Approach to the Patient with Cushing’s Syndrome: Use of Anticoagulation Therapy

Posted on December 19, 2025 by MaryO

Abstract

There is an increased awareness on the higher hypecoagulability risks in patients with Cushing’s syndrome (CS) but management remains controversial. Here, we present four illustrative cases of CS that exemplify some “grey areas” on venous thromboembolism (VTE) prevention—when to start, how long to continue, what to use, and when to stop.

The cases span: initiation of prophylaxis at diagnosis of active CS; periprocedural management around inferior petrosal sinus sampling; peri-operative prophylaxis after transsphenoidal surgery (TSS); and discontinuation decisions in medically controlled disease. We synthesise current evidence and expert practice and recommend considering low-molecular-weight heparin at diagnosis of active CS, continuing through surgery, and extending for approximately three months after biochemical remission in selected patients to address the highest-events risk window.

Based on recent data, we discourage routine use of graduated compression stockings for VTE prevention. Though bleeding complications appear uncommon, they need to be carefully considered on an individualized basis. Finally, scenarios where prophylaxis can be safely discontinued once eucortisolaemia is achieved are outlined. This case-anchored framework translates heterogeneous data into actionable guidance and highlights priorities for prospective evaluation.

The Journal of Clinical Endocrinology & Metabolism, dgaf671, https://doi.org/10.1210/clinem/dgaf671

Filed under: Cushing's, pituitary, Treatments | Tagged: , , , , | Leave a comment »

Ultrasound-Guided Jugular Vein Access for Inferior Petrosal Sinus Sampling: A Safe and Feasible Technique

Posted on December 11, 2025 by MaryO

Abstract

Pituitary Cushing’s disease (CD) results from excessive adrenocorticotropic hormone (ACTH) secretion, usually due to a pituitary adenoma. This report describes the diagnostic approach and management of a complex case of CD in a patient with multiple comorbidities, highlighting a hybrid technique for inferior petrosal sinus sampling (IPSS) when standard access fails.

A woman with poorly controlled diabetes, obesity, chronic kidney disease (CKD), and hypertension presented with suspected Cushing’s syndrome. Despite normal urinary free cortisol (UFC) levels (likely influenced by renal dysfunction), clinical suspicion prompted further testing, which revealed an inverted cortisol rhythm and lack of suppression on low-dose dexamethasone. High-dose suppression indicated a pituitary source. MRI findings were inconclusive. To confirm the diagnosis, bilateral IPSS was attempted. Right petrosal sinus catheterization via femoral access was successful; however, left-sided access failed. An alternative, ultrasound-guided direct left internal jugular puncture was performed, allowing complete sampling. A central-to-peripheral ACTH gradient >2 at baseline and >3 after desmopressin confirmed a pituitary source. The patient subsequently underwent successful transsphenoidal resection, achieving postoperative biochemical remission.

IPSS remains the gold standard for distinguishing central from ectopic ACTH production. While bilateral femoral access is standard, anatomical variants may necessitate alternative routes. This case demonstrates the feasibility and safety of combining femoral and direct jugular access to complete IPSS when conventional approaches are limited.

This is the first reported case of IPSS performed using a hybrid right femoral and left ultrasound-guided jugular approach, offering a practical alternative when femoral access is not feasible and reinforcing the diagnostic value of IPSS in challenging cases.

Introduction

Pituitary Cushing’s disease (CD) is caused by excessive secretion of adrenocorticotropic hormone (ACTH), typically due to a pituitary adenoma. It represents the most common cause of endogenous Cushing’s syndrome, accounting for approximately 70% of ACTH-dependent cases [1,2]. The diagnostic approach often requires dynamic hormonal testing and neuroimaging; however, distinguishing pituitary from ectopic ACTH secretion remains a clinical challenge [3].

Inferior petrosal sinus sampling (IPSS), first described by Oldfield EH and Doppman JL in 1977, is considered the gold standard for confirming a pituitary origin when biochemical and imaging findings are inconclusive [4-6]. Bilateral catheterization via femoral venous access is the usual approach, guided by digital subtraction angiography (DSA) [4,5]. However, anatomical variants, thrombosis, and technical difficulties can impede standard catheterization, necessitating alternative strategies such as direct ultrasound-guided internal jugular puncture [7].

This report presents a patient with multiple comorbidities and suspected CD in whom a hybrid IPSS approach was successfully performed after failed standard access.

Case Presentation

A female patient with a history of poorly controlled diabetes, obesity, chronic kidney disease (CKD), and hypertension was admitted with suspected Cushing’s syndrome. Initial evaluation revealed normal urinary free cortisol (UFC), likely underestimated due to renal dysfunction. Because of high clinical suspicion, circadian cortisol rhythm was assessed, showing inversion with higher evening than morning levels, supporting hypercortisolism.

A low-dose dexamethasone suppression test (LDDST; 1 mg) failed to suppress cortisol, confirming endogenous hypercortisolism. A high-dose dexamethasone suppression test (HDDST; 8 mg) demonstrated 80% cortisol suppression, suggesting a pituitary source of ACTH overproduction.

Pituitary MRI revealed a poorly defined hypointense nodular area, inconclusive for microadenoma (Figure 1A). To confirm the central origin, bilateral inferior petrosal sinus sampling (IPSS) was performed (Figures 1B–1E).

(A)-Contrast-enhanced-pituitary-MRI-showing-a-hypointense-nodule-in-the-left-half-of-the-gland,-which-was-inconclusive;-(B)-right-internal-jugular-vein-access-achieved,-while-left-jugular-access-was-not-possible-via-this-route;-(C-and-D)-dual-inferior-petrosal-sinus-catheterization-with-right-sided-access-via-the-femoral-vein-and-left-sided-access-via-direct-jugular-puncture;-(E)-ultrasound-guided-placement-of-the-venous-sheath.
Figure 1: (A) Contrast-enhanced pituitary MRI showing a hypointense nodule in the left half of the gland, which was inconclusive; (B) right internal jugular vein access achieved, while left jugular access was not possible via this route; (C and D) dual inferior petrosal sinus catheterization with right-sided access via the femoral vein and left-sided access via direct jugular puncture; (E) ultrasound-guided placement of the venous sheath.

