Diabetic Ketoacidosis as the First Manifestation of Ectopic Cushing’s Syndrome

Posted on December 9, 2025 by MaryO

Abstract

Diabetic ketoacidosis is an exceptionally rare initial manifestation of ectopic adrenocorticotropic hormone (ACTH) syndrome. A 42-year-old woman with multiple cardiovascular risk factors was admitted to the emergency room with diabetic ketoacidosis. During stabilization, florid Cushing’s syndrome was suspected and confirmed biochemically as ACTH-dependent. Further biochemical and imaging surveys led to the diagnosis of a 25×15 mm nodule in the lingula. Thoracic surgery was performed, and pathology revealed a neuroendocrine tumor positive for ACTH.

We reviewed eight additional cases of diabetic ketoacidosis associated with Cushing’s syndrome from PubMed. Clinicians should bear in mind this etiology of diabetic ketoacidosis based on clinical signs and younger patients with multiple, age-atypical comorbidities. This would permit the expedited targeted stabilization of Cushing’s syndrome and the suitable institution of the diagnostic approach and treatment for this challenging syndrome.

Introduction

Endogenous Cushing’s syndrome (CS) is a rare disease resulting from pathological glucocorticoid excess of neoplastic origin, with an annual incidence of two/three cases per 1.000.000 inhabitants [1]. The severity of CS varies widely from mild to severe and, if left untreated, can be fatal due to the increased risk of cardiovascular events and opportunistic infections. Endogenous CS is classified as adrenocorticotropic hormone (ACTH)-dependent (80%) and -independent (20%) forms. ACTH-dependent CS is further divided into Cushing’s disease (68%) when the pituitary is the source of excess ACTH, or ectopic ACTH syndrome (EAS; 12%) when the cause is a non-pituitary neoplasia of neuroendocrine origin. EAS has an annual incidence of one case per 1.250.000 inhabitants and is more frequent in men [1]. It can be secondary to an aggressive small-cell lung carcinoma (19%), but the majority of cases arise from indolent lesions such as bronchial and thymic (combined: 33%) or pancreatic (12%) neuroendocrine tumors (NET) [1-3]. These indolent lesions usually evolve clinically over 6 to 24 months, whereas carcinomas have a faster onset. Symptoms and signs of excess cortisol in EAS are usually indistinguishable from Cushing’s disease. The most discriminatory signs of CS are plethora, purplish striae, proximal myopathy, and spontaneous ecchymosis. Multiple vascular risk factors, namely, hypertension, diabetes mellitus (DM), dyslipidemia, and obesity (especially central adiposity), occurring in a young patient, should also raise suspicion for CS [2]. Diabetic ketoacidosis (DKA) as the inaugural presentation of CS is very rare [1-3]. We searched through PubMed and reviewed articles in English where this association was reported using keywords such as “Cushing’s syndrome”, “Diabetic ketoacidosis”, “hypercortisolism”, and “Ectopic ACTH syndrome”. CS presenting initially with DKA is, as to this day, limited to eight case reports [4-11]. The clinical recognition of this syndrome as a very rare etiology of DKA is of paramount importance, as it is usually severe and relates to sepsis and several biochemical, hematologic, and hemodynamic derangements that should be addressed expeditiously with targeted drugs [3].

Here, we describe a female patient with florid clinical EAS uncovered upon her admission to the Emergency Room (ER) due to DKA. We searched through PubMed and reviewed articles in English where this association was reported, using keywords such as “Cushing’s syndrome”, “Diabetic ketoacidosis”, “hypercortisolism”, and “Ectopic ACTH syndrome”.

This article was previously presented as a meeting abstract at the 2024 ENDO, The Endocrine Society Annual Meeting on June 3, 2024.

Case Presentation

A 42-year-old woman was admitted in June 2022 to the ER due to severe DKA and hypokalemia (Table 1) and mild coronavirus disease. Physical examination at initial presentation was also remarkable for grade 2 hypertension with hypertensive retinopathy. Florid Cushingoid features, including a “buffalo hump”, plethora, hirsutism, abdominal ecchymosis, and marked proximal limb sarcopenia were noted (Figure 1).

Patient's-Cushingoid-features
Figure 1: Patient’s Cushingoid features

The patient was transferred to the intensive care unit (ICU). A multimodal treatment plan was initiated, including intravenous insulin (total daily dose: 1.2U/Kg) as per the protocol for DKA, antihypertensives, and prophylactic doses of low-molecular-weight heparin. After resolution of DKA and hydroelectrolytic disturbances, a gasometric follow-up revealed metabolic alkalosis (pH 7.529). The patient was then able to report a six-month history of weight gain, secondary amenorrhea, impaired concentration and memory, ecchymoses, and proximal myopathy with frequent falls and dependency on relatives for daily life activities. No chronic diarrhea or flushing was reported. She also reported a fungal pneumonia, dyslipidemia, and hypertension in the last four months, and a diagnosis of DM treated with metformin two weeks before her admission to the ER. Family history was unremarkable. Biochemical surveys (Table 1) revealed ACTH-dependent hypercortisolism, low thyroid-stimulating hormone (TSH), and hypogonadotropic hypogonadism. High-dose dexamethasone suppression (HDDS) and corticotropin-releasing hormone (CRH) stimulation tests were not suggestive of a pituitary source of ACTH (Table 1). Pituitary magnetic resonance imaging was normal. While waiting for further investigations regarding the source of excess ACTH, the patient was started on 750 mg/day of metyrapone in three divided doses. The patient was started and discharged from the ward with hydrocortisone 10 mg in the morning and 5 mg at midday and in the afternoon. The dose of metyrapone was carefully adjusted during two months according to morning serum cortisol, but was rapidly decreased and stopped due to spontaneous clinical resolution of CS. In the postoperative follow-up (total: 23 months), Cushingoid features (plethora, dorsal fat pad, ecchymosis, central adiposity) continued to disappear, and she regained muscle mass and independence in her daily activities and remission from all glucocorticoid related-comorbidities was maintained (fasting glucose: 91 mg/dL; glycated hemoglobin (HbA1c): 5.8%; low-density lipoprotein (LDL) cholesterol: 138 mg/dL; triglycerides: 80 mg/dL). Twelve months after surgery, the patient was able to discontinue hydrocortisone upon biochemical evidence of restoration of adrenal function (cortisol peak at Synacthen test: 21.1 ug/dL; basal ACTH: 15.6 pg/mL). Her last (23 months after surgery) endocrine surveys (midnight salivary cortisol: 0.14 ug/dL; ACTH: 18 pg/mL) and thoracic CT showed no evidence of disease relapse.

