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Open access

Beryl Stütz, Marta Korbonits, Karl Kothbauer, Werner Müller, and Stefan Fischli

Summary

The coincidence of a pheochromocytoma or paraganglioma and a pituitary adenoma in the same patient is a rare condition. In the last few years SDHx and MAX mutations have been identified and discussed as a potential causal connection in cases of coincidence. We describe a case of a middle-aged female patient which presented with acromegaly, a growth hormone-secreting pituitary adenoma and a symptomatic neck paraganglioma. The patient was cured by surgery from both the pituitary tumour and the paraganglioma and is well after ten years follow-up. Due to the unusual coexistence of two neuroendocrine tumours, further molecular genetic testing was performed which revealed a variant in the TMEM127 gene (c245-10C>G).

Learning points:

  • Pheochromocytoma/paraganglioma and coexisting functioning pituitary adenoma are a very rare condition. An appropriate treatment of each tumour entity with a multi-disciplinary approach and regular follow-up is needed.

  • The possibility of a hereditary disease should be considered and genetic workup is recommended. Genetic testing should focus primarily on the genes with mutations related to pheochromocytomas and paragangliomas.

  • Next-generation sequencing with multi-gene panel testing is the currently suggested strategy.

  • Genes associated with paragangliomas and pituitary adenomas are SDHA, SDHB, SDHC, SDHD, SDHAF2, MAX and MEN1, while case reports with VHL, RET and NF1 may represent coincidences.

  • Variants of uncertain significance may need ongoing vigilance, in case novel data become available of these variants.

Open access

Julien Ducry, Fulgencio Gomez, John O Prior, Ariane Boubaker, Maurice Matter, Matteo Monti, Yan Pu, Nelly Pitteloud, and Luc Portmann

Summary

Ectopic ACTH Cushing's syndrome (EAS) is often caused by neuroendocrine tumors (NETs) of lungs, pancreas, thymus, and other less frequent locations. Localizing the source of ACTH can be challenging. A 64-year-old man presented with rapidly progressing fatigue, muscular weakness, and dyspnea. He was in poor condition and showed facial redness, proximal amyotrophy, and bruises. Laboratory disclosed hypokalemia, metabolic alkalosis, and markedly elevated ACTH and cortisol levels. Pituitary was normal on magnetic resonance imaging (MRI), and bilateral inferior petrosal sinus blood sampling with corticotropin-releasing hormone stimulation showed no significant central-to-periphery gradient of ACTH. Head and neck, thoracic and abdominal computerized tomography (CT), MRI, somatostatin receptor scintigraphy (SSRS), and 18F-deoxyglucose-positron emission tomography (FDG-PET) failed to identify the primary tumor. 18F-dihydroxyphenylalanine (F-DOPA)-PET/CT unveiled a 20-mm nodule in the jejunum and a metastatic lymph node. Segmental jejunum resection showed two adjacent NETs, measuring 2.0 and 0.5 cm with a peritoneal metastasis. The largest tumor expressed ACTH in 30% of cells. Following surgery, after a transient adrenal insufficiency, ACTH and cortisol levels returned to normal values and remain normal over a follow-up of 26 months. Small mid-gut NETs are difficult to localize on CT or MRI, and require metabolic imaging. Owing to low mitotic activity, NETs are generally poor candidates for FDG-PET, whereas SSRS shows poor sensitivity in EAS due to intrinsically low tumor concentration of type-2 somatostatin receptors (SST2) or to receptor down regulation by excess cortisol. However, F-DOPA-PET, which is related to amine precursor uptake by NETs, has been reported to have high positive predictive value for occult EAS despite low sensitivity, and constitutes a useful alternative to more conventional methods of tumor localization.

Learning points

  • Uncontrolled high cortisol levels in EAS can be lethal if untreated.

  • Surgical excision is the keystone of NETs treatment, thus tumor localization is crucial.

  • Most cases of EAS are caused by NETs, which are located mainly in the lungs. However, small gut NETs are elusive to conventional imaging and require metabolic imaging for detection.

  • FDG-PET, based on tumor high metabolic rate, may not detect NETs that have low mitotic activity. SSRS may also fail, due to absent or low concentration of SST2, which may be down regulated by excess cortisol.

  • F-DOPA-PET, based on amine-precursor uptake, can be a useful method to localize the occult source of ACTH in EAS when other methods have failed.

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.