Objectives: • Recognize histiocytoid Sweet syndrome (HSS) as a potential dermatologic manifestation of MDS and AML. • Assess the role of hypomethylating agents (decitabine and azacitidine) in triggering HSS.

Introduction: Sweet syndrome (SS) is an acute febrile neutrophilic dermatosis, and its histiocytoid variant (HSS) is a rare, yet increasingly recognized form characterized as an infiltrate of immature myeloid cells that resemble histiocytes. Common triggers of HSS discussed in literature include underlying hematologic malignancies, especially MDS, as well as certain drugs, including hypomethylating agents 1, 2, 3, 4. These cases mainly focus on the initial presentation of HSS but to our information, no published case reports have described occurrence and recurrence of HSS by two distinct hypomethylating agents. We present a case of elderly female patient with MDS with progression to AML who initially presented with biopsy-diagnosed HSS and had recurrence of HSS after initiation of Azacitadine. Recognizing this rare syndrome and its common triggers can have significant diagnostic and therapeutic implications.

Case Presentation: An 83-year-old woman with a history of DCIS and newly diagnosed MDS-EB-2, who had completed her first cycle of decitabine one week earlier, presented with a painful ulcerative lesion on the left lower extremity along with widespread purple papules and plaques. A skin punch biopsy demonstrated histiocytic and neutrophilic inflammation consistent with the diagnosis of Histiocytoid Sweet syndrome. Patient was initially treated with topical steroids with improvement of her dermatologic symptoms. Of note, during this time, patient did not receive any additional Decitabine therapy and had lab findings significant for 28% blasts, consistent with progression of disease to AML. Given new diagnosis AML, patient was started on Azacitidine (and Venotoclax) with recurrence and worsening of her rash requiring topical and oral steroids.

Discussion: This case highlights several important and underrecognized aspects of histiocytoid Sweet syndrome (HSS) in myeloid malignancies. HSS is most often triggered by underlying hematologic disease, such as MDS or AML, and by certain chemotherapy agents. While decitabine and azacitidine have both been linked to Sweet syndrome, we found no prior reports of sequential HSS flares from two different hypomethylating agents in the same patient. Our patient first developed biopsy-proven HSS shortly after receiving decitabine and during progression of MDS to AML. The timing suggests that both the progression of her leukemia and exposure to decitabine may have played a role. It remains unclear whether worsening hematologic disease itself increases the risk of HSS, or whether drug exposure simply unmasks the underlying inflammatory response. The second episode, following initiation of azacitidine, is also notable. While azacitidine-induced Sweet syndrome has been documented, recurrence with another hypomethylating agent has not been reported. Our case suggests that in some patients, the broader class of hypomethylating agents may predispose to recurrence of HSS, especially when underlying disease is active. Overall, this case adds to the limited literature on drug-induced HSS and raises important clinical questions: Does disease progression increase susceptibility to Sweet syndrome? Should clinicians be cautious about recurrence of Sweet syndrome when re-exposing patients to similar hypomethylating agents? Answering these questions will require further study, but awareness of this potential complication is key to early recognition and treatment.