Adrenocortical carcinoma is a rare, aggressive malignant neoplasm arising from the adrenal cortex, often presenting with hormonal excess (particularly cortisol or androgens) and/or a large abdominal mass.

Exam domain	One-glance essentials
Definition / diagnosis	Adrenocortical carcinoma (ACC) is a rare malignant tumour of the adrenal cortex ^[1] May be functional or non-functional; functional tumours often produce cortisol, androgens, aldosterone or oestrogens ^[1] Malignancy is assessed by invasion, metastases and resection histology; FNA is not diagnostic ^[1]
Epidemiology / risks	Incidence is approximately 0.7–2.0 per million/year; peaks occur in children and adults aged 40–60 years ^[1] About 50–60% are functional; mixed cortisol-androgen secretion is particularly suspicious ^[1] Consider Li-Fraumeni syndrome/TP53 in paediatric ACC and metastasis in patients with known extra-adrenal cancer ^[1]
Core mechanism	ACC may secrete steroid hormones autonomously, causing ACTH-independent Cushing syndrome or virilisation ^[1] Inefficient steroidogenesis produces mixed hormones and steroid precursors such as DHEA-S ^[1] Aggressive growth causes necrosis, haemorrhage, capsular/vascular invasion and early metastatic spread ^[1]
Clinical picture	Presents with a rapidly enlarging adrenal mass, abdominal/flank pain or mass effect; some are incidentalomas ^[1] Cortisol excess: hypertension, diabetes, hypokalaemia, proximal weakness and Cushingoid features ^[1] Androgen excess/virilisation, feminisation in men or mixed endocrine syndromes strongly suggest ACC ^[1]
Investigations	Assess every adrenal mass for function: 1-mg overnight dexamethasone suppression, metanephrines and ARR if hypertensive ^[1] Adrenal-protocol CT: suspicious features include >4 cm, >10 HU, irregular heterogeneity, necrosis, poor washout or invasion ^[1] Exclude phaeochromocytoma before biopsy or surgery; FNA is not indicated for suspected primary ACC ^[1]
Management	Potentially resectable disease requires complete R0 resection, usually open adrenalectomy with intact capsule ^[1] En-bloc resection of invaded kidney, liver, spleen, pancreas or IVC may be required; avoid tumour rupture ^[1] Consider adjuvant mitotane, especially after high-risk resection; advanced disease may require EDP-mitotane chemotherapy ^[1]
Complications	Cortisol excess causes severe VTE risk, infection, poor wound healing, diabetes and cardiovascular complications ^[1] Local invasion may cause IVC/renal-vein thrombosis or hepatic, pancreatic and splenic involvement ^[1] Postoperative acute adrenal insufficiency/Addisonian crisis can occur from suppressed contralateral adrenal function ^[1]
Prevention / follow-up	Prevent perioperative crisis by excluding phaeochromocytoma and correcting hypertension, hypokalaemia and hyperglycaemia ^[1] Give perioperative glucocorticoid cover for cortisol-secreting ACC and monitor for postoperative adrenal insufficiency ^[1] Reduce recurrence risk with appropriate adjuvant therapy and close imaging/endocrine surveillance, especially in the first 2 years ^[1]
Exam traps	Do not assume a large adrenal mass is ACC: in known extra-adrenal cancer, metastasis is more likely ^[1] FNA does not distinguish adenoma from ACC and may seed tumour or precipitate a phaeochromocytoma crisis ^[1] Do not default to laparoscopy: suspected large or invasive ACC generally requires open surgery to preserve R0 resection ^[1]

References

^[1] Senior notes: maxim.md (Section 9.3 — Adrenocortical carcinoma, Adrenalectomy)

Adrenocortical Carcinoma (ACC)

Adrenocortical carcinoma (ACC) is a rare, highly aggressive malignant neoplasm arising from the adrenal cortex — the outer functional layers of the adrenal gland (zona glomerulosa, zona fasciculata, zona reticularis). Let's break the name down:

Adreno- = relating to the adrenal gland (Latin: ad = near, renes = kidneys)
Cortical = arising from the cortex (the outer layer, as opposed to the medulla)
Carcinoma = malignant epithelial tumour

ACC may be functional (producing excess steroid hormones — cortisol, androgens, aldosterone, or oestrogens) or non-functional (hormonally silent, presenting purely as a mass). Approximately 50–60% of ACCs are functional, which distinguishes them clinically from many other adrenal masses ^[1]^[2].

Key Distinction from Adrenal Adenoma

Adrenal adenomas are benign cortical tumours and are extremely common (present in up to 10% of adults at autopsy). Histology alone can be difficult in distinguishing benign adenoma from carcinoma — the diagnosis of malignancy relies on a composite scoring system (Weiss criteria), tumour size, evidence of local invasion, and metastatic spread. This is precisely why FNA biopsy is NOT indicated for primary adrenal tumours — it cannot reliably differentiate benign from malignant, and risks tumour seeding ^[1]^[2].

2. Epidemiology

Extremely rare: incidence approximately 0.7–2.0 per million population per year worldwide ^[3].
Accounts for only ~2–5% of adrenal incidentalomas ^[2].
Bimodal age distribution: first peak in children < 10 years and second peak in adults aged 40–60 years ^[2]^[4].
Female preponderance in functional tumours (F:M ≈ 2.5–4:1), especially those secreting cortisol or sex steroids ^[2]^[4].
In children, ACC is more common relative to other adrenal tumours and is often associated with TP53 germline mutations (Li-Fraumeni syndrome), particularly in southern Brazil where a specific founder mutation (R337H) dramatically increases incidence.

ACC is rare in Hong Kong, as in the rest of the world. However, clinicians must remain vigilant because:
- Hepatitis B–related hepatocellular carcinoma is very common in Hong Kong and can metastasise to the adrenals, so metastatic disease must always be excluded in any adrenal mass ^[5].
- The high prevalence of lung cancer in Hong Kong (both smoking-related and non-smoking adenocarcinoma in women) also means adrenal metastases are frequent — the adrenal is the 4th most common site of metastatic disease ^[2].

Risk Factor	Mechanism
Li-Fraumeni syndrome (TP53 germline mutation)	Loss of tumour suppressor function → uncontrolled cell proliferation
Beckwith-Wiedemann syndrome (11p15 — IGF2 overexpression)	Overexpression of insulin-like growth factor 2 → adrenal cortical hyperplasia and carcinogenesis
MEN1 syndrome (menin gene, 11q13)	Rare association; menin is a tumour suppressor in endocrine tissues
Lynch syndrome (mismatch repair gene mutations)	General predisposition to multiple cancers including ACC
Familial adenomatous polyposis (APC gene, 5q21)	APC/Wnt signalling pathway dysregulation → adrenocortical tumourigenesis
Carney complex (PRKAR1A mutation)	Dysregulated protein kinase A signalling → adrenal nodular disease / rare ACC
Sporadic mutations: CTNNB1 (β-catenin), ZNRF3, DAXX, TERT	Various pathways of oncogenesis identified in genomic studies

High Yield: Genetic Syndromes

In paediatric ACC, always think of Li-Fraumeni syndrome (TP53) and Beckwith-Wiedemann syndrome (IGF2 at 11p15). In adults, most ACCs are sporadic, but genetic predisposition syndromes should be considered in young patients or those with personal/family history of multiple cancers.

3. Anatomy and Function of the Adrenal Cortex

Understanding the anatomy is essential because ACC can arise from any cortical zone, and the specific zone of origin determines which hormones are overproduced.

The adrenal glands sit superomedially on each kidney in the retroperitoneum.
- Right adrenal: triangular, sits between the right crus of the diaphragm and the posterosuperior surface of the right lobe of the liver; intimately related to the IVC posteriorly (this is why right adrenalectomy risks IVC injury) ^[1].
- Left adrenal: crescent-shaped, related to the pancreatic tail, spleen, and left kidney (hence left adrenalectomy risks injury to these structures) ^[1].
Average weight: 4–6 g each.
Arterial supply: superior suprarenal arteries (from inferior phrenic artery), middle suprarenal arteries (from aorta), inferior suprarenal arteries (from renal artery). — Rich blood supply, which is why adrenal tumours are highly vascular and can bleed.
Venous drainage:
- Right adrenal vein → IVC directly (short, ~1 cm; easily torn during surgery).
- Left adrenal vein → left renal vein (longer, easier to control surgically).

Zone	Hormone	Regulation	Key Functions
Zona Glomerulosa	Aldosterone (mineralocorticoid)	RAAS (angiotensin II), K⁺	Na⁺ retention, K⁺ excretion, BP regulation
Zona Fasciculata	Cortisol (glucocorticoid)	ACTH (HPA axis)	Glucose metabolism, anti-inflammatory, stress response
Zona Reticularis	Androgens (DHEA, DHEA-S, androstenedione)	ACTH	Pubic/axillary hair, libido; converted to testosterone/oestrogen peripherally

Mnemonic: "Go Find Rex — Salt, Sugar, Sex" — Glomerulosa/Salt, Fasciculata/Sugar, Reticularis/Sex.

ACC can secrete hormones from any or multiple zones, and often does so inefficiently, producing steroid precursors and multiple hormones simultaneously. This chaotic, multi-hormone secretion pattern is a hallmark feature that helps differentiate ACC from benign functioning adenomas (which typically produce a single hormone efficiently).

4. Etiology and Pathophysiology

4.1 Molecular Pathogenesis

ACC arises through a multi-step process of adrenocortical cell transformation. The key molecular pathways include:

IGF2 (insulin-like growth factor 2) gene is located at 11p15 and is normally imprinted (only the paternal allele is expressed).
In ACC, loss of imprinting or uniparental disomy leads to biallelic IGF2 expression → massive overexpression (up to 90% of ACCs).
IGF2 activates the IGF1 receptor → downstream PI3K/AKT/mTOR and RAS/MAPK signalling → cell proliferation and survival.
This is the same locus affected in Beckwith-Wiedemann syndrome, explaining the paediatric association.

TP53 on chromosome 17p13 encodes p53, the "guardian of the genome."
Somatic TP53 mutations are found in ~25–30% of sporadic adult ACC and in the majority of paediatric ACC (especially Li-Fraumeni).
Loss of p53 → failure of cell cycle arrest and apoptosis in response to DNA damage → unchecked proliferation.

Activating mutations in CTNNB1 (encoding β-catenin) or inactivating mutations in ZNRF3 (a negative regulator of Wnt signalling) are found in ~40% of ACCs.
Constitutive Wnt signalling → nuclear accumulation of β-catenin → transcription of pro-proliferative genes.
Interestingly, CTNNB1 mutations and TP53 mutations are usually mutually exclusive, suggesting two distinct oncogenic pathways.

TERT promoter mutations or TERT amplification → telomere maintenance → cellular immortality.
DAXX mutations → alternative lengthening of telomeres.
Chromatin remodelling gene mutations (MED12, ARID1A) → epigenetic dysregulation.

ACC frequently produces hormones in a disorganised, inefficient manner. The steroidogenic enzymes may be expressed abnormally, leading to:

Cortisol hypersecretion (most common, ~50–60% of functional ACCs) → Cushing's syndrome.
Androgen hypersecretion (~20–30%) → virilisation in women, precocious puberty in children.
Mixed cortisol + androgens (very common in ACC; rare in adenomas — this combination is a red flag).
Oestrogen hypersecretion (rare but almost pathognomonic for ACC in males → gynaecomastia, testicular atrophy).
Aldosterone hypersecretion (uncommon, < 5%) → Conn's-like syndrome.
Steroid precursor overproduction (e.g., 11-deoxycortisol, 17-hydroxyprogesterone, DHEA-S) — because ACC cells have deranged steroidogenic enzyme expression → accumulation of intermediates. This is diagnostically useful and distinguishes ACC from efficient adenomas.

Clinical Pearl: Mixed Hormone Secretion = Think Malignancy

A benign adrenal adenoma typically secretes one hormone efficiently. If you see mixed hypersecretion (e.g., cortisol + androgens, or oestrogen in a male), your index of suspicion for ACC should be very high. An isolated elevation of DHEA-S in the setting of an adrenal mass is particularly concerning for malignancy.

ACC is a highly aggressive malignancy with a propensity for:

Local invasion: into adjacent structures — kidney, IVC (especially right-sided tumours), liver, diaphragm, pancreatic tail and spleen (left-sided), retroperitoneal fat.
Venous invasion: ACC has a particular tendency for tumour thrombus extending into the adrenal vein → renal vein → IVC (similar to renal cell carcinoma). This is critical for surgical planning.
Lymphatic spread: to para-aortic and paracaval lymph nodes.
Haematogenous metastasis: most commonly to lungs (most frequent), liver, bone, and peritoneum.

At the time of diagnosis, ~30–40% of patients already have metastatic disease (Stage IV), reflecting the aggressive biology and often delayed presentation of non-functional tumours.

5. Classification

Type	Proportion	Hormones	Clinical Syndrome
Functional	~50–60%	Cortisol, androgens, oestrogens, aldosterone, mixed	Cushing's, virilisation, feminisation, Conn's
Non-functional	~40–50%	None (or only steroid precursors without clinical effect)	Mass effect, incidental finding

The Weiss system is the most widely used histopathological criteria to distinguish adrenocortical adenoma from carcinoma. A score ≥ 3 out of 9 criteria suggests malignancy:

Criterion	What It Assesses
1. High nuclear grade (Fuhrman grade III/IV)	Degree of nuclear atypia
2. Mitotic rate > 5 per 50 HPF	Rate of cell division
3. Atypical mitoses	Abnormal mitotic figures
4. Clear cells ≤ 25% of tumour	Loss of lipid-rich clear cells (normal cortical cells are lipid-rich)
5. Diffuse architecture > 33%	Loss of normal cortical architecture
6. Necrosis	Tumour outgrowing its blood supply
7. Venous invasion	Aggressive local behaviour
8. Sinusoidal invasion	Aggressive local behaviour
9. Capsular invasion	Risk of local recurrence and spread

Score ≥ 3 = adrenocortical carcinoma. The higher the score, the worse the prognosis. A mitotic rate > 20/50 HPF is associated with particularly poor outcomes.

For paediatric ACC, the Weiss system is less reliable (overestimates malignancy) — the Wieneke criteria are preferred.

This is the standard staging system for ACC and is preferred over the older UICC/WHO system:

Stage	Definition	5-Year Survival
I	Tumour ≤ 5 cm, confined to adrenal, no local invasion	~65–80%
II	Tumour > 5 cm, confined to adrenal, no local invasion	~50–70%
III	Tumour of any size with local invasion (periadrenal fat, adjacent organs) OR positive regional lymph nodes OR tumour thrombus in renal vein/IVC	~20–40%
IV	Distant metastases	~0–15%

High Yield: Staging Determines Management

Stage I–II: Potentially curative with complete surgical resection (R0) ± adjuvant mitotane.
Stage III: Surgery ± adjuvant mitotane ± adjuvant chemotherapy; prognosis is guarded.
Stage IV: Palliative intent; mitotane ± cytotoxic chemotherapy (EDP regimen) ± debulking surgery for symptom control.

