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

 

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

Münchausen By Media

Posted on August 30, 2025 by MaryO

The Internet makes it so easy to develop weird and unusual diseases.  Just plop a symptom into Google and suddenly you find yourself with stomach cancer, Cushing’s or other dread diseases.

Even on TV, the ads for lawyers almost convince people they might have mesothelioma and other rare illnesses that might bring you – and them! – bundles of money if you just sue someone.

Magazine ads implore you to “ask your doctor about…” this drug or that you might or might not need.  Your doctor might just give it to you to keep you from asking.  And there’s a needless medication that brings profit to the drug company and side effects to you.

TV shows like House and Mystery Diagnosis will show you diseases you never dreamed about.

There’s a great topic on the Power Surge message boards, What’s the worst “disease or ailment” you’ve had, where the women discuss the diseases they thought that they had, based on symptoms, what they’ve seen online, in the news but not based on reality.

I’ve done it myself.  About the only time I was right was with my Cushing’s diagnosis. That one was a good call. But my thoughts of kidney cancer metastasis haven’t come true (yet, anyway!).

There’s been information online lately about Münchausen Syndrome.  Wikipedia says:

“…the affected person exaggerates or creates symptoms of illnesses in themselves or their child/children in order to gain investigation, treatment, attention, sympathy, and comfort from medical personnel. In some extremes, people suffering from Münchausen’s Syndrome are highly knowledgeable about the practice of medicine, and are able to produce symptoms that result in multiple unnecessary operations. For example, they may inject a vein with infected material, causing widespread infection of unknown origin, and as a result cause lengthy and costly medical analysis and prolonged hospital stay. The role of “patient” is a familiar and comforting one, and it fills a psychological need in people with Münchausen’s. It is distinct from hypochondriasis in that patients with Münchausen syndrome are aware that they are exaggerating, whereas sufferers of hypochondriasis believe they actually have a disease.”

I think we’ve all see this, especially online.  It’s so easy to sit in the comfort of ones home and add “just a little” to the symptoms, making it more impressive for the readers.

From A Strange Case of Münchausen By Internet:

“…When I first got online, I “met” a young woman who claimed to be a vet, and offered me all kinds of advice about my cat and my tropical fish. She got cancer, slowly declined, then died. We wanted to send flowers, and maybe attend the funeral, and got her ISP to contact her family for us. To our shock, her parents said there was no funeral. She wasn’t dead, she wasn’t even sick. At least not physically. She’d pulled this kind of “pretend death” several times before, and was in therapy, but every time life got stressful, she’d do it again.

And the Internet is the ideal place for a Munchausen sufferer. With the click of a button, you can find out all kinds of information, to help you pose as anyone you want. People don’t expect to see you in person or even talk to you except by e-mail, making deception easier. And often, mailing lists, message boards, etc., will give unqualified support to their members…”

And Media Makes Me Sick:

“…The Internet is hands-down the worst thing to ever happen to the medical world. With Web sites like WebMD, any paranoid hypochondriac like me can jump online, look for symptoms and immediately convince himself he has cancer or Cushing’s disease or non-Hodgkin’s lymphoma or any other of a million things.

WebMD allows you to find one symptom and then “helps” you by listing 15,000 things it could mean.

Oh my God. I do have a slight ache! That’s it. I must have a brain tumor. I’m not kidding, I recently scared myself into thinking I had cancer. It took a specialist, a CT scan and an ultra-sound to convince me otherwise…”

Karen found this older article at http://www.villagevoice.com/2001-06-26/news/cybersickness/1

“…Over nearly three years, from 1998 to 2000, a woman—let’s call her Anna—posted to an online support group for people with mental illness. To the larger circle of readers, she acted mostly as friendly counselor. But to a select few, she e-mailed stories of escalating catastrophes. Her husband and two children had perished in a plane crash, she wrote. As a kid, her father had molested her, and she had suffered multiple personality disorder. Finally, she told her trusted—and trusting—confidants that she had just been diagnosed with leukemia.

Gwen Grabb, a psychotherapy intern and mother of three in Los Angeles, says the group believed Anna because she took on the role of helping others, revealing her own difficulties much later, and to an intimate audience. “She was very bright,” recalls Grabb. “She was very supportive and kind. One day, she started telling me about `the crash,’ what they found in the black box, how you could hear her daughter screaming. I had known her a year. I believed her.”

But as the tales became more elaborate and grotesque, Grabb grew suspicious. Along with another group member—Pam Cohen, a bereavement counselor in the Mid-Atlantic region—she did some research and discovered Anna was making it up. It was a shock to all, but worse than that to Cohen. “It is like an emotional rape,” she says. People may have been upset over the online life and fatal cancer of the fictional Kaycee, whose creator admitted last month she’d invented the high school character for expressive purposes. But that was geared to a general audience, however easily suckered. Pretenders like Anna hurt a much more vulnerable group—folks who may be seriously ill and are seeking help…”

So – use caution and remember that not everything you read will happen to you!

Filed under: Cancer, Cushing's, General Health, Rare Diseases | Tagged: , , , , , , , | 5 Comments »

Johns Hopkins Pituitary Patient Education Day

Posted on June 16, 2025 by MaryO

October 25 @ 9:00 am – 1:00 pm

The annual Pituitary Patient Education Day is a free event that features presentations from Johns Hopkins pituitary experts.

To RSVP, please email pituitaryday@jhmi.edu. Space is limited. Each person can bring up to one guest. If you RSVP yes but you cannot make it, please inform us as soon as possible by email, so that the slot can be offered to someone else.

List of presentations will be posted when finalized. Topics covered in previous years include:

Free
1800 Orleans Street, Zayed 2117
Baltimore, Maryland 21287 United States

410-955-5000

Filed under: Cushing's, Helpful Doctors, Meetings and Conferences, pituitary, Rare Diseases | Tagged: , , , , , , , , , , , , , , , , , , , , | Leave a comment »

Therapeutic Options for the Prevention of Thromboses in Cushing’s Syndrome

Posted on May 26, 2025 by MaryO

Abstract

Introduction

Cushing’s syndrome, or hypercortisolism, occurs after prolonged exposure to excess cortisol, and can be characterized by moon facies, central fat redistribution, proximal limb muscle weakness and wasting, and abdominal striae. Medical literature points to a relationship between hypercortisolism and hypercoagulability, with higher rates of venous thromboembolism noted. Current guidelines recommend prophylaxis with low-molecular weight heparin (LMWH), but there is little evidence to support LMWH over other forms of anticoagulation.

Methods

We utilized TriNetX US Collaborative Network (TriNetX, LLC, Cambridge, Massachusetts, United States) to investigate the efficacy of different forms of anticoagulation in patients with hypercortisolism, defined by International Classification of Diseases, Tenth Revision (ICD-10) codes. Adult patients with hypercortisolism and prescribed enoxaparin, a form of LMWH, were compared to patients with hypercortisolism prescribed unfractionated heparin, warfarin, apixaban, and aspirin at 81 mg. Groups were propensity-matched according to age at index event, sex, race, ethnicity, and comorbid conditions. The outcomes studied included pulmonary embolism (PE), upper extremity deep vein thrombosis (UE DVT), lower extremity deep venous thrombosis (LE DVT), superficial venous thrombosis (superficial VT), bleeding, transfusion, and all-cause mortality.

Results

No significant differences in outcomes were noted between enoxaparin and heparin, warfarin, or apixaban in patients with hypercortisolism of any cause. Uniquely, the enoxaparin cohort had significantly higher risk of PE, LE DVT, and all-cause mortality compared to the aspirin 81 mg cohort (PE: hazard ratio (HR) 1.697, 95%CI 1.444-1.994, p=0.0345; LE DVT: HR 1.492, 95%CI 1.28-1.738, p=0.0017; mortality: HR 1.272, 95%CI 1.167-1.386, p=0.0002). With further sub-analysis of pituitary-dependent (Cushing’s Disease), enoxaparin continued to demonstrate a higher risk for LE DVT (HR 1.677, 95%CI 1.353-2.079, p=0.0081), and all-cause mortality (HR 1.597, 95%CI 1.422-1.794, p=0.0005).

