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Adrenal Cortical Tumors

Sub-section: Adrenal Section: Endocrine

Hyperaldosteronism

Definition

Primary hyperaldosteronism

  • Conn’s Syndrome
  • Autonomous release of excess aldosterone from one or both adrenal glands
    • From Zona Glomerulosa
  • Commonest cause of 2° HTN
    • 5-13% of all HTN
  • Mean age presentation = 50yrs
  • M > F (slight)

Secondary Hyperaldosteronism

  • Inactivation of RAS mechanism in Liver Failure, HF, Nephrotic Syndrome etc.

Presentation and Sequelae

  • Classically manifests as
    • Hypertension (unusually only sign)
    • +/- Hypokalaemia
      • Most have normal K+
      • More likely in severe cases/late stage
    • Patients often asymptomatic
    • May have muscle cramps, weakness, paraesthesias from low K+
    • Often moderate/severe hypertension, refractory to medical rx
      • Often on 2-4 antihypertensives
      • May get responsiveness to spironolactone
        • Predictive of good response to surgical treatment also
  • Associated with increased risk of:
    • Stroke, MI, AF and VF, CHF
    • More pronounced than effect of HTN alone
  • Surgical removal reverses the risk

Aetiology

  • Most commonly
    • Bilateral Hyperplasia
    • Unilateral Aldosteronoma
    • Others (All rare, < 1%)
      • Aldosterone-Secreting Adrenocortical Carcinoma
      • Unilateral Adrenal Hyperplasia
      • Familial Hyperaldosteronism
        • Type 1 – Glucocorticoid suppressible
        • Type 2 – Unable to be suppressed by glucocorticoids

Diagnosis

  • Consider biochemical screening if
    • Hypertension and hypokalaemia
    • Hypertension alone that is treatment resistant or if < 40yrs old
    • Incidentalomas
  • Workup
    • Screening
      • Renin/aldosterone ratio
      • ⇧ Plasma Aldosterone concentration (PAC)
      • Decreased Plasma Renin activity or concentration (PRA/PRC)
      • Net effect is that there is a high PAC:PRA ratio > 20-30
      • NB: Aldosterone antagonists, beta-blockers, CCBs, ACEI’s can interfere with results and should be stopped prior
    • Confirmation
      • Oral sodium loading
      • Saline infusion test
      • Or less commonly fludrocortisone suppression test
      • If no suppression, diagnosis confirmed

Localisation

  • Preferred initial imaging is fine slice adrenal CT
    • Most aldosteronomas are < 2cm
      • Tend to be homogenous
      • C.f. carcinomas which are heterogenous, often > 4cm
      • NB: Can have false +ve
        • Primary hyperaldosteronism attributed to a non-functioning adenoma seen on imaging
          • Non-functioning adenomas more common > 40yrs
  • Adrenal vein sampling
    • Standard test to distinguish between unilateral adenoma and bilateral hyperplasia or if bilateral lesions to localise a side for treatment

Adrenal Vein Sampling

  • Simultaneously measures cortisol and aldosterone ratios in peripheral circulation and L+ R Adrenal Veins
  • Indications:
    • If CT normal or has bilateral abnormalities
    • If unilateral abnormality and age > 35
      • As a young patient is unlikely to have an incidental adenoma
  • Can give bolus or infusion of cosyntropin (ACTH)
  • Confirm successful catheterization
    • Adrenal vein to IVC cortisol ratio 3:1
  • Measure Aldosterone/Cortisol ratio
    • Accounts dilutional effect of the inferior phrenic vein flow into the left adrenal vein; these are termed “cortisol-corrected ratios.”
    • If one side ratio is > 4x the opposite, confirms localisation
  • In skilled hands – Sensitivity 95%, Specificity 100%
    • NB: Often fails due to inability to cannulate Right Adrenal Vein (success rates 40-80%)

