Clinical Overview > Condition/ Syndrome > Adrenocortical carcinoma

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Impana Shetty Pediatric Oncology Branch, Rare Tumor Initiative, Center for Cancer Research, National Cancer Institute, Clinical Center

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Sarah Fuller Pediatric Oncology Branch, Rare Tumor Initiative, Center for Cancer Research, National Cancer Institute, Clinical Center

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Margarita Raygada Pediatric Oncology Branch, Rare Tumor Initiative, Center for Cancer Research, National Cancer Institute, Clinical Center

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Maria J Merino Laboratory of Pathology, National Cancer Institute, Clinical Center

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B J Thomas Pediatric Oncology Branch, Rare Tumor Initiative, Center for Cancer Research, National Cancer Institute, Clinical Center

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Brigitte C Widemann Pediatric Oncology Branch, Rare Tumor Initiative, Center for Cancer Research, National Cancer Institute, Clinical Center

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Karlyne M Reilly Pediatric Oncology Branch, Rare Tumor Initiative, Center for Cancer Research, National Cancer Institute, Clinical Center

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Karel Pacak Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

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Jaydira Del Rivero Pediatric Oncology Branch, Rare Tumor Initiative, Center for Cancer Research, National Cancer Institute, Clinical Center

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Summary

Adrenocortical carcinoma (ACC) is an aggressive cancer that originates in the cortex of the adrenal gland and generally has a poor prognosis. ACC is rare but can be more commonly seen in those with cancer predisposition syndromes (e.g. Li-Fraumeni and Lynch Syndrome). The diagnosis of ACC is sometimes uncertain and it requires the use of precise molecular pathology; the differential diagnosis includes pheochromocytoma, adrenal adenoma, renal carcinoma, or hepatocellular carcinoma. We describe a case of a 57-year-old woman with Lynch Syndrome and metastatic ACC who was initially diagnosed as having pheochromocytoma. The tumor was first identified at 51 years of age by ultrasound followed by a CT scan. She underwent a left adrenalectomy, and the histopathology identified pheochromocytoma. Two years later, she had tumor recurrence with imaging studies showing multiple lung nodules. Following a wedge resection by video-assisted thoracoscopic surgery (VATS), histopathology was read as metastatic pheochromocytoma at one institution and metastatic ACC at another institution. She later presented to the National Institutes of Health (NIH) where the diagnosis of ACC was confirmed. Following her ACC diagnosis, she was treated with mitotane and pembrolizumab which were stopped due to side effects and progression of disease. She is currently receiving etoposide, doxorubicin, and cisplatin (EDP). This case highlights the importance of using a multi-disciplinary approach in patient care. Thorough evaluation of the tumor’s pathology and analysis of the patient’s genetic profile are necessary to obtain the correct diagnosis for the patient and can significantly influence the course of treatment.

Learning points:

  • Making the diagnosis of ACC can be difficult as the differential diagnosis includes pheochromocytoma, adrenal adenoma, renal carcinoma, or hepatocellular carcinoma.

  • Patients with Lynch Syndrome should undergo surveillance for ACC as there is evidence of an association between Lynch Syndrome and ACC.

  • Conducting a complete tumor immunoprofile and obtaining a second opinion is very important in cases of suspected ACC in order to confirm the proper diagnosis.

  • A multi-disciplinary approach including genetic testing and a thorough evaluation of the tumor’s pathology is imperative to ensuring that the patient receives an accurate diagnosis and the appropriate treatment.

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Skand Shekhar Section on Endocrinology & Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

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Sriram Gubbi Diabetes, Endocrinology, and Obesity Branch, National Institute of Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA

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Georgios Z Papadakis Department of Medical Imaging, Heraklion University Hospital, Medical School, University of Crete, Crete, Greece
Computational Biomedicine Laboratory (CBML), Institute of Computer Science (ICS), Foundation for Research and Technology Hellas (FORTH), Heraklion, Greece

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Naris Nilubol Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

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Fady Hannah-Shmouni Section on Endocrinology & Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

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Summary

Adrenococortical carcinoma (ACC) is a rare cancer, occurring at the rate of one case in two million person years. Cushing syndrome or a mixed picture of excess androgen and glucocorticoid production are the most common presentations of ACC. Other uncommon presentations include abdominal pain and adrenal incidentalomas. In the present report, a 71-year-old male presented with abdominal pain and was eventually diagnosed with ACC. He was found to have pulmonary thromboembolism following an investigation for hypoxemia, with the tumor thrombus extending upto the right atrium. This interesting case represents the unique presentation of a rare tumor, which if detected late or left untreated is associated with poor outcomes, highlighting the need for a low index of suspicion for ACC when similar presentations are encountered in clinical practice.