Conclusion

Although LMWH is currently recommended as the gold standard for anticoagulation in patients with hypercortisolism, our evidence suggests that low-dose antiplatelets such as aspirin 81 mg could outperform it. Further research is warranted to confirm and replicate our findings.

Introduction

Cortisol is produced within the zona fasciculata of the adrenal cortex and is typically released under stress [1]. Cushing’s Syndrome, first defined in 1912 by American neurosurgeon Harvey Cushing, is a state of prolonged hypercortisolism, presenting with classic phenotypic manifestations, including moon facies, central fat deposition, proximal limb muscle weakness and muscle wasting, and abdominal striae [2]. Cushing’s syndrome can be exogenous (medication-induced/iatrogenic) or endogenous (ectopic adrenocorticotrophic hormone (ACTH), pituitary-dependent, or adrenal adenoma/carcinoma) [3]. Pituitary adenomas causing ACTH-dependent cortisol excess account for 80% of endogenous cases of Cushing’s Syndrome and are more specifically termed Cushing’s Disease [4]. Overall, however, the most common cause of Cushing’s Syndrome is iatrogenic, from exogenous corticosteroid administration [5].

Hypercortisolism has also been demonstrated to affect coagulation, though the mechanism is unclear [6]. Both venous thromboemboli and pulmonary emboli rates are increased among these patients [7]. The Endocrine Society Guidelines for Treatment of Cushing Syndrome describe altered coagulation profiles that take up to one year to normalize [8]. As a result, limited guidelines recommend prophylactic anticoagulation in Cushing syndrome; while low-molecular-weight heparin (LMWH) is the gold standard, there is little evidence behind this recommendation [9]. Furthermore, few studies assessed individual Cushing’s Syndrome subtypes and associated clotting risks or anticoagulation impact. It is currently unknown whether the antagonistic effects of cortisol will be augmented or hindered by anticoagulation other than LMWH.

This retrospective multicenter study aimed to address this paucity in data by analyzing differences among various forms of anticoagulation. Patients with Cushing syndrome who were on one of three common anticoagulants, or aspirin, were compared to patients with Cushing’s Syndrome on enoxaparin, an LMWH considered the gold standard for prophylaxis in this population. Primary objectives included end-points concerning thromboses (such as pulmonary embolism (PE), upper and lower extremity deep vein thromboses (DVTs), and superficial venous thrombosis (VT)). Secondary objectives included analyzing safety profiles (bleeding, transfusion requirements, and all-cause mortality).

Materials & Methods

Eligibility criteria

TriNetX Global Collaborative network (TriNetX, LLC, Cambridge, Massachusetts, United States), a nationwide database of de-identified health data across multiple large healthcare organizations (HCOs), was utilized to compile patients according to International Classification of Diseases, Tenth Revision (ICD-10) codes (Figure 1).

Flow-chart-for-inclusion-and-exclusion-criteria-for-the-study
Figure 1: Flow chart for inclusion and exclusion criteria for the study

PE: pulmonary embolism; VT: venous thrombosis; DVT: deep vein thrombosis; UE: upper extremity; LE: lower extremity

ICD-10 codes included those related to Cushing’s Syndrome and one of five studied medications: enoxaparin, heparin, apixaban, warfarin, and aspirin, included in Tables 1 and 2, respectively. ICD-10 codes also included those related to outcomes, including PE, upper extremity (UE) DVT, lower extremity (LE) DVT, superficial VT, bleeding, transfusion, and all-cause mortality (Table 3). Measures of association involved calculating risk differences and relative risks (RRs) with 95% confidence intervals (CIs) to compare the proportion of patients experiencing each outcome across cohorts.

Cushing’s Syndrome Type ICD-10 Code
Cushing Syndrome (unspecified) Drug-Induced Cushing Syndrome (UMLS:ICD10CM:E24.2)
Other Cushing Syndrome (UMLS:ICD10CM:E24.8)
Cushing Syndrome, Unspecified (UMLS:ICD10CM:E24.9)
Pituitary-Dependent Cushing Disease (UMLS:ICD10CM:E24.0)
Cushing Syndrome (UMLS:ICD10CM:E24)
Ectopic ACTH Syndrome (UMLS:ICD10CM:E24.3)
Cushing Syndrome (pituitary) Pituitary-Dependent Cushing Disease (UMLS:ICD10CM:E24.0  )
Table 1: International Classification of Disease (ICD)-10 codes utilized to identify patients with Cushing Syndrome in the TriNetX database
Medication ICD-10 Code
Enoxaparin NLM:RXNORM:67108
Warfarin NLM:RXNORM:11289
Heparin NLM:RXNORM:5224
Apixaban NLM:RXNORM:1364430
Aspirin NLM:RXNORM:1191
Table 2: International Classification of Disease (ICD)-10 codes utilized to identify anticoagulants and antiplatelets studied in the TriNetX database
Outcome ICD-10 Codes
Pulmonary Embolism Pulmonary Embolism UMLS:ICD10CM:I26
Upper Extremity DVT Acute embolism and thrombosis of deep veins of unspecified upper extremity UMLS:ICD10CM:I82.629
Chronic embolism and thrombosis of deep veins of unspecified upper extremity UMLS:ICD10CM:I82.729
Acute embolism and thrombosis of deep veins of right upper extremity UMLS:ICD10CM:I82.621
Acute embolism and thrombosis of deep veins of left upper extremity UMLS:ICD10CM:I82.622
Acute embolism and thrombosis of deep veins of upper extremity, bilateral UMLS:ICD10CM:I82.623
Chronic embolism and thrombosis of deep veins of right upper extremity UMLS:ICD10CM:I82.721
Chronic embolism and thrombosis of deep veins of left upper extremity UMLS:ICD10CM:I82.722
Chronic embolism and thrombosis of deep veins of upper extremity, bilateral UMLS:ICD10CM:I82.723
Lower Extremity DVT Acute embolism and thrombosis of unspecified deep veins of unspecified lower extremity UMLS:ICD10CM:I82.409
Chronic embolism and thrombosis of unspecified deep veins of unspecified lower extremity UMLS:ICD10CM:I82.509
Chronic embolism and thrombosis of unspecified deep veins of lower extremity UMLS:ICD10CM:I82.50
Chronic embolism and thrombosis of unspecified deep veins of lower extremity, bilateral UMLS:ICD10CM:I82.503
Acute embolism and thrombosis of unspecified deep veins of lower extremity UMLS:ICD10CM:I82.40
Acute embolism and thrombosis of unspecified deep veins of left lower extremity UMLS:ICD10CM:I82.402
Acute embolism and thrombosis of unspecified deep veins of right lower extremity UMLS:ICD10CM:I82.401
Chronic embolism and thrombosis of unspecified deep veins of left lower extremity UMLS:ICD10CM:I82.502
Chronic embolism and thrombosis of unspecified deep veins of right lower extremity UMLS:ICD10CM:I82.501
Chronic embolism and thrombosis of left femoral vein UMLS:ICD10CM:I82.512
Chronic embolism and thrombosis of right femoral vein UMLS:ICD10CM:I82.511
Acute embolism and thrombosis of right iliac vein UMLS:ICD10CM:I82.421
Chronic embolism and thrombosis of femoral vein, bilateral UMLS:ICD10CM:I82.513
Chronic embolism and thrombosis of unspecified deep veins of unspecified distal lower extremity UMLS:ICD10CM:I82.5Z9
Chronic embolism and thrombosis of unspecified tibial vein UMLS:ICD10CM:I82.549
Acute embolism and thrombosis of deep veins of lower extremity UMLS:ICD10CM:I82.4
Chronic embolism and thrombosis of deep veins of lower extremity UMLS:ICD10CM:I82.5
Chronic embolism and thrombosis of other specified deep vein of unspecified lower extremity UMLS:ICD10CM:I82.599
Acute embolism and thrombosis of unspecified deep veins of unspecified proximal lower extremity UMLS:ICD10CM:I82.4Y9
Superficial VT Embolism and thrombosis of superficial veins of unspecified lower extremity UMLS:ICD10CM:I82.819
Acute embolism and thrombosis of superficial veins of unspecified upper extremity UMLS:ICD10CM:I82.619
Chronic embolism and thrombosis of superficial veins of unspecified upper extremity UMLS:ICD10CM:I82.719
Bleeding Hematemesis UMLS:ICD10CM:K92.0
Hemoptysis UMLS:ICD10CM:R04.2
Hemorrhage from respiratory passages UMLS:ICD10CM:R04
Hemorrhage from other sites in respiratory passages UMLS:ICD10CM:R04.8
Hemorrhage from other sites in respiratory passages UMLS:ICD10CM:R04.89
Melena UMLS:ICD10CM:K92.1
Hemorrhage of anus and rectum UMLS:ICD10CM:K62.5
Epistaxis UMLS:ICD10CM:R04.0
Transfusion Transfusion of Nonautologous Whole Blood into Peripheral Vein, Percutaneous Approach UMLS:ICD10PCS:30233H1
Transfusion of Nonautologous Whole Blood into Central Vein, Percutaneous Approach UMLS:ICD10PCS:30243H1
Transfusion of Nonautologous Red Blood Cells into Peripheral Vein, Percutaneous Approach UMLS:ICD10PCS:30233N1
Transfusion, blood or blood components UMLS:CPT:36430
Transfusion of Nonautologous Red Blood Cells into Central Vein, Percutaneous Approach UMLS:ICD10PCS:30243N1
Transfusion of Nonautologous Frozen Red Cells into Peripheral Vein, Percutaneous Approach UMLS:ICD10PCS:30233P1
Transfusion of Nonautologous Red Blood Cells into Peripheral Artery, Percutaneous Approach (deprecated 2020) UMLS:ICD10PCS:30253N1
Transfusion of Nonautologous Frozen Red Cells into Central Vein, Percutaneous Approach UMLS:ICD10PCS:30243P1
Transfusion of Nonautologous Red Blood Cells into Central Artery, Percutaneous Approach (deprecated 2020) UMLS:ICD10PCS:30263N1
Transfusion of Nonautologous Frozen Red Cells into Peripheral Artery, Percutaneous Approach (deprecated 2020) UMLS:ICD10PCS:30253P1
Transfusion of Nonautologous Frozen Red Cells into Central Artery, Percutaneous Approach (deprecated 2020) UMLS:ICD10PCS:30263P1
Transfusion of blood product UMLS:SNOMED:116859006
Transfusion of red blood cells UMLS:SNOMED:116863004
Mortality Deceased Deceased (demographic)
Table 3: International Classification of Disease (ICD)-10 codes utilized to identify outcomes followed in the TriNetX database

