MON-505 Genetic Dissection by Whole Exome Analysis of Unilateral Coexisting Adrenal Cortical Adenoma and Carcinoma in the Context of MEN1 Syndrome

Abstract Disclosure: F. Cioppi: None. T. Orioli: None. G. Cantini: None. T. Ercolino: None. F. Cioppi: None. G. Assié: None. A. Jouinot: None. A.A. Dedonno: None. M. Maggi: None. M. Benelli: None. L. Canu: None. G. Nesi: None. M. Luconi: None. Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant inherited syndrome that predisposes to the development of multiple endocrine tumors including adrenal lesions. In the general population, adrenal masses occur with a 3% frequency, with a distribution of 80-85% of adrenal adenoma (ACA) or bilateral hyperplasia and 0.4-4% adrenocortical carcinoma (ACC). The occurrence of an adrenal incidentaloma dramatically increases in patients with MEN1 between 20-34%, where ACC cases raise up to 4.4-5.4%, according to the different cohorts, posing the problem of active surveillance with few predictors. In this MEN1 context, the possible evolution of a malignant from a benign lesion is particularly relevant to be clarified for the patient’s management. Malignant evolution from a benign form or the independent origin is still a matter of debate for adrenocortical tumors. Here, we report a unique case of a MEN1 patient operated for the rapid progression of a stable adrenal incidentaloma which was diagnosed as a large central ACC coexistent with a small peripheral ACA. Interestingly, the patient relapsed in 2-years in the diaphragmatic lodge. The availability of samples from the two coexistent masses and recurrence allowed a unique comparative pathological characterization associated with a deep genetic profiling by Whole Exome Sequencing (WES) of the three masses with the aim of assessing a collision hypothesis of the origin of the benign and malignant masses versus a sequence progression hypothesis, in a MEN1 presentation. Comparative immunohistochemistry confirmed the malignant features shared by the recurrence and ACC (marked positivity for SF1 and TP53, high Ki67, with disruption of the reticulum), while ACA was almost negative for Ki67, TP53, with intact reticulum. Expression profile signatures coherently classified ACA and ACC. WES analysis revealed a different mutational pattern between the benign and malignant forms with a total of 169 and 81 somatic Single Nucleotide Variants (SNVs) exclusively present in the benign (ACA) and in the malignant (ACC+recurrence) tissues, respectively. Among them, none SNV in known ACA-predisposing genes has been identified in the ACA sample. Conversely, a missense mutation in the exon 5 of TP53 (NM_000546.6:c.376T>G, p.Tyr126Asp) along with a NF1 donor splice site mutation (NM_001042492.3:c.4333-1G>C) were reported in both ACC and recurrence. TP53 and NF1 genes are well-known driver genes in ACC, and their alteration in the malignant forms suggests that they are mainly involved in the clonal evolution of the patient’s ACC. Interestingly, MEN1 locus showed Loss of Heterozygosity (LOH) in both ACC and recurrence but not in ACA. These findings support the hypothesis of an independent origin of the malignant and benign adrenocortical tumors, and remark the importance of tumor profiling by WES towards a better clinical management of these patients. Presentation: Monday, July 14, 2025