Learning points:

  • ACC is a rare but aggressive tumor.

  • ACC commonly presents with rapid onset of hypercortisolism, combined hyperandrogenism and hypercortisolism, or uncommonly with compressive symptoms.

  • Clinicians should have a low index of suspicion for ACC in patients presenting with rapid onset of symptoms related to hypercortisolism and/or hyperandrogenism.

  • Venous thromboembolism and extension of the tumor thrombus to the right side of the heart is a very rare but serious complication of ACC that clinicans should be wary of.

  • The increased risk of venous thromboembolism in ACC could be explained by direct tumor invasion, tumor thrombi or hypercoagulability secondary to hypercortisolism.

  • Early diagnosis and prompt treatment can improve the long-term survival of patients with ACC.

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Pedro Marques Department of Endocrinology, St. Bartholomew’s Hospital, West Smithfield, London, UK

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Nicola Tufton Department of Endocrinology, St. Bartholomew’s Hospital, West Smithfield, London, UK

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Satya Bhattacharya Hepatobiliary and Pancreatic Surgery Unit, The Royal London Hospital, London, UK

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Mark Caulfield Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, UK

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Scott A Akker Department of Endocrinology, St. Bartholomew’s Hospital, West Smithfield, London, UK

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Summary

Mineralocorticoid hypertension is most often caused by autonomous overproduction of aldosterone, but excess of other mineralocorticoid precursors can lead to a similar presentation. 11-Deoxycorticosterone (DOC) excess, which can occur in 11-β hydroxylase or 17-α hydroxylase deficiencies, in DOC-producing adrenocortical tumours or in patients taking 11-β hydroxylase inhibitors, may cause mineralocorticoid hypertension. We report a 35-year-old woman who in the third trimester of pregnancy was found to have a large adrenal mass on routine obstetric ultrasound. On referral to our unit, persistent hypertension and long-standing hypokalaemia was noted, despite good compliance with multiple antihypertensives. Ten years earlier, she had hypertension noted in pregnancy which had persisted after delivery. A MRI scan confirmed the presence of a 12 cm adrenal mass and biochemistry revealed high levels of DOC and low/normal renin, aldosterone and dehydroepiandrosterone, with normal catecholamine levels. The patient was treated with antihypertensives until obstetric delivery, following which she underwent an adrenalectomy. Histology confirmed a large adrenal cortical neoplasm of uncertain malignant potential. Postoperatively, blood pressure and serum potassium normalised, and the antihypertensive medication was stopped. Over 10 years of follow-up, she remains asymptomatic with normal DOC measurements. This case should alert clinicians to the possibility of a diagnosis of a DOC-producing adrenal tumours in patients with adrenal nodules and apparent mineralocorticoid hypertension in the presence of low or normal levels of aldosterone. The associated diagnostic and management challenges are discussed.

Learning points:

  • Hypermineralocorticoidism is characterised by hypertension, volume expansion and hypokalaemic alkalosis and is most commonly due to overproduction of aldosterone. However, excess of other mineralocorticoid products, such as DOC, lead to the same syndrome but with normal or low aldosterone levels.

  • The differential diagnosis of resistant hypertension with low renin and low/normal aldosterone includes congenital adrenal hyperplasia, syndrome of apparent mineralocorticoid excess, Cushing’s syndrome, Liddle’s syndrome and 11-deoxycorticosterone-producing tumours.

  • DOC is one intermediate product in the mineralocorticoid synthesis with weaker activity than aldosterone. However, marked DOC excess seen in 11-β hydroxylase or 17-α hydroxylase deficiencies in DOC-producing adrenocortical tumours or in patients taking 11-β hydroxylase inhibitors, may cause mineralocorticoid hypertension.

  • Excessive production of DOC in adrenocortical tumours has been attributed to reduced activity of the enzymes 11-β hydroxylase and 17-α hydroxylase and increased activity of 21-α hydroxylase.

  • The diagnosis of DOC-producing adrenal tumours is challenging because of its rarity and poor availability of DOC laboratory assays.