DVT: Deep Venous Thrombosis; VT: Venous Thrombosis

Cohort definitions

For each medication listed, two cohorts were compared: (i) a cohort of patients with hypercortisolism on enoxaparin and (ii) a cohort of patients with hypercortisolism on heparin, warfarin, apixaban, or aspirin at 81 mg (Table 4). The cohorts strictly assessed only adult patients (defined as at least 18 years of age); pediatric patients were not analyzed.

Cohort Run
Enoxaparin 146 HCOs with 99 providers responding with 12,885 patients
Heparin 145 HCOs with 97 providers responding with 16,376 patients
Warfarin 145 HCOs with 82 providers responding with 3,230 patients
Apixaban 146 HCOs with 91 providers responding with 3,982 patients
Aspirin (81 mg) 144 HCOs with 51 providers responding with 8,200 patients
Table 4: Outputs of healthcare organization queries as defined in corresponding tables

HCO: Healthcare Organization

Statistical analysis

Index events and time windows were defined to analyze patient outcomes. The index event was defined as the first date a patient met the inclusion criteria for a cohort. The time window was defined as the five years after the index event during which a pre-defined outcome could occur. Outcomes of interest were identified using ICD-10 codes as outlined in Table 1, and included PE, UE DVT, LE DVT, superficial VT, bleeding, transfusion, and all-cause mortality. Cohorts were propensity score-matched 1:1 according to age at index event, sex, race and ethnicity, and comorbid conditions, including endocrine, cardiac, pulmonary, gastrointestinal, and genitourinary conditions (Table 5). Propensity score-matching was performed using TriNetX, with a greedy (nearest) neighbor matching algorithm (caliper of 0.1 pooled standard deviations).

Variable ICD-10 Code
Demographics Age at Index (AI)
Female (F)
Black/African American (2054-5)
Male (M)
White (2106-3)
American Indian/Alaskan Native (1002-5)
Unknown Race (UNK)
Native Hawaiian/Other Pacific Islander (2076-8)
Unknown Gender (UN)
Not Hispanic/Latino (2186-5)
Hispanic/Latino (2135-2)
Other Race (2131-1)
Asian (2028-9)
Diagnosis Endocrine, nutritional and metabolic diseases (E00-E89)
Factors influencing health status and contact with health services (Z00-Z99)
Diseases of the musculoskeletal system and connective tissue (M00-M99)
Diseases of the circulatory system (I00-I99)
Diseases of the digestive system (K00-K95)
Diseases of the nervous system (G00-G99)
Diseases of the respiratory system (J00-J99)
Diseases of the genitourinary system (N00-N99)
Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism (D50-D89)
Neoplasms (C00-D49)
Diseases of the skin and subcutaneous tissue (L00-L99)
Table 5: International Classification of Disease (ICD)-10 codes utilized to propensity match cohorts in the TriNetX database

Three analytical approaches were performed for this study, including measures of association, survival analysis, and frequency analysis. The measure of association analysis involved calculating RRs (and risk differences) with 95%CIs, comparing the proportion of patients across each cohort experiencing an outcome. Survival analysis was performed with Kaplan-Meier estimators (evaluating time-to-event outcomes), with Log-Rank testing incorporated to compare the survival curves. Furthermore, Cox proportional hazard models were incorporated to provide an estimate of the hazard ratios (HR) and 95%CIs. Patients who exited a cohort before the end of the time window were excluded from the survival analysis. The frequency analysis was performed by calculating the proportion of patients in each cohort who experienced an outcome during the defined period of five years.

For statistically significant associations, an E-value was calculated to assess the potential impact of unmeasured confounders, quantifying the minimum strength of association that would be required by an unmeasured confounder to explain the observed effect (beyond our measured covariates); an E-value of above 2.0 was considered modestly robust, and above 3 was considered strongly robust. Additionally, a limited sensitivity analysis assessing Pituitary Cushing’s (the most common cause of endogenous Cushing’s Syndrome) was performed. All analyses were conducted through TriNetX, with statistical significance defined as a p-value < 0.05.

