Functional endocrine tumours: symptoms and signs

Definition / Overview

Functional pancreatic neuroendocrine tumours (PNETs) and other endocrine tumours produce and secrete biologically active hormones that drive characteristic clinical syndromes. Recognition of these syndromes, often before imaging or biochemistry confirms the diagnosis, is a core surgical skill. The five classical functional PNET syndromes are insulinoma, gastrinoma (Zollinger-Ellison syndrome), VIPoma (Verner-Morrison syndrome), glucagonoma, and somatostatinoma. Beyond the pancreas, adrenal endocrine tumours (phaeochromocytoma, Conn's syndrome, Cushing's syndrome) and thyroid pathology round out the surgical endocrine curriculum. This note focuses on symptom and sign recognition as the gateway to investigation and operative planning.

Insulinoma

Pathophysiology

Autonomous insulin secretion from a beta-cell tumour produces episodic hypoglycaemia independent of fasting state. The neuroglycopenic and adrenergic responses to falling blood glucose generate the clinical picture.

Clinical Features

Whipple's triad remains the cornerstone of clinical recognition:

1. Symptoms consistent with hypoglycaemia during fasting or exercise
2. Documented low plasma glucose ($< 2.5\,\text{mmol/L}$) at the time of symptoms
3. Relief of symptoms with glucose administration

Neuroglycopenic symptoms (reflect cerebral glucose deprivation):

• Confusion, disorientation, behavioural change
• Visual disturbance, diplopia
• Seizures
• Obtundation, coma in severe episodes

Adrenergic/sympathomimetic symptoms (catecholamine surge):

• Diaphoresis, tremor, palpitations, tachycardia
• Anxiety, sense of impending doom
• Hunger

Examination findings:

• Often normal interictally
• During an episode: pallor, diaphoresis, tachycardia
• Weight gain is common, patients learn to snack frequently to abort symptoms
• Neuropsychiatric presentations are frequently misdiagnosed as epilepsy or psychiatric illness

Key epidemiology:

• 90% solitary, 90% sporadic, 90% benign
• Evenly distributed throughout the pancreas
• 10% associated with MEN1 (often multiple)

Gastrinoma (Zollinger-Ellison Syndrome)

Pathophysiology

Unregulated gastrin secretion drives parietal cell hyperplasia and massive acid hypersecretion. This overwhelms duodenal buffering capacity, causing peptic ulceration, diarrhoea, and oesophagitis.

Clinical Features

Cardinal features of ZES:

• Peptic ulceration, often multiple, recurrent, refractory to standard therapy, or in atypical locations (distal duodenum, jejunum)
• Secretory diarrhoea, occurs in up to 50%; acid inactivates pancreatic lipase causing steatorrhoea
• Gastro-oesophageal reflux, severe, often with oesophageal stricture
• Abdominal pain, epigastric, often post-prandial

Red flags suggesting ZES over ordinary peptic ulcer disease:

• Ulcers at unusual locations (post-bulbar, jejunal)
• Failure of standard acid-suppression therapy
• Recurrent ulceration after adequate H. pylori treatment
• Diarrhoea accompanying ulcer disease
• Ulcer disease in the absence of NSAIDs or H. pylori
• Family history of MEN1 or hypercalcaemia (parathyroid disease)

Examination findings:

• Epigastric tenderness
• Signs of complications: perforation (peritonitis), bleeding (haemodynamic instability)
• Stigmata of MEN1: renal calculi, anterior pituitary symptoms (headache, visual field defects)

Epidemiology:

• 75% sporadic, 25% MEN1-associated
• Majority arise in the "gastrinoma triangle" (junction of cystic and common bile duct superiorly, junction of second and third duodenum inferiorly, junction of neck and body of pancreas medially)
• 60-90% malignant with nodal or hepatic metastases at presentation

VIPoma (Verner-Morrison / WDHA Syndrome)

Pathophysiology

Vasoactive intestinal peptide (VIP) stimulates adenylyl cyclase in intestinal epithelium, driving massive chloride and water secretion into the gut lumen. Simultaneously, VIP inhibits gastric acid secretion and relaxes smooth muscle.