Molecular profiling has identified two major clusters:

C1A (aggressive): associated with TP53/RB pathway alterations, high mitotic rate, poor prognosis.
C1B (indolent): associated with CTNNB1 mutations, lower mitotic rate, better prognosis.

This is increasingly used in research settings but not yet standard clinical practice.

6. Clinical Features

6.1 Symptoms

ACC can present through three main mechanisms: hormonal excess, mass effect, or incidental discovery.

i. Cushing's Syndrome (cortisol excess — most common functional presentation)

Rapid onset of Cushingoid features (weeks to months, unlike the slow progression of Cushing's disease from pituitary adenoma) — this is because ACC produces cortisol in a large, unregulated burst.
Weight gain (central obesity): cortisol stimulates visceral fat deposition via upregulation of lipoprotein lipase in visceral adipocytes and stimulates appetite centrally.
Proximal myopathy / muscle weakness: cortisol promotes protein catabolism → skeletal muscle breakdown.
Easy bruising and thin skin: cortisol inhibits collagen synthesis → dermal atrophy.
Purple striae (not pink — purple striae indicate rapid stretching of atrophic skin with visible underlying vasculature; the purple colour specifically suggests pathological cortisol excess).
Hyperglycaemia / new-onset diabetes: cortisol promotes gluconeogenesis and opposes insulin action.
Hypertension: cortisol has mineralocorticoid activity (overwhelms 11β-HSD2 when in excess) → Na⁺ and water retention.
Psychiatric symptoms: insomnia, depression, psychosis — cortisol affects the limbic system.
Infections / poor wound healing: cortisol is immunosuppressive.
Osteoporosis: cortisol inhibits osteoblasts and intestinal Ca²⁺ absorption.
Hypokalaemic metabolic alkalosis: due to mineralocorticoid activity of excess cortisol → renal K⁺ wasting (ominous sign when severe, often seen in ectopic ACTH or ACC rather than Cushing's disease).

Why Is ACC-Related Cushing's More Severe?

Pituitary Cushing's disease usually causes modest cortisol elevation because negative feedback is partially preserved. In ACC, cortisol secretion is autonomous and often massive — there is no feedback regulation. The ACTH will be suppressed (non-ACTH-dependent Cushing's). This leads to more florid, rapidly progressive Cushingoid features, severe hypokalaemia, and a higher rate of complications like infections and VTE.

ii. Virilisation (androgen excess — common, especially in women)

Hirsutism: androgen-stimulated conversion of vellus to terminal hair in androgen-sensitive areas (upper lip, chin, chest, abdomen, back).
Acne: androgens stimulate sebaceous gland hypertrophy.
Deepening of voice: androgens cause vocal cord thickening and laryngeal growth.
Temporal hair recession / male-pattern baldness in women: androgenic alopecia.
Clitoromegaly: androgenic stimulation of clitoral growth.
Amenorrhoea / oligomenorrhoea: excess androgens disrupt the HPG axis.
Increased muscle mass / libido: direct androgenic effects.
In children: precocious puberty (accelerated growth, pubic/axillary hair, advanced bone age).

Clinical Pearl: Rapid-onset virilisation in a woman should always raise suspicion for an androgen-secreting adrenal tumour (ACC or rarely adenoma) or an ovarian tumour (e.g., Sertoli-Leydig cell tumour).

iii. Feminisation (oestrogen excess — rare, almost pathognomonic of ACC in males)

Gynaecomastia in men: oestrogen stimulates breast ductal and stromal proliferation.
Testicular atrophy: oestrogen suppresses GnRH → ↓LH/FSH → ↓testosterone production.
Erectile dysfunction / decreased libido: combined effect of low testosterone and high oestrogen.
In prepubertal girls: premature thelarche (breast development), early menarche.

High Yield: Oestrogen-Secreting Adrenal Mass in a Male = ACC Until Proven Otherwise

Feminisation from an adrenal mass in a male patient is highly suspicious for adrenocortical carcinoma. Benign oestrogen-producing adrenal adenomas are exceedingly rare.

iv. Conn's-Like Syndrome (aldosterone excess — uncommon, < 5%)

Hypertension: aldosterone → ENaC activation → Na⁺/water retention → volume expansion.
Hypokalaemia: aldosterone activates ROMK channels → K⁺ excretion.
Muscle weakness, cramps: severe hypokalaemia affects muscle membrane potential.
Polyuria/polydipsia: hypokalaemia causes nephrogenic DI (downregulates AQP2 channels).

v. Mixed Syndromes

Cushing's + virilisation is the most common combination in ACC and is a major red flag for malignancy.

Abdominal/flank pain or fullness: direct stretching of the adrenal capsule or compression of adjacent structures. ACC tumours at presentation are often very large (mean diameter 10–13 cm).
Palpable abdominal mass: detectable when the tumour is large (often > 10 cm).
Early satiety, nausea, vomiting: compression of the stomach or duodenum.
Back pain: retroperitoneal extension or vertebral metastasis.
Lower limb oedema: IVC compression or invasion by tumour thrombus → obstructed venous return.
Varicocele (especially left-sided): left adrenal vein tumour thrombus extending into left renal vein → obstructed gonadal venous drainage.

Constitutional symptoms: weight loss, anorexia, fatigue, malaise — typical cancer cachexia from TNF-α, IL-6.
Bone pain: skeletal metastases.
Dyspnoea / cough: pulmonary metastases.
Hepatomegaly / jaundice: liver metastases.
Venous thromboembolism (VTE): ACC (especially with Cushing's) carries a very high risk of DVT/PE due to cortisol-induced hypercoagulability (↑clotting factors, ↑PAI-1, ↓fibrinolysis).

Found on imaging performed for unrelated reasons — the classic "adrenal incidentaloma" scenario ^[1]^[2].

6.2 Signs

Cushing's Syndrome Signs:

Moon face (facial plethora): redistribution of fat to facial region.
Buffalo hump (dorsocervical fat pad): cortisol-mediated fat redistribution to supraclavicular and dorsocervical areas.
Central obesity with thin extremities: visceral fat deposition + peripheral muscle wasting (catabolic effect of cortisol on skeletal muscle protein).
Purple abdominal striae (> 1 cm wide): rapid stretching of cortisol-thinned skin.
Thin, fragile skin with easy bruising: cortisol inhibits collagen synthesis and capillary fragility increases.
Proximal muscle wasting (stand from sitting with difficulty, unable to raise arms overhead): cortisol-mediated protein catabolism.
Hypertension (measured on exam).
Hyperglycaemia (bedside glucose).
Pedal oedema: mineralocorticoid effect of cortisol → Na⁺/water retention.
Acanthosis nigricans: insulin resistance from cortisol excess.

Virilisation Signs (in women/children):

Hirsutism (Ferriman-Gallwey score): androgen-dependent terminal hair.
Acne (face, back, chest): sebaceous gland hyperactivity.
Temporal balding: androgenic alopecia.
Clitoromegaly: androgen stimulation.
Deepened voice (assessed on speaking).
Increased muscle bulk: anabolic effect of androgens.

Feminisation Signs (in men):

Gynaecomastia (bilateral, tender): oestrogen stimulation of breast tissue.
Testicular atrophy (small, soft testes): negative HPG axis feedback.
Female pattern fat distribution: oestrogen effect.

Palpable abdominal mass: usually in the flank or upper abdomen.
Abdominal tenderness: capsular stretching or local invasion.
Hepatomegaly: direct invasion (right-sided) or metastatic deposits.
Lower limb oedema (bilateral): IVC obstruction.
Dilated abdominal wall veins (caput medusae variant — collateral pathways): IVC obstruction.
Left varicocele (new onset, does not decompress when supine): left renal vein obstruction.

Hepatomegaly (hard, irregular, nodular): liver metastases.
Lymphadenopathy: regional or distant.
Pleural effusion / decreased breath sounds: pulmonary metastases.
Bone tenderness: skeletal metastases.
Jaundice: extensive liver metastases.

Cachexia (temporal wasting, prominent clavicles): advanced malignancy.
Pallor: anaemia of chronic disease or bone marrow infiltration.
Fever: tumour necrosis or concurrent infection (immunosuppression from cortisol).

Clinical Feature	Pathophysiological Basis
Rapid-onset Cushing's	Autonomous, massive cortisol secretion without HPA feedback
Hypokalaemia in ACC Cushing's	Cortisol overwhelms 11β-HSD2 → acts on mineralocorticoid receptor → renal K⁺ wasting
Mixed cortisol + androgen secretion	Inefficient steroidogenesis by malignant cells; deranged enzyme expression
Elevated DHEA-S	Overproduction of adrenal androgens by reticularis-derived malignant cells
IVC obstruction (oedema, varicocele)	Tumour thrombus extending from adrenal vein → renal vein → IVC
VTE risk	Cortisol-induced hypercoagulability: ↑factors VIII, vWF, PAI-1; ↓fibrinolysis
Rapid growth / large size at presentation	Aggressive biology; doubling time often weeks to months
Peritoneal carcinomatosis after biopsy	Tumour seeding — this is why FNA is NOT indicated ^[1]^[2]

Feature	Adrenal Adenoma	Adrenocortical Carcinoma
Size	Usually < 4 cm	Usually > 4 cm (mean 10–13 cm)
Growth rate	Slow/stable	Rapid (> 1 cm/year)
Hormonal secretion	Single hormone, efficient	Mixed hormones, inefficient; steroid precursors elevated
CT density (unenhanced)	< 10 HU (lipid-rich) ^[2]	> 10 HU (lipid-poor)
Contrast washout	> 50% absolute washout at 10 min (rapid)	< 50% washout (retains contrast) ^[2]
Borders	Smooth, homogeneous ^[2]	Irregular, heterogeneous (necrosis, haemorrhage, calcification)
Capsular/vascular invasion	Absent	Often present
Calcification	Rare	Present in ~30%
Weiss score	< 3	≥ 3
FNA biopsy	NOT indicated ^[1]^[2]	NOT indicated — cannot differentiate and risks seeding ^[1]^[2]

"Histology is NOT useful in differentiating between benign/malignant adrenal tumours (same appearance). Biopsy may cause precipitation of HTN crisis and tumour seeding if the tumour is a phaeochromocytoma or primary adrenal cancer." ^[2]

High Yield Summary

Definition: Rare, highly aggressive malignancy of adrenal cortex; may be functional (50–60%) or non-functional.

Epidemiology: Incidence ~1–2/million/year; bimodal (children < 10y, adults 40–60y); F > M in functional tumours.

Key Risk Factors: Li-Fraumeni (TP53), Beckwith-Wiedemann (IGF2, 11p15), sporadic (CTNNB1, ZNRF3, TERT).

Molecular Hallmark: IGF2 overexpression in ~90% of ACCs.

Functional Red Flags for Malignancy: Mixed cortisol + androgen secretion; elevated DHEA-S; oestrogen secretion in males; rapid-onset Cushing's.

Clinical Presentation: Cushing's syndrome (most common), virilisation, feminisation, Conn's-like syndrome, abdominal mass/pain, constitutional symptoms, incidental finding.

Key Radiological Features of Malignancy: Size > 4 cm, heterogeneous, > 10 HU on unenhanced CT, < 50% contrast washout, irregular borders, calcification, local invasion.

FNA biopsy is NOT indicated for primary adrenal tumours — cannot differentiate benign vs. malignant, risks tumour seeding.

ENSAT Staging: Stage I (≤ 5 cm), II (> 5 cm), III (local invasion/LN/thrombus), IV (distant metastases).

Prognosis: 5-year overall survival ~35–50% for localised disease; < 15% for Stage IV.

Treatment Principles: Surgery (open adrenalectomy ± en-bloc resection) + adjuvant mitotane ± chemotherapy (EDP-M regimen for advanced disease). Mitotane disrupts cortisol synthesis and is adrenolytic (requires high-dose glucocorticoid replacement due to CYP3A4 induction) ^[1].

Active Recall - Adrenocortical Carcinoma (Part 1)

^[1] Senior notes: maxim.md (Section 9.3 — Adrenocortical carcinoma, Adrenalectomy) ^[2] Senior notes: Ryan Ho Endocrine.pdf (Section 3.5 — Adrenal Incidentaloma and Adrenal Surgery, p. 68) ^[3] Harrison's Principles of Internal Medicine, 21st Edition; UpToDate: "Adrenocortical carcinoma" ^[4] Senior notes: Ryan Ho Endocrine.pdf (Section 3.3.2 — Cushing's Syndrome, p. 60); Adrian Lui Pediatrics.pdf (Section 8.3.2, p. 284) ^[5] Lecture slides: Advanced liver surgery for HBP malignancy_ACY Chan.pdf (context of HCC and adrenal metastases in HK)

Differential Diagnosis of Adrenocortical Carcinoma

When a patient presents with an adrenal mass — whether found incidentally on imaging, or detected during workup for hormonal excess — the critical clinical question is always the same two-part question: "Is it functional? Is it malignant?" ^[2]^[6]. ACC sits at the intersection of both: it is a primary adrenal malignancy that is often functional. But the differential diagnosis is broad, and systematically working through it is essential to avoid missing a treatable condition or, worse, performing an unnecessary biopsy on a phaeochromocytoma.

Let me walk you through this the way you'd approach it on the ward.

The adrenal gland has two embryologically and functionally distinct components:

Cortex (mesodermal origin) → produces steroids (cortisol, aldosterone, androgens)
Medulla (neural crest origin) → produces catecholamines (adrenaline, noradrenaline)

Any mass in or around the adrenal can be:

Primary adrenal — arising from the cortex or medulla
Secondary (metastatic) — the adrenal is a common site for metastases because of its rich arterial blood supply
Non-neoplastic — cysts, haemorrhage, infection, infiltration

The DDx also depends on how the patient presents:

As an adrenal incidentaloma (most common scenario — the mass is found on imaging done for another reason)
With hormonal excess (Cushing's, virilisation, feminisation, Conn's, catecholamine excess)
With mass effect / pain (large tumour causing local symptoms)
With known extra-adrenal malignancy (is this a metastasis?)

1. Differential Diagnosis of an Adrenal Mass (The Incidentaloma Framework)

This is the most clinically relevant framework because ACC is most commonly encountered during the workup of an adrenal incidentaloma ^[1]^[2]^[6].

The Two Fundamental Questions for Any Adrenal Incidentaloma

"Is it functional? Is it malignant?" — Every adrenal incidentaloma must be assessed for both hormonal activity and malignant potential. These two axes are independent: a mass can be functional and benign (e.g., Conn's adenoma), non-functional and malignant (e.g., adrenal metastasis), or both functional and malignant (e.g., ACC with Cushing's) ^[1]^[2]^[6].