Results

Cushing’s syndrome, unspecified

Enoxaparin and Heparin

After propensity-score matching, 8,658 patients were identified in each cohort. The average age at index event for the enoxaparin cohort was 54.5 + 16.5 years, compared to 53.1 + 17.3 years for the heparin cohort. The enoxaparin cohort had 6,216 females (71.8%), compared to 6,000 (69.3%) in the heparin cohort. Within the enoxaparin cohort, 6035 (69.7%) were Caucasian patients, followed by 987 (11.4%) African American patients, 753 (8.7%) Hispanic/Latino patients, and 216 (2.5%) Asian patients. The heparin cohort was similar in ethnicity, with 5,800 (67.0%) Caucasian patients, 1,099 (12.7%) African American patients, 753 (8.7%) Hispanic/Latino patients, and 268 (3.1%) Asian patients. The enoxaparin and heparin cohorts demonstrated no significant differences in PE (HR 1.171, 95%CI 1.017-1.348, p=0.1797), UE DVT (HR 1.067, 95%CI 0.837-1.362, p=0.8051), LE DVT (HR 1.066, 95%CI 0.931-1.222, p=0.1922), superficial VT (HR 0.974, 95%CI 0.672-1.41, p=0.4576), bleeding (HR 0.948, 95%CI 0.855-1.05, p=0.3547), transfusion (HR 0.873, 95%CI 0.786-0.969, p=0.1767), or all-cause mortality (HR 1.036, 95%CI 0.966-1.11, p=0.9954). A comprehensive summary of the results is demonstrated in Table 6.

p-value Medication 1 Medication 2 PE UE DVT LE DVT S VT Bleeding Transfusion Mortality
enoxaparin heparin 0.1797 0.8051 0.1922 0.4576 0.3547 0.1767 0.9954
enoxaparin warfarin 0.3828 0.6 0.1963 0.0995 0.7768 0.5715 0.15
enoxaparin apixaban 0.6491 0.6275 0.723 0.4198 0.4356 0.4299 0.2628
enoxaparin aspirin 81 mg 0.0345 0.587 0.0017 0.4218 0.246 0.2057 0.0002
– – – – – – – – – –
HR Medication 1 Medication 2 PE UE DVT LE DVT S VT Bleeding Transfusion Mortality
enoxaparin heparin 1.171 1.067 1.066 0.974 0.948 0.873 1.036
enoxaparin warfarin 0.936 0.969 0.708 0.655 0.961 1.127 1.042
enoxaparin apixaban 0.798 0.666 0.684 4.059 0.933 1.089 1.041
enoxaparin aspirin 81 mg 1.697 1.398 1.492 1.718 1.107 1.347 1.272
– – – – – – – – – –
95% CIs Medication 1 Medication 2 PE UE DVT LE DVT Superficial VT Bleeding Transfusion Mortality
enoxaparin heparin 1.017-1.348 0.837-1.362 0.931-1.222 0.672-1.41 0.855-1.05 0.786-0.969 0.966-1.11
enoxaparin warfarin 0.755-1.161 0.692-1.356 0.583-0.859 0.376-1.142 0.812-1.137 0.95-1.336 0.93-1.167
enoxaparin apixaban 0.608-1.047 0.431-1.03 0.593-0.788 1.156-14.258 0.771-1.129 0.892-1.33 0.912-1.189
enoxaparin aspirin 81 mg 1.444-1.994 1.06-1.845 1.28-1.738 1.011-2.92 0.986-1.243 1.185-1.532 1.167-1.386
Table 6: Hazard Ratio, 95% Confidence Intervals and p-values for anticoagulation and antiplatelet comparisons in all causes of Cushing’s Syndrome

HR: hazard ratio; CI: confidence interval; PE: pulmonary embolism; VT: venous thrombosis; DVT: deep vein thrombosis; UE: upper extremity; LE: lower extremity

Enoxaparin and Warfarin

After propensity-score matching, 2,786 patients were identified in each cohort. The average age at index event for the enoxaparin cohort was 54.8 + 16.4 years, compared to 58.9 + 15.9 years for the warfarin cohort. The enoxaparin cohort had 2,020 female patients (72.5%) compared to 1,861 (66.8%) in the warfarin cohort. Within the enoxaparin cohort, 2,000 (71.8%) were Caucasian patients, followed by 334 (12.0%) African American patients, 220 (7.98%) Hispanic/Latino patients, and 64 (2.3%) Asian patients. The warfarin cohort was similar, with 2,056 (73.8%) Caucasian patients, 312 (11.2%) African American patients, 170 (6.1%) Hispanic/Latino patients, and 92 (3.3%) Asian patients. The enoxaparin and warfarin cohorts demonstrated no significant differences in PE (HR 0.936, 95%CI 0.755-1.161, p=0.3828), UE DVT (HR 0.969, 95%CI 0.692-1.356, p=0.6), LE DVT (HR 0.708, 95%CI 0.583-0.859, p=0.1963), superficial VT (HR 0.655, 95%CI 0.376-1.142, p=0.0995), bleeding (HR 0.961, 95%CI 0.812-1.137, p=0.7768), transfusion (HR 1.127, 95%CI 0.95-1.336, p=0.5715), or all-cause mortality (HR 1.042, 95%CI 0.93-1.167, p=0.15) (Table 6).

Enoxaparin and Apixaban

After propensity-score matching, 2,429 patients were identified in each cohort. The average age at index event for the enoxaparin cohort was 54.6 + 16.4 years, compared to 61.2 + 15.2 years for the apixaban cohort. The enoxaparin cohort had 1,746 female patients (71.9%) compared to 1,571 (64.7%) in the apixaban cohort. Within the enoxaparin cohort, 1632 (67.2%) were Caucasian patients, 318 (13.1%) African American patients, 219 (9.0%) Hispanic/Latino patients, and 68 (2.8%) Asian patients. A similar composition was noted in the apixaban cohort, with 1,683 (69.3%) Caucasian patients, 321 (13.2%) African American patients, 141 (5.8%) Hispanic/Latino patients, and 53 (2.2%) Asian patients. The enoxaparin and apixaban cohorts demonstrated no significant differences in PE (HR 0.798, 95%CI 0.608-1.047, p=0.6491), UE DVT (HR 0.666, 95%CI 0.431-1.03, p=0.6275), LE DVT (HR 0.684, 95%CI 0.593-0.788, p=0.723), superficial VT (HR 4.059, 95%CI 1.156-14.258, p=0.4198), bleeding (HR 0.933, 95%CI 0.771-1.129, p=0.4356), transfusion (HR 1.089, 95%CI 0.892-1.33, p=0.4299), or all-cause mortality (HR 1.041, 95%CI 0.912-1.189, p=0.2628) (Table 6).

Enoxaparin and Aspirin 81 mg

After propensity-score matching, 6,433 patients were identified in each cohort. The average age at index event for the enoxaparin cohort was 54.5 + 16.6 years, compared to the aspirin 81 mg cohort at 58.8 + 14.9 years. The enoxaparin cohort had 4664 female patients (72.5%) compared to 4,445 (69.1%) in the aspirin 81 mg cohort. Within the enoxaparin cohort, 4,522 (70.3%) were Caucasian patients, followed by 766 (11.9%) African American patients, 521 (8.1%) Hispanic/Latino patients, and 193 (3.0%) Asian patients. Similar demographics were noted within the Aspirin 81 mg cohort, with 4,670 (72.6%) Caucasian patients, 817 (12.7%) African American patients, 425 (6.6%) Hispanic/Latino patients, and 167 (2.6%) Asian patients. The enoxaparin cohort demonstrated a significantly higher risk of PE (HR 1.697, 95%CI 1.444-1.994, p=0.0345), LE DVT (HR 1.492, 95%CI 1.28-1.738, p=0.0017), and all-cause mortality (HR 1.272, 95%CI 1.167-1.386, p=0.0002) compared to the aspirin 81 mg cohort (Figure 2). There was no significant difference in rates of UE DVT (HR 1.398, 95%CI 1.06-1.845, p=0.587), superficial VT (HR 1.718, 95%CI 1.011-2.92, p=0.4268), bleeding (HR 1.107, 95%CI 0.986-1.243, p=0.246), or transfusion (HR 1.347, 95%CI 1.185-1.532, p=0.2057) (Table 6). Due to a significant difference between enoxaparin and Aspirin 81 mg, an E-value was calculated for PE (E-value = 2.783), LE DVT (E-value = 2.348), and all-cause mortality (E-value = 1.860).