Initial access was established via the bilateral femoral veins with placement of 5 Fr introducer sheaths in both. Due to anatomical complexity and inability to access the left internal jugular vein via the femoral route, a direct ultrasound-guided left jugular puncture was performed. A separate 5 Fr introducer sheath was placed directly into the left internal jugular vein under ultrasound guidance (US guidance). Catheterization was performed using 5 Fr vertebral diagnostic catheters, facilitated by a micro-guidewire.

Correct positioning within the petrosal sinuses was subsequently confirmed by contrast injection. The results demonstrated accurate catheter placement in the inferior petrosal sinuses (adequate prolactin levels), with an ACTH central-to-peripheral gradient greater than 2 at baseline and greater than 3 after desmopressin, thus confirming a pituitary source for the pathology (Tables 1–2).

Peripheral Right IPS Left IPS
16.5 ng/mL 41.2 ng/mL 63.7 ng/mL
Table 1: Prolactin concentrations obtained via inferior petrosal sinus sampling at baseline.

IPS: Inferior Petrosal Sinus.

Time Point Peripheral Right IPS Left IPS
Basal 27.5 pg/mL 77.1 pg/mL 106 pg/mL
Desmopressin 5 min 28.3 pg/mL 168 pg/mL 221 pg/mL
Desmopressin 10 min 27.9 pg/mL 32 pg/mL 80 pg/mL
Table 2: ACTH concentrations obtained via inferior petrosal sinus sampling at baseline and at 5 and 10 minutes after desmopressin stimulation.

IPS: Inferior Petrosal Sinus; ACTH: Adrenocorticotropic hormone.

The patient underwent endonasal transsphenoidal resection of an ACTH-secreting pituitary microadenoma. Postoperatively, serum cortisol fell to <5 µg/dL, indicating secondary adrenal insufficiency, and physiologic glucocorticoid replacement was initiated. Urine output remained normal (no evidence of vasopressin deficiency), and steroid replacement was titrated without adrenal crisis.

Discussion

Diagnostic considerations

CKD can lead to falsely normal UFC values due to impaired renal clearance of cortisol metabolites [8]. Therefore, alternative biochemical tests such as late-night serum cortisol or dexamethasone suppression are recommended in these patients [1,3]. The high-dose dexamethasone suppression observed here supported a pituitary origin, but confirmation by IPSS was critical given the inconclusive MRI findings.

Inferior petrosal sinus sampling

Since its introduction, IPSS has become the reference standard for distinguishing pituitary from ectopic ACTH production, with reported sensitivity and specificity of approximately 96% and 100%, respectively [4-6,9]. The test involves measuring ACTH gradients between central (petrosal) and peripheral samples, values ≥2 at baseline or ≥3 after corticotropin-releasing hormone (CRH) or desmopressin stimulation indicate a central source [5,9].

Desmopressin stimulation

Although CRH has traditionally been used, desmopressin is an effective and safe alternative that achieves comparable diagnostic accuracy [10]. In our case, desmopressin successfully elicited a diagnostic gradient, confirming the pituitary source.

Technical challenges and hybrid approach

Although the conventional IPSS technique uses bilateral femoral access, the procedure was originally performed via direct jugular puncture [2]. Variations in venous anatomy, hypoplasia, or catheterization failure may necessitate alternative routes. Direct ultrasound-guided jugular puncture offers an effective solution, minimizing procedural time and radiation exposure, and reducing the risk of complications such as cervical hematoma. Our case illustrates that combining femoral and direct jugular access allows complete bilateral sampling without compromising safety.

Conclusions

This case demonstrates the feasibility and safety of a hybrid IPSS approach combining right femoral and ultrasound-guided direct left jugular access. This method enabled successful completion of bilateral sampling when standard femoral catheterization failed. The case reinforces IPSS as a critical diagnostic tool for confirming pituitary Cushing’s disease, even in technically challenging circumstances.

References

  1. Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM: The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008, 93:1526-1540. 10.1210/jc.2008-0125
  2. Perlman JE, Johnston PC, Hui F, et al.: Pitfalls in performing and interpreting inferior petrosal sinus sampling: personal experience and literature review. J Clin Endocrinol Metab. 2021, 106:e1953-e1967. 10.1210/clinem/dgab012
  3. Findling JW, Raff H: Diagnosis and differential diagnosis of Cushing’s syndrome. Endocrinol Metab Clin North Am . 2021, 30:729-747. 10.1016/s0889-8529(05)70209-7
  4. Oldfield EH, Doppman JL, Nieman LK, et al.: Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing’s syndrome. N Engl J Med. 1991, 325:897-905. 10.1056/NEJM199109263251301
  5. Zampetti B, Grossrubatscher E, Dalino Ciaramella P, Boccardi E, Loli P: Bilateral inferior petrosal sinus sampling. Endocr Connect. 2016, 5:R12-R25. 10.1530/EC-16-0029
  6. Vassiliadi DA, Mourelatos P, Kratimenos T, Tsagarakis S: Inferior petrosal sinus sampling in Cushing’s syndrome: usefulness and pitfalls. Endocrine. 2021, 73:530-539. 10.1007/s12020-021-02764-4
  7. Yeh CH, Wu YM, Toh CH, Chen YL, Wong HF: A safe and efficacious alternative: sonographically guided internal jugular vein puncture for intracranial endovascular intervention. AJNR Am J Neuroradiol. 2012, 33:E7-E12. 10.3174/ajnr.A2416
  8. Kidambi S, Raff H, Findling JW: Limitations of nocturnal salivary cortisol and urine free cortisol in the diagnosis of mild Cushing’s syndrome. Eur J Endocrinol. 2007, 157:725-731. 10.1530/EJE-07-0424
  9. Wind JJ, Lonser RR, Nieman LK, DeVroom HL, Chang R, Oldfield EH: The lateralization accuracy of inferior petrosal sinus sampling in 501 patients with Cushing’s disease. J Clin Endocrinol Metab. 2013, 98:2285-2293. 10.1210/jc.2012-3943
  10. Malerbi DA, Mendonça BB, Liberman B, et al.: The desmopressin stimulation test in the differential diagnosis of Cushing’s syndrome. Clin Endocrinol (Oxf). 1993, 38:463-472. 10.1111/j.1365-2265.1993.tb00341.x