Parameter Presentation 12-month follow-up Reference
Hemoglobin (g/dL) 12.8 – 12-15.5
White blood count (×103/uL) 11.3 – 4.0-11.5
Platelets (×103/uL) 331 – 150-400
Fasting blood glucose (mg/dL) 427 76 74-106
HbA1c (%) 9.6 5.6 <6.5
Serum sodium (mmol/L) 146 – 135-145
Serum potassium (mmol/L) 2.7 – 3.5-5.1
Serum creatinine (mg/dL) 0.32 0.59 0.67-1.17
pH 7.17 – 7.35-7.45
HCO3– (mmol/L) 4.4 – 21-26
Anion gap 35 – 7
IGF-1 (ng/mL) 89.8 – 77-234
FSH (mUI/mL) 0.9 –¥ 3.5-12.5
LH (mUI/mL) <0.1 –¥ 2.4-12.6
Prolactin (ng/mL) 8.8 – 4.0-24.3
TSH (UI/mL) 0.02 0.61 0.35-4.94
Free T4 (ng/dL) 1.26 1.02 0.7-1.48
Midnight salivary cortisol (ug/dL) 25.5 2.4* <7.5
UFC (ug/dL) 1072.5 74.5* <176
Cortisol at 1 mg overnight DST (ug/dL) 25.7 – <1.8
Cortisol, baseline (ug/dL) 30.9 11.4* 5-18
Cortisol after HDDS test (ug/dL) 42.1 – Refer to reference 2
ACTH, baseline (pg/mL) 93.4 22.1* 7.2- 63.3
ACTH, maximum after CRH (pg/mL) 101.8 – Refer to reference 2
Table 1: Biochemical surveys of the patient at baseline and at the 12-month follow-up

* After metyrapone washout

¥ Gonadotropins not repeated due to resumption of regular menses

Abbreviations: ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; DST, dexamethasone suppression test; FSH, follicle-stimulating hormone; HbA1c, hemoglobin A1c; HDDS, high-dose dexamethasone suppression; IGF-1, insulin-like growth factor type 1; LH, luteinizing hormone; TSH, thyroid-stimulating hormone; UFC, urinary free cortisol

She was referred for inferior petrosal sinus sampling (IPSS) but it was postponed for several months due to healthcare strikes. While waiting for IPSS, she performed a thoracic computerized tomography (CT) scan to exclude EAS, which revealed thymic hyperplasia and a 25×15 mm, well-defined nodule in the lingula (Figure 2).

Thoracic-CT-scan-revealed-a-25x15-mm,-well-defined-nodule-in-the-lingula
Figure 2: Thoracic CT scan revealed a 25×15 mm, well-defined nodule in the lingula

A 68Ga-DOTANOC positron emission tomography-computed tomography (PET/CT) was then performed and showed a single uptake in the same lung region (Figure 3).

68Ga-DOTANOC-PET/CT-showing-a-single-uptake-in-the-lingula.
Figure 3: 68Ga-DOTANOC PET/CT showing a single uptake in the lingula.

Abbreviations: PET/CT, positron emission tomography-computed tomography

The patient was referred to thoracic surgery and underwent lingulectomy plus excisional biopsy of the interlobar lymph nodes. Pathology revealed a typical carcinoid/neuroendocrine tumor (NET), grade one (Ki67<2% and <2 mitosis per high-power field (HPF)) without involved lymph nodes, which showed positivity for ACTH (Figure 4).

Immunohistochemistry-findings
Figure 4: Immunohistochemistry findings

a- hematoxylin and eosin x400 magnification, b- synaptophysin x100 magnification, c- chromogranin A x400 magnification, d- ACTH x400 magnification, e- Ki-67 x100 magnification.

The patient was started on hydrocortisone 10 mg in the morning and 5 mg at midday and afternoon, which was discontinued 11 months later due to restoration of adrenal function (cortisol peak at Synacthen test: 21.1 ug/dL; basal ACTH: 15.6 pg/mL). In the postoperative follow-up, Cushingoid features continued to disappear, and she regained muscle mass and independence in her daily activities. Her last CT showed no evidence of disease.

Discussion

Severe CS (SCS) is defined by random serum cortisol above 41 ng/dL and/or a urinary free cortisol (UFC) more than fourfold the upper limit of normal and/or severe hypokalemia (<3.0 mmol/L), along with the recent onset of one or more of the following: sepsis, opportunistic infection, refractory hypokalemia, uncontrolled hypertension, edema, heart failure, gastrointestinal bleeding, glucocorticoid-induced acute psychosis, progressive debilitating myopathy, thromboembolism, uncontrolled hyperglycemia and ketoacidosis [3]. SCS results in high morbidity and mortality, requiring a rapid recognition and targeted therapy of the uncontrolled hypercortisolism [3]. Patients with SCS usually have florid signs, and straightforward clinical suspicion is possible, except in cases of ECS due to small-cell lung carcinoma, where the rapid onset of hypercortisolism and related morbidity precedes the development of clinical stigmata [2,3]. The gasometric parameters in DKA associated with SCS can also provide clues for the presence of CS. The mineralocorticoid effect of excess cortisol leads to metabolic alkalosis through increased hydrogen excretion in the distal nephron, which is masked by metabolic acidosis due to excess β-hydroxybutyrate and acetoacetate [6,12,13]. This mixed acid-basic disorder can be suspected by a ratio of ∆anion gap to ∆HCO3 of higher than one, which is not seen in pure metabolic acidosis. Additionally, after treating the DKA by decreasing ketones through the inhibition of its production by insulin and increased renal excretion with improved renal perfusion, metabolic alkalosis may supervene in gasometric monitoring, as seen in our report and others [6,9]. In rare cases, SCS can also lead to diabetic ketoalkalosis instead of DKA [1]. Several factors may contribute to the predominant alkalosis, namely, decreased hydrogen due to high renal excretion (excess mineralocorticoid effect), intracellular shift (due to severe hypokalemia), gastrointestinal losses (vomiting), and hyperventilation due to pulmonary diseases (as in heavy smokers) [13,14].

