Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2016 Jun 1.
Published in final edited form as: Clin Lymphoma Myeloma Leuk. 2014 Dec 24;15(6):358–363. doi: 10.1016/j.clml.2014.12.009

Characteristics of Sweet's syndrome in patients with acute myeloid leukemia

Syed M Kazmi 1,#, Naveen Pemmaraju 2,#, Keyur P Patel 3, Philip R Cohen 4, Naval Daver 2, Kathy M Tran 2, Farhad Ravandi 2, Madeleine Duvic 5, Guillermo Garcia-Manero 2, Sherry Pierce 2, Aziz Nazha 2, Gautam Borthakur 2, Hagop Kantarjian 2, Jorge Cortes 2
PMCID: PMC4457594  NIHMSID: NIHMS658632  PMID: 25630528

Abstract

Introduction

Sweet's syndrome (SS) is associated with hematologic malignancies including acute myeloid leukemia (AML).

Methods

Patients with AML treated at our institution were reviewed to identify those with SS. Patient characteristics, laboratory values, and cytogenetic and molecular abnormalities were retrospectively reviewed.

Results

We identified 21 out of 2,178 (1%) AML patients that demonstrated clinical signs and symptoms, and histological features consistent with SS. Eleven patients (52%) were classified as AML with myelodysplasia-related features while three patients had therapy-related AML. Three patients had received treatment with granulocyte colony stimulation factor, one patient liposomal all-trans retinoic acid and two patients received hypomethylating agents prior to development of SS. Cytogenetic analysis revealed diploid karyotype in seven patients (33%), -5/del(5q) in eight patients {38%; three patients had -5/del(5q) as sole abnormality and five patients had -5/del(5q) as part of complex cytogenetics}, and complex cytogenetics in five patients (24%). Gene mutations in fms-related tyrosine kinase-3 (FLT3) gene were identified in seven of 18 evaluable patients (39%), including FLT3 –internal tandem duplication in four patients and FLT3 -D835 tyrosine kinase domain mutation in three patients.

Conclusions

SS occurs in 1% of AML patients; -5/del(5q) karyotype, FLT3 mutations, and AML with myelodysplasia-related features were more frequent among patients with SS.

Keywords: Acute myeloid leukemia, Myelodysplastic syndrome, Sweet's syndrome, -5/del(5q), fms-related tyrosine kinase-3

Introduction

Sweet's syndrome (SS), or acute febrile neutrophilic dermatosis, is characterized by recurrent fevers and presence of a dense papillary or upper reticular dermal infiltrate of normal appearing mature polymorphonuclear cells (PMNs).1, 2 SS was originally reported by Robert Douglas Sweet in 1964, when he described a case series of eight women between the ages of 32 and 55 years, who presented with fever, tender erythematous cutaneous plaques, neutrophilia and a dense neutrophilic infiltrate in the upper dermis on the histology. All eight patients responded promptly to glucocorticoid therapy.3 Generally, the cutaneous lesions in SS manifest as erythematous plaques and nodules of variable size that mostly involve the extremities or head and neck and less frequently trunk, back and mucosal surfaces.4 SS can occasionally cause an intense systemic response involving the lungs, liver and musculoskeletal system, sometimes resulting in shock, multi-organ failure and death. However, in most instances the manifestations of SS may be reversible with rapid initiation of glucocorticoid therapy.5-7

SS is frequently idiopathic; however, in a minority of cases a possible etiologic association can be identified with infections, autoimmune disorders, medications (drug associated Sweet's syndrome, DA-SS) or malignancies (also called malignancy-associated Sweet's Syndrome; MASS). Von den Driesch in 1994 proposed the currently used diagnostic criteria for SS, in turn a modification of diagnostic criteria for SS previously proposed by Su and Liu. These criteria consist of major and minor criteria (see patients and methods). Both major and at least two minor criteria must be fulfilled to confirm a diagnosis of SS.4, 8 Fever, neutrophilia and elevated ESR remain part of the diagnostic criteria for idiopathic SS and MA-SS, however, these findings can occasionally be absent in MA-SS.9 For DA-SS, the diagnosis requires establishment of a temporal association between development of SS rash, initiation of therapy with the responsible drug, and improvement once the drug is withheld.10

MA-SS, constituting only 15-20% of cases of SS, has been reported in association with both hematological and visceral malignancies, with acute myeloid leukemia (AML) being the most common malignancy associated with MA-SS.11-14 SS may also occur as a paraneoplastic condition in other hematological conditions such as myelodysplastic syndrome (MDS), B and T cell non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), myeloproliferative neoplasms (MPN), or in the setting of visceral malignancies such as genitourinary, breast or colorectal cancer. In MA-SS the cutaneous manifestations of SS can occur before, during or after the diagnosis of the malignancy and thus its onset may herald the diagnosis of malignancy in individuals with no prior malignancy or may indicate a recurrence in patients with a prior history of cancer.2, 15 In SS associated with hematological diseases such as AML, MDS and MPN, the PMNs in the dermal infiltrate may be clonally derived from either the malignant or non-malignant cells.16-18 Occasionally, malignant cells can be found among the PMNs (representing concurrent leukemia cutis.18 Similarly, medications used in management of hematological malignancies such as granulocyte colony stimulation factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), all-trans retinoic acid (ATRA) and hypomethylating agents such as azacytidine and decitabine have been associated with SS, supporting the role of cytokines, maturation defects and epigenetic changes in the pathogenesis of SS.15, 19-24

Although AML is the most common hematological malignancy associated with SS, the exact incidence and molecular characteristics of AML patients who develop SS remains undefined. In this study, we sought to identify specific disease features and cytogenetic or molecular aberrations occurring in patients with AML and SS.

