PHEOCHROMOCYTOMA (based on Harrisons) Flashcards
1
Q
What are pheochromocytomas and paragangliomas?
A
Catecholamine-producing tumors derived from the sympathetic or parasympathetic nervous system.
2
Q
What inherited syndromes are associated with pheochromocytomas?
A
Multiple endocrine neoplasia type 2 (MEN 2), von Hippel–Lindau (VHL) disease, and other pheochromocytoma-associated syndromes.
3
Q
Why is the diagnosis of pheochromocytoma important?
A
It identifies a potentially correctable cause of hypertension and prevents lethal hypertensive crises.
4
Q
What is the estimated annual incidence of pheochromocytoma?
A
2–8 cases per 1 million persons per year.
5
Q
What percentage of hypertensive patients have a pheochromocytoma?
A
Approximately 0.1%.
6
Q
What is the mean age at diagnosis for pheochromocytoma?
A
Around 40 years, though it can occur at any age.
7
Q
What is the ‘rule of tens’ for pheochromocytoma?
A
~10% are bilateral, 10% are extra-adrenal, and 10% are metastatic.
8
Q
Where do pheochromocytomas arise from?
A
The adrenal medulla or sympathetic trunk.
9
Q
Where do paragangliomas arise from?
A
The skull base, neck, and other extra-adrenal sites (e.g., carotid body, glomus jugulare, glomus vagale).
10
Q
How does WHO define pheochromocytomas and paragangliomas?
A
WHO restricts ‘pheochromocytoma’ to adrenal tumors and applies ‘paraganglioma’ to tumors at all other sites.
11
Q
What percentage of pheochromocytomas have a genetic basis?
A
25–33%.
12
Q
Which proto-oncogene is involved in pheochromocytoma pathogenesis?
A
RET (rearranged during transfection).
13
Q
What enzyme of the Krebs cycle is mutated in some pheochromocytomas?
A
Succinate dehydrogenase (SDH).
14
Q
Which gene mutations lead to a pseudohypoxia-driven pheochromocytoma?
A
SDHx, FH, VHL, and HIF2A.
15
Q
What cluster of genes drives kinase signaling in pheochromocytoma?
A
RET, NF1, TMEM127, MAX, HRAS, KIF1Bβ, PDH.
16
Q
What cluster of genes is associated with Wnt signaling in pheochromocytoma?
A
CSDE1 and MAML3.
17
Q
Why is pheochromocytoma called ‘the great masquerader’?
A
Its clinical presentation is highly variable.
18
Q
What are the classic triad symptoms of pheochromocytoma?
A
Palpitations, headache, and profuse sweating.
19
Q
What is the most common clinical sign of pheochromocytoma?
A
Hypertension, which may be sustained or episodic.
20
Q
What cardiovascular complications can pheochromocytoma cause?
A
Heart failure, pulmonary edema, arrhythmias, and intracranial hemorrhage.
21
Q
What triggers catecholamine release in pheochromocytoma?
A
Surgery, positional changes, exercise, pregnancy, urination (bladder pheochromocytomas), and certain medications.
22
Q
What is the first step in diagnosing pheochromocytoma?
A
Biochemical testing for catecholamine excess.
23
Q
What biochemical tests confirm pheochromocytoma?
A
Plasma and urinary catecholamines and metanephrines.
24
Q
Which biochemical test is most sensitive for pheochromocytoma?
A
Plasma metanephrines.
25
What can cause false-positive catecholamine test results?
Physiologic stress, medications (e.g., tricyclic antidepressants, beta-blockers), and dietary factors.
26
What pharmacologic test can help confirm pheochromocytoma?
Clonidine suppression test.
27
What imaging modalities are best for localizing pheochromocytoma?
CT, MRI, and PET with specific radiotracers.
28
What MRI feature suggests pheochromocytoma?
T2-weighted hyperintensity with gadolinium contrast.
29
What nuclear imaging techniques help localize pheochromocytoma?
123I-MIBG scintigraphy, 18F-DOPA PET, 68Ga-DOTATATE PET, and 18F-FDG PET.
30
What histological pattern is characteristic of pheochromocytoma?
'Zellballen' pattern (nests of neuroendocrine cells with sustentacular cells).
31
What immunohistochemical markers are positive in pheochromocytoma?
Chromogranin, synaptophysin (chief cells), and S-100 (sustentacular cells).
32
What other conditions mimic pheochromocytoma?
Essential hypertension, anxiety, amphetamine or cocaine use, carcinoid syndrome, intracranial lesions, and autonomic epilepsy.
33
What are common symptoms of pheochromocytoma?
Headaches, sweating, palpitations, hypertension, anxiety, pallor, nausea, and abdominal pain.
34
What paradoxical response can occur with antihypertensives in pheochromocytoma?
Exaggerated hypotension or resistance to treatment.
35
What metabolic abnormalities can be seen in pheochromocytoma?
Hyperglycemia, erythrocytosis, and hypercalcemia.