The main priorities in managing SCS are to control opportunistic infections, hypokalemia, DM, hypertension, and psychosis, and, importantly, investigations of the etiology of CS should be postponed until clinical stabilization [3]. The control of glucocorticoid-induced complications should encompass therapies to stabilize/reverse the CS induced morbidity (e.g., large-spectrum antibiotics for opportunistic infections; spironolactone for hypokalemia; insulin for DM) followed by targeted treatment of hypercortisolism [3]. Several oral adrenolytic agents are available and have proved their usefulness in SCS, namely, metyrapone (onset: hours; UFC normalization: 83%), ketoconazole/levoketoconazole (onset: days; UFC normalization: 70-81%), osilodrostat (onset: hours; UFC normalization: 82%), and mitotane (onset: days to weeks; UFC normalization: 72-82%). They can be used in monotherapy or in combination therapy, the latter strategy increasing the efficacy with lower doses of drugs and a lower risk of side effects [3,14]. Additionally, as first-line therapy for patients with an unavailable oral route (e.g., glucocorticoid-induced psychosis), or as second-line therapy when other adrenolytic agents have failed to control hypercortisolism, the anesthetic etomidate can be used under multidisciplinary supervision in an ICU, and it is highly effective (~100%) in controlling SCS within hours, in doses that do not induce anesthesia [3]. If medical therapy proves unsuccessful, bilateral adrenalectomy may be considered after careful clinical judgement, as it is highly effective in life-threatening SCS uncontrolled by medical therapy. Nevertheless, all attempts should be made to reduce hypercortisolemia with medical therapy before surgery [3].

DKA, as the inaugural presentation of CS, was previously published in eight case reports [4-11] (Table 2). Briefly, and including our case, almost all reports were severe (77.8%), mainly from EAS (55.6%) or pituitary adenomas (33.3%), and with a female preponderance (77.8%).

Reference Gender Age Florid CS signs Severe CS Etiology of CS Definitive treatment
Uecker JM, et al. [4] Female 43 Yes Yes EAS (duodenal NET) Pancreaticoduodenectomy
Kahara T, et al. [5] Male 53 No No ACTH-independent Adrenalectomy
Weng Y, et al. [6] Female 28 Yes Yes Cushing’s disease (macroadenoma) Transsphenoidal surgery
Catli G, et al. [7] Female 16 Yes Yes Cushing’s disease (microadenoma) Transsphenoidal surgery
Sakuma I, et al. [8] Female 56 Yes Yes EAS (pheochromocytoma) Adrenalectomy
Achary R, et al. [9] Female 48 Yes Yes Cushing’s disease (microadenoma) Transsphenoidal surgery
Cheong H, et al. [10]* Female 22 Unknown Unknown EAS (medullary thyroid carcinoma) None
Shangjian L, et al. [11] Male 46 Unknown Yes EAS (pheochromocytoma) Adrenalectomy
Our case Female 42 Yes Yes EAS (bronchial NET) Thoracic surgery
Table 2: Review of published cases of DKA as the inaugural presentation of CS

*Deceased

Abbreviations: ACTH, adrenocorticotropic hormone; CS, Cushing’s syndrome; EAS, ectopic ACTH syndrome; NET, neuroendocrine tumor

The etiology of CS should be investigated in diagnostic steps. After confirming hypercortisolism (low-dose dexamethasone suppression test, UFC, and/or late-night salivary cortisol) and its ACTH dependence (usually well above 20 pg/mL in EAS), the source of excess ACTH should be pursued. The CRH test is the most accurate dynamic test to distinguish between pituitary and ectopic sources of ACTH, followed by the desmopressin and HDDS tests. The combination of CRH and HDDS tests has an accuracy close to the IPSS, the gold standard to distinguish pituitary from ectopic sources of ACTH. If the investigation approach points to EAS, the most accurate exam to detect a lesion is 68Ga-DOTA-somatostatin analogue PET/CT, followed by 18F-FDG PET and conventional cross-sectional imaging [1-3].

After being discharged from the ward, our patient showed spontaneous resolution of hypercortisolism requiring the withdrawal of metyrapone and all medications to control glucocorticoid-induced morbidity, suggesting cyclic CS. This very rare variant of CS is present when periods of hypercortisolism alternate with periods of normal cortisol secretion, each phase lasting from days to years, which makes this type of CS very challenging to manage. The pituitary is the main source of cyclic CS, followed by EAS and, infrequently, the adrenal gland. The criteria of three peaks and two periods of normal or low cortisol levels needed to diagnose cyclic CS were not seen in the follow-up period of our patient, as after one peak and trough, we found and removed the source of EAS [1].

Conclusions

In the context of DKA, florid Cushing signs and multiple vascular risk factors occurring in a young patient should raise suspicion for Cushing’s Syndrome. The severity of this syndrome varies widely from mild to severe and, if left untreated, can be fatal due to the increased risk of cardiovascular events and opportunistic infections. Diabetic ketoacidosis precipitated by an endogenous excess of glucocorticoid is usually associated with severe Cushing’s syndrome and more frequently with EAS, which can have an abrupt onset. Prompt recognition and targeted stabilization of severe Cushing’s syndrome are crucial and should precede a definitive etiologic investigation.

