalemia, and recurrent epistaxis. Laboratory evaluation revealed marked hypercortisolism and elevated plasma ACTH. Imaging demonstrated an expansile ethmoid sinus mass. Inferior petrosal sinus sampling excluded a pituitary source of ACTH. Endoscopic biopsy confirmed Hyams grade 2 ONB with positive immunohistochemical staining for neuroendocrine markers and ACTH. The patient received preoperative cortisol-lowering therapy and underwent complete endoscopic tumor resection followed by adjuvant radiotherapy. Postoperative assessment showed biochemical remission, resolution of Cushingoid features, and eventual recovery of the hypothalamic–pituitary–adrenal axis.
Discussion
This case highlights the importance of a systematic diagnostic approach that includes biochemical testing, imaging, inferior petrosal sinus sampling, and histopathology to identify ectopic ACTH sources. It demonstrates the necessity of collaboration among endocrinology, otolaryngology, neurosurgery, radiology, and oncology teams in managing rare ACTH-secreting tumors.
Conclusion
Timely diagnosis and definitive surgical resection of ACTH-producing ONB, along with endocrine stabilization and adjuvant radiotherapy, can lead to endocrine remission and improved long-term outcomes.
Key words
cushing syndrome
ectopic ACTH syndrome
neuroendocrine tumor
olfactory neuroblastoma
paraneoplastic syndrome
Abbreviations
ACTH
adrenocorticotropic hormone
AM
morning (ante meridiem)
DDAVP
desmopressin acetate
DHEA-S
dehydroepiandrosterone sulfate
EAS
ectopic ACTH syndrome
ENT
otolaryngology
IPSS
inferior petrosal sinus sampling
ONB
olfactory neuroblastoma
UFC
urinary free cortisol
Highlights
•
Rare case of ectopic adrenocorticotropic hormone syndrome secondary to olfactory neuroblastoma
•
Diagnostic challenges highlighted, including nondiagnostic inferior petrosal sinus sampling results
•
Multidisciplinary approach enabled complete tumor resection and hormonal remission
Adjuvant radiotherapy optimized local control in intermediate-risk olfactory neuroblastoma
Clinical Relevance
This case emphasizes the importance of recognizing olfactory neuroblastoma as a rare source of ectopic adrenocorticotropic hormone production. It demonstrates the value of integrated biochemical, radiologic, surgical, and histopathologic strategies to achieve endocrine remission and prevent recurrence.
Introduction
Ectopic ACTH syndrome (EAS) is a rare paraneoplastic disorder resulting in ACTH-dependent hypercortisolism, which manifests clinically as Cushing syndrome. Although it accounts for approximately 10% to 15% of ACTH-dependent cases, EAS is most frequently caused by bronchial carcinoids, small cell lung carcinoma, and pancreatic neuroendocrine tumors.1,2 In contrast, olfactory neuroblastoma (ONB), also known as esthesioneuroblastoma—a neuroendocrine malignancy of the upper nasal cavity—is a highly uncommon cause, with fewer than 1% of ONB cases associated with EAS.2,3
ONB arises from the olfactory epithelium and represents 2% to 3% of all sinonasal cancers.4,5 Its nonspecific presentation—ranging from nasal obstruction to epistaxis or anosmia—can delay diagnosis, and advanced tumors may invade adjacent structures such as the orbit or anterior cranial fossa.4,5 Histological overlap with other small round blue cell tumors necessitates immunohistochemical markers such as synaptophysin, chromogranin A, and S-100 for accurate identification.4,6 Factors such as age may influence tumor behavior, treatment selection, and prognosis.7
When ONB presents with ectopic ACTH secretion, the resulting hypercortisolism can lead to profound metabolic and cardiovascular complications.8,9 Due to its extreme rarity, this combination may not be initially suspected, delaying targeted therapy. This report presents a rare case of ACTH-dependent Cushing syndrome caused by ONB, highlighting the diagnostic complexity and need for multidisciplinary management.3,10
Case Presentation
A 70-year-old male presented with 6 weeks of progressively worsening generalized, proximal muscle weakness, intermittent headaches, recurrent nosebleeds, abdominal fullness, leg swelling, and an unexplained 20-pound (9.1 kg) weight gain.
His medical history includes asthma, benign prostatic hyperplasia, hyperlipidemia, and retained shrapnel in the neck from military service in Vietnam. He has no history of hypertension, diabetes, or smoking. His family history includes a father who suffered a myocardial infarction at 51 years old, a mother with rheumatoid arthritis and osteoporosis, and a maternal uncle with lupus. His current medications include rosuvastatin 5 mg daily, tamsulosin 0.4 mg daily, and an albuterol inhaler as needed.