Kaplan-Meier-survival-curve-for-pituitary-Cushing's-subtype-(mortality,-LE-DVT,-and-PE)
Figure 2: Kaplan-Meier survival curve for pituitary Cushing’s subtype (mortality, LE DVT, and PE)

(A) Mortality of enoxaparin compared to aspirin 81mg (HR 1.272, 95% CI 1.167-1.386, p=0.0002); (B) LE DVT risk with enoxaparin compared to aspirin 81 mg (HR 1.492, 95%CI 1.28-1.738, p=0.0017); (C) PE risk with enoxaparin compared to aspirin 81 mg (HR: 1.697, 95%CI 1.444-1.994, p=0.0345)

DVT: deep vein thrombosis; LE: lower extremity; PE: pulmonary embolism

Pituitary hypercortisolism (Cushing’s disease)

Enoxaparin and Heparin

Propensity-score matching identified 5,602 patients per cohort. The average age at index for the enoxaparin cohort was 53.9 + 16.7 years, compared to 53.7 + 16.9 years in the heparin cohort. The enoxaparin cohort had 4,088 female patients (72.97%) compared to 4,066 (72.58%) in the heparin cohort. The enoxaparin cohort was predominantly Caucasian patients (n=3,948; 70.47%), followed by 641 (11.45%) African American patients, 424 (7.57%) Hispanic/Latino patients, and 139 (2.48%) Asian patients. The heparin cohort was also predominantly Caucasian (n=3,947; 70.46%), followed by 669 (11.94%) African American patients, 401 (7.16%) Hispanic/Latino patients, and 148 (2.64%) Asian patients. There were no significant differences in rates of PE (HR 1.208, 95%CI 1.007 – 1.451, p=0.5803), UE DVT (HR 1.156, 95%CI 0.841 – 1.59, p=0.6863), LE DVT (HR 1.246, 95%CI 1.063 – 1.46, p=0.8996), superficial VT (HR 1.347, 95%CI 0.874 – 2.075, p=0.3731), bleeding (HR 0.916, 95%CI 0.809 – 1.037, p=0.1578), transfusion (HR 0.912, 95%CI 0.798 – 1.042, p=2119), or all-cause mortality (HR 1.02, 95%CI 0.935 – 1.112, p=0.8734). A comprehensive summary of the results is demonstrated in Table 7.

p-value Medication 1 Medication 2 PE UE DVT LE DVT Superficial VT Bleeding Transfusion Mortality
enoxaparin heparin 0.5189 0.2468 0.7586 0.7708 0.5894 0.6273 0.8433
enoxaparin warfarin 0.4842 0.7763 0.9651 0.682 0.1996 0.5309 0.399
enoxaparin apixaban 0.1047 0.0423 0.647 0.4824 0.2698 0.1122 0.1044
enoxaparin aspirin 81 mg 0.9651 0.6358 0.8448 0.9765 0.1167 0.4854 0.5001
– – – – – – – – – –
HR Medication 1 Medication 2 PE UE DVT LE DVT Superficial VT Bleeding Transfusion Mortality
enoxaparin heparin 1.186 1.332 1.232 1.183 0.876 0.963 1.016
enoxaparin warfarin 0.804 0.76 0.688 0.815 1.008 1.009 0.976
enoxaparin apixaban 0.875 0.761 0.954 3.068 1.084 1.359 1.115
enoxaparin aspirin 81 mg 1.173 1.157 1.226 1.165 0.908 0.915 1.028
– – – – – – – – – –
95% CIs Medication 1 Medication 2 PE UE DVT LE DVT Superficial VT Bleeding Transfusion Mortality
enoxaparin heparin 0.983-1.433 0.941-1.885 1.032-1.47 0.776-1.803 0.769-0.998 0.808-1.147 0.929-1.112
enoxaparin warfarin 0.612-1.055 0.467-1.235 0.539-0.877 0.447-1.489 0.816-1.246 0.76-1.34 0.843-1.13
enoxaparin apixaban 0.659-1.162 0.456-1.271 0.736-1.236 0.843-11.166 0.845-1.381 0.962-1.921 0.944-1.317
enoxaparin aspirin 81mg 0.969-1.419 0.827-1.619 1.03-1.46 0.763-1.78 0.797-1.035 0.772-1.085 0.938-1.127
Table 7: Hazard ratio, 95% confidence intervals, and p-values for anticoagulation and antiplatelet comparisons in pituitary Cushing’s syndrome

HR: hazard ratio; CI: confidence interval; PE: pulmonary embolism; VT: venous thrombosis; DVT: deep vein thrombosis; UE: upper extremity; LE: lower extremity

Enoxaparin and Warfarin

Propensity-score matching was performed with 1,694 patients per cohort identified. The average age at index for the enoxaparin cohort was 58.1 + 15.8 years, compared to 58.1 + 15.9 years in the warfarin cohort. The enoxaparin cohort had 1,142 female patients (67.41%) compared to 1,143 (67.47%) in the warfarin cohort. Within the enoxaparin cohort, 1,224 (72.2%) were Caucasian patients, followed by 194 (11.45%) African American patients, 97 (5.73%) Hispanic/Latino patients, and 57 (3.37%) Asian patients. The warfarin cohort had similar demographics, with 1,223 (72.2%) Caucasian patients, followed by 194 (11.45%) African American patients, 102 (6.02%) Hispanic/Latino patients, and 65 (3.84%) Asian patients. There were no significant differences in rates of PE (HR 0.907, 95%CI 0.694 – 1.186, p=0.8117), UE DVT (HR 0.988, 95%CI 0.628 – 1.555, p=0.9848), LE DVT (HR 0.739, 95%CI 0.589 – 0.929, p=0.4445), superficial VT (HR 0.815, 95%CI 0.44 – 1.511, p=0.8098), bleeding (HR 1.001, 95%CI 0.814 – 1.231, p=0.0987), transfusion (HR 1.106, 95%CI 0.889 – 1.376, p=0.4904), or all-cause mortality (HR 0.951, 95%CI 0.83 – 1.089, p=0.1656) (Table 7).

Enoxaparin and Apixaban

Propensity-score matching identified 1,489 patients per cohort. The enoxaparin cohort was 61.1 + 15.1 years old at the index event, versus the apixaban cohort at 61.4 + 14.9 years. The enoxaparin cohort had 1,054 (70.79%) female patients compared with 1,029 (69.11%) in the apixaban cohort. The enoxaparin cohort was primarily Caucasian patients (n=1,105; 74.21%), followed by 179 (12.02%) African American patients, 74 (4.97%) Hispanic/Latino patients, and 27 (1.81%) Asian patients. The apixaban cohort demonstrated similar demographics with 1,080 (72.53%) Caucasian patients, followed by 180 (12.09%) African American patients, 76 (5.1%) Hispanic/Latino patients, and 27 (1.81%) Asian patients. There were no significant differences in rates of PE (HR 0.949, 95%CI 0.673 – 1.339, p=0.4372), UE DVT (HR 0.832, 95%CI 0.472 – 1.466, p=0.1538), LE DVT (HR 1.166, 95%CI 0.869 – 1.566, p=0.8595), superficial VT (HR 5.323, 95%CI 1.19 – 23.815, p=0.493), bleeding (HR 1.218, 95%CI 0.948 – 1.565, p=0.4021), transfusion (HR 1.319, 95%CI 0.993 – 1.753, p=0.1663), or all-cause mortality (HR 1.131, 95%CI 0.966 – 1.325, p=0.0839) (Table 7).

