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Open access

Lima Lawrence, Peng Zhang, Humberto Choi, Usman Ahmad, Valeria Arrossi, Andrei Purysko and Vinni Makin

Summary

Ectopic adrenocorticotropic hormone (ACTH) production leading to ectopic ACTH syndrome accounts for a small proportion of all Cushing’s syndrome (CS) cases. Thymic neuroendocrine tumors are rare neoplasms that may secrete ACTH leading to rapid development of hypercortisolism causing electrolyte and metabolic abnormalities, uncontrolled hypertension and an increased risk for opportunistic infections. We present a unique case of a patient who presented with a mediastinal mass, revealed to be an ACTH-secreting thymic neuroendocrine tumor (NET) causing ectopic CS. As the diagnosis of CS from ectopic ACTH syndrome (EAS) remains challenging, we emphasize the necessity for high clinical suspicion in the appropriate setting, concordance between biochemical, imaging and pathology findings, along with continued vigilant monitoring for recurrence after definitive treatment.

Learning points:

  • Functional thymic neuroendocrine tumors are exceedingly rare.

  • Ectopic Cushing’s syndrome secondary to thymic neuroendocrine tumors secreting ACTH present with features of hypercortisolism including electrolyte and metabolic abnormalities, uncontrolled hypertension and hyperglycemia, and opportunistic infections.

  • The ability to undergo surgery and completeness of resection are the strongest prognostic factors for improved overall survival; however, the recurrence rate remains high.

  • A high degree of initial clinical suspicion followed by vigilant monitoring is required for patients with this challenging disease.

Open access

Su Ann Tee, Earn Hui Gan, Mohamad Zaher Kanaan, David Ashley Price, Tim Hoare and Simon H S Pearce

Summary

Primary adrenal insufficiency secondary to syphilis is extremely rare, with only five cases being reported in the literature. We report a case of adrenal insufficiency as a manifestation of Treponema pallidum infection (tertiary syphilis). A 69-year-old, previously fit and well Caucasian male was found to have adrenal insufficiency after being admitted with weight loss, anorexia and postural dizziness resulting in a fall. Biochemical testing showed hyponatraemia, hyperkalaemia, and an inadequate response to Synacthen testing, with a peak cortisol level of 302 nmol/L after administration of 250 µg Synacthen. Abdominal imaging revealed bilateral adrenal hyperplasia with inguinal and retroperitoneal lymphadenopathy. He was started on hydrocortisone replacement; however, it was not until he re-attended ophthalmology with a red eye and visual loss 1 month later, that further work-up revealed the diagnosis of tertiary syphilis. Following a course of penicillin, repeat imaging 5 months later showed resolution of the abnormal radiological appearances. However, adrenal function has not recovered and 3 years following initial presentation, the patient remains on both glucocorticoid and mineralocorticoid replacement. In conclusion, this case highlights the importance of considering syphilis as a potential differential diagnosis in patients presenting with adrenal insufficiency and bilateral adrenal masses, given the recent re-emergence of this condition. The relative ease of treating infectious causes of adrenal lesions makes accurate and timely diagnosis crucial.

Learning points:

  • Infectious causes, including syphilis, should be excluded before considering adrenalectomy or biopsy for any patient presenting with an adrenal mass.

  • It is important to perform a full infection screen including tests for human immunodeficiency virus, other blood-borne viruses and concurrent sexually transmitted diseases in patients presenting with bilateral adrenal hyperplasia with primary adrenal insufficiency.

  • Awareness of syphilis as a potential differential diagnosis is important, as it not only has a wide range of clinical presentations, but its prevalence has been increasing in recent times.

Open access

Carine Ghassan Richa, Khadija Jamal Saad, Georges Habib Halabi, Elie Mekhael Gharios, Fadi Louis Nasr and Marie Tanios Merheb

Summary

The objective of this study is to report three cases of paraneoplastic or ectopic Cushing syndrome, which is a rare phenomenon of the adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome. Three cases are reported in respect of clinical presentation, diagnosis and treatment in addition to relevant literature review. The results showed that ectopic ACTH secretion can be associated with different types of neoplasm most common of which are bronchial carcinoid tumors, which are slow-growing, well-differentiated neoplasms with a favorable prognosis and small-cell lung cancer, which are poorly differentiated tumors with a poor outcome. The latter is present in two out of three cases and in the remaining one, primary tumor could not be localized, representing a small fraction of patients with paraneoplastic Cushing. Diagnosis is established in the setting of high clinical suspicion by documenting an elevated cortisol level, ACTH and doing dexamethasone suppression test. Treatment options include management of the primary tumor by surgery and chemotherapy and treating Cushing syndrome. Prognosis is poor in SCLC. We concluded that in front of a high clinical suspicion, ectopic Cushing syndrome diagnosis should be considered, and identification of the primary tumor is essential.

Learning points:

  • Learning how to suspect ectopic Cushing syndrome and confirm it among all the causes of excess cortisol.

  • Distinguish between occult and severe ectopic Cushing syndrome and etiology.

  • Providing the adequate treatment of the primary tumor as well as for the cortisol excess.