Patients and Methods

The charts of all patients with AML who had been diagnosed, received treatment, and had follow-up at MD Anderson Cancer Center (MDACC) between January 2000 and December 2011 were retrospectively reviewed after receiving approval from our Institutional Review Board (IRB, protocol, PA11-0878). Patients who had a skin biopsy during the management of AML were identified and only patients with skin biopsy consistent with neutrophilic dermatosis (Sweet's syndrome) were included. To identify the patients who met von den Driesch-modified Su and Liu diagnostic criteria for SS, the clinical characteristics were reviewed. This diagnostic criteria consists of major criteria (i.e. abrupt onset of tender erythematous papules and nodules, and dense neutrophilic infiltrate in the dermis without leukocytoclastic vasculitis) and minor criteria including: presence of fever > 38°C, at least two of four abnormal laboratory values (WBC>8000, neutrophils >70%, ESR >20mm/hour and positive C - reactive protein), a disease condition associated with SS (e.g., infections, malignancies, inflammatory disorder etc.) and an excellent response to treatment with glucocorticoids. To diagnose SS, both major criteria and at least two minor criteria had to be fulfilled. Patients who fulfilled the von den Driesch diagnostic criteria were included in our analysis. Patients were excluded from this analysis if the clinical signs and symptoms were consistent with skin infection, abscess or if infectious organisms were isolated from skin culture. Similarly, patients were excluded if the signs and symptoms or skin biopsy were more consistent with other causes of neutrophilic dermatosis (such as pyoderma gangrenosum) or if there was histological evidence of vasculitis. In addition, patient characteristics, and AML characteristics at initial diagnosis and at the time of diagnosis of SS were reviewed. The later included cytogenetics and molecular aberrations by banding karyotype, fluorescence in situ hybridization (FISH) analysis, and reverse transcriptase polymerase chain reaction (RT-PCR).

Additionally, after obtaining separate IRB protocol approval from our institution (PA13-0840), FLT3 mutational analysis (codon 835 and ITD) was performed on DNA extracted from formalin fixed paraffin embedded (FFPE) tissue sections of the skin lesions from patients who were found to have FLT3 mutations, using previously described methods.25

Descriptive statistics including median, and range for continuous variables such as age and laboratory measurements, and time to improvement of SS signs and symptoms are provided. Frequency counts and percentages for categorical variables such as gender, classification of AML, and cytogenetic and genetic mutations expression are also described. Kaplan-Meier method was used for analysis of overall survival from diagnosis of AML and reported as median months with a 95% confidence interval. Statistical software IBM SPSS Statistics 19.0 (IBM Corp., Armonk, NY) was used for the statistical analyses.

Results

A total of 2,178 newly diagnosed AML patients underwent induction chemotherapy and had follow-up at our institution between year 2000 and 2011. Six hundred and ninety-seven patients (32%) had documented skin biopsies during the course of their AML therapy or during follow-up during this time period. Twenty-nine of these patients received a histological diagnosis of neutrophilic dermatosis. Of these, eight patients did not meet the von den Driesch modified criteria for diagnosis of SS (three patients were considered to have skin infections as the underlying etiology, four patients had neutrophilic dermatosis but not SS based on histological assessment by pathologist, and one patient was diagnosed with vasculitis). Thus, 21 patients met the von den Driesch modified criteria for diagnosis of SS and were included in our analysis. This represents approximately 1% of all AML patients treated at our institution in the stated time frame and 3% of all AML patients who underwent skin biopsy.

Table 1 summarizes the baseline characteristics of the patients at the time of diagnosis of AML and SS. Median age at diagnosis of AML and SS was 55 years (range, 27-87) and 56 years (range, 27-83), respectively. The majority of SS patients in this analysis were female (66%). At the time of diagnosis of AML the median percentage of myeloid blast cells in the bone marrow, median absolute neutrophil count (ANC), median hemoglobin (Hgb), and median platelet count at diagnosis of AML were 43% (range, 14-92%), 0.8 × 109/L (range 0.1-45), 9 g/dl (range 7.3-11), and 52 ×109/L (8-156), respectively. Based on the 2008 revised World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia, 11 patients (52%) were classified as having AML with MDS-related features, 3 patients (14.5%) each as AML with recurrent genetic abnormalities or as therapy related AML, and 4 patients (19%) were classified as AML not-otherwise specified (AML-NOS).26 Of note, one patient in our population had past medical history of relapsing polychondritis (a disease entity that has a known association with SS),27, 28 before the diagnosis of AML and SS, and had been treated with high dose steroids in the past for polychondritis.

Table 1.