36
What cardiovascular manifestation is linked to pheochromocytoma?
Dilated cardiomyopathy.
37
Why is pheochromocytoma considered life-threatening?
Catecholamine surges can cause fatal cardiovascular and cerebrovascular events.
38
What is the definitive treatment for pheochromocytoma?
Surgical removal of the tumor.
39
What preoperative medication is required before pheochromocytoma surgery?
Alpha-blockers (e.g., phenoxybenzamine) to prevent hypertensive crises.
40
What is the role of beta-blockers in pheochromocytoma treatment?
Used only after alpha-blockade to prevent unopposed alpha-mediated vasoconstriction.
41
What drugs should be avoided in pheochromocytoma?
Beta-blockers without prior alpha-blockade, tricyclic antidepressants, and sympathomimetics.
42
What is the recurrence risk of pheochromocytoma?
Higher in patients with genetic syndromes or metastatic disease.
43
What is the prognosis for metastatic pheochromocytoma?
Variable, but can be poor if widespread metastases are present.
44
What is the definitive treatment for pheochromocytoma?
Complete tumor removal via partial or total adrenalectomy.
45
Why is it important to preserve the normal adrenal cortex during adrenalectomy for pheochromocytoma?
To prevent Addison’s disease, especially in hereditary disorders where bilateral pheochromocytomas are common.
46
What is the preoperative blood pressure goal for pheochromocytoma patients?
Consistently <160/90 mmHg.
47
What class of drugs is used to control blood pressure preoperatively in pheochromocytoma?
Alpha-adrenergic blockers (e.g., oral phenoxybenzamine).
48
Why is liberal salt intake and hydration necessary in pheochromocytoma patients?
To avoid severe orthostasis since these patients are volume-constricted.
49
What medications can be used for managing paroxysmal hypertensive episodes in pheochromocytoma?
Oral prazosin or intravenous phentolamine.
50
When should beta-blockers be added to pheochromocytoma treatment?
Only after adequate alpha blockade to prevent unopposed alpha-mediated vasoconstriction.
51
What other antihypertensive classes can be used in pheochromocytoma?
Calcium channel blockers and angiotensin-converting enzyme inhibitors.
52
What are the intraoperative risks associated with pheochromocytoma surgery?
Labile blood pressure, hypertensive crises, and hypotension.
53
What drug is useful for intraoperative hypertensive crises in pheochromocytoma?
Nitroprusside infusion.
54
What is the standard surgical approach for pheochromocytoma removal?
Minimally invasive techniques such as laparoscopy or retroperitoneoscopy.
55
What postoperative test should be done after bilateral adrenal cortex-sparing surgery?
ACTH stimulation test to exclude cortisol deficiency.
56
What is a major surgical challenge in head and neck paragangliomas?
Risk of damaging adjacent tissue, including vessels and cranial nerves.
57
What alternative treatment may be considered for large head and neck paragangliomas?
Radiotherapy.
58
What percentage of pheochromocytomas and paragangliomas are metastatic?
5–10%.
59
How is metastatic pheochromocytoma defined?
By the presence of lymph node or distant metastases (e.g., lungs, bone, liver).
60
What is the first-line treatment for metastatic pheochromocytoma with documented metastases?
Nuclear medicine therapy with 131 I-MIBG.
61
What are alternative radionuclide treatments for metastatic pheochromocytoma?
Somatostatin receptor ligands like DOTATOC labeled with yttrium-90 or lutetium-177.
62
What chemotherapy regimen is used for metastatic pheochromocytoma?
Averbuch’s protocol: dacarbazine, cyclophosphamide, and vincristine every 21 days for 3–6 cycles.
63
What is the prognosis for metastatic pheochromocytoma?
Variable, with a 5-year survival rate of 30–60%.
64
When is pheochromocytoma typically diagnosed in pregnancy?
Occasionally during pregnancy, presenting a management challenge.
65
What is the preferred treatment for pheochromocytoma in pregnancy?
Endoscopic removal, ideally in the fourth to sixth month of gestation.
66
What percentage of pheochromocytoma patients have an inherited syndrome?
25–33%.
67
Which inherited syndrome is most commonly associated with pheochromocytoma?
Multiple endocrine neoplasia type 2 (MEN 2).
68
What genetic mutation causes MEN 2?
Mutations in the RET proto-oncogene.
69
What is the difference between MEN 2A and MEN 2B?
MEN 2A includes medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism, while MEN 2B includes MTC, pheochromocytoma, multiple mucosal neuromas, and a marfanoid habitus.
70
What is the most common feature of MEN 2?
Medullary thyroid carcinoma (MTC).
71
What are the main features of von Hippel–Lindau (VHL) syndrome?
Retinal and cerebellar hemangioblastomas, clear cell renal carcinomas, pancreatic neuroendocrine tumors, and pheochromocytoma.
72
What mutation is associated with von Hippel–Lindau (VHL) syndrome?
Mutations in the VHL gene.
73
What percentage of VHL patients develop pheochromocytoma?
