Functional metastatic adrenocortical carcinoma is an uncommon cause of Cushing's syndrome, which rarely responds to conventional treatment. A patient presenting with Cushing's syndrome secondary to adrenocortical carcinoma underwent surgical resection. Post-operatively, she developed metastatic disease resistant to conventional chemotherapy. Octreotide, a somatostatin analogue which is effective in the treatment of several types of neuroendocrine tumour, was tried to ameliorate her secretory symptoms, but without any therapeutic effect.
- adrenocortical carcinoma
- Cushing's syndrome
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Adrenocortical carcinoma is a highly malignant tumour which is usually diagnosed late in its course. In some cases, the tumours are functional leading to Cushing's syndrome and other endocrine manifestations. There is no effective cure in this condition and the prognosis is very poor. Octreotide has recently been reported as effective in controlling the secretory symptoms in a single case with only short-term follow-up.1 We describe a patient with Cushing's syndrome due to metastatic adrenocortical carcinoma whose secretory symptoms were not improved with somatostatin analogue therapy.
A 42-year-old woman presented in July 1996 with rapid onset of weight gain, facial fullness, easy bruising and proximal myopathy. Examination revealed floridly Cushingoid features, with no signs of virilization. Her blood pressure was 160/98 mmHg; 09.00 h cortisol was 848 (normal range 200–700) nmol/l with loss of diurnal variation and urinary free cortisol (UFC) was 2930 (normal range 0–340) nmol/l/24 h. High-dose dexamethasone failed to suppress both plasma and UFC. Adrenocorticotropin (ACTH) was undetectable. Serum testosterone was 0.7 (normal range 0–3) nmol/l. Magnetic resonance imaging (MRI) scan confirmed a 6 × 4 cm right-sided adrenal mass (figure 1). Metyrapone 250 mg tid was commenced and the patient subsequently underwent a right adrenalectomy. Histology confirmed adrenocortical carcinoma. Postoperatively, her UFC fell to 106 nmol/l/24 h. However, her Cushingoid symptoms worsened 2 weeks later with raised UFC. Computed tomography (CT) showed intrapulmonary metastases without evidence of intra-abdominal local recurrence. Despite being given six cycles of chemotherapy with cisplatin, 5-fluorouracil, epirubicin and increasing doses of metyrapone, the patient's symptoms failed to improve, her UFC level remained markedly elevated and there was CT evidence of progression of pulmonary metastases.
Octreotide therapy was subsequently commenced at a dose of 50 μg subcutaneously bid and gradually increased to 300 μg tid but without symptomatic relief and UFC excretion continued to rise (figure 2). Octreotide therapy was discontinued one month after initiation as the patient felt unwell with symptoms of bloating and abdominal pain. Metyrapone was increased to 750 mg qid and aminoglutethimide 250 mg tid was subsequently added, followed by a course of mitotane. These treatments failed to achieve any clinical or biochemical benefit. The patient developed skeletal metastases and UFC increased further eventually reaching 16450 nmol/l prior to her death 16 months after diagnosis.
Adrenocortical carcinoma is a rare cause of Cushing's syndrome. Metastasis occurs in more than half of these patients at diagnosis2 and the rate of surgical cure is low3 with a median survival of 6 months in patients with metastatic disease.4 Regular monitoring of UFC is important to detect early recurrence, enabling prompt initiation of chemotherapy to improve survival. Mitotane therapy has been reported to improve survival in patients with metastatic disease following surgical resection,4 but only when high serum levels are achieved.5 Efficacy has been claimed for other agents, but usually on the basis of single case studies and negative results tend to go unreported.
functional adrenal cortical carcinoma is a rare cause of Cushing's syndrome which produces disabling secretory symptoms
most cases present late with evidence of metastasis and hence prognosis is poor
early detection with surgical resection is the most effective treatment
mitotane therapy has limited success in metastatic disease following surgical resection
the role of octreotide therapy in symptom relief has not been established
Somatostatin therapy has been shown to be effective in several neuroendocrine tumours including acromegaly,6thyrotropin-secreting adenomas,7 pancreatic and gastrointestinal endocrine tumours,8 and functional carcinoid tumours.9 It has also been shown to inhibit pathological ACTH secretion in Nelson's syndrome and ectopic ACTH-producing tumours but to be ineffective in ACTH-dependent Cushing's disease.10 Furthermore, there is no clear rationale for its use in ACTH-independent Cushing's syndrome and despite one favourable report,1 its efficacy in metastatic adrenocortical carcinoma has not been established. Somatostatin analogue therapy is expensive and is not without side-effects including gastrointestinal disturbances, hyperglycaemia and gall stone formation (on long-term use).
We conclude that a trial of octreotide, if justified at all, should be reserved for patients with functional metastatic adrenocortical carcinoma who have failed to respond to, or are intolerant of, conventional adrenal blocking agents and cytotoxic chemotherapy. Close monitoring is mandatory with prompt discontinuation of therapy in the absence of clinical and biochemical improvement.
We thank Dr C A Foster for referring the patient and Drs R H Phillips and D H Cove for help in her management.