Sweet's Syndrome (SS) in acute myelogenous leukemia (AML) patients

Patient characteristics N Percentage or (Range)
Total AML patients 2178
Total patients undergoing skin biopsies during treatment of AML 697 32%
Patients fulfilling diagnostic criteria of SS1 21 1% of all patients
3% of all patients biopsied
Age
    At diagnosis of AML 55 (27-87)
    At diagnosis of SS 56 (27-83)
Gender
    Female 14 / 66%
Laboratory values at diagnosis of AML
    Median Total white cell count (WBC; 109/L) 4.5 (1.1-116.6)
    Median AML Blast % 43 (14-92)
    Median absolute neutrophil count (ANC; 109/L) 0.8 (0.1-45)
    Median hemoglobin (Hb; g/dl) 9 (7.3-11)
    Median platelets (109/L) 52 (8-156)
Classification of AML (2008 WHO)
    AML with recurrent chromosomal abnormalities 3 14.5%
    AML related to MDS 11 52%
    Therapy related AML 3 14.5%
    AML NOS 4 19%
SS diagnosis before allogeneic SCT 5/6 83%
Status of AML at time of SS diagnosis
    SS diagnosis before AML diagnosis 1 5%
    SS diagnosis at the time of AML diagnosis 7 33%
    SS diagnosis during primary induction therapy 6 29%
    SS diagnosis during treatment for relapsed AML 7 33%
Symptoms at presentation of SS
    Fever 14 66%
    Tenderness in the skin lesions 10 48%
    Systemic involvement 3 14%
    History of filgrastim (G-CSF) use 3 14%
Location of skin lesions2
    Head and Neck 9 43%
    Upper extremity 10 48%
    Trunk and back 8 38%
    Lower extremity 10 48%
Laboratory values at diagnosis of SS
    Median AML blast% 25 (0-92)
    Neutrophilia (ANC ≥6 × 109/L) 2 10%
    Neutropenia (ANC ≤1.5× 109/L) 11 52%
    Anemia (Hb <10g/dl) 19 90%
    Thrombocytopenia (≤100× 109/L) 21 100%
    Kidney dysfunction (GFR<60 ml/min) 2 10%
Open in a new tab

Abbreviations used: AML: Acute Myelogenous leukemia, AML NOS: AML not-otherwise specified, MDS: Myelodysplastic syndrome, SS: Sweet's syndrome. G-CSF: granulocyte colony stimulating factor.

1

Von den Driesch modified Su and Liu diagnostic criteria for SS; Major criteria: abrupt onset of tender erythematous papules and nodules, and dense neutrophilic infiltrate in dermis without leukocytoclastic vasculitis. Minor criteria: presence of fever > 38 °C, at least two of four abnormal laboratory values (WBC>8000, neutrophils >70%, ESR >20mm/hour and positive C - reactive protein), a disease condition associated with SS (such as infections, malignancies, inflammatory disorder etc.) and an excellent response to treatment with glucocorticoids. Diagnosis of SS requires both major criteria and at least two minor criteria should be fulfilled.

2

Several patients had lesions at more than one

SS was diagnosed before development of AML in one AML patient, at the time of diagnosis of AML in seven patients (33%), during primary induction chemotherapy in six patients (29%), and during treatment for relapsed disease in seven patients (33%). In terms of frontline/induction chemotherapies received for AML treatment: 16 of the 21 patients (76%) received intensive chemotherapy regimens containing high dose ARA-C and 5 patients received other regimens [1 each: Liposomal ATRA-based (1 patient with APL); Azacytidine plus SAHA; Decitabine plus Gemtuzumab ozogamicin; Laramustine-based therapy, and clofarabine plus low dose ARA-C]. Among the 21 patients with Sweet's syndrome after induction therapy, 14 patients (67%) achieved CR or CRp; 7 patients were primary refractory to induction chemotherapy. Among the 14 patients who achieved CR/CRp: 3 patients underwent allogeneic stem cell transplantation in CR1; 2 patients died in CR1; 2 patients alive in CR; the 7 remaining patients relapsed/died. Pyrexia >38°C was documented in 14 patients (66%) while tenderness in the erythematous nodules was noted in 10 (48%) patients.

Three patients had been treated with G-CSF, one patient had received liposomal ATRA, and two patients had received hypomethylating agents (one each: azacytidine and decitabine) prior to the diagnosis of SS as part of their management of AML or MDS. In almost all of the patients, the SS-manifested lesions were asymmetrical, diffuse and multifocal. At the time of diagnosis of SS the median percentage of malignant myeloid blast cells in bone marrow was 25% (range, 0-92%), neutrophilia i.e. ANC >6.0 × 109K/L was seen in two patients (10%), neutropenia i.e. ANC <1.5 × 109 /L was seen in 11 patients (52%), Hb <10 g/dl was observed in 19 patients (90%), platelet count <100× 109 /L was noted in 21 (100%) while kidney dysfunction (GFR <60 ml/min) was identified in two patients (10%).

