BRIEF REPORTAcute Febrile Neutrophilic Dermatosis (Sweet Syndrome) as Initial Presentation

in a Child With Acute Myelogenous Leukemia

Dominik T. Schneider, MD,1* Hans-Christian Schuppe, MD,3

Dorothea Schwamborn, MD,2 Dieter Koerholz, MD,1 Percy Lehmann, MD,3

and Ulrich Goebel, MD1

Key words: Sweet syndrome; acute febrile neutrophilic dermatosis; acutemyelogenous leukemia; paraneoplasia; childhood

INTRODUCTION

Sweet syndrome (acute febrile neutrophilic dermato-sis; SS) has been described in adult patients in associa-tion with a variety of infectious [1–3], autoimmunologic[3–5], chronic granulomatous [6], and neoplastic disor-ders [3,5,7]. It is most prevalent in patients with hema-topoietic neoplasia, predominantly myeloid [5,8,9] andless often lymphoid malignancies [5], or solid tumors(primarily of the genitourinary tract) [3,5] and in patientsreceiving granulocyte-colony-stimulating factor (G-CSF)therapy [10]. Only in a few patients is SS the initialsymptom of hematological disease [11].

SS is characterized by the triad: fever, leukocytosiswith neutrophilia, and characteristic skin lesions [12–14].Additional symptoms may be flu-like prodromi, arthral-gia, and conjunctivitis [5,15]. Patients usually show adramatic response to glucocorticosteroid therapy, whichis believed to be an important retrospective diagnosticfeature [5].

Until 1997, only 20 children with SS have been re-ported in the literature [2,7,16–18]. Only one child suf-fered from acute leukemia [8] so that our experience witha girl with acute myelogenous leukemia, in whom SSwas the leading presenting sign of leukemia, is instruc-tive.

She was a previously healthy 13-year-old girl whowas referred to our hospital with a 3-day history of feverand painful swelling with erythema of her right ankle.She had been treated with oral and intravenous (i.v.)antibiotics for suspected erysipelas. On admission, thepatient was in poor clinical condition. The temperaturewas 39°C, and there was faint pallor of the skin andmucosae without any hemorrhagic signs. Slight inguinaland cervical lymphadenopathy was present along withhepatosplenomegaly (liver 3 cm and spleen 2 cm belowthe costal margin).

The right ankle was grossly swollen and erythema-tous. Disseminated red papules with a tendency to co-

alesce forming sharply bordered plaques with pseudove-sicular and -pustular appearance were found on all otherparts of the integument. Some older lesions showed truevesicles and pustules studded on the tops of the plaquesand papules (Fig. 1). A faint morbilliform macular ex-anthema was also noticed, which was interpreted as anallergic response to antibiotics.

Her clinical condition further deteriorated despitebroad antibiotic therapy with clindamycin, cefotaxim,netilmycin, and acyclovir. Temperatures were up to 40°Cmost of the time, and the skin lesions increased in num-ber and size. The clinical dermatologic features sug-gested SS as the most likely diagnosis.

Laboratory investigations on admission were hemo-globin level 9.7 g/dl, white blood cell (WBC) count44,300/ml (differential count: 25% myeloblast typesI and II [some of them with Auer rods], 8% band-forms, 53% neutrophils, 7% lymphocytes, 7% mono-cytes), platelet count 95,000/ml, C-reactive protein(CRP) 6.9 mg/dl (normal: <0.5 mg/dl; rising to 27.6 mg/dl during the next 2 days), lactate dehydrogenase (LDH)655 U/l (normal: <300 U/l). Bone marrow puncture con-firmed the diagnosis of acute myelogenous leukemia(FAB-M2 with Auer rods).

Microbiologic examination of punctuated pustules and

Grant sponsor: Elterninitiative Kinderkrebsklinik Duesseldorf e.V.1Clinic of Pediatric Hematology and Oncology, Heinrich-Heine-University of Duesseldorf, Duesseldorf, Germany2Clinic of Pediatric Hematology and Oncology, University of Co-logne, Cologne, Germany3Clinic of Dermatology, Heinrich-Heine-University of Duesseldorf,Duesseldorf, Germany

*Correspondence to: D.T. Schneider, Clinic of Pediatric Hematologyand Oncology, Moorenstr. 5, D-40225 Duesseldorf, Germany. E-mail:dominik.schneider@uni-koeln.de

Received 1 December 1997; Accepted 21 April 1998

Medical and Pediatric Oncology 31:178–181 (1998)

© 1998 Wiley-Liss, Inc.

multiple blood and urine cultures remained sterile. Elec-tron microscopy of the punctuates did not show signs ofviral infection. There was no serologic evidence of acutebacterial, fungal, or viral infection.

Skin biopsy revealed exocytosis of segmented nuclearneutrophils through the epidermis, subepidermal edema,and band-like, sometimes patchy infiltrates of the dermis,consisting of lymphocytes, histiocytes, and numerousneutrophils with signs of leukocytoclasia (Fig. 2).