Enoxaparin and Aspirin 81 mg

Propensity-score matching revealed 3,475 patients per cohort. The enoxaparin cohort was 58.8 + 15.3 years at index event, compared to the aspirin cohort at 58.2 + 14.3 years. The enoxaparin cohort had 2,438 (70.16%) female patients compared to the aspirin cohort with 2,445 (70.36%). Within the enoxaparin cohort, 2,539 (73.06%) were Caucasian patients, followed by 378 (10.88%) African American patients, 182 (5.24%) Hispanic/Latino patients, and 74 (2.13%) Asian patients. The aspirin cohort demonstrated similar demographics with 2,554 (73.5%) Caucasian patients, followed by 363 (10.45%) African American patients, 196 (5.64%) Hispanic/Latino patients, and 68 (1.96%) Asian patients. The enoxaparin cohort demonstrated significantly increased risk of LE DVT (HR 1.677, 95%CI 1.353 – 2.079, p=0.0081) and all-cause mortality (HR 1.597, 95%CI 1.422 – 1.794, p=0.0005) (Figure 3). There were no significant differences in rates of PE (HR 1.74, 95%CI 1.354 – 2.236, p=0.2408), UE DVT (HR 1.773, 95%CI 1.108 – 2.837, p=0.8625), superficial VT (HR 4.273, 95%CI 1.969 – 9.273, p=0.5196), bleeding (HR 1.093, 95%CI 0.937 – 1.275, p=0.8554), or transfusion (HR 1.896, 95%CI 1.556 – 2.311, p=0.2609) (Table 7). Due to a significant difference between enoxaparin and Aspirin 81 mg, an E-value was calculated for LE DVT (E-value = 2.744) and all-cause mortality (E-value = 2.574).

Kaplan-Meier-survival-curve-for-pituitary-Cushing's-subtype-(mortality-and-LE-DVT)
Figure 3: Kaplan-Meier survival curve for pituitary Cushing’s subtype (mortality and LE DVT)

(A) Mortality of enoxaparin compared to aspirin 81 mg (HR 1.597, 95%CI 1.422-1.794, p=0.0005); (B) LE DVT of enoxaparin compared to aspirin 81 mg (HR 1.677, 95%CI: 1.353-2.079, p=0.0081)

HR: hazard ration; DVT: deep vein thrombosis; LE: lower extremity

Discussion

The concept of hypercoagulability in the setting of hypercortisolemia has been documented since the 1970s [10]. Estimates suggest an 18-fold risk of venous thromboembolism in patients with Cushing’s syndrome compared to the general population [11]. Furthermore, venous thromboembolism accounts for up to 11% of all deaths in Cushing’s syndrome [12]. Patients are often noted to have a “coagulation paradox” in Cushing’s syndrome, whereby there is a heightened risk for thrombosis, with concurrent bruising of the skin; thromboembolism is due to an imbalance between pro- and anti-coagulant pathways, whereas bruising is due to atrophy of the skin and capillary fragility [11]. As noted by Feelders and Nieman, two prominent phases for the development of thromboembolic events include the untreated (active) hypercortisolemia and the postoperative phases [11]. Population-based studies have demonstrated a heightened risk for venous thromboembolism prior to diagnosis (in some studies as early as three years before diagnosis) [9].

Despite this heightened risk for venous thromboembolic events, there appears to be a lack of awareness amongst institutions (and individual practitioners), along with improper management. Fleseriu and colleagues, however, do note that in 2020, the awareness of hypercoagulability in Cushing’s syndrome increased around fourfold in two years, with routine prophylaxis increasing to 75% (from 50%) perioperatively (however, most patients only received prophylaxis for up to two weeks postoperatively) [13]. Another survey was performed by the European Reference Network on Rare Endocrine Conditions, noting concerns of heterogeneity with timing, type, and duration of prophylaxis, noting most centers do not have a thromboprophylaxis protocol (identifying only one reference center had a standardized thromboprophylaxis protocol for Cushing’s syndrome) [14]. From the European survey, it was noted that prophylaxis was initiated at diagnosis in 48% of patients, with 17% preoperatively, 26% on the day before (or of) surgery, 13% postoperatively, and 9% “depending on the presentation”. With regards to discontinuation of thromboprophylaxis, in centers with a standardized protocol (35% of reference centers), 38% of centers stopped at one month post-operatively, 25% between two and four weeks, and 37% between one week before and two weeks after surgery, between four and six days postoperatively, and at three months postoperatively. When cessation was individualized (in the remaining 65% of reference centers), 60% discontinued thromboprophylaxis once the patient was mobile, 40% with achievement of remission, 27% regarding patient status, and 7% dependent upon hemostatic parameters [14].

There is limited guidance concerning thromboprophylaxis recommendations in Cushing’s syndrome. For example, the Endocrine Society merely recommends assessing the risk of thrombosis in Cushing’s syndrome and administering perioperative prophylaxis if undergoing surgery, but provides no further recommendations [8]. The Pituitary Society highlights the absence of standardized practice for both pre- and postoperative thromboprophylaxis in patients with Cushing’s syndrome [15]. There appears to only be one set of guidelines for thromboprophylaxis in Cushing’s syndrome, known as the “Delphi Panel Consensus”, which forms the basis for the guidelines from the European Society for Endocrinology [9]. The Delphi Panel Consensus recommends considering anticoagulation for all patients with Cushing’s syndrome (in the absence of contraindications), regardless of the underlying etiology, and is recommended in the presence of risk factors [9]. Moreover, thromboprophylaxis is advised to begin at the time of diagnosis [9]. Currently, there is not enough evidence to provide a recommendation for thromboprophylaxis in mild autonomous cortisol secretion [9]. As with any medical patient, thromboprophylaxis should be initiated in all patients with active Cushing’s syndrome who are hospitalized (without contraindications) [9, 15]. Apart from chemical prophylaxis, anti-embolic stockings are not recommended due to the risk of skin fragility and friability [9]. The Delphi Consensus Panel furthermore advises to continue prophylactic anticoagulation for at least three months after biochemical remission (eucortisolemia) has occurred, and note those without additional risk factors (such as obesity, immobility, prior history of venous thromboembolism, or cardiac risk factors) can be considered candidates to stop the medication; one caveat, however, is for patients medically managed with mitotane (which can alter liver function and coagulation factor metabolism), there is an increased risk of bleeding, for which careful monitoring of renal function and bleeding risk is advised [9]. The Pituitary Society provides additional recommendations, such as discontinuing estrogen therapy in women (if used for contraception) [15]. While the Delphi Consensus Panel does not comment upon pediatric patients, the Pituitary Society advises against the use of thromboprophylaxis in the pediatric population due to bleeding risks [15].

The Delphi Consensus Panel furthermore recommend considering thromboprophylaxis at the time of inferior petrosal sinus sampling (if not started before this), due to the risk of thrombosis associated with this intervention; for those who are receiving prophylaxis, it is recommended to continue throughout the procedure, however, if has not been started, it is advised to initiate 12 hours post procedure. Similarly, if thromboprophylaxis was not considered earlier in a patient’s course, it should be reconsidered in the perioperative period, with the last dose of LMWH administered 24 hours prior to surgery and reinitiated 24 hours postoperatively [9]. Isand et al. recommend continuing thromboprophylaxis for three months after cortisol levels normalize (< 5 μg/dL) and when patients can mobilize [9]. In patients for whom a venous thromboembolism develops, patients are advised to receive a therapeutic dose of anticoagulation (preferably LMWH) for three to six months, followed by prophylaxis for three months after resolution of Cushing’s syndrome [9]. The Delphi Consensus Panel provides a summary of their recommendations, shown in Figure 4.

Algorithm-for-thromboprophylaxis-in-Cushing's-syndrome
Figure 4: Algorithm for thromboprophylaxis in Cushing’s syndrome

IPSS: inferior petrosal sinus sampling; VTE: venous thromboembolism; LMWH: low-molecular-weight heparin; DOAC: direct oral anticoagulant

Source: Isand et al., 2025 [9]; Published with permission.