From https://www.cureus.com/articles/429423-ultrasound-guided-jugular-vein-access-for-inferior-petrosal-sinus-sampling-a-safe-and-feasible-technique#!/

Filed under: Cushing's, Diagnostic Testing, pituitary | Tagged: , , , | Leave a comment »

Ectopic Adrenocorticotropic Hormone (ACTH)-Dependent Cushing Syndrome Secondary to Olfactory Neuroblastoma

Posted on September 15, 2025 by MaryO

Abstract

Background/Objective

Ectopic adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome is a rare paraneoplastic disorder caused by excessive cortisol production from nonpituitary tumors. Olfactory neuroblastoma (ONB), a rare neuroendocrine malignancy of the sinonasal cavity, is an exceedingly uncommon source of ectopic ACTH production, with fewer than 25 cases reported worldwide. This report presents a case of ACTH-dependent Cushing syndrome due to ONB, emphasizing the diagnostic complexity, multidisciplinary management, and favorable clinical outcomes.

Case Presentation

A 70-year-old male presented with progressive muscle weakness, facial rounding, weight gain, hypertension, hypokalemia, and recurrent epistaxis. Laboratory evaluation revealed marked hypercortisolism and elevated plasma ACTH. Imaging demonstrated an expansile ethmoid sinus mass. Inferior petrosal sinus sampling excluded a pituitary source of ACTH. Endoscopic biopsy confirmed Hyams grade 2 ONB with positive immunohistochemical staining for neuroendocrine markers and ACTH. The patient received preoperative cortisol-lowering therapy and underwent complete endoscopic tumor resection followed by adjuvant radiotherapy. Postoperative assessment showed biochemical remission, resolution of Cushingoid features, and eventual recovery of the hypothalamic–pituitary–adrenal axis.

Discussion

This case highlights the importance of a systematic diagnostic approach that includes biochemical testing, imaging, inferior petrosal sinus sampling, and histopathology to identify ectopic ACTH sources. It demonstrates the necessity of collaboration among endocrinology, otolaryngology, neurosurgery, radiology, and oncology teams in managing rare ACTH-secreting tumors.

Conclusion

Timely diagnosis and definitive surgical resection of ACTH-producing ONB, along with endocrine stabilization and adjuvant radiotherapy, can lead to endocrine remission and improved long-term outcomes.

Key words

cushing syndrome
ectopic ACTH syndrome
neuroendocrine tumor
olfactory neuroblastoma
paraneoplastic syndrome

Abbreviations

ACTH

adrenocorticotropic hormone

AM

morning (ante meridiem)

DDAVP

desmopressin acetate

DHEA-S

dehydroepiandrosterone sulfate

EAS

ectopic ACTH syndrome

ENT

otolaryngology

IPSS

inferior petrosal sinus sampling

ONB

olfactory neuroblastoma

UFC

urinary free cortisol

Highlights

  • •
    Rare case of ectopic adrenocorticotropic hormone syndrome secondary to olfactory neuroblastoma
  • •
    Diagnostic challenges highlighted, including nondiagnostic inferior petrosal sinus sampling results
  • •
    Multidisciplinary approach enabled complete tumor resection and hormonal remission
  • •
    Preoperative ketoconazole minimized perioperative cortisol-related morbidity
  • •
    Adjuvant radiotherapy optimized local control in intermediate-risk olfactory neuroblastoma

Clinical Relevance

This case emphasizes the importance of recognizing olfactory neuroblastoma as a rare source of ectopic adrenocorticotropic hormone production. It demonstrates the value of integrated biochemical, radiologic, surgical, and histopathologic strategies to achieve endocrine remission and prevent recurrence.

Introduction

Ectopic ACTH syndrome (EAS) is a rare paraneoplastic disorder resulting in ACTH-dependent hypercortisolism, which manifests clinically as Cushing syndrome. Although it accounts for approximately 10% to 15% of ACTH-dependent cases, EAS is most frequently caused by bronchial carcinoids, small cell lung carcinoma, and pancreatic neuroendocrine tumors.1,2 In contrast, olfactory neuroblastoma (ONB), also known as esthesioneuroblastoma—a neuroendocrine malignancy of the upper nasal cavity—is a highly uncommon cause, with fewer than 1% of ONB cases associated with EAS.2,3
ONB arises from the olfactory epithelium and represents 2% to 3% of all sinonasal cancers.4,5 Its nonspecific presentation—ranging from nasal obstruction to epistaxis or anosmia—can delay diagnosis, and advanced tumors may invade adjacent structures such as the orbit or anterior cranial fossa.4,5 Histological overlap with other small round blue cell tumors necessitates immunohistochemical markers such as synaptophysin, chromogranin A, and S-100 for accurate identification.4,6 Factors such as age may influence tumor behavior, treatment selection, and prognosis.7
When ONB presents with ectopic ACTH secretion, the resulting hypercortisolism can lead to profound metabolic and cardiovascular complications.8,9 Due to its extreme rarity, this combination may not be initially suspected, delaying targeted therapy. This report presents a rare case of ACTH-dependent Cushing syndrome caused by ONB, highlighting the diagnostic complexity and need for multidisciplinary management.3,10

