A Prospective Trial With Ketoconazole Induction Therapy and Octreotide Maintenance Treatment for Cushing’s Disease

Posted on June 21, 2025 by MaryO

Abstract

Context and Objective

The lack of efficacy of somatostatin receptor subtype 2 (SST2) preferring somatostatin analogs in patients with Cushing’s disease (CD) results from a downregulating effect of hypercortisolism on SST2 expression. Our objective is to evaluate the efficacy of a strategy with sequential treatment of ketoconazole to reduce cortisol levels and potentially restore SST2 expression followed by octreotide as maintenance therapy in patients with CD.

Patients and Design

Fourteen adult patients with CD were prospectively enrolled. Patients started with ketoconazole. Once cortisol levels were normalized, octreotide was initiated. After 2 months of combination therapy, patients were maintained on octreotide monotherapy until the end of the study period (9 months). Treatment success was defined by normalization of urinary free cortisol (UFC) levels.

Results

Ketoconazole was able to normalize UFC levels in 11 (79%) patients. Octreotide effectively sustained normal levels of UFC in 3 patients (27%) (responders). Four patients (36%) showed a partial response. The remaining 4 (36%) patients developed hypercortisolism as soon as ketoconazole was stopped (nonresponders). Octreotide responders had lower UFC levels at baseline when compared to partial responders and nonresponders (1.40 ± 0.07 vs 2.05 ± 0.20 UNL, P = 0.083). SST2 mRNA was highly expressed in adenomas of 2 responder patients (0.803 and 0.216 copies per hprt).

Conclusion

Sequential treatment with ketoconazole to lower cortisol levels followed by octreotide to maintain biochemical remission according to UFC may be effective in a subset of patients with mild CD, suggesting that cortisol-mediated suppression of SST2 expression is a reversible process.

Transsphenoidal adenomectomy is the first-line treatment of Cushing’s disease (CD) [1-3]. Medical therapy can be used as an adjunctive preoperative treatment or in persistent or recurrent disease [2, 4, 5]. Pharmacological treatment of CD can be divided into 3 approaches: pituitary-directed therapy, steroids synthesis inhibitors, and glucocorticoid receptor antagonists [4]. Because of limited efficacy and side effects, a combination of drugs is often necessary to achieve biochemical control [2, 5-8].

Steroid synthesis inhibitors are often used as a first-line medical treatment modality. Ketoconazole and metyrapone can normalize cortisol production in about 50% to 60% of patients, whereas the recently introduced steroidogenic enzyme inhibitor osilodrostat has an efficacy of up to 80% [9-11]. Pharmacotherapy targeting the corticotroph tumor itself may be a more rational approach since it exerts effects at the cause of the disease [2, 5, 12]. The most commonly used drugs in this category are cabergoline, a dopamine agonist, and pasireotide, a second-generation somatostatin analog [2, 3, 13]. Cabergoline inhibits ACTH secretion through agonism of the dopamine type 2 receptor, expressed in the majority of corticotroph tumors [14, 15]. However, cabergoline is able to normalize the cortisol secretion in less than half the patients, and a substantial number of patients escape from treatment [4, 8, 16, 17]. Several small studies show promising effects of cabergoline combined with ketoconazole [7, 8]. Pasireotide exhibits high-affinity binding to somatostatin receptor subtype (SST) 5, which is the SST expressed at the highest level in corticotroph pituitary adenomas. Pasireotide shows moderate efficacy in normalizing cortisol levels in a subset of patients with mild to moderate hypercortisolism, with hyperglycemia as an important side effect [13, 18, 19].

Octreotide, a somatostatin analog with high binding affinity to SST2, was shown to lower ACTH production in patients with corticotroph tumor progression following bilateral adrenalectomy but was unsuccessful in patients with active CD [20, 21]. Table 1 provides an overview of the clinical studies using octreotide in CD. Tumoral pituitary corticotroph cells express about 5 to 10 times higher SST5 compared to SST2, which may explain the reduced efficacy of octreotide compared to pasireotide in inhibiting ACTH secretion in primary cultures of human corticotroph tumors as well as in vivo [13, 28]. This is explained by selective suppressive effects of high cortisol concentrations in active CD on SST2 expression, resulting in an absent treatment response to octreotide [13, 29, 30]. Hence, it may be hypothesized that normalizing or lowering cortisol levels in patients with CD can result in a reciprocal increase in SST2 expression by corticotroph tumor cells. Under such conditions, the use of octreotide could play a potential role in CD management based on its safer toxicity profile compared to pasireotide [31].

 
Table 1.

Literature review: octreotide treatment in patients with Cushing’s disease

Study n Maximal octreotide dose Response criteria Full response Partial response No response Maximal treatment duration
Invitti et al, 1990 [22] 3 1200 µg/day UFC 1 2 49 days
Lamberts et al, 1989 [20] 3 100 µg (single injection) Serum cortisol 3 Trial 12 hours
Arregger et al, 2012 [21] 2 Oct-lar (20 mg/month) UFC 2 4 months
Woodhouse et al, 1993 [23] 4 100-500 µg (every 8 hours) Serum cortisol 4 Trial 24-72 hours
El-Shafie et al, 2015 [24] 6 100 µg (every 8 hours) Serum cortisol 6 Trial 72 hours
Ambrosi et al, 1990 [25] 4 100 µg (single injection) Serum cortisol 4 Trial 7 hours (CRH stimulus)
Stalla et al, 1994 [26] 5 100 µg (30 and 180 minutes) serum cortisol 5 Trial 400 minutes (CRH stimulus)
Vignati et al, 1996 [27] 3 100 µg (single injection)/300 µg/day Serum cortisol/UFC 1 2 Trial 8 hours/75 days
Total 30 0 2 (7%) 28

Abbreviation: Oct-lar, long acting repeatable octreotide; UFC, urinary free cortisol.

We previously demonstrated that in corticotroph adenomas obtained from CD patients who were in biochemical remission before surgery, induced by medical treatment, SST2 mRNA expression was significantly higher compared to corticotroph tumor tissue from patients with hypercortisolism at the time of operation [32]. In fact, SST2 mRNA levels in adenomas from these normocortisolemic patients were comparable to those of GH-producing adenomas, which are usually responsive to SST2-preferring somatostatin analogs [32]. In this pilot study, we, therefore, aim to evaluate the clinical efficacy of a sequential regimen with ketoconazole induction therapy to reduce cortisol levels in CD and potentially restore SST2 expression at the level of the corticotroph adenoma, followed by octreotide treatment to reduce ACTH secretion.

Methods

Study Population

Adult patients with recently diagnosed treatment-naïve CD or with persistent or recurrent hypercortisolism after transsphenoidal surgery were eligible for enrollment. Patients already on medical treatment for CD were included only after a drug washout period of 4 weeks and following confirmation of hypercortisolism. Exclusion criteria included elevated liver enzymes, renal insufficiency, history of pituitary radiotherapy, symptomatic cholelithiasis, and pregnancy.

The study protocol was approved by the ethical committees of the participating centers. All patients gave their written informed consent. The trial was registered by the Dutch Trial Register (nr. NL37105.078.11).

Diagnostic Workup of CD

Upon clinical evidence of CD, the diagnosis was biochemically established by elevated 24-h urinary free cortisol (UFC) concentrations (3 samples), failure in suppressing plasma cortisol after 1 mg of dexamethasone, and increased midnight saliva cortisol levels. ACTH dependency was defined on the basis of normal to high ACTH plasma levels. Additionally, plasma cortisol diurnal rhythm was assessed with measurement at 9 Am, 5 Pm, 10 Pm, and midnight. Once a diagnosis of ACTH-dependent hypercortisolism was confirmed, magnetic resonance imaging was performed to detect a pituitary tumor. In the absence of a lesion, or a lesion of less than 6 mm, bilateral inferior petrosal sinus sampling was performed to confirm central ACTH overproduction.

Drug Regimen Protocol

After inclusion, patients were followed monthly for up to 9 months. All patients started with ketoconazole; the initial dose depended on the severity of hypercortisolism, with 600 mg per day for mild hypercortisolism [UFC ≤ 1.5 times the upper limit of normal (ULN)] and 800 mg per day for a higher level of hypercortisolism (UFC >1.5 times the ULN). (Fig. 1). If necessary, the dose of ketoconazole could be uptitrated to 1200 mg per day after 2 months to achieve biochemical remission according to UFC excretion. Once UFC levels were normalized, long acting repeatable (LAR) octreotide treatment was initiated at a dose of 20 mg every 4 weeks. If UFC concentrations remained normal after 2 months of combined therapy (ketoconazole plus octreotide), ketoconazole was discontinued and patients were maintained on octreotide monotherapy until the end of the study period. If the UFC level (mean of 2 samples) was increased above the ULN, the octreotide dose was increased from 20 to 30 mg every 4 weeks. This may have occurred earlier, while octreotide was still combined with ketoconazole, or later, on octreotide monotherapy.

 

Study protocol. If UFC excretion (mean of 2 collections) increases again (above the ULN) under octreotide/ketoconazole combination therapy or octreotide monotherapy (20 mg every 4 weeks), the octreotide dosage will be increased to 30 mg every 4 weeks.

Figure 1.

Study protocol. If UFC excretion (mean of 2 collections) increases again (above the ULN) under octreotide/ketoconazole combination therapy or octreotide monotherapy (20 mg every 4 weeks), the octreotide dosage will be increased to 30 mg every 4 weeks.