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Philip D Oddie Medical School, University of Oxford, Oxford, UK

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Benjamin B Albert Liggins Institute, University of Auckland, Auckland, New Zealand

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Paul L Hofman Liggins Institute, University of Auckland, Auckland, New Zealand
Starship Children’s Health, Auckland District Health Board, Auckland, New Zealand

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Craig Jefferies Starship Children’s Health, Auckland District Health Board, Auckland, New Zealand
Starship Children’s Health, Auckland District Health Board, Auckland, New Zealand

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Stephen Laughton Starship Children’s Health, Auckland District Health Board, Auckland, New Zealand

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Philippa J Carter Starship Children’s Health, Auckland District Health Board, Auckland, New Zealand

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Summary

Adrenocortical carcinoma (ACC) during childhood is a rare malignant tumor that frequently results in glucocorticoid and/or androgen excess. When there are signs of microscopic or macroscopic residual disease, adjuvant therapy is recommended with mitotane, an adrenolytic and cytotoxic drug. In addition to the anticipated side effect of adrenal insufficiency, mitotane is known to cause gynecomastia and hypothyroidism in adults. It has never been reported to cause precocious puberty. A 4-year-old girl presented with a 6-week history of virilization and elevated androgen levels and 1-year advancement in bone age. Imaging revealed a right adrenal mass, which was subsequently surgically excised. Histology revealed ACC with multiple unfavorable features, including high mitotic index, capsular invasion and atypical mitoses. Adjuvant chemotherapy was started with mitotane, cisplatin, etoposide and doxorubicin. She experienced severe gastrointestinal side effects and symptomatic adrenal insufficiency, which occurred despite physiological-dose corticosteroid replacement. She also developed hypothyroidism that responded to treatment with levothyroxine and peripheral precocious puberty (PPP) with progressive breast development and rapidly advancing bone age. Five months after discontinuing mitotane, her adrenal insufficiency persisted and she developed secondary central precocious puberty (CPP). This case demonstrates the diverse endocrine complications associated with mitotane therapy, which contrast with the presentation of ACC itself. It also provides the first evidence that the known estrogenic effect of mitotane can manifest as PPP.

Learning points:

  • Adrenocortical carcinoma is an important differential diagnosis for virilization in young children

  • Mitotane is a chemotherapeutic agent that is used to treat adrenocortical carcinoma and causes adrenal necrosis

  • Mitotane is an endocrine disruptor. In addition to the intended effect of adrenal insufficiency, it can cause hypothyroidism, with gynecomastia also reported in adults.

  • Patients taking mitotane require very high doses of hydrocortisone replacement therapy because mitotane interferes with steroid metabolism. This effect persists after mitotane therapy is completed

  • In our case, mitotane caused peripheral precocious puberty, possibly through its estrogenic effect.

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Katia Regina Marchetti Department of General Medicine

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Maria Adelaide Albergaria Pereira Department of Endocrinology, Clinics Hospital, University of Sao Paulo School of Medicine, Sao Paulo, SP, Brazil

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Arnaldo Lichtenstein Department of General Medicine

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Edison Ferreira Paiva Department of General Medicine

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Summary

Adrenacarcinomas are rare, and hypoglycemic syndrome resulting from the secretion of insulin-like growth factor II (IGF-II) by these tumors have been described infrequently. This study describes the case of a young woman with severe persistent hypoglycemia and a large adrenal tumor and discusses the physiopathological mechanisms involved in hypoglycemia. The case is described as a 21-year-old woman who presented with 8 months of general symptoms and, in the preceding 3 months, with episodes of mental confusion and visual blurring secondary to hypoglycemia. A functional assessment of the adrenal cortex revealed ACTH-independent hypercortisolism and hyperandrogenism. Hypoglycemia, hypoinsulinemia, low C-peptide and no ketones were also detected. An evaluation of the GH–IGF axis revealed GH blockade (0.03; reference: up to 4.4 ng/mL), greatly reduced IGF-I levels (9.0 ng/mL; reference: 180–780 ng/mL), slightly reduced IGF-II levels (197 ng/mL; reference: 267–616 ng/mL) and an elevated IGF-II/IGF-I ratio (21.9; reference: ~3). CT scan revealed a large expansive mass in the right adrenal gland and pulmonary and liver metastases. During hospitalization, the patient experienced frequent difficult-to-control hypoglycemia and hypokalemia episodes. Octreotide was ineffective in controlling hypoglycemia. Due to unresectability, chemotherapy was tried, but after 3 months, the patient’s condition worsened and progressed to death. In conclusion, our patient presented with a functional adrenal cortical carcinoma, with hyperandrogenism associated with hypoinsulinemic hypoglycemia and blockage of the GH–IGF-I axis. Patient’s data suggested a diagnosis of hypoglycemia induced by an IGF-II or a large IGF-II-producing tumor (low levels of GH, greatly decreased IGF-I, slightly decreased IGF-II and an elevated IGF-II/IGF-I ratio).