On examination, his vital signs were notable for an elevated blood pressure of 171/84 mmHg (normal: <120/<80 mmHg), a temperature of 37.2 C (99 F) (normal: 36.1–37.2°C [97–99 F]), a heart rate of 91 bpm (normal: 60–100 bpm), a respiratory rate of 16 breaths per minute (normal: 12–20 breaths per minute), an oxygen saturation of 92% on room air (normal: ≥95%), and a weight of 78.9 kg (174 lb). Physical examination revealed a round plethoric face (“moon facies,”) a prominent dorsocervical fat pad (“buffalo hump,”) supraclavicular fullness, mild abdominal tenderness, violaceous striae across the abdomen, diffuse soft tissue swelling, and bilateral 2+ pitting edema in the lower extremities.
Diagnostic Assessment
Laboratory evaluation demonstrated severe hypokalemia (1.6 mEq/L [1.6 mmol/L]; normal: 3.5–5.0 mEq/L [3.5–5.0 mmol/L]) and marked fasting hyperglycemia (244.0 mg/dL [13.5 mmol/L]; normal: 70–99 mg/dL [3.9–5.5 mmol/L]), in addition to leukocytosis, hypochloremia, acute kidney injury, hypoproteinemia, and hypoalbuminemia.
Hormonal evaluation (Table 1) was consistent with ACTH-dependent hypercortisolism, characterized by elevated serum cortisol and ACTH concentrations, lack of suppression with dexamethasone, and suppressed dehydroepiandrosterone sulfate (DHEA-S). Aldosterone and plasma renin activity were within normal limits, effectively excluding primary hyperaldosteronism. Plasma free metanephrines and normetanephrines were also within reference ranges, ruling out pheochromocytoma. Repeat morning cortisol remained markedly elevated, and late-night salivary cortisol levels on 2 occasions were significantly above the reference range. Twenty-four-hour urinary free cortisol (UFC) was profoundly elevated on both collections. Following a 1 mg overnight dexamethasone suppression test, serum cortisol, ACTH, and dexamethasone levels confirmed a lack of cortisol suppression despite adequate dexamethasone absorption (Table 1). These results were consistent with ACTH-dependent Cushing syndrome.
Table 1. Hormone Panel Results
Test
Value
Normal Range
AM cortisol
29 μg/dL (800.11 nmol/L) (high)
3.7–19.4 μg/dL (102–535 nmol/L)
Repeated AM cortisol
26 μg/dL (717.34 nmol/L) (high)
3.7–19.4 μg/dL (102–535 nmol/L)
ACTH
250 pg/mL (30.03 pmol/L) (high)
10–60 pg/mL (2.2–13.2 pmol/L)
Plasma renin activity
1.2 ng/mL/h (1.2 μg/L/h) (normal)
0.2–4.0 ng/mL/h (0.2–4.0 μg/L/h)
DHEA-S
50 μg/dL (1.25 μmol/L) (low)
65–380 μg/dL (1.75–10.26 μmol/L)
Aldosterone, blood
4. 9 ng/dL (0.14 nmol/L) (normal)
4.0–31.0 ng/dL (110–860 pmol/L)
Plasma free metanephrines
0.34 nmol/L (0.034 μg/L) (normal)
<0.50 nmol/L (<0.09 μg/L)
Plasma free normetanephrines
0.75 nmol/L (0.075 μg/L) (normal)
<0.90 nmol/L (<0.16 μg/L)
Late-night salivary cortisol (1st)
0.27 μg/dL (7.45 nmol/L) (high)
≤0.09 μg/dL (≤2.5 nmol/L) (10 PM–1 AM)
Late-night salivary cortisol (2nd)
0.36 μg/dL (9.93 nmol/L) (high)
≤0.09 μg/dL (≤2.5 nmol/L) (10 PM–1 AM)
24-h urinary free cortisol (1st)
5880.0 μg/d (16 223 nmol/d) (high)
≤60.0 μg/d (≤165 nmol/d)
24-h urinary free cortisol (2nd)
4920.0 μg/d (13 576 nmol/d) (high)
≤60.0 μg/d (≤165 nmol/d)
AM cortisol level (after 1 mg dexamethasone)
12.3 μg/dL (339 nmol/L) (high)
<1.8 μg/dL (<50 nmol/L) adequate suppression
Dexamethasone level(after 1 mg dexamethasone)
336 ng/dL (8.64 nmol/L) (normal)
>200 ng/dL (>5.2 nmol/L) adequate absorption
ACTH level (after 1 mg dexamethasone)
242 pg/mL (53.27 pmol/L) (not suppressed)
10–60 pg/mL (2.2–13.2 pmol/L)
Abbreviations: μg/d = micrograms per day; μg/dL = Micrograms per deciliter; μg/L = micrograms per liter; μmol/L = micromoles per liter; AM = morning (Ante Meridiem); nmol/L = nanomoles per Liter; ng/mL/h = nanograms per milliliter per hour; pmol/L = picomoles per liter; pg/mL = picograms per milliliter; μg/L/h = micrograms per liter per hour; ng/dL = nanograms per deciliter; nmol/d = nanomoles per day.