Abbreviations: CAB, cabergoline; UFC, urinary free cortisol.; ULN, upper limit of normal.

Response to octreotide was defined as the maintenance of normal UFC levels after ketoconazole discontinuation until the end of the study period, while partial response was defined as normal UFC levels maintained for at least 1 month after ketoconazole discontinuation and/or a >50% decrease of UFC levels at the last follow-up visit compared to the baseline value. Lack of response to octreotide was defined by the inability of octreotide to maintain normal UFC levels after discontinuation of ketoconazole. In this respect, a persistently elevated UFC concentration for 2 consecutive months was considered as treatment failure, after which the study protocol was terminated earlier, before the study period of 9 months. In case of biochemical remission, octreotide monotherapy was maintained until the end of the study period of 9 months, after which octreotide could be continued or replaced by another treatment modality.

In case ketoconazole therapy for 3 months failed to control cortisol production, a different treatment regimen was introduced. Cabergoline instead of octreotide was added to ketoconazole in an attempt to achieve biochemical control. Cabergoline, starting at 0.5 mg every other day, was gradually increased up to 1 and eventually 2 mg every other day, as needed, and ketoconazole was gradually reduced from 1200 to 400 mg per day within 4 weeks. If successful, this combination treatment (ketoconazole and cabergoline) was maintained until the end of the study period.

Side-effects Monitoring

Between the visits, patients were contacted by telephone for monitoring of adverse events. At each visit, laboratory evaluation was performed of pituitary function, hematology, blood chemistry, liver enzymes and renal function, hemoglobin A1c, glucose, and insulin levels.

During treatment with ketoconazole, concentrations of liver enzymes (aspartate transaminase, alanine transaminase, alkaline phosphatase, and gamma glutamyl transferase) were regularly measured. In case of an increase in liver enzymes (>4x ULN), the ketoconazole dose was decreased by 50%. If dose reduction did not lead to normalization of liver enzyme concentrations, ketoconazole was stopped with termination of the study. If relative adrenal insufficiency developed with steroid withdrawal complaints, the cortisol-lowering medication was stopped and eventually restarted at a lower dose. In case of absolute adrenal insufficiency hydrocortisone replacement therapy was started in addition to interruption of study medication. Electrocardiography was performed at baseline and at follow-up visits.

Assessment of Treatment Efficacy

Twenty-four-hour urinary cortisol excretion (2 collections) was measured at each monthly visit. Plasma cortisol diurnal rhythm (CDR) was assessed at baseline and at 3, 6, and 9 months. Recovery of CDR was defined by a serum cortisol concentration at midnight of less than 67% of that at 0900 hours (Pm/am ratio >0.67) [33]. Biochemical remission was defined as normalization of UFC concentrations, ie, the mean of 2 collections below the ULN.

Assessment of Clinical Parameters

Physical examination including measurement of blood pressure, heart rate, weight, height, body mass index, and waist circumference was performed at baseline and assessed monthly. Additionally, a routine laboratory examination, including full blood count, electrolytes, creatinine, blood urea nitrogen, liver enzymes, lipase, amylase, bilirubin, glucose, insulin, and glycosylated hemoglobin, was conducted at each visit.

Quantitative PCR

Eleven patients underwent surgery after the study period. In 4 patients, sufficient corticotroph pituitary adenoma tissue was available to assess SST2 mRNA expression. To assess the purity of the samples, GH mRNA relative to pro-opiomelanocortin (POMC) mRNA was calculated. Only samples with a GH/POMC ratio less than 10% for normal pituitary tissue were used in this analysis [34].

Quantitative PCR was performed following a protocol as previously described [35]. Briefly, poly A+ mRNA was isolated from corticotroph adenoma cells using oligo (dT)25 dynabeads (Invitrogen, Breda, The Netherlands). Subsequently, 23 µL H2O was added for elution, and 10 µL of poly A mRNA was used to synthesize cDNA using a commercial RevertAid First Strand cDNA synthesis kit (Thermo Scientific, Breda, The Netherlands). The assay for RT-qPCR was performed using Taqman Universal PCR mastermix (Applied Biosystems, Breda, The Netherlands) supplemented with sst2 forward and reverse primers and probes. (Supplementary Table S1) [36]. The expression of SST2 mRNA was determined relative to the hypoxanthine phosphoribosyltransferase (HPRT) housekeeping gene.

Immunohistochemistry

From 4 patients, representative adenoma tissue was available for immunohistochemistry (IHC). IHC was performed on 4-µm thick whole slide sections from formalin-fixed paraffin-embedded tissue blocks, on a validated and accredited automated slide stainer (Benchmark ULTRA System, VENTANA Medical Systems, Tucson, AZ, USA) according to the manufacturer’s instructions. Briefly, following deparaffinization and heat-induced antigen retrieval, the tissue samples were incubated with rabbit anti-SST2A antibody (Biotrend; NB-49-015-1ML, dilution 1:25) for 32 minutes at 37°C, followed by Optiview detection (#760-500 and #760-700, Ventana). Counterstain was done by hematoxylin II for 12 minutes and a blue coloring reagent for 8 minutes. Each tissue slide contained a fragment of formalin-fixed paraffin-embedded pancreatic tissue as an on-slide positive control. A semiquantitative immunoreactivity scoring system (IRS) was used by 2 independent investigators to assess SST2 immunostaining. IRS is based on 2 scales: first, the fraction of positive-stained cells > 80%, 51% to 80%, 10% to 50%, <10% and 0 and second, the intensity of immunostaining as strong, moderate, weak, and negative. The product of these 2 factors was used to calculate the IRS final score (range from 0 to 12) [37].

Statistical Analysis

Given the proof-of-concept nature of the present study, no formal statistical power and sample size calculations were performed. Patients were grouped according to the level of response to treatment in responders, partial responders, and nonresponders. For statistical comparisons, partial responders and nonresponders were grouped together and compared to responders.

Continuous variables are expressed as mean ± SEM. Categorical variables are expressed as counts and percentages. For comparisons between groups, Student’s t-test was used. For paired comparisons (baseline vs follow-up), paired t-test was used. Statistical significance was set at P < .05. GraphPad Prism version 5.01 was used for statistical analysis.

Results

Study Population

Sixteen patients with CD were prospectively enrolled, of whom 14 started the study protocol. One patient withdrew at baseline, and 1 patient was excluded because of pseudo-Cushing’s syndrome due to a psychiatric disorder. The mean age was 48.6 years; 64% (n = 9) were female; 86% (n = 12) were newly diagnosed and naïve in treatment; and 71% (n = 10) presented with mild hypercortisolism, defined as a UFC level <2 times the ULN, at baseline. The average treatment duration in this study was 6 months. Hypertension was the most common comorbidity (93%), followed by diabetes mellitus (50%) and dyslipidemia (43%). The majority of patients (79%, n = 11) exhibited a flattened cortisol rhythm with persistently high levels of plasma cortisol throughout the day (Table 2).

 
Table 2.

Baseline demographic and clinical characteristics of the study population

Characteristics Population (n = 14)
Female sex, no. (%) 9 (64.28)
Age at study, mean (median), years 48.64 (48)
Status of CD, no. (%)
 Newly diagnosed 12 (86)
 Persistent 1 (7.1)
 Recurrent 1 (7.1)
UFC level, times ULN, mean (median) 1.84 (1.76)
ACTH, mean, pg/mL 10.23 ± 6.8
Severity of CD, no. (%)a
 Mild 10 (71.42)
 Moderate 4 (28.57)
 Severe 0 (0)
Disturbed circadian diurnal rhythm, no. (%)b 11 (78.6)
Months of study completed, mean (median) 6.43 (7)
MRI, no. (%)
 Nonvisible adenomas 3 (21)
 Microadenomas 9 (64)
 Macroadenomas 2 (14)
Comorbidities, no. (%)
 Diabetes 7 (50)
 Hypertension 13 (92.85)
 Heart/vascular disease 3 (21.42)
 Dyslipidemia 6 (42.85)
 Obesity 5 (35.71)

Abbreviations: CD, Cushing’s disease; MRI, magnetic resonance imaging; UFC, urinary free cortisol; ULN, upper limit of normal.

aMild hypercortisolism was defined as UFC level less than 2 times the ULN, moderate hypercortisolism as UFC level between 2 and 5 times the ULN, and severe hypercortisolism as UFC level above 5 times the ULN.

bDisturbed circadian diurnal rhythm was defined as serum cortisol concentration at 2400 hours/serum cortisol concentration at 0900 hours (Pm/am ratio) above 0.67 [33].

Ketoconazole Treatment

All patients started treatment with ketoconazole monotherapy at a dose of 600 to 800 mg per day depending on baseline UFC level. In 11 patients (79%), normal values of UFC were achieved after 1 or 2 months of treatment. One patient developed symptoms of hypocortisolism with nausea, vomiting, and dizziness. Ketoconazole was discontinued and restarted a week later with a lower dose (200 mg/day), also resulting in normal UFC levels. Another patient discontinued the treatment in the first week because of clinical intolerance. A transient increase in liver enzymes was observed in 5 patients (39%), but no patient had to stop the study protocol because of liver toxicity. Most patients who achieved normal values of UFC (n = 11 out of 14; 79%) lost weight (mean weight loss = 7 ± 4.6 kg) during ketoconazole treatment. No abnormalities were found on electrocardiography during treatment with ketoconazole and octreotide mono- or combination therapy.