Learning points:

  • Hypoglycemyndrome resulting from the secretion of insulin-like growth factor II (IGF-II) by adrenal tumors is a rare condition.

  • Hypoinsulinemic hypoglycemia associated with hyperandrogenism and blockage of the GH–IGF-I axis suggests hypoglycemia induced by an IGF-II or a large IGF-II-producing tumor.

  • Hypoglycemia in cases of NICTH should be treated with glucocorticoids, glucagon, somatostatin analogs and hGH.

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Angelo Paci Pharmacology and Drug Analysis Department, Gustave Roussy, Villejuif, France

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Ségolène Hescot INSERM U1185, Fac Med Paris Sud, Le Kremlin-Bicêtre, France
Nuclear Medicine and Endocrine Oncology Department, Gustave Roussy, Villejuif, France

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Atmane Seck Pharmacology and Drug Analysis Department, Gustave Roussy, Villejuif, France

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Christel Jublanc Assistance Publique-Hôpitaux de Paris, La Pitié-Salpetriere Hospital, Department of Endocrinology, Paris, France

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Lionel Mercier Pharmacology and Drug Analysis Department, Gustave Roussy, Villejuif, France

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Delphine Vezzosi CHU Larrey, Department of Endocrinology, Toulouse, France

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Delphine Drui CHU Nantes, Department of Endocrinology, Nantes, France

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Marcus Quinkler Endocrinology in Charlottenburg, Berlin, Germany

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Martin Fassnacht Endocrine and Diabetes Unit, Department of Medicine 1, University Hospital, University of Würzburg, Würzburg, Germany

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Eric Bruckert Assistance Publique-Hôpitaux de Paris, La Pitié-Salpetriere Hospital, Department of Endocrinology, Paris, France

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Marc Lombès INSERM U1185, Fac Med Paris Sud, Le Kremlin-Bicêtre, France

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Sophie Leboulleux Nuclear Medicine and Endocrine Oncology Department, Gustave Roussy, Villejuif, France

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Sophie Broutin Pharmacology and Drug Analysis Department, Gustave Roussy, Villejuif, France

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Eric Baudin INSERM U1185, Fac Med Paris Sud, Le Kremlin-Bicêtre, France
Nuclear Medicine and Endocrine Oncology Department, Gustave Roussy, Villejuif, France

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Summary

Mitotane (o,p′-DDD) is the standard treatment for advanced adrenocortical carcinoma (ACC). Monitoring of plasma mitotane levels is recommended to look for a therapeutic window between 14 and 20mg/L, but its positive predictive value requires optimization. We report the case of an ACC patient with a history of dyslipidemia treated with mitotane in whom several plasma mitotane levels >30mg/L were found together with an excellent neurological tolerance. This observation led us to compare theoretical or measured o,p′-DDD and o,p′-DDE levels in a series of normolipidemic and dyslipidemic plasma samples to explore potential analytical issues responsible for an overestimation of plasma mitotane levels. We demonstrate an overestimation of mitotane measurements in dyslipidemic patients. Mitotane and o,p′-DDE measurements showed a mean 20% overestimation in hypercholesterolemic and hypertriglyceridemic plasma, compared with normolipidemic plasma. The internal standard p,p′-DDE measurements showed a parallel decrease in hypercholesterolemic and hypertriglyceridemic plasma, suggesting a matrix effect. Finally, diluting plasma samples and/or using phospholipid removal cartridges allowed correcting such interference.

Learning points

  • Hypercholesterolemia (HCH) and hypertriglyceridemia (HTG) induce an overestimation of plasma mitotane measurements.

  • We propose a routine monitoring of lipidemic status.

  • We propose optimized methodology of measurement before interpreting high plasma mitotane levels.

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S Hussain Department of Endocrinology, St Bartholomew's Hospital, London, UK

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E Panteliou Department of Endocrinology, St Bartholomew's Hospital, London, UK

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D M Berney Department of Pathology, St Bartholomew's Hospital, London, UK

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R Carpenter Department of Surgery, St Bartholomew's Hospital, London, UK

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M Matson Department of Radiology, St Bartholomew's Hospital, London, UK

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A Sahdev Department of Radiology, St Bartholomew's Hospital, London, UK

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M Bell Department of Endocrinology, Galway University Hospital, Galway, UK

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E O'Sullivan Department of Endocrinology, Galway University Hospital, Galway, UK

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W M Drake Department of Endocrinology, St Bartholomew's Hospital, London, UK

