Adrenal masses and adrenocortical carcinoma

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

ACC arises from adrenal cortex and may secrete cortisol, androgens, mineralocorticoid precursors or oestrogens. Mixed secretion is a biological clue. Non-functioning tumours often present later through mass effect or metastasis, so an apparently asymptomatic large heterogeneous lesion still needs urgent cancer-centre evaluation.

The preoperative pathway must preserve cure. Cross-sectional staging determines local resectability and distant burden; biochemical work-up prevents an unsuspected catecholamine catastrophe and anticipates cortisol suppression after surgery. Percutaneous biopsy generally does not answer the decisive cortical malignancy question and can compromise an intact operative field.

Management is longitudinal and toxic. Mitotane has a long, variable pharmacokinetic profile, induces hepatic enzymes, alters binding proteins and commonly causes adrenal insufficiency, gastrointestinal, neurological and lipid effects. Patients need experienced pharmacy, endocrine and oncology teams, therapeutic drug monitoring and unusually high replacement doses guided individually.

Key points

Adrenocortical carcinoma is rare and aggressive; presentation may be an incidental mass, abdominal or back discomfort, mass effect, constitutional decline or rapid steroid-hormone excess.
Rapid virilisation, combined androgen and cortisol secretion, severe new Cushing syndrome or feminisation is particularly concerning for cortical malignancy.
Dedicated adrenal imaging should define size, heterogeneity, necrosis, local invasion, venous extension, nodes and metastases, with staging of chest, abdomen and pelvis before definitive surgery.
Complete endocrine assessment before biopsy or operation, including metanephrines to exclude phaeochromocytoma and a broad cortical steroid profile when ACC is suspected.
Do not biopsy a potentially resectable primary adrenal cortical tumour routinely; it risks seeding or delay and cannot reliably separate adenoma from carcinoma.
The best chance of cure is complete en-bloc, capsule-intact resection by a high-volume adrenal cancer surgeon, avoiding tumour rupture and unplanned piecemeal laparoscopy.
Pathology requires expert endocrine reporting of margin status, stage, mitotic activity, invasion, validated malignancy criteria and Ki-67; the current RCPath dataset and TNM edition should be used.
Mitotane, adjuvant decisions, systemic chemotherapy, radiotherapy and surveillance are specialist choices based on stage, resection, proliferation, hormone secretion, performance status and commissioning.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Functioning cortical tumour

Most adrenocortical carcinomas are sporadic cortical malignancies; some autonomously secrete cortisol, androgens, mineralocorticoid precursors or oestrogens, often in mixed and rapidly progressive patterns.

Non-functioning cortical tumour

A clinically non-functioning cortical carcinoma may remain silent until mass effect, local invasion or metastasis appears; a minority arises with inherited cancer susceptibility such as Li-Fraumeni or Lynch syndrome.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Cortical cells become malignant
Disordered adrenal cortical growth produces a heterogeneous mass capable of necrosis, haemorrhage, capsular disruption and invasion into adjacent structures or veins.
2
Steroid production becomes autonomous
Tumour steroidogenesis escapes normal feedback, creating cortisol, androgen, mineralocorticoid or oestrogen effects that may evolve more rapidly than benign endocrine disease.
3
Invasion and dissemination progress
Local extension, venous tumour thrombus and spread to lung, liver, bone or nodes reduce resectability and make durable control dependent on specialist multimodal care.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Rapid virilisation

New deep voice, clitoromegaly, temporal hair recession, marked hirsutism or rapid androgenic change suggests a high-output adrenal source and merits urgent imaging.

Cortisol excess

Proximal weakness, bruising, purple striae, hypertension, diabetes, infection, hypokalaemia or thrombosis may accompany an aggressive cortisol-secreting cortical tumour.

Feminising effect

Gynaecomastia, testicular atrophy or reduced libido with an adrenal mass is unusual and increases concern for malignant steroid secretion.

Mass effect

Persistent flank, abdominal or back pain, early satiety, palpable fullness or renal and hepatic displacement can reflect a large retroperitoneal tumour.

Imaging concern

Irregular heterogeneous architecture, haemorrhage, necrosis, invasion, venous tumour thrombus, nodes or distant lesions is incompatible with routine benign incidentaloma management.

Metastatic pattern

Lung, liver, bone or nodal disease may be the first clue, but tissue origin and hormone safety still require adrenal MDT coordination.