According to the study protocol, octreotide (20 mg every 28 days) was added to ketoconazole in the 11 patients who achieved normal cortisoluria. With the combination treatment, 9 patients (82%) sustained normal UFC levels. In 2 patients with recurrent hypercortisolism, increasing the dose of octreotide from 20 to 30 mg/4 weeks normalized UFC levels. Ketoconazole treatment was then stopped, and all patients continued octreotide (20 or 30 mg per month) monotherapy.

Octreotide Treatment

Octreotide monotherapy maintained normal levels of UFC in 3 patients (27%) (responders, Fig 2A). Four (36%) other patients showed a partial response to octreotide (Fig. 2B shows the responses in the individual patients). In 3 of these patients, normal UFC levels were sustained for 1 or 2 months following discontinuation of ketoconazole, and in the other partial responder, the UFC levels at the last follow-up visit had decreased by 57% compared to the baseline levels. The remaining 4 patients developed hypercortisolism as soon as ketoconazole was stopped (nonresponders, Fig. 2C). Responders to octreotide monotherapy had lower UFC levels at baseline when compared to partial responders and nonresponders, with a trend to statistical significance (P = .083) (Table 3). No differences were observed between the 2 groups (responders vs partial responders and nonresponders) related to age, sex, number of comorbidities, and baseline and follow-up cortisol diurnal rhythm (Table 3).

 

Levels of UFC under sequential KTC and Octr treatment. (A) Octr responders (n = 3, patients 7, 8, 13). All patients started treatment with KTC monotherapy at a dose of 600 mg per day. Subsequently, Octr (20 mg every 28 days) was added to the treatment regimen. After 2 months of combined therapy, KTC was discontinued. In 2 cases, this led to a gradual increase in UFC levels requiring a higher dose of Octr (30 mg/month). All 3 patients then remained in remission under Octr monotherapy. (B) Octr partial responders (n = 4, patients 5, 10, 14, and 16). The patients followed different treatment schedules. Patient 5 started with KTC monotherapy followed by 1 month of combined treatment (KTC + Octr) and subsequent Octr monotherapy. Under Octr treatment, the patient was in remission for 2 months. Patient 10 started with KTC monotherapy, followed by 3 months of combined treatment (KTC + Octr) because of an escape of the treatment requiring an increase in the dose of Octr from 20 to 30 mg/month and subsequently went on Octr 30 mg/month monotherapy. Under Octr treatment, the patient was in remission for 2 months. Patient 14 started with KTC monotherapy, achieving remission of the disease in the second month, followed by 2 months of combined treatment (KTC + Octr) and subsequent Octr monotherapy. Under Octr treatment, the patient was in remission for 1 month. The last patient (no. 16) started with KTC monotherapy, achieving a normal cortisol level, followed by combined treatment and subsequent Octr monotherapy. UFC levels at follow-up had decreased by 57% compared to baseline. (C) Octr nonresponders (n = 4, patients 2, 4, 12, and 15). All patients started treatment with KTC monotherapy at a dose of 600 to 800 mg per day. Subsequently, Octr was added to the treatment for 2 months. KTC was discontinued in the third month, which led to a gradual increase in UFC levels. Despite the increased dose of Octr (30 mg/month), all patients failed to maintain disease remission. Data represent mean ± SEM.

Figure 2.

Levels of UFC under sequential KTC and Octr treatment. (A) Octr responders (n = 3, patients 7, 8, 13). All patients started treatment with KTC monotherapy at a dose of 600 mg per day. Subsequently, Octr (20 mg every 28 days) was added to the treatment regimen. After 2 months of combined therapy, KTC was discontinued. In 2 cases, this led to a gradual increase in UFC levels requiring a higher dose of Octr (30 mg/month). All 3 patients then remained in remission under Octr monotherapy. (B) Octr partial responders (n = 4, patients 5, 10, 14, and 16). The patients followed different treatment schedules. Patient 5 started with KTC monotherapy followed by 1 month of combined treatment (KTC + Octr) and subsequent Octr monotherapy. Under Octr treatment, the patient was in remission for 2 months. Patient 10 started with KTC monotherapy, followed by 3 months of combined treatment (KTC + Octr) because of an escape of the treatment requiring an increase in the dose of Octr from 20 to 30 mg/month and subsequently went on Octr 30 mg/month monotherapy. Under Octr treatment, the patient was in remission for 2 months. Patient 14 started with KTC monotherapy, achieving remission of the disease in the second month, followed by 2 months of combined treatment (KTC + Octr) and subsequent Octr monotherapy. Under Octr treatment, the patient was in remission for 1 month. The last patient (no. 16) started with KTC monotherapy, achieving a normal cortisol level, followed by combined treatment and subsequent Octr monotherapy. UFC levels at follow-up had decreased by 57% compared to baseline. (C) Octr nonresponders (n = 4, patients 2, 4, 12, and 15). All patients started treatment with KTC monotherapy at a dose of 600 to 800 mg per day. Subsequently, Octr was added to the treatment for 2 months. KTC was discontinued in the third month, which led to a gradual increase in UFC levels. Despite the increased dose of Octr (30 mg/month), all patients failed to maintain disease remission. Data represent mean ± SEM.

Abbreviations: KTC, ketoconazole; Octr, octreotide; UFC, urinary free cortisol (24 hours).

 
Table 3.

Clinical characteristics of responder compared to partial/nonresponder patients

Characteristics Responders Partial/nonresponders P-value
No. of patients 3 8
Age (years) (mean ± SEM) 39.67 ± 6.88 52 ± 4.30 .163
Number of comborbidities (mean ± SEM) 2.33 ± 0.33 2.38 ± 0.57 .967
Initial UFC (mean ± SEM) 1.40 ± 0.07 2.05 ± 0.20 .083
Baseline CDR, Pm/am ratio (mean ± SEM) 0.85 ± 0.14 0.91 ± 0.10 .752
Follow-up CDR, Pm/am ratio (mean ± SEM) 0.61 ± 0.17 0.81 ± 0.11 .43

Abbreviations: CDR, circadian diurnal rhythm; UFC, urinary free cortisol.

Responders

Individual patient numbers in brackets refer to the patient numbers in Figs. 2 and 3 and Supplementary Table S1 [36]. In 2 (patients 8 and 13) of the 3 responders, UFC levels gradually increased after discontinuation of ketoconazole treatment, requiring an increase in the octreotide dose from 20 to 30 mg that ultimately induced sustained normalization of UFC levels (Fig. 2A). Overall, among responders, the mean UFC levels at baseline was 1.40 ± 0.07 times the ULN and 0.62 ± 0.19 times the ULN at follow-up at the end of the study period (P = .09). Regarding the CDR, 2 patients (no. 7 and 13) at baseline exhibited disturbed CDR, and in 1 patient (no. 8), it was slightly altered. Full recovery of the CDR at follow-up was observed in 2 patients (no. 7 and 8), including the 1 (no. 8) with discrete alteration, while in another (patient 13), there was a partial recovery. On average, patients exhibited a numerically lower cortisol Pm/am ratio at follow-up as compared to baseline (baseline Pm/am ratios 0.86 ± 0.14 and 0.62 ± 0.09 at follow-up, P = .15). In terms of clinical features of CD, 2 (no. 7 and 13) of the 3 patients showed improvement in weight, waist circumference, and systolic and diastolic blood pressure during the treatment period, with the remaining patient (no. 8) showing a worsening of these parameters (Supplementary Table S2) [36].

 

mRNA expression level of SST2 in corticotroph tumors. SST2 mRNA expression in responder (n = 2), partial responder (n = 1), and nonresponder (n = 1). SST2 mRNA expression level in somatotroph tumors (filled bar) was included for comparison (n = 10; ratio over HPRT, mean ± SEM: 0.27 ± 0.08), as published previously by our group using a similar protocol [32].

Figure 3.

mRNA expression level of SST2 in corticotroph tumors. SST2 mRNA expression in responder (n = 2), partial responder (n = 1), and nonresponder (n = 1). SST2 mRNA expression level in somatotroph tumors (filled bar) was included for comparison (n = 10; ratio over HPRT, mean ± SEM: 0.27 ± 0.08), as published previously by our group using a similar protocol [32].

Abbreviations: HPRT, hypoxanthine phosphoribosyltransferase; non-resp, nonresponder; partial resp, partial responder; pt, patient.

Partial Responders

Among the 4 patients (patients 5, 10, 14, and 16) with a partial response to octreotide monotherapy, UFC levels were sustained for 1 to 2 months in 3 patients with a gradual increase after ketoconazole discontinuation (Fig. 2B). In another patient, UFC levels at follow-up had decreased by at least 50% compared to baseline, albeit still at abnormal levels (Fig. 2B, patient 16). For all 4 patients, the mean UFC at baseline was 2.32 ± 0.33 and 2.18 ± 0.34 times the ULN at follow-up at the end of the study period (P = .83). No significant change in CDR was observed, with a plasma cortisol Pm/am ratio of 0.99 ± 0.14 at baseline compared to 0.94 ± 0.07 at follow-up. Three out of 4 partial responders (patients 5, 14, and 16) showed improvement in weight and waist circumference at follow-up. Blood pressure control improved in 2 patients (no. 14 and 16). In 1 patient (no. 5), blood pressure was normal at baseline and remained unchanged throughout the study period. One partial responder (patient 10) showed worsening of all these clinical parameters (Supplementary Table S2) [36].

