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sweet s syndrome , or acute febrile neutrophilic dermatosis , is characterized by fever , neutrophilia , multiple painful asymmetric erythematous cutaneous plaques , dermal infiltrates consisting of mature neutrophils and rapid response to steroid therapy .
sweet s syndrome is associated with malignancy , most typically with acute myelogenous leukemia , in almost 1020% out of all its cases .
all - trans retinoic acid ( atra ) induces complete remission out of a large proportion of patients suffering from acute promyelocytic leukemia ( apl ) .
compared with conventional cytotoxic anticancer drugs , atra is considered relatively safe with only a few side effects .
cases of sweet s syndrome associated with atra have scarcely been reported worldwide , however . the cases of sweet s syndrome related with atra mean a big challenge to physicians .
it is because sweet s syndrome appearing with atra treatment should be differentiated from the possibility of infectious conditions .
we report a patient with apl who developed fever and multiple painful erythematous skin lesions during atra treatment .
a 35-year - old korean woman presented with dizziness , dyspnea on exertion , ecchymoses and menorrhagia .
investigation showed a hemoglobin of 3.5 g / dl , a hematocrit of 10.8% , a white blood cell count of 18.0810/l ( 70% promyelocytes , 14% band and polymorphonuclear cells , and 11% lymphocytes ) , and a platelet count of 2910/l .
bone marrow aspirate and biopsy showed hypercellular marrow with 31% myeloblasts and 38.5% hypergranulated promyelocytes containing auer rods with faggot formation . by flow cytometric analysis , leukemic cells expressed cd13 and cd33 .
cytogenetic analysis showed the characteristic t ( 15;17 ) translocation in 12 of 18 metaphases .
pml / rara mrna was also detected by the reverse transcription polymerase chain reaction ( rt - pcr ) method .
fever developed during the evaluation period and empirical antibiotics , including a third generation cephalosporin combined with an aminoglycoside were started .
induction therapy with atra was initiated at a dose of 70 mg / day ( 45 mg / m / day ) .
on the 4th day from the start of atra , white blood cell count increased up to 28.310/l and chemotherapy with idarubicin ( 12 mg / m / day for 3 days ) and cytarabin ( 100 mg / m / day for 7 days ) was instituted . on day 24 , multiple painful erythematous plaques appeared on both cheeks , right wrist and both shins and the temperature rose to 40c . at that point ,
all blood cultures and urine cultures were negative ; her chest x - ray was unremarkable . skin biopsy was performed from both cheeks and left shin , which revealed a dermal infiltrate of mature neutrophils and subepithelial edema ( figure 2 ) .
all - trans retinoic acid was discontinued and oral prednisone ( 1 mg / kg / day ) started to be administered . as a result , her lesions were outstandingly improved within 48 hours without recurrence after tapering the corticosteroids . on day 37 , bone marrow aspiration and biopsy with cytogenetic analysis and rt - pcr were repeated and complete remission was confirmed based on the above studies .
sweet s syndrome develops under lots of conditions such as autoimmune disorders , infections , hematologic malignancies and solid tumors .
there are some differences between idiopathic sweet s syndrome and the malignancy - associated one in terms of clinical characteristics .
idiopathic sweet s syndrome is mainly found in middle - aged women with a prior upper respiratory tract infection .
it is characterized by fever , neutrophilia , an elevated erythrocyte sedimentation rate and a neutrophilic dermal infiltrate .
the skin lesions are mostly found on the upper extremities , head and neck in the forms of red pseudovesicular plaques and nodules .
in contrast to idiopathic sweet s syndrome , sweet s syndrome shown in patients with hematologic malignancy is characterized by no sexual predilection , typical and/or more severe ( vesicular , bullous , ulcerative ) cutaneous lesions , extracutaneous involvement in nearly 50% of the patients , absence of neutrophilia in over one - half of the patients , frequent anemia and abnormal platelet counts and a high rate of recurrence which often herald a tumor relapse .
