A 28-year-old woman with Cushing's syndrome has suppressed ACTH on plasma assay, elevated 24h urinary cortisol, failure to suppress on high-dose dexamethasone, and unilateral adrenal mass on CT. Adrenalectomy specimen shows a 5 cm cortical tumor with 6 mitoses per 50 HPF, necrosis, and venous invasion. Using the Weiss scoring system, what is the threshold for malignancy and what is the most important molecular alteration distinguishing adrenocortical carcinoma from benign adrenocortical adenoma?

• A Weiss score ≥ 5 indicates malignancy; BRAF V600E mutation distinguishes ACC from adenoma
• B Weiss score ≥ 1 indicates malignancy; RAS mutation is the most common molecular alteration in ACC
• C Weiss score ≥ 3 indicates malignancy; methylation of the MGMT promoter is the molecular hallmark of ACC
• D Weiss score ≥ 3 indicates malignancy; IGF2 overexpression (at 11p15.5 due to loss of imprinting) is the most common molecular alteration in ACC, seen in >80% of cases, while TP53 mutations (Li-Fraumeni) and CTNNB1 (Wnt pathway) are other key alterations ✓

Explanation

The Weiss scoring system for adrenocortical tumors assigns one point each for: high nuclear grade (III/IV), mitotic rate > 5/50 HPF, atypical mitoses, clear cells ≤ 25%, diffuse architecture > 33%, necrosis, venous invasion, sinusoidal invasion, and capsular invasion. A Weiss score ≥ 3 indicates adrenocortical carcinoma (ACC). Molecularly, the most frequent alteration in ACC is biallelic loss of IGF2 imprinting at 11p15.5, causing overexpression of the growth factor IGF2 in >80% of cases, driving autocrine IGF1R-PI3K-AKT-mTOR signaling. TP53 mutations occur in ~25% (and account for ~70% of pediatric ACC in Li-Fraumeni syndrome). CTNNB1 (beta-catenin) mutations and ZNRF3 alterations (Wnt pathway) occur in ~15-20%.

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

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Written and medically reviewed by the StethoPrep medical team.