Nonresponders

In the nonresponder group, UFC increased in all 4 patients (no. 2, 4, 12, and 15) immediately after ketoconazole discontinuation despite increased doses of octreotide up to 30 mg/month (Fig. 2C). In 3 (patients 2, 4, and 15) out of 4 nonresponders, UFC levels were unchanged during follow-up compared to baseline. In 1 patient (no. 12), the UFC level at follow-up was doubled compared to baseline. The cortisol Pm/am ratio did not improve during treatment (P = .20). Three (patients 2, 4, and 12) of 4 nonresponders lost weight at follow-up. Blood pressure remained unchanged in all 4 patients (Supplementary Table S2) [36].

Ketoconazole-Cabergoline Combination Treatment

Finally, in 2 patients with baseline UFC levels of 2.31 and 1.55 ULN, hypercortisolism could not be controlled with ketoconazole monotherapy. The addition of cabergoline did not result in a normalization of UFC. Patients remained uncontrolled during the study period, and an alternative treatment modality was implemented.

In Vitro Studies

Corticotroph tumor tissue was available for the assessment of SST2 mRNA in 4 patients: 2 responders (patients 8 and 13), 1 partial responder (patient 5), and 1 nonresponder (patient 15) (Fig. 3) who underwent transsphenoidal surgery after the trial. Of these, all but 1 patient had normalized UFC levels before surgery. The nonresponder (patient 15) had slightly elevated UFC (1.22 times the ULN). SST2 mRNA expression was highest in the tissue of the 2 responder patients (patient 8, relative expression 0.803 and patient 13, 0.216 normalized to hprt). It is important to highlight that these SST2 mRNA expression values (0.803 and 0.216) were comparable to SST2 expression in GH-secreting tumors (mean of 0.27 ± 0.30, normalized to hprt, n = 10) as we have previously published [32]. Corticotroph tumor tissue of the partial responder (patient 5) also expressed SST2, albeit at a lower level than the 2 responder patients (0.146 normalized to hprt). SST2 expression was low in corticotroph tumor tissue of the nonresponder (0.08 normalized to hprt).

Paraffin-embedded tissue was available for IHC in 4 patients, of which 1 was a responder (patient 7), 2 were partial responders (patients 5 and 10), and 1 was a nonresponder (patient 15). Both mRNA and protein expression were available and assessed for 2 patients who were a partial responder (patient 5) and a nonresponder (patient 15). Before surgery, UFC levels were slightly elevated in 1 partial responder (patient 10) and the nonresponder (patient 15; UFC 1.17 and 1.22 times the ULN, respectively) but normal in the other patients. The IRS for SST2 was higher in the responder compared to the nonresponder patient (IRS 4 and 0, respectively) (Fig. 4). One partial responder (patient 5) had a high IRS for SST2 (IRS 8) with more than 80% of the adenoma cells staining positive for SST2. The second partial responder (patient 10) had no adenoma cells staining positive for SST2 (IRS 0). This patient had slightly elevated UFC levels prior to surgery (described earlier).

 

Representative immunohistochemistry of SST2 in corticotroph tumors. Representative photomicrographs of SST2 immunohistochemical staining in formalin-fixed paraffin-embedded tissue sections of 4 corticotroph adenomas of patients included in this study. (A) Adenoma patient 7 (responder) (IRS 4); (B) adenoma patient 5 (partial responder) (IRS 8); (C) adenoma patient 10 (partial responder) (IRS 0); (D) adenoma patient 15 (nonresponder) (IRS 0). (E) Positive control SST2 staining in human pancreatic islets. In most corticotroph adenomas, small blood vessels were SST2 positive (see arrows in panel D).

Figure 4.

Representative immunohistochemistry of SST2 in corticotroph tumors. Representative photomicrographs of SST2 immunohistochemical staining in formalin-fixed paraffin-embedded tissue sections of 4 corticotroph adenomas of patients included in this study. (A) Adenoma patient 7 (responder) (IRS 4); (B) adenoma patient 5 (partial responder) (IRS 8); (C) adenoma patient 10 (partial responder) (IRS 0); (D) adenoma patient 15 (nonresponder) (IRS 0). (E) Positive control SST2 staining in human pancreatic islets. In most corticotroph adenomas, small blood vessels were SST2 positive (see arrows in panel D).

Abbreviation: IRS, immunoreactivity scoring system.

Discussion

Selective downregulation of SST2 expression in corticotroph tumor cells by high cortisol levels is thought to impair the efficacy of SST2 preferring somatostatin analogs in the treatment of CD [29, 30]. The transcriptional regulation of SST2 is modulated by glucocorticoids (GC), as it was demonstrated that GC inhibits SST2 promoter activity through GC-responsive elements, resulting in a decrease in SST2 expression [29]. Because this process may be reversible, we examined in a prospective pilot study whether lowering cortisol production with ketoconazole can enhance inhibition of ACTH secretion via subsequent treatment with octreotide in patients with CD. The existing literature of clinical studies using octreotide in CD consisted of case reports (Table 1). This is the first prospective study to evaluate the clinical efficacy of octreotide in CD. Our data may indicate that the sequential strategy treatment with ketoconazole and octreotide can induce sustained biochemical remission in a subset of patients with mild CD.

Several in vivo and in vitro studies provide evidence that SST2 expression in corticotroph tumor cells can recover after suppression of cortisol production or antagonizing cortisol action [27, 33, 38, 39]. As mentioned, we previously demonstrated that SST2 expression is higher in corticotroph tumors of patients operated under controlled cortisol production compared to those of patients with hypercortisolism at the time of operation [32]. However, SST2 expression was only significantly higher at the mRNA level but not at the protein level. Evidence that SST2 expression can also increase at the protein level was provided by case descriptions of 2 patients with ectopic ACTH syndrome [38]. In both patients, the source of ectopic ACTH production was initially occult with negative somatostatin receptor scintigraphy. However, after treatment with mifepristone, antagonizing the effects of cortisol at a tissue level, somatostatin receptor scintigraphy could identify a neuroendocrine lung tumor in both patients, indicating SST2 protein expression. This was recently confirmed by similar observations in 2 patients with an ACTH-producing neuroendocrine lung tumor [39]. In addition, in vitro studies with the selective GC receptor antagonist relacorilant demonstrated the reversal of GC-induced downregulation of SST2 expression in the AtT20 corticotroph tumor cell line [39]. Finally, indirect evidence comes from an older preliminary study in which a further decrease in UFC levels was observed in 4 ketoconazole-treated patients after the addition of octreotide. The ketoconazole dose could subsequently be reduced in 3 patients [27].

The sequential treatment with ketoconazole and octreotide in the present study led to a partial or complete response in 7 out of 11 patients, with 3 of them exhibiting sustained biochemical remission throughout the follow-up period. At the first stage, ketoconazole monotherapy led to normal UFC levels in 79% of the cases. This efficacy is higher compared to previous studies that reported an efficacy of approximately 50% to 60% and can be explained by the fact that the majority of patients had mild hypercortisolism [11, 40-43]. Additionally, the clinical benefit of controlling cortisol secretion was evident with the observed weight loss in most responders to ketoconazole.

Subsequently, the combined therapy (ketoconazole and octreotide) was able to maintain biochemical remission according to UFC levels. No additive effect was observed with add-on treatment during a period of 2 months of combined ketoconazole-octreotide therapy. Following this stage, ketoconazole was stopped, and treatment was continued with octreotide monotherapy that was able to maintain normal UFC levels in 3 (27%) patients. Since the majority of reported cases using octreotide for CD treatment showed failure to induce biochemical remission, as summarized in Table 1, these results suggest that, in a subset of patients, ketoconazole-induced biochemical remission may have indeed led to upregulation of SST2 with subsequent effectiveness of octreotide.

This is supported by the observed dose dependency in the response to octreotide in both the ketoconazole-octreotide combination phase and the octreotide monotherapy phase. In 2 patients treated with ketoconazole and octreotide, UFC levels increased above the ULN after initial normalization but returned to normal values after a dose increase of octreotide. In 2 of the 3 responders to octreotide monotherapy, an increased dose of octreotide was required, and effective, after an initial increase in UFC levels was observed following ketoconazole discontinuation. Of note, given the size of the present study, a starting dose of octreotide cannot be defined based on our data. A previous study showed that ketoconazole can inhibit ACTH secretion in rat corticotroph cells in vitro; therefore, central effects of ketoconazole in vivo cannot be fully excluded [44]. However, sustained normal UFC levels under octreotide monotherapy in 1 responder patient and the dose-dependent response to octreotide in 2 other responders suggest that a central residual effect of ketoconazole is unlikely to explain the response to octreotide.

Interestingly, among the 3 patients considered as responders based on the UFC levels, clinical improvement was observed in 2 patients in terms of weight loss, waist circumference, and blood pressure control. Notably, the small sample size and limited follow-up reduce our ability to assess the long-term clinical impact of the ketoconazole-octreotide sequential strategy.

A common feature of the 3 patients in whom the strategy was most effective is that they had mildly elevated UFC levels at baseline as compared to patients in whom the strategy failed. This is similar to what was observed in studies with another somatostatin analog, pasireotide, which has been shown to be more effective in patients with less severe hypercortisolism [18, 19]. It is important to acknowledge that octreotide has a safer side-effect profile as compared to pasireotide, which is known to induce or worsen hyperglycemia via inhibition of incretin release. Octreotide could, therefore, be a potentially interesting option to maintain remission in (mild) CD after induction therapy with a steroid synthesis inhibitor [31].