20–30%, though some families have incidences as high as 90%.
74
What is the classic skin finding in neurofibromatosis type 1 (NF1)?
Café au lait spots.
75
What is the prevalence of pheochromocytoma in NF1 patients?
~1%.
76
What are paraganglioma syndromes (PGLs) caused by?
Mutations in genes encoding subunits of succinate dehydrogenase (SDH).
77
Which SDH mutation is most associated with metastatic pheochromocytoma?
SDHB (PGL4).
78
What is unique about SDHD and SDHAF2 mutations in paraganglioma syndromes?
Tumors only develop if the mutation is inherited from the father.
79
Which paraganglioma syndrome subtype has the highest metastatic risk?
PGL4 (SDHB mutations).
80
What newer targeted therapies are being investigated for metastatic pheochromocytoma?
Sunitinib and temozolomide/thalidomide.
81
What two genes are linked to hereditary pheochromocytoma outside of SDH mutations?
TMEM127 and MAX.
82
What is the inheritance pattern of MAX and TMEM127 mutations?
Autosomal dominant.
83
What is the most common site for pheochromocytomas in MEN 2?
The adrenal glands, often bilaterally.
84
Which pheochromocytoma-associated syndromes have a higher risk of metastases?
VHL, NF1, PGL1, and PGL4.
85
What are the general features suggesting an inherited syndrome in pheochromocytoma?
Young age, multifocal tumors, extra-adrenal tumors, and metastatic tumors.
86
Why is genetic screening recommended even in pheochromocytoma patients without a known family history?
Because of the relatively high prevalence of familial syndromes among pheochromocytoma or paraganglioma patients.
87
What is the first step in identifying an inherited syndrome in pheochromocytoma patients?
Searching for clinical features of inherited syndromes and obtaining an in-depth, multigenerational family history.
88
What is the inheritance pattern of pheochromocytoma-associated syndromes?
Autosomal dominant with variable penetrance.
89
Which mutations are not inherited maternally in pheochromocytoma syndromes?
PLG1 (SDHD mutation) and PGL2 (SDHAF2 mutation).
90
What clinical signs suggest neurofibromatosis type 1 (NF1) in pheochromocytoma patients?
Cutaneous neurofibromas, café au lait spots, and axillary freckling.
91
Why is NF1 genetic testing usually unnecessary in sporadic pheochromocytomas?
Germline NF1 mutations are rarely reported in sporadic pheochromocytomas.
92
What personal or family history suggests MEN 2 in pheochromocytoma patients?
Medullary thyroid carcinoma (MTC) or elevated serum calcitonin.
93
What personal or family history suggests von Hippel–Lindau (VHL) syndrome?
History of visual impairment or tumors in the cerebellum, brainstem, spinal cord, or kidney.
94
What personal or family history suggests PGL1 or PGL4?
A history of head and neck paragangliomas.
95
Which gene mutations are most commonly associated with a single adrenal pheochromocytoma?
VHL, RET, SDHB, and SDHD (in decreasing order of frequency).
96
What percentage of extra-adrenal pheochromocytomas are associated with an inherited syndrome?
Two-thirds.
97
Which mutations are most commonly associated with multifocal pheochromocytomas?
RET, SDHD, VHL, SDHB, and MAX (in decreasing order of frequency).
98
What percentage of head and neck paragangliomas are associated with germline mutations?
About 30%.
99
Which gene is most commonly mutated in head and neck paragangliomas?
SDHD.
100
Which gene mutations are rare in head and neck paragangliomas?
VHL, RET, MAX, and TMEM127.
101
How can immunohistochemistry help in identifying hereditary pheochromocytomas?
Negative staining for SDHB, TMEM127, and MAX may predict mutations in SDHx, TMEM127, and MAX genes, respectively.
102
What sequencing method is increasingly replacing targeted Sanger sequencing for pheochromocytoma genetic testing?
Whole genome sequencing.
103
What is a limitation of sequencing protocols in detecting pheochromocytoma-associated mutations?
They may not detect large deletions of one or more exons.
104
Why is genetic testing of relatives important in hereditary pheochromocytoma?
To determine whether they carry the germline mutation and may develop the disease.
105
What is required before testing relatives of a pheochromocytoma patient for genetic mutations?
Identifying the germline mutation in the proband and providing genetic counseling.
106
What is the purpose of biochemical screening in relatives with germline mutations?
To detect paraganglial tumors early.
107
Why are asymptomatic paraganglial tumors challenging to manage?
They are often detected in hereditary cases and may require watchful waiting.
108
What is a common treatment for head and neck paragangliomas?
Radiation therapy.
109
Why is surgery often avoided for head and neck paragangliomas?
It is frequently associated with permanent cranial nerve palsy (II, VII, IX, X, XI, XII).
110
Which type of paraganglioma is often symptomatic early and amenable to surgery?
Tympanic paragangliomas.
111
What are the benefits of resecting tympanic paragangliomas?
Improved hearing and alleviation of tinnitus.