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, 93:1526-40. 10.1210/jc.2008-0125
  2. Hayes AR, Grossman AB: Distinguishing Cushing’s disease from the ectopic ACTH syndrome: needles in a haystack or hiding in plain sight?. J Neuroendocrinol. 2022, 34:e13137. 10.1111/jne.13137
  3. Alexandraki KI, Grossman AB: Therapeutic strategies for the treatment of severe Cushing’s syndrome. Drugs. 2016, 76:447-58. 10.1007/s40265-016-0539-6
  4. Uecker JM, Janzow MT: A case of Cushing syndrome secondary to ectopic adrenocorticotropic hormone producing carcinoid of the duodenum. Am Surg. 2005, 71:445-6.
  5. Kahara T, Seto C, Uchiyama A, et al.: Preclinical Cushing’s syndrome resulting from adrenal black adenoma diagnosed with diabetic ketoacidosis. Endocr J. 2007, 54:543-51. 10.1507/endocrj.k06-071
  6. Weng YM, Chang MW, Weng CS: Pituitary apoplexy associated with cortisol-induced hyperglycemia and acute delirium. Am J Emerg Med. 2008, 26:1068.e1-3. 10.1016/j.ajem.2008.03.023
  7. Catli G, Abaci A, Tanrisever O, Kocyigit C, Sule Can P, Dundar BN: An unusual presentation of pediatric Cushing disease: diabetic ketoacidosis. AACE Clinical Case Reports. 2015, 1:53-8. 10.4158/EP14284.CR
  8. Sakuma I, Higuchi S, Fujimoto M, et al.: Cushing syndrome due to ACTH-secreting pheochromocytoma, aggravated by glucocorticoid-driven positive-feedback loop. J Clin Endocrinol Metab. 2016, 101:841-6. 10.1210/jc.2015-2855
  9. Acharya R, Kabadi UM: Case of diabetic ketoacidosis as an initial presentation of Cushing’s syndrome. Endocrinol Diabetes Metab Case Rep. 2017, 2017:10.1530/EDM-16-0123
  10. Cheong H, Koo HL: Medullary thyroid carcinoma with diabetic ketoacidosis: an autopsy case report and literature review. Forensic Sci Med Pathol. 2021, 17:711-4. 10.1007/s12024-021-00407-8
  11. Li S, Guo X, Wang H, Suo N, Mi X, Jiang S: Ectopic adrenocorticotropic hormone-secreting pheochromocytoma with severe metabolic disturbances: a case report. Int J Surg Case Rep. 2024, 116:109341. 10.1016/j.ijscr.2024.109341
  12. Kraut JA, Madias NE: Serum anion gap. Its uses and limitations in clinical medicine. Clin J Am Soc Nephrol. 2007, 2:162-74. 10.2215/CJN.03020906
  13. Uwaifo G, Varughese AG: ODP245 Syndrome of diabetic ketoalkalosis due to severe hypercortisolemia: a case series. J Endocr Soc. 2022, 6:A334. 10.1210/jendso/bvac150.693
  14. Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO, Tabarin A: Treatment of Cushing’s syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015, 100:2807-31. 10.1210/jc.2015-1818

From https://www.cureus.com/articles/426071-diabetic-ketoacidosis-as-the-first-manifestation-of-ectopic-cushings-syndrome#!/

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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).

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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.

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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

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Paraneoplastic Cushing Syndrome Unmasking Small Cell Lung Cancer: A Rare Presentation

Posted on August 31, 2025 by MaryO

Abstract

We present a case of a middle-aged woman who presented with chest pain and shortness of breath. Laboratory tests revealed persistent hypokalaemia, hyperglycaemia, and metabolic alkalosis despite treatment. Imaging identified a mass near the right hilum suggestive of lung malignancy. Endocrine evaluation showed markedly elevated cortisol and adrenocorticotropic hormone levels, consistent with paraneoplastic Cushing syndrome caused by ectopic hormone production. The analysis of the lung biopsy obtained through bronchoscopy confirmed the diagnosis of small cell lung cancer (SCLC). The patient was treated with metyrapone and spironolactone to stabilise her metabolic abnormalities and was subsequently referred for chemotherapy following a multidisciplinary team review. This case highlights the importance of recognising paraneoplastic syndromes as atypical presentations of malignancy and emphasises the role of a coordinated, multidisciplinary approach in diagnosis and management.

Introduction

Paraneoplastic syndromes, although relatively uncommon, can serve as important early clues to an underlying cancer. One such rare and often overlooked condition is ectopic adrenocorticotropic hormone (ACTH) secretion, a form of paraneoplastic Cushing’s syndrome. This occurs when a non-pituitary tumor, most commonly small cell lung carcinoma (SCLC) or another neuroendocrine tumor, produces ACTH, leading to overstimulation of the adrenal glands and excessive cortisol production.

Unlike the more familiar presentation of Cushing’s syndrome, ectopic ACTH production tends to manifest with severe metabolic disturbances, such as persistent hypokalemia, metabolic alkalosis, hyperglycemia, and muscle weakness, often without the typical physical features like moon facies or central obesity. These atypical and rapidly progressing symptoms can delay diagnosis, especially in patients with aggressive malignancies.

A thorough diagnostic workup, including hormone assays, suppression testing, and imaging, is essential to pinpoint the source of ectopic hormone production. Early identification is critical, as the metabolic derangements associated with this syndrome can lead to significant morbidity if left untreated.

In this report, we present the case of a middle-aged woman whose initial symptoms of chest pain and shortness of breath led to the discovery of SCLC with ectopic ACTH production. Her case highlights the importance of considering paraneoplastic syndromes in the differential diagnosis of unexplained electrolyte abnormalities and metabolic dysfunction.

Case Presentation

We report the case of a 52-year-old Caucasian woman who presented with a one-week history of diffuse chest pain, progressive shortness of breath, and MRC dyspnea grade 1 initially and then progressing to grade 2. She had no prior history of similar symptoms, and her past medical history was unremarkable. On examination, there were no significant findings on systemic review.

Initial laboratory investigations revealed marked hypokalaemia, with a serum potassium level of 2.4 mmol/L, alongside significant hyperglycaemia (blood glucose: 20 mmol/L) and metabolic alkalosis (arterial pH: 7.52, bicarbonate: 32 mmol/L). Notably, the patient had no known history of diabetes mellitus (Table 1).