Red flags requiring action

A suspected resectable ACC should not undergo local biopsy or non-specialist partial removal because capsule breach can convert a potentially curable field into disseminated disease.
Severe cortisol excess with infection, uncontrolled diabetes, hypokalaemia, psychosis or thrombosis needs urgent endocrine stabilisation while cancer staging proceeds.
Catecholamine symptoms or uncompleted metanephrine testing before any adrenal procedure demands pause and phaeochromocytoma exclusion.
Inferior vena cava extension, pulmonary embolic symptoms, rapidly increasing pain or haemodynamic compromise requires emergency specialist surgical and oncological assessment.
Vomiting, hypotension, hyponatraemia or collapse during mitotane therapy can represent adrenal crisis and needs immediate stress hydrocortisone rather than waiting for a drug level.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Adrenal-protocol CT chest abdomen pelvisFirst step
Why
Define primary tumour anatomy, resectability, venous involvement and metastatic stage.
Interpretation and limitations
Heterogeneity, necrosis, invasion and distant lesions increase suspicion, but absence of metastasis does not prove benignity; specialist radiology review should precede the surgical route.
02
MRI adrenal and venous assessment
Why
Clarify liver, vascular or soft-tissue relationships when CT is incomplete or contrast use is constrained.
Interpretation and limitations
MRI can delineate inferior vena cava tumour thrombus and operative planes; chemical shift alone does not overrule clearly aggressive morphology.
03
Comprehensive adrenal hormone panel
Why
Identify cortisol, androgen, oestrogen or mineralocorticoid-precursor secretion and create tumour markers for follow-up.
Interpretation and limitations
Use dexamethasone suppression, ACTH, sex steroids and precursors according to phenotype; mixed precursor secretion supports cortical malignancy but remains part of a composite diagnosis.
04
Plasma or urinary metanephrines
Why
Exclude phaeochromocytoma before biopsy, surgery or another invasive adrenal procedure.
Interpretation and limitations
Marked elevation requires catecholamine-tumour preparation, while borderline results need controlled repeat sampling and medicine review without unsafe intervention in the interim.
05
Expert histopathology dataset
Why
Establish cortical origin, malignancy criteria, margins, stage and proliferation after adequate resection or justified tissue acquisition.
Interpretation and limitations
Interpret Weiss or alternative validated systems, reticulin, mitoses, vascular or capsular invasion and Ki-67 through an endocrine pathologist using current RCPath standards.
06
Germline genetics assessment
Why
Identify hereditary cancer predisposition when age, family history, bilateral disease or tumour features warrant it.
Interpretation and limitations
Li-Fraumeni, Lynch and other syndromic considerations affect relatives and surveillance; test selection and consent belong with clinical genetics and the specialist MDT.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Benign adrenal adenoma

A homogeneous, stable lesion with benign adrenal imaging characteristics and limited secretion is less concerning than an irregular mass with necrosis, invasion or meaningful growth.

Phaeochromocytoma

Catecholamine symptoms and raised metanephrines suggest medullary rather than cortical origin; exclusion is essential before biopsy or intervention because manipulation can provoke crisis.

Adrenal metastasis

Known extra-adrenal cancer and bilateral or otherwise metastatic-pattern lesions favour secondary involvement, although tissue origin and hormone safety still require adrenal multidisciplinary review.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01SUSPECTConcerning adrenal massFirst stepImaging, growth or steroid phenotype makes adrenocortical carcinoma a realistic diagnosis.

1Contact a specialist adrenal cancer MDT before biopsy or surgery and transfer all original imaging for endocrine-radiology review.
2Complete chest-abdomen-pelvis staging and a cortisol, androgen, precursor and metanephrine assessment without delaying treatment of dangerous hormone excess.
3Assess performance status, thrombosis, infection, metabolic complications and genetic context while determining resectability.
4DefinitiveAgree an oncological operation, systemic plan or carefully justified tissue strategy in the centre responsible for definitive care.

02OPERATEPotentially resectable ACCDisease appears confined enough for complete oncological removal and the patient can undergo major surgery.

1Optimise cortisol excess, blood pressure, potassium, glucose, infection and thrombosis risk with endocrinology and anaesthesia.
2Plan en-bloc capsule-preserving resection by an experienced adrenal cancer surgeon, including involved adjacent structures when required for clear margins.
3Avoid tumour fragmentation, unplanned adrenal-sparing excision and routine laparoscopic technique when size or invasion threatens oncological integrity.
4Route the intact specimen to expert pathology and review stage, margins and Ki-67 promptly to decide adjuvant therapy and surveillance.

03MITOTANEStarting adrenolytic treatmentThe cancer MDT recommends adjuvant or advanced-disease mitotane under the relevant policy.

1Record neurological, gastrointestinal, liver, lipid, thyroid and adrenal baselines and reconcile interacting medicines before the first dose.
2Titrate under the specialist SmPC and local protocol with serial plasma concentrations, recognising slow accumulation and a prolonged washout.
3Provide glucocorticoid replacement and stress-dose education, often requiring specialist dose adjustment because mitotane accelerates steroid metabolism.
4Modify or interrupt treatment for toxicity, extreme concentration or clinical decline while maintaining adrenal-crisis protection.

04ADVANCEDUnresectable recurrent or metastatic diseaseComplete resection is not feasible or disease returns after local treatment.

1Obtain adequate expert pathology if not already secure and profile hormone secretion as a treatable source of morbidity.
2Select mitotane, combination chemotherapy, radiotherapy, ablation, surgery or trials according to burden, tempo, symptoms and current commissioning.
3Treat cortisol or androgen consequences, pain, thrombosis and psychological distress concurrently with tumour-directed therapy.
4Reassess benefit, toxicity and patient priorities at defined intervals, integrating specialist palliative care without implying abandonment.

