CASE REPORT

A rare case of subcutaneous Sweet’s syndrome in a patientwith chronic myelogenous leukemia: a case reportand review of the literature

Congli Wang & Mary Ellen Martin & Roberta E. Smith &

Deline DaCosta & Raghava Levaka Veera & Irma E. Palazzo

Received: 18 February 2014 /Accepted: 23 May 2014# Springer-Verlag Berlin Heidelberg 2014

Abstract Subcutaneous Sweet’s syndrome (SS) is a rare var-iant of classic SS characterized by a neutrophilic infiltrateexclusively or predominantly in the subcutaneous tissue, withminimal or absent dermal involvement.We report the case of apatient with a history of chronic myelogenous leukemia whodeveloped subcutaneous SS. Although it has been describedin patients with myelodysplastic syndromes and acute mye-loid leukemia, this is the first report, to our knowledge, of thisrare entity occurring in the setting of a myeloproliferativedisorder.

Keywords Subcutaneous Sweet’s syndrome . Chronicmyelogenous leukemia . Neutrophilic infiltrates . Myeloiddisorders

Introduction

Sweet’s syndrome (SS), also known as acute febrile neutro-philic dermatosis, is characterized by the sudden onset offever, multiple tender erythematous papules and plaques,and the presence of intense neutrophilic infiltrates on skinbiopsy that are typically located in the upper dermis. SS isoften associated with hematologic disease, and to a lesserextent with solid tumors [1–5].

Subcutaneous SS is a rare variant in which the neutrophilicinfiltrate is exclusively or predominantly located in the sub-cutaneous tissue, with minimal or no dermal involvement [6,7]. Subcutaneous SS is almost exclusively associated withmyeloid disorders. To the best of our knowledge, only 16cases have been reported in such a setting in the English-language literature to date [8–19], including ten cases withmyelodysplastic syndromes (MDS) and six cases with acutemyeloid leukemia (AML). We describe the case of a patientwith chronic myelogenous leukemia (CML) who developedsubcutaneous SS, an association which has not been previ-ously reported.

Case report

The patient is a 43-year-old black female from Bermuda witha history of CML admitted for anemia, thrombocytopenia,fever, fatigue, splenomegaly and abdominal pain, and severeright leg pain. She was diagnosed with CML that was con-firmed by the expression of BCR-ABL by FISH, in January2009. She failed therapy with multiple tyrosine kinase inhib-itors including ponatinib. At the time of hospital admission,her hemoglobin was 4 g/dl, platelet count was 5,000/ul, andthe white blood cell count was 2,500/ul with 9 % circulatingblasts. She received two units of packed red blood cells andtwo units of platelets. Plain films and MRI of the right hip

C. WangDepartment of Pathology & Laboratory Medicine, TempleUniversity Hospital, Philadelphia, PA 19140, USA

M. E. MartinDepartment of Medical Oncology, Fox Chase Cancer Center,Philadelphia, PA 19111, USA

R. E. Smith :D. DaCosta : I. E. PalazzoDepartment of Pathology, Jeanes Hospital, Philadelphia, PA 19111,USA

R. Levaka VeeraDepartment of Hematology/Oncology, Temple University Hospital/Fox Chase Cancer Center, Philadelphia, PA 19111, USA

C. Wang (*)Department of Pathology and Laboratory Medicine, TempleUniversity School of Medicine, 3401 North Broad Street,Philadelphia, PA 19140, USAe-mail: congli.wang@tuhs.temple.edu

J HematopatholDOI 10.1007/s12308-014-0206-3

joint excluded a pathological fracture. Additionally, Cefepimewas started for fever. On physical examination at the time ofadmission, two firm, tender subcutaneous nodules were notedon the medial side of the right thigh measuring 4×4 and 3×2 cm, respectively. Within 24 h of admission, she developednew left arm pain and worsening abdominal pain. A thirdnodule developed on the left arm measuring 2×2 cm(Fig. 1). The overlying skin appeared erythematous withoutfluctuance or pustule. CT scan of the chest, abdomen, andpelvis with contrast showed multiple nodular densities in bothlungs as well as hepatosplenomegaly. Micafungin was addedfor suspected disseminated fungal infection. On day 5 of herhospitalization, two more firm, tender, erythematous noduleswere noted on the right arm and forearm. Given the concernfor disease evolution and for leukemia cutis, biopsies of thebone marrow and one of the subcutaneous nodules wereperformed.

Bone marrow biopsy revealed a hypercellular marrowwith prominent myeloid hyperplasia, left-shiftedgranulopoiesis, and markedly decreased megakaryocyticand erythroid precursors. CD34 positive cells comprised5 % of the marrow. The peripheral blood smear re-vealed 8 % blasts and 67 % segmented neutrophils.Biopsy of the subcutaneous nodule showed organizingfat necrosis and a dense neutrophilic infiltrate in thelobules, with associated fibrinoid necrosis and numerousmacrophages (Fig. 2). There was no significant dermalinvolvement and no evidence of vasculitis. In addition,no blasts were seen; this was confirmed by the absenceof staining for CD34 on immunohistochemistry. Specialstains for fungus, acid-fast bacilli, and bacteria were allnegative. A diagnosis of subcutaneous SS was made.

