Neutrophilic skin infiltrates in patients with acute myeloid leukemia (AML) are clonal and associate with poor overall survival

Background: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy. While blast infiltration (leukemia cutis, LC) is a known extramedullary disease, reactive neutrophilic dermatoses (like Sweet's syndrome) are common, but their etiology remains unclear. We aimed to determine if these lesions represent an atypical leukemic process. Methods: We analyzed the clinical and molecular characteristics, including survival outcomes, in 1,019 consecutive AML patients for histopathologically evaluated skin lesions (10 days prior and up to 60 days post-diagnosis). Patients with reactive neutrophilic dermatoses underwent confirmation for absence of leukemic blasts. We then performed paired tumor/normal whole-exome sequencing on bone marrow (BM) and FFPE-derived skin biopsy tissues for 8 such patients. Results: Dermatology consultation was required in 31% of patients. While reactive inflammation generally showed high complete remission (CR) rates (91%), patients with reactive neutrophilic dermatoses had the shortest disease-free survival (DFS) of all patient groups, with a median DFS of only 13 months. Clinically, these patients frequently harbored NPM1 (27%), IDH1/2 (41%), and FLT3-ITD (23%) mutations. Next, we sequenced paired samples from 4 patients whose skin lesions were confirmed as blast-free. Remarkably, sequencing of the skin lesions revealed AML gene mutations identical to those found in the BM blasts, with near-identical variant allele fractions (VAFs) in both tissues. Three of four patients also harbored mutations in genes encoding keratin-associated proteins. Conclusions: Morphologically normal, mutationally clonal, neutrophilic infiltrates represent a distinct extramedullary manifestation of leukemia that differs from classical leukemia cutis but has significant clinical and biological relevance (poor survival). A similar phenomenon is known for chronic myelomonocytic leukemia (CMML). If validated, this may identify an underappreciated type of leukemic involvement and possible escape mechanism.