Case Presentation

A 70-year-old male presented with 6 weeks of progressively worsening generalized, proximal muscle weakness, intermittent headaches, recurrent nosebleeds, abdominal fullness, leg swelling, and an unexplained 20-pound (9.1 kg) weight gain.
His medical history includes asthma, benign prostatic hyperplasia, hyperlipidemia, and retained shrapnel in the neck from military service in Vietnam. He has no history of hypertension, diabetes, or smoking. His family history includes a father who suffered a myocardial infarction at 51 years old, a mother with rheumatoid arthritis and osteoporosis, and a maternal uncle with lupus. His current medications include rosuvastatin 5 mg daily, tamsulosin 0.4 mg daily, and an albuterol inhaler as needed.
On examination, his vital signs were notable for an elevated blood pressure of 171/84 mmHg (normal: <120/<80 mmHg), a temperature of 37.2 C (99 F) (normal: 36.1–37.2°C [97–99 F]), a heart rate of 91 bpm (normal: 60–100 bpm), a respiratory rate of 16 breaths per minute (normal: 12–20 breaths per minute), an oxygen saturation of 92% on room air (normal: ≥95%), and a weight of 78.9 kg (174 lb). Physical examination revealed a round plethoric face (“moon facies,”) a prominent dorsocervical fat pad (“buffalo hump,”) supraclavicular fullness, mild abdominal tenderness, violaceous striae across the abdomen, diffuse soft tissue swelling, and bilateral 2+ pitting edema in the lower extremities.

Diagnostic Assessment

Laboratory evaluation demonstrated severe hypokalemia (1.6 mEq/L [1.6 mmol/L]; normal: 3.5–5.0 mEq/L [3.5–5.0 mmol/L]) and marked fasting hyperglycemia (244.0 mg/dL [13.5 mmol/L]; normal: 70–99 mg/dL [3.9–5.5 mmol/L]), in addition to leukocytosis, hypochloremia, acute kidney injury, hypoproteinemia, and hypoalbuminemia.
Hormonal evaluation (Table 1) was consistent with ACTH-dependent hypercortisolism, characterized by elevated serum cortisol and ACTH concentrations, lack of suppression with dexamethasone, and suppressed dehydroepiandrosterone sulfate (DHEA-S). Aldosterone and plasma renin activity were within normal limits, effectively excluding primary hyperaldosteronism. Plasma free metanephrines and normetanephrines were also within reference ranges, ruling out pheochromocytoma. Repeat morning cortisol remained markedly elevated, and late-night salivary cortisol levels on 2 occasions were significantly above the reference range. Twenty-four-hour urinary free cortisol (UFC) was profoundly elevated on both collections. Following a 1 mg overnight dexamethasone suppression test, serum cortisol, ACTH, and dexamethasone levels confirmed a lack of cortisol suppression despite adequate dexamethasone absorption (Table 1). These results were consistent with ACTH-dependent Cushing syndrome.

Table 1. Hormone Panel Results

Test Value Normal Range
AM cortisol 29 μg/dL (800.11 nmol/L) (high) 3.7–19.4 μg/dL (102–535 nmol/L)
Repeated AM cortisol 26 μg/dL (717.34 nmol/L) (high) 3.7–19.4 μg/dL (102–535 nmol/L)
ACTH 250 pg/mL (30.03 pmol/L) (high) 10–60 pg/mL (2.2–13.2 pmol/L)
Plasma renin activity 1.2 ng/mL/h (1.2 μg/L/h) (normal) 0.2–4.0 ng/mL/h (0.2–4.0 μg/L/h)
DHEA-S 50 μg/dL (1.25 μmol/L) (low) 65–380 μg/dL (1.75–10.26 μmol/L)
Aldosterone, blood 4. 9 ng/dL (0.14 nmol/L) (normal) 4.0–31.0 ng/dL (110–860 pmol/L)
Plasma free metanephrines 0.34 nmol/L (0.034 μg/L) (normal) <0.50 nmol/L (<0.09 μg/L)
Plasma free normetanephrines 0.75 nmol/L (0.075 μg/L) (normal) <0.90 nmol/L (<0.16 μg/L)
Late-night salivary cortisol (1st) 0.27 μg/dL (7.45 nmol/L) (high) ≤0.09 μg/dL (≤2.5 nmol/L) (10 PM–1 AM)
Late-night salivary cortisol (2nd) 0.36 μg/dL (9.93 nmol/L) (high) ≤0.09 μg/dL (≤2.5 nmol/L) (10 PM–1 AM)
24-h urinary free cortisol (1st) 5880.0 μg/d (16 223 nmol/d) (high) ≤60.0 μg/d (≤165 nmol/d)
24-h urinary free cortisol (2nd) 4920.0 μg/d (13 576 nmol/d) (high) ≤60.0 μg/d (≤165 nmol/d)
AM cortisol level (after 1 mg dexamethasone) 12.3 μg/dL (339 nmol/L) (high) <1.8 μg/dL (<50 nmol/L) adequate suppression
Dexamethasone level(after 1 mg dexamethasone) 336 ng/dL (8.64 nmol/L) (normal) >200 ng/dL (>5.2 nmol/L) adequate absorption
ACTH level (after 1 mg dexamethasone) 242 pg/mL (53.27 pmol/L) (not suppressed) 10–60 pg/mL (2.2–13.2 pmol/L)
Abbreviations: μg/d = micrograms per day; μg/dL = Micrograms per deciliter; μg/L = micrograms per liter; μmol/L = micromoles per liter; AM = morning (Ante Meridiem); nmol/L = nanomoles per Liter; ng/mL/h = nanograms per milliliter per hour; pmol/L = picomoles per liter; pg/mL = picograms per milliliter; μg/L/h = micrograms per liter per hour; ng/dL = nanograms per deciliter; nmol/d = nanomoles per day.
Inferior petrosal sinus sampling (IPSS) was performed using contrast-enhanced fluoroscopy to confirm accurate catheter placement in both inferior petrosal sinuses. Absolute ACTH values obtained during IPSS are shown in (Table 2). The central-to-peripheral ACTH gradient at baseline was 1.1, which is below the diagnostic threshold of 2.0 typically required to support a pituitary source of ACTH. Following desmopressin acetate (DDAVP) stimulation, peak left: peripheral and right: peripheral ACTH ratios reached 1.7 and 1.5, respectively—well below the accepted post-stimulation cut-off of 3.0. In addition, the left: right petrosal ACTH ratios remained between 1.03 and 1.15 throughout the sampling period, indicating no significant lateralization of ACTH secretion. These findings are not consistent with Cushing’s disease and instead support a diagnosis of ectopic ACTH syndrome.

