Which of the following is most reliable feature suggestive of malignant transformation of pheochromocytoma excusively?
Ans. D. None of the above. (Ref. Robbin's 8th/pg. 1159).Robbins pathology 8th/ pg. 1159......."Both capsular and vascular invasion may be encountered in benign lesions, and the presence of mitotic figures per se does not imply malignancy. Therefore, the definitive diagnosis of malignancy in pheochromocytomas is based exclusively on the presence of metastases. These may involve regional lymph nodes as well as more distant sites, including liver, lung, and bone."PHEOCHROMOCYTOMAPheochromocytomas are neoplasms composed of chromaffin cells, which, like their non-neoplastic counterparts, synthesize and release catecholamines and, in some cases, other peptide hormones. These tumors are of special importance because, although uncommon, they (like aldosterone-secreting adenomas) give rise to a surgically correctable form of hypertension.Pheochromocytomas = "rule of 10s":# 10% = familial .# 10% = extra-adrenal, occurring most commonly at the organ of Zuckerkandl.# 10% = bilateral.# 10% = malignant: Frank malignancy is somewhat more common in tumors arising in extra-adrenal sites.Histopathology:# Microscopically, pheochromocytomas are composed of polygonal to spindle-shaped chromaffin cells and their sup- porting cells, compartmentalized into small nests, or "Zellballen," by a rich vascular network.6# Electron microscopy reveals variable numbers of membrane-bound, electron-dense granules, representing catechola- mines and sometimes other peptides. The nuclei of the neoplastic cells are often quite pleomorphic.# Both capsular and vascular invasion may be encountered in benign lesions, and the presence of mitotic figures per se does not imply malignancy.# Therefore, the definitive diagnosis of malignancy in pheochromocytomas is based exclusively on the presence of metastases. These may involve regional lymph nodes as well as more distant sites, including liver, lung, and bone.Clinical features:# The dominant clinical manifestation of pheochromocytoma is episodic hypertension. 6# Classically, this is described as an abrupt, precipitous elevation in blood pressure, associated with tachycardia, palpitations, headache, sweating, tremor, and a sense of apprehension. Such episodes may also be associated with pain in the abdomen or chest, nausea, and vomiting.# In practice, isolated, paroxysmal episodes of hypertension occur in fewer than half of individuals with pheochro- mocytoma.# Sudden cardiac death may occur.Biochemical Tests:# Unclear which is the best test, although most patients will have clearly abnormal values.# 24h urine metanephrines, vanillylmandelic acid (VMA), and free catecholamines: Most feel this is the first best test, as the values are usually elevated. Urine metanephrines: >1.2mg/d. Can see falsely elevated levels if patient is on labetolol or buspirone (metabolite of buspirone mistakenly read as metanephrine).6# Plasma catecholamines: Must be drawn under strict guidelines including patient fasting, supine for 30 minutes, and needle inserted at least 20 minutes prior to blood draw. Norepinephrine >2000pg/ml or epinephrine >200pg/ml is 95% specific and 85% sensitive. Metanephrine and normetanephrine plasma measurement are probably the most sensitive because these metabolites released directly from adrenals (>90% and 24-40%, respectively).# Clonidine suppression test: indicated if urine and plasma studies non-diagnostic and history still suggestive. Biopsy: contraindicated. 6Radiologic tests:# CT scan: 87% sensitive because it may miss tumors < 1cm which means in MEN-2 can miss up to 25%.# MRI: 98-100% sensitive, bonus ability to differentiate an adrenal pheo from other adrenal masses by T2 weighted images showing hyperintensity of pheos.6# I131-MIBG scan: scan detect tumors missed by CT or MRI and is excellent for evaluation of metastasis. Patients should not be on phenoxybenzamine prior to scan.6# DOPA-PET scan: can detect tumors in unusual locations most sensitively and specifically. 6# Adrenal Vein sampling; only needed when work up is inconclusive .Rx:# Surgical removal is Rx of choice and are now being successfully removed laparoscopically.# Pre-operative Rx: Treat hypertension and volume contraction.# Hypertensive Rx:- Alpha blockade with phenoxybenzamine, a long acting alpha pre and post-synaptic adrenergic antagonist. 10mg BID and increase to 0.5mg/kg daily in divided doses as needed to control HTN for 2-3weeks prior to surgery. Hold the morning of surgery.Prazosin may be used but requires more frequent dosing. Phenoxybenzamine can be used as definitive therapy for inoperable and malignant tumours.- Beta blockade can be added to treat tachycardia after adequate alpha blockade has been started. Labetolol best with its alpha 1 and beta-adrenergic antagonist activity.- Metyrosine (alpha-methyl-para-tyrosine) inhibits catecholamine synthesis.- Calcium channel blockers may be used if beta-blocker not tolerated.# Highest risk periods are during anesthesia induction and when tumor is manipulated. Nitroprusside should be available. Post-operatively hypotension and shock may occur. Hypoglycemia may develop in 10-15% secondary to release of suppression of insulin by excess catecholamines. Catecholamine secretion should return to normal in about one week.Prognosis:# Can be cured with surgery, although recurrence rate 14% in one series, with half of those being malignant. Risk of recurrence highest in familial disorders. Pain from metastatic bone lesions can be relieved with radiation therapy +/- chemotherapy. Disorders of Adrenal MedullaPheochromoclytoma# Neoplasm of neural crest-derived chromaffin cells that secrete catecholamines (usually norepinephrine) - hypertension# Highest incidence in children and adults age 30-50 - Clinical: paroxysmal or constant hypertension is most classic symptom; also, sweating, headache, arrhythmias, palpitations# Lab values: elevated urinary homovanillic acid (HVA) and vanillylmandelic acid (VMA)# The Rule of 10s for pheochromocytoma:- 10% extra-adrenal- 10% bilateral- 10% malignant- 10% affect children- 10% familialNeuroblastoma# Most common malignant extracranial solid tumor of childhood# Occurs most frequently in the adrenal medulla, but may arise in sympathetic chain# Amplification of the N-myc oncogene--more copies=more aggressive# Clinical: tumors grow rapidly, metastasize widely (especially to bone); prognosis in younger patients (less than 1 year old) better than for older children# Pathology: lobulated with areas of necrosis, hemorrhage, calcification# Microscopic appearance: rosette pattern of small cells
Presence of mitotic figures
Capsular invasion
Vascular invasion
None of the above
Neoplasia