Surgical Management

  • Correct HTN and hypokalaemia prior to surgery
  • If unilateral disease localised
    • Minimally invasive Adrenalectomy
  • If not surgical candidate
    • Aldosterone antagonist – Spironolactone
      • Side effects include gynaecomastia, libido loss, menstrual irregularity, erectile dysfunction
  • Need to consider risk of malignancy prior to advocating surgery
  • If Bilateral Adrenal Hyperplasia
    • Spironolactone
  • If Type 1 Familial Hyperaldosteronism
    • Steroids

Outcomes after Adrenalectomy for Aldosteronoma

  • Cure defined as
    • Reduction of hypertension
    • Reduction of aldosterone levels
    • Resolution of hypokalaemia (if present)
  • Cure rates 75-95%

    • 80% have normalization of BP or significant reduction in anti- HTN needed

  • NB: Can have overlap with essential HTN
    • BP may not completely normalise

Cushing’s Syndrome

Definition and Incidence

  • Cushing’s Syndrome
    • Disorder characterised by a no. of signs and symptoms, caused by long term effects of elevated glucocorticoid levels
  • Cushing’s Disease
    • Glucocorticoid excess caused by an ACTH-secreting Pituitary Adenoma

Clinical Presentation

  • Symptoms
    • Central obesity
    • Buffalo hump
    • Moon faces
      • Facial Plethora ****
      • Reddening due to thin skin
    • Striae****
    • Hirsutism
    • Loss of libido
    • Menstrual irregularity
    • Depression/psychosis
    • Proximal myopathy****
    • Easy bruising****
  • Signs
    • Diabetes Mellitus
    • Osteoporosis
    • Hypertension (> 70%)
    • Hypokalaemia

Aetiology

  • Most common cause is exogenous steroid use
  • Endogenous Cushing’s syndrome is rare (F > M)
    • ACTH-Dependent (80%)
      • Pituitary-related (Cushing’s disease) (70%)
      • Ectopic (10%)
        • E.g. NET’s, Bronchogenic Carcinoid, Medullary Thyroid, Phaeo, or Small Cell Lung Ca
    • ACTH-Independent (15-20%)
      • Primary adrenal Cushing syndrome
        • Adenoma (90%)
        • Carcinoma (10%)
        • Bilateral micronodular/ macronodular Hyperplasia (<1%)

Diagnosis

  • Screening tests
    • 24hr Urinary Free Cortisol
      • Reflects average cortisol levels
      • Levels > 4x normal - diagnostic of Cushing’s
      • Less sensitive at diagnosing subclinical Cushing’s
      • Do at least 2 measurements, may need 3
    • Late-night Salivary Cortisol
      • Cushing’s syndrome shows loss of normal circadian rhythm of cortisol secretion
      • Resting midnight plasma cortisol > 50nmol/L is 100% sensitive for Cushing’s
      • Salivary results closely correlated to plasma
      • High sensitivity and specificity for Cushing’s (> 92%)
      • Need to do in low stress environment
        • Hence: At home
    • Low Dose Dexamethasone Suppression Test
      • Exploits loss of negative feedback loop for cortisol
      • 1-2mg dexamethasone, given at midnight
      • Should suppress cortisol level taken at 9am following am
      • If cortisol > 50nmol/L the following am
        • Sensitivity for Cushing’s 95%
        • Specificity 80%
      • Some units may do 2mg/day, 48hr testing
        • Gives higher specificity
  • Establishing a cause
    • Corticotropin dependent or ACTH-independent disease
      • High ACTH = ACTH-dependent

