High-grade appendiceal mucinous neoplasm (HAMN) was recently proposed as a disease entity histologically analogous to low-grade appendiceal mucinous neoplasm (LAMN) but characterized by high-grade cytological atypia. The pathogenesis and clinical features of HAMN have not been fully elucidated.Nine cases of HAMN, 8 LAMN, 10 appendiceal mucinous adenocarcinomas (MACA) and 5 appendiceal serrated polyps resected between 2008 and 2017 contributed by three medical centers underwent targeted next generation sequencing of 50 cancer-related genes. The patients in each category had similar profiles with respect to gender, age, tumor stage, and follow-up intervals. Both LAMN and HAMN harbored mutations of KRAS (9/9 and 8/8 [100%], respectively) and GNAS (5/8 [63%] and 5/9 [56%], respectively) in significantly higher proportions than MACA (KRAS, 7/10 [70%, P=0.04]; GNAS: 1/10 [10%, P=0.02]) and serrated polyps (KRAS, 1/5 [20%, P=.0007]; GNAS: 0/5 [0%, P=0.04]). Four cases of HAMN, but none of LAMN, harbored mutations of TP53 (4/9 [44%]) and/or ATM (2/9 [22%]). Three cases of HAMN (33%) showed extraappendiceal spread with retention of the same mutational profiles in the intra- and extraappendiceal components. The 10 cases of MACA harbored a similar prevalence of TP53 mutations (n=5, 50%) as HAMN but, unlike LAMN and HAMN, some harbored mutations in PIK3CA, APC, FBXW7, PTEN, and SMAD4.HAMN and LAMN share high rates of KRAS and GNAS co-mutations supporting a common histogenesis and distinguishing them from MACA. Acquisition of TP53 or ATM mutations by HAMN may drive its progression to a more advanced phenotype. This article is protected by copyright. All rights reserved.