Table 2. Bilateral Petrosal Sinus and Peripheral Adrenocorticotropin Levels Before and After Intravenous Injection of Desmopressin Acetate (DDAVP) 10 mcg

Time post DDAVP, min Left petrosal ACTH Left: peripheral ACTH Right petrosal ACTH Right: peripheral ACTH Peripheral ACTH Left: right petrosal ACTH
0 165 pg/mL (36.3 pmol/L) 1.1 160 pg/mL (35.2 pmol/L) 1.1 150 pg/mL (33.0 pmol/L) 1.03
3 270 pg/mL (59.4 pmol/L) 1.6 245 pg/mL (53.9 pmol/L) 1.4 170 pg/mL (37.4 pmol/L) 1.10
5 320 pg/mL (70.4 pmol/L) 1.7 285 pg/mL (62.7 pmol/L) 1.5 185 pg/mL (40.7 pmol/L) 1.12
10 350 pg/mL (77.0 pmol/L) 1.4 305 pg/mL (67.2 pmol/L) 1.2 250 pg/mL (55.0 pmol/L) 1.15
Abbreviations: ACTH = adrenocorticotropin; DDAVP = desmopressin acetate; pg/mL = picograms per milliliter; pmol/L = picomoles per liter.
Magnetic resonance imaging of the head could not be performed due to a history of retained shrapnel in the neck from combat in Vietnam. Noncontrast computed tomography (CT) images of the head and paranasal sinuses revealed no evidence of a pituitary tumor but demonstrated an expansile mass measuring approximately 2.4 × 4.3 × 3.3 cm, centered within the bilateral ethmoid sinuses with extension into both the anterior and posterior ethmoidal air cells (Fig. 1A, B). A contrast-enhanced CT scan of the abdomen, performed following improvement in renal function, demonstrated marked bilateral adrenal gland enlargement (Fig. 1C).

  1. Download: Download high-res image (566KB)
  2. Download: Download full-size image

Fig. 1. (A) Axial and (B) coronal noncontrast computed tomography (CT) images of the head demonstrate a heterogeneous soft tissue mass at the anterior skull base extending toward the cribriform plate and into the right nasal cavity, involving the ethmoid sinus and eroding the lamina papyracea, resulting in medial displacement of the right orbital contents (blue arrows). (C) Axial contrast-enhanced CT of the abdomen reveals bilateral adrenal gland enlargement. (D) Whole-body single-photon emission computed tomography/computed tomography (SPECT/CT) using indium-111 pentetreotide demonstrates intense radiotracer uptake localized to the biopsy-confirmed esthesioneuroblastoma in the ethmoid sinuses, with no evidence of metastatic octreotide-avid lesions. (G) Coronal contrast-enhanced CT scan of the abdomen, performed after surgery, shows normalization in the size of both adrenal glands. (E) Coronal and (F) axial noncontrast CT images of the paranasal sinuses obtained postoperatively demonstrate complete surgical resection of the tumor.

The otolaryngology (ENT) team was consulted and recommended an endoscopic biopsy of the nasal mass. Histopathologic examination revealed a Hyams Grade 2 olfactory neuroblastoma (Fig. 2A, B), characterized by well-circumscribed lobules of small round blue cells with scant cytoplasm, a neurofibrillary background matrix, and low mitotic activity, without necrosis or rosette formation—findings typical of a moderately differentiated tumor in the Hyams grading system.

  1. Download: Download high-res image (1MB)
  2. Download: Download full-size image

Fig. 2. (A) Low-power H&E (4×) shows well-circumscribed lobules of small round blue cells with fibrovascular stroma and a neurofibrillary matrix; no necrosis or rosettes are seen. (B) High-power H&E (40×) reveals neoplastic cells with high nuclear-to-cytoplasmic ratio, hyperchromatic nuclei, and granular chromatin, consistent with Hyams Grade 2 ONB. (C) Chromogranin A shows granular cytoplasmic positivity in tumor nests, confirming neuroendocrine differentiation. (D) Synaptophysin shows diffuse granular cytoplasmic staining in tumor clusters, with negative stromal background. (E) S-100 highlights sustentacular cells in a peripheral pattern around tumor nests. (F) ACTH staining shows patchy to diffuse cytoplasmic positivity in tumor cells, confirming ectopic ACTH production in ONB. A nuclear medicine octreotide scan (111 Indium-pentetreotide scintigraphy) with single-photon emission computed tomography/computed tomography (SPECT/CT) demonstrated intense radiotracer uptake in the biopsy-proven esthesioneuroblastoma centered within the ethmoid sinuses, confirming the tumor’s expression of somatostatin receptors. There was no evidence of locoregional or distant metastatic disease demonstrating octreotide avidity (Fig. 1D).

Immunohistochemical staining supported the diagnosis: tumor cells were positive for chromogranin A (Fig. 2C), synaptophysin (Fig. 2D), and S-100 (Fig. 2E). Chromogranin A and synaptophysin are markers of neuroendocrine differentiation, confirming the tumor’s neuroendocrine origin. S-100 positivity in the sustentacular cells surrounding tumor nests is a classic feature of olfactory neuroblastoma. Staining was negative for neurofilament protein, AE1/AE3, and epithelial membrane antigen, helping exclude other small round blue cell tumors, such as neuroendocrine carcinoma or sinonasal undifferentiated carcinoma. Importantly, the tumor cells showed positive cytoplasmic staining for ACTH (Fig. 2F), confirming ectopic ACTH production by the tumor itself. This finding definitively links the olfactory neuroblastoma as the source of paraneoplastic ACTH secretion, consistent with the patient’s clinical picture of ectopic Cushing’s syndrome.

