CORTICOTROPH PITUITARY ADENOMAS (CUSHING'S DISEASE

Cushing’s Disease Guidelines. Written by: Dr Christina Daousi, Senior Lecturer/Consultant Endocrinologist Agreed by: Merseyside and Cheshire Neuro‐oncology CNG, December 2012 For review: December 2014

CORTICOTROPH PITUITARY ADENOMAS (CUSHING’S DISEASE) The Diagnostic Pathway (11-2K-234)

Common presenting symptoms: Reddish/purple striae Facial plethora Proximal muscle weakness/proximal myopathy Bruising Unexplained osteoporosis Centripetal Obesity Dorsocervical fat pad (“buffalo hump”) Facial fullness Supraclavicular fullness Thin skin Acne Peripheral oedema Hirsutism Depression Hypertension Diabetes mellitus Menstrual irregularity Hypokalaemia

Clinical and Biochemical assessment: 

Complex endocrine syndrome

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Series of tests in a logical sequence, attention to potential pitfalls

Initial testing to confirm hypercortisolism (Cushing’s syndrome) 

Urine free cortisol (UFC) (at least 2 measurements)

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1-mg overnight dexamethasone suppression test (DST)

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Longer low-dose DST (2 mg/day for 48 hours)

ACTH measurement 

ACTH < 10pg/ml (2 pmol/L) at 0900 h with concomittant increased production of cortisol suggest an ACTH-independent cause of CS



ACTH > 20 pg/ml (4pmol/L) suggest an ACTH-dependent cause

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Differentiating between pituitary driven Cushing’s (Cushing’s Disease-CD) and ectopic ACTH secretion: High dose dexamethasone suppression test  Sensitivity 60-80%  Good specificity when a cut-off of cortisol suppression > 80 % is used CRH test

Radiological assessment: All patients with a suspected corticotroph adenoma should have a MRI scan as per current WCFT imaging protocol for pituitary tumours which includes the following sequences: -T2 axial brain images -T1 sagittal and coronal images of pituitary -Post gadolinium T1 sagittal and coronal images of pituitary

If conventional MR imaging is negative then Dynamic Pituitary MRI should be performed as per current WCFT protocol which includes the following sequences: -T2 axial Brain images -T1 Coronal Pituitary images -T1 Coronal Dynamic Post Gadolinium -T1 Coronal/Sagittal Post Gadolinium -T2 Coronal High resolution images of. Pituitary -T1 Coronal delayed Post Gadolinium images

Things to consider following radiological assessment: 

Discrete pituitary adenoma is found in 35-60% of patients with CD.

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Size of the tumour < 5 mm in half of the cases

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> 10 mm in only a fifth of cases of imaging positive CD

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10% of normal people harbour pituitary incidentalomas but most are < 6 mm

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Classic clinical presentation, dynamic testing compatible with pituitary Cushing’s syndrome (CS), the presence of a focal lesion > 6 mm may provide a definitive diagnosis and no further evaluation may be required.

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Inferior Petrosal Sinus Sampling (IPSS) 

Reserved for cases of ACTH-dependent CS where clinical, biochemical and radiological studies are discordant or equivocal.



Overall sensitivity of 85-97%

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Specificity 95-99%

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The absence of a significant inferior petrosal sinus to peripheral (IPS:P) ACTH ratio does not imply ectopic secretion of ACTH nor does it exclude Cushing’s disease

False negative results 

Anomalous venous drainage

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Hypoplastic inferior petrosal sinus

False positive results 

Treatment that leads to normocortisolaemia

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Periodic hormonogenesis in ectopic CS

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Ectopic CRH-ACTH secretion

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ACTH-secreting pituitary adenomas in the sphenoid sinus

IPSS for localization of pituitary microadenomas 

Controversial

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Interpetrosal sinus ratio > 1.4 has been suggested as consistent with ipsilaeteral localization of a corticotroph adenoma

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Accuracy 75% using findings at pituitary surgery as the “gold standard”

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Some of the cases of mis-lateralization can be explained by anomalous venous drainage

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The results of lateralization when performing IPSS cannot be relied upon in patients with CD who have asymmetric drainage

MRI & IPSS 

IPSS accurately localizes the pituitary lesion more frequently than imaging studies (70% vs 49%)

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When MRI is normal, IPSS localizes the lesion in 89%

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When the two tests disagree, IPSS is more commonly correct.

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When the two tests agree, however, both are sometimes wrong.

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All patients to be put through the Regional Pituitary MDT

The Treatment Pathway (11-2K-235) Transsphenoidal selective adenomectomy: - Optimal treatment is surgical resection by selective adenomectomy -Careful sectioning through the pituitary gland may be required to locate the tumour, because some tumours have an identifiable pseudocapsule, whereas others do not exhibit a discrete border between the tumour and normal pituitary tissue -If a discrete microadenoma cannot be located by sellar exploration, total or partial hypophysectomy may be indicated (lower remission rate and higher complication and hypopituitarism rates) Favourable prognostic factors associated with successful adenomectomy: -pre-operative detection of the microadenoma by MRI -a well-defined tumour that is not invading either the basal dura or cavernous sinus -histological confirmation of an ACTH-secreting tumour -low postoperative serum cortisol levels - longlasting adrenal insufficiency post-surgery

In patients with a macroadenoma, remission rates are lower, recurrence rates higher and recurrence also occurs sooner than in those with a microadenoma.

