Digestive Tract Neuroendocrine Tumours and Pheochromocytomas/Paragangliomas
Sympathetic paraganglia have a neck-to-pelvis distribution and parasympathetic paraganglia are found in the neck and skull base.
Paragangliomas that are localised in the adrenal medulla are called pheochromocytomas (or more uncommonly termed adrenal medullary paragangliomas).54
Tumours arising from extra-adrenal chromaffin cells are termed paragangliomas. They can be found along the paravertebral and para-aortic axes.53
Missense mutations in the VHL tumour suppressor gene, usually in codon 167, 3p25–26, are commonly implicated in the pathogenesis of VHL syndrome. Twenty to 50% of subjects have mostly benign adrenal pheochromocytomas, and slightly less than 50% have bilateral disease.62
The term extra-adrenal
pheochromocytomas is used to describe tumours of the sympathoadrenal system. There are no universally established criteria for defining malignancy in pheochromocytomas/ paragangliomas. However, capsular invasion, large tumour size (>5cm) and weight (>80g) may be indicators of malignancy. The clinical course may indicate malignancy, particularly with recurrent or metastatic disease.
Furthermore, 0.5% of subjects with hypertension and 4% of those with an incidental adrenal mass have pheochromocytoma.55
The caveat is that these figures are
approximate, since until a few years ago 18–60% of tumours remained undiagnosed.54
The average lag time from the onset of
hypertension to the diagnosis of pheochromocytoma is three years.56 Peak age for diagnosis of pheochromocytomas is between 40 and 50 years, with an almost equal female/male ratio. In most cases (downgraded from 90 to 85% or less with the advent of newer molecular genetics studies, see below for details) these tumours are adrenal, sporadic and solitary.
The symptoms of pheochromocytomas vary. The triad of tachycardia with diaphoresis and cephalalgia is encountered in 40–80% of patients and is highly sensitive and specific for a presumptive diagnosis of pheochromocytoma.57,58
Hypertension – newly diagnosed or an
exacerbation of known hypertension, most often paroxysmal – is common, occurring in over 90% of patients, but is non-specific.58
Most paragangliomas are intra-abdominal and adjacent to the adrenals (approximately 85%). Less than 15% are intrathoracic and 1–3% are cervical.59
Chromaffin-negative neuroendocrine tumours in the head and neck that are related to the parasympathetic nervous system, such as those originating from the carotid bodies or jugular bulbs, are also termed paragangliomas.60
Genetics
Familial syndromes with pheochromocytomas/paragangliomas include55 MEN type 2 (MEN 2); von Hippel-Lindau (VHL) syndrome; neuroectodermal dysplasias – neurofibromatosis type 1 (NF-1), tuberous sclerosis and Sturge-Weber syndrome; and other familial paragangliomas, especially those related to succinate dehydrogenase (SDH) gene mutations. In children, familial tumours are found twice as often as in adults.61
Activating germline mutations in the REarranged during Transfection (RET) proto-oncogene, usually in codons 634 or 918 (10q11.2) are implicated in the abnormal cellular proliferation of MEN 2 syndrome. Pheochromocytomas are usually adrenal and benign in MEN 2 and are bilateral in more than 50% of patients.55
EUROPEAN ENDOCRINOLOGY
Pheochromocytomas (i.e. adrenal medullary paragangliomas) are rare tumours with an annual incidence of one to four per million population.55
The genetic background of pheochromocytomas observed in subjects with neuroectodermal dysplasias is yet to be elucidated. Mutations in the NF-1 tumour suppressor gene – associated with von Recklinghausen’s disease – have been observed (17q11.2; in 90% of cases). The risk of pheochromocytoma in patients with NF-1 is approximately 1–5%.56,63
Familial pheochromocytomas or head/neck paragangliomas are seen in subjects with germline mutations in subunits B, C and D of the SDH gene. The risk of extra-adrenal and/or malignant disease is high for SDHB mutation carriers.62 and neck paragangliomas.64 head and neck paragangliomas.64
SDHB mutations also predispose to head SDHC mutations are a rare cause of SDHD mutations are associated with
benign adrenal and extra-adrenal paragangliomas or multifocal head and neck paragangliomas.64
SDHB/SDHD mutations have been found
in patients with Carney-Stratakis syndrome (they also have paragangliomas).65
gastrointestinal stroma cancer and thyroid cancer.61
The former are also associated with renal tumours, Mutations in the
SDHA and SDHAF2 (SDH 5) family were recently found and linked to hereditary, but not sporadic, paragangliomas.66–69
Expression of SNAIL (a zinc-finger transcription factor) may predict the metastatic potential of pheochromocytoma.71
It has been suggested that the transmembrane-encoding gene TMEM127 (chromosome 2q11) is a newly discovered pheochromocytoma susceptibility gene. Pheochromocytomas with TMEM127 mutations are transcriptionally related to tumours bearing NF1 mutations.70
Approximately 15% of all pheochromocytomas/paragangliomas are associated with germline SDH mutations. Immunohistochemistry is apparently the most cost-effective method of genetic testing – particularly if biochemistry is not available or considered, or results are negative.61,72,73
Furthermore, there is sufficient evidence to suggest that genetic testing should be carried out in all patients with pheochromocytomas-paragangliomas. If cost is a concern, then testing should at least be available to those
Biochemical Diagnosis
Chromaffin tumours that are hormonally active may secrete catecholamines episodically, however, they metabolise catecholamines to metanephrines continuously. Free metanephrines in plasma and 24-hour urinary fractionated free metanephrines are the most accurate methods for establishing the diagnosis of pheochromocytoma. Their respective sensitivity ranges from 99–100 (plasma) and 97–100% (urine) and their specificity is 89–94 (plasma) and 69–95% (urine).61
Biochemistry is not only useful for establishing the diagnosis of pheochromocytoma/paraganglioma but can also guide further testing (including genetic testing). In subjects with MEN2 or NF1, there is predominantly elevation in metadrenaline, whereas in subjects with VHL there is predominantly elevation in normetadrenaline.61
Care
must be taken to normalise metadrenaline levels for populations with normal blood pressure, match them for gender and age74 interference from medications.75
and avoid
61
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