Clinical Features

WDHA triad:

• Watery diarrhoea, profuse, secretory (persists with fasting), often $> 3\,\text{L/day}$
• Hypokalaemia, from massive faecal potassium loss; $K^+ < 3.0\,\text{mmol/L}$ common
• Achlorhydria (or hypochlorhydria)

Additional features:

• Dehydration, hypovolaemia, shock in severe cases
• Flushing, episodic, involving face and trunk
• Hypercalcaemia (seen in a subset)
• Hyperglycaemia
• Lethargy and muscle weakness from hypokalaemia

Examination findings:

• Cachexia and muscle wasting from chronic losses
• Signs of dehydration: dry mucous membranes, reduced skin turgor, tachycardia
• Abdominal distension without peritonism
• Absent or reduced bowel sounds (intestinal atony)

Epidemiology:

• Predominantly pancreatic in adults; extra-pancreatic (ganglioneuromas, ganglioneuroblastomas) in children
• Majority malignant at presentation ($> 50\%$ with metastases)

Glucagonoma

Pathophysiology

Excess glucagon drives hepatic gluconeogenesis and glycogenolysis, causing hyperglycaemia. A poorly understood mechanism, possibly related to amino acid depletion and zinc deficiency, causes the pathognomonic skin rash.

Clinical Features

The 4 Ds:

• Dermatitis, necrolytic migratory erythema (NME)
• Diabetes mellitus, usually mild, often manageable without insulin
• Deep vein thrombosis, markedly elevated thromboembolic risk
• Depression / neuropsychiatric symptoms

Necrolytic migratory erythema (NME), key to diagnosis:

• Begins as erythematous macules that evolve to vesicles, bullae, and superficial erosions
• Crusts, heals, and migrates, hence "migratory"
• Predilection for perineum, perianal skin, groin, lower limbs, and perioral area
• Cyclical pattern; may precede diagnosis by years
• Pathognomonic when present, but can occur in other conditions (cirrhosis, coeliac disease)

Additional features:

• Weight loss and cachexia, profound amino acid catabolism
• Glossitis, angular cheilitis, stomatitis, from amino acid depletion
• Normochromic normocytic anaemia
• Hypercoagulable state, venous thromboembolism in up to 30%

Examination findings:

• NME rash in characteristic distribution
• Pallor
• Glossitis and oral mucosal changes
• Signs of DVT or PE

Epidemiology:

• Almost universally malignant ($> 60\%$ with hepatic metastases at presentation)
• Located in body and tail of pancreas in majority

Somatostatinoma

Pathophysiology

Excess somatostatin exerts broad inhibitory effects on gastrointestinal and pancreatic function: it suppresses gastric acid secretion, inhibits pancreatic exocrine function, impairs gallbladder contraction, and inhibits insulin/glucagon release.

Clinical Features

The inhibitory triad:

• Steatorrhoea / diarrhoea, from exocrine pancreatic inhibition and malabsorption
• Diabetes mellitus, from inhibition of insulin secretion (typically mild)
• Cholelithiasis, from inhibition of gallbladder motility

Additional features:

• Hypochlorhydria (reduced gastric acid)
• Weight loss
• Anaemia
• Abdominal pain, often non-specific

Examination findings:

• Jaundice if periampullary location causing biliary obstruction
• Epigastric or right upper quadrant mass in large tumours
• Features of malabsorption (weight loss, peripheral oedema from hypoalbuminaemia)

Epidemiology:

• Rarest functional syndrome ($< 1\,\text{in}\,40\,\text{million}$)
• Predominantly pancreatic head and periampullary region
• Frequently malignant with metastases at diagnosis
• Duodenal somatostatinomas are often associated with NF1 (von Recklinghausen disease)

Adrenal Endocrine Syndromes

Phaeochromocytoma / Paraganglioma

Rule of 10s (classic teaching, though modern series suggest higher rates):

• 10% bilateral, 10% extra-adrenal, 10% malignant, 10% in children, 10% familial (now likely higher, consider germline mutation in all cases)

Clinical features, driven by catecholamine excess:

• Hypertension, may be sustained or paroxysmal; resistant to standard antihypertensives
• Paroxysmal spells (classic triad): headache, diaphoresis, palpitations
• Pallor (not flushing) during spells, due to vasoconstriction
• Anxiety, sense of impending doom during attacks
• Tremor, nausea, vomiting
• Weight loss and hyperglycaemia from metabolic effects

Triggers of crises:

• Physical exertion, abdominal compression
• Induction of anaesthesia, intubation, direct tumour manipulation
• Certain drugs: glucagon, metoclopramide, tricyclics, beta-blockers (without alpha-blockade)

Examination:

• Hypertension (often labile), tachycardia, diaphoresis
• Postural hypotension (from plasma volume depletion)
• Pallor during paroxysms
• Signs of MEN2, VHL syndrome, or NF1 if syndromic

Conn's Syndrome (Primary Hyperaldosteronism)

Pathophysiology: Autonomous aldosterone excess drives sodium retention, potassium wasting, and hydrogen ion excretion, producing hypertension, hypokalaemia, and metabolic alkalosis.