Parameter Result Reference range Remarks
Serum potassium 2.4 mmol/L 3.5–5.0 mmol/L Marked hypokalaemia
Blood glucose 20 mmol/L 3.9–7.8 mmol/L (fasting) Significant hyperglycaemia; no known diabetes
Arterial pH 7.52 7.35–7.45 Metabolic alkalosis
Serum bicarbonate (HCO₃⁻) 32 mmol/L 22–28 mmol/L Elevated, consistent with metabolic alkalosis
Table 1: Initial laboratory investigations

This table summarizes the patient’s initial biochemical abnormalities, which include marked hypokalaemia, significant hyperglycaemia in the absence of known diabetes mellitus, and evidence of metabolic alkalosis on arterial blood gas analysis.

Despite intravenous and oral potassium supplementation, hypokalaemia persisted (Table 2). Hyperglycaemia also remained uncontrolled initially and was subsequently managed with insulin therapy.

Day Serum potassium (mmol/L) Reference range (mmol/L)
Day 1 2.4 3.5–5.0
Day 2 2.2 3.5–5.0
Day 3 2.8 3.5–5.0
Day 4 3.0 3.5–5.0
Day 5 2.9 3.5–5.0
Day 6 2.6 3.5–5.0
Day 7 2.7 3.5–5.0
Table 2: Daily serum potassium levels (day 1–day 7)

This table presents serum potassium levels measured over a seven-day period, demonstrating persistently low values consistent with hypokalaemia despite Intra-venous and oral pottasium replacement.

The patient presented with chest pain with respiratory symptoms, and an initial chest radiograph was suggestive of lung cancer (Figure 1).

Initial-chest-X-ray-
Figure 1: Initial chest X-ray

Posteroanterior chest radiograph showing a spiculated opacity in the right mid-zone (black arrow), suggestive of a pulmonary mass. The lesion projects over the right hilum and may represent a primary bronchogenic carcinoma. No gross pleural effusion or pneumothorax is identified.

Further evaluation with contrast-enhanced CT of the thorax revealed a right hilar mass suspicious for a bronchogenic malignancy (Figure 2).

Computed-tomography-(CT)-thorax-
Figure 2: Computed tomography (CT) thorax

Contrast-enhanced axial CT of the thorax demonstrating a spiculated right hilar mass (black arrow) measuring approximately 4 cm in greatest diameter. The mass is abutting the right main bronchus and associated with enlargement of adjacent mediastinal lymph nodes. No evidence of pleural effusion, chest wall invasion, or direct mediastinal involvement is seen on this image.

Given the persistent hypokalaemia, hyperglycaemia, and metabolic alkalosis, the possibility of a paraneoplastic endocrine syndrome was considered.

Endocrine workup showed markedly elevated serum cortisol levels (>2000 nmol/L), which failed to suppress following both low- and high-dose dexamethasone suppression tests. Plasma ACTH levels were also significantly elevated at 615 ng/L, consistent with ectopic ACTH secretion (Table 3).

Test Result Reference range Interpretation
Serum cortisol >2000 nmol/L Morning: 140–690 nmol/L Markedly elevated
Low-dose dexamethasone suppression test No suppression observed Cortisol suppressed to <50 nmol/L Abnormal; cortisol not suppressed
High-dose dexamethasone suppression test No suppression observed Cortisol suppressed by >50% Abnormal; cortisol not suppressed
Plasma ACTH 615 ng/L 10–60 ng/L Significantly elevated; ectopic ACTH secretion
Table 3: Endocrine workup results demonstrating elevated cortisol and adrenocorticotropic hormone (ACTH) levels with lack of suppression on dexamethasone testing

Serum cortisol  levels during low- and high-dose dexamethasone suppression tests. Despite administration of both low- and high-dose dexamethasone, serum cortisol levels remained markedly elevated. Plasma ACTH was also significantly elevated at 615 ng/L, consistent with ectopic ACTH secretion. Reference ranges are included for comparison.

Flexible bronchoscopy was performed, and biopsy of the right endobronchial tumour confirmed the diagnosis of SCLC (Figures 3, 4).

Bronchoscopic-view-of-the-right-hilar-mass-
Figure 3: Bronchoscopic view of the right hilar mass

Bronchoscopic view of the right bronchial tree demonstrating an irregular, lobulated endobronchial mass (black arrow). The lesion appears friable and hypervascular, partially obstructing the bronchial lumen, suggestive of a malignant endobronchial tumor.

Histological-section-of-small-cell-lung-cancer-(SCLC)
Figure 4: Histological section of small cell lung cancer (SCLC)

The arrow indicates a dense cluster of small, hyperchromatic tumour cells characteristic for SCLC.

The combination of persistent metabolic derangements, imaging findings, and histological confirmation supported the diagnosis of paraneoplastic Cushing’s syndrome secondary to ectopic ACTH production by SCLC. This rare clinical entity results from autonomous ACTH secretion by the tumour, leading to adrenal hyperplasia and excessive cortisol production.

Further staging workup was performed to assess the extent of the disease. Contrast-enhanced CT of the abdomen and MRI of the brain showed no evidence of distant metastasis. The disease was therefore classified as limited-stage SCLC.

The patient was commenced on metyrapone and spironolactone following a comprehensive discussion with the endocrinology team. This intervention resulted in the stabilisation of her potassium levels (Figure 5). Furthermore, in the context of her diagnosis of SCLC, a multidisciplinary team (MDT) was convened to discuss her case. Following this collaborative discourse, it was determined that a referral to the oncology department was warranted for the initiation of chemotherapy.

-Serum-potassium-trend-showing-initial-treatment-resistance-and-subsequent-stabilization-after-initiation-of-metyrapone-and-spironolactone
Figure 5: Serum potassium trend showing initial treatment resistance and subsequent stabilization after initiation of metyrapone and spironolactone

The graph demonstrates persistently low serum potassium levels despite aggressive intravenous and oral supplementation. Notable stabilization and eventual normalization of potassium values are observed following the initiation of metyrapone and spironolactone, indicated toward the end of the monitoring period. The shaded green area represents the normal reference range for serum potassium (3.5–5.5 mmol/L).