Key medicines and prescribing safety4 treatments · regimens, roles and cautions

Provide adrenolytic systemic therapy in selected adjuvant, unresectable, metastatic or recurrent adrenocortical carcinoma pathways.

Mitotane

Initiate and escalate only under an experienced ACC protocol, using serial plasma levels and the current UK SmPC rather than a fixed empirical target dose.

Long persistence, neurological and gastrointestinal toxicity, hepatotoxicity, dyslipidaemia, reproductive harm and potent enzyme induction require specialist monitoring; ensure cortisol replacement and emergency planning.

Prevent adrenal insufficiency caused by tumour destruction, adrenalectomy and the adrenolytic effects of mitotane.

Hydrocortisone replacement during mitotane

Use an endocrinologist-adjusted divided regimen that may exceed standard replacement because mitotane increases binding proteins and steroid clearance, with stress doses for illness.

Clinical status is more useful than total serum cortisol alone during altered binding; provide injection kits and avoid under-replacement during vomiting, fever or procedures.

Reduce dangerous cortisol production before surgery or during advanced hormone-secreting ACC treatment.

Metyrapone or another steroidogenesis inhibitor

Use the specialist-selected rapidly titrated regimen with cortisol and electrolyte monitoring when severe tumour-related hypercortisolism requires control.

Hypoadrenalism can emerge quickly; metyrapone can increase androgen or mineralocorticoid precursors, and block-and-replace strategies need expert laboratory interpretation.

Treat selected fit patients with advanced progressive ACC when combination cytotoxic therapy offers a realistic disease-control benefit.

EDP-mitotane systemic therapy

Administer etoposide, doxorubicin and cisplatin with mitotane only through the specialist oncology regimen, supportive protocol and current commissioning route.

Myelosuppression, infection, renal and cardiac toxicity, nausea, neuropathy and adrenal insufficiency require regimen-specific review; goals and stopping rules must be explicit.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Severe cortisol morbidity

Tumour cortisol excess can cause diabetes, hypertension, hypokalaemia, infection, osteoporosis and thrombosis, increasing risk before and after cancer-directed treatment.

Metastatic disease

Spread to lung, liver, bone or lymph nodes causes organ-specific morbidity and commonly changes treatment from potentially curative resection to systemic control.

Treatment-related adrenal insufficiency

Removal of a cortisol-producing tumour or mitotane therapy can suppress or impair remaining cortisol physiology, requiring experienced replacement and monitoring.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

After resection, follow cross-sectional imaging and previously elevated steroid markers at the specialist interval, because recurrence can be radiological or biochemical before symptoms.
Record margin, current TNM stage, Ki-67 or mitotic risk and tumour rupture status in a shared oncological summary that travels between services.
During mitotane, monitor plasma concentration, neurological function, gastrointestinal tolerance, liver tests, lipids, thyroid indices, blood count and medicine interactions.
Review glucocorticoid adequacy, sick-day confidence, injection kits and emergency card at every treatment change, not only when sodium falls.
Screen and manage hypertension, diabetes, potassium loss, infection, osteoporosis and thrombosis in functioning cancer throughout tumour therapy.
Offer genetics, fertility preservation where feasible, sexual health, psychological and palliative support according to age, prognosis and individual priorities.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Hormones can stage urgency

A modest-sized lesion causing rapid mixed steroid secretion may be more biologically alarming than a larger non-functioning mass with long stability.

First surgery is decisive

Capsule-intact complete resection offers the main curative opportunity, so referral before the first incision matters more than salvage after rupture.

Mitotane rewrites pharmacology

Enzyme induction changes glucocorticoid, anticoagulant, antiseizure, contraceptive and many other medicine exposures long after dosing changes.

Pathology needs the whole specimen

Architecture, invasion, margins and heterogeneous proliferation cannot be captured reliably by a small needle core from a suspected primary cortical cancer.

Secreted steroids are markers

Androgens or precursors elevated before treatment can become useful personalised surveillance signals when interpreted beside imaging.

11Common pitfallsFrequent interpretation and management errors.

01
Do not permit routine adrenal biopsy to delay expert resection or attempt to settle adenoma versus ACC from a small sample.
02
Do not operate on a suspicious lesion before metanephrine evaluation and endocrine preparation have addressed possible catecholamine secretion.
03
Do not fragment or shell out a tumour whose capsule and margins determine oncological outcome and pathological interpretation.
04
Do not prescribe mitotane without therapeutic levels, interaction review, adrenal replacement and a rapid route for toxicity advice.
05
Do not interpret total cortisol conventionally during mitotane treatment because altered binding and clearance complicate adequacy assessment.
06
Do not restrict follow-up to tumour imaging when hormone complications, fertility, bone, thrombosis and psychological burden require parallel care.