Inferior petrosal sinus sampling (IPSS) was performed using contrast-enhanced fluoroscopy to confirm accurate catheter placement in both inferior petrosal sinuses. Absolute ACTH values obtained during IPSS are shown in (Table 2). The central-to-peripheral ACTH gradient at baseline was 1.1, which is below the diagnostic threshold of 2.0 typically required to support a pituitary source of ACTH. Following desmopressin acetate (DDAVP) stimulation, peak left: peripheral and right: peripheral ACTH ratios reached 1.7 and 1.5, respectively—well below the accepted post-stimulation cut-off of 3.0. In addition, the left: right petrosal ACTH ratios remained between 1.03 and 1.15 throughout the sampling period, indicating no significant lateralization of ACTH secretion. These findings are not consistent with Cushing’s disease and instead support a diagnosis of ectopic ACTH syndrome.
Table 2. Bilateral Petrosal Sinus and Peripheral Adrenocorticotropin Levels Before and After Intravenous Injection of Desmopressin Acetate (DDAVP) 10 mcg
Time post DDAVP, min
Left petrosal ACTH
Left: peripheral ACTH
Right petrosal ACTH
Right: peripheral ACTH
Peripheral ACTH
Left: right petrosal ACTH
0
165 pg/mL (36.3 pmol/L)
1.1
160 pg/mL (35.2 pmol/L)
1.1
150 pg/mL (33.0 pmol/L)
1.03
3
270 pg/mL (59.4 pmol/L)
1.6
245 pg/mL (53.9 pmol/L)
1.4
170 pg/mL (37.4 pmol/L)
1.10
5
320 pg/mL (70.4 pmol/L)
1.7
285 pg/mL (62.7 pmol/L)
1.5
185 pg/mL (40.7 pmol/L)
1.12
10
350 pg/mL (77.0 pmol/L)
1.4
305 pg/mL (67.2 pmol/L)
1.2
250 pg/mL (55.0 pmol/L)
1.15
Abbreviations: ACTH = adrenocorticotropin; DDAVP = desmopressin acetate; pg/mL = picograms per milliliter; pmol/L = picomoles per liter.
Magnetic resonance imaging of the head could not be performed due to a history of retained shrapnel in the neck from combat in Vietnam. Noncontrast computed tomography (CT) images of the head and paranasal sinuses revealed no evidence of a pituitary tumor but demonstrated an expansile mass measuring approximately 2.4 × 4.3 × 3.3 cm, centered within the bilateral ethmoid sinuses with extension into both the anterior and posterior ethmoidal air cells (Fig. 1A, B). A contrast-enhanced CT scan of the abdomen, performed following improvement in renal function, demonstrated marked bilateral adrenal gland enlargement (Fig. 1C).
Fig. 1. (A) Axial and (B) coronal noncontrast computed tomography (CT) images of the head demonstrate a heterogeneous soft tissue mass at the anterior skull base extending toward the cribriform plate and into the right nasal cavity, involving the ethmoid sinus and eroding the lamina papyracea, resulting in medial displacement of the right orbital contents (blue arrows). (C) Axial contrast-enhanced CT of the abdomen reveals bilateral adrenal gland enlargement. (D) Whole-body single-photon emission computed tomography/computed tomography (SPECT/CT) using indium-111 pentetreotide demonstrates intense radiotracer uptake localized to the biopsy-confirmed esthesioneuroblastoma in the ethmoid sinuses, with no evidence of metastatic octreotide-avid lesions. (G) Coronal contrast-enhanced CT scan of the abdomen, performed after surgery, shows normalization in the size of both adrenal glands. (E) Coronal and (F) axial noncontrast CT images of the paranasal sinuses obtained postoperatively demonstrate complete surgical resection of the tumor.
