Evidence of Differentiation in Myeloid Malignancies Associated Neutrophilic Dermatosis

Neutrophilic dermatoses are a group of disease characterized by dense infiltrate of mature neutrophils that are typically located in the upper dermis. Around 20 percent of patients with Sweet's syndrome have an underlying haematological malignancy, especially myeloid neoplasm, but the pathophysiology of this association is unknown. We formulated the hypothesis that skin infiltrating neutrophils are differentiated from the malignant clone in myeloid malignancies associated with neutrophilic dermatosis.

We studied 20 patients with neutrophilic dermatosis (19 Sweet Syndrome and 1 pyoderma gangrenosum) associated with an haematological malignancy diagnosed in a tertiary care hospital between 2004 and 2009. To test the hypothesis of “differentiated” infiltrate, we assessed the clonality of the infiltrate by Fluorescent In Situ Hybridization (FISH) on skin biopsy in patients (n= 6) with recurrent clonal cytogenetic abnormality. FISH was performed either on formalin fixed paraffin-embedded specimen (n=5) or on frozen specimen (n=1).

Compared with patients with lymphoid neoplasm (n=5), patients with an underlying myeloid neoplasm (n=15, AML n= 7, MDS n=6, MPN n=2) were more often febrile (93% vs 0%, Fischer Test p<0.001), more prone to have extracutaneous neutrophilic infiltration (33% vs 0%), and more often treated with general corticosteroids (73% vs 14%), which probably reflects more aggressive disease. These unrecognized clinical discrepancies may reflect differences in the mechanisms that drive dermic invasion by neutrophils.

Cytogenetic study (FISH) was performed on skin biopsy from 6 patients with MDS or AML. Blastic cells were never observed in the skin lesions, neither with standard histology nor with anti CD34 immunohistochemical staining in ambiguous cases. In 4 patients, we found that the vast majority of the neutrophils in the skin carried the cytogenetic abnormality found in blast cells on bone marrow analysis (Table 1 ). In one of these patients, the absolute neutrophil count was less than 100/mm³ when the eruption began, suggesting that the differentiation occurred in the dermis itself.

This study is the first demonstration that infiltrating neutrophils in neutrophilic dermatosis are clonally related to the underlying myeloid malignancy. In these cases, we conclude that neutrophilic dermatosis is a manifestation of differentiation of the underlying myeloid malignancy. This observation explains the clinical similarities between the neutrophilic dermatosis and the differentiation syndrome observed in APL patients under ATRA, namely the high fever, the possibility of neutrophilic invasion and the dramatic response to corticosteroids.

Five more patients are currently being studied (and will be presented) to confirm these results. Further studies will be necessary to test if differentiated neutrophils present functional abnormalities that explain their ability to invade skin.

No relevant conflicts of interest to declare.