Published 4 March 2009, doi:10.1136/bmj.b333
Cite this as: BMJ 2009;338:b333

Endgames

Picture Quiz

A woman with a suprarenal mass and hypertension

H Kahal, specialist trainee 3 in diabetes and endocrinology, E Cooper, foundation year 2, R Sriraman, specialist registrar in general medicine, diabetes, and endocrinology, D V Coppini, consultant physician, honorary senior lecturer in diabetes and endocrinology

1 Department of Diabetes and Endocrinology, Poole Hospital NHS Foundation Trust, Poole BH15 2JB

Correspondence to: H Kahal hassoon011{at}yahoo.com

A woman presented to surgeons with abdominal discomfort in 1990. She underwent abdominal computed tomography, which showed a large incidental right suprarenal mass (fig 1Go). Follow-up scans suggested a benign stable adenoma, measuring 49x60 mm, and the decision was made not to operate. An endocrine opinion was not sought. Her medical history included hypertension.


Figure 1
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  		Fig 1 Abdominal computed tomography scan showing a suprarenal mass (arrow)

 
In June 2006, at the age of 69, she re-presented with peritonitis, and a laparotomy showed a thickened wall cyst at the duodeno-jejunal junction. During elective excision of the cyst in April 2007, it was difficult to achieve haemodynamic stability. An unplanned resection of the suprarenal mass was performed concomitantly. The cyst stained strongly positive for CD117. Figure 2Go shows the patient’s clinical features.


Figure 2
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  		Fig 2 The patient’s clinical features

 

Questions

1 What is the patient’s underlying condition?
2 What is the cause of her hypertension?
3 What is the incidental finding in this case, as suggested by the cyst’s histology?

Show Answers

Answers

Short answers

1 The presence of numerous neurofibromas and café au lait macules (fig 3Go) is diagnostic for neurofibromatosis type 1.


Figure 3
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  		Fig 3 The patient’s clinical features. The black arrow points to a neurofibroma and the pink arrow points to a café au lait macule

 
2 Phaeochromocytoma, which has an overall incidence of <1% in patients with neurofibromatosis type 1.
3 Gastrointestinal stromal tumour, which typically stains positive for CD117.

Long answers
1 Diagnosis
Neurofibromatosis type 1, also known as von Recklinghausen disease, is an autosomal dominant disorder caused by mutation of a gene on chromosome 17.1 Its incidence is one in 3000 live births.2

Neurofibromatosis type 1 is diagnosed clinically by the presence of two of the following: six or more café au lait macules >5.0 mm in diameter (before puberty) or >15 mm (after puberty); two or more neurofibromas or plexiform, axillary, or inguinal freckling; two or more Lisch nodules (tiny tumours on the iris of the eye); distinctive osseous lesions; or a first degree relative with the disease (according to the above criteria).3 Neurofibromatosis type 1 is commonly associated with cognitive and learning disabilities.4 Our patient had numerous truncal and upper limb neurofibromas, café au lait macules, axillary freckling, and relative macrocephaly. Her mother and the eldest of her two daughters had a similar phenotype. One daughter had learning difficulties.

2 The cause of hypertension
Her hypertension is caused by phaeochromocytoma. Phaeochromocytoma occurs in 0.1-5.7% of patients with neurofibromatosis type 1, but this rises to 20-50% in patients with this disease plus hypertension.5 Phaeochromocytomas are catecholamine producing neuroendocrine tumours arising from the chromaffin cells of the adrenal medulla or the extra-adrenal paraganglia.