The otolaryngology (ENT) team was consulted and recommended an endoscopic biopsy of the nasal mass. Histopathologic examination revealed a Hyams Grade 2 olfactory neuroblastoma (Fig. 2A, B), characterized by well-circumscribed lobules of small round blue cells with scant cytoplasm, a neurofibrillary background matrix, and low mitotic activity, without necrosis or rosette formation—findings typical of a moderately differentiated tumor in the Hyams grading system.
Fig. 2. (A) Low-power H&E (4×) shows well-circumscribed lobules of small round blue cells with fibrovascular stroma and a neurofibrillary matrix; no necrosis or rosettes are seen. (B) High-power H&E (40×) reveals neoplastic cells with high nuclear-to-cytoplasmic ratio, hyperchromatic nuclei, and granular chromatin, consistent with Hyams Grade 2 ONB. (C) Chromogranin A shows granular cytoplasmic positivity in tumor nests, confirming neuroendocrine differentiation. (D) Synaptophysin shows diffuse granular cytoplasmic staining in tumor clusters, with negative stromal background. (E) S-100 highlights sustentacular cells in a peripheral pattern around tumor nests. (F) ACTH staining shows patchy to diffuse cytoplasmic positivity in tumor cells, confirming ectopic ACTH production in ONB. A nuclear medicine octreotide scan (111 Indium-pentetreotide scintigraphy) with single-photon emission computed tomography/computed tomography (SPECT/CT) demonstrated intense radiotracer uptake in the biopsy-proven esthesioneuroblastoma centered within the ethmoid sinuses, confirming the tumor’s expression of somatostatin receptors. There was no evidence of locoregional or distant metastatic disease demonstrating octreotide avidity (Fig. 1D).
Immunohistochemical staining supported the diagnosis: tumor cells were positive for chromogranin A (Fig. 2C), synaptophysin (Fig. 2D), and S-100 (Fig. 2E). Chromogranin A and synaptophysin are markers of neuroendocrine differentiation, confirming the tumor’s neuroendocrine origin. S-100 positivity in the sustentacular cells surrounding tumor nests is a classic feature of olfactory neuroblastoma. Staining was negative for neurofilament protein, AE1/AE3, and epithelial membrane antigen, helping exclude other small round blue cell tumors, such as neuroendocrine carcinoma or sinonasal undifferentiated carcinoma. Importantly, the tumor cells showed positive cytoplasmic staining for ACTH (Fig. 2F), confirming ectopic ACTH production by the tumor itself. This finding definitively links the olfactory neuroblastoma as the source of paraneoplastic ACTH secretion, consistent with the patient’s clinical picture of ectopic Cushing’s syndrome.
Treatment
Hypokalemia was corrected, and oral ketoconazole 200 mg twice daily was initiated preoperatively to mitigate the metabolic complications of hypercortisolism. Ketoconazole was discontinued on the day of surgery. The tumor was resected via an endoscopic endonasal approach. A blood sample was obtained immediately following tumor removal for measurement of ACTH and cortisol levels. Intravenous hydrocortisone (100 mg every 6 h) was initiated promptly thereafter. Postoperative cortisol and ACTH levels were undetectable: cortisol <5 μg/dL [<138 nmol/L] (normal: 5–25 μg/dL [138–690 nmol/L]); ACTH <5 pg/mL [<1.1 pmol/L] (normal: 10–60 pg/mL [2.2–13.3 pmol/L]). These findings confirmed successful surgical resection of the ACTH-secreting tumor. These issues extended the hospital stay and required treatment with antiseizure medications, antibiotics, and additional surgeries by ENT and Neurosurgery teams.
Outcome and Follow-Up
The patient demonstrated significant normalization of blood pressure (124/78 mmHg), fasting blood glucose (95 mg/dL [5.3 mmol/L]), and potassium (4.3 mEq/L [4.3 mmol/L]) within 2 weeks postoperatively. ACTH levels decreased from preoperative values of 220–250 pg/mL (48.4–55.2 pmol/L) to 29 pg/mL (5.5 pmol/L), and morning (AM) cortisol levels decreased from preoperative values of 29 μg/dL (800 nmol/L) to 12 μg/dL (331 nmol/L). These values were obtained at 2 weeks postoperatively. While early normalization of ACTH and cortisol levels could raise concern for residual disease, the patient’s subsequent sustained biochemical remission, clinical recovery, and a robust response to cosyntropin stimulation at 3 months post-op were reassuring. Adjuvant radiotherapy was also administered to mitigate any potential risk of recurrence.