Condition	Key Features	Why It's in the DDx
Non-functioning adrenal adenoma (85% of incidentalomas) ^[1]^[2]^[6]	Small (< 4 cm), homogeneous, smooth borders, lipid-rich (< 10 HU on unenhanced CT), rapid contrast washout (> 50% at 10 min) ^[2]^[6]	By far the most common adrenal mass. The main challenge is distinguishing this from early/small ACC. Size, lipid content, and washout characteristics are key differentiators.
Functioning cortical adenoma (Cushing's, Conn's)	Usually < 3 cm, single hormone produced efficiently. Conn's adenoma: HTN + hypokalaemia + ↑ARR ^[1]; Cortisol-producing adenoma: subclinical or overt Cushing's with suppressed ACTH	ACC also produces cortisol, but adenomas produce a single hormone efficiently whereas ACC often shows mixed/inefficient steroidogenesis with elevated steroid precursors (DHEA-S, 11-deoxycortisol).
Adrenal myelolipoma	Contains macroscopic fat (very low HU, often < -30 HU on CT) — pathognomonic. Benign hamartoma of fat and haematopoietic elements.	Can be large (> 4 cm) and mimic ACC on size criteria alone, but the macroscopic fat on CT is diagnostic. ACC does not contain macroscopic fat.
Adrenal cyst	Thin-walled, fluid density (0–20 HU), no enhancement. Types: endothelial (lymphangiomatous), epithelial, parasitic, pseudocyst (post-haemorrhagic).	Usually straightforward on imaging. However, a cystic degeneration of ACC can rarely mimic a benign cyst — look for thick, irregular walls and enhancing solid components.
Adrenal haemorrhage	History of trauma, anticoagulation, stress (e.g., sepsis, post-surgical). Acute: hyperdense (50–70 HU). Subacute/chronic: decreasing density over weeks. No enhancement.	Acute adrenal haemorrhage can look alarming on CT. Lack of enhancement and clinical context (anticoagulation, critical illness) help distinguish it. Follow-up imaging shows resolution.
Granulomatous disease (TB, histoplasmosis, sarcoidosis)	Often bilateral, may show calcification. TB adrenalitis is an important cause of Addison's disease in Hong Kong / East Asia.	Bilateral adrenal enlargement with calcification in a patient from an endemic area should raise suspicion for TB. Unlike ACC, granulomatous disease does not produce hormonal excess (it destroys cortical tissue → insufficiency).

Condition	Key Features	Why It's in the DDx
Phaeochromocytoma	Catecholamine-secreting tumour from chromaffin cells of adrenal medulla ^[1]^[7]. Classic triad: paroxysmal headache, sweating, palpitations ^[1]. 10% rule: 10% bilateral, 10% extra-adrenal, 10% malignant ^[1]. CT: often > 3 cm, heterogeneous with cystic/necrotic areas, very bright on T2W MRI. Screen with 24h urine fractionated metanephrines / plasma metanephrines ^[1]^[2]^[6].	Must always be excluded before any biopsy or surgical manipulation — undiagnosed phaeochromocytoma can cause fatal hypertensive crisis during anaesthesia or biopsy. This is one of the main reasons FNA biopsy is NOT indicated for primary adrenal tumours ^[2]^[6].
Malignant phaeochromocytoma	Histologically and biochemically indistinguishable from benign disease, defined only by the presence of metastasis ^[1].	Can mimic ACC on imaging. Biochemical catecholamine profile distinguishes it from ACC (which produces steroids, not catecholamines).
Neuroblastoma (paediatric)	Malignant tumour of neural crest cells. Most common extracranial solid tumour in children. Elevated urinary VMA/HVA. Often calcified on CT.	In children with an adrenal mass, the DDx between neuroblastoma, ACC, and Wilms' tumour (renal origin, not adrenal) is critical. Neuroblastoma arises from the medulla; ACC from the cortex ^[7].

Condition	Key Features	Why It's in the DDx
Adrenocortical carcinoma	The subject of these notes. Large (> 4–6 cm), heterogeneous, lipid-poor (> 10 HU), retains contrast (< 50% washout) ^[2]^[6], often with necrosis/haemorrhage/calcification. May be functional (mixed hormones, elevated DHEA-S).	—
Primary adrenal lymphoma	Extremely rare. Usually bilateral (70%). Often in immunocompromised or elderly patients. Homogeneous soft-tissue density mass on CT. Associated with elevated LDH.	Bilateral adrenal masses + adrenal insufficiency + elevated LDH in an elderly patient should raise suspicion. Unlike ACC, lymphoma responds to chemotherapy — tissue biopsy is indicated here (one of the few situations where adrenal biopsy is justified).
Adrenal sarcoma (angiosarcoma, leiomyosarcoma)	Exceedingly rare. Aggressive, large, heterogeneous masses. No hormonal secretion.	Indistinguishable from ACC on imaging alone; histopathology required (at surgery, not by biopsy).

Adrenal Metastases Are More Common Than Primary Adrenal Malignancies

In a patient with a known extra-adrenal malignancy and a new adrenal mass, the most likely diagnosis is adrenal metastasis, not ACC. The adrenal gland is the 4th most common site for metastases after lung, liver, and bone. Biopsy is usually only reserved for confirmation of adrenal metastasis ^[2]^[6] — this is one of the few situations where adrenal biopsy is appropriate (after phaeochromocytoma has been excluded).

Primary Cancer	Notes
Lung cancer (most common source of adrenal mets)	CT thorax coverage must include liver and adrenals ^[8]. Often bilateral. In Hong Kong, lung cancer is extremely common (both smoking-related and non-smoking adenocarcinoma in women).
Breast cancer	Can cause hypervascular adrenal metastases ^[9].
Renal cell carcinoma	RCC uniquely invades into the renal vein, IVC ^[10]^[7] and can directly extend to the ipsilateral adrenal. Also haematogenous metastasis to the contralateral adrenal.
Melanoma	High propensity for adrenal metastasis. Often bilateral, enhancing masses.
Colorectal cancer, gastric cancer, HCC	HCC and colorectal cancer are particularly relevant in the Hong Kong setting ^[5].
Lymphoma	As above — usually bilateral, may present with adrenal insufficiency.

Condition	Key Features
Adrenal hyperplasia (bilateral)	Diffuse or nodular bilateral adrenal enlargement. Seen in Cushing's disease (ACTH-driven bilateral hyperplasia), congenital adrenal hyperplasia (CAH), or ACTH-independent macronodular hyperplasia. Not a discrete mass — both glands are enlarged.
Adrenal haemorrhage	As above. Can be unilateral or bilateral. Important cause in neonates (birth trauma), anticoagulated patients, and Waterhouse-Friderichsen syndrome (meningococcal sepsis → bilateral adrenal haemorrhagic necrosis).
Adrenal abscess	Rare. Fever, leucocytosis, rim-enhancing lesion on CT. Usually in immunocompromised patients.
Extramedullary haematopoiesis	Bilateral adrenal enlargement in patients with chronic haemolytic anaemia (e.g., thalassaemia — relevant in Hong Kong's Southeast Asian population).

2. Differential Diagnosis by Clinical Presentation

If the patient presents with features of cortisol excess, the DDx is broader than just adrenal lesions:

Category	Cause	Key Distinguishing Feature
Iatrogenic (most common overall) ^[4]^[11]	Exogenous glucocorticoids, including herbal medicines, OTC drugs for arthritis ^[4]	History of steroid use. Must always be excluded first ^[11].
ACTH-dependent (80% of endogenous)	Cushing's disease (pituitary adenoma, 65–70%) ^[4]	Suppressed by high-dose DST. MRI pituitary shows adenoma.
	Ectopic ACTH (10–15%) — SCLC, carcinoid, thymic NET ^[4]^[8]	Very high ACTH, severe hypokalaemia, not suppressed by high-dose DST. Often rapid onset with marked metabolic derangement.
Non-ACTH-dependent (20%)	Adrenal adenoma (15%) ^[4]	Low ACTH, single hormone, small (< 4 cm), lipid-rich mass.
	Adrenocortical carcinoma (~5%) ^[4]	Low ACTH, mixed hormones (cortisol + androgens), large mass, elevated DHEA-S.
	Bilateral macronodular adrenal hyperplasia, primary pigmented nodular adrenal disease (Carney complex)	Bilateral, often aberrant receptor expression.

ACTH is the single most important initial test in a patient with confirmed Cushing's syndrome. If ACTH is suppressed (< 10 pg/mL), the cause is adrenal → image the adrenals. If ACTH is elevated or normal-high, the cause is ACTH-dependent → proceed to pituitary MRI and high-dose DST / CRH test / IPSS ^[4]^[11].

Category	Cause	Key Distinguishing Feature
Adrenal	ACC (most common adrenal cause of rapid virilisation)	Very high DHEA-S (> 600 μg/dL), large adrenal mass, rapid onset
	Androgen-secreting adenoma (rare)	Mild DHEA-S elevation, small mass, slow onset
	Non-classic CAH (21-hydroxylase deficiency)	Elevated 17-OH-progesterone, no mass, bilateral adrenal hyperplasia
Ovarian	Sertoli-Leydig cell tumour, hilus cell tumour	Normal DHEA-S, elevated testosterone, ovarian mass on pelvic imaging
	PCOS (most common cause overall)	Mild hyperandrogenism, oligo-ovulation, polycystic ovaries. Slow onset.
Other	Exogenous androgens	Drug history (anabolic steroids, testosterone therapy)

Key point: A very high serum DHEA-S (> 600 μg/dL or > 15.5 μmol/L) points to an adrenal source (DHEA-S is almost exclusively adrenal in origin). A very high testosterone with normal DHEA-S points to an ovarian source. Androgen profile should be checked for androgen-secreting tumours in virilized women ^[2]^[6].

This is covered in the table in Section 1 above. The key algorithmic approach is summarised in the flow diagram below.

Key Point: Never Biopsy a Primary Adrenal Tumour

FNA biopsy is NOT indicated for suspected primary adrenal lesions (ACC or phaeochromocytoma). Reasons: (1) histology is NOT useful in differentiating between benign/malignant adrenal tumours (same appearance) ^[2]^[6]; (2) risk of tumour seeding along the needle tract; (3) risk of precipitation of HTN crisis if phaeochromocytoma ^[2]^[6]. Biopsy is usually only reserved for confirmation of adrenal metastasis in patients with known extra-adrenal cancer ^[2]^[6].

Feature	Adrenal Adenoma	Adrenocortical Carcinoma	Phaeochromocytoma	Adrenal Metastasis
Frequency	85% of incidentalomas ^[2]^[6]	2–5% of incidentalomas ^[2]	~5%	Variable (depends on cancer Hx)
Size	Usually < 4 cm	Usually > 4 cm (often > 6 cm)	Variable (often 3–5 cm)	Variable
Unenhanced CT (HU)	< 10 HU (lipid-rich) ^[2]^[6]	> 10 HU (lipid-poor)	> 10 HU (lipid-poor)	> 10 HU
Contrast washout	> 50% absolute washout ^[2]^[6]	< 50% (retains contrast) ^[2]^[6]	Variable	< 50%
Homogeneity	Homogeneous, smooth ^[2]^[6]	Heterogeneous (necrosis, haemorrhage, calcification)	Heterogeneous (cystic, necrotic)	Variable
T2W MRI	Isointense to liver	Heterogeneous, high signal	Very bright ("light-bulb sign")	Variable
Hormones	Single, efficient	Mixed, inefficient; ↑DHEA-S, steroid precursors	Catecholamines (metanephrines)	Usually none
Bilateral	Can be	Rarely	10%	Often
Biopsy role	NOT indicated ^[2]^[6]	NOT indicated ^[2]^[6]	Absolutely contraindicated ^[2]^[6]	Indicated (after excluding phaeo)

Hepatitis B prevalence: HCC is extremely common in Hong Kong. HCC can metastasise to the adrenals, and the adrenal mass may be the first presentation. Always check HBsAg and AFP in a patient with a suspicious adrenal mass ^[5]^[9].
Lung cancer: Very high incidence of both smoking-related and non-smoking lung adenocarcinoma. CT thorax coverage must include liver and adrenals ^[8] — an adrenal mass found during lung cancer staging is most likely a metastasis.
Tuberculosis: Hong Kong is an intermediate-endemic area for TB. Bilateral adrenal enlargement with calcification should raise suspicion for TB adrenalitis, which causes adrenal insufficiency (Addison's disease), not hormonal excess.
RCC: RCC uniquely invades into renal vein, IVC ^[10] and may involve the ipsilateral adrenal by direct extension. A mass that appears to involve both the kidney and adrenal on imaging may be RCC with adrenal invasion rather than a primary ACC.

High Yield Summary - Differential Diagnosis of ACC

Most common adrenal mass: Non-functioning adenoma (85% of incidentalomas). Distinguished from ACC by size (< 4 cm), lipid-rich (< 10 HU), rapid contrast washout (> 50%), smooth/homogeneous.
Most dangerous mimic to miss before intervention: Phaeochromocytoma — always screen with plasma/urine metanephrines before any biopsy or surgery.
Most common malignant adrenal mass overall: Adrenal metastasis (not ACC) — especially from lung, breast, RCC, melanoma. Biopsy is appropriate here (after excluding phaeo).
FNA biopsy is NOT indicated for suspected primary adrenal tumours — cannot differentiate benign from malignant cortical tumours, risks seeding and hypertensive crisis.
Red flags for ACC over adenoma: Size > 4 cm, mixed hormone secretion (cortisol + androgens), elevated DHEA-S or steroid precursors, lipid-poor on CT (> 10 HU), contrast retention, heterogeneous with necrosis/calcification.
In Cushing's syndrome: Suppressed ACTH → adrenal cause → image adrenals. Mixed cortisol + androgens or rapid-onset virilisation → think ACC.
In virilised women: Very high DHEA-S (adrenal source) vs. high testosterone with normal DHEA-S (ovarian source).

Active Recall - DDx of Adrenocortical Carcinoma

References

^[1] Senior notes: maxim.md (Section: Adrenal incidentaloma, Phaeochromocytoma, Adrenocortical carcinoma) ^[2] Senior notes: Ryan Ho Endocrine.pdf (Section 3.5 — Adrenal Incidentaloma, p. 68) ^[4] Senior notes: Ryan Ho Endocrine.pdf (Section 3.3.2 — Cushing's Syndrome, p. 60) ^[5] Lecture slides: Advanced liver surgery for HBP malignancy_ACY Chan.pdf ^[6] Senior notes: Ryan Ho Fundamentals.pdf (Section B — Adrenal Incidentaloma, p. 438) ^[7] Senior notes: felixlai.md (Classification of adrenal tumours; Renal cell carcinoma) ^[8] Senior notes: Ryan Ho Respiratory.pdf (Metastatic spread of lung cancer, p. 142–143) ^[9] Senior notes: Ryan Ho GI.pdf (Appearance of liver mass lesions on triphasic CT, p. 263) ^[10] Senior notes: Ryan Ho Urogenital.pdf (Section 7.3 — Renal Cell Carcinoma, p. 145–147) ^[11] Senior notes: Ryan Ho Chemical Path.pdf (Section 4.1 — Diagnosis of Cushing Syndrome, p. 29)

Diagnosis of Adrenocortical Carcinoma: Criteria, Algorithm, and Investigations

There is no single "diagnostic criterion" for ACC the way there is for, say, rheumatoid arthritis or diabetes. Instead, the diagnosis of ACC is built on converging evidence from three pillars:

Hormonal workup — Is the mass functional? Does it show the chaotic, multi-hormone secretion pattern typical of ACC?
Radiological characterisation — Does the mass have imaging features of malignancy?
Histopathology (at surgical resection, not by biopsy) — Does the specimen meet criteria for carcinoma on the Weiss scoring system?