Treatment

Hypokalemia was corrected, and oral ketoconazole 200 mg twice daily was initiated preoperatively to mitigate the metabolic complications of hypercortisolism. Ketoconazole was discontinued on the day of surgery. The tumor was resected via an endoscopic endonasal approach. A blood sample was obtained immediately following tumor removal for measurement of ACTH and cortisol levels. Intravenous hydrocortisone (100 mg every 6 h) was initiated promptly thereafter. Postoperative cortisol and ACTH levels were undetectable: cortisol <5 μg/dL [<138 nmol/L] (normal: 5–25 μg/dL [138–690 nmol/L]); ACTH <5 pg/mL [<1.1 pmol/L] (normal: 10–60 pg/mL [2.2–13.3 pmol/L]). These findings confirmed successful surgical resection of the ACTH-secreting tumor. These issues extended the hospital stay and required treatment with antiseizure medications, antibiotics, and additional surgeries by ENT and Neurosurgery teams.

Outcome and Follow-Up

The patient demonstrated significant normalization of blood pressure (124/78 mmHg), fasting blood glucose (95 mg/dL [5.3 mmol/L]), and potassium (4.3 mEq/L [4.3 mmol/L]) within 2 weeks postoperatively. ACTH levels decreased from preoperative values of 220–250 pg/mL (48.4–55.2 pmol/L) to 29 pg/mL (5.5 pmol/L), and morning (AM) cortisol levels decreased from preoperative values of 29 μg/dL (800 nmol/L) to 12 μg/dL (331 nmol/L). These values were obtained at 2 weeks postoperatively. While early normalization of ACTH and cortisol levels could raise concern for residual disease, the patient’s subsequent sustained biochemical remission, clinical recovery, and a robust response to cosyntropin stimulation at 3 months post-op were reassuring. Adjuvant radiotherapy was also administered to mitigate any potential risk of recurrence.
He was subsequently transferred to an inpatient rehabilitation facility while receiving oral hydrocortisone replacement therapy, during which his functional status progressively improved. The patient was later discharged home on oral hydrocortisone replacement therapy with plans for continued outpatient physical therapy. Hydrocortisone was gradually tapered and discontinued 3 months after surgery, at which point blood pressure (122/76 mmHg), fasting glucose (90 mg/dL [5.0 mmol/L]), potassium (4.2 mEq/L [4.2 mmol/L]), ACTH (25 pg/mL [4.9 pmol/L]), and AM cortisol (15 μg/dL [414 nmol/L]) demonstrated sustained normalization. Following administration of 250 mcg intramuscular cosyntropin, serum cortisol peaked at 21 μg/dL (580 nmol/L), confirming an adequate adrenal reserve and complete recovery of the hypothalamic–pituitary–adrenal axis. Additionally, late-night salivary cortisol was remeasured on 2 occasions after hydrocortisone discontinuation and found to be 0.04 μg/dL (1.10 nmol/L) and 0.03 μg/dL (0.83 nmol/L), both within normal reference limits (≤0.09 μg/dL [≤2.5 nmol/L]). A 24-hour UFC collected at the same time measured 38 μg/d (105 nmol/d), confirming biochemical resolution of hypercortisolism. Cushing’s stigmata, including muscle weakness and skin changes, showed marked improvement by 3 months postoperatively (Table 3).

Table 3. Timeline of Clinical and Biochemical Recovery Following Resection of Ectopic ACTH-Secreting Olfactory Neuroblastoma

Parameter Preoperative value 24–48 h Postop 2 wks postop 3 mo postop Normal range
Blood pressure 171/84 mmHg 140/80 mmHg 124/78 mmHg 122/76 mmHg <130/80 mmHg
Fasting glucose 244 mg/dL (13.5 mmol/L) 160 mg/dL (8.9 mmol/L) 95 mg/dL (5.3 mmol/L) 90 mg/dL (5.0 mmol/L) 70–99 mg/dL (3.9–5.5 mmol/L)
Potassium 1.6 mEq/L (1.6 mmol/L) 3.8 mEq/L (3.8 mmol/L) 4.3 mEq/L (4.3 mmol/L) 4.2 mEq/L (4.2 mmol/L) 3.5–5.0 mEq/L (3.5–5.0 mmol/L)
ACTH 220–250 pg/mL (48.4–55.2 pmol/L) <10 pg/mL (<2.2 pmol/L) 29 pg/mL (5.5 pmol/L) 25 pg/mL (4.9 pmol/L) 10–60 pg/mL (2.2–13.3 pmol/L)
AM cortisol 29 μg/dL (800 nmol/L) <5 μg/dL (<138 nmol/L) 12 μg/dL (331 nmol/L) 15 μg/dL (414 nmol/L); Cosyntropin peak: 21 μg/dL (580 nmol/L) 5–25 μg/dL (138–690 nmol/L); adequate response >18 μg/dL (500–550 nmol/L)
LNSC 0.27/0.36 μg/dL (7.45/9.93 nmol/L) — — 0.04/0.03 μg/dL (1.10/0.83 nmol/L) ≤0.09 μg/dL (≤2.5 nmol/L) (10 PM–1 AM)
UFC (24-h) 5880/4920 μg/d (16 223/13 576 nmol/d) — — 38 μg/d (105 nmol/d) ≤60 μg/d (≤165 nmol/d)
Cushing’s Stigmata Moon facies, dorsocervical fat pad, violaceous striae, severe muscle weakness No change Partial improvement: BP/glucose control; decreased edema Marked improvement; muscle strength restored; striae fading Not applicable
Abbreviations: ACTH = adrenocorticotropin; mmHg = illimeters of mercury; mEq/L = milliequivalents per liter; mg/dL = milligrams per deciliter; mmol/L = millimoles per liter; μg/dL = micrograms per deciliter; AM = morning (Ante Meridiem); pg/mL = picograms per milliliter; pmol/L = picomoles per liter; nmol/L = nanomoles per liter.
dfA follow-up CT scan of the adrenals with contrast, performed following improvement in renal function, confirmed normalization in the size of the previously enlarged adrenal glands (Fig. 1E). A follow-up CT of sinuses without contrast confirmed complete resection of the tumor (Fig. 1F, G).
Adjuvant radiotherapy was recommended in view of the patient’s Kadish stage B tumor, Hyams grade 2 histology, and the elevated risk of local recurrence inherent to olfactory neuroblastoma. Despite complete surgical excision, radiotherapy was pursued to mitigate recurrence risk, particularly considering the tumor’s ectopic ACTH secretion, which suggested biologically aggressive behavior, as well as the patient’s satisfactory functional status and anticipated favorable treatment tolerance. A total of 30 fractions of 2 Gy were administered using volumetric modulated arc therapy.