Clinical features:

• Hypertension, often severe, resistant to multiple agents
• Hypokalaemia ($K^+ < 3.5\,\text{mmol/L}$): muscle weakness, cramps, fatigue, polyuria/polydipsia (nephrogenic diabetes insipidus), constipation
• Metabolic alkalosis
• Headache
• Absence of oedema (aldosterone escape maintained)

Key examination finding:

• Hypertension without peripheral oedema in a patient with hypokalaemia should trigger investigation

Cushing's Syndrome

Pathophysiology: Chronic cortisol excess drives central adiposity, protein catabolism, immune suppression, and metabolic dysregulation.

Clinical features:

• Central obesity with moon face and buffalo hump
• Proximal myopathy, difficulty rising from chair, climbing stairs
• Thin skin, easy bruising, poor wound healing
• Violaceous striae (wide, $> 1\,\text{cm}$, typically abdominal and axillary)
• Hypertension, hyperglycaemia/diabetes
• Osteoporosis, pathological fractures
• Hirsutism, acne, menstrual irregularity (adrenal androgen excess)
• Psychiatric features: depression, psychosis, cognitive impairment
• Susceptibility to infection

Distinguishing exogenous from endogenous Cushing's:

• Exogenous: most common cause; history of corticosteroid use; typically no androgen excess; adrenal atrophy on imaging
• Endogenous: pituitary (Cushing's disease, ACTH-dependent), adrenal adenoma/carcinoma (ACTH-independent), ectopic ACTH (small cell lung cancer, carcinoid)

MEN Syndromes, Recognising the Syndromic Context

Early recognition of multiple endocrine neoplasia (MEN) syndromes fundamentally changes operative planning and family screening obligations.

Clinical clues to MEN1:

• Recurrent nephrolithiasis (hypercalcaemia from HPT) + peptic ulcer disease (ZES) in a young patient
• Multiple pancreatic lesions on imaging
• Pituitary tumour + pancreatic NET

Clinical clues to MEN2A/2B:

• Medullary thyroid carcinoma at young age
• Bilateral phaeochromocytoma
• Marfanoid body habitus, mucosal neuromas on lips/tongue/conjunctiva (MEN2B)
• Family history of thyroid cancer or sudden unexplained death (undiagnosed phaeochromocytoma)

Complications & Special Considerations

Missed Diagnoses and Diagnostic Delay

• Insulinoma: misdiagnosed as epilepsy or psychiatric illness for years; mean diagnostic delay $> 2$ years
• Glucagonoma: NME rash misattributed to eczema, psoriasis, or contact dermatitis
• ZES: attributed to H. pylori disease; recurrence after apparently adequate treatment should prompt fasting gastrin measurement
• Phaeochromocytoma: "incidentaloma", all adrenal incidentalomas must be biochemically screened before operative planning regardless of size

Malignant Potential, Clinical Relevance

Certain syndromes are overwhelmingly malignant at presentation, fundamentally altering the urgency and extent of staging:

Perioperative Considerations Relevant to Symptom Recognition

• Phaeochromocytoma: Unrecognised perioperative crisis is life-threatening; any patient with resistant hypertension undergoing adrenalectomy must be fully alpha-blocked preoperatively
• Insulinoma: Intraoperative glucose monitoring essential; hypoglycaemia can occur with anaesthetic induction
• VIPoma: Severe electrolyte derangement (hypokalaemia, metabolic acidosis) must be corrected before elective surgery; aggressive IV fluid and potassium replacement required
• Glucagonoma: DVT prophylaxis critical given the markedly elevated thromboembolic risk; consider therapeutic anticoagulation in high-risk patients perioperatively

Summary: Symptom-Sign Pattern Recognition Table

Viva Pearls

• Always consider MEN when endocrine tumours occur in young patients, are multiple, or when there is a family history, this changes the operative approach and triggers genetic counselling
• Functional status trumps imaging for insulinoma, the biochemical diagnosis must be confirmed before embarking on localisation studies
• Glucagonoma NME is often present for 2-8 years before the tumour is identified; biopsy of the skin lesion showing necrolytic changes in a diabetic patient should prompt glucagon measurement
• Somatostatin analogues (octreotide, lanreotide) are useful for symptom control in VIPoma, glucagonoma, and carcinoid, not just for localisation scans
• Phaeochromocytoma first: in MEN2, phaeochromocytoma must be excluded and treated before thyroidectomy to avoid an intraoperative crisis

Sources

• RACS position statements & curriculum (Royal Australasian College of Surgeons)
• ASCO clinical practice guidelines (American Society of Clinical Oncology)