The diagnosis is typically suspected pre-operatively on hormonal + radiological grounds and confirmed post-operatively on histopathology. Let me walk you through each step systematically.

1. Diagnostic Criteria

There is no formal "diagnostic criteria checklist" that definitively confirms ACC pre-operatively. Instead, ACC is strongly suspected when the following features converge:

Domain	Findings Suggestive of ACC
Size	> 4 cm (90% of malignant adrenal tumours are > 4 cm) ^[1]^[2]^[6]
Growth	> 0.5 cm growth over 6 months on serial imaging ^[1]
CT density	> 10 HU on unenhanced CT (lipid-poor → not a typical adenoma) ^[1]^[2]^[6]
Contrast washout	< 40% relative washout or < 60% absolute washout on delayed phase ^[1]. Alternatively expressed as < 50% absolute washout at 10–15 min ^[2]^[6] — malignant tumours retain contrast because of their dense, disorganised vasculature and lack of lipid-rich cytoplasm.
Morphology	Irregular shape, heterogeneous, ill-defined borders, hypervascularity, central necrosis ^[1], calcification (~30%)
Local invasion	Vascular and adjacent organ invasion on contrast CT/MRI ^[1]^[12]
Hormonal pattern	Mixed hormone secretion (cortisol + androgens), very elevated DHEA-S, elevated steroid precursors (11-deoxycortisol, 17-OHP), oestrogen secretion in males
ACTH	Almost invariably undetectable if the tumour secretes cortisol (non-ACTH-dependent Cushing's) ^[4]^[6]^[13]

Why Can't We Diagnose ACC by Biopsy Pre-operatively?

This is a critical concept. FNA biopsy is NOT indicated: cannot differentiate between benign and malignant mass, risk of tumor seeding ^[1]^[12]. The reason is two-fold:

Histological limitation: Individual adrenocortical cells from an adenoma and a carcinoma can look identical on cytology. The diagnosis of malignancy depends on architectural features (capsular invasion, sinusoidal invasion, necrosis pattern, mitotic count across 50 HPF) that require a complete surgical specimen, not a needle aspirate.
Safety concern: Needle biopsy risks tumour seeding along the needle tract (converting a potentially curable localised disease into incurable peritoneal carcinomatosis) and may precipitate a hypertensive crisis if the mass turns out to be a phaeochromocytoma ^[2]^[6].

The only exception is biopsy for confirmation of adrenal metastasis in a patient with a known extra-adrenal malignancy ^[2]^[6], and even then, phaeochromocytoma must be excluded first with metanephrines.

The definitive diagnosis of ACC is made on the surgical specimen using the Weiss system. This was developed by Dr. Lawrence Weiss in 1984 and remains the gold standard:

#	Criterion	Rationale
1	High nuclear grade (Fuhrman III/IV)	Severe nuclear atypia indicates loss of differentiation — hallmark of malignancy
2	Mitotic rate > 5 per 50 HPF	High proliferative activity — tumour cells are dividing rapidly
3	Atypical mitotic figures	Abnormal spindle formations (tripolar, ring) → genomic instability
4	Clear cells ≤ 25% of tumour	Normal adrenocortical cells are lipid-rich (clear cytoplasm); loss of lipid content reflects dedifferentiation
5	Diffuse architecture > 33%	Loss of the normal trabecular/nested architecture of the adrenal cortex → disorganised growth
6	Tumour necrosis	Tumour outgrowing its blood supply → central ischaemic necrosis
7	Venous invasion	Invasion into veins → capacity for haematogenous spread
8	Sinusoidal invasion	Invasion into adrenal sinusoidal spaces → local aggressive behaviour
9	Capsular invasion	Breaching the tumour capsule → risk of local recurrence and peritoneal dissemination

Score ≥ 3 out of 9 = adrenocortical carcinoma. Sensitivity ~96%, specificity ~99% for malignancy in adult adrenocortical tumours.

High Yield: Weiss Score ≥ 3 = ACC

Remember "3 of 9" — any three of the nine Weiss criteria are sufficient for a diagnosis of ACC. The mitotic rate (criterion 2) is particularly important: Ki-67 proliferation index > 10% and mitotic rate > 20/50 HPF are associated with the worst prognosis and guide decisions about adjuvant therapy.

Supplementary/Alternative Histopathological Tools:

Ki-67 proliferation index: > 10% suggests aggressive behaviour; used for prognostication (not part of Weiss criteria but increasingly used in clinical decision-making regarding adjuvant mitotane).
Reticulin staining: disruption of the reticulin framework is a sensitive marker for ACC (reticulin algorithm by Duregon et al.).
SF-1 (steroidogenic factor 1) immunohistochemistry: a nuclear transcription factor specific to adrenocortical origin. Positive in ACC, negative in metastases, phaeochromocytoma, and RCC. Useful when the origin of the tumour is uncertain.
Wieneke criteria: used instead of Weiss in paediatric ACC (Weiss over-diagnoses malignancy in children).

The diagnostic workup of a suspected ACC follows a logical sequence. Let me explain the reasoning behind each step before presenting the algorithm:

Step 1 — Clinical Assessment: History and physical examination for signs of hormonal excess (Cushing's, virilisation, feminisation, Conn's-like features) and mass effect. Also assess for features of known extra-adrenal cancer (is this a metastasis?).

Step 2 — Hormonal Workup (Functional Assessment): Every adrenal mass > 1 cm requires hormonal screening ^[1]^[2]^[6]. This is done in parallel with imaging, not sequentially, because the results affect both differential diagnosis and surgical planning.

Step 3 — Radiological Assessment (Malignancy Assessment): CT adrenal protocol is the cornerstone. MRI and PET-CT are adjuncts for specific scenarios.

Step 4 — Staging (if ACC suspected): Once ACC is suspected, staging determines operability and guides the extent of surgery and adjuvant therapy.

Step 5 — Histopathological Confirmation (post-operative): Definitive diagnosis at resection. Weiss scoring, Ki-67, SF-1 IHC.

3. Investigation Modalities — Detailed Breakdown

3A. Hormonal Investigations

The purpose is two-fold: (1) determine if the tumour is functional (affects surgical planning — need steroid cover perioperatively if cortisol-secreting), and (2) identify the pattern of hormone secretion (mixed secretion = red flag for ACC).

Screening tests for functional tumors: ONDST + spot ARR + 24h urine metanephrines ^[1]

Test	Procedure	Interpretation	Why This Test?
1 mg Overnight Dexamethasone Suppression Test (ONDST) ^[1]^[11]	Give 1 mg dexamethasone PO at 11 pm → measure serum cortisol at 8 am next morning	Normal: cortisol < 50 nmol/L (1.8 μg/dL) = HPA axis appropriately suppressed. Abnormal: > 50 nmol/L = failure of suppression → cortisol is being produced autonomously ^[1]^[11]	Dexamethasone is a synthetic glucocorticoid that should suppress ACTH via negative feedback → ↓cortisol. In autonomous cortisol production (adenoma or ACC), the tumour ignores the feedback signal.
24h Urinary Free Cortisol (UFC) ×2 ^[1]^[11]	Collect all urine for 24 hours; measure free cortisol (unbound, filtered fraction)	> 3–4× ULN strongly suggests Cushing's; 1–3× ULN is indeterminate	Directly measures total daily cortisol output. Elevated in any cause of hypercortisolism. Caveats: incomplete collection (underfill), renal impairment, very high cortisol can saturate binding protein giving falsely ↑ free fraction.
Late-night salivary cortisol ×2 ^[1]^[11]	Saliva sample collected at 11 pm–midnight	Elevated = loss of circadian nadir (normally cortisol is lowest at midnight)	Only free cortisol enters saliva (ultrafiltration). Tests whether the normal diurnal rhythm is preserved. Not suitable for shift workers.

Confirmation of Cushing's: 2 out of 3 screening tests positive ± high pre-test probability ^[1]. Then proceed to ACTH level to determine ACTH-dependent vs. non-ACTH-dependent cause.

ACTH Level	Interpretation	Implication for ACC
Almost invariably undetectable (< 5–10 pg/mL) ^[4]^[6]^[13]	Non-ACTH-dependent Cushing's — the cortisol is coming from the adrenal itself, suppressing pituitary ACTH via negative feedback	This is the expected finding in ACC secreting cortisol and in cortisol-producing adenoma. Distinguishes from pituitary (normal-high ACTH) and ectopic ACTH (high ACTH).
Normal to high (> 20 pg/mL)	ACTH-dependent — cortisol production is being driven by ACTH (pituitary or ectopic)	Argues against a primary adrenal cortisol-secreting tumour. The adrenal mass may be: (a) an incidental non-functioning adenoma with a separate pituitary cause; (b) bilateral adrenal hyperplasia from ACTH excess.

Biochemical Fingerprint of ACC vs Other Causes of Cushing's

	Cushing's Disease	Ectopic ACTH	Adrenal Adenoma or Carcinoma	Iatrogenic
Cortisol	↑	↑↑	↑	↓
LDDST	No suppression	No suppression	No suppression	/
ACTH	Normal-high	Very high	Almost invariably undetectable	Low
HDDST	Usually suppressed	Usually NOT suppressed	No suppression	/
CRH test	Exaggerated rise	No significant rise	/ (not applicable)	/
Localisation	Pituitary adenoma on MRI	ACTH-secreting tumour on PET/CT	Adrenal tumour on CT abdomen	+ve drug Hx

Source: ^[4]^[6]^[13] — This table is extremely high yield for exams.

This is where you distinguish ACC from a benign adenoma. ACC cells have deranged steroidogenic enzyme expression → they produce hormones inefficiently → accumulation of steroid precursors and multiple hormone classes simultaneously.

Analyte	Expected in ACC	Expected in Adenoma	Why?
DHEA-S (dehydroepiandrosterone sulphate)	Markedly elevated (often > 600 μg/dL)	Normal or mildly elevated	DHEA-S is produced almost exclusively by the zona reticularis. Massive elevation indicates adrenal cortical overproduction, and very high levels (> 600 μg/dL) are almost pathognomonic of ACC.
11-Deoxycortisol	Elevated	Normal	An intermediate in cortisol synthesis (converted to cortisol by 11β-hydroxylase/CYP11B1). Accumulates when the tumour has deficient 11β-hydroxylase activity — a feature of malignant dedifferentiation.
17-Hydroxyprogesterone (17-OHP)	Often elevated	Normal	Another steroid precursor that accumulates due to inefficient enzyme activity.
Androstenedione	Elevated	Normal	Adrenal androgen; elevated in androgen-secreting ACC.
Testosterone (in women)	Elevated	Normal or slightly elevated	Direct production by ACC or peripheral conversion from androstenedione.
Oestradiol (in men)	May be elevated	Normal	Oestrogen-producing ACC (rare but pathognomonic in males). Due to aromatase activity within the tumour converting androgens to oestrogens.
Urine steroid metabolome (GC-MS)	Characteristic "fingerprint" with elevations of multiple steroid metabolites including tetrahydro-11-deoxycortisol (THS)	Normal	Emerging diagnostic tool with ~90% sensitivity and specificity for ACC vs adenoma. Not yet universally available but increasingly used in specialist centres (ESE/ENSAT 2024 guidelines).

High Yield: The Urine Steroid Metabolome

Gas chromatography–mass spectrometry (GC-MS) of a 24-hour urine sample can produce a steroid metabolite fingerprint that distinguishes ACC from adenoma with high accuracy (~90% sensitivity, ~90% specificity). The hallmark is elevation of tetrahydro-11-deoxycortisol (THS), reflecting the accumulation of 11-deoxycortisol due to deficient CYP11B1 in malignant tissue. This is recommended by the 2024 ESE/ENSAT guidelines for all indeterminate adrenal masses and is increasingly becoming a standard of care in high-volume centres.

Must exclude phaeochromocytoma before any biopsy or surgery ^[1]^[2]^[6].

Test	Procedure	Interpretation
24h urine fractionated metanephrines (normetanephrine + metanephrine) ^[1]^[2]^[6]	24-hour urine collection	> 2× ULN is highly suggestive; values within reference range effectively exclude phaeochromocytoma (NPV > 99%)
Plasma free metanephrines	Single blood draw (patient supine for 30 min)	Higher sensitivity (~99%) but lower specificity than urine. Any elevation requires further workup.
Clonidine suppression test ^[1]	Confirmatory test: give clonidine (central α2-agonist) → measure plasma normetanephrine/noradrenaline at 3h	Normal: clonidine suppresses sympathetic outflow → ↓catecholamines. Phaeochromocytoma: autonomous secretion → no suppression

Why fractionated metanephrines and not total catecholamines? Metanephrines (normetanephrine and metanephrine) are metabolites of catecholamines produced continuously within chromaffin cells by COMT. They are more stable, less affected by episodic secretion, and have higher sensitivity than measuring the catecholamines themselves (which are secreted in paroxysms and have very short half-lives).

Test	Procedure	Interpretation
Spot aldosterone:renin ratio (ARR) ^[1]^[2]^[6]	Morning blood sample (seated for 15 min); stop interfering drugs if possible (diuretics, β-blockers, ACEi, ARBs) for ≥ 2 weeks; α-blockers and CCBs are acceptable ^[6]	Elevated ARR (usually aldosterone > 15 ng/dL and renin suppressed) → primary hyperaldosteronism
Confirmatory: Salt loading test / Saline suppression test ^[1]	IV 0.9% NaCl 2L over 4h, then measure aldosterone	Aldosterone remains > 10 ng/dL → confirms autonomous aldosterone secretion

Note: Aldosterone-secreting ACC is rare (< 5% of functional ACCs). If present, the mass is usually large and has other features of malignancy.

3B. Radiological Investigations

This is the single most important imaging modality for adrenal mass characterisation and should be the first-line imaging ^[1]^[2]^[6]^[12].

Protocol: Unenhanced → arterial phase → portal venous phase → 15-minute delayed phase

Phase	What It Shows	Key Findings in ACC
Unenhanced	Baseline density (HU) — assesses lipid content	> 10 HU (lipid-poor). Most adenomas are lipid-rich with < 10 HU (intracytoplasmic fat droplets attenuate X-rays less) ^[1]^[2]^[6]. ACC cells lose their lipid content as they dedifferentiate → higher density.
Arterial/Portal venous	Enhancement pattern, tumour vascularity, invasion	Heterogeneous enhancement; look for vascular and adjacent organ invasion ^[12] — renal vein/IVC tumour thrombus, invasion of kidney, liver, diaphragm, spleen, pancreatic tail
15-minute delayed	Contrast washout calculation	< 40% relative washout or < 60% absolute washout ^[1]. Adenomas have fenestrated capillaries → contrast washes out quickly. Malignant tumours have dense, chaotic neovasculature → contrast is retained.

