Adrenocortical carcinoma (ACC) is a rare but aggressive malignancy. The Weiss criteria for malignancy include 9 histological parameters. Which molecular alteration, found in ~90% of pediatric and ~50% of adult ACCs, most strongly supports TP53 germline testing?

• A IGF2 overexpression due to loss of imprinting at 11p15 — present in most ACCs but not specifically linked to germline TP53
• B CTNNB1 (beta-catenin) activating mutation causing Wnt pathway activation — present in ~30% of ACCs
• C DAXX/ATRX mutations causing telomere instability — seen in pancreatic NETs and pheochromocytoma, not ACC
• D TP53 mutation/loss — especially R337H germline variant in Southern Brazilian patients (Li-Fraumeni spectrum); ACC diagnosis should prompt germline TP53 testing ✓

Explanation

TP53 germline mutations (Li-Fraumeni syndrome) are the most important germline association with ACC, and pediatric ACC in particular (where nearly all cases in Southern Brazil carry R337H TP53, a founder effect). Any patient diagnosed with ACC should be offered germline TP53 testing, as Li-Fraumeni syndrome predisposes to multiple cancers (osteosarcoma, brain tumors, leukemia, breast cancer). IGF2 overexpression (11p15 LOI) is the most frequent somatic alteration in adult ACC but does not specifically indicate germline TP53 risk; CTNNB1 mutations occur in ~30% but are somatic; DAXX/ATRX are relevant to pancreatic NETs.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.