Discussion

Diagnostic Considerations

EAS poses a significant diagnostic challenge due to its variable presentation and the urgency of identifying the source of ACTH excess. ONB, although rare, should be considered in patients with ACTH-dependent Cushing syndrome who present with sinonasal masses. ONB accounts for only 2% to 3% of all malignant sinonasal tumors,4,6 with fewer than 25 cases documented as sources of ectopic ACTH production.3,11,12
While ectopic ACTH syndrome remains the most well-recognized endocrine manifestation of ONB, a broader spectrum of paraneoplastic syndromes has also been described. These include syndrome of inappropriate antidiuretic hormone secretion, paraneoplastic hypercalcemia—often mediated by parathyroid hormone–related protein—and catecholamine excess mimicking pheochromocytoma.11 These atypical presentations underscore the neuroendocrine complexity of ONB and the diagnostic challenges they pose.
Diagnosis involves biochemical confirmation of hypercortisolism using low-dose dexamethasone suppression, 24-hour UFC, late-night salivary cortisol, and plasma ACTH levels. Interestingly, despite markedly elevated ACTH levels, our patient exhibited a low DHEA-S concentration and a normal aldosterone level. This biochemical pattern supports previous observations that EAS may present with a dissociation in adrenal steroidogenesis. Chronic hypercortisolemia may suppress the zona reticularis,13 while ectopic ACTH-producing tumors may secrete aberrant precursors that preferentially stimulate glucocorticoid rather than androgen synthesis.14 Cortisol excess can also downregulate key enzymes such as 17,20-lyase and SULT2A1, thereby impairing DHEA-S production.15 Moreover, the rapid onset and severity of ectopic ACTH production may preclude the compensatory DHEA-S rise typically observed in pituitary-driven Cushing disease. Although cortisol excess is known to suppress the renin-angiotensin-aldosterone system, aldosterone levels may remain detectable in certain EAS cases, particularly in early-stage or physiologically variable presentations.16
Once ACTH-dependence is established, localization of the tumor becomes essential. IPSS, although considered the gold standard for distinguishing pituitary from ectopic ACTH sources, may yield inconclusive results in cases of ONB due to altered venous drainage pathways.3 Functional imaging with 111In-octreotide single-photon emission computed tomography/computed tomography or 68Ga-DOTATATE positron emission tomography/computed tomography facilitates localization of neuroendocrine tumors that express somatostatin receptors. Histopathologic confirmation using ACTH immunostaining and neuroendocrine markers such as chromogranin A, synaptophysin, and S-100 is essential to confirm diagnosis.

Therapeutic Approach and Challenges

Surgical resection remains the cornerstone of management for ACTH-producing ONB.9 Endoscopic endonasal approaches are preferred when anatomically feasible due to their minimally invasive nature and favorable access to the anterior skull base. Preoperative pharmacologic inhibition of cortisol biosynthesis (utilizing ketoconazole, which was specifically selected for our patient, metyrapone, or etomidate) represents a critical intervention to attenuate hypercortisolism-related metabolic complications and minimize perioperative morbidity.3,8 Intraoperative glucocorticoid replacement should be administered following tumor resection to prevent adrenal insufficiency. Postoperative complications—such as cerebrospinal fluid leak or infection—require prompt multidisciplinary intervention.
Adjuvant radiotherapy is generally recommended for intermediate-to high-grade ONBs, even after gross total resection, given their aggressive behavior and high risk of recurrence. Volumetric modulated arc therapy delivers precise radiation doses while minimizing toxicity to adjacent structures.5,9 Platinum-based chemotherapy remains a therapeutic option in patients with unresectable or metastatic disease.9
Emerging therapeutic strategies include somatostatin receptor–directed theranostics. Zhi et al (2025) recently demonstrated the dual diagnostic and therapeutic potential of 68Ga-DOTATATE positron emission tomography/computed tomography imaging and 177Lu-DOTATATE peptide receptor radionuclide therapy in ONB, offering promising future directions for patients with advanced or somatostatin receptor–positive disease.17

Prognosis and Future Directions

The prognosis of ONB is influenced by Kadish staging, Hyams histologic grading, and treatment strategy. Recurrence rates are reported to range from 30% to 60%,9,18 and 5-year survival rates vary from 45% to 80% depending on tumor grade, stage, and completeness of resection.6,19 Early detection, complete surgical resection, and multimodal therapy, including radiotherapy, are associated with improved outcomes. Lifelong follow-up with serial imaging and endocrine evaluation is essential to monitor for recurrence and late-onset adrenal insufficiency.10,19
Continued advancements in molecular imaging and targeted therapies, particularly those leveraging somatostatin receptor biology, may expand the therapeutic landscape for patients with recurrent or progressive ONB.

Conclusion

This case highlights the importance of timely diagnosis, comprehensive biochemical and radiologic assessment, and coordinated multidisciplinary management in ACTH-producing ONB. In addition to surgery and preoperative endocrine stabilization, adjuvant radiotherapy and long-term surveillance are critical components of care. As somatostatin receptor–based imaging and theranostic therapies evolve, they offer exciting opportunities to individualize treatment in this rare but challenging neuroendocrine malignancy.

Statement of Patient Consent

Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Disclosure

The author has no conflict of interest to disclose.