Washout Calculation Formulas:

$\text{Absolute washout} = \frac{\text{Enhanced HU} - \text{Delayed HU}}{\text{Enhanced HU} - \text{Unenhanced HU}} \times 100\%$

$\text{Relative washout} = \frac{\text{Enhanced HU} - \text{Delayed HU}}{\text{Enhanced HU}} \times 100\%$

Absolute washout > 60% or relative washout > 40% → likely adenoma ^[1]
Absolute washout < 60% or relative washout < 40% → indeterminate/suspicious → further workup needed

Additional CT Features of ACC:

Size > 4 cm ^[1]^[2]^[6] (90% of malignant adrenal tumours are > 4 cm) ^[2]^[6]
Irregular shape, heterogeneous, ill-defined borders, hypervascularity, central necrosis ^[1]
Calcification (~30% of ACCs)
Para-aortic lymphadenopathy ^[1]
Contralateral adrenal involvement ^[1]
Local invasion of adjacent structures ^[1]^[12]

When to use: Adjunct to CT, particularly useful for:

Chemical shift imaging (in-phase and opposed-phase sequences): Adenomas contain intracellular lipid → signal drop on opposed-phase. ACC does not drop signal (lipid-poor). This is an alternative to unenhanced CT HU measurement.
Assessment of IVC tumour thrombus: MRI is superior to CT for delineating the cranial extent of IVC thrombus (critical for surgical planning — determines whether cardiopulmonary bypass is needed).
Characterisation of indeterminate lesions on CT.
Patients who cannot receive iodinated contrast (e.g., contrast allergy, severe renal impairment).

MRI Feature	Adenoma	ACC
Chemical shift (opposed-phase signal drop)	Yes (> 20% signal drop)	No signal drop (lipid-poor)
T2W signal	Isointense to liver	Heterogeneous, often hyperintense
Gadolinium enhancement	Homogeneous, rapid washout	Heterogeneous, persistent enhancement
IVC assessment	N/A	Tumour thrombus clearly delineated

MRI adrenal: compare signal intensity with spleen ^[1] — on chemical shift imaging, if the adrenal mass drops signal intensity compared to the spleen on opposed-phase images, it is lipid-rich and likely benign.

PET-CT: ↑Sn & ↑Sp to differentiate benign vs malignant lesion; compare SUV with liver ^[1]

PET Tracer	Role	Interpretation
18F-FDG PET/CT	Differentiating benign from malignant; staging for distant metastases	Compare SUV of adrenal mass with liver: if adrenal SUVmax > liver SUVmax → suspicious for malignancy (sensitivity ~89%, specificity ~94% for ACC vs adenoma). Also detects occult lung, bone, and liver metastases that would change management (upstage to Stage IV → no curative surgery).
68Ga-DOTATATE PET/CT	If phaeochromocytoma or neuroendocrine tumour suspected	Somatostatin receptor–positive tumours light up. Not typically used for ACC (ACC is DOTATATE-negative). Helps differentiate ACC from a neuroendocrine tumour.
11C-Metomidate PET	Research/specialist use: highly specific for adrenocortical tissue	Metomidate binds to CYP11B enzymes (specific to adrenal cortex). Positive in adenoma AND ACC (both adrenocortical origin). Not useful for differentiating benign from malignant, but can confirm adrenocortical origin if uncertain.

Required for staging once ACC is suspected.
Lungs are the most common site of distant metastasis from ACC.
Low-dose non-contrast CT chest is acceptable for screening; contrast-enhanced CT chest is done if pulmonary nodules are found.

Not routine; indicated if the patient has bone pain, elevated ALP, or known advanced disease.
ACC can metastasise to bone (osteolytic lesions).

FNA biopsy is NOT indicated: cannot differentiate between benign and malignant mass, risk of tumor seeding ^[1]^[12]

Biopsy: rarely indicated. Usually only reserved for confirmation of adrenal metastasis. NOT for primary adrenal tumours (esp avoid if phaeochromocytoma) ^[2]^[6]

Scenario	Biopsy Indicated?	Rationale
Suspected primary adrenal tumour (ACC, adenoma)	NO	Histology is NOT useful in differentiating between benign/malignant adrenal tumours (same appearance) ^[2]^[6]; risk of tumour seeding; risk of hypertensive crisis if undiagnosed phaeochromocytoma
Known extra-adrenal malignancy + new adrenal mass	YES (after excluding phaeochromocytoma)	This is the one scenario where adrenal biopsy is justified — to confirm metastasis and guide systemic therapy. Must check metanephrines first.
Suspected adrenal lymphoma	YES	Lymphoma is treated with chemotherapy, not surgery. Tissue diagnosis is essential for subtyping and treatment planning.
Suspected adrenal infection (TB, fungal)	Consider	Culture and histology of aspirate can confirm diagnosis and guide antimicrobial therapy.

Once ACC is suspected or confirmed, staging determines the extent of disease and guides treatment:

Investigation	What It Assesses	Findings That Affect Staging
CT chest	Pulmonary metastases	Pulmonary nodules → Stage IV
CT/MRI abdomen	Local extent, lymph nodes, liver metastases, IVC thrombus	Periadrenal invasion → Stage III; Liver mets → Stage IV
MRI with IVC assessment	Tumour thrombus extent	Renal vein/IVC involvement → Stage III
18F-FDG PET/CT	Whole-body metastatic survey	Detects occult distant metastases → upstages to Stage IV
Bone scan / MRI spine	Skeletal metastases (if symptomatic)	Bone mets → Stage IV
Brain MRI	Brain metastases (if neurological symptoms)	Brain mets → Stage IV (rare in ACC, unlike lung cancer)

ENSAT Staging Criteria (2009) — for reference (previously covered in Part 1):

Stage	Criteria
I	Tumour ≤ 5 cm, confined to adrenal
II	Tumour > 5 cm, confined to adrenal
III	Any size + local invasion (periadrenal fat, adjacent organs) OR regional lymph nodes OR tumour thrombus in renal vein/IVC
IV	Distant metastases

Investigation	Purpose	Expected Findings in ACC
CBC	Baseline; assess for polycythaemia, anaemia	Polycythaemia (cortisol stimulates erythropoiesis); or anaemia of chronic disease in advanced ACC
RFT (renal function)	Baseline; assess for hypokalaemia	Hypokalaemic metabolic alkalosis if cortisol excess overwhelms 11β-HSD2
LFT	Baseline; assess for liver metastases	Elevated ALP, GGT, transaminases if liver involvement
Glucose / HbA1c	Screen for DM (cortisol-induced insulin resistance)	Hyperglycaemia / new-onset DM
Coagulation profile	VTE risk assessment (cortisol → hypercoagulability)	May show ↑fibrinogen; ACC + Cushing's = very high VTE risk
Calcium, phosphate	Metabolic assessment	Usually normal in ACC (unlike hypercalcaemia of malignancy from PTHrP-secreting tumours)
CRP / ESR	Inflammatory markers	May be elevated in advanced disease

When	What	Why
Age < 40 years	TP53 germline testing (Li-Fraumeni)	Paediatric and young adult ACC has high prevalence of TP53 mutations; affects cancer surveillance for patient and family
Clinical features of Beckwith-Wiedemann	11p15 methylation analysis	Macrosomia, macroglossia, omphalocele, hemihyperplasia — increased risk of childhood ACC
Suspected MEN1	MEN1 gene (menin)	Multiple endocrine tumours in patient/family (parathyroid, pituitary, pancreatic NET)
Suspected Lynch syndrome	Mismatch repair genes (MLH1, MSH2, MSH6, PMS2)	Personal/family history of colorectal, endometrial, ovarian cancers
Any ACC at diagnosis	Consider genetic counselling referral	ESMO/ENSAT 2024 guidelines recommend considering germline genetic testing for all ACC patients, as ~5–10% harbour a pathogenic germline variant

High Yield Summary - Diagnosis of ACC

Pre-operative diagnosis is based on converging hormonal + radiological evidence:

Hormonal red flags for ACC: Mixed cortisol + androgen secretion; very high DHEA-S (> 600 μg/dL); elevated steroid precursors (11-deoxycortisol); suppressed ACTH (non-ACTH-dependent); oestrogen secretion in males.
CT adrenal protocol features of ACC: Size > 4 cm; > 10 HU unenhanced (lipid-poor); < 60% absolute washout (contrast retention); heterogeneous with necrosis/haemorrhage/calcification; irregular borders; local invasion.
FNA biopsy is NEVER indicated for suspected primary adrenal tumours — cannot distinguish benign from malignant; risks tumour seeding and hypertensive crisis.
Definitive diagnosis: Post-operative histopathology using Weiss score ≥ 3/9 = ACC. Ki-67 > 10% indicates aggressive behaviour.
Staging: ENSAT system (I–IV). CT chest, MRI abdomen (IVC), PET-CT for metastatic survey.
Key screening tests for adrenal incidentaloma: ONDST + plasma/urine metanephrines + ARR (if HTN) + androgen profile (if virilised).
Biochemical hallmark of adrenal Cushing's (adenoma or ACC): Elevated cortisol, no suppression on LDDST, ACTH almost invariably undetectable, no suppression on HDDST.

Active Recall - Diagnosis of Adrenocortical Carcinoma

References

^[1] Senior notes: maxim.md (Section: Adrenal incidentaloma — Investigations, CT features, management criteria) ^[2] Senior notes: Ryan Ho Endocrine.pdf (Section 3.5.1 — Adrenal Incidentaloma, p. 68) ^[4] Senior notes: Ryan Ho Endocrine.pdf (Section 3.3.2 — Cushing's Syndrome, biochemical summary table, p. 63) ^[6] Senior notes: Ryan Ho Fundamentals.pdf (Section B — Adrenal Incidentaloma, p. 438) ^[11] Senior notes: Ryan Ho Chemical Path.pdf (Section 4.1 — Diagnosis of Cushing Syndrome, p. 29) ^[12] Senior notes: maxim.md (Section: Adrenocortical carcinoma — Investigations and Treatment) ^[13] Senior notes: Ryan Ho Fundamentals.pdf (Section: Cushing's syndrome biochemical summary, p. 437); Adrian Lui Pediatrics.pdf (Section 8.3.2, biochemical summary table, p. 287)

Management of Adrenocortical Carcinoma

Before diving into the specifics, let's establish the management philosophy for ACC. Think of it in three layers:

Surgery is the only curative modality — complete (R0) surgical resection is the single most important prognostic factor. Everything else is adjunctive.
Mitotane is the cornerstone of adjuvant/palliative systemic therapy — it is the only drug specifically approved for ACC. It is both adrenolytic (destroys adrenal cortical cells) and steroidogenesis inhibitor.
Cytotoxic chemotherapy is reserved for advanced/refractory disease — the standard regimen is EDP-M (etoposide, doxorubicin, cisplatin + mitotane).

The management approach is stage-dependent, guided by the ENSAT staging system established in the prior section.

2. Surgical Management — The Cornerstone

2A. Principles of Surgery

Surgery: open adrenalectomy ± en-bloc resection of kidney / spleen (if invaded) ^[12]

Basic principles of endocrine surgery: (1) Confirm endocrine diagnosis, (2) Localization of tumour, (3) Render patient medically fit, (4) Establish need to operate, (5) Surgical tactics ^[2]

The goal of surgery in ACC is complete macroscopic and microscopic resection (R0) — this is the single most important determinant of long-term survival. Let me break down the surgical considerations:

Approach	When to Use	Rationale
Open adrenalectomy ^[1]^[12]^[14]	Preferred if mass > 6 cm or malignant ^[1]	ACC tumours are typically large, locally invasive, and friable. Open surgery allows: (1) direct visualisation and tactile assessment of tumour extent; (2) en-bloc resection of invaded adjacent structures; (3) complete lymph node dissection; (4) avoidance of tumour capsule rupture (which would upstage to Stage III and dramatically worsen prognosis).
Laparoscopic approach ^[1]^[14]	Only if tumour is < 6 cm and imaging shows no evidence of local invasion	Laparoscopic adrenalectomy is standard for benign adrenal lesions. However, for known or suspected ACC, laparoscopic resection carries a higher risk of incomplete resection, tumour capsule rupture, and port-site metastasis — particularly for larger tumours. The 2024 ESE/ENSAT guidelines recommend open surgery for all confirmed or suspected ACC, unless the tumour is small, appears confined, and is being resected at a high-volume centre with expertise.

Why Open and Not Laparoscopic for ACC?

This is a common exam mistake. Students often default to "laparoscopic is better because it's minimally invasive." For ACC, this is wrong. The risk of tumour capsule rupture during laparoscopic mobilisation converts a potentially curable R0 resection into an R2 (macroscopic residual disease) with peritoneal seeding — essentially converting Stage I/II into incurable Stage IV. The ADIUVO trial and multiple retrospective series have shown that laparoscopic resection of ACC > 6 cm is associated with higher recurrence rates. Open approach is preferred for suspected ACC. ^[1]^[14]

Scenario	Surgical Procedure	Rationale
Localised ACC (Stage I–II)	Open radical adrenalectomy with wide periadrenal fat excision	Remove the entire adrenal gland with an intact capsule and wide margin of surrounding fat to achieve R0
Locally invasive ACC (Stage III)	Open adrenalectomy ± en-bloc resection of kidney / spleen (if invaded) ^[12]	If the tumour invades adjacent structures, en-bloc resection of those structures is mandatory to achieve R0. Right-sided: may require right nephrectomy, partial hepatectomy, IVC resection/thrombectomy. Left-sided: may require left nephrectomy, distal pancreatectomy, splenectomy.
IVC tumour thrombus	Adrenalectomy + IVC thrombectomy ± vascular reconstruction	Similar to RCC with IVC thrombus — the extent of thrombus (infrahepatic, intrahepatic, suprahepatic/intra-atrial) determines the surgical complexity (may require liver mobilisation, Pringle manoeuvre, or even cardiopulmonary bypass with hypothermic circulatory arrest for intra-atrial thrombus).
Regional lymph nodes	Ipsilateral regional lymphadenectomy	Lymph node involvement occurs in ~20–30% of ACC. Routine regional lymphadenectomy is recommended by 2024 ENSAT guidelines for accurate staging and potential therapeutic benefit.