importantly , the onset of sweet s syndrome occurred prior to or coincident with that of the associated malignancy in nearly two - thirds of these patients .
corticosteroids are the treatment of choice for both idiopathic and malignant - associated sweet s syndrome . besides many conditions related with sweet s syndrome , only a few drugs seem to be associated with it .
atra causes the brief proliferation of the malignant cells through maturation , terminal differentiation and ultimately apoptotic death of the cell via binding to rar. by the introduction of induction therapy with atra into the treatment of apl , high complete remission rates ( 80% to 90% ) in apl patients could be attained without the toxic effects of the standard chemotherapy
. however , there are side effects with atra ; headache , bone pain , intracranial hypertension , hypertriglycemia , lymphadenopathy , hypercalcemia , liver function impairment , skin pruritus , bone marrow necrosis , thromboembolic events , retinoic acid syndrome and rarely , in a few cases , sweet s syndrome .
but the role of the immunologic mechanism can be inferred from the following three : the clinical response to corticosteroids , systemic organ manifestation , and the similarity to other hypersensitivity reactions .
also , the role of g - csf in pathogenesis is suspected by the fact that sweet s syndrome may develop during g - csf administration for granulocytopenia .
the increase of il-1 and g - csf production in the presence of atra was highly correlated to the increase in apl cell count . in this case , the leukocyte count was increased from the initial state during atra treatment .
cases with increased white blood cell counts during atra administration were reported , and even the occurrence of retinoic acid syndrome following on sweet s syndrome was reported .
the association of g - csf level with sweet s syndrome and leukocytosis is not proved in these cases because serum g - csf measurement was not done . to elucidate the pathogenesis ,
it is recommended that various cytokines , including g - csf , be measured when sweet s syndrome is suspected .
one of the most important clinical differential diagnoses of sweet s syndrome is an infectious condition . in this case
the authors launched prompt and thorough investigation for all possible foci of infection because neutropenia is strongly correlated with an increased risk of infection , and delay in therapy may even be fatal .
especially , it is very important to discern the characteristic skin lesions associated with infections , like ones by clostridium spp , candida spp , and pseudomonas aeruginosa , in febrile neutropenic patients , for it makes the appropriate therapy to bo taken promptly . in this
regard , skin lesions in febrile neutropenic patients provide important clues to accurate diagnosis and warrant immediate biopsy .
in addition to infectious conditions , sweet s syndrome should be one of the differential diagnoses in febrile neutropenic patients with skin lesions .
when sweet s syndrome is not considered , it is so difficult to differentiate infection from sweet s syndrome that the use of antibiotics could be continued too long and the use of corticosteroid could be delayed . in conclusion , it is important to notice the side effects and complications caused by the treatment of apl with atra because sweet s syndrome is not simply differentiated from infection .
unexplained fever and skin lesions , shown in neutropenic patients during atra administration , require us to be alert to the possibility of infection and atra - induced side effects , including sweet s syndrome .
all - trans retinoic acid ( atra ) is the standard induction treatment for acute promyelocytic leukemia ( apl ) . 
 quite many atra - related side effects , including retinoic acid syndrome , were reported . 
 so far , it has rarely been reported that sweet s syndrome , characterized by fever , neutrophilia , painful erythematous cutaneous plaques , dense dermal infiltrates of mature neutrophils and rapid response to steroid therapy , is associated with atra . in the case that sweet s syndrome associated with atra is found , physicians will have to face a great challenge over the possibility of infectious conditions . 
 we present here a case of sweet s syndrome associated with atra . a 35-year - old female with apl developed fever , painful erythematous cutaneous plaques on both cheeks , right wrist and both shins during induction chemotherapy with atra . 
 a skin biopsy revealed a dense dermal infiltrate , consisting of mature neutrophils without vasculitis or cutaneous immunoglobulin deposits , which is compatible with sweet s syndrome . 
 oral prednisone was administered and the lesions started to improve within 48 hours .