He was subsequently transferred to an inpatient rehabilitation facility while receiving oral hydrocortisone replacement therapy, during which his functional status progressively improved. The patient was later discharged home on oral hydrocortisone replacement therapy with plans for continued outpatient physical therapy. Hydrocortisone was gradually tapered and discontinued 3 months after surgery, at which point blood pressure (122/76 mmHg), fasting glucose (90 mg/dL [5.0 mmol/L]), potassium (4.2 mEq/L [4.2 mmol/L]), ACTH (25 pg/mL [4.9 pmol/L]), and AM cortisol (15 μg/dL [414 nmol/L]) demonstrated sustained normalization. Following administration of 250 mcg intramuscular cosyntropin, serum cortisol peaked at 21 μg/dL (580 nmol/L), confirming an adequate adrenal reserve and complete recovery of the hypothalamic–pituitary–adrenal axis. Additionally, late-night salivary cortisol was remeasured on 2 occasions after hydrocortisone discontinuation and found to be 0.04 μg/dL (1.10 nmol/L) and 0.03 μg/dL (0.83 nmol/L), both within normal reference limits (≤0.09 μg/dL [≤2.5 nmol/L]). A 24-hour UFC collected at the same time measured 38 μg/d (105 nmol/d), confirming biochemical resolution of hypercortisolism. Cushing’s stigmata, including muscle weakness and skin changes, showed marked improvement by 3 months postoperatively (Table 3).
Table 3. Timeline of Clinical and Biochemical Recovery Following Resection of Ectopic ACTH-Secreting Olfactory Neuroblastoma
Abbreviations: ACTH = adrenocorticotropin; mmHg = illimeters of mercury; mEq/L = milliequivalents per liter; mg/dL = milligrams per deciliter; mmol/L = millimoles per liter; μg/dL = micrograms per deciliter; AM = morning (Ante Meridiem); pg/mL = picograms per milliliter; pmol/L = picomoles per liter; nmol/L = nanomoles per liter.
dfA follow-up CT scan of the adrenals with contrast, performed following improvement in renal function, confirmed normalization in the size of the previously enlarged adrenal glands (Fig. 1E). A follow-up CT of sinuses without contrast confirmed complete resection of the tumor (Fig. 1F, G).
Adjuvant radiotherapy was recommended in view of the patient’s Kadish stage B tumor, Hyams grade 2 histology, and the elevated risk of local recurrence inherent to olfactory neuroblastoma. Despite complete surgical excision, radiotherapy was pursued to mitigate recurrence risk, particularly considering the tumor’s ectopic ACTH secretion, which suggested biologically aggressive behavior, as well as the patient’s satisfactory functional status and anticipated favorable treatment tolerance. A total of 30 fractions of 2 Gy were administered using volumetric modulated arc therapy.
Discussion
Diagnostic Considerations
EAS poses a significant diagnostic challenge due to its variable presentation and the urgency of identifying the source of ACTH excess. ONB, although rare, should be considered in patients with ACTH-dependent Cushing syndrome who present with sinonasal masses. ONB accounts for only 2% to 3% of all malignant sinonasal tumors,4,6 with fewer than 25 cases documented as sources of ectopic ACTH production.3,11,12
While ectopic ACTH syndrome remains the most well-recognized endocrine manifestation of ONB, a broader spectrum of paraneoplastic syndromes has also been described. These include syndrome of inappropriate antidiuretic hormone secretion, paraneoplastic hypercalcemia—often mediated by parathyroid hormone–related protein—and catecholamine excess mimicking pheochromocytoma.11 These atypical presentations underscore the neuroendocrine complexity of ONB and the diagnostic challenges they pose.