Complications of adrenalectomy ^[1]^[2]^[14]:

Timing	Complication	Mechanism	Prevention/Management
Intra-op	Intraoperative haemorrhage: adrenal capsular, IVC ^[14]	Rich arterial supply; short right adrenal vein drains directly into IVC	Meticulous technique; vascular surgical support for IVC involvement
Intra-op	Injury to organs: spleen, liver, pneumothorax ^[14]	Right adrenalectomy: IVC, right lobe of liver. Left adrenalectomy: pancreatic tail, spleen ^[1]	Knowledge of anatomical relationships; en-bloc resection if already invaded
Intra-op	Adrenal insufficiency ^[1]^[14]	In cortisol-secreting ACC: the contralateral adrenal is suppressed by chronic cortisol excess (HPA axis suppression). On removal of the tumour, cortisol drops precipitously → Addisonian crisis	IV hydrocortisone upon removal of adrenal gland ^[1]; then taper to PO replacement
Intra-op	Tumour rupture / spillage	Friable, necrotic tumour capsule; excessive manipulation	Open approach; minimal tumour handling; immediate washout if rupture occurs
Early post-op	Acute adrenal insufficiency ^[1]^[14]	As above — HPA axis takes months to recover	PO hydrocortisone post-op ^[1]; may need replacement for 6–18 months
Early post-op	Electrolyte disturbances ^[14]	Loss of aldosterone if bilateral; hypokalaemia correction in previously Cushing's patients	Monitor K⁺, Na⁺ closely; mineralocorticoid replacement if bilateral
Late	Local recurrence	Microscopic residual disease (R1/R2), capsule violation	Adjuvant mitotane; adjuvant radiotherapy to tumour bed

Pre-operative optimisation is essential in ACC, particularly when the tumour is functional. The adage applies: "Render patient medically fit" before surgery ^[2]^[14].

Issue	Pre-operative Management	Rationale
Cortisol-secreting ACC (Cushing's)	Peri-op steroid cover, antibiotic prophylaxis ^[1]; Control and correct HTN, DM, hypoK ^[6]; Consider pre-op metyrapone to reduce cortisol levels	Chronic hypercortisolism causes: immunosuppression (↑infection risk), poor wound healing, hypercoagulability (↑VTE risk), hyperglycaemia, and hypokalaemia. Steroid cover is needed because the HPA axis is suppressed → patient cannot mount a stress cortisol response post-op.
VTE prophylaxis	Prophylaxis for DVT ^[6]; LMWH pre-op and post-op; compression stockings	ACC with Cushing's has one of the highest VTE rates of any cancer (~20–30% perioperative VTE risk) — due to cortisol-induced ↑factor VIII, ↑vWF, ↑PAI-1, ↓fibrinolysis
Hypokalaemia	Aggressive K⁺ replacement pre-op; target K⁺ > 3.5 mmol/L	Hypokalaemia from mineralocorticoid effect of excess cortisol → risk of cardiac arrhythmias under anaesthesia
Hyperglycaemia	Insulin sliding scale or protocol to target normoglycaemia	Cortisol-induced insulin resistance → hyperglycaemia → impaired wound healing and ↑infection risk
Exclude phaeochromocytoma	Confirm metanephrines are negative before surgery	A co-existing or misdiagnosed phaeochromocytoma would cause fatal intra-operative catecholamine crisis
Aldosterone-secreting ACC	Correct electrolyte imbalance, e.g. K ^[1]; spironolactone 4 weeks pre-op	Pre-op MRA normalises potassium and blood pressure

Perioperative Steroid Management — Step by Step

For a cortisol-secreting ACC undergoing adrenalectomy:

Pre-op: Continue monitoring cortisol; consider metyrapone to reduce levels. Prepare IV hydrocortisone.
Intra-op: IV hydrocortisone 50–100 mg on-call ^[4]^[14], then 50 mg Q8h.
Post-op Day 1–3: Rapid taper from 50 mg Q8h → 25 mg Q8h → 15–25 mg/day (physiological replacement).
Long-term: Post-op glucocorticoid ± mineralocorticoid supplement until HPA axis recovers ~1 year later ^[1]. Taper guided by 8 am cortisol and/or ACTH stimulation testing.

If the patient is started on adjuvant mitotane post-op, they will need higher-than-physiological glucocorticoid doses because mitotane both destroys the contralateral adrenal tissue AND induces CYP3A4 → accelerated cortisol metabolism (see below).

3. Adjuvant Mitotane — The Central Systemic Agent

Adjuvant mitotane for at least 2 years (disrupt cortisol synthesis) ^[12]

Let's break this drug down from first principles because it is unique and important:

Mitotane (o,p'-DDD or 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethane) — originally an insecticide derivative related to DDT. It was discovered to be selectively toxic to adrenal cortical cells in the 1960s.

Property	Detail	Clinical Implication
Mechanism 1: Adrenolytic	Directly toxic to zona fasciculata and reticularis cells → mitochondrial destruction → cell death	Destroys both tumour and normal adrenocortical tissue → mandatory glucocorticoid replacement
Mechanism 2: Steroidogenesis inhibition	Inhibits multiple steroidogenic enzymes (CYP11A1, CYP11B1, CYP11B2) → blocks cholesterol side-chain cleavage and 11β-hydroxylation	Rapidly reduces cortisol production — useful in functional ACC with Cushing's
Mechanism 3: CYP3A4 induction	Potent inducer of hepatic CYP3A4	High-dose glucocorticoid replacement: mitotane induces CYP3A4 → rapid activation [i.e., metabolism/clearance] of glucocorticoids ^[12]. Patients need 2–3× physiological hydrocortisone doses (or use dexamethasone, which is not a CYP3A4 substrate)
Pharmacokinetics	Highly lipophilic → stored in adipose tissue → very long half-life (18–159 days). Therapeutic window is narrow.	Requires therapeutic drug monitoring (TDM): target plasma mitotane level 14–20 mg/L. Takes 2–3 months to reach therapeutic levels. Below 14 mg/L = subtherapeutic. Above 20 mg/L = toxicity.

Indication	Evidence/Rationale
Stage I with high-risk features (Ki-67 > 10%, R1 margin, Weiss score high)	Reduces recurrence risk in high-risk resected ACC. The ADIUVO trial (2024) was the first RCT of adjuvant mitotane — it showed a non-significant trend toward improved recurrence-free survival in the overall population, but a significant benefit in the high-risk subgroup (Ki-67 > 10%). Therefore, current guidelines (ESMO/ENSAT 2024) recommend mitotane for patients with Ki-67 > 10% or other high-risk features.
Stage II–III after R0/R1 resection	Standard recommendation — adjuvant mitotane for at least 2 years ^[12]. Most guidelines recommend continuing for 2–5 years if tolerated and therapeutic levels are maintained.
Any ACC with R1/Rx margin	Microscopic positive margin → high recurrence risk → mitotane is recommended.
Functional ACC with persistent hormonal excess post-op	Mitotane controls cortisol hypersecretion even if residual/recurrent disease is present — acts as medical adrenalectomy.
Metastatic ACC (Stage IV)	Used as part of systemic therapy (monotherapy for slow progression or combined with EDP for rapid progression).

Side Effect	Mechanism	Management
GI: nausea, vomiting, diarrhoea, anorexia (most common, ~80%)	Direct GI irritation; central effects	Take with fatty food (↑absorption of lipophilic drug); antiemetics; dose titration
Adrenal insufficiency (inevitable at therapeutic doses)	Adrenolytic — destroys normal adrenal cortex	Mandatory glucocorticoid replacement; consider fludrocortisone for mineralocorticoid replacement
Neurological: dizziness, ataxia, confusion, lethargy	CNS toxicity at supratherapeutic levels (> 20 mg/L)	TDM — keep levels 14–20 mg/L; dose reduction if neurological symptoms
Hepatotoxicity	Direct hepatic toxicity + CYP induction	Monitor LFTs regularly
Hypercholesterolaemia, hypertriglyceridaemia	Mitotane stimulates hepatic VLDL/LDL production	Monitor lipids; statins if needed (avoid simvastatin — CYP3A4 substrate, levels reduced by mitotane)
Thyroid dysfunction	Increases TBG → may lower free T4 levels	Monitor TSH and free T4
↑CBG (cortisol-binding globulin)	Hepatic stimulation → total cortisol measurement unreliable	Monitor free cortisol or use clinical assessment + ACTH stimulation test for adequacy of replacement
Gynaecomastia, hypogonadism	Anti-androgenic effects	Monitor gonadal function
Teratogenicity	Toxic to fetal adrenal glands	Absolutely contraindicated in pregnancy; women of childbearing age need reliable contraception; long washout period (months after stopping) due to lipophilic accumulation

Critical Drug Interaction: Mitotane + Glucocorticoid Replacement

Mitotane induces CYP3A4 → rapid clearance of glucocorticoids ^[12]. Therefore:

Hydrocortisone doses must be 2–3× physiological (e.g., 40–60 mg/day instead of 15–25 mg/day).
Alternatively, use dexamethasone (0.5–1 mg/day), which is NOT a major CYP3A4 substrate and therefore maintains more reliable levels.
Many centres prefer dexamethasone for simplicity and reliability during mitotane therapy.
Always educate the patient about sick day rules (double/triple the dose during illness) and provide a steroid emergency card — they are functionally adrenally insufficient.

4. Cytotoxic Chemotherapy

Chemotherapy for refractory disease ^[12]

The landmark FIRM-ACT trial (Fassnacht et al., NEJM 2012) established the standard first-line chemotherapy for advanced ACC:

Component	Drug	Dose (per cycle)	Mechanism
E	Etoposide	100 mg/m² D2–4	Topoisomerase II inhibitor → DNA strand breaks → apoptosis
D	Doxorubicin	40 mg/m² D1	Intercalates DNA + topoisomerase II inhibitor → DNA damage
P	Cisplatin	40 mg/m² D3–4	Platinum cross-links DNA → prevents replication
+ M	Mitotane	Continuous, target 14–20 mg/L	Adrenolytic + steroidogenesis inhibitor + synergistic with cytotoxic agents (mitotane reverses multidrug resistance by inhibiting P-glycoprotein)

Cycle: Repeated every 4 weeks for up to 6 cycles.
FIRM-ACT results: EDP-M was superior to streptozotocin-mitotane in terms of response rate (23% vs 9%) and progression-free survival (5.0 vs 2.1 months), though overall survival was not significantly different (~15 months in both arms for advanced disease).

Indication	Scenario
First-line for rapidly progressive metastatic ACC	High tumour burden, rapidly growing metastases, symptomatic disease
Neoadjuvant therapy for locally advanced, initially unresectable ACC	Stage III tumour that encases major vessels or invades structures making R0 resection impossible → EDP-M to downstage → reassess for surgery
Adjuvant chemotherapy (EDP + mitotane)	May be considered in very high-risk resected ACC (Stage III with R1 margin, Ki-67 > 30%) — not standard, but discussed in MDT

Regimen	Evidence	Role
Gemcitabine + capecitabine (± mitotane)	Retrospective data; response rate ~10–15%	Second-line after EDP-M failure
Streptozotocin + mitotane	FIRM-ACT comparator arm; inferior to EDP-M	Historical; rarely used as first-line now
Temozolomide	Limited data; modest activity in some cases	Third-line / salvage
Immunotherapy (pembrolizumab, nivolumab ± ipilimumab)	Emerging evidence; MSI-high or TMB-high ACC may respond	Clinical trials preferred; may consider if MSI-H (rare in ACC, ~3%) or high TMB; limited efficacy in unselected patients (~10% response rate)

ACC was traditionally considered "radioresistant," but modern data has nuanced this view:

Indication	Type	Rationale
Adjuvant RT to tumour bed	External beam RT (50–60 Gy in 25–30 fractions)	For patients with R1/Rx margin or local recurrence risk (Stage III). Retrospective data suggests ↓local recurrence rates from ~70% to ~30–40% with adjuvant RT. Recommended by ENSAT/ESMO 2024 guidelines for R1 resection and Stage III disease.
Palliative RT	Various schedules	For symptomatic bone metastases (pain relief), brain metastases, or local symptoms from unresectable primary (pain, compression)
Stereotactic body RT (SBRT)	Ablative doses to oligometastases	For limited metastatic disease (e.g., 1–3 lung metastases) where surgery is not feasible. Emerging role; limited evidence but growing use.

Why was ACC thought to be radioresistant? Old data used suboptimal doses and techniques. Modern conformal RT and IMRT can deliver adequate doses to the tumour bed while sparing surrounding structures. The issue is not true radioresistance but rather the high propensity for distant metastasis — local RT cannot prevent haematogenous spread.

6. Medical Management of Hormonal Excess

Medical Mx for preoperative Mx of hypercortisolism ^[4]^[6]^[14]

Agent	Mechanism	Notes
Metyrapone: first-line ^[4]^[6]	CYP11B (11β-hydroxylase) inhibitor → ↓cortisol synthesis ^[4]	Short-acting, effective within 2h but requires BD/TDS dosing ^[4]. Rapidly controls cortisol. Side effect: accumulation of 11-deoxycortisol and androgens → hirsutism in women.
Ketoconazole ^[4]	Azole antifungal; inhibits multiple CYP enzymes in steroidogenesis (CYP17, CYP11A1, CYP11B1)	S/E: hepatotoxicity, ↓androgen (gynaecomastia, ↓libido, impotence) ^[4]. Second-line due to hepatotoxicity risk.
Osilodrostat (newer agent, 2020)	CYP11B1 and CYP11B2 inhibitor (more selective than metyrapone)	Approved for Cushing's syndrome (any cause). Potent, oral, BD dosing. S/E: adrenal insufficiency, hypokalaemia (via CYP11B2 inhibition → ↑aldosterone precursors), hirsutism.
Mitotane ^[4]^[12]	Cytotoxic to adrenal → adjunct "medical" adrenalectomy for CA adrenal ^[4]	Used both pre-operatively (to control cortisol) and as definitive adjuvant therapy. Slow onset (~2–3 months to therapeutic levels).
Etomidate (IV)	Inhibits CYP11B1 at subanaesthetic doses	Only for emergency use in severe Cushing's-related crises (e.g., Cushing's crisis with sepsis, psychosis, severe hypokalaemia) — requires ICU monitoring. Given as continuous IV infusion at subanaesthetic dose (0.03 mg/kg/h).

Two approaches to pre-operative cortisol control ^[4]:

Approach	Method	When to Use
Block-and-replace	Total ablation of cortisol with high-dose steroidogenesis inhibitor + exogenous hydrocortisone replacement	Used in patients with wide variability in cortisol production and UFC ^[4]. Gives more stable cortisol levels. Easier to manage. Preferred in ACC (cortisol secretion is often erratic and unpredictable).
Normalisation	Titrate steroidogenesis inhibitor to achieve normal cortisol levels without replacement	Used in patients with relatively invariable hypercortisolism ^[4]. More physiological but requires frequent monitoring and dose adjustment.