Although intuitively, one may expect the procoagulant profile of Cushing’s syndrome to resolve upon attainment of eucortisolemia with medical management, studies have failed to demonstrate a reduction in venous thromboembolism with medical therapy [16]. Additionally, while one may expect resolution of hypercoagulability with surgical intervention (transsphenoidal sinus surgery or adrenalectomy), the risk maintains in the postoperative period, comparable to that of orthopedic surgery, at times up to one year and beyond to normalize [17]; data from European Register on Cushing’s Syndrome (ERCUSYN) database suggest the risk is greatest six months postoperatively [18]. The estimated risk for postoperative venous thromboembolism in pituitary-dependent Cushing’s is around 4.3% (compared to 0% with a non-functional pituitary adenoma); regarding adrenal surgery, the risk is estimated at around 2.6% [11]. Although the underlying mechanism for the persistent risk for venous thromboembolism remains unknown, it is hypothesized that a sudden drop in cortisol can lead to an inflammatory response (itself activating the coagulation cascade) [16]. Lopes and colleagues note an increase in the number of lymphocytes (because of loss of Th1 cell suppression), with increases in cytokines (such as interferon-gamma, interleukin-2, and transforming growth factor-beta) [16]. Comorbidities such as osteoporosis and myopathy (from hypercortisolemia) may be associated with decreased mobility in the postoperative period, influencing the risk for thrombosis [16].

Whilst all subtypes of Cushing’s syndrome can be associated with a heightened risk for venous thromboembolism (pituitary adenoma, adrenal adenoma, medication-induced, ectopic ACTH, and adrenal carcinoma), the latter two are often associated with malignant disease, which itself poses a risk for hypercoagulability from the underlying neoplasm [11]. Patients with Cushing’s syndrome have been found to demonstrate a reduction in activated partial thromboplastin time (aPTT), alongside increases in clot lysis time, procoagulant factors (such as factor VIII, von-Willebrand factor and fibrinogen) and fibrinolysis inhibitors (including plasminogen activator-inhibitor-1, thrombin activatable fibrinolysis inhibitor, and alpha-2 antiplasmin) [11,12,17]. Varlamov et al. have also noted an increase in thrombin, thromboxane A2, and platelets. Other studies have additionally demonstrated elevated proteins C and S as well as antithrombin III, which are hypothesized to be increased as a compensatory mechanism from the state of hypercoagulability [12]. Barbot et al. demonstrate elevation in factor VIII and von-Willebrand factor within the first few months after transsphenoidal sinus surgery, along with abnormally large von-Willebrand multimers (which are typically found in the cellular components), which can induce spontaneous platelet aggregation [17].

Lopes et al. note that altered von-Willebrand factor levels are not a constant feature reported in Cushing’s syndrome, and state it depends upon the polymorphism of the gene promoter, providing an example of haplotype 1 of the gene promoter conferring the greatest risk for elevated von-Willebrand factor levels by cortisol [16]. Barbot and colleagues furthermore note ABO blood groupings as an additional influencer of the procoagulant state; as an example, blood group-O patients have a near one-quarter reduction in levels of von-Willebrand factor [17]. Feelders and Nieman note heterogeneity in coagulation profiles based on individual characteristics and differing assay techniques [11]. van Haalen and colleagues note an absence of a correlation between severity of hypercortisolism and hemostatic abnormalities [14]; this is echoed by Varlamov et al., stating there is no linear relationship between coagulation parameters and venous thromboembolic events, nor with urinary free cortisol elevation [12]. Varlamov and colleagues further note that a subset of patients may have unaltered coagulation parameters, for which they advise against stratifying patients’ risk based on coagulation parameters [12].

In 2016, Zilio and colleagues posed a scoring system to stratify patients with active Cushing’s syndrome, including both clinical and biochemical parameters, including age (> 69 = 2 points), reduction in mobility (2 points), acute severe infection (1 point), prior cardiovascular event(s) (1 point), midnight plasma cortisol (> 3.15 times upper limit of normal = 1 point), and shortened aPTT (1 point) [19]. Lopes et al. describe the stratification as follows: 2 points (low risk), 3 points (moderate risk), 4 points (high risk), and > 5 points (very high risk) [16]. It should be noted, however, that Zilio et al.’s study was performed on only 176 patients and has not been validated in other studies [19]. Further drawbacks include the failure to account for postoperative events (a major source of venous thromboembolism in Cushing’s syndrome), and despite the stratification categories, no recommendations for treatment are provided.

LMWH is the first-line medication, consistent across differing societies. Despite being the gold standard, there are limited studies demonstrating a beneficial reduction in venous thromboembolic events in such cohorts; similarly, studies are lacking in analysis of the other classes of anticoagulants in head-to-head comparisons against LMWH for thromboprophylaxis in hypercortisolism. Another limitation is the fact that certain studies solely address thromboprophylaxis in the postoperative period. As an example, McCormick et al. performed one of the only trials comparing unfractionated heparin and LMWH (enoxaparin), noting no differences in hemorrhagic complications or thromboses; however, this was analyzed in patients undergoing transsphenoidal sinus surgery [10].

The current study retrospectively analyzed the various anticoagulant agents for the prevention of venous thromboembolism in Cushing’s syndrome (of any subtype), compared to the gold standard, LMWH (in this study, enoxaparin). When analyzing Cushing’s syndrome, our study demonstrated no significant differences in outcomes between enoxaparin and warfarin, apixaban, or unfractionated heparin; however, aspirin 81 mg demonstrated a lower risk of all-cause mortality, PE, and LE DVT. With subanalysis of Cushing’s disease (pituitary-related), there was no significant difference between enoxaparin and warfarin, apixaban or unfractionated heparin; aspirin 81 mg again noted a reduced all-cause mortality and LE DVT (but did not lower the risk of PE, compared with Cushing’s syndrome of all types combined). With E-value sensitivity analysis, the association remained moderately robust with PE (all Cushing’s types combined), LE DVT (all Cushing’s types and pituitary Cushing’s), and mortality (solely pituitary Cushing’s), however, mortality was weak-to-moderate with Cushing’s syndrome of all types (Table 8).

Outcome Hazard Ratio E-value Interpretation
PE (All Cushing’s Types) 1.697 2.783 Moderate
LE DVT (All Cushing’s Types) 1.492 2.348 Moderate
LE DVT (Pituitary) 1.677 2.744 Moderate
Mortality (All Cushing’s Types) 1.272 1.860 Weak
Mortality (Pituitary) 1.597 2.574 Moderate
Table 8: E-value sensitivity analyses for significant findings

DVT: deep vein thrombosis; LE: lower extremity; PE: pulmonary embolism

Aspirin, a non-steroidal anti-inflammatory drug, was first identified to irreversibly inhibit platelet function in the 1950s by Dr. Lawrence Craven [20]. Data is scarce in terms of aspirin’s role in thromboprophylaxis in hypercortisolemia. In 1999, Semple and Laws Jr. initially reported the use of aspirin postoperatively for six weeks (starting postoperative day one) in patients with Cushing’s disease who underwent transsphenoidal sinus surgery; while the authors mentioned a reduction in rates of venous thromboemboli, no factual data was provided (including dose of aspirin, complications experienced, and number of venous thromboemboli before and after) [21]. In 2015, Smith et al. performed an additional study with 81 mg of aspirin again administered starting postoperative day one (alongside sequential compression devices and mobilization), reporting that none of the 82 patients developed DVTs (with only two cases of epistaxis) [22]. It was not until 1994, however, in the Antiplatelet Trialists’ Collaborations’ meta-analysis, that aspirin demonstrated a reduced risk for venous thromboembolism, with similar findings replicated in the Pulmonary Embolism Prevention trial in 2000 and the WARFASA (Warfarin and Aspirin) and ASPIRE (Aspirin to prevent recurrent venous thromboembolism) trials in 2012 [23]. In 2012, the American College of Chest Physicians [24,25] were the first to recommend aspirin as thromboprophylaxis following total hip or knee replacement, followed by the National Institute for Health and Care Excellence in 2018 (advising LMWP followed by aspirin) and the American Society of Hematology in 2019 (advising either aspirin or oral anticoagulation after total hip or knee replacement) [25]. Despite recognition of the reduction in venous thromboembolism by aspirin (and its incorporation into guidelines), its role in thromboprophylaxis is largely limited to orthopedic surgery. The mechanisms of aspirin and its reduction in venous thromboembolism is not entirely understood, but believed to occur via differing mechanisms, including inhibition of cyclooxygenase-1 (which reduces thromboxane A2, a promoter of platelet aggregation), prevention of thrombin formation and thrombin-mediated coagulant reactions, acetylation of proteins involved in coagulation (such as fibrinogen), and enhancing fibrinolysis [23,26].

