• Credits
  • Section Writer: Dr. Om J Lakhani
  • Section Editor: Dr. Om J Lakhani

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• Q. What are the recommendations for genetic screening for pheochromocytoma?
  • Endocrine society guidelines – it should be offered to all patients as a part of shared decision making
• Q. How common are pheochromocytomas hereditary?
  • 30-40% are hereditary in adults
  • More than 80% are hereditary in children
• Pearl
  • Catecholamine-secreting pheochromocytoma are more likely to be bilateral
• Q. Enlist the various genes associated with pheochromocytoma.
  • RET
  • NF1
  • VHL
  • SDHAF2
  • SDHA
  • SDHB
  • SDHC
  • SDHD
  • TMEM127
  • MAX
  • FH
  • EPAS1
  • MDH2
• Q. How common is pheochromocytoma in each of these syndromes – MEN2, VHL, and Neurofibromatosis?
  • VHL- 10-20%
  • MEN 2- 50%
  • NF 1 – 0.1-6%
• Von hippel lindau
  • Pearl- PHEOCHROMOCYTOMA occurs under the age of 30 in these people
• Q. What are the clinical features of VHL?
  • Hemangioblastoma- Cerebellum, Spinal cord, or brainstem
  • Pheochromocytoma
  • Paraganglioma
  • Retinal angioma
  • Clear cell carcinoma
  • Pancreatic NET
  • Endolymphatic sac tumors of the middle ear
  • Serous cystadenoma of the pancreas
  • Papillary cystadenoma of epididymis and broad ligament
• Q. What does the VHL gene do?
  • It is a tumor suppressor gene
• Q. Where is it located?
  • 3p25-26
• Q. What are the subtypes of VHL?
  • 
  • Type II VHL- higher risk of Pheochromocytoma
• Q. Which subgroup of VHL mutation has more risk of Pheochromocytoma?
  • Missense mutation higher likelihood of pheochromocytoma
• Q. When should screening for pheochromocytoma start in VHL patients?
  • At age 5 years
• Q. What is the characteristic of Pheochromocytoma in VHL?
  • Bilateral
  • Adrenal
  • Norepinephrine secreting
    • (most adrenal pheochromocytoma secrete epinephrine, this one is unusual)
• Q. What about extra-adrenal, do VHL have paraganglioma also?
  • Yes
  • They may have paraganglioma also
• MEN 2
• Q. How common is pheochromocytoma in MEN2?
  • 50% of cases
• Q. Are they adrenal or extradrenal?
  • Mainly adrenal
• Q. Which are the high-risk mutations in MEN 2?
  • Codon
    • 634
    • 918
    • 883
• Q. When should surveillance for pheochromocytoma begin in high-risk mutations?
  • New guidelines- At age 11
• Q. What about moderate risk mutations?
  • Age 16
• Q. What are the features of MEN 2A?
  • MTC- 100%
  • Pheochromocytoma – 50%
  • Hyperparathyroidism – 20%
  • Cutaneous lichen amyloidosis
  • Hirscpung disease- having Janus mutation
• Q. Which is the commonest mutation associated with MEN2A?
  • In codon 634- in 85% of cases
• Q. What are the clinical features of MEN 2B?
  • MTC- in all
  • Pheochromocytoma – 50%
  • Mucocutaneous neuromas- tongue, lips, and eyelid
  • Joint laxity
  • Skeletal deformities- lordosis or kyphoscoliosis
  • Intestinal ganglioneuroma
• Q. Give the difference in pheochromocytoma between VHL and MEN2.
  • 
• **Neurofibromatosis type 1 **
• Q. What are the diagnostic criteria for NF1?
  • Any two of below
    • 6 or more Café-au-luit spots
    • 2 or more Lisch nodule
    • 2 or more cutaneous neurofibroma
    • Sphenoid dysplasia
    • Optic glioma
    • Axillary Freckling
    • Relative having NF1
• Q. What is the prevalence of Pheochromocytoma in NF1?
  • 0.5-6%
• Q. Which NF1 patients must be screened for PCC?
  • Only those with hypertension
• Q. What type of PCC tumors are common in NF1?
  • Bilateral and mainly adrenal
• Q. What kind of biochemical release is common with NF1 and RET?
  • Epinephrine predominance
• SDH mutation
• Q. Describe the SDH mutation based on the PGL numbering.
  • PGL1- SDHD
  • PGL2- SDHAF2
  • PGL3- SDHC
  • PGL4- SDHB
  • PGL5- SDHA
• Q. Which SDH mutation are Autosomal dominant ?
  • SDHB or SDHC
• Q. Which are SDH mutations paternally inherited?
  • SDHD or SDHAF2 (maternal imprinting)
• Q. Which SDH has a higher risk of metastasis?
  • SDHB – B for bad
  • About 20-30% risk of Mets
  • Other is less than 5%
• Q. Summarize the clinical manifestations of various SDH mutations.
  • EA PGL- extraadrenal paraganglioma
  • PCC- pheochromocytoma
  • HNPGL- head and neck paraganglioma
• Q. How common is renal cell carcinoma in patients with SDHB mutation?
  • Very common
  • 30-40%
• Q. Summarize the lesions seen with SDHB mutation.
  • Metastatic Paraganglioma
  • Head and neck paraganglioma
  • Pheochromocytoma
  • Renal cell carcinoma (common)
  • Pituitary adenoma
  • GIST
• Q. Which SDH produces head and neck PGL?
  • SDHAF2, SDHB, SDHC and SDHD (all except SHDA)
• Q. What are the features of head and neck PGL?
  • They are often asymptomatic
  • Sometimes secrete a parasympathetic neurotransmitter
• Q. Which is most commonly associated with Pituitary adenoma?
  • SDHD
• Q. Enlist the other tumors associated with SDH.