ACC has a very high recurrence rate — ~50–80% of patients recur even after R0 resection. Recurrence is managed as follows:

Scenario	Management
Isolated local recurrence	Re-resection if R0 feasible + adjuvant RT to tumour bed + mitotane
Isolated/oligometastatic distant recurrence	Metastasectomy (e.g., pulmonary metastasectomy) if complete resection feasible + mitotane
Widespread recurrence/progression	Systemic therapy: EDP-M if not previously used, or second-line regimens

Modality	Schedule	Rationale
CT chest/abdomen/pelvis	Q3 months for first 2 years → Q6 months for years 3–5 → annually thereafter	Detects recurrence early; most recurrences occur within 2 years
Hormonal markers (if previously functional)	At each imaging visit	Rising hormone levels (cortisol, DHEA-S, urine steroid metabolome) often precede radiological recurrence by weeks to months → early biochemical detection
Mitotane levels (if on adjuvant mitotane)	Q4–8 weeks until therapeutic; then Q3 months	Maintain 14–20 mg/L; dose adjust accordingly

Stage	Surgery	Adjuvant Mitotane	Adjuvant Chemo	Adjuvant RT	Prognosis (5-year OS)
I	Open adrenalectomy, R0	Consider if Ki-67 > 10% or other high-risk features	No	No	~65–80%
II	Open adrenalectomy, R0	At least 2 years ^[12]	No (unless very high risk)	Consider if R1	~50–70%
III	Open adrenalectomy ± en-bloc resection ^[12]; regional LN dissection	At least 2 years ^[12]	Consider EDP-M if very high risk	Recommended if R1/Rx	~20–40%
IV	Cytoreductive surgery if feasible (to control hormone excess / limited mets)	Yes (continuous)	EDP-M first-line for rapid progression; mitotane alone for slow progression	Palliative RT for symptoms	~0–15%

High Yield Summary — Management of ACC

Surgical Principles:

Open adrenalectomy is preferred for confirmed/suspected ACC (NOT laparoscopic for masses > 6 cm or malignant) ^[1].
En-bloc resection of kidney/spleen if invaded ^[12]; regional lymphadenectomy recommended.
Goal is R0 resection — the single most important prognostic factor.

Perioperative Management:

Steroid cover (HPA axis suppressed), antibiotic prophylaxis, DVT prophylaxis ^[1]^[6].
IV hydrocortisone upon removal of adrenal gland → taper to PO replacement ^[1].
Correct HTN, DM, hypokalaemia pre-operatively ^[6].

Adjuvant Mitotane:

At least 2 years for Stage II–III and high-risk Stage I ^[12].
Disrupts cortisol synthesis and is adrenolytic ^[12].
High-dose glucocorticoid replacement mandatory because mitotane induces CYP3A4 → rapid clearance of glucocorticoids ^[12].
Therapeutic drug monitoring: target 14–20 mg/L.

Chemotherapy:

Chemotherapy for refractory disease ^[12]: EDP-M regimen (FIRM-ACT trial).
First-line for rapidly progressive or high-burden metastatic ACC.

Pre-operative Cortisol Control:

Metyrapone: first-line (CYP11B inhibitor) ^[4].
Mitotane: cytotoxic to adrenal — adjunct "medical" adrenalectomy for CA adrenal ^[4].
Block-and-replace or normalisation approach ^[4].

Active Recall - Management of Adrenocortical Carcinoma

References

^[1] Senior notes: maxim.md (Section: Adrenalectomy — Indications, Approach, Pre-op preparation, Complications; Cushing's syndrome — Perioperative cautions) ^[2] Senior notes: Ryan Ho Endocrine.pdf (Section 3.5.1 — Adrenal Incidentaloma, p. 68; Section 3.5.2 — Adrenal Surgery, p. 69) ^[4] Senior notes: Ryan Ho Endocrine.pdf (Section 3.3 — Cushing's Syndrome: Medical Mx, p. 64); Adrian Lui Pediatrics.pdf (Section 8.3.2 — Cushing's Syndrome: Medical Mx, p. 288) ^[6] Senior notes: Ryan Ho Fundamentals.pdf (Section: Cushing's syndrome management — Perioperative management, p. 437; Section B — Adrenal Incidentaloma, p. 438) ^[12] Senior notes: maxim.md (Section: Adrenocortical carcinoma — Treatment) ^[14] Senior notes: Ryan Ho Endocrine.pdf (Section 3.5.2 — Adrenal Surgery: Indications, Approach, Complications, p. 69)

Complications of Adrenocortical Carcinoma

Complications of ACC arise from three interrelated sources: the disease itself (hormonal excess and tumour behaviour), the surgery (perioperative and post-operative), and the adjuvant/systemic therapy (particularly mitotane and chemotherapy). Let me systematically work through each category, explaining the "why" behind every complication from first principles.

1. Complications of the Disease Itself

1A. Complications of Hormonal Excess

The majority of morbidity and mortality from functional ACC derives from the metabolic, cardiovascular, and immunological consequences of chronic cortisol excess. Remember that ACC produces cortisol in a massive, autonomous, unregulated fashion — far more severe than typical pituitary Cushing's disease. Untreated Cushing's syndrome is often fatal due to cardiovascular and thromboembolic complications ^[4]^[15].

Complication	Pathophysiology	Clinical Impact
DVT and pulmonary embolism	Cortisol excess creates a hypercoagulable state via multiple mechanisms: (1) ↑hepatic synthesis of clotting factors (especially factor VIII and vWF); (2) ↑plasminogen activator inhibitor-1 (PAI-1) → impaired fibrinolysis; (3) ↑fibrinogen; (4) direct endothelial dysfunction from cortisol. Additionally, immobility (from myopathy) and polycythaemia contribute to Virchow's triad.	ACC with Cushing's syndrome carries a perioperative VTE rate of ~20–30%, one of the highest of any cancer. PE is a leading cause of death in the perioperative period. Prophylaxis by steroid cover, Abx and for DVT (hypercoagulable state in CS) ^[1]^[4]^[15].

VTE in ACC — A Leading Cause of Death

Students often underestimate the VTE risk in Cushing's syndrome. The combination of cortisol-induced hypercoagulability + cancer-associated hypercoagulability (tissue factor, cancer procoagulant) + surgical immobility makes VTE prophylaxis absolutely mandatory. Perioperative LMWH should be started pre-operatively and continued for at least 4–6 weeks post-operatively. Some centres use extended thromboprophylaxis for the duration of active Cushing's syndrome.

Complication	Pathophysiology
Hypertension	Cortisol has inherent mineralocorticoid activity (30–40% of physiological mineralocorticoid effect). When cortisol is produced in massive excess, it overwhelms 11β-HSD2 in the kidney → activates mineralocorticoid receptors → Na⁺ retention, K⁺ excretion, volume expansion → hypertension. Additionally, cortisol upregulates angiotensinogen and sensitises vascular smooth muscle to catecholamines.
Left ventricular hypertrophy / cardiomyopathy	Chronic pressure overload from hypertension + direct cardiotoxic effect of cortisol → concentric LVH → diastolic dysfunction → eventual systolic heart failure.
Accelerated atherosclerosis	Cortisol promotes dyslipidaemia (↑LDL, ↑triglycerides, ↓HDL), insulin resistance/DM, central obesity → all major risk factors for atherosclerotic CVD. Patients with Cushing's have ↑risk of MI and stroke even after biochemical cure.
Cardiac arrhythmias	Secondary to severe hypokalaemia (see below) → predisposes to prolonged QT interval, U waves, ventricular tachycardia/fibrillation. This is particularly dangerous during anaesthesia.

Complication	Pathophysiology
Hypokalaemic metabolic alkalosis	Massive cortisol excess saturates renal 11β-HSD2 → unmetabolised cortisol activates mineralocorticoid receptors (ENaC, ROMK) in the distal nephron → K⁺ wasting, Na⁺ reabsorption, H⁺ excretion. In ACC-related Cushing's, hypokalaemia is often severe (K⁺ < 2.5 mmol/L) — much more so than in pituitary Cushing's disease, where cortisol levels are lower and 11β-HSD2 copes better.
Diabetes mellitus / hyperglycaemia	Cortisol promotes hepatic gluconeogenesis (↑PEPCK, ↑G6Pase), opposes insulin signalling in peripheral tissues (↓GLUT4 translocation), and stimulates proteolysis to provide gluconeogenic amino acid substrates. New-onset or worsening DM is common and impairs wound healing and ↑infection risk.
Osteoporosis / pathological fractures	Cortisol: (1) directly inhibits osteoblast activity; (2) ↓intestinal Ca²⁺ absorption; (3) ↑renal Ca²⁺ excretion; (4) suppresses gonadotropins → hypogonadism → ↓bone-protective sex steroids. Vertebral compression fractures can occur even in relatively young patients.
Dyslipidaemia	Cortisol stimulates hepatic VLDL synthesis and lipoprotein lipase → ↑triglycerides, ↑LDL.

Complication

Pathophysiology

Opportunistic and serious infections

Cortisol is profoundly immunosuppressive: (1) inhibits NF-κB → ↓inflammatory cytokine production; (2) induces lymphocyte apoptosis → lymphopaenia; (3) impairs neutrophil chemotaxis and macrophage phagocytosis; (4) suppresses cell-mediated immunity. Patients with severe Cushing's are at risk of infections typically seen in immunocompromised hosts: Pneumocystis jirovecii pneumonia, invasive fungal infections, reactivation TB. Prophylactic antibiotics are indicated perioperatively ^[1]^[4]^[15].

Poor wound healing

Cortisol inhibits fibroblast proliferation, collagen synthesis, and angiogenesis → impaired wound healing post-operatively. Surgical site infections are more common.

Complication	Pathophysiology
Depression, psychosis, cognitive impairment	Cortisol crosses the blood-brain barrier and binds to glucocorticoid receptors in the hippocampus, amygdala, and prefrontal cortex. Chronic excess causes hippocampal atrophy (→ memory impairment), limbic dysfunction (→ depression, emotional lability), and at very high levels, steroid psychosis (→ paranoia, hallucinations).
Insomnia	Cortisol disrupts the normal circadian rhythm and sleep architecture.

Complication	Pathophysiology
Virilisation in women (hirsutism, acne, clitoromegaly, amenorrhoea)	ACC produces androgens (DHEA-S, androstenedione, testosterone) in excess. While not life-threatening, these cause significant psychological distress and are often the presenting complaint. Amenorrhoea results from androgen-mediated suppression of the GnRH pulse generator.
Precocious puberty in children	Androgen and/or oestrogen excess accelerates epiphyseal maturation → premature growth spurt followed by early epiphyseal closure → ultimately short adult height despite appearing tall in childhood.

Complication	Pathophysiology
Gynaecomastia and testicular atrophy in males	Oestrogen suppresses GnRH → ↓LH/FSH → ↓testicular testosterone production → gonadal atrophy. Oestrogen directly stimulates breast ductal proliferation.

ACC is a large, aggressive tumour that grows rapidly and invades locally. The specific complications depend on the side of the tumour and the structures invaded:

Structure Invaded	Complication	Mechanism
IVC (especially right-sided ACC)	Lower limb oedema, Budd-Chiari syndrome, PE from tumour embolism	Tumour thrombus extends from adrenal vein → renal vein → IVC. Obstruction of IVC causes venous congestion below the level of obstruction. If thrombus extends above hepatic veins, hepatic venous outflow obstruction → Budd-Chiari (ascites, hepatomegaly, liver failure). Friable tumour thrombus can embolise to pulmonary arteries → massive PE.
Renal vein	Renal vein thrombosis; left varicocele (left-sided)	Left adrenal vein drains into left renal vein → tumour thrombus obstructs left gonadal vein drainage → new-onset left varicocele that does not decompress supine (pathological varicocele).
Kidney	Renal dysfunction, haematuria	Direct parenchymal invasion or renal vein obstruction
Liver (right-sided)	Hepatic pain, hepatomegaly, jaundice	Right adrenalectomy risks injury to IVC, right lobe of liver ^[1]^[14]. Direct invasion into the liver can cause obstructive jaundice if near the hilum.
Pancreatic tail / spleen (left-sided)	Pancreatitis, splenic haemorrhage	Left adrenalectomy risks injury to pancreatic tail, spleen ^[1]^[14]. Direct tumour invasion may necessitate distal pancreatectomy and splenectomy en bloc.
Diaphragm	Pleural effusion, diaphragmatic dysfunction	Invasion through the diaphragm can cause sympathetic pleural effusion or direct extension into the thorax.
Retroperitoneal nerves / structures	Flank/back pain, radiculopathy	Tumour compression or invasion of lumbar plexus, psoas muscle, or retroperitoneal nerves.

ACC metastasises most commonly to lungs, liver, bone, and peritoneum. Each metastatic site carries specific complications:

Site	Complications	Pathophysiology
Lungs (most common)	Dyspnoea, cough, haemoptysis, pleural effusion	Haematogenous spread via adrenal vein → IVC → right heart → pulmonary arteries → lung parenchyma. Multiple pulmonary nodules or lymphangitic carcinomatosis impair gas exchange.
Liver	Hepatomegaly, right upper quadrant pain, jaundice, deranged LFTs, liver failure	Haematogenous spread via portal system or direct invasion (right-sided). Massive hepatic replacement → synthetic failure, coagulopathy.
Bone	Bone pain, pathological fractures, hypercalcaemia, spinal cord compression	Osteolytic metastases weaken bone architecture. Hypercalcaemia may be due to local osteolysis (not typically PTHrP-mediated in ACC). Vertebral metastases can cause epidural compression → neurological emergency.
Brain (rare)	Headache, seizures, focal neurological deficits	Haematogenous spread. Less common than in lung cancer but can occur in advanced disease.
Peritoneum	Ascites, bowel obstruction, peritoneal carcinomatosis	Can result from direct extension through the tumour capsule (especially if capsule ruptured during surgery) or from peritoneal seeding after biopsy/incomplete resection.

2. Complications of Surgery (Adrenalectomy)

These were introduced in the management section but deserve detailed exploration here as they are frequently examined:

Complications of adrenalectomy ^[1]^[14]:

Complication	Mechanism	Prevention / Management
Intraoperative haemorrhage: adrenal capsular, IVC ^[14]	The adrenal glands have an extremely rich arterial supply (3 arterial sources) and the right adrenal vein is short (~1 cm) and drains directly into the IVC — easily torn during mobilisation. ACC tumours are large, vascular, and often invade the IVC.	Meticulous surgical technique; vascular surgical support on standby; autologous blood available; cell salvage (controversial in cancer surgery due to theoretical risk of tumour cell reinfusion).
Injury to organs: spleen, liver, pneumothorax ^[14]	Right adrenalectomy: IVC, right lobe of liver. Left adrenalectomy: pancreatic tail, spleen ^[1]. Anatomical proximity means en-bloc resection may be intentional, but inadvertent injury is a recognised complication. Diaphragmatic injury → pneumothorax.	Knowledge of anatomical relationships; pre-operative cross-sectional imaging to plan surgical approach; post-op CXR to detect pneumothorax.
Adrenal insufficiency ^[1]^[14]	In cortisol-secreting ACC, the contralateral adrenal gland is chronically suppressed because exogenous cortisol from the tumour has been suppressing ACTH via negative feedback → contralateral adrenal cortex atrophies. When the tumour is removed, cortisol drops precipitously and the atrophic contralateral gland cannot respond → Addisonian crisis (hypotension, shock, hypoglycaemia, hyperkalaemia, hyponatraemia).	IV hydrocortisone 50–100 mg immediately upon removal of adrenals ^[1]^[4]^[15]. Prepared in advance; anaesthetic team informed.
Tumour capsule rupture / spillage	ACC capsules are often thin, friable, and infiltrated by tumour. Excessive manipulation during mobilisation can rupture the capsule → tumour cell spillage into the peritoneal cavity → peritoneal carcinomatosis → upstages to Stage III/IV → dramatically worsens prognosis.	Open approach (not laparoscopic) for suspected ACC; minimal tumour handling ("no-touch" technique); avoid grasping tumour directly; immediate peritoneal washout if rupture occurs.