When analyzing the 4 nonresponders and 4 partial responders in the trial, in whom, despite ketoconazole effectively reducing cortisol secretion, octreotide monotherapy was unable to maintain normocortisolism, the reasons for a failed response remain speculative. It is possible that because of more severe baseline hypercortisolism in these patients, as compared to the responders, a longer duration of biochemical remission is necessary in order to restore SST2 expression to adequate levels. Alternatively, corticotroph tumors in these cases may not express an adequate amount of SST2, regardless of the cortisolemic state.

Expression of SST2, defined by either immunohistochemical or mRNA level, is positively correlated with octreotide efficacy in GH-secreting tumors [45, 46]. Accordingly, the 2 responder patients to octreotide in whom cortisol levels were normalized before surgery had higher SST2 mRNA expression compared to partial/nonresponder patients, and these SST2 mRNA expression levels were comparable to the levels in somatotroph tumors [32]. The strategy of lowering cortisol levels to increase SST2 expression may have contributed to octreotide efficacy in these patients. Accordingly, an intermediate level of SST2 mRNA was found in the partial responder, whereas the nonresponder patient had a low level of SST2 mRNA. Regarding SST2 protein expression, a responder patient had an intermediate level of SST2, which may explain the efficacy of octreotide treatment. Consistently, the nonresponder patient to octreotide had no SST2 expression as determined by IHC, which may be explained by preoperative hypercortisolism with concomitant effects on SST2 expression level (mRNA and protein). The partial responders had contradictory results, 1 with high and the other with no SST2 expression by IHC. The partial responder with no SST2 protein expression also had high cortisol levels, which may have contributed to this negative result.

The present study needs to be analyzed in light of its inherent limitations. The single-arm design and small sample size, ie, 14 patients with 3 full responders to octreotide, only permits a descriptive analysis without more robust statistics. This is an important limitation, even considering that, given the rarity of CD, the existing literature consists mostly of case reports. Additionally, the period of 9 months of follow-up limited our ability to more thoroughly appreciate the potential clinical benefits associated with the reduction of UFC levels observed with the sequential treatment strategy tested in this trial. The protocol included ACTH measurements every 3 months, so the impact of octreotide treatment on ACTH secretion was not evaluated in the present study. Finally, in corticotroph tumors, only in selected cases sufficient appropriate tissue was available for mRNA and protein analysis. Generally, adenoma tissue pieces in CD are (very) small, representing a challenge to obtaining enough tissue for molecular studies. This is a well-known problem with respect to in vitro studies with corticotroph adenomas.

In conclusion, a treatment strategy consisting of sequential treatment with ketoconazole to lower cortisol levels, followed by octreotide to maintain biochemical remission, may be effective in a subset of patients with mild CD. Additional studies with longer follow-up are warranted to confirm the long-term efficacy of this strategy for the medical treatment of CD.

Funding

The authors received no financial support for this manuscript.

Disclosures

R.A.F. received speakers fees and research grants from Recordati and Corcept.

Data Availability

Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

Clinical Trial Information

Dutch Trial Register nr. NL37105.078.11.

© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. See the journal About page for additional terms.

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Thymic Neuroendocrine Tumor With Metastasis to the Breast Causing Ectopic Cushing’s Syndrome

Posted on April 9, 2025 by MaryO

Ectopic adrenocorticotropic hormone secretion (EAS) is responsible for approximately 10%–18% of Cushing’s syndrome cases. Thymic neuroendocrine tumors (NETs) comprise 5%–16% of EAS; therefore, they are very rare and the data about this particular tumors is scarce.

We present a case of a 34-year-old woman with a rapid onset of severe hypercortisolism in April 2016. After initial treatment with a steroid inhibitor (ketoconazole) and diagnostics including 68Ga DOTA-TATE PET/CT, it was shown to be caused by a small thymic NET.

After a successful surgery and the resolution of all symptoms, there was a recurrence after 5 years of observation caused by a metastasis to the breast, shown in the 68Ga DOTA-TATE PET/CT result and confirmed with a breast biopsy.

Treatment with a steroid inhibitor (metyrapone) and tumor resection were again curative. The last disease relapse appeared 7 years after the initial treatment, with severe hypercortisolism treated with osilodrostat. There was a local recurrence in the mediastinum, and a thoracoscopic surgery was performed with good clinical and biochemical effect.

The patient remains under careful follow-up. Our case stays in accordance with recent literature data, showing that patients with thymic NETs are younger than previously considered and that the severity of hypercortisolism does not correlate with the tumor size. The symptoms of EAS associated with thymic NET may develop rapidly and may be severe as in our case. Nuclear medicine improves the effectiveness of the tumor search, which is crucial in successful EAS therapy. Our case also underlines the need for lifelong monitoring of patients with thymic NETs and EAS.

1 Introduction

Ectopic adrenocorticotropic hormone secretion (EAS) represents between 9% and 18% of adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome (CS) cases (1–3). The tumors secreting ACTH may occur in many locations and present with different histopathological differentiation, resulting in various clinical outcomes. In the past, most of the EAS cases were associated with small cell lung cancer, characterized by rapid tumor progression and unfavorable prognosis. Recently, well-differentiated neuroendocrine tumors (NETs) from the foregut prevail in the clinical series of EAS, with most common locations in the lungs, thymus, and pancreas (1).

EAS is often associated with severe hypercortisolism. Typical Cushing’s appearance may not be present due to the rapid onset of the disease. Patients with this type of hypercortisolism need urgent treatment because they have the highest mortality of all forms of CS (4). A retrospective review of 43 patients with EAS reported deaths in 27 patients (62.8%) and a median overall survival of 32.2 months. The leading causes of mortality were the progression of primary malignancies and systemic infections; two patients died from pulmonary embolism (5).

Prompt surgical removal of the tumor secreting ACTH is the mainstay of the therapy. However, finding the tumor causing EAS can be challenging due to its small size and variety of locations. Most authors recommend a combination of computed tomography (CT) scanning of the chest, abdomen, and pelvis, with additional magnetic resonance imaging (MRI) of the pituitary, as the first-line examinations (1, 6, 7). However, the sensitivity of standard imaging modalities is suboptimal (8). In the analysis of 231 patients with EAS, cross-sectional imaging revealed the source of ACTH in 52.4% of them at initial evaluation, and another 29% was found during follow-up or due to nuclear medicine functional imaging, while 18.6% remained occult (9). Nuclear medicine improves the sensitivity of conventional radiology in the case of EAS, with the use of 18-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/CT (18F-FDG PET/CT) expected to be useful in identifying EAS tumors with high proliferative activity and 68gallium-labeled somatostatin analogues (68Ga DOTA-TATE) PET/CT with the potential to detect NETs. In the head-to-head comparison, the detection rate of the source of EAS was 75% for 68Ga DOTA-TATE and 60% for 18F-FDG PET/CT, while the highest sensitivity (90%) was achieved when both methods were combined (10).

Thymic NETs comprise 2%–5% of all thymic neoplasms and may cause some paraneoplastic syndromes, with the most frequent being myasthenia gravis, syndrome of inappropriate antidiuretic hormone secretion, and hypercortisolism (11). EAS associated with thymic NETs are rare, representing between 5% and 16% of EAS in published case series (1). Because of the rarity and heterogeneity of the disease, no evidence-based guidelines are available.

We present a case of a patient with thymic NET causing EAS, with metastasis to the breast after 5 years of post-surgical remission and another local recurrence 7 years after the first operation.

Our case is unique because thymic NETs causing EAS are known as an aggressive disease with a median recurrence time of 24 months after thymectomy (12). There are only a few cases described of metastases to the breast from thymic NETs causing EAS (13–16). Moreover, 68Ga-SSTR PET/CT was very helpful in detecting both primary and metastatic ectopic ACTH-secreting tumor, which underlines its role in the diagnostic workout of EAS.

2 Case description

A 32-year-old woman with no relevant medical history was admitted to the endocrinology department in April 2016 due to the rapid onset of symptoms: weight gain, hypertension, skin changes, and oligomenorrhoea.

The measurements at initial physical examination were as follows: body mass index (BMI)—29 kg/m2, blood pressure—180/90 mmHg, and heart rate—88/min. She had plethora, acne, moon face, buffalo hump, central obesity, many red striae in the abdominal area, and mild hirsutism. The baseline laboratory findings are presented in Table 1, with hypokalemia, diabetes, leukocytosis, high levels of serum cortisol, ACTH, and chromogranin A, and increased urine-free cortisol (UFC) secretion. There was no suppression of serum cortisol or UFC after a high-dose dexamethasone test. ACTH-dependent CS was diagnosed, and EAS was suspected. The patient’s family history was negative for endocrine diseases or genetic disorders.

Table 1

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Table 1. Laboratory results at diagnosis (April 2016).

The first-line cross-sectional imaging studies (chest, abdomen, and pelvis CT and MRI of the pituitary gland) did not reveal the source of ACTH. Only a symmetrical enlargement of adrenals was observed. 68Ga DOTA-TATE PET/CT revealed an oval lesion in the anterior mediastinum (1.9 × 1.3 cm) with a subtle overexpression of somatostatin receptors (SUV max. 2.8, Figures 1A, B). The chest MRI confirmed a mass 1.5 × 2.0 × 2.5 cm, with high T2-weighted signal and high contrast enhancement, suggestive of NET. The patient was given ketoconazole (600 mg daily), spironolactone, potassium supplementation, antihypertensive drugs, and thromboembolic prophylaxis. In June 2016, thoracoscopic removal of the mediastinal tumor was performed. In the histopathological examination, the tumor was encapsulated, without evidence of invasion, and no lymph node metastases were described. The immunophenotype of the tumor was as follows: CgA (+), Syn (+), CKAE1+E3 (+) “dot-like”, S100 (-), calcitonin (-), EMA (+/-), Ki67 3% to 4% in hot spots, no necrosis, mitotic index 0/10HPF with conclusion: thymic NET—typical carcinoid (low-grade). The presence of paraganglioma was also taken into consideration, as such cases were described (17). However, the significant reaction with cytokeratin and lack of S100 protein expression made this diagnosis less probable.

