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modpathol2016248a PGL-PCC.pdf (6.38 MB)

Biologic and Genetic Basis of a Histological Risk Assessment of Early Recurrence/Metastasis in Paragangliomas

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posted on 2017-03-23, 17:49 authored by Salvador J. Diaz-CanoSalvador J. Diaz-Cano, Nadia Talat, Alfredo Blanes, Klaus-Martin Schulte
Background: Mid-term outcome information in risk stratified patient cohort is needed to inform prognosis in individual patients with paragangliomas (PGL), adjuvant therapy choice and future research. The objective is to define the genetic features setting a PGL histological risk stratification scheme of early recurrences/metastasis. Design: A classification scheme for PGLs was devised, and specimens were assessed for invasion capacity (infiltrative edges, extra-adrenal extension, capsular and peritumoral vascular invasion), tumorigenic expansion, necrosis, and mitogenic activity. Patients were prospectively stratified as low histological risk (LHR) or high risk (HHR, presence of at least one feature of invasive capacity and two features of tumorigenic expansion). Patients underwent regular treatment and follow-up for their PGLs in a tertiary referral center. Whole-exome sequencing was performed on tumor and normal tissue samples, using a Random Forest machine learning approach to compare LHR vs. HHR for early recurrence/metastasis. Predictive Model Analysis Pipeline and Methods ► Functional somatic mutations unique to tumors were identified and represented as a samples x genes mutation matrix (mutated=1, non-mutated=0). ► Pairwise Random Forest models were built for each diagnostic category ► Variable selection was conducted using Fisher's Exact test with 5x10 fold cross validation design, measuring predictive accuracy in independent test sets. Results: Disease-free survival was significantly lower in HHR patients 0% vs 78.4% (p=0.004). Histological risk stratification predicts DFS with AUC of 0.8 (95% CI: 0.69-0.90; p<0.01). 7/37 HHR patients had a synchronous diagnosis of malignancy based on other criteria and four patients suffered a local recurrence. The HHR-predictive genes included ARID1A (P=5.13E-09), AKT3 (P=3.57E-08), MAX gene associated (P=6.86E-11), PIK3CA (P=1.35E-09), ELK3 (P=8.03E-16), MAP3K12 (P=4.17E-21), and TP53 (P=3.12E-40), being the accumulation of genetic abnormalities the best predictor. Conclusions: Histologic risk stratification of early recurrence/metastasis is genetically defined by the accumulation of alterations in the proliferation and cell survival pathways. A high-risk status is associated with high risk of malignancy and disease recurrence.

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