Diagnosis and Treatment > Medication
Search for other papers by Ayanthi A Wijewardene in
Google Scholar
PubMed
Kolling Institute of Medical Research
Sydney Medical School, University of Sydney, Sydney, Australia
Search for other papers by Sarah J Glastras in
Google Scholar
PubMed
Sydney Medical School, University of Sydney, Sydney, Australia
Search for other papers by Diana L Learoyd in
Google Scholar
PubMed
Sydney Medical School, University of Sydney, Sydney, Australia
Search for other papers by Bruce G Robinson in
Google Scholar
PubMed
Sydney Medical School, University of Sydney, Sydney, Australia
Search for other papers by Venessa H M Tsang in
Google Scholar
PubMed
Summary
Medullary thyroid cancer (MTC) is a rare neuroendocrine tumour that originates from the parafollicular cells of the thyroid gland. The most common presentation of MTC is with a single nodule; however, by the time of diagnosis, most have spread to the surrounding cervical lymph nodes. Cushing’s syndrome is a rare complication of MTC and is due to ectopic adrenocorticotrophic hormone (ACTH) secretion by tumour cells. Cushing’s syndrome presents a challenging diagnostic and management issue in patients with MTC. Tyrosine kinase inhibitors (TKI) previously used for the management of metastatic MTC have become an important therapeutic option for the management of ectopic ACTH in metastatic MTC. The article describes three cases of ectopic ACTH secretion in MTC and addresses the significant diagnostic and management challenges related to Cushing’s syndrome in metastatic MTC.
Learning points:
-
Medullary thyroid cancer (MTC) is a rare neuroendocrine tumour.
-
Cushing’s syndrome is a rare complication of MTC that has a significant impact on patients’ morbidity and mortality.
-
Tyrosine kinase inhibitors (TKI) provide an important therapeutic option for the management of ectopic ACTH in metastatic MTC.
Faculty of Medicine, Westmead Hospital, University of Sydney, Sydney, 2145, Australia
Search for other papers by Kharis Burns in
Google Scholar
PubMed
Department of Endocrinology, Royal North Shore Hospital, St Leonards, 2065, Australia
Search for other papers by Darshika Christie-David in
Google Scholar
PubMed
Faculty of Medicine, Westmead Hospital, University of Sydney, Sydney, 2145, Australia
St Vincent's Clinical School, University of New South Wales, Sydney, 2010, Australia
Diabetes and Transcription Factors Group, Garvan Institute of Medical Research (GIMR), Sydney, 2010, Australia
Department of Diabetes, Obesity and Endocrinology, The Westmead Institute for Medical Research, The University of Sydney, Sydney, 2045, Australia
Search for other papers by Jenny E Gunton in
Google Scholar
PubMed
Summary
Ketoconazole was a first-line agent for suppressing steroidogenesis in Cushing's disease. It now has limited availability. Fluconazole, another azole antifungal, is an alternative, although its in vivo efficacy is unclear. A 61-year-old female presented with weight gain, abdominal striae and worsening depression. HbA1c increased to 76 mmol/mol despite increasing insulin. Investigations confirmed cortisol excess; afternoon serum cortisol was 552 nmol/l with an inappropriate ACTH of 9.3 pmol/l. In total, 24-h urinary free cortisol (UFC):creatinine ratio was 150 nmol/mmol with failure to suppress after 48 h of low-dose dexamethasone. Pituitary MRI revealed a 4-mm microadenoma. Inferior petrosal sinus sampling confirmed Cushing's disease. Transsphenoidal resection was performed and symptoms improved. However, disease recurred 6 months later with elevated 24-h UFC >2200 nmol/day. Metyrapone was commenced at 750 mg tds. Ketoconazole was later added at 400 mg daily, with dose reduction in metyrapone. When ketoconazole became unavailable, fluconazole 200 mg daily was substituted. Urine cortisol:creatinine ratio rose, and the dose was increased to 400 mg daily with normalisation of urine hormone levels. Serum cortisol and urine cortisol:creatinine ratios remain normal on this regimen at 6 months. In conclusion, to our knowledge, this is the first case demonstrating prolonged in vivo efficacy of fluconazole in combination with low-dose metyrapone for the treatment of Cushing's disease. Fluconazole has a more favourable toxicity profile, and we suggest that it is a potential alternative for medical management of Cushing's disease.
Learning points
-
Surgery remains first line for the management of Cushing's disease with pharmacotherapy used where surgery is unsuccessful or there is persistence of cortisol excess.
-
Ketoconazole has previously been used to treat cortisol excess through inhibition of CYP450 enzymes 11-β-hydroxylase and 17-α-hydroxylase, though its availability is limited in many countries.
-
Fluconazole shares similar properties to ketoconazole, although it has less associated toxicity.
-
Fluconazole represents a suitable alternative for the medical management of Cushing's disease and proved an effective addition to metyrapone in the management of this case.
Search for other papers by Harish Venugopal in
Google Scholar
PubMed
Search for other papers by Katherine Griffin in
Google Scholar
PubMed
Search for other papers by Saima Amer in
Google Scholar
PubMed
Summary
Resection of primary tumour is the management of choice in patients with ectopic ACTH syndrome. However, tumours may remain unidentified or occult in spite of extensive efforts at trying to locate them. This can, therefore, pose a major management issue as uncontrolled hypercortisolaemia can lead to life-threatening infections. We present the case of a 66-year-old gentleman with ectopic ACTH syndrome from an occult primary tumour with multiple significant complications from hypercortisolaemia. Ectopic nature of his ACTH-dependent Cushing's syndrome was confirmed by non-suppression with high-dose dexamethasone suppression test and bilateral inferior petrosal sinus sampling. The primary ectopic source remained unidentified in spite of extensive anatomical and functional imaging studies, including CT scans and Dotatate-PET scan. Medical adrenolytic treatment at maximum tolerated doses failed to control his hypercortisolaemia, which led to recurrent intra-abdominal and pelvic abscesses, requiring multiple surgical interventions. Laparoscopic bilateral adrenalectomy was considered but decided against given concerns of technical difficulties due to recurrent intra-abdominal infections and his moribund state. Eventually, alcohol ablation of adrenal glands by retrograde adrenal vein approach was attempted, which resulted in biochemical remission of Cushing's syndrome. Our case emphasizes the importance of aggressive management of hypercortisolaemia in order to reduce the associated morbidity and mortality and also demonstrates that techniques like percutaneous adrenal ablation using a retrograde venous approach may be extremely helpful in patients who are otherwise unable to undergo bilateral adrenalectomy.
Learning points
-
Evaluation and management of patients with ectopic ACTH syndrome from an unidentified primary tumour can be very challenging.
-
Persisting hypercortisolaemia in this setting can lead to debilitating and even life-threatening complications and hence needs to be managed aggressively.
-
Bilateral adrenalectomy should be considered when medical treatment is ineffective or poorly tolerated.
-
Percutaneous adrenal ablation may be considered in patients who are otherwise unable to undergo bilateral adrenalectomy.
