• Rare, 0.5-2 cases per million annually in US
  
• No gender preference, mean age 50 years, small peak before age 20 years
  
• Associated with Li Fraumeni syndrome, Beckwith-Wiedemann syndrome and congenital adrenal hyperplasia
  
• 50% are functional and associated with virilizing and other syndromes; cannot determine function from morphology
  
• Lack of function may be due to deletions in enzymes required for cortisol synthesis
  
• Highly necrotic tumors may cause fever and clinically simulate an infectious process
  
• Tend to invade adrenal vein, vena cava, adjacent kidney and retroperitoneum; may cause thromboemboli
  
• Metastases to liver (60%), regional lymph nodes (40%), lungs (40%), peritoneal and pleural surfaces, bone, skin (anaplastic tumors) or retroperitoneum
  
• 2 year survival is 50%, 5 year survival is 20-35%
  

• Only definitive criteria for malignancy are distant metastasis or local invasion
  
• Often cannot differentiate between adenoma and carcinoma; call adrenocortical neoplasm, and estimate risk of recurrent or metastatic tumor
  
• In children, malignant appearing tumors often have good prognosis, particularly if < 5 years old at diagnosis, complete resection, tumor < 400g, < 15 mitotic figures/20 HPF and minimal tumor necrosis
  
  Original Weiss criteria for malignancy (Am J Surg Pathol 1984;8:163), modified as indicated below, requires 3+ of these factors:
  
  • Nuclear grade III or IV based on criteria of Fuhrman
    
  • > 5 mitotic figures/50 HPF (40x objective), counting 10 random fields in area of greatest number of mitotic figures on 5 slides with greatest number of mitoses
    
  • Presence of atypical mitotic figures (abnormal distribution of chromosomes or excessive number of mitotic spindles)
    
  • Clear or vacuolated cells comprising 25% or less of tumor
    
  • Diffuse architecture (more than 1/3 of tumor forms patternless sheets of cells; trabecular, cord, columnar, alveolar or nesting pattern is not considered to be diffuse)
    
  • Microscopic necrosis
    
  • Venous invasion (veins must have smooth muscle in wall; tumor cell clusters or sheets forming polypoid projections into vessel lumen or polypoid tumor thrombi covered by endothelial layer)
    
  • Sinusoidal invasion (sinusoid is endothelial lined vessel in adrenal gland with little supportive tissue; consider only sinusoids within tumor)
    
  • Capsular invasion (nests or cords of tumor extending into or through the capsule with a stromal reaction); either incomplete or complete
  
  
• Note: above criteria may not apply to childhood tumors
  
  Modified Weiss criteria (using 1 if above factor is present in tumor, 0 otherwise):
  
  • 2x mitotic rate score + 2x clear cytoplasm score + abnormal mitoses + necrosis + capsular invasion (score of 3 or more suggests malignancy, Am J Surg Pathol 2002;26:1612)

• Mitotic activity, venous invasion and weight of 50g+; diameter of 6.5 cm+, Ki-67/MIB1 labeling index of 4%+ and p53+ (Am J Surg Pathol 1997;21:556)
  

• 18 month boy with coexistent choroid plexus carcinoma, both tumors p53+ (Arch Pathol Lab Med 2002;126:70)
  
• MSH2 carrier without MSH2 mutation in adrenal tumor (Hum Pathol 2000;31:1522)
  
• 40g histologically benign tumor that metastasized (Arch Pathol Lab Med 1986;110:1076)
  

• Surgical excision; excision of solitary lung metastases
  

• Unencapsulated; large (200 g, 20 cm)
  
• Variegated cut surface due to hemorrhage, cysts and necrosis
  
• Often has soft, friable intratumoral nodules; often invasion of major veins
  

Large tumor with hemorrhage       250 g, 10 cm tumor

Large tumor compressing kidney

Large tumor dwarfing kidney      Large tumor displacing kidney and spleen

• Various growth patterns of well differentiated to anaplastic cells (giant cells with bizarre hyperchromatic nuclei)
  
• Capsular invasion, marked mitotic activity with atypical forms
  
• May have neutrophils, tumor giant cells, sarcomatoid features, eosinophilic globular inclusions and necrosis
  

Tumor cells have abundant    Polygonal cells with vascular   A: H&E; B: calretinin+ eosinophilic cytoplasm, mildly stroma and focal necrosis   C: MelanA+; D: inhibin negative pleomorphic and vesicular nuclei, prominent nucleoli

Capsular infiltration      Synaptophysin+         Adrenal vein invasion       Mitotic figure (arrow)

Various images

Adrenocortical carcinoma

• Single cells, poorly cohesive cell clusters in necrotic background and often, but not always marked nuclear atypia and mitotic activity
  
