Abstract
Background There are limited effective systemic therapies for refractory or unresectable lymphatic malformations (LM). Due to the prevalence of activating PIK3CA mutations in LM, mTOR inhibitors have been used in unresectable LM; however, only a subset of patients respond. Given the need for improving therapies in LM, we examined the genomic landscape of LMs, which identified two mutually exclusive genomic subtypes with strong histologic-genomic correlations. Methods 30 LM underwent comprehensive genomic profiling using a hybrid-capture based next-generation sequencing panel of 300-plus cancer genes. Pathology reports were reviewed for patient demographic data, specimen site, and IHC results. Histopathologic features were reviewed by a board-certified dermatopathologist. Results The patients had a median age of 9 years (range 1 – 45). Seven patients had a history of prior mTOR inhibitor treatment. Seven patients carried diagnoses of overgrowth syndromes. Twelve patients had multifocal disease and eight patients had involvement of bone and visceral sites. Genomic profiling detected activating hot-spot alterations in PIK3CA (67%), and NRAS (16.7%). Of the five patients (16.6%) with no alterations in PIK3CA and NRAS, one patient had an activating GOPC-ROS1 fusion. Histologic evaluation showed 26 LM had conventional morphology; of these, 77% were PIK3CA-mutant while 1 sample (a small core needle biopsy of a large visceral tumor) was NRAS-mutant. In contrast, the 4 LM with kaposiform cytomorphology were all NRAS-mutant, consistent with enrichment of NRAS mutation (< 0.05) and lack of PIK3CA mutation in this histologic subtype (p < 0.05). Discussion Our findings establish that LMs with conventional and kaposiform histology have distinct, but potentially targetable, driver mutations. Importantly PIK3CA mutant LM may be highly responsive to PI3K inhibitors, thus offering a non-surgical option for lymphatic, vascular and other benign tumors with similar driver mutations.Financial Disclosure: The oral presenter listed below disclosed the following information about their financial interests. The ASDP Ethics Committee has reviewed these disclosures and determined that no conflicts of interest exist between financial relationships and educational content being presented:
| Speaker | Company | Affiliation/Relationship |
| Julie Tse, MD | Foundation Medicine, Inc. | Ownership Interest, Salary |