Figure 1

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Figure 1. 68Ga-DOTATATE PET/CT scans. (A, B) Before the first surgery (April 2016). (C, D) Before the second surgery (May 2021). (E, F) Before the third surgery (January 2023).

The postoperative morning serum cortisol concentration was below 5 µg/dL, indicating biochemical remission. The patient received hydrocortisone substitution for a month. The clinical signs of CS disappeared, and there was a normalization of UFC.

During 5 years of follow-up, the patient got pregnant and delivered a healthy child. Genetic counseling was performed, and no germline mutation of MEN1 gene was identified. Other clinical manifestations of MEN1 (like primary hyperparathyroidism and pituitary secreting tumors) were excluded.

In May 2021, the patient experienced a sudden recurrence of CS symptoms. The laboratory findings confirmed severe hypercortisolism (Table 2); therefore, treatment with steroid inhibitor metyrapone was administered. The patient tolerated only 750 mg daily; there were side effects (skin rash and tachycardia) with higher doses. The chest MRI revealed no recurrence in the location of the primary tumor, only a lesion in the right breast (1.2 × 1.0 × 1.1 cm) with atypical contrast enhancement. The 68Ga-DOTA-TATE PET/CT result showed a subtle overexpression of the tracer (SUV max 1.9) in the right breast (Figures 1C, D). Breast ultrasonography confirmed a hypoechogenic, hypervascular mass in the right breast, BIRADS 3/4, diagnosed as NET in the breast biopsy. The tumor was removed in July 2021 without complications. The histopathological samples were compared with the primary lesion, confirming the metastasis from thymic NET to the breast—tumor size 0.7 × 1.5 cm, clear surgical margins (8 mm) with Ki67 3% (NET G2), and no lymph node metastases. After the breast surgery, the cortisol levels normalized in blood and urine and the CS symptoms disappeared. 18F-FDG PET/CT and 68Ga-DOTA-TATE PET/CT were performed, showing no pathological increase of radiotracer uptake in post-operative locations or mediastinal lymph nodes. The patient consulted with the oncology team, and no adjuvant therapy was recommended.

Table 2

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Table 2. Laboratory results during 7 years of observation.

The next recurrence of the disease occurred in February 2023, with the symptoms developing suddenly during a very short period (1 to 2 weeks), additionally with significant mental deterioration (concentration disorders, anxiety, severe mood swing). The laboratory findings confirmed excessive hypercortisolism (Table 2). The patient was given osilodrostat (the initial dose was 20 mg daily but later reduced to 10 mg daily for 2 weeks until surgery) and symptomatic treatment with good clinical and biochemical effect. The 68Ga-DOTA-TATE PET/CT result showed a slightly increased uptake of the tracer in the left mediastinum, between cervical vessels, 0.9 × 1.2 cm (Figures 1E, F)—probably a local recurrence. Thoracotomy was performed in February 2023, with subsequent clinical and biochemical improvement (Table 2). In the histopathological examination, mediastinal NET G1 was diagnosed, without necrosis, mitotic activity 0/2 mm2, immunophenotype CgA (+), CD56 (+), Ki 67 1%, CK AE1/AE3 (+), CD117 (+), p40 (-), TdT (-), PAX8 (-), and the presence of tumor cell embolism in the vessels. One metastatic lesion was found in the pericardium (the maximal dimension of the tissue was 13 mm, resected radically). Two metastatic lesions in the fat tissue were found (one tissue fragment from the mediastinum, max. 16 mm diameter, and the second tissue fragment was surrounding the jugular vein, max. diameter up to 40 mm, both resected radically). Two of the 10 resected lymph nodes had metastatic lesions: one from the area of the jugular vein, diameter 11 mm, with capsular invasion, and the second lymph node N2R with capsular invasion, both resected radically. The symptoms of hypercortisolism disappeared, and the cortisol values were normalized after the operation. The patient is currently under careful monitoring, without signs of clinical or biochemical recurrence. 68Ga-DOTA-TATE PET/CT is performed every 6 months.

3 Discussion

Our case is representative for thymic NETs causing EAS presented in literature, but it also shows some distinct features, giving new insight into this rare condition.

In recent series, ACTH-secreting thymic NETs occurred often in young adults, like our patient. The typical age of presentation is 21–35 years in the largest case series, and 7.4% were children under 15 years (12, 13). In contrast, the former series of thymic NETs showed a peak incidence in the sixth decade of life (11).

ACTH-secreting thymic NETs show a slight male preponderance (58.6%); however, the patient’s gender does not seem to relate with the disease outcome (12). There was only an association between male sex and larger tumor size preoperatively as found in one case series (13).

Thymic NETs causing EAS are very rarely associated with MEN1; we have also excluded it in our patient. On the contrary, 30% of thymic NETs not associated with CS are found in patients with MEN1, mostly male smokers (18). It is not clear why thymic NETs with EAS are less likely caused by MEN1 gene mutation, but the possibility of this genetic predisposition should always be taken into consideration.

Thymic NETs associated with EAS are generally considered aggressive, presenting significant cellular atypia in the histopathological examination (19). However, the biology of the tumors is variable. In the histopathological examination of 92 thymic NETs secreting ACTH, the most common subtype was atypical NET (46.7%), while 30.4% of the cases were typical NETs and 21.7% were carcinomas, with the median Ki-67 10%, ranging from 1% to 40%. The median tumor size among 112 patients was 4.7 cm, ranging from 1 to 20 cm, and 55.7% of patients had metastases at presentation (12). It proves the significant heterogeneity of the disease.

Our patient had typical NET with small dimensions and localized disease at the time of diagnosis. Despite this, we observed aggressive Cushing’s syndrome with a short duration of symptoms and life-threatening hypokalemia. It has been observed that there is no correlation between tumor size and hormone levels (12). Thymic NETs associated with EAS are often large, which simplifies the diagnosis and localization. However, in the case of incidental sellar mass or small thymic tumor, the differential diagnosis might be difficult. The highest sensitivity in distinguishing thymic EAS from Cushing’s disease was documented in inferior petrosal sinus sampling and corticotropin-releasing hormone (CRH) stimulation test (12, 20).

In severe cases, when small ACTH-secreting NET needs to be found urgently, PET/CT is a very helpful diagnostic tool. In a prospective study comprising 20 patients with histologically proven EAS, the 68Ga-DOTATATE PET/CT result correctly identified the tumor in 75%, with SUV max. ranging from 1.4 to 20.7, while the 18F-FDG PET/CT findings had a slightly worse result (identified 60% tumors), with SUV max. ranging from 1.8 to 10.0. Those methods are believed to be complementary in case of localization and discrimination of EAS. The 68Ga-DOTATATE PET/CT result revealed tumor in six cases with a negative 18F-FDG PET/CT result, while the 18F-FDG PET/CT procedure was diagnostic in three cases with a negative 68Ga-DOTATATE uptake; the combined sensitivity of both methods was 90% (10). The typical first-line diagnostic modalities’ (CT and MRI) sensitivities range from 52% to 66% (9). Our case remains in accordance with those results, showing difficulties in localizing the ACTH source in first-line radiological methods and with 68Ga-DOTATATE PET/CT being the most useful diagnostic tool. It should also be noted that the 68Ga-DOTATATE uptake was only mildly elevated both in primary tumor and its recurrences despite excessive hormonal activity. We did not perform 18F-FDG PET/CT until second operation, as it was believed to be rather helpful in poorly differentiated tumors and 68Ga-DOTATATE PET/CT was diagnostic. Later, we performed it in search for other metastatic tumors, but the examination showed no tumor spread.

The recommended treatment of thymic NETs regarded radically resectable is thymectomy by median sternotomy or thoracotomy and lymph node dissection (11, 21, 22). According to the last version of the ESMO Guidelines, available literature suggests no benefit from adjuvant therapy in ThCs. The majority of the authors of the Guidelines panel suggest individually discussing eventual postoperative therapies, including RT and/or systemic therapies, balancing the pros and cons only in selected patients with advanced stage R0 or R1-2 resection (22). Data on systemic therapies in thymic NETs are scarce; therefore, they should be discussed in a multidisciplinary expert team in case of morphologically progressive tumors, high tumor burden, or refractory hormonal syndromes. Somatostatin analogs are recommended as the first-line systemic therapy in typical carcinoids (22). We considered the adjuvant therapy with somatostatin analogs; however, due to the low uptake in PET examination and complete resolution of symptoms as well as the radical type of surgical removal, we did not decide to initiate such therapy. Other systemic treatment options include everolimus (second line in typical carcinoids or first line in atypical carcinoids), chemotherapy, peptide receptor radionuclide therapy (PRRT), and interferon-α (22, 23). There is also data on the benefits of combining long-acting lanreotide with temozolomide in progressive thymic NETs (24).