Strengths and limitations

To the best of our knowledge, a study specifically comparing the impact of aspirin with that of LMWP in Cushing’s syndrome has not been performed; as a result, our study adds to the paucity of literature pertaining to this topic. Notable strengths in the study include a large sample size (allowing robust comparisons amongst treatment arms), incorporation of propensity-score matching (allowing for internal validity through balancing baseline comparison groups), and comprehensive measurable outcomes.

Limitations to our study are multifold, and include retrospective design, for which intrinsic biases are inherent and can affect causal inference (despite matching techniques). Furthermore, data collection (via TriNetX) relied on correct ICD-10 coding, which could be a source of potential error if conditions and medications are coded improperly, or if our queries missed ICD-10 codes that could also correspond with outcomes. Similarly, TriNetX also relies on queries of healthcare organizations, many of which may not have responded with data, which could inaccurately skew the results. Although TriNetX uses global data, the majority of patient data was derived from the United States population, which could result in less generalizable data to the global public. These findings should be interpreted within the correct context and with caution to prevent misrepresentation. Compliance was a variable that could not be controlled for. Moreover, those who had taken the medication before the index event were excluded from analysis. While aspirin 81 mg demonstrated a reduction in LE DVT and mortality in Cushing’s disease along with PE with Cushing’s syndrome, we only performed a subgroup analysis concerning pituitary-related causes of Cushing’s syndrome (Cushing’s disease); it remains unclear why the risk of PE was not reduced in the latter subgroup. Due to limitations in ICD-10 coding, further subgroup analyses were not performed (such as adrenal adenoma, adrenal adenocarcinoma, or ectopic ACTH syndrome), for which the implications of treating with aspirin 81 mg cannot be inferred from our data. Similarly, further subgroup analyses, such as gender and race, were not performed. Our study assessed adult patients with Cushing’s syndrome, and not pediatric patients, which limits the applicability of our findings to such a cohort. Further studies are required to confirm and replicate our findings in a prospective fashion, stratifying subtypes of Cushing’s Syndrome.

Conclusions

Cushing’s syndrome is associated with a heightened risk for venous thromboembolism, regardless of the underlying etiology. Currently, LMWHs such as enoxaparin remain the gold standard for both thromboprophylaxis and treatment in such patients. There is limited data to support superiority over alternative agents. Our study analyzed enoxaparin against warfarin, unfractionated heparin, and apixaban, for which there was no significant risk difference. When compared to aspirin, enoxaparin demonstrated a greater risk for the development of PE, LE DVT, and all-cause mortality. Further prospective trials are required to replicate our findings and confirm the superiority of aspirin over LMWH.

References

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  6. Suarez MG, Stack M, Hinojosa-Amaya JM, et al.: Hypercoagulability in Cushing syndrome, prevalence of thrombotic events: a large, single-center, retrospective study. J Endocr Soc. 2020, 4:bvz033. 10.1210/jendso/bvz033
  7. St-Jean M, Lim DS, Langlois F: Hypercoagulability in Cushing’s syndrome: from arterial to venous disease. Best Pract Res Clin Endocrinol Metab. 2021, 35:101496. 10.1016/j.beem.2021.101496
  8. 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
  9. Isand K, Arima H, Bertherat J, et al.: Delphi panel consensus on recommendations for thromboprophylaxis of venous thromboembolism in endogenous Cushing’s syndrome: a position statement. Eur J Endocrinol. 2025, 192:R17-27. 10.1093/ejendo/lvaf017
  10. McCormick JP, Sun M, Shafqat I, Heaney AP, Bergsneider M, Wang MB: Venous thromboembolic (VTE) prophylaxis in Cushing Disease patients undergoing transsphenoidal surgery. Interdiscip Neurosurg. 2022, 27:10.1016/j.inat.2021.101371
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  12. Varlamov EV, Langlois F, Vila G, Fleseriu M: Management of endocrine disease: cardiovascular risk assessment, thromboembolism, and infection prevention in Cushing’s syndrome: a practical approach. Eur J Endocrinol. 2021, 184:R207-24. 10.1530/EJE-20-1309
  13. Fleseriu M, Biller BM, Grossman A, Swearingen B, Melmed S: Hypercoagulability in Cushing’s disease: a risk awareness and prophylaxis survey on behalf of the Pituitary Society. 15th International Pituitary Congress: Program and Abstracts. The Pituitary Society, Orlando, FL; 2017. 35.
  14. van Haalen FM, Kaya M, Pelsma IC, et al.: Current clinical practice for thromboprophylaxis management in patients with Cushing’s syndrome across reference centers of the European Reference Network on Rare Endocrine Conditions (Endo-ERN). Orphanet J Rare Dis. 2022, 17:178. 10.1186/s13023-022-02320-x
  15. Fleseriu M, Auchus R, Bancos I, et al.: Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol. 2021, 9:847-75. 10.1016/S2213-8587(21)00235-7
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  19. Zilio M, Mazzai L, Sartori MT, et al.: A venous thromboembolism risk assessment model for patients with Cushing’s syndrome. Endocrine. 2016, 52:322-32. 10.1007/s12020-015-0665-z
  20. Zaorsky NG, Buyyounouski MK, Li T, Horwitz EM: Aspirin and statin nonuse associated with early biochemical failure after prostate radiation therapy. Int J Radiat Oncol Biol Phys. 2012, 84:e13-7. 10.1016/j.ijrobp.2012.02.050
  21. Semple PL, Laws ER Jr: Complications in a contemporary series of patients who underwent transsphenoidal surgery for Cushing’s disease. J Neurosurg. 1999, 91:175-9. 10.3171/jns.1999.91.2.0175
  22. Smith TR, Hulou MM, Huang KT, Nery B, de Moura SM, Cote DJ, Laws ER: Complications after transsphenoidal surgery for patients with Cushing’s disease and silent corticotroph adenomas. Neurosurg Focus. 2015, 38:E12. 10.3171/2014.10.FOCUS14705
  23. Diep R, Garcia 😧 Does aspirin prevent venous thromboembolism?. Hematology Am Soc Hematol Educ Program. 2020, 2020:634-41. 10.1182/hematology.2020000150
  24. Maddukuri RK, Chava H, Kondaveeti ST, Mutthineni MV, Vegesana BP: Aspirin for prophylaxis of VTE in patients with hip/ knee replacement: systematic review and meta-analysis of non-randomized studies. Indian J Pharmacol. 2024, 56:420-9. 10.4103/ijp.ijp_732_21
  25. Spoladore R, Milani M, Spreafico LP, Agnelli G, Savonitto S: Prevention of thromboembolism after a fracture: is aspirin enough?. Eur Heart J Suppl. 2024, 26:i102-7. 10.1093/eurheartjsupp/suae025
  26. Undas A, Brummel-Ziedins KE, Mann KG: Antithrombotic properties of aspirin and resistance to aspirin: beyond strictly antiplatelet actions. Blood. 2007, 109:2285-92. 10.1182/blood-2006-01-010645

From https://www.cureus.com/articles/371036-therapeutic-options-for-the-prevention-of-thromboses-in-cushings-syndrome-a-propensity-matched-retrospective-cohort-analysis?score_article=true#!/

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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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