Spotlight on Cushing’s Syndrome in Neuroendocrine Neoplasms

Intro

Cushing’s syndrome is one of the most challenging hormonal complications seen in people with neuroendocrine neoplasms (NENs). It can be subtle, severe, or even life‑threatening — and it is often misunderstood. Many patients struggle for months or years before receiving a correct diagnosis, partly because the symptoms overlap with everyday conditions such as weight gain, diabetes, hypertension, fatigue, and mood changes.

This Spotlight aims to bring clarity. It explains what Cushing’s syndrome is, how it relates to NETs, why ectopic ACTH matters, and what recent evidence tells us about the tumours most likely to cause it. As always, the goal is simple: better understanding leads to better outcomes.

🧩 What is Cushing’s syndrome?

Cushing’s syndrome is the clinical state of chronic cortisol excess. Cortisol is essential for life, but too much becomes toxic — driving metabolic, cardiovascular, musculoskeletal, skin, and neuropsychiatric changes.

Causes include:

Exogenous steroids
Pituitary ACTH‑secreting adenoma (PitNET) → Cushing’s disease
Adrenal cortical tumours → autonomous cortisol secretion
Ectopic ACTH secretion → often from NETs or NECs
Rare CRH‑secreting tumours

🎯 Cushing’s Disease vs Cushing’s Syndrome

Cushing’s syndrome = cortisol excess from any cause. Cushing’s disease = cortisol excess caused specifically by an ACTH‑secreting pituitary adenoma (PitNET).

Cushing’s disease is caused by an ACTH‑secreting pituitary adenoma (PitNET). These tumours are uncommon, representing only around 2–6% of all pituitary adenomas — but they remain the most frequent cause of endogenous ACTH‑dependent Cushing’s syndrome.

This statistic is important for reassurance: Most pituitary adenomas — including those seen in MEN1 — do not produce ACTH

For clarity: PitNETs cause Cushing’s disease (pituitary ACTH). Non‑pituitary NETs and NECs cause ectopic ACTH‑dependent Cushing’s syndrome.

🧪 Symptoms of Cushing’s syndrome

Central weight gain, thin limbs
Moon face
Buffalo hump
Skin fragility, bruising, purple striae
Proximal muscle weakness
Mood changes
Hirsutism, menstrual irregularity
Low libido
Children: obesity + growth failure

NET patients often have overlapping symptoms, making Cushing’s easy to miss.

🧪 How to Test for Cushing’s Syndrome

Screening tests

Late‑night salivary cortisol
24‑hour urinary free cortisol
Low‑dose dexamethasone suppression test

Localisation

Plasma ACTH
Pituitary MRI
Adrenal CT/MRI
Chest/abdomen imaging
^68Ga‑DOTATATE PET for NETs
Inferior petrosal sinus sampling (IPSS)

🫁 Cushing’s Syndrome in Non‑Pituitary NETs and NECs

Cushing’s syndrome in neuroendocrine neoplasms is almost always ACTH‑dependent, caused by ectopic ACTH secretion.

Key features:

Rapid, severe hypercortisolism
Profound hypokalaemia
High infection risk
Muscle weakness
Often indicates aggressive tumour biology
May present before the tumour is diagnosed

📊 Epidemiology

Cushing’s syndrome: ~2–3 cases per million/year
Cushing’s disease: most common endogenous ACTH‑dependent cause
Ectopic ACTH: ~10–20% of endogenous cases
Lung and thymic NETs: dominant ectopic sources
Pancreatic and GI NETs: less common
NET incidence rising globally (Dasari et al.)

🧭 NET and NEC primaries known to cause ectopic ACTH

These are non‑pituitary neuroendocrine tumours (NETs) and neuroendocrine carcinomas (NECs) capable of producing ACTH:

Lung NETs (typical & atypical carcinoids)
Thymic NETs
Pancreatic NETs
GI NETs
Phaeochromocytoma / Paraganglioma (ACTH secretion extremely rare; cortisol co‑secretion documented)
Small‑cell lung cancer (SCLC) — a poorly differentiated neuroendocrine carcinoma (NEC)
- Historically the most common ectopic ACTH tumour
- Still relevant
- Very aggressive
- High ACTH‑producing potential

🧭 Endocrine adrenal tumours causing ACTH‑independent Cushing’s

These are not neuroendocrine tumours:

Adrenal cortical adenoma
Adrenal cortical carcinoma (ACC)
Adrenal hyperplasia

These produce cortisol directly, leading to:

ACTH‑independent Cushing’s syndrome

🧭 New Evidence: Bronchial and Thymic Carcinoids as Leading Causes of Ectopic Cushing’s

Two independent studies — one global (ScienceDirect 2023) and one regional (PGIMER India, 35‑year cohort) — now confirm that bronchial and thymic NETs are the leading causes of ectopic ACTH‑dependent Cushing’s syndrome.