References

Filed under: Cushing's, Rare Diseases | Tagged: , , , , , , , , , , , | Leave a comment »

A Case Series of Bilateral Inferior Petrosal Sinus Sampling Using Desmopressin for Evaluation of ACTH-Dependent Cushing’s Syndrome in Pediatric Patients

Posted on June 11, 2025 by MaryO

Abstract

Background

Pediatric Cushing Syndrome (CS) is rare and difficult to diagnose, especially when distinguishing ACTH-dependent subtypes. Bilateral inferior petrosal sinus sampling (BIPSS) is an essential but technically challenging procedure for this purpose. Because corticotropin-releasing hormone (CRH), the standard stimulant, has limitations, desmopressin is being explored as an alternative. This study assesses desmopressin-stimulated BIPSS for its diagnostic accuracy and tumor localization in pediatric CS within an Iranian cohort, addressing a gap in pediatric-specific diagnostic strategies and offering insights into the applicability of desmopressin in this context.

Methods

Four pediatric patients with inconclusive pituitary imaging and suspected Cushing’s disease (CD) underwent BIPSS with desmopressin at Taleghani Hospital, Tehran, Iran, between August 2015 and March 2019. Sensitivity of BIPSS for CD diagnosis was assessed, and tumor localization accuracy was evaluated during surgery.

Results

Bilateral IPSS demonstrated a sensitivity of 100% for diagnosing CD in pediatric patients. However, accuracy for tumor lateralization was moderate, with only 50% concordance between BIPSS lateralization and surgical findings. Specifically, two out of four patients had correct lateralization confirmed during surgery, while one patient with left lateralization was consistent with hypophysectomy findings. These discrepancies highlight challenges such as anatomical and drainage variations that can lead to mislocalization.

Conclusion

Desmopressin enhances the sensitivity of BIPSS for diagnosing pediatric CD, presenting as a viable alternative to CRH stimulation. Despite high sensitivity, caution is advised when interpreting BIPSS results for tumor localization. Further research is needed to optimize diagnostic strategies for pediatric CS management.

From https://link.springer.com/article/10.1007/s40200-025-01634-4

Filed under: Cushing's, Diagnostic Testing, pituitary | Tagged: , , , , , , | Leave a comment »

PET/MRI may improve diagnosis of Cushing disease

Posted on April 5, 2024 by MaryO

PET/MRI could become the diagnostic method of choice over MRI alone for identifying small pituitary tumors associated with Cushing disease, according to a study published March 21 in the Journal of Nuclear Medicine.

In patients diagnosed with the disease yet who had inconclusive MRI results, PET/MRI was positive in 100% of cases, noted lead author Ilanah Pruis, a doctoral student at Erasmus University Medical Center in Rotterdam, Netherlands.

“This multimodal imaging technique provides a welcome improvement for diagnosis, planning of surgery, and clinical outcome in patients with Cushing disease,” the authors wrote.

Cushing disease is characterized by small tumors in pituitary glands, which causes them to secrete excess cortisol, the authors explained. While it is a rare disease, over time it can cause severely disabling conditions, such as high blood pressure or type II diabetes.

Currently, guidelines recommend the use of MRI and inferior petrosal sinus sampling (IPSS) to diagnose these tumors. IPSS is an invasive procedure in which cortisol hormone levels are sampled from the veins that drain the pituitary gland.

In up to 40% of patients, however, MRI is inconclusive, as the lesions are smaller than 10 millimeters in diameter. Even advanced MRI techniques, such as dynamic perfusion imaging, can leave small lesions undetected in up to one third of patients, the authors noted.

In preclinical work, PET imaging using a radiotracer named F-18 FET has been shown to bind with high affinity to a molecular target in pituitary tumors, and in this study, the researchers aimed to test this technique combined with MRI in a multimodal approach.

The researchers analyzed results from 22 patients (68% women; mean age 48 years) who underwent F-18 FET PET/MRI at Erasmus MC between February 2021 and December 2022. All patients showed a clear pituitary tumor F-18 FET-PET/MRI, whereas reading of the MRI alone yielded a suspected lesion in only 50%, the authors found.

T1-weighted postgadolinium MR images (A and C) and F-18 FET-PET/MR images (B and D) centered at pituitary before (A and B) and after (C and D) transsphenoidal surgery. This patient with Cushing disease showed clear focal uptake (B) but no clear lesion on previously obtained and accompanying MRI (A). Postoperative tissue analysis did confirm resection of small pituitary adenoma/PitNET, and postoperative F-18 FET-PET showed no residual uptake (D). Image courtesy of the Journal of Nuclear Medicine.T1-weighted postgadolinium MR images (A and C) and F-18 FET-PET/MR images (B and D) centered at pituitary before (A and B) and after (C and D) transsphenoidal surgery. This patient with Cushing disease showed clear focal uptake (B) but no clear lesion on previously obtained and accompanying MRI (A). Postoperative tissue analysis did confirm resection of small pituitary adenoma/PitNET, and postoperative F-18 FET-PET showed no residual uptake (D). Image courtesy of the Journal of Nuclear Medicine.

Importantly, 16 patients underwent treatment based on the results — either surgery, Gamma Knife, or CyberKnife therapy — with 12 of these patients achieving short-term remission, the authors noted.

“[F-18 FET-PET/MRI] is of great clinical value because it allows precision surgery and targeted Gamma Knife or CyberKnife therapy,” the group wrote.

The researchers noted that only one previous study evaluated F-18 FET-PET/MRI in these patients and that their study was limited, given the relatively small number of patients.

“Future studies will be directed at head-to-head comparisons of the performance of F-18 FET- PET and other diagnostic techniques, including advanced MRI sequences… preferably in patients at the time of initial clinical presentation,” the authors concluded.

A link to the full study can be found here.

From https://www.auntminnie.com/clinical-news/molecular-imaging/article/15667496/petmri-may-improve-diagnosis-of-cushing-disease

Filed under: Cushing's, Diagnostic Testing, pituitary | Tagged: , , , , , | Leave a comment »

Next Page »