  • Renal cell carcinoma (clear cell carcinoma) - SDHB
  • GIST – SDHA
  • Pituitary adenoma – usually SDHD
• Q. Which is the commonest location for the paragangliomas?
  • Abdominal
• Q. Which biochemistry alone is not enough in the above case?
  • Many PPGLs may be non-secreting
  • To pick up other tumors associated with SDHB like renal cell carcinoma
• Q. If metastasis is considered in this case- is PET better or MIBG better?
  • PET is better
• Q. How frequently should you do biochemistry and imaging?
  • No guidelines
  • Annual biochemistry
  • MRI/CT- every 2 years
• Q. What do you do for asymptomatic patients picked up with SDHB mutation?
  • Annual biochemistry + 2 Year imaging
  • Youngest age may be age 5
  • However, we do not have population-based data
• Q. How long to follow up?
  • Lifelong
• Pearl
  • Head and neck paraganglioma are usually non-secretory
  • If there is a secretory pattern in a patient with a history of H and N PPGL- look for tumors elsewhere
• Pearl
  • Patients with pheochromocytoma ANY procedure → preparation similar to surgery is required
• **Genetic screening **
• Q. Which patients are more likely to have a genetic cause of pheochromocytoma?
  • Age of onset <45 years
  • Bilateral
  • Extra-adrenal
  • Family history
  • Syndromic features present
• **Others **
• Q. Which are cluster 1 and cluster 2 genes associated with pheochromocytoma?
  • Cluster 1 – genes dealing with hypoxia
  • Cluster 2- genes dealing with kinase signaling
  • 
  • 
• Q. What is the difference between cluster 1 and cluster 2 genes?
  • 
• MUTATION TESTING ALGORITHM
• Q. Which mutation to test first in case of malignancy?
  • SDHB
• Q. Which mutation to test in the case of head and neck PPGL?
  • SDHD
  • SDHC
  • SDHAF2
• Q. Which mutation to test in the case of dopaminergic?
  • SDHB
• Q. Which mutation to test in case of extra-adrenal Norepinephrine?
  • SDHB
• Q. What about adrenal but norepinephrine?
  • VHL
• Q. What about adrenergic with epinephrine?
  • RET
• Q. Give an algorithm for genetic testing in pheochromocytoma.
  • 
• Q. Should all the involved genes be tested at once?
  • No
  • Target gene approach to be applied as described above
• Q. Which genes to test in bilateral adrenal pheochromocytoma?
  • Adrenergic- MEN 2 (RET)
  • Noradrenergic – VHL
• Pearl
  • Remember in RET- MTC is more common than pheochromocytoma – hence in the absence of MTC, MEN2 is less likely, however not impossible
• Q. Which gene to test first in case of abdominal paraganglioma?
  • SDHB
  • Then other SDH and VHL
• **Mode of inheritance **
• Q. What is the mode of inheritance of hereditary Paraganglioma syndromes?
  • Most are autosomal dominant except SDHD and SDHAF2 which have the parent of origin effect- paternally inherited – paternal imprinting effect
• Other notes
• Q. What is the definition of malignant pheochromocytoma?
  • WHO definition- the presence of distant metastasis
  • In other tumors breach of the capsule defines malignancy
  • Not so in pheochromocytoma
• Q. Which patients are more likely to have metastatic disease?
  • extra-adrenal pheochromocytoma
  • SDHB mutation
  • Size >4-5 cm
• Q. What is the best way for drawing a plasma metanephrine sample?
  • Supine for 20 min
  • Patient resting before doing the test (no exercise)
• Q. What is the role of chromogranin A in Pheochromocytoma / PPGL?
  • It is raised in 80% of cases
  • However, it is not specific
  • It is a useful tumor marker for follow-up of patients with metastatic disease
  • PPI often increases CgA
• Q. Acetaminophen interferes with which assays?
  • Liquid chromatography assays
  • Stop for 1 week
• Q. Do SSRI /SNRI interfere ?
  • Yes
• Q. Enlist the medication list which interferes with testing.
  • Acetaminophen
  • Sympathomimetics
  • Tricyclic antidepressants
  • Selective serotonin reuptake inhibitors
  • Serotonin-norepinephrine reuptake inhibitors
  • Levodopa
  • Monoamine oxidase inhibitors
  • Some beta-blockers (especially non-selective)
  • Some alpha-blockers (i.e. phenoxybenzamine)
  • Marijuana and other illicit drugs
• Q. Which is the best first-line imaging?
  • Cross-section CT/ MRI is the best first-line test
• Q. Are all tumors MIBG avid?
  • No
  • Only 60% are MIBG avid
  • 40% are not
• Q. What is the difference between Phenoxybenzamine vs prazosin?
  • Phenoxybenzamine is non selective alpha blocker
  • Prazosin is a selective alpha1 blocker
  • Also phenoxybenzamine is irreversible binding while prazosin is reversible binding
• Q. What are the advantage and disadvantages of one over the other?
  • Prazosin – can potentially be knocked off if there is a surge in catecholamine this can cause a problem in the case of an intraoperative period when a tumor is manipulated. This is not seen over phenoxybenzamine
  • Phenoxybenzamine produces more problems post-op because since there is irreversible binding → new receptors need to be generated post-op to prevent hypotension. This is not seen with prazosin
• Q. What is the mechanism of action of tyrosine?
  • It blocks tyrosine hydroxylase
• Q. Is metyrosine beneficial?
  • Studies have shown less CV complication in metyrosine + Pheoxybenzamine vs PBZ alone
• Q. the regimen used in adults, is it the same as in children?
  • Yes
• Q. When is cortical sparing surgery done?
  • Experience surgeons who can do that for patients with bilateral adrenal disease or susceptibility to bilateral disease