KRAS and GNAS Co-Mutation in Metastatic Low-Grade Appendiceal Mucinous Neoplasm (LAMN) to the Ovaries: A Practical Role for Next-Generation Sequencing

Abstract

Patient: Female, 49Final Diagnosis: Metastatic LAMNSymptoms: Abdominal discomfortMedication: —Clinical Procedure: Laparoscopic total abdominal hysterectomy • bilateral salpingo-oophorectomy • complete supracolic omentectomy • appendectomySpecialty: OncologyObjective:Unknown ethiologyBackground:Low-grade appendiceal mucinous neoplasms (LAMNs) are cytologically low-grade tumors of the appendix and are a frequent cause of pseudomyxoma peritonei. They can become a diagnostic challenge when they metastasize to the ovaries, where they may mimic primary ovarian mucinous tumors.Case Report:We report the case of a patient with very large bilateral ovarian mucinous tumors and a concurrent minute LAMN incidentally discovered in a grossly normal appendix. A primary ovarian tumor was suspected, but histological analysis of the ovaries suggested an appendiceal origin. Immunohistochemical studies were not informative and a consensus regarding the source of the ovarian tumors could not be reached within our department. Subsequent next-generation sequencing of tumors from the right ovary, left ovary, appendix, and matched normal tissue demonstrated identical somatic point mutations in KRAS and GNAS present in all tumors. The patient was diagnosed with metastatic LAMN and did not receive further treatment. She remains disease-free after 15 months of close observation.Conclusions:Determining the tissue of origin in low-grade mucinous tumors of the ovaries can be challenging when a concurrent LAMN is identified in the appendix. In cases where histology and immunohistochemistry are insufficient to render a diagnosis, the presence of concurrent KRAS and GNAS mutations in both tumors strongly favors a diagnosis of metastatic LAMN. We emphasize the utility of targeted next-generation sequencing to establish tissue of origin in challenging cases when LAMN is suspected as the source of mucinous ovarian tumors.

Mutation profile of high‐grade appendiceal mucinous neoplasm

“…In agreement with our results, several previous reports have also identified KRAS and GNAS co‐mutations in LAMN and associated MCP at similar frequencies, but their roles in the pathogenesis of LAMN/HAMN were unclear. KRAS is a proto‐oncogene encoding a protein that mediates the mitogen‐activated protein kinase (MAPK) pathway, which plays a pivotal role in cellular proliferation and differentiation .…”

Using protein microarray to identify and evaluate autoantibodies to tumor‐associated antigens in ovarian cancer

“…The mutations in KRAS and GNAS were identified in a series of mucinous ovarian tumors, and the presence of concurrent KRAS and GNAS mutations was also observed. Both of these mutations were associated with oncogenesis 50 . Ryland et al 49 also demonstrated that there was a significant difference in p53 mutation frequency among the three tumor subtypes ( P = .003), suggesting that aberrant p53 contributes to the invasive phenotype in a proportion of these OCs.…”

International study of primary mucinous ovarian carcinomas managed at tertiary medical centers

“…The genomic analysis of PMOC may identify key driver mutations and therapeutic targets, aid in establishing an accurate diagnosis, and stratify patients to appropriate treatment (20). However, it is critical that expert pathologists carefully review all banked tumor specimens with well-annotated correlative clinical data, particularly in stage II and greater cases, to ensure the tumor studied is indeed a PMOC.…”