Diagnosis involves biochemical confirmation of hypercortisolism using low-dose dexamethasone suppression, 24-hour UFC, late-night salivary cortisol, and plasma ACTH levels. Interestingly, despite markedly elevated ACTH levels, our patient exhibited a low DHEA-S concentration and a normal aldosterone level. This biochemical pattern supports previous observations that EAS may present with a dissociation in adrenal steroidogenesis. Chronic hypercortisolemia may suppress the zona reticularis,13 while ectopic ACTH-producing tumors may secrete aberrant precursors that preferentially stimulate glucocorticoid rather than androgen synthesis.14 Cortisol excess can also downregulate key enzymes such as 17,20-lyase and SULT2A1, thereby impairing DHEA-S production.15 Moreover, the rapid onset and severity of ectopic ACTH production may preclude the compensatory DHEA-S rise typically observed in pituitary-driven Cushing disease. Although cortisol excess is known to suppress the renin-angiotensin-aldosterone system, aldosterone levels may remain detectable in certain EAS cases, particularly in early-stage or physiologically variable presentations.16
Once ACTH-dependence is established, localization of the tumor becomes essential. IPSS, although considered the gold standard for distinguishing pituitary from ectopic ACTH sources, may yield inconclusive results in cases of ONB due to altered venous drainage pathways.3 Functional imaging with 111In-octreotide single-photon emission computed tomography/computed tomography or 68Ga-DOTATATE positron emission tomography/computed tomography facilitates localization of neuroendocrine tumors that express somatostatin receptors. Histopathologic confirmation using ACTH immunostaining and neuroendocrine markers such as chromogranin A, synaptophysin, and S-100 is essential to confirm diagnosis.
Therapeutic Approach and Challenges
Surgical resection remains the cornerstone of management for ACTH-producing ONB.9 Endoscopic endonasal approaches are preferred when anatomically feasible due to their minimally invasive nature and favorable access to the anterior skull base. Preoperative pharmacologic inhibition of cortisol biosynthesis (utilizing ketoconazole, which was specifically selected for our patient, metyrapone, or etomidate) represents a critical intervention to attenuate hypercortisolism-related metabolic complications and minimize perioperative morbidity.3,8 Intraoperative glucocorticoid replacement should be administered following tumor resection to prevent adrenal insufficiency. Postoperative complications—such as cerebrospinal fluid leak or infection—require prompt multidisciplinary intervention.
Adjuvant radiotherapy is generally recommended for intermediate-to high-grade ONBs, even after gross total resection, given their aggressive behavior and high risk of recurrence. Volumetric modulated arc therapy delivers precise radiation doses while minimizing toxicity to adjacent structures.5,9 Platinum-based chemotherapy remains a therapeutic option in patients with unresectable or metastatic disease.9
Emerging therapeutic strategies include somatostatin receptor–directed theranostics. Zhi et al (2025) recently demonstrated the dual diagnostic and therapeutic potential of 68Ga-DOTATATE positron emission tomography/computed tomography imaging and 177Lu-DOTATATE peptide receptor radionuclide therapy in ONB, offering promising future directions for patients with advanced or somatostatin receptor–positive disease.17
Prognosis and Future Directions
The prognosis of ONB is influenced by Kadish staging, Hyams histologic grading, and treatment strategy. Recurrence rates are reported to range from 30% to 60%,9,18 and 5-year survival rates vary from 45% to 80% depending on tumor grade, stage, and completeness of resection.6,19 Early detection, complete surgical resection, and multimodal therapy, including radiotherapy, are associated with improved outcomes. Lifelong follow-up with serial imaging and endocrine evaluation is essential to monitor for recurrence and late-onset adrenal insufficiency.10,19
Continued advancements in molecular imaging and targeted therapies, particularly those leveraging somatostatin receptor biology, may expand the therapeutic landscape for patients with recurrent or progressive ONB.
Conclusion
This case highlights the importance of timely diagnosis, comprehensive biochemical and radiologic assessment, and coordinated multidisciplinary management in ACTH-producing ONB. In addition to surgery and preoperative endocrine stabilization, adjuvant radiotherapy and long-term surveillance are critical components of care. As somatostatin receptor–based imaging and theranostic therapies evolve, they offer exciting opportunities to individualize treatment in this rare but challenging neuroendocrine malignancy.
Statement of Patient Consent
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
Disclosure
The author has no conflict of interest to disclose.
Dr. Friedman will be joined by Brittany Henderson, MD, ECNU for an exciting GoodHormoneHeath Webinar on Dueling Academic-Based Endocrinologists discussing state-of-the-art hypothyroidism diagnosis and treatment: Commonalities and Differences
Each expert will discuss the following topics:
How is mild hypothyroidism diagnosed?
Why are full thyroid panels and not just TSH needed?
What is the role of rT3?
How to optimally use all types of thyroid hormone including NDT
Why both conventional and alternative providers have it wrong?
They will briefly discuss the proposed ban on desiccated thyroid by the FDA.
We’re looking for caregivers to loved ones diagnosed with Cushing’s Disease or patients diagnosed with Cushing’s Diseaseto participate in a research study.
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Who: Patients and caregivers of loved ones
What: 30-minute Online Survey
Compensation: $60.00
CushieBlog 