Cytogenetic and molecular analyses are summarized in Table 2. Cytogenetics revealed diploid karyotype in seven patients (33%), complex cytogenetics (> 3 unrelated chromosomal abnormalities) in five patients (24%), and -5/del(5q) in three patients (14%), t(6;9) in two patients (10%) and trisomy 8, t(11;17), t(15;17) and t(3;3) in one patient each (5%). Common karyotype abnormalities that constituted the “complex cytogenetics” in the five patients are detailed in Table 2, with -5/del(5q) seen in five patients, and deletion 3 and deletion 13 in three patients each. Therefore, changes in chromosome 5 were the most common abnormality found in the study occurring in overall eight patients (38%). The most common genetic molecular abnormality identified through FISH or RT-PCR analysis was in fms-related tyrosine kinase 3 (FLT3) gene which was mutated in seven of 18 analyzed patients (39%). Of these, four patients had internal tandem duplication (ITD) and three had codon-835 tyrosine kinase domain (TKD) mutations. Six out of these 7 FLT3 mutations were in patients who had diploid karyotype on cytogenetic analysis. Additionally, two of 7 analyzed patients (28%) harbored nucleophosmin 1 (NPM1) gene mutations. One patient had concurrent FLT3-835 TKD and NPM1 mutations. No genetic mutations were identified in rat sarcoma (RAS), mast/stem cell growth factor receptor Kit (C-KIT) and CCAAT and/enhancer binding protein alpha (CEBPα) genes (total patients tested for these mutations 13, 5 and 3 respectively).

Table 2.

Cytogenetic and molecular genetic analysis in acute myelogenous leukemia patients with Sweet's Syndrome

Patient Characteristics N Percentage
Cytogenetic analysis (n=21)
    Diploid cytogenetics 7 33%
    Complex cytogenetics (≥ 3 chromosomal abnormalities) 5 24%
    −5/del(5q) (as sole abnormality) 3 14%
    t(6;9) 2 10%
    Trisomy 8 1 5%
    t(11;17) 1 5%
    t(15;17) 1 5%
    t(3;3) 1 5%
Karyotype abnormalities constituting “complex cytogenetics” (n=5)1
    −5/del(5q) 5 100%
    −3 3 60%
    −13/del(13q) 3 60%
    −7/del(7q) 2 40%
    −12 2 40%
    −17 2 40%
    Others2 1 each 20%
Molecular genetics analysis
    FLT3 (total tested = 18)
        Internal Tandem Duplication 4 22%
                D835 3 17%
    NPM1 (total tested=7) 2 28%
    RAS (total tested=13) 0 0
    C-KIT (total tested=5) 0 0
    CEBPα (total tested=3) 0 0
Open in a new tab

Abbreviations used: CG: cytogenetics; FLT3: fms-related tyrosine kinase 3; NPM1: nucleophosmin 1, RAS: rat sarcoma, C-KIT: mast/stem cell growth factor receptor Kit; CEBPα: CCAAT/enhancer binding protein alpha

1

Complex cytogenetics patients only (n=5)

2

Others: −1, del(6q), −9, −11, −12, −14, −15, del(20q), add(2p), add(3q), add(6q), add7, add(8q), +11, add(16p), add(17p), add(22q)

We further investigated FLT3 (n=13) mutational status in FFPE skin lesions (ITD=4, D835=9), with the aim to attempt to correlate the mutational aberration in both skin and bone marrow samples. Results for FLT3- D835 testing in seven skin samples were concordant with BM findings in five samples including one positive and four negative results. In two cases, BM sample showed FLT3-D835 mutation, whereas, the skin sample was negative for the mutation. FLT3-ITD analysis was unsuccessful in all 4 FFPE skin samples likely due to the large size of the PCR product and degradation of DNA on the FFPE preservation.

Glucocorticoids, antibiotics and supportive wound care were the most frequent therapeutic interventions in patients with AML and SS. Eight patients (38%) received systemic glucocorticoids and two (10%) received topical steroids. Nineteen (90%) received antibiotics and all patients received supportive wound care. Clinical documentation regarding improvement or progression of SS lesions was available for 16 of 21 patients (76%) and improvement in the skin lesions was documented in all of these patients. However, SS relapsed in 3 patients requiring multiple courses of glucocorticoids. In the remaining cohort (5 of 21; 24%) of the patients, follow- up documentation about clinical improvement or progression was not available mainly due to loss of follow-up or death during treatment of the AML. The median time to documentation of clinical improvement in SS signs and symptoms was 14 days (range, 4-153). The median overall survival for the 21 AML patients from the date of AML diagnosis to the time of death was 14 months (95% confidence interval, 12.6 - 15.4 months); this was not significantly different from the rest of the 2,166 AML patients initially screened (median overall survival 13 months; 95% confidence interval 11.8 -14.1 months).