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Summary

We describe a young male patient with longstanding hypertension, who was diagnosed with primary hyperaldosteronism and treated by an attempted retroperitoneoscopic total unilateral adrenalectomy for a left-sided presumed aldosterone-secreting adenoma. Imaging had shown an unremarkable focal adrenal lesion with normal contralateral adrenal morphology, and histology of the resected specimen showed no adverse features. Post-operatively, his blood pressure and serum aldosterone levels fell to the normal range, but 9 months later, his hypertension recurred, primary aldosteronism was again confirmed and he was referred to our centre. Repeat imaging demonstrated an irregular left-sided adrenal lesion with normal contralateral gland appearances. Adrenal venous sampling was performed, which supported unilateral (left-sided) aldosterone hypersecretion. Redo surgery via a laparoscopically assisted transperitoneal approach was performed and multiple nodules were noted extending into the retroperitoneum. It was thought unlikely that complete resection had been achieved. His blood pressure returned to normal post-operatively, although hypokalaemia persisted. Histological examination, from this second operation, showed features of an adrenocortical carcinoma (ACC; including increased mitoses and invasion of fat) that was assessed as malignant using the scoring systems of Weiss and Aubert. Biochemical hyperaldosteronism persisted post-operatively, and detailed urine steroid profiling showed no evidence of adrenal steroid precursors or other mineralocorticoid production. He received flank radiotherapy to the left adrenal bed and continues to receive adjunctive mitotane therapy for a diagnosis of a pure aldosterone-secreting ACC.

Learning points

  • Pure aldosterone-secreting ACCs are exceptionally uncommon, but should be considered in the differential diagnosis of patients presenting with primary aldosteronism.

  • Aldosterone-producing ACCs may not necessarily show typical radiological features consistent with malignancy.

  • Patients who undergo surgical treatment for primary aldosteronism should have follow-up measurements of blood pressure to monitor for disease recurrence, even if post-operative normotension is thought to indicate a surgical ‘cure’.

  • Owing to the rarity of such conditions, a greater understanding of their natural history is likely to come from wider cooperation with, and contribution to, large multi-centre outcomes databases.

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Ravi Kumar Menon Department of Endocrinology, University College Hospital NHS Foundation Trust, NW1 2PG London, UK

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Francesco Ferrau Centre for Endocrinology, Barts and the London School of Medicine, Queen Mary University of London, EC1A 7BE London, UK

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Tom R Kurzawinski Department of Endocrine Surgery, University College Hospital NHS Foundation Trust, NW1 2PG London, UK

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Gill Rumsby Department of Clinical Biochemistry, University College Hospital NHS Foundation Trust, NW1 2PG London, UK

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Alexander Freeman Department of Pathology, University College Hospital NHS Foundation Trust, NW1 2PG London, UK

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Zahir Amin Department of Radiology, University College Hospital NHS Foundation Trust, NW1 2PG London, UK

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Márta Korbonits Centre for Endocrinology, Barts and the London School of Medicine, Queen Mary University of London, EC1A 7BE London, UK

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Teng-Teng L L Chung Department of Endocrinology, University College Hospital NHS Foundation Trust, NW1 2PG London, UK

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Summary

Adrenal cortical carcinoma (ACC) has previously only been reported in eight patients with type 1 neurofibromatosis (NF1). There has not been any clear evidence of a causal association between NF1 gene mutations and adrenocortical malignancy development. We report the case of a 49-year-old female, with no family history of endocrinopathy, who was diagnosed with ACC on the background of NF1, due to a novel germline frame shift mutation (c.5452_5453delAT) in exon 37 of the NF1 gene. A left adrenal mass was detected by ultrasound and characterised by contrast computerised tomography (CT) scan. Biochemical tests showed mild hypercortisolism and androgen excess. A 24-h urinary steroid profile and 18flouro deoxy glucose PET suggested ACC. An open adrenalectomy was performed and histology confirmed ACC. This is the first reported case with DNA analysis, which demonstrated the loss of heterozygosity (LOH) at the NF1 locus in the adrenal cancer, supporting the hypothesis of an involvement of the NF1 gene in the pathogenesis of ACC. LOH analysis of the tumour suggests that the loss of neurofibromin in the adrenal cells may lead to tumour formation.

Learning points

  • ACC is rare but should be considered in a patient with NF1 and adrenal mass when plasma metanephrines are normal.

  • Urinary steroid metabolites and PET/CT are helpful in supporting evidence for ACC.

  • The LOH at the NF1 region of the adrenal tumour supports the role of loss of neurofibromin in the development of ACC.

Open access