SDL 10 - Phaechromocytoma BMS16091064 Jonathan

Introduction
Pheochromocytomas are catecholamine producing tumors derived from the
sympathetic or parasympathetic nervous system. These tumors may arise sporadically
or be inherited as features of multiple endocrine neoplasia type 2 (MEN 2), von
Hippel–Lindau (VHL) disease, or several other pheochromocytoma-associated
syndromes. The diagnosis of pheochromocytomas identifies a potentially correctable
cause of hypertension, and their removal can prevent hypertensive crises that can be
lethal. The clinical presentation is variable, ranging from an adrenal incidentaloma to
a hypertensive crisis with associated cerebrovascular or cardiac complications.

Epidemiology
Pheochromocytoma is estimated to occur in 2–8 of 1 million persons. per year, and
~0.1% of hypertensive patients harbor a pheochromocytoma. The mean age at
diagnosis is ~40 years, although the tumors can occur from early childhood until late
in life. The classic “rule of tens” for pheochromocytomas states that ~10% are
bilateral, 10% are extraadrenal, and 10% are malignant.

Pathology
Pheochromocytomas are found at the classical sites of the adrenal medulla
Histologically the tumors often show a characteristic “Zellballen” pattern, consisting
of nests of neuroendocrine chief cells with peripheral glial-like sustentacular cells.
However, a broad spectrum of architectural and cytological features can be seen.
Immunohistochemistry is positive for chromogranin and synaptophysin in the chief
cells and S-100 in the sustentacular cells.Increasingly, staining with antibodies against
the proteins encoded by susceptibility genes for hereditary pheochromocytomas, such
as SDHB, is used to histologically demonstrate defects of these proteins, thereby
making germline mutations more likely
ETIOLOGY AND PATHOGENESIS
Pheochromocytomas are well-vascularized tumors that arise from cells derived from
the sympathetic (e.g., adrenal medulla). The name pheochromocytoma reflects the
formerly used black-colored staining caused by chromaffin oxidation of
catecholamines; although a variety of terms have been used to describe these tumors,
most clinicians use this designation to describe symptomatic catecholamine-producing
tumors, including those in extra-adrenal retroperitoneal, pelvic, and thoracic sites. In
contrast to common clinical parlance, the World Health Organization (WHO) restricts
the term pheochromocytoma to adrenal tumors.
The etiology of sporadic pheochromocytomas are unknown. However, 25–33% of
patients have an inherited condition, including germline mutations in the classically
recognized RET(rearranged during transfection), VHL, NF1 (neurofibromatosis type
1), SDHB, SDHC, and SDHD (subunits of SDH) genes or in the more recently
recognized SDHA, SDHAF2, TMEM127 (transmembrane protein 127), MAX
(myc-associated factor X), FH (fumarate hydratase), PDH1, PDH2 (pyruvate
dehydrogenase), HIF1alpha (hypoxia-inducible factor), MDH2 (malate
dehydrogenase), and KIF1Bß (kinesin family member) genes. Biallelic gene
inactivation, a characteristic of tumor suppressor genes has been demonstrated for the
VHL, NF1, SDHx, TMEM127, MAX, FH, PDH1, PDH2, MDH2, and KIF1Bß genes.
In contrast, RET is a protooncogene, and mutations activate receptor tyrosine kinase
activity. Succinate dehydrogenase (SDH) is an enzyme of the Krebs cycle and the
mitochondrial respiratory chain. The VHL protein is a component of an ubiquitin E3
ligase. VHL mutations reduce protein degradation, resulting in upregulation of
components involved in cell cycle progression, glucose metabolism, and oxygen
sensing. Currently, pheochromocytoma susceptibility genes are attributed to two
clusters. Cluster 1 mutations are associated with pseudohypoxia and aberrant VEGF
signaling (VHL, PHD, FH, or SDHx [subunits of SDH]) whereas cluster 2 mutations
are associated with abnormal activation of kinase signaling pathways (RET, NF1,
TMEM127, MAX, or KIF1Bb).

Clinical Features
The classic triad of episodes of palpitation, headache and profuse sweating in
association with hypertension are the defining features.
Investigations
Specific tests are:

• Measurement of urinary catecholamines and metabolites (metanephrines are most

sensitive and specific) is a useful screening test; normal levels on three 24-h
collections of metanephrines virtually exclude the diagnosis. Many drugs, e.g.
tricyclics, and dietary vanilla interfere with these tests.

• Resting plasma metanephrines are raised.

• Plasma chromogranin A (a storage vesicle protein) is raised

. • Clonidine suppression test may be appropriate but should only be performed in

specialist centres.

• CT/MRI scans, initially of the abdomen, are helpful to localize the tumours, which
are often large

• Scanning with [131I]meta-iodobenzylguanidine (MIBG) produces specific uptake in

sites of sympathetic activity with about 90% success. It is particularly useful with
extra-adrenal tumours. 18F-deoxyglucose positron emission tomography (PET) is also
used by some centres in the localization of phaeochromocytomas.

• Genetic testing for MEN2, VHL, SDHB and SDHD mutations should be performed
in all people with confirmed phaeochromocytoma or paraganglioma.
Differential Diagnosis
When the possibility of a pheochromocytoma is being entertained, other disorders to
consider include essential hypertension, anxiety attacks, use of cocaine or
amphetamines, mastocytosis or carcinoid syndrome (usually without hypertension),
intracranial lesions, clonidine withdrawal, autonomic epilepsy, and factitious crises
(usually from use of sympathomimetic amines). When an asymptomatic adrenal mass
is identified, likely diagnoses other than pheochromocytoma include a nonfunctioning
adrenal adenoma, an aldosteronoma, and a cortisol-producing adenoma (Cushing’s
syndrome).

Management
Tumours should be removed if this is possible; 5-year survival is about 95% for
non-malignant tumours. Medical preoperative and perioperative treatment is vital and
includes complete alpha- and beta-blockade with phenoxybenzamine (20–80 mg daily
initially in divided doses), then propranolol (120–240 mg daily), plus intravenous
hydration to re-expand the contracted plasma volume. The alpha-blockade must
precede the beta-blockade, as worsened hypertension may otherwise result. Labetalol
is not recommended. Surgery in the unprepared patient is fraught with dangers of both
hypertension and hypotension; expert anaesthesia and an experienced surgeon are
both vital, and sodium nitroprusside and phentolamine (a rapid-acting α-blocker)
should be available in case sudden severe hypertension develops. When operation is
not possible, combined alpha- and beta-blockade can be used long-term.
Radionucleotide treatment with MIBG has been employed but has had limited success
in malignant phaeochromocytoma.