Discussion

In this study we sought to characterize the clinicopathological features of AML patients who developed SS and to document recurring cytogenetic or molecular aberrations in these patients. These recurring aberrations may serve to identify those patients who are at greatest risk of developing SS during therapy or follow-up of AML. As previously reported, SS in AML patients may present as a paraneoplastic manifestation or as a drug-induced SS due to medications commonly used in the treatment of AML.1 The clinical manifestations of SS are the result of site-specific infiltration of mature neutrophils to sites such as the dermis and occasionally in other visceral organs (e.g. lung, kidney) leading to systemic manifestations like fever, arthralgia, and cutaneous lesions, and sometimes an inflammatory response syndrome. Since SS is associated with various benign and malignant conditions, it has been hypothesized that altered levels of various cytokines and signaling molecules such as G-CSF, Interleukin (IL)-1, IL-2, IL-6, IL-8, IL-17, tumor necrosis-alpha (TNFα) and Interferon γ (IFN γ) may contribute to alterations in neutrophil function. Indeed case-reports of SS in individual patients have confirmed alterations in levels of these molecules in the plasma.29-34 Aberrant production of pro-inflammatory cytokines IL-6, TNFα and anti-inflammatory cytokine IL-10 is observed in AML patients that may also ultimately affect survival.35 Also both AML and MDS have been associated with defective neutrophil functions including adhesion, migration, chemotaxis and phagocytosis.36-38 Thus, such alterations in pro- and anti-inflammatory cytokines and neutrophil function may prevent the occurrence of normal chemotaxis, thereby contributing to the dermal clumping of the mature neutrophils.

Our results show that skin disorders are a relatively frequent occurrence in AML patients with skin biopsies performed in 32% of all AML patients treated at our institution. In the general population, SS is a relatively rare phenomenon with some estimates quoting an incidence of 2.7 cases per million people per year. In our study, however, the observed incidence was less than 1% of AML patients. Based on 2008 revised WHO classification of myeloid neoplasms and acute leukemia, we were able to classify 11 of our patients as having AML with MDS-related features which is considered a high-risk for relapse and poor response to therapy with hematopoietic stem cell transplant.39 MDS has a known association with SS, so this result was not unexpected.40-43

The cytogenetic profile of our population showed increased frequency of high-risk AML cytogenetics anomalies including complex cytogenetics, -5/del(5q) and t(6,9). In patients who had diploid cytogenetics, the most commonly identified molecular mutations involved the FLT3 gene (either ITD or TKD mutation of D835) that encodes a class III receptor tyrosine kinase expressed in 70-100% of leukemia cells. Constitutional activation of FLT3 due to ITD or TKD mutations confers a high-risk for relapse and inferior overall survival.44, 45 The reason for increased frequency of SS in AML patients with poor-risk cytogenetic and molecular abnormalities is unclear. The median overall survival of approximately 14 months in our study population may be attributable to multiple etiologies, including the higher frequency of poor-risk cytogenetics and molecular aberrations in this cohort of patients. Performing FISH or RT-PCR analysis using molecular probes for the above mentioned cytogenetic and molecular aberrations in skin samples from SS patients may help to determine the clonality of the neutrophilic infiltrates thus furthering our understanding of the pathogenesis of SS in AML. Recently, an SS-like clinical entity involving the skin, soft tissues and lung was noted in several FLT3-ITD mutated AML patients who were being treated with a FLT3 inhibitor, quizartinib (AC220). One hypothesis explaining the putative mechanism is that this is due to induction of terminal differentiation of myeloid blasts to mature neutrophils.46 Treatment related terminal myeloid differentiation of AML blasts into mature neutrophils, as described with quizartinib, may explain development of SS in some of our patients after G-CSF, liposomal ATRA and azacitadine treatments.19, 20, 24, 46

Our study, similar to previous studies, shows that SS was more common in females and occurred at various stages of AML including pre-diagnosis, at diagnosis, at primary induction therapy or during remission or at time of relapse, suggesting that SS may actually act as an indicator of underlying malignancy or its relapse.9, 34, 47 Although fever, neutrophilia, and elevated ESR are part of the diagnostic criteria for idiopathic-SS and MA-SS, these were observed in only a subset of our patients. Only two-thirds of our patients presented with fever, however, a majority had neutropenia with an ANC below 1.5 × 109K/μL, and almost all had anemia and thrombocytopenia (notably, the cytopenias observed in our population could be a manifestation of AML/ MDS or a result of therapy for myeloid malignancy). Our findings are similar to previous reports that SS in hematological malignancies may occur even in the face of neutropenia and that it may not always manifest the classical signs and symptoms of idiopathic SS.9, 48-50 In our study population, documented improvement of the SS-associated skin lesions occurred in 16 of 21 (76%) patients for whom adequate follow-up data was available. This is notable, especially because approximately half of the patients received glucocorticoids and the majority received antibiotics. The improvement in SS skin manifestations without glucocorticoids may be attributable to treatment of underlying AML or infection resulting in restoration of normal granulocyte function.

Conclusion

Sweet's syndrome should be considered in the differential diagnosis of any AML patient presenting with skin rash (differential diagnosis includes infection, leukemia cutis, drug-induced reaction). Sweet's syndrome occurred in approximately 1% of AML patients at our institute, and is AML with myelodysplasia-related features, -5/del(5q) and FLT3 mutations were common in patients with SS. The diagnosis of SS in AML did not affect the median survival of the patients in this limited sample size.

Clinical Practice Points.

  • Sweet's Syndrome should be considered in the differential diagnosis of any AML patient presenting with skin rash (differential diagnosis includes infection, leukemia cutis, drug-induced reaction)

  • Sweet's syndrome occurs in 1% of AML patients, and is AML with myelodysplasia-related features, -5/del(5q) and FLT3 mutations are frequent in patients with Sweet's syndrome

  • Sweet's syndrome generally responds promptly to treatment with glucocorticoids

Acknowledgements

The authors would like to thank Ronald Craig Cason for technical assistance with regards to FLT3 mutational testing. This research is supported in part by the MD Anderson Cancer Center Support Grant CA016672.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Conflict of interest:

All authors have no conflicts of interest.