Discussion

This case illustrates a rare but clinically significant presentation of paraneoplastic Cushing’s syndrome secondary to ectopic ACTH secretion from SCLC. The patient’s initial symptoms of chest pain and breathlessness were non-specific, but persistent metabolic derangements, including hypokalaemia, hyperglycaemia, and metabolic alkalosis, proved refractory to standard treatment. These findings raised suspicion for an underlying endocrine disorder, leading to targeted hormonal evaluation [1,2].

Diagnostic workup revealed markedly elevated cortisol and ACTH levels, with failure to suppress during low- and high-dose dexamethasone suppression tests. Imaging and histological analysis subsequently identified a right hilar mass consistent with SCLC as the source of ectopic ACTH production. Although rare, ectopic ACTH syndrome is a well-recognised paraneoplastic manifestation of SCLC, reported in approximately 1-5% of cases [3]. It can lead to severe metabolic derangements that complicate management and worsen prognosis if unrecognised [4].

Management of ectopic Cushing’s syndrome requires prompt biochemical stabilisation to mitigate life-threatening complications such as hypokalaemia and hypertension. In this case, metyrapone, an 11β-hydroxylase inhibitor, effectively reduced cortisol synthesis, while spironolactone antagonised mineralocorticoid receptors to correct hypokalaemia. Other agents such as ketoconazole, mitotane, or intravenous etomidate may be considered in similar cases, especially when rapid cortisol control is needed or oral therapy is contraindicated [1,5]. However, these therapies carry risks of hepatotoxicity, adrenal insufficiency, or sedation, underscoring the importance of careful monitoring.

Definitive treatment of the underlying malignancy remains the cornerstone of care, as sustained control of ectopic ACTH production depends on tumour response. Early initiation of chemotherapy in SCLC can lead to a reduction in tumour burden and, in some cases, resolution of the paraneoplastic syndrome [4]. However, the metabolic instability associated with hypercortisolism often complicates oncologic management, highlighting the need for coordinated multidisciplinary care.

This case underscores the diagnostic challenge posed by ectopic Cushing’s syndrome and the importance of recognising paraneoplastic endocrine presentations in patients with unexplained metabolic derangements.

Conclusions

This case underscores the importance of considering paraneoplastic syndromes in patients with persistent, unexplained metabolic derangements such as hypokalaemia, hyperglycaemia, and metabolic alkalosis. In this patient, early recognition of ectopic ACTH secretion prompted targeted investigations, leading to the timely diagnosis of SCLC. This facilitated the initiation of appropriate endocrine therapy with metyrapone and spironolactone to stabilise the biochemical abnormalities and allowed safe progression to oncological management.

The case also highlights the complexities of managing ectopic Cushing’s syndrome, where severe metabolic disturbances can delay definitive cancer treatment. A coordinated, multidisciplinary approach involving endocrinology, oncology, and respiratory teams was crucial in optimising patient care and improving the likelihood of a favourable outcome.

For clinicians, this case reinforces the need to maintain a high index of suspicion for paraneoplastic endocrine disorders in patients with unexplained electrolyte and metabolic abnormalities, particularly when accompanied by respiratory symptoms or imaging suggestive of a pulmonary lesion. Early identification and intervention in such cases are critical for minimising morbidity and enabling timely cancer-directed therapy.

References

  1. Jeong C, Lee J, Ryu S, et al.: A case of ectopic adrenocorticotropic hormone syndrome in small cell lung cancer. Tuberc Respir Dis (Seoul). 2015, 78:436-9. 10.4046/trd.2015.78.4.436
  2. Ilias I, Torpy DJ, Pacak K, Mullen N, Wesley RA, Nieman LK: Cushing’s syndrome due to ectopic corticotropin secretion: twenty years’ experience at the National Institutes of Health. J Clin Endocrinol Metab. 2005, 90:4955-62. 10.1210/jc.2004-2527
  3. Coe SG, Tan WW, Fox TP: Cushing’s syndrome due to ectopic adrenocorticotropic hormone production secondary to hepatic carcinoid: diagnosis, treatment, and improved quality of life. J Gen Intern Med. 2008, 23:875-8. 10.1007/s11606-008-0587-z
  4. Perakakis N, Laubner K, Keck T, et al.: Ectopic ACTH-syndrome due to a neuroendocrine tumour of the appendix. Exp Clin Endocrinol Diabetes. 2011, 119:525-9. 10.1055/s-0031-1284368
  5. 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, 93:1526-40. 10.1210/jc.2008-0125

https://www.endocrine.org/journals/jcem-case-reports/unilateral-adrenalectomy-for-pediatric-cyclical-cushing-syndrome

 

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Osilodrostat Treatment for Adrenal and Ectopic Cushing Syndrome

Posted on May 9, 2025 by MaryO

Integration of Clinical Studies With Case Presentations

Maria Fleseriu, Richard J Auchus, Irina Bancos, Beverly MK Biller
Journal of the Endocrine Society, Volume 9, Issue 4, April 2025, bvaf027
https://doi.org/10.1210/jendso/bvaf027

Abstract

Although most cases of endogenous Cushing syndrome are caused by a pituitary adenoma (Cushing disease), approximately one-third of patients present with ectopic or adrenal causes.

Surgery is the first-line treatment for most patients with Cushing syndrome; however, medical therapy is an important management option for those who are not eligible for, refuse, or do not respond to surgery.

Clinical experience demonstrating that osilodrostat, an oral 11β-hydroxylase inhibitor, is effective and well tolerated comes predominantly from phase III trials in patients with Cushing disease. Nonetheless, reports of its use in patients with ectopic or adrenal Cushing syndrome are increasing. These data highlight the importance of selecting the most appropriate starting dose and titration frequency while monitoring for adverse events, including those related to hypocortisolism and prolongation of the QT interval, to optimize treatment outcomes. Here we use illustrative case studies to discuss practical considerations for the management of patients with ectopic or adrenal Cushing syndrome and review published data on the use of osilodrostat in these patients.

The case studies show that to achieve the goal of reducing cortisol levels in all etiologies of Cushing syndrome, management should be individualized according to each patient’s disease severity, comorbidities, performance status, and response to treatment. This approach to osilodrostat treatment maximizes the benefits of effective cortisol control, leads to improvements in comorbid conditions, and may ameliorate quality of life for patients across all types and severities of Cushing syndrome.