Between 80% and 85% of phaeochromocytomas occur in the adrenal medulla, whereas 15-20% arise from extra-adrenal chromaffin tissue.6 7 Patients usually present with episodes of headache, sweating, palpitations, and hypertension. In most patients the disease is cured by surgery, and laparoscopic surgery is the treatment of choice.8 Medical management preoperatively is vital for preventing hypertensive crises and arrhythmias as a result of catecholamine release. Careful preoperative preparation of the patient with an {alpha} adrenoceptor blocker (prazosin or phenoxybenzamine) and volume expansion can greatly reduce perioperative mortality.9 If β adrenoceptor blockers are used, they should be preceded by {alpha} adrenoceptor blockade, to prevent worsening of hypertension.10

Patients should be kept under close clinical and biochemical scrutiny after resection of the tumour. The risk of tumour recurrence in the remnant adrenal gland is 10%.11 12 13 All patients should be followed up annually for at least 10 years after surgery. Patients with extra-adrenal or familial phaeochromocytoma should be followed up indefinitely.14

3 Incidental finding
The cyst’s histology showed that it was a gastrointestinal stromal tumour. These are rare mesenchymal tumours that originate from pacemaker cells (the interstitial cells of Cajal) and comprise 1-3% of all malignant gastrointestinal tumours. The tumour cells usually express the KIT tyrosine kinase receptor, also called CD117 or C-Kit receptor.15 16 17 18 Strong immunohistochemical staining for CD117 is characteristic of these tumours.

Most gastrointestinal stromal tumours express germline mutations either of the KIT gene (which encodes KIT receptor tyrosine kinase)—most commonly on exons 9, 11, 13, and 17—or of the KIT related platelet derived growth factor receptor {alpha} (PDGFRA) gene.18 19 20 Expression of the KIT proto-oncogene and the production of tyrosine kinase lead to uncontrolled growth and suppression of apoptosis.

Patients with neurofibromatosis type 1 have an increased risk of developing gastrointestinal stromal tumours. Clinical studies indicate that these tumours occur in 5-25% of patients with neurofibromatosis type 12 20 21 22 23 24; studies with higher estimates included symptom-free tumours diagnosed at autopsy only. Mutations of the NF2 gene have been reported in single cases of gastrointestinal stromal tumour and contribute to a small subset of these tumours, presumably as a result of increased genetic instability.25 The tumour can also be associated with paraganglioma and pulmonary chondroma as part of Carney’s triad.26 27 Most gastrointestinal stromal tumours associated with neurofibromatosis type 1 reported to date do not express KIT gene mutations.

In one study of 45 patients with neurofibromatosis type 1 and gastrointestinal stromal tumours, the median age of the patients was 49 years (10 years lower than that of general patients with gastrointestinal stromal tumours).28 Most tumours occurred in the jejunum or ileum, and the most common presentations were gastrointestinal bleeding and anaemia. None of the 16 tumours from 15 patients had the KIT exon 9, 11, 13, or 17 mutations or the PDGFRA exon 12 or 18 mutations that are typically seen in sporadic gastrointestinal stromal tumours.

Our literature search indicates that gastrointestinal stromal tumours have different pathogenetic mechanisms when they occur in the context of neurofibromatosis type 1 rather than as sporadic tumours. Patients with neurofibromatosis type 1 have an increased incidence of both benign and malignant tumours.2 29 The coincidence of gastrointestinal stromal tumour and phaeochromocytoma in neurofibromatosis type 1 is rare, having been reported only 10 times (table)Go.30


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  		Reported cases of neuroendocrine tumour, gastrointestinal stromal tumour, and neurofibromatosis type 1

 
Further studies may help identify specific mutations in the NF1 gene that may be responsible for an increased risk of neoplasia in patients with neurofibromatosis. Such studies may help develop possible gene therapies.

Summary
Phaeochromocytomas are rare, often overlooked, causes of hypertension. Patients presenting with hypertension on a background of neurofibromatosis type 1 should be investigated for the presence of phaeochromocytoma.

Gastrointestinal symptoms are not uncommon in patients with phaeochromocytoma. Such symptoms in patients with neurofibromatosis type 1 should alert the clinician to the possibility of coexisting gastrointestinal stromal tumours.

Cite this as: BMJ 2009;338:b333

Competing interests: None declared.

Provenance and peer review: Not commissioned; externally peer reviewed.

Patient consent obtained.

References

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