• Cytoplasm is vacuolated to densely eosinophilic
  

• Vimentin, MelanA / MART1 (Arch Pathol Lab Med 2002;126:170, Am J Surg Pathol 1998;22:57), synaptophysin and inhibin (usually, Mod Pathol 1998;11:1160)
  
• Also bcl2 (Mod Pathol 1998;11:716), adrenal 4 binding protein (regulates expression of steroid enzymes, Hum Pathol 1995;26:1154) and p53
  
• Variable synaptophysin, neurofilament, neuron specific enolase, calretinin, HepPar1, S100 and CAM 5.2
  

• CK7, CK20, EMA, CEA, B72.3 and chromogranin
  

• More likely to be aneuploid or tetraploid (Hum Pathol 1998;29:518), but ploidy is not helpful in determining behavior
  
• Malignant cases compared to adenomas usually show loss of heterozygosity (61%) at some loci; retinoblastoma gene (80%), p53 (44%), 9p (26%), 1p (22%) and 3p (22%)
  

• Tubular cristae in mitochondria and droplets of cytoplasmic fat
  
• Occasionally dense core granules (associated with neuroendocrine immunostains)
  

Figure 3D

• Adrenal cortical adenoma - see Weiss criteria above
  
• Adrenal medullary tumors - inhibin-, MelanA-, calretinin- and chromogranin+
  
• Hepatocellular carcinoma
  
• Renal cell carcinoma - usually contains glands which may contain red blood cells, glycogen+, keratin+, EMA+, CD10+, MelanA-, synaptophysin- and inhibin-
  
  

• 63 year old man with glandular and squamous differentiation (Arch Pathol Lab Med 1995;119:260)
  

• Metastases
  
  

• Has sarcoma-like elements
  

• 29 year old woman with virilization and rhabdomyosarcomatous elements (Am J Surg Pathol 1992;16:626)
  
• 79 year old man with osteoid differentiation and hyperaldosteronism (Am J Surg Pathol 1993;17:941)
  
  

• Negative for albumin ISH, which differentiates adrenal tumors metastatic to liver from liver primaries (Am J Surg Pathol 2000;24:177)
  
  

• Rare, < 20 cases reported (Am J Surg Pathol 2000;24:396)
• Presence of myxoid change does not appear to influence tumor behavior
  

• 38 year old man with myxoid change and extensive lipomatous metaplasia (Arch Pathol Lab Med 2003;127:227)
  
• 41 year old woman with coexisting parathyroid hyperplasia and pituitary tumor (Arch Pathol Lab Med 1979;103:635)
  
• With abundant acidic mucosubstances and a myxomalike appearance (Arch Pathol Lab Med 1994;118:1151)
  

• Atypical round cells with eosinophilic to vacuolated cytoplasm, stroma with copious mucinous materia
  

• Alcian blue; usual stains for adrenocortical carcinoma
  

• PAS, mucicarmine
  
  

• Rare, < 50 cases reported; ages 39-71
  
• Usually non-functional
  
• One tumor invaded the inferior vena cava and extended into the right atrium, another metastasized to bone
  
• Weiss system for malignancy not applicable because all tumors have eosinophilic tumor cytoplasm, diffuse architecture and nuclear atypia
  
• Better to use criteria of large tumor size, necrosis, invasion of vessels or adjacent tissue, extracapsular extension, metastasis (Mod Pathol 2002;15:973)

• Large yellow-tan tumors (8.5 to 17.0 cm), well-demarcated from adjacent kidney
  
• Thin rim of normal adrenal gland
  

Large multinodular yellow tumor with central necrosis

• Diffuse proliferation of polygonal cells with abundant granular and eosinophilic cytoplasm, large nuclei and prominent nucleoli
  
• Occasional mononuclear and binucleated giant cells
  
• Often extracapsular extension, blood vessel invasion and necrosis
  
• Variable atypia; rare mitotic figures
  

Cells have abundant eosinophilic  Cords of tumor cells separated  Large polygonal eosinophilic tumor cells cytoplasm and prominent nucleoli  by dilated sinusoids

Aggregates of foamy cells    AE1/AE3+            Inhibin+

• AE1-AE3, CAM5.2, variable inhibin
  

• Numerous mitochondria
  

Prominent nucleoli, perinuclear rough endoplasmic reticulum, mitochondria and lipid droplets

• Adrenocortical oncocytoma: well circumscribed, no capsular extension and no vascular invasion
  
• Conventional adrenocortical carcinoma
  
• Eosinophilic variant of chromophobe renal cell carcinoma: EMA+, microvesicles by EM
  
• Metastatic hepatocellular carcinoma: Hepar1 positive
  
• Pheochromocytoma: episodic hypertension, zellballen pattern, chromogranin+, S100+ in sustentacular cells and abundant dense-core membrane-bound granules on EM
  

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