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From https://www.endocrine.org/journals/journal-of-the-endocrine-society/osilodrostat-treatment-for-adrenal-and-ectopic-cushing-syndrome

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Ectopic ACTH-secreting Pheochromocytoma Without Typical Signs of Cushing Syndrome

Posted on May 3, 2025 by MaryO

Abstract

This case report describes a 42-year-old female with a rare pheochromocytoma presenting without classic Cushingoid features but with uncontrolled hypertension, type 2 diabetes, and recurrent headaches. Despite the absence of typical signs, biochemical analysis revealed elevated cortisol and ACTH levels, and imaging showed a 6 cm adrenal mass. The patient was stabilized preoperatively with alpha-blockers and metyrapone before undergoing a successful laparoscopic adrenalectomy. Histopathology confirmed pheochromocytoma with aggressive features. Postoperatively, her blood pressure and symptoms improved, and her cortisol levels normalized. This case underscores the diagnostic challenges of ACTH-secreting pheochromocytomas without classic hypercortisolism signs and emphasizes the need for thorough endocrine and imaging assessments. Surgical resection remains the definitive treatment, with long-term follow-up essential to monitor for recurrence. This case contributes to the limited literature on the coexistence of pheochromocytoma and ectopic ACTH secretion.

Introduction

Ectopic ACTH-dependent tumors are rare, comprising approximately 5%–10% of Cushing syndrome cases, and are infrequently associated with pheochromocytomas, making this a unique presentation [1, 2]. Pheochromocytomas, though rare, can present as adrenal incidentalomas, often discovered during imaging for unrelated conditions. They represent 7% of adrenal incidentalomas and pose clinical challenges due to the risk of hormonal hypersecretion, including excess catecholamines and cortisol [1]. This case highlights the coexistence of an ectopic ACTH-producing tumor and pheochromocytoma, a combination rarely reported in the literature [3, 4]. While Cushing syndrome typically arises from adrenal or pituitary sources, ectopic ACTH secretion from pheochromocytomas presents a diagnostic and therapeutic challenge due to its rarity and aggressive potential [4–6]. Early diagnosis is crucial, particularly in cases with comorbidities like hypertension and diabetes, which are common in pheochromocytomas [1, 2]. This case underscores the need for a multidisciplinary approach to managing rare endocrine tumors.

Case report

A 42-year-old female from Mexico City presented with a history of treatment-resistant hypertension and a newly identified adrenal mass. She had no history of alcohol or tobacco use and led a generally healthy lifestyle. She was diagnosed with type 2 diabetes five years before symptoms appeared and developed hypertension five years before hospitalization, managed with valsartan and amlodipine verapamil.

The patient’s hypertension worsened, with blood pressure readings reaching 200/160 mmHg. She presented with asthenia and adynamia, and a CT scan revealed a 4 cm right adrenal mass, confirmed as 4.7 cm on a subsequent scan (Fig. 1). No signs of metastasis were observed. Upon hospital admission, her physical examination revealed a blood pressure of 95/84 mmHg, a heart rate of 95 beats per minute, a respiratory rate of 28 breaths per minute, and a systolic murmur. She exhibited no Cushingoid features.

 

The imaging identified a hyperdense area at the lower pole of the left kidney. A heterogeneous image was visualized in the right adrenal gland, characterized by a hypodense lesion measuring 40 × 47 × 43 mm, with a density of 36 Hounsfield units (HU) in the simple phase, 107 HU in the venous phase and 61 HU in the delayed phase (15 min), with an absolute washout of 64%.

Figure 1

The imaging identified a hyperdense area at the lower pole of the left kidney. A heterogeneous image was visualized in the right adrenal gland, characterized by a hypodense lesion measuring 40 × 47 × 43 mm, with a density of 36 Hounsfield units (HU) in the simple phase, 107 HU in the venous phase and 61 HU in the delayed phase (15 min), with an absolute washout of 64%.

Initial laboratory tests showed elevated white blood cells (11 000/mm3), hemoglobin of 12.5 g/dl, and platelet count of 305 000/mm3. Blood chemistry indicated hyperglycemia (132 mg/dl), hyponatremia (129 mEq/l), and hypokalemia (3.4 mEq/l). Cortisol levels were elevated at 31.53 μg/dl, and a 1 mg low-dose dexamethasone suppression test showed cortisol levels of 16.65 μg/dl and 14.63 μg/dl, suggesting ACTH-dependent Cushing syndrome.

ACTH levels were 24 pg/ml, which, while elevated, were not suppressed. However, elevated 24-h urinary metanephrines (9881 μg/24 h) confirmed the presence of pheochromocytoma. The patient’s aldosterone-to-renin ratio was measured, revealing a ratio of 4. The serum aldosterone level was 5 ng/dl (138 pmol/l), while plasma renin activity was recorded at 1.1 ng/ml/h.

Imaging revealed a 4.7 cm right adrenal mass with a density of 36 Hounsfield Units and an absolute washout of 64%, with no signs of malignancy (Fig. 1).

The patient’s hypertension was initially managed with prazosin and metoprolol, but her blood pressure spiked to 200/160 mmHg during a hypertensive crisis, requiring nitroprusside. Surgical intervention was planned after diagnosis was confirmed.

The patient underwent a successful laparoscopic right adrenalectomy. The tumor measured 6 cm, and histopathology confirmed a pheochromocytoma with a PASS score of 4, indicating potential for aggressive behavior (Table 1). Histological and immunohistochemical analysis revealed the tumor’s characteristic organoid pattern (Zellballen) with chromogranin and synaptophysin positivity in principal cells and S100 protein staining in sustentacular cells, consistent with pheochromocytoma (Fig. 2). Postoperatively, her blood pressure stabilized, and symptoms of palpitations and sweating resolved. She has weaned off antihypertensives, and a follow-up dexamethasone suppression test showed a significant reduction in cortisol levels (1.2 μg/dl), indicating successful tumor removal.

 

Table 1

Histopathological report.