  • Prognosis depends on the differentiation and type of the primary malignancy.

Open access

Ayanthi A Wijewardene, Sarah J Glastras, Diana L Learoyd, Bruce G Robinson and Venessa H M Tsang

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.

Open access

Elise Flynn, Sara Baqar, Dorothy Liu, Elif I Ekinci, Stephen Farrell, Jeffrey D Zajac, Mario De Luise and Ego Seeman

Summary

ACTH-secreting phaeochromocytoma (ASP) is a rare cause of ACTH-dependent Cushing’s syndrome (CS). We report the case of a 63-year-old female presenting with CS secondary to an ASP complicated by bowel perforation. This case report highlights ASP as an uncommon but important cause of ectopic ACTH secretion (EAS). There have been 29 cases of ASP, all of which were unilateral and benign, but associated with significant complications. Patients presenting with ASP have the potential for cure with unilateral adrenalectomy. Given this promising prognosis if recognised, ASP should be considered in the diagnostic workup of ACTH-dependent CS. As this case demonstrates, gastrointestinal complications can arise from severe hypercortisolaemia associated with CS. Early medical and surgical intervention is imperative as mortality approaches 50% once bowel perforation occurs.

Learning points

  • Consider phaeochromocytoma in the diagnostic workup of ACTH-dependent CS; screen with plasma metanephrines or urinary catecholamines.

  • Serial screening may be required if ACTH-secreting phaeochromocytoma is suspected, as absolute levels can be misleading.

  • Early catecholamine receptor blockade and adrenal synthesis blockade may avoid the need for rescue bilateral adrenalectomy in ACTH-secreting phaeochromocytoma.

  • Consider early medical or surgical management when gastrointestinal features are present in patients with CS, as bowel perforation due to severe hypercortisolaemia can occur and is associated with significant mortality.

Open access

Kharis Burns, Darshika Christie-David and Jenny E Gunton

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.

Open access

Harish Venugopal, Katherine Griffin and Saima Amer

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.

Open access

Sophie Comte-Perret, Anne Zanchi and Fulgencio Gomez

Summary

Medical therapy for Cushing's syndrome due to bilateral macronodular adrenal hyperplasia (BMAH) is generally administered for a limited time before surgery. Aberrant receptors antagonists show inconsistent efficacy in the long run to prevent adrenalectomy. We present a patient with BMAH, treated for 10 years with low doses of ketoconazole to control cortisol secretion. A 48-year-old woman presented with headaches and hypertension. Investigations showed the following: no clinical signs of Cushing's syndrome; enlarged lobulated adrenals; normal creatinine, potassium, and aldosterone; normal urinary aldosterone and metanephrines; elevated urinary free cortisol and steroid metabolites; and suppressed plasma renin activity and ACTH. A screening protocol for aberrant adrenal receptors failed to show any illegitimate hormone dependence. Ketoconazole caused rapid normalisation of cortisol and ACTH that persists over 10 years on treatment, while adrenals show no change in shape or size. Ketoconazole decreases cortisol in patients with Cushing's syndrome, and may prevent adrenal overgrowth. Steroid secretion in BMAH is inefficient as compared with normal adrenals or secreting tumours and can be controlled with low, well-tolerated doses of ketoconazole, as an alternative to surgery.

Learning points

  • Enlarged, macronodular adrenals are often incidentally found during the investigation of hypertension in patients harboring BMAH. Although laboratory findings include low ACTH and elevated cortisol, the majority of patients do not display cushingoid features.

  • Bilateral adrenalectomy, followed by life-long steroid replacement, is the usual treatment of this benign condition, and alternative medical therapy is sought. Therapy based on aberrant adrenal receptors gives disappointing results, and inhibitors of steroidogenesis are not always well tolerated.

  • However, ketoconazole at low, well-tolerated doses appeared appropriate to control adrenal steroid secretion indefinitely, while preventing adrenal overgrowth. This treatment probably constitutes the most convenient long-term alternative to surgery.

Open access

F Serra, S Duarte, S Abreu, C Marques, J Cassis and M Saraiva

Summary

Ectopic secretion of ACTH is an infrequent cause of Cushing's syndrome. We report a case of ectopic ACTH syndrome caused by a nasal paraganglioma, a 68-year-old female with clinical features of Cushing's syndrome, serious hypokalaemia and a right paranasal sinus' lesion. Cranial magnetic resonance image showed a 46-mm mass on the right paranasal sinuses. Endocrinological investigation confirmed the diagnosis of ectopic ACTH production. Resection of the tumour normalised ACTH and cortisol secretion. The tumour was found to be a paraganglioma through microscopic analysis. On follow-up 3 months later, the patient showed nearly complete clinical recovery. Ectopic ACTH syndrome due to nasal paraganglioma is extremely uncommon, as only two other cases have been discussed in the literature.

Learning points

  • Ectopic Cushing's syndrome accounts for 10% of Cushing's syndrome etiologies.

  • Most paraganglioma of the head and neck are not hormonally active.

  • Nasal paraganglioma, especially ACTH producing, is a very rare tumour.