        • 20 pg/mL, 4.4 pmol/L

      • Low ACTH = ACTH-independent
        • <5 pg/mL (1.1 pmol/L
      • Intermediate
        • Repeat testing
    • ACTH-dependent
      • Pituitary vs ectopic
        • Noninvasive biochemical testing with
          • CRH (if available) or desmopressin (DDAVP) stimulation test
            • Both stimulate ACTH
            • Increases in ACTH and cortisol is consistent with pituitary adenoma
        • High dose dexamethasone suppression
          • Pituitary tumours retain some negative feedback control and ectopic source does not
          • Give single dose 8mg dexamethasone, or 2mg QID for 48hrs
            • If cortisol level drops to < 50% baseline
            • Suggests Pituitary Cushing’s
          • If no significant drop - Ectopic cause (or Adrenal cause, but will have already ruled this out with prior investigations)
        • Imaging
          • MRI
        • Invasive testing
          • Bilateral Inferior Petrosal Sinus Sampling
            • To differentiate pituitary Cushing’s from ectopic if dexamethasone suppression test equivocal
            • Invasive
              • Catheter measures ACTH in each Petrosal Sinus and peripheral ACTH levels
                • Central-to-peripheral ACTH gradient
        • Further Investigations of Ectopic ACTH Dependent Cushing’s
          • Basic tumour markers
            • Urinary 5-HIAA
            • Serum Calcitonin
            • Chromogranin A
            • Other GI neuroendocrine hormones as indicated
            • CT neck/chest/abdo/pelvis
            • Somatostatin receptor scintigraphy
    • ACTH Independent
      • Adrenal Cushing’s
      • Next step is Localisation
        • CT is the initial modality of choice
          • Will see adenoma, carcinoma, and macronodular hyperplasia
          • Won’t see micronodular hyperplasia
          • NB: Overlap in appearances of adrenal adenoma and carcinoma on cross sectional imaging
        • Risk of malignancy increased if
          • High attenuation
          • Irregular outline
          • Delayed contrast washout
          • Heterogenous

          • 4cm in size

        • If concerned about malignancy:
          • MRI with Gadolinium can help to differentiate
          • High water content of carcinoma c.f. adenoma

Management

  • Peri- and Post-op glucocorticoid administration
    • Essential
    • Initial high dose with taper post-op
      • Some units withhold initially post-op
        • To assess cortisol levels, ? biochemical cure
      • Beware of Adrenal Crisis – Endocrinologist should manage
  • Surgery
    • Primary adrenal Cushing’s syndrome
    • Cushing’s disease
    • Ectopic ACTH independent Cushing’s syndrome

Surgical Management of Primary Adrenal Cushing’s

  • Unilateral Adrenalectomy

    • 90% effective, but resolution of symptoms takes months-to-years

    • Failure could be due to missed or recurrent malignant disease
  • Perform in specialised center
    • High risk of infections, Skin injury, Fractures, Hyperglycaemia
    • DVT risk increased (up to 5%) so use clexane

Surgical Management of Cushing’s Disease (Pituitary)

  • Initial approach
    • Pituitary microsurgery for Cushing’s disease
    • Trans-nasal, trans-sphenoidal approach
  • If fails, consider:
    • Re-operation
    • Danger of causing pan-hypopituitarism
  • Radiation
    • If fail
  • Bilateral Adrenalectomy
    • Will need lifelong glucocorticoids and mineralocorticoid supplementation

Management Ectopic Cushing’s Syndrome

  • Treatment of primary tumour is preferable
    • But not always possible
  • Controlling symptoms paramount if removing primary not possible
    • Ketoconazole inhibits cortisol production
    • Bilateral Adrenalectomy best way to achieve symptom palliation
      • Even in patients with limited life expectancy
      • Esp. if laparoscopic

Sex Steroid Excess

  • Very rare
  • Most virilising (as opposed to feminising)
    • 1/3 virilising are malignant
    • Almost all feminising lesions are malignant
    • 20% of adrenocortical carcinomas cause virilisation
    • 24% of adrenocortical carcinomas show mixed virilization and Cushing’s Syndrome
  • Tests
    • 24hr urine Testosterone, DHEA and DHEAs
  • Treatment
    • Laparoscopic Adrenalectomy
    • High probability of malignancy so close radiographic and intra-op inspection needed
    • If any concerns – Open Adrenalectomy

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