Due to the variable availability of steroid inhibitors during the course of the disease, our patient received three different preparations at each disease relapse. Both ketoconazole and osilodrostat were well tolerated and reduced the hypercortisolism within a few days, but metyrapone caused significant side effects (see below—”Patient’s perspective”), and it was not possible to normalize the cortisol values with this steroid inhibitor. It is worth noting that when using the most recent steroid inhibitor—osilodrostat—we initiated the therapy with a high dose without a previous dose titration. This strategy might be used in the case of severe hypercortisolism and proved effective and safe in our patient (25).

Most commonly, metastases from thymic NET producing ACTH are localized in lymph nodes, bone, lung, pleura, and, less commonly, liver and parotid gland (13). There are very few cases of EAS-related thymic NETs with breast metastases described in the literature, with some histopathological variability (one case related to atypical carcinoid, another to combined large-cell neuroendocrine carcinoma and atypical carcinoid, and third case of neuroendocrine carcinoma). All of them were female patients between 24 and 36 years of age, with mediastinal lymph nodes metastases at the time of presentation; one also had distant metastases to the bones (13–15). Contrary to the reported cases, our patient had typical carcinoid (confirmed by three independent pathologists from different centers) but similarly presented with severe hypercortisolism. It suggests that there is no connection between tumor differentiation and the severity of hypercortisolism. Interestingly, in a review of 661 patients with metastatic NETs from Sweden, there were 20 patients with NETs and breast metastases, and among them only one case of thymic NET (Ki 67 12%), but without EAS. A total of 11 patients with breast metastases had a primary tumor in the small intestine and eight in the lung (16).

Our case underlines the necessity of long-term follow-up in EAS, as the recurrences occurred 5 and 7 years after the initial successful treatment. According to guidelines, follow-up after treatment of thymic NETs should be life-long (22).

The strength of our report is the presentation of a thymic NET with metastasis to the breast, diagnosed and treated with many currently available tools and with a long period of follow-up. The limitation is the low number of other similar cases to compare, which is a consequence of the rarity of this disease.

In conclusion, our case proves that thymic NETs with EAS might present in young patients with well-differentiated character in histopathological examination and severe, life-threatening hypercortisolism despite the small size of the primary lesion. 68Ga-DOTATATE PET/CT is a very helpful tool to localize the tumor. Finally, life-long follow-up should be performed despite complete remission after surgery.

4 Patient’s perspective

The first symptoms that I observed were face edema and mood changes. I rapidly lost muscle mass (approximately 6 kg in 2 weeks), and I was not able to climb stairs, especially with my child’s pram. The most difficult to accept were changes in my appearances—hirsutism, losing hair, changes of my facial features. My sense of pain (for example, during medical procedures) was diminished. Other disruptive symptoms were intensive sweating, increased appetite, thirst, brain fog, and digestive problems. At every relapse, the disease manifestations were fluctuating, all of them intensifying at the same time, which was very difficult for me. Also stress evoked disease symptoms. I experienced a strange feeling of warm during cortisol outbursts.

As for the treatment, I did not tolerate metyrapone well. I had skin rash, anxiety attacks with heart palpitations, and a metallic taste in my mouth. Other drugs (ketoconazole, osilodrostat) were better for me.

After operations of the relapses, the symptoms diminished very quickly, especially the most difficult ones. My blood pressure and glycemia normalized within a few days. Other manifestations, like loss of hair or skin changes, persisted up to 3 months.

Data availability statement

The datasets presented in this article are not readily available because the data are potentially identifiable. Requests to access the datasets should be directed to Aleksandra Zdrojowy-Wełna, aleksandra.zdrojowy-welna@umw.edu.pl.

Ethics statement

This study was exempt from ethical approval procedures being a case report of a single patient who has voluntarily provided oral and written consent to participate in the study and to have her case published for the sake of helping us better understand the clinical picture and the course of thymic neuroendocrine tumors with EAS and share it with the medical community for awareness about it. Written informed consent was obtained from the participant/patient(s) for the publication of this case report.

Author contributions

AZ-W: Conceptualization, Data curation, Investigation, Methodology, Software, Writing – original draft. MB: Conceptualization, Supervision, Writing – review & editing. JS: Data curation, Investigation, Methodology, Writing – review & editing. AJ-P: Data curation, Investigation, Writing – review & editing. JK-P: Conceptualization, Data curation, Investigation, Methodology, Supervision, Writing – original draft.

Funding

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

Acknowledgments

We would like to thank Prof. Barbara Górnicka and Prof. Michał Jeleń for their collaboration throughout the patient’s treatment.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The handling editor AJ declared a past co-authorship with the author MB.

The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Publisher’s note

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.

 

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2025.1492187/full#supplementary-material

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Keywords: ectopic Cushing`s syndrome, thymic neuroendocrine tumor, thymic NET, ectopic ACTH secretion, case report

Citation: Zdrojowy-Wełna A, Bolanowski M, Syrycka J, Jawiarczyk-Przybyłowska A and Kuliczkowska-Płaksej J (2025) Case Report: Thymic neuroendocrine tumor with metastasis to the breast causing ectopic Cushing’s syndrome. Front. Oncol. 15:1492187. doi: 10.3389/fonc.2025.1492187

Received: 11 September 2024; Accepted: 31 January 2025;
Published: 25 February 2025.

Edited by:

Aleksandra Gilis-Januszewska, Jagiellonian University Medical College, Poland

Reviewed by:

Piero Ferolla, Umbria Regional Cancer Network, Italy
Lukasz Dzialach, Warsaw Medical University, Poland

Copyright © 2025 Zdrojowy-Wełna, Bolanowski, Syrycka, Jawiarczyk-Przybyłowska and Kuliczkowska-Płaksej. 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) and the copyright owner(s) 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: Aleksandra Zdrojowy-Wełna, aleksandra.zdrojowy-welna@umw.edu.pl

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.

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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.

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

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Insights on Diagnosing and Managing Cushing’s Syndrome

Posted on August 18, 2024 by MaryO

Cushing’s syndrome, or endogenous hypercortisolemia, is a rare condition that both general practice clinicians and endocrinologists should be prepared to diagnose and treat. Including both the pituitary and adrenal forms of the disease, the Endocrine Society estimates that the disorder affects 10 to 15 people per million every year in the United States. It is more common in women and occurs most often in people between the ages of 20 and 50.

Even though Cushing’s remains a rare disease, cortisol recently made waves at the American Diabetes Association 84th Scientific Session. A highlight of the meeting was the initial presentation of data from the CATALYST trial, which assessed the prevalence of hypercortisolism in patients with difficult-to-control type 2 diabetes (A1c 7.5+).

CATALYST is a prospective, Phase 4 study with two parts. In the prevalence phase, 24% of 1,055 enrolled patients had hypercortisolism, defined as an overnight dexamethasone suppression test (ODST) value greater than 1.8 µg/dL and dexamethasone levels greater than 140 µg/dL. Results of CATALYST’s randomized treatment phase are expected in late 2024.

Elena Christofides, MD, FACE, founder of Endocrinology Associates, Inc., in Columbus, OH, believes the CATALYST results will be a wake-up call for both physicians and patients seeking to advocate for their own health. “This means that nearly 1 in 4 patients with type 2 diabetes have some other underlying hormonal/endocrine dysfunction as the reason for their diabetes, or significant contribution to their diabetes, and they should all be screened,” she said. “All providers need to get comfortable with diagnosing and treating hypercortisolemia, and you need to do it quickly because patients are going to pay attention as well.”

In Dr. Christofides’ experience, patients who suspect they have a hormonal issue may start with their primary care provider or they may self-refer to an endocrinologist. “A lot of Cushing’s patients are getting diagnosed and treated in primary care, which is completely appropriate. But I’ve also met endocrinologists who are uncomfortable diagnosing and managing Cushing’s because it is so rare,” she said. “The important thing is that the physician is comfortable with Cushing’s or is willing to put in the work get comfortable with it.”

According to Dr. Christofides, the widespread popular belief that “adrenal fatigue” is causing millions of Americans to feel sick, tired, and debilitated may be creating barriers to care for people who may actually have Cushing’s. “As physicians, we know that adrenal fatigue doesn’t exist, but we should still be receptive to seeing patients who raise that as a concern,” said Dr. Christofides. “We need to acknowledsalige their lived experience as being very real and it can be any number of diseases causing very real symptoms. If we don’t see these patients, real cases of hypercortisolemia could be left undiagnosed and untreated.”

Dr. Christofides, who also serves as a MedCentral Editor-at-Large, said she reminds colleagues that overnight dexamethasone suppression test (ODST) should always be the first test when you suspect Cushing’s. “While technically a screening test, the ODST can almost be considered diagnostic, depending on how abnormal the result is,” she noted. “But I always recommend that you do the ODST, the ACTH, a.m. cortisol, and the DHEAS levels at the same time because it allows you to differentiate more quickly between pituitary and adrenal problems.”

Dr. Christofides does see a place for 24-hour urine collection and salivary cortisol testing at times when diagnosing and monitoring patients with Cushing’s. “The 24-hour urine is only positive in ACTH-driven Cushing’s, so an abnormal result can help you identify the source, but too many physicians erroneously believe you can’t have Cushing’s if the 24-hour urine is normal,” she explained. “Surgeons tend to want this test before they operate and it’s a good benchmark for resolution of pituitary disease.” She reserves salivary cortisol testing for cases when the patient’s ODST is negative, but she suspects Cushing’s may be either nascent or cyclical.