Persistent Disease after Transsphenoidal Surgery In the event of failure after initial pituitary surgery or relapse after a period of remission, a choice of second line therapeutic options needs to be discussed with the patient, including repeat pituitary surgery, radiotherapy, or bilateral adrenalectomy.

Pituitary surgery for persistent or recurrent disease -Remission rates lower than that seen after the first operation and higher rates of hypopituitarism -Remission rates are higher if an adenoma is located -Improved success rates are achieved in patients with radiologically detectable tumours

-Repeat transsphenoidal surgery for residual disease as soon as active, persistent disease is evident. A delay of 4–6 wk may be required to confirm the need for re-operation because of continued partial improvement in cortisol levels after the initial surgery.

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Conventional fractionated radiotherapy and stereotactic radiosurgery 

Remission rates 50-60% within 3-5 years

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Long-term follow-up is necessary to detect relapse, which can occur after an initial response to both types of radiotherapy.

Bilateral adrenalectomy 

Definitive cure



Lifelong glucocorticoid and mineralocorticoid replacement therapy

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25% risk of Nelson’s syndrome

Medical Treatment 

Agents that act at hypothalamic-pituitary level (dopamine agonists-cabergoline)

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Tumour-directed medical therapy (new somatostatin analogue pasireotide)

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Inhibitors of cortisol secretion at adrenal level (Inhibitors of steroid biosynthesis): -Metyrapone (monotherapy and combination, side effects (S/E): acne, hypertension,

hirsutism, nausea -Ketoconazole (monotherapy and combination, benign spectrum of S/E, severe hepatitis 1:1500, initial daily dose 400-600 mg max 1600 mg)

The Follow Up Pathway (11-2K-236) To minimise duplication of clinic appointments, biochemical testing and MRI scans the following is proposed: 

A joint neurosurgery / neuro-endocrinology clinic appointment is desirable – this minimises clinic appointments and avoids duplication of follow-up imaging and follow up pituitary function testing



MRI may not be required during the initial post-operative follow-up period as the majority of corticotroph adenomas are microadenomas and many are not radiologically evident before TSS

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MRI is the modality of choice for follow up in patients with macroadenomas and persistent disease, and should be performed as per current WCFT imaging protocol for pituitary tumours

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

Once biochemical control of the disease has been established following the appropriate treatment modalities, follow-up could be transferred and / or shared with the patient’s local hospital-based Endocrinology team. Follow-up should be life-long.



Referral back to the joint neurosurgery / neuro-endocrinology clinic and the regional Pituitary MDT can take place at any time during the follow-up pathway when evidence of recurrent disease emerges

Biochemical assessment of disease control:

Post-operative serum cortisol -Persistent postoperative morning serum cortisol levels < 50 nmol/L are generally associated with remission and a low recurrence rate of approximately 10% at 10 years -Persistent serum cortisol level above 140 nmol/liter for up to 6 wk requires further evaluation -If serum cortisol levels are between 50-140 the patient can be considered in remission and can be observed without additional treatment for Cushing’s disease

24-h UFC -UFC values below the lower end of the normal range of the assay used to measure UFC suggest remission -values in the normal range are equivocal -values above the normal range indicate persistent tumour and disease activity

Glucocorticoid Replacement 

Tumour resection leads to corticosteroid deficiency because the remaining normal corticotroph cells have been suppressed by longstanding hypercortisolism. Hypocortisolism provides an index of surgical success.

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Glucocorticoid withdrawal symptoms (e.g. fatigue, nausea, and joint aches) should be anticipated in all patients; hypocortisolism and symptoms are managed with physiological glucocorticoid therapy until the axis recovers.

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Replacement therapy can be stopped when the morning cortisol level or the cortisol response to tetracosactide 250 mcg (Short Synacthen Test; SST) is > 500 nmol/l.

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REFERENCES

1. Nieman LK, Biller BM, Findling JW et al. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008; 93(5):1526-1540. 2. Lindsay JR, Oldfield EH, Stratakis CA, Nieman LK. The postoperative basal cortisol and CRH tests for prediction of long-term remission from Cushing's disease after transsphenoidal surgery. J Clin Endocrinol Metab 2011; 96(7):2057-2064. 3. Daousi C, Nixon T, Javadpour M, Hayden K, Macfarlane IA. Inferior petrosal sinus ACTH and prolactin responses to CRH in ACTH-dependent Cushing's syndrome: a single centre experience from the United Kingdom. Pituitary 2010; 13(2):95-104. 4. Biller BM, Grossman AB, Stewart PM et al. Treatment of adrenocorticotropindependent Cushing's syndrome: a consensus statement. J Clin Endocrinol Metab 2008; 93(7):2454-2462. 5. Aghi MK. Management of recurrent and refractory Cushing disease. Nat Clin Pract Endocrinol Metab 2008; 4(10):560-568.

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CORTICOTROPH PITUITARY ADENOMAS (CUSHING'S DISEASE

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