References

  • 1.Anzalone CL, Cohen PR. Acute febrile neutrophilic dermatosis (Sweet's syndrome). Current opinion in hematology. 2013;20(1):26–35. doi: 10.1097/MOH.0b013e32835ad132. [DOI] [PubMed] [Google Scholar]
  • 2.Cohen PR. Sweet's syndrome--a comprehensive review of an acute febrile neutrophilic dermatosis. Orphanet journal of rare diseases. 2007;2:34. doi: 10.1186/1750-1172-2-34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Sweet RD. An Acute Febrile Neutrophilic Dermatosis. The British journal of dermatology. 1964;76:349–56. doi: 10.1111/j.1365-2133.1964.tb14541.x. [DOI] [PubMed] [Google Scholar]
  • 4.von den Driesch P. Sweet's syndrome (acute febrile neutrophilic dermatosis). Journal of the American Academy of Dermatology. 1994;31(4):535–56. doi: 10.1016/s0190-9622(94)70215-2. quiz 57-60. [DOI] [PubMed] [Google Scholar]
  • 5.Astudillo L, Sailler L, Launay F, et al. Pulmonary involvement in Sweet's syndrome: a case report and review of the literature. International journal of dermatology. 2006;45(6):677–80. doi: 10.1111/j.1365-4632.2006.02585.x. [DOI] [PubMed] [Google Scholar]
  • 6.Garg R, Soud Y, Lal R, Mehta N, Kone BC. Myelodysplastic syndrome manifesting as Sweet's Syndrome and bronchiolitis obliterative organizing pneumonia. The American journal of medicine. 2006;119(11):e5–7. doi: 10.1016/j.amjmed.2006.03.032. [DOI] [PubMed] [Google Scholar]
  • 7.Watanabe T, Nakashima K, Shindo M, Yoshida Y, Yamamoto O. Multiorgan involvement in Sweet's syndrome. Clinical and experimental dermatology. 2009;34(7):e343–4. doi: 10.1111/j.1365-2230.2009.03290.x. [DOI] [PubMed] [Google Scholar]
  • 8.Su WP, Liu HN. Diagnostic criteria for Sweet's syndrome. Cutis; cutaneous medicine for the practitioner. 1986;37(3):167–74. [PubMed] [Google Scholar]
  • 9.Bourke JF, Keohane S, Long CC, et al. Sweet's syndrome and malignancy in the U.K. The British journal of dermatology. 1997;137(4):609–13. doi: 10.1111/j.1365-2133.1997.tb03796.x. [DOI] [PubMed] [Google Scholar]
  • 10.Walker DC, Cohen PR. Trimethoprim-sulfamethoxazole-associated acute febrile neutrophilic dermatosis: case report and review of drug-induced Sweet's syndrome. Journal of the American Academy of Dermatology. 1996;34(5 Pt 2):918–23. doi: 10.1016/s0190-9622(96)90080-8. [DOI] [PubMed] [Google Scholar]
  • 11.Goodfellow A, Calvert H. Sweet's syndrome and acute myeloid leukaemia. Lancet. 1979;2(8140):478–9. doi: 10.1016/s0140-6736(79)91538-1. [DOI] [PubMed] [Google Scholar]
  • 12.Burton JL. Sweet's syndrome, pyoderma gangrenosum and acute leukaemia. The British journal of dermatology. 1980;102(2):239. doi: 10.1111/j.1365-2133.1980.tb05700.x. [DOI] [PubMed] [Google Scholar]
  • 13.Spector JI, Zimbler H, Levine R, Ross JS, Valigorsky JM, Cole LM. Sweet's syndrome. Association with acute leukemia. JAMA : the journal of the American Medical Association. 1980;244(10):1131–2. doi: 10.1001/jama.244.10.1131. [DOI] [PubMed] [Google Scholar]
  • 14.Cohen PR, Kurzrock R. Sweet's syndrome and malignancy. The American journal of medicine. 1987;82(6):1220–6. doi: 10.1016/0002-9343(87)90229-4. [DOI] [PubMed] [Google Scholar]
  • 15.Aractingi S, Bachmeyer C, Dombret H, Vignon-Pennamen D, Degos L, Dubertret L. Simultaneous occurrence of two rare cutaneous markers of poor prognosis in myelodysplastic syndrome: erythema elevatum diutinum and specific lesions. The British journal of dermatology. 1994;131(1):112–7. doi: 10.1111/j.1365-2133.1994.tb08467.x. [DOI] [PubMed] [Google Scholar]
  • 16.Magro CM, De Moraes E, Burns F. Sweet's syndrome in the setting of CD34-positive acute myelogenous leukemia treated with granulocyte colony stimulating factor: evidence for a clonal neutrophilic dermatosis. Journal of cutaneous pathology. 2001;28(2):90–6. doi: 10.1034/j.1600-0560.2001.280205.x. [DOI] [PubMed] [Google Scholar]
  • 17.Magro CM, Kiani B, Li J, Crowson AN. Clonality in the setting of Sweet's syndrome and pyoderma gangrenosum is not limited to underlying myeloproliferative disease. Journal of cutaneous pathology. 2007;34(7):526–34. doi: 10.1111/j.1600-0560.2006.00654.x. [DOI] [PubMed] [Google Scholar]