Why Tumour Rupture Is Catastrophic

Capsule rupture during surgery converts a potentially curable R0 resection into R2 (macroscopic residual) disease. Retrospective data shows that intraoperative tumour spillage is associated with near-100% local recurrence and a dramatic drop in 5-year survival (from ~60% to < 20%). This is the primary reason open surgery is preferred over laparoscopic for suspected ACC — to minimise the risk of capsule violation.

Complication	Mechanism	Management
Acute adrenal insufficiency ^[1]^[14]	HPA axis suppression (as above) — takes 6–18 months for the contralateral adrenal to recover. Presents as hypotension refractory to fluids, hypoglycaemia, altered consciousness, nausea/vomiting.	PO hydrocortisone post-op ^[1] → gradual taper over months. Sick day rules: double/triple dose during intercurrent illness. Steroid emergency card. May also need fludrocortisone for mineralocorticoid replacement if the remaining adrenal is severely atrophic.
Electrolyte disturbances ^[14]	Acute loss of cortisol → hyperkalaemia, hyponatraemia (loss of cortisol's permissive effect on free water excretion + loss of mineralocorticoid effect). Conversely, patients who were previously hypokalaemic from cortisol excess may have rapid K⁺ shifts during correction.	Close monitoring of K⁺, Na⁺, glucose in the first 48–72 hours. Insulin/dextrose if hyperkalaemic; cautious K⁺ replacement if hypokalaemic.
VTE (DVT / PE)	Hypercoagulable state from Cushing's persists for days to weeks post-operatively even after tumour removal (clotting factor half-lives). Combined with surgical immobility and cancer-associated hypercoagulability.	Extended LMWH prophylaxis for at least 4–6 weeks post-op; early mobilisation; compression stockings.
Surgical site infection / wound dehiscence	Cortisol-impaired wound healing + immunosuppression.	Prophylactic antibiotics ^[1]^[4]^[15]; meticulous wound care; close monitoring for wound breakdown.
HTN crisis ^[14]	If the ACC also produced catecholamines (rare mixed tumours) or if a co-existing phaeochromocytoma was missed → massive catecholamine surge during tumour manipulation. Also, rebound hypertension from withdrawal of previous antihypertensives or fluid shifts.	Pre-operative exclusion of phaeochromocytoma is mandatory. IV phentolamine or nitroprusside available in theatre.

Complication	Mechanism	Management
Local recurrence	Microscopic residual disease at resection margin (R1/Rx), capsule violation, lymph node micrometastases. ACC has a very high local recurrence rate: ~50–80% even after apparently complete R0 resection.	Adjuvant mitotane (reduces recurrence risk); adjuvant radiotherapy for R1 margins; close surveillance imaging (CT Q3 months).
Distant metastatic recurrence	Haematogenous micrometastases present at the time of surgery but undetectable by imaging. Most recurrences occur within the first 2 years post-resection.	Adjuvant mitotane; surveillance; EDP-M chemotherapy for progressive disease.
Late hypertension ^[1]	Renal artery injury during surgery (particularly if en-bloc nephrectomy performed or extensive retroperitoneal dissection) → renal ischaemia → RAAS activation → renovascular hypertension.	Monitor BP long-term; renal duplex ultrasound if new-onset or worsening HTN; ACEi/ARB first-line treatment.
Chronic adrenal insufficiency	If the contralateral adrenal fails to recover (rare if it was not diseased), or if the patient is on mitotane (which is adrenolytic to the remaining gland).	Lifelong glucocorticoid ± mineralocorticoid replacement; regular ACTH stimulation testing to assess recovery. Post-op glucocorticoid ± mineralocorticoid supplement until HPA axis recovers ~1 year later ^[1].
Incisional hernia	Large open surgical incision (often subcostal or thoraco-abdominal) → abdominal wall weakness, especially in patients with Cushing's (cortisol-impaired collagen synthesis).	Delayed heavy lifting; mesh reinforcement at primary closure if high risk.

Mitotane has a narrow therapeutic window and significant toxicity. These complications are common and require careful monitoring:

Complication	Mechanism	Frequency	Management
GI toxicity (nausea, vomiting, diarrhoea, anorexia)	Direct GI mucosal irritation + central chemoreceptor trigger zone stimulation	~80%	Take with fatty food; antiemetics (ondansetron); gradual dose escalation
Adrenal insufficiency (inevitable)	Adrenolytic — destroys all adrenal cortical tissue, including the normal contralateral gland	~100% at therapeutic doses	High-dose glucocorticoid replacement ^[12]; mitotane induces CYP3A4 → rapid clearance of glucocorticoids ^[12] → need 2–3× physiological hydrocortisone or use dexamethasone
Neurological toxicity (ataxia, dizziness, confusion, cognitive slowing, lethargy)	CNS toxicity — mitotane accumulates in lipid-rich CNS tissue; dose-related, usually at supratherapeutic levels ( > 20 mg/L)	~40% at therapeutic levels	TDM: maintain 14–20 mg/L; dose reduction or temporary hold if neurological symptoms; symptoms usually reversible
Hepatotoxicity (↑transaminases)	Direct hepatotoxic effect + CYP induction–related metabolic changes	~10–15%	Monitor LFTs Q4–8 weeks; dose reduction if AST/ALT > 3× ULN
Hypercholesterolaemia / hypertriglyceridaemia	Mitotane stimulates hepatic VLDL/LDL production; also increases cholesterol synthesis	~40%	Lipid monitoring; statins (avoid simvastatin — CYP3A4 substrate with reduced efficacy; use atorvastatin or rosuvastatin)
Thyroid dysfunction	↑TBG synthesis → ↑total T4 (but free T4 may decrease); also direct effect on thyroid hormone metabolism	~15%	Monitor TSH and free T4; levothyroxine if clinically or biochemically hypothyroid
Gynaecomastia / hypogonadism	Anti-androgenic effects; ↑SHBG → ↓free testosterone	Variable	Monitor testosterone; consider testosterone replacement if symptomatic
Teratogenicity	Toxic to fetal adrenal development	N/A	Absolutely contraindicated in pregnancy; reliable contraception mandatory; long washout needed post-cessation
Prolonged post-cessation effect	Extremely lipophilic → stored in adipose tissue → half-life 18–159 days	N/A	Mitotane can persist for months after stopping; adrenal insufficiency may persist; inform patients about prolonged effects

Drug	Major Toxicities	Pathophysiology
Cisplatin	Nephrotoxicity, ototoxicity, peripheral neuropathy, severe nausea/vomiting	Cisplatin accumulates in renal tubular cells → direct tubular necrosis. Damages cochlear hair cells (irreversible). Disrupts peripheral nerve axonal transport.
Doxorubicin	Cumulative dose-dependent cardiotoxicity (dilated cardiomyopathy), myelosuppression, alopecia	Doxorubicin generates free radicals via iron-dependent redox cycling → cardiomyocyte mitochondrial damage → irreversible cardiomyopathy. Lifetime cumulative dose limit: 450 mg/m².
Etoposide	Myelosuppression (especially leucopaenia), secondary leukaemia (rare, long-term)	Topoisomerase II inhibition in haematopoietic stem cells → DNA breaks → cytopenia; can cause secondary AML (especially MLL-rearranged) years later.
All agents combined	Severe pancytopaenia, febrile neutropaenia, mucositis, fatigue	Bone marrow suppression from multiple cytotoxic agents acting synergistically. Febrile neutropaenia is a medical emergency requiring empirical broad-spectrum antibiotics.

Complication	Detail
Very high recurrence rate	~50–80% of patients with apparently R0-resected ACC will recur within 5 years. Most recurrences occur within the first 2 years. This necessitates intensive surveillance.
Progression to unresectable / metastatic disease	Progressive disease despite surgery and adjuvant therapy. Transition to palliative care with focus on quality of life, symptom control (cortisol control with medical agents), and psychosocial support.
Death from disease	Overall 5-year survival across all stages is ~35–50%. Stage IV: < 15%. The combination of treatment-refractory cancer, severe Cushing's syndrome, infections, and VTE makes advanced ACC one of the most lethal endocrine malignancies.

Category	Key Complications	Key Mechanisms
Disease — Hormonal	VTE, HTN, DM, hypokalaemia, infections, osteoporosis, psychiatric	Cortisol excess → hypercoagulability, mineralocorticoid effect, gluconeogenesis, immunosuppression
Disease — Local invasion	IVC obstruction, renal vein thrombosis, hepatic/splenic/pancreatic invasion	Direct tumour invasion of adjacent retroperitoneal structures
Disease — Metastatic	Pulmonary nodules, liver failure, bone pain/fractures, cord compression	Haematogenous spread (lung > liver > bone > brain)
Surgery — Intra-op	Haemorrhage (IVC), organ injury (liver/spleen/pancreas), adrenal crisis, tumour rupture ^[1]^[14]	Rich adrenal vasculature; anatomical proximity; HPA suppression; friable tumour capsule
Surgery — Post-op	Adrenal insufficiency, electrolyte disturbance, VTE, wound infection ^[1]^[14]	HPA axis suppression; cortisol-impaired healing; hypercoagulability
Mitotane	GI toxicity, adrenal insufficiency, neurological, hepatic, metabolic	Adrenolytic; CYP3A4 induction; CNS lipophilic accumulation
Chemotherapy	Nephrotoxicity, cardiotoxicity, myelosuppression	Cisplatin tubular toxicity; doxorubicin free radical cardiomyocyte damage; bone marrow suppression

High Yield Summary — Complications of ACC

Most dangerous complications of ACC are from cortisol excess:

VTE is a leading cause of perioperative death — prophylaxis mandatory ^[1]^[4]^[15]
Severe hypokalaemia (K⁺ < 2.5) → arrhythmias — must correct pre-operatively
Infections (immunosuppression) — prophylactic antibiotics perioperatively
Hyperglycaemia — impairs wound healing

Most feared surgical complications:

Intra-op haemorrhage from IVC (right-sided) ^[14]
Tumour capsule rupture → peritoneal carcinomatosis → incurable disease
Acute adrenal insufficiency → Addisonian crisis → IV hydrocortisone on removal ^[1]^[4]^[15]

Mitotane complications to remember:

Mandatory glucocorticoid replacement (adrenolytic + CYP3A4 induction) ^[12]
Neurological toxicity (ataxia, confusion) — dose-related, monitor levels 14–20 mg/L
GI intolerance (~80%) — take with fatty food

Overall prognosis: 5-year OS ~35–50% (all stages); Stage IV < 15%. Recurrence rate ~50–80% even after R0.

Active Recall - Complications of Adrenocortical Carcinoma

References

^[1] Senior notes: maxim.md (Section: Adrenalectomy — Complications; Cushing's syndrome — Perioperative cautions) ^[4] Senior notes: Ryan Ho Endocrine.pdf (Section 3.3 — Cushing's Syndrome: Mx, Perioperative management, Prognosis, p. 64) ^[12] Senior notes: maxim.md (Section: Adrenocortical carcinoma — Treatment: mitotane, CYP3A4 induction) ^[14] Senior notes: Ryan Ho Endocrine.pdf (Section 3.5.2 — Adrenal Surgery: Complications, p. 69) ^[15] Senior notes: Adrian Lui Pediatrics.pdf (Section 8.3.2 — Cushing's Syndrome: Perioperative management, Nelson syndrome, p. 288)

Adrenocortical Carcinoma

1. Definition

2. Epidemiology

Incidence

Hong Kong / East Asian Context

Risk Factors

3. Anatomy and Function of the Adrenal Cortex

Gross Anatomy

Cortical Zones — "GFR" Mnemonic (from outside inward)

Why Does This Matter for ACC?

4. Etiology and Pathophysiology

4.1 Molecular Pathogenesis

a) IGF2 Overexpression (most common molecular alteration)

b) TP53 Pathway Inactivation

c) Wnt/β-catenin Pathway Activation

d) Other Pathways

4.2 Hormonal Overproduction — Pathophysiology

4.3 Tumour Behaviour and Spread

5. Classification

5.1 Functional Classification

5.2 Histopathological Classification — Weiss Scoring System

5.3 ENSAT Staging System (European Network for the Study of Adrenal Tumors, 2009)

5.4 Molecular Classification (The Cancer Genome Atlas — TCGA, 2016)

6. Clinical Features

6.1 Symptoms

A. Symptoms from Hormonal Excess (~50–60%)

B. Symptoms from Mass Effect (~30–40%, especially non-functional tumours)

C. Systemic / Metastatic Symptoms

D. Incidental Discovery (~10–15%)

6.2 Signs

A. Signs of Hormonal Excess

B. Signs of Mass Effect and Local Invasion

C. Signs of Metastatic Disease

D. General Examination

7. Important Pathophysiological Connections — Summary Table

8. Key Points Distinguishing ACC from Benign Adrenal Adenoma

Active Recall - Adrenocortical Carcinoma (Part 1)

References

Conceptual Framework: Why Is the DDx Structured This Way?

1. Differential Diagnosis of an Adrenal Mass (The Incidentaloma Framework)

A. Benign Adrenal Cortical Lesions

B. Adrenal Medullary Lesions

C. Malignant Lesions — Primary

D. Malignant Lesions — Secondary (Metastatic)

E. Non-Neoplastic Mimics

2. Differential Diagnosis by Clinical Presentation

A. Presenting with Cushing's Syndrome

B. Presenting with Virilisation / Hyperandrogenism in Women

C. Presenting with an Adrenal Mass on Imaging (Incidentaloma)

3. Diagnostic Approach Algorithm — Mermaid Diagram

4. Key Differentiating Features — Summary Table

5. Special Considerations in Hong Kong

Active Recall - DDx of Adrenocortical Carcinoma

Overview of Diagnostic Philosophy

1. Diagnostic Criteria

1A. Pre-operative Diagnostic Criteria (Clinical + Radiological Suspicion)

1B. Histopathological Diagnostic Criteria — The Weiss Scoring System (Post-operative)

2. Comprehensive Diagnostic Algorithm

3. Investigation Modalities — Detailed Breakdown

3A. Hormonal Investigations

i. Screening for Cortisol Excess (Cushing's Syndrome)

ii. ACTH Level — The Pivotal Test

iii. Adrenal Steroid Profile — The ACC-Specific Panel

iv. Screening for Phaeochromocytoma

v. Screening for Conn's Syndrome (if Hypertensive)

3B. Radiological Investigations

i. CT Abdomen with Adrenal Protocol — The Cornerstone

ii. MRI Abdomen

iii. PET-CT

iv. Chest CT

v. Bone Scan / MRI Spine

vi. Fine Needle Aspiration (FNA) Biopsy

3C. Staging Investigations (ENSAT Staging)

3D. Laboratory Investigations — Baseline and Supportive

3E. Genetic Testing

4. Integrated Diagnostic Algorithm — Summary Mermaid Diagram

Active Recall - Diagnosis of Adrenocortical Carcinoma

Guiding Principles

1. Management Algorithm — Overview

2. Surgical Management — The Cornerstone