Following the skin biopsy, antibiotics were reduced toacyclovir and clindamycin, and methylprednisolonetherapy was started at a dose of 2 mg/kg/d, after whichthe fever abated within hours. The skin lesions healedwithin days; only mild hyperpigmentation and local skinatrophy remained. Glucocorticosteroid therapy was con-tinued for 3 weeks in tapering doses.

On the day of admission, antileukemic therapy wasinitiated according to the AML-BFM-93 protocol [19],

starting with cytoreductive therapy with cytarabine (40mg/m2/d) and thioguanine (40 mg/m2/d). Complete re-mission was achieved by induction chemotherapy, docu-mented by bone marrow examination on day 15 and onday 28 of induction therapy. She has remained in com-plete remission until the time of this report (22 monthsafter diagnosis).

Administration of Imipenem for severe bacterial in-fection during consolidation chemotherapy was followedby a marked allergic exanthema. Interestingly, skin areasformerly affected by SS were spared by the allergic ex-anthema (Fig. 3). After intensification chemotherapy,she developed pronounced neutropenia (WBCø100/mland absolute neutrophil count [ANC]ø50/ml for 15days) and septicemia withEscherichia coli.Hemato-poiesis recovered, and the ANC rose to normal levelswithin 21 days of G-CSF treatment, which did not reac-tivate SS.

DISCUSSION

Children with acute myelogenous leukemia often pre-sent with concurrent severe septic infection, and in manycases severe infections finally lead to the diagnosis ofleukemia. Our patient presented with a clinical picturemimicking severe infectious disease of the skin, unre-sponsive to broad antibiotic and antiviral therapy. Anunderlying infection could be excluded by multiple mi-crobiologic and serologic examinations. Both fever andtypical skin lesions were attributed to SS, which wasconfirmed on histological examination of the skin.

Recently we saw another patient with a very similarclinical picture. The 8-year-old boy with acute myelog-enous leukemia (FAB-M2 with Auer rods) presentedwith flu-like prodromi, fever, stomatitis, arthralgia, anddisseminated papules with pseudopustules. Since the

Fig. 1. Lesion with inflammatory edema, pseudopustules, and cen-tral vesicle.

Fig. 2. Skin biopsy showing exocytosis of neutrophils through thedermis, subepidermal edema with band-like neutrophilic infiltrates.(HE; ×100.)

Fig. 3. Allergic exanthema sparing skin areas formerly affectedby SS.

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parents refused a skin biopsy, the diagnostic criteria pro-posed by Su and Liu [20] could not be fulfilled, but thedramatic response to glucocorticosteroid treatmentstrongly supports the clinical diagnosis of SS in this pa-tient.

Notably, both cases seen at our hospital were acutemyelogenous leukemia of FAB-M2 type with Auer rods.In this FAB-type, some maturation of the leukemic clonecan be observed [21]. One might speculate that in chronicmyeloid neoplasia and in acute myelogenous leukemiawith signs of maturation, maturing neoplastic neutrophilsmay migrate into the skin and provoke both the SS typi-cal skin lesions and systemic symptoms such as fever[22]. In accordance with this hypothesis, van Kamp et al.[23] have been able to demonstrate the clonality of theneutrophilic infiltrates by in situ hybridization in a pa-tient with myelodysplasia (refractory anemia with excessof blasts in transformation).

No recurrence of SS was seen after G-CSF treatment.At this time, the girl had been in complete remission for6 months. This observation suggests that in our patient,only leukemic cells were able to cause SS while “nor-mal” nonleukemic neutrophils, although stimulated byG-CSF, could not.

SS has been interpreted as a hypersensitivity reactionto infectious, chronic inflammatory, or malignant disease[3]. It may be due to imbalances in the cytokine networkwith increased levels of G-CSF and IL-6 but normallevels ofg-IFN and IL-1b [24,25]. Examination of bothcytokine levels in blood and responsiveness of granulo-cytes to cytokine stimulation will allow further under-standing of the pathophysiology of SS. Furthermore, dis-turbances of chemotactic activity and intracellular killinghave been described in SS [26]. Other authors have re-ported a high incidence of autoantibodies against neutro-phil cytoplasmatic antigens (six of seven patients) [27].Even if these antibodies might be an epiphenomenon,they could be of diagnostic importance in the future.

Only 20 cases of histologically proven SS in child-hood have been described in the literature until now[2(review),7,8,11,16–18,28], the youngest child being 3months old at diagnosis [29]. Five children with SS con-comitantly suffered from hematologic disease, two hav-ing Fanconi anemia [28], one myelodysplastic syndrome[7], one juvenile chronic [11], and one acute myeloge-nous leukemia [8]. Including our patient with histologi-cally proven SS, 19% of the reported children with SSsuffer from simultaneous myeloid neoplasia. Thus, theincidence of SS and simultaneous leukemia in childhoodseems to be comparable to that observed in adults [3,5].In our opinion, SS should be taken into consideration inall children with the combination of a severe febrile ill-ness, suspicious skin lesions, and hematologic disease orgrowth factor treatment with G-CSF [10].

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