  • 18.Van Loon K, Gill RM, McMahon P, et al. 20q- clonality in a case of oral sweet syndrome and myelodysplasia. American journal of clinical pathology. 2012;137(2):310–5. doi: 10.1309/AJCP9I7NRWYLTJHV. [DOI] [PubMed] [Google Scholar]
  • 19.Arun B, Berberian B, Azumi N, Frankel SR, Luksenburg H, Freter C. Sweet's syndrome during treatment with all-trans retinoic acid in a patient with acute promyelocytic leukemia. Leukemia & lymphoma. 1998;31(5-6):613–5. doi: 10.3109/10428199809057622. [DOI] [PubMed] [Google Scholar]
  • 20.Bidyasar S, Montoya M, Suleman K, Markowitz AB. Sweet syndrome associated with granulocyte colony-stimulating factor. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008;26(26):4355–6. doi: 10.1200/JCO.2008.16.2933. [DOI] [PubMed] [Google Scholar]
  • 21.Conesa V, Morales A, Majado MJ, Gonzalez C, Candel R. Post-chemotherapy Sweet's syndrome in three patients with AML. American journal of hematology. 1998;57(2):179. doi: 10.1002/(sici)1096-8652(199802)57:2<179::aid-ajh15>3.0.co;2-7. [DOI] [PubMed] [Google Scholar]
  • 22.Oiso N, Watanabe K, Kawada A. Granulocyte colony-stimulating factor-induced Sweet syndrome in a healthy donor. British journal of haematology. 2006;135(2):148. doi: 10.1111/j.1365-2141.2006.06222.x. [DOI] [PubMed] [Google Scholar]
  • 23.Reuss-Borst MA, Muller CA, Waller HD. The possible role of G-CSF in the pathogenesis of Sweet's syndrome. Leukemia & lymphoma. 1994;15(3-4):261–4. doi: 10.3109/10428199409049722. [DOI] [PubMed] [Google Scholar]
  • 24.Trickett HB, Cumpston A, Craig M. Azacitidine-associated Sweet's syndrome. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. 2012;69(10):869–71. doi: 10.2146/ajhp110523. [DOI] [PubMed] [Google Scholar]
  • 25.Murphy KM, Levis M, Hafez MJ, et al. Detection of FLT3 internal tandem duplication and D835 mutations by a multiplex polymerase chain reaction and capillary electrophoresis assay. J Mol Diagn. 2003;5(2):96–102. doi: 10.1016/S1525-1578(10)60458-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009. 114(5):937–51. doi: 10.1182/blood-2009-03-209262. [DOI] [PubMed] [Google Scholar]
  • 27.Washio K, Oka M, Ohno K, et al. Case of recurrent Sweet's syndrome in a patient with relapsing polychondritis and myelodysplastic syndrome. The Journal of dermatology. 2012;39(8):731–3. doi: 10.1111/j.1346-8138.2011.01403.x. [DOI] [PubMed] [Google Scholar]
  • 28.Cohen PR. Sweet's syndrome and relapsing polychondritis: is their appearance in the same patient a coincidental occurrence or a bona fide association of these conditions? International journal of dermatology. 2004;43(10):772–7. doi: 10.1111/j.1365-4632.2004.02197.x. [DOI] [PubMed] [Google Scholar]
  • 29.Reuss-Borst MA, Pawelec G, Saal JG, Horny HP, Muller CA, Waller HD. Sweet's syndrome associated with myelodysplasia: possible role of cytokines in the pathogenesis of the disease. British journal of haematology. 1993;84(2):356–8. doi: 10.1111/j.1365-2141.1993.tb03083.x. [DOI] [PubMed] [Google Scholar]
  • 30.Going JJ. Is the pathogenesis of Sweet's syndrome mediated by interleukin-1? The British journal of dermatology. 1987;116(2):282–3. doi: 10.1111/j.1365-2133.1987.tb05836.x. [DOI] [PubMed] [Google Scholar]
  • 31.Giasuddin AS, El-Orfi AH, Ziu MM, El-Barnawi NY. Sweet's syndrome: is the pathogenesis mediated by helper T cell type 1 cytokines? Journal of the American Academy of Dermatology. 1998;39(6):940–3. doi: 10.1016/s0190-9622(98)70266-x. [DOI] [PubMed] [Google Scholar]
  • 32.Hofmann WK, Stauch M, Hoffken K. Impaired granulocytic function in patients with acute leukaemia: only partial normalisation after successful remission-inducing treatment. Journal of cancer research and clinical oncology. 1998;124(2):113–6. doi: 10.1007/s004320050142. [DOI] [PubMed] [Google Scholar]
  • 33.Marzano AV, Cugno M, Trevisan V, et al. Inflammatory cells, cytokines and matrix metalloproteinases in amicrobial pustulosis of the folds and other neutrophilic dermatoses. International journal of immunopathology and pharmacology. 2011;24(2):451–60. doi: 10.1177/039463201102400218. [DOI] [PubMed] [Google Scholar]