HISTOPATHOLOGICAL DIAGNOSIS
Specimen from right adrenalectomy:
Pheochromocytoma measuring 6×6 cm (positive for chromogranin 7, synaptophysin +S100, with sustentacular cells staining positive)

  • Marked nuclear pleomorphism: 1 point
  • Diffuse growth pattern: 2 points
  • Capsular invasion: 1 point
Total: 4 points.
Tumors with a score greater than 4 may exhibit aggressive biological behavior.

 

Histological and microscopic findings of adrenal Pheochromocytoma. (A) Macroscopic appearance. The ovoid tissue specimen has a light, smooth, soft external surface. The cut surface reveals a dark inner surface with light and hemorrhagic areas. Two cystic lesions with smooth walls are observed in the center (gross view). (B) A well-demarcated hypercellular lesion with an organoid pattern (Zellballen), separated by thin fibrovascular septa (Hematoxylin and eosin stain, 40×). (C) Nest of polygonal principal cells with ample eosinophilic granular cytoplasm, well-defined plasma membranes, hyperchromatic nuclei, and mild nuclear pleomorphism. Adjacent to the principal cells are spindle-shaped sustentacular cells with eosinophilic cytoplasm (Hematoxylin and eosin stain, 400×). (D) Positive immunoreactivity for chromogranin in principal cells. (E) Intense cytoplasmic reaction for synaptophysin in principal cells (immunohistochemistry, 400×). (F) Positive immunoreactivity for S100 protein, showing nuclear and cytoplasmic staining in sustentacular cells (immunohistochemistry, 400×).

Figure 2

Histological and microscopic findings of adrenal Pheochromocytoma. (A) Macroscopic appearance. The ovoid tissue specimen has a light, smooth, soft external surface. The cut surface reveals a dark inner surface with light and hemorrhagic areas. Two cystic lesions with smooth walls are observed in the center (gross view). (B) A well-demarcated hypercellular lesion with an organoid pattern (Zellballen), separated by thin fibrovascular septa (Hematoxylin and eosin stain, 40×). (C) Nest of polygonal principal cells with ample eosinophilic granular cytoplasm, well-defined plasma membranes, hyperchromatic nuclei, and mild nuclear pleomorphism. Adjacent to the principal cells are spindle-shaped sustentacular cells with eosinophilic cytoplasm (Hematoxylin and eosin stain, 400×). (D) Positive immunoreactivity for chromogranin in principal cells. (E) Intense cytoplasmic reaction for synaptophysin in principal cells (immunohistochemistry, 400×). (F) Positive immunoreactivity for S100 protein, showing nuclear and cytoplasmic staining in sustentacular cells (immunohistochemistry, 400×).

Postoperatively, her course was uneventful, with stable blood pressure without antihypertensives. A follow-up evaluation revealed normal cortisol levels, and 24-h urinary metanephrines returned to normal (312 μg/24 h for metanephrines; 225 μg/24 h for normetanephrines). Repeat imaging showed no residual adrenal mass. At her most recent follow-up, the patient remained asymptomatic with normal laboratory values, and no recurrence has been detected.

Discussion

Ectopic ACTH-secreting pheochromocytomas are rare, accounting for a small percentage of ACTH-dependent Cushing syndrome cases [1, 4–6]. These tumors present diagnostic challenges, mainly when typical signs of Cushing syndrome, such as moon face, abdominal striae, or muscle weakness, are absent [3]. In this case, the patient exhibited only diabetes, uncontrolled hypertension, and recurrent headaches, symptoms that can also be attributed to pheochromocytoma itself [1]. The absence of Cushingoid features delayed the identification of ectopic ACTH secretion, making this case particularly difficult and unusual.

According to Gabi JN et al., most patients with ACTH-secreting pheochromocytomas present with severe hypercortisolism, including rapid weight gain and characteristic facial changes [3]. The absence of such features in this patient highlights the need to consider ectopic ACTH secretion in cases of adrenal masses, even without typical Cushing syndrome symptoms. This case illustrates how subtle presentations can lead to delayed diagnoses, emphasizing the importance of thorough evaluation in patients with adrenal tumors and metabolic abnormalities [1, 3].

The diagnostic approach for pheochromocytomas includes hormonal assays and imaging [7, 8]. Preoperative management for pheochromocytomas typically includes alpha-blockers to manage catecholamine excess [4, 7, 8]. This patient was managed with prazosin for blood pressure control and metyrapone to suppress cortisol production, consistent with clinical guidelines for managing ACTH-secreting tumors [5, 7, 8]. Despite the absence of Cushingoid features, careful preoperative preparation was essential to prevent complications during surgery.

Surgical resection is the definitive treatment for pheochromocytomas, particularly those secreting ACTH [8]. In this case, the patient underwent a successful laparoscopic adrenalectomy with no intraoperative complications. Histopathology confirmed a pheochromocytoma with marked nuclear pleomorphism and capsular invasion, suggesting potential aggressive behavior. Postoperatively, the patient’s blood pressure normalized, and her diabetes improved, aligning with outcomes reported in similar cases [4, 6]. Cortisol levels also returned to normal, demonstrating the effectiveness of adrenalectomy in resolving hypercortisolism.

A limitation in this case was the delayed recognition of ectopic ACTH secretion due to the absence of typical Cushingoid signs. The literature underscores the importance of considering this diagnosis, even in nonspecific cases [5].

Long-term management of pheochromocytomas, particularly those with aggressive features like capsular invasion, requires close follow-up [5, 7, 8]. Genetic testing should be considered, especially in patients with unusual presentations or family histories of endocrine disorders [1, 5]. Although not performed in this case, genetic testing could have provided further insight into the tumor’s etiology.

Acknowledgements

We thank the radiology department for interpreting the CT.

Conflict of interest

The authors declare no conflicts of interest related to this case report.

Funding

No external funding was received for this study.

Ethical approval

No approval was required.

Consent

Written informed consent was obtained from the patient and her parents to publish this case report and any accompanying images.

Guarantor

Froylan D. Martinez-Sanchez is the guarantor for this publication and accepts full responsibility for the work.

© The Author(s) 2025. Published by Oxford University Press.
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.

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