Surgical resection has long been considered first-line treatment in both the pituitary and adrenal forms of Cushing’s. For example, data shared from Massachusetts General Hospital showed that nearly 90% of patients with microadenomas did not relapse within a 30-year period. A recent study found an overall recurrence rate of about 25% within a 10-year period. When reoperation is necessary, remission is achieved in up to 80% of patients.

As new medications for Cushing’s syndrome have become available, Dr. Christofides said she favors medical intervention prior to surgery. “The best part about medical therapy is you can easily stop it if you’re wrong,” she noted. “I would argue that every patient with confirmed Cushing’s deserves nonsurgical medical management prior to a consideration of surgery to improve their comorbidities and surgical risk management, and give time to have a proper informed consent discussion.”

In general, medications to treat Cushing’s disease rely on either cortisol production blockade or receptor blockade, said Dr. Christofides. Medications that directly limit cortisol production include ketoconazole, osilodrostat (Isturisa), mitotane (Lysodren), levoketoconazole (Recorlev), and metyrapone (Metopirone). Mifepristone (Korlym, Mifeprex) is approved for people with Cushing’s who also have type 2 diabetes to block the effects of cortisol. Mifepristone does not lower the amount of cortisol the body makes but limits its effects. Pasireotide (Signifor) lowers the amount of ACTH from the tumor. Cabergoline is sometimes used off-label in the US for the same purpose.

Following surgery, people with Cushing’s need replacement steroids until their adrenal function resumes, when replacement steroids must be tapered. But Dr. Christofides said she believes that all physicians who prescribe steroids should have a clear understanding of when and how to taper patients off steroids.

“Steroid dosing for therapeutic purposes is cumulative in terms of body exposure and the risk of needing to taper. A single 2-week dose of steroids in a year does not require a taper,” she said. “It’s patients who are getting repeated doses of more than 10 mg of prednisone equivalent per day for 2 or more weeks multiple times per year who are at risk of adrenal failure without tapering.”

Physicians often underestimate how long a safe, comfortable taper can take, per Dr. Christofides. “It takes 6 to 9 months for the adrenals to wake up so if you’re using high-dose steroids more frequently, that will cause the patient to need more steroids more frequently,” she explained. “If you’re treating an illness that responds to steroids and you stop them without tapering, the patient’s disease will flare, and then a month from then to 6 weeks from then you’ll be giving them steroids again, engendering a dependence on steroids by doing so.”

When developing a steroid taper plan for postoperative individuals with Cushing’s (and others), Dr. Christofides suggests basing it on the fact that 5 mg of prednisone or its equivalent is the physiologic dose. “Reduce the dose by 5 mg per month until you get to the last 5 mg, and then you’re going to reduce it by 1 mg monthly until done,” she said. “If a patient has difficulty during that last phase, consider a switch to hydrocortisone because a 1 mg reduction of hydrocortisone at a time may be easier to tolerate.”

Prednisone, hydrocortisone, and the other steroids have different half-lives, so you’ll need to plan accordingly, adds Dr. Christofides. “If you do a slower taper using hydrocortisone, the patient might feel worse than with prednisone unless you prescribe it BID.” She suggests thinking of the daily prednisone equivalent of hydrocortisone as 30 mg to allow for divided dosing, rather than the straight 20 mg/day conversion often used.

What happens after a patient’s Cushing’s has been successfully treated? Cushing’s is a chronic disease, even in remission, Dr. Christofides emphasized. “Once you have achieved remission, my general follow-up is to schedule visits every 6 months to a year with scans and labs, always with the instruction if the patient feels symptomatic, they should come in sooner,” she said.

More on Cushing’s diagnosis and therapies.

https://www.medcentral.com/endocrinology/cushings-syndrome-a-clinical-update

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Hormones and High Blood Pressure: Study Reveals Endocrine Culprits and Targeted Treatments

Posted on October 20, 2023 by MaryO

In a recent study published in Hypertension Research, scientists examine the endocrine causes of hypertension (HTN) and investigate the efficacy of treatments to alleviate HTN.

 

What is HTN?

About 30% of the global population is affected by HTN. HTN is a modifiable cardiovascular (CV) risk factor that is associated with a significant number of deaths worldwide.

There are two types of HTN known as primary and secondary HTN. As compared to primary HTN, secondary HTN causes greater morbidity and mortality.

The most common endocrine causes of HTN include primary aldosteronism (PA), paragangliomas and pheochromocytomas (PGL), Cushing’s syndrome (CS), and acromegaly. Other causes include congenital adrenal hyperplasia, mineralocorticoid excess, cortisol resistance, Liddle syndrome, Gordon syndrome, and thyroid and parathyroid dysfunction.

What is PA?

PA is the most common endocrine cause of hypertension, which is associated with excessive aldosterone secretion by the adrenal gland and low renin secretion. It is difficult to estimate the true prevalence of PA due to the complexity of its diagnosis.

Typically, the plasma aldosterone-to-renin ratio (ARR) is measured to diagnose PA. The diagnosis of PA can also be confirmed using other diagnostic tools like chemiluminescent enzyme immunoassays (CLEIAs) and radio immune assay (RIA).

Continuous aldosterone secretion is associated with organ damage due to chronic activation of the mineralocorticoid (MR) receptor in many organs, including fibroblasts and cardiomyocytes. An elevated level of aldosterone causes diastolic dysfunction, endothelial dysfunction, left ventricular hypertrophy, and arterial stiffness.

Increased aldosterone secretion also leads to obstructive sleep apnea and increases the risk of osteoporosis. This is why individuals with PA are at a higher risk of cardiovascular events (CVDs), including heart failure, myocardial infarction, coronary artery disease, and atrial fibrillation.

PA is treated by focusing on normalizing potassium and optimizing HTN and aldosterone secretion. Unilateral adrenalectomy is a surgical procedure proposed to treat PA.

Young patients who are willing to stop medication are recommended surgical treatment. The most common pharmaceutical treatment for PA includes mineralocorticoid receptor antagonists such as spironolactone and eplerenone.

Pheochromocytomas and paragangliomas

PGL are tumors that develop at the thoracic-abdominal-pelvic sympathetic ganglia, which are present along the spine, as well as in the parasympathetic ganglia located at the base of the skull. The incidence rate of PGL is about 0.6 for every 100,000 individuals each year. PGL tumors synthesize excessive catecholamines (CTN), which induce HTN.

Some of the common symptoms linked to HTN associated with PGL are palpitations, sweating, and headache. PGL can be diagnosed by determining metanephrines (MN) levels, which are degraded products of CTN. Bio-imaging tools also play an important role in confirming the diagnosis of PGL.

Excessive secretion of CTN increases the risk of CVDs, including Takotsubo adrenergic heart disease, ventricular or supraventricular rhythm disorders, hypertrophic obstructive or ischaemic cardiomyopathy, myocarditis, and hemorrhagic stroke. Excessive CTN secretion also causes left ventricular systolic and diastolic dysfunction.

Typically, PGL treatment is associated with surgical procedures. Two weeks before the surgery, patients are treated with alpha-blockers. For these patients, beta-blockers are not used as the first line of treatment without prior use of alpha-adrenergic receptors.

Patients with high CTN secretion are treated with metyrosine, as this can inhibit tyrosine hydroxylase. Hydroxylase converts tyrosine into dihydroxyphenylalanine, which is related to CTN synthesis.

What is CS?

CS, which arises due to persistent exposure to glucocorticoids, is a rare disease with an incidence rate of one in five million individuals each year. The most common symptoms of CS include weight gain, purple stretch marks, muscle weakness, acne, and hirsutism. A high cortisol level causes cardiovascular complications such as HTN, hypercholesterolemia, and diabetes.

CS is diagnosed based on the presence of two or more biomarkers that can be identified through pathological tests, such as salivary nocturnal cortisol, 24-hour urinary-free cortisol, and dexamethasone suppression tests.

CS is treated through surgical procedures based on the detected lesions. Patients with severe CS are treated with steroidogenic inhibitors, such as metyrapone, ketoconazole, osilodrostat, and mitotane. Pituitary radiotherapy and bilateral adrenalectomy are performed when other treatments are not effective.

Acromegaly

Acromegaly arises due to chronic exposure to growth hormone (GH), leading to excessive insulin-like growth factor 1 (IGF1) synthesis. This condition has a relatively higher incidence rate of 3.8 million person-years. Clinical symptoms of acromegaly include thickened lips, widened nose, a rectangular face, prominent cheekbones, soft tissue overgrowth, or skeletal deformities.

Prolonged exposure to GH leads to increased water and sodium retention, insulin resistance, reduced glucose uptake, and increased systemic vascular resistance. These conditions increase the risk of HTN and diabetes in patients with acromegaly. Acromegalic patients are also at a higher risk of cancer, particularly those affecting the thyroid and colon.

Acromegaly is diagnosed using the IGF1 assay, which determines IGF1 levels in serum. After confirming the presence of high IGF1 levels, a GH suppression test must be performed to confirm the diagnosis. Bioimaging is also conducted to locate adenoma.

Acromegaly is commonly treated through surgical procedures. Patients who refuse this line of treatment are treated with somatostatin receptor ligands, growth hormone receptor antagonists, dopaminergic agonists, or radiotherapy.

Journal reference:
  • De Freminville, J., Amar, L., & Azizi, M. (2023) Endocrine causes of hypertension: Literature review and practical approach. Hypertension Research; 1-14. doi:10.1038/s41440-023-01461-1

From https://www.news-medical.net/news/20231015/Hormones-and-high-blood-pressure-Study-reveals-endocrine-culprits-and-targeted-treatments.aspx

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