  • 34.Cohen PR, Kurzrock R. The pathogenesis of Sweet's syndrome. Journal of the American Academy of Dermatology. 1991;25(4):734. doi: 10.1016/s0190-9622(08)80689-5. [DOI] [PubMed] [Google Scholar]
  • 35.Sanchez-Correa B, Bergua JM, Campos C, et al. Cytokine profiles in acute myeloid leukemia patients at diagnosis: survival is inversely correlated with IL-6 and directly correlated with IL-10 levels. Cytokine. 2013;61(3):885–91. doi: 10.1016/j.cyto.2012.12.023. [DOI] [PubMed] [Google Scholar]
  • 36.Ruutu P, Ruutu T, Repo H, et al. Defective neutrophil migration in monosomy-7. Blood. 1981;58(4):739–45. [PubMed] [Google Scholar]
  • 37.Ruutu P, Ruutu T, Vuopie P, Kosunen TU, de la Chapelle A. Defective chemotaxis in monosomy-7. Nature. 1977;265(5590):146–7. doi: 10.1038/265146a0. [DOI] [PubMed] [Google Scholar]
  • 38.Ruutu P, Ruutu T, Vuopio P, Kosunen TU, de la Chapelle A. Function of neutrophils in preleukaemia. Scandinavian journal of haematology. 1977;18(4):317–25. doi: 10.1111/j.1600-0609.1977.tb01202.x. [DOI] [PubMed] [Google Scholar]
  • 39.Garcia-Manero G. Myelodysplastic syndromes: 2012 update on diagnosis, risk-stratification, and management. American journal of hematology. 2012;87(7):692–701. doi: 10.1002/ajh.23264. [DOI] [PubMed] [Google Scholar]
  • 40.Buck T, Gonzalez LM, Lambert WC, Schwartz RA. Sweet's syndrome with hematologic disorders: a review and reappraisal. International journal of dermatology. 2008;47(8):775–82. doi: 10.1111/j.1365-4632.2008.03859.x. [DOI] [PubMed] [Google Scholar]
  • 41.Nishie W, Kimura T, Kanagawa M. Sweet's syndrome evolved from recurrent erythema nodosum in a patient with myelodysplastic syndrome. The Journal of dermatology. 2002;29(2):91–5. doi: 10.1111/j.1346-8138.2002.tb00172.x. [DOI] [PubMed] [Google Scholar]
  • 42.Vazquez Garcia J, Almagro Sanchez M, Fonseca Capdevila E. Multiple neutrophilic dermatoses in myelodysplastic syndrome. Clinical and experimental dermatology. 2001;26(5):398–401. doi: 10.1046/j.1365-2230.2001.00844.x. [DOI] [PubMed] [Google Scholar]
  • 43.Vignon-Pennamen MD, Juillard C, Rybojad M, et al. Chronic recurrent lymphocytic Sweet syndrome as a predictive marker of myelodysplasia: a report of 9 cases. Archives of dermatology. 2006;142(9):1170–6. doi: 10.1001/archderm.142.9.1170. [DOI] [PubMed] [Google Scholar]
  • 44.O'Donnell MR, Abboud CN, Altman J, et al. Acute myeloid leukemia. Journal of the National Comprehensive Cancer Network : JNCCN. 2012;10(8):984–1021. doi: 10.6004/jnccn.2012.0103. [DOI] [PubMed] [Google Scholar]
  • 45.Pemmaraju N, Kantarjian H, Ravandi F, Cortes J. FLT3 inhibitors in the treatment of acute myeloid leukemia: the start of an era? Cancer. 2011;117(15):3293–304. doi: 10.1002/cncr.25908. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Sexauer A, Perl A, Yang X, et al. Terminal myeloid differentiation in vivo is induced by FLT3 inhibition in FLT3/ITD AML. Blood. 2012;120(20):4205–14. doi: 10.1182/blood-2012-01-402545. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Cho KH, Han KH, Kim SW, Youn SW, Youn JI, Kim BK. Neutrophilic dermatoses associated with myeloid malignancy. Clinical and experimental dermatology. 1997;22(6):269–73. [PubMed] [Google Scholar]
  • 48.Ozcelik T, Ozkocaman V, Ali R, et al. Sweet's syndrome: dilemma in febrile neutropenic patient with acute myeloid leukemia. Leukemia research. 2006;30(11):1466–8. doi: 10.1016/j.leukres.2006.01.019. [DOI] [PubMed] [Google Scholar]
  • 49.Ozlem C, Deram B, Mustafa S, Koray T, Cuyan D, Ertugrul T. Propylthiouracil-induced anti- neutrophil cytoplasmic antibodies and agranulocytosis together with granulocyte colony-stimulating factor induced Sweet's syndrome in a patient with Graves' disease. Intern Med. 2011;50(18):1973–6. doi: 10.2169/internalmedicine.50.4483. [DOI] [PubMed] [Google Scholar]
  • 50.Aractingi S, Mallet V, Pinquier L, et al. Neutrophilic dermatoses during granulocytopenia. Archives of dermatology. 1995;131(10):1141–5. [PubMed] [Google Scholar]

RESOURCES