Fig.20.43Adrenalcarcinomawithmarkedanaplasia.
Frank malignancy is somewhat more common in tumors arising in extraadrenal sites.
• 10% of adrenal pheochromocytomas are not associated with hypertension. Of the 90% that present with hypertension, approximately two-thirds have “paroxysmal” episodes associated with sudden rise in blood pressure and palpitations, which can, on occasion, be fatal.
One “traditional” 10% rule that has since been modified pertains to familial cases. It is now recognized that as many as 25% of individuals with pheochromocytomas and paragangliomas harbor a germ line mutation in one of at least six known genes, including RET, which causes type 2 MEN syndromes (described later); NF1, which causes type 1 neurofibromatosis (Chapter 22); VHL, which causes von Hippel-Lindau disease (Chapters 14 and 23); and three genes encoding subunits within the succinate dehydrogenase complex (SDHB, SDHC, and SDHD), which is involved in mitochondrial electron transport and oxygen sensing. It is postulated that loss of function in one or more of these subunits leads to stabilization of the transcription factor hypoxia-inducible factor 1α (HIF-1α), promoting tumorigenesis.
MORPHOLOGYPheochromocytomasrangeinsizefromsmall,circumscribedlesionsconfinedtotheadrenaltolarge,hemorrhagicmassesweighingseveralkilograms.Oncutsurface,smallerpheochromocytomasareyellow-tan,well-definedlesionsthatcompress theadjacentadrenalgland(Fig.20.44 ).Largerlesionstendtobehemorrhagic,necrotic,andcysticandtypicallyeffacetheadrenalgland.Incubationofthefreshtissuewithpotassiumdichromatesolutionsturnsthetumordarkbrown,asnotedearlier.
Onmicroscopicexamination,pheochromocytomasarecomposedofpolygonaltospindle-shapedchromaffincellsandtheirsupportingcells,compartmentalizedintosmallnests,byarichvascularnetwork(
Fig.20.45 ).Thecytoplasmoftheneoplasticcellsoftenhasafinelygranularappearance,highlightedbyavarietyofsilverstains,becauseofthepresenceofgranulescontainingcatecholamines.Electronmicroscopyrevealsvariablenumbersofmembrane-bound,electron-densegranules,representingcatecholaminesandsometimesotherpeptides.Thenucleioftheneoplasticcellsareoftenquitepleomorphic.Bothcapsularandvascularinvasion,aswellascellularpleomorphism,maybeencounteredinsomebenignlesions.Therefore,thedefinitivediagnosisofmalignancyinpheochromocytomasisbasedonthepresenceofmetastases.Thesemayinvolveregionallymphnodesaswellasmoredistantsites,includingliver,lung,andbone.
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Fig.20.44Pheochromocytoma.Thetumorisenclosedwithinanattenuatedcortexanddemonstratesareasofhemorrhage.Thecomma-shapedresidualadrenalglandisseen(lower portion).