ScienceDirect 2023 (Global Cohort)

Thoracic NETs (bronchial + thymic) were the dominant ectopic ACTH sources
Pancreatic NETs present but less common
GI NETs rare
Small‑cell lung cancer (SCLC) still relevant but no longer the leading cause
ACTH‑producing NETs showed more aggressive behaviour
High‑dose dexamethasone suppression often misleading
DOTATATE PET recommended for localisation

PGIMER India (35‑Year Cohort)

Bronchial carcinoids = 33.3%
Thymic carcinoids = 33.3% → Together 66.6% of all ectopic ACTH cases
Hyperpigmentation + proximal weakness in >75%
Hypertension in 90.5%
Paradoxical cortisol rise after high‑dose dexamethasone in 22.2%
Ga‑68 DOTATATE PET‑CT detected 100% of NET primaries tested

Combined Interpretation

Across both datasets:

Bronchial and thymic NETs are now the leading causes of ectopic ACTH‑dependent Cushing’s syndrome worldwide.

This shift reflects:

Better NET‑specific imaging
Increased awareness of thoracic NETs
Recognition of pancreatic ectopic ACTH NETs in the 2022 WHO Blue Book
Reduced reliance on older assumptions that SCLC was the dominant cause

SCLC remains important, but modern evidence shows that well‑differentiated thoracic NETs are now the most common ectopic ACTH tumours in contemporary practice.

💊 Treatment of Cushing’s Syndrome in NETs and NECs

Treat the tumour

Surgery
PRRT
Somatostatin analogues
Targeted therapy
Chemotherapy

Control cortisol

Metyrapone
Ketoconazole
Osilodrostat
Etomidate
Bilateral adrenalectomy (refractory cases)

Manage complications

Hypertension
Diabetes
Infections
Osteoporosis
Thromboembolism

🧬 MEN Syndromes and Cushing’s Syndrome (Updated with 2026 JCEM Evidence)

MEN1 → Yes, multiple pathways

PitNETs → Cushing’s disease
Rare pancreatic NETs → ectopic ACTH/CRH

MEN4 → Similar but rarer

PitNETs

MEN2 → Traditionally “no”, but new nuance

2026 JCEM shows:

Some phaeochromocytomas/paragangliomas can co‑secrete cortisol
Or stimulate cortisol production
Or contain mixed medullary–cortical components

MEN2 is not a recognised cause of Cushing’s syndrome, but rare cortisol‑related cases are now biologically possible.

🧩 Adrenal Cortex vs Adrenal Medulla — Why Classification Matters

Adrenal cortex (endocrine)

Produces cortisol
Tumours: adenoma, ACC
Causes ACTH‑independent Cushing’s
Not NETs

Adrenal medulla (neuroendocrine)

Produces catecholamines
Tumours: phaeochromocytoma, paraganglioma
Are NETs
Rare cortisol co‑secretion possible

🟦 Sidebar: 10 Things to Know About Cushing’s in NETs

Ectopic ACTH from NETs is rare but dangerous.
Bronchial and thymic NETs are now the top causes.
SCLC (NEC) remains relevant historically and clinically.
Symptoms often mimic common conditions.
High‑dose dex tests can mislead.
Ga‑68 DOTATATE PET is the most sensitive imaging tool.
ACTH‑producing NETs behave more aggressively.
Cortisol control is often the most urgent step.
Adrenal cortical tumours cause ACTH‑independent Cushing’s.
MEN syndromes can contribute (MEN1, MEN4; MEN2 rarely).

🟦 Summary

Cushing’s syndrome in NETs is complex, serious, and often under‑recognised. But with better imaging, better awareness, and better multidisciplinary care, outcomes continue to improve. Understanding the difference between pituitary disease, ectopic ACTH, and adrenal causes is essential — and recognising the modern shift toward thoracic NETs is equally important. As always, knowledge empowers patients. If you recognise these symptoms, or if your clinical team suspects hormonal involvement, early testing and NET‑specific imaging can make a significant difference.

This Spotlight is part of my ongoing commitment to help patients and caregivers navigate the evolving landscape of neuroendocrine cancer. Awareness saves lives.

🟦 Patient‑Friendly Summary (for readers)

Cushing’s syndrome happens when the body makes too much cortisol, a hormone that normally helps us deal with stress. When cortisol stays high for too long, it can cause weight gain, muscle weakness, high blood pressure, diabetes, mood changes, and skin problems. These symptoms often appear slowly and can be mistaken for everyday health issues.

Most people with Cushing’s syndrome do not have a neuroendocrine tumour (NET). But in some cases, a NET can produce a hormone called ACTH, which tells the adrenal glands to make more cortisol. This is called ectopic ACTH syndrome, and it can be serious.

The NETs most likely to cause ectopic ACTH are found in the lungs and thymus. These tumours can be small and hard to find, which means diagnosis is sometimes delayed. Modern scans such as Ga‑68 DOTATATE PET have made it much easier to locate these tumours.

A different type of lung cancer called small‑cell lung cancer (SCLC) can also produce ACTH. It is not a NET, but it is still important because it has a long history of causing Cushing’s syndrome.

Some adrenal tumours can also cause Cushing’s syndrome, but they do this by making cortisol directly, not ACTH. These adrenal tumours are not NETs.

Treatment usually involves controlling cortisol levels quickly and then treating the tumour. This may include medication, surgery, targeted therapy, or PRRT. Managing cortisol is often the most urgent step because high levels can be dangerous.

Cushing’s syndrome can be frightening, but with the right tests and the right team, it is treatable. Early recognition makes a big difference.

Thanks for reading
Ronny

Disclaimer

I am not a doctor or any form of medical professional, practitioner or counsellor. None of the information on my website, or linked to my website(s), or conveyed by me on any social media or presentation, should be interpreted as medical advice given or advised by me.

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