During her hospitalization, the percentage of peripheralcirculating blasts rose to 18 %. With a concern for diseaseprogression, induction chemotherapy was started withcytarabine and idarubicin (7+3 regimen). The patient had asignificant clinical improvement, and she is currently awaiting

haploidentical hematopoietic stem cell transplantation. Inter-estingly, she did not receive steroids, and her nodulesresponded to chemotherapy. The two nodules on her rightarm completely disappeared within a week, and the rest ofthe nodules decreased in size and became non-tender.

Discussion

Subcutaneous SS is an extremely rare entity. Although it hasbeen described to occur after treatment with vemurafenib, aBRAF inhibitor [20], the majority of reported cases have beenassociated with underlying myeloid disorders. Following acomprehensive literature search, we identified 16 cases ofsubcutaneous SS that developed in such a clinical setting.The clinical and histopathologic features of those lesions aretabulated in Table 1.

Among the16 previously reported cases, different termshave been used, including neutrophilic panniculitis [11–13,16, 18], SS-like (Sweet’s-like) neutrophilic panniculitis [14],and Sweet’s panniculitis [10]. In all the cases, the patients hadeither MDS or AML and presented with multiple erythema-tous nodules that frequently involved the limbs, especially thelower extremities [8–19]. Most of the nodules were accompa-nied by fever, and some were painful. On histological exam-ination, all lesions showed an extensive neutrophilic infiltrate

Fig. 1 Subcutaneous firm, erythematous nodule on the left arm. Similarnodules were present on the right thigh and right arm (not shown)

Fig. 2 Histological examination showing organizing fat necrosis anddense lobular neutrophilic infiltrate, with associated fibrinoid necrosisand numerous macrophages (hematoxylin-eosin stain; original magnifi-cations: a×20, b×200)

J Hematopathol

Tab

le1

Summaryof

subcutaneous

Sweet’s

syndromeassociated

with

myeloid

disorders

Reference

Age/

sex

Myeloid

disorder

Clin

icalmanifestatio

nsof

thelesion

General

symptom

sHistopathologicfindings

ofthelesion

Clin

icalcourse

852/F

Preleukemicstateevolving

toacutemyeloid

ormyelomonocytic

leukem

ia

Multip

leerythematousnodules(2–3

cm)on

the

armsandinnerthighs

Low

-grade

fever

Dense,patchyneutrophilicinfiltratein

the

subcutaneous

lobules

Resolvedspontaneously;

developedclassicSS11

weeks

later,andwas

diagnosedwith

AML

948/F

MDS

Recurrent

cutaneousnoduleson

thelegs

Fever,arthralgia

Dense

neutrophilicinfiltrateinthefatty

tissue;

nuclearsegmentatio

nanom

aliesin25

%of

theneutrophils

Controlledby

oralprednisolone;

laterdevelopedRAEB

1065/F

MDStransformingto

AML

Tender,inflamed

plaqueson

therightcheek

andleft

supraclavicularfossa

Spikingfever

Dense

neutrophilicinfiltrateand

leukocytoclasisin

subcutaneous

adipose

tissue

Controlledby

prednisolone

50mg/day

1174/F

MDS(RARS)

Multip

letender,erythem

atousnodulesandplaques

ontheleftforearm

andleftleg

Spiking

fever,

edem

atous

legs

Dense,patchysubcutaneous

neutrophilic

infiltratespreadingoutfrom

septato

lobules

Responded

toprednisolone

30mg/day

1259/ M

MDS(RAEB)

Num

erous,tender,smallp

ustularlesionsand

erythematouspapulesrandom

lydistributedover

entirebody

Highfever,

malaise

Dense

subcutaneous

neutrophilicinfiltrate

with

alobulardistributio

nRapid

improvem

entafter

oral

prednisolone

40mg/day

1357/ M

MDS

Multip

lesubcutaneous

tender,erythem

atous

noduleson

thelegs,arm

sandtrunk

Spikingfever

Neutrophilic

infiltratein

thefatlobules

Rapid

improvem

entafter

oral

prednisone

60mg/day

1419/ M

APM

Lon

ATRA

1cm

,discrete,erythematousnoduleon

theright

shin

N/A

Subcutaneousneutrophil-rich

lobularinfiltrate

with

admixed

lymphocytes,histio

cytes,

andim

maturemyeloid

cells

Resolvedspontaneously

1564/ M

AML(M

6)on

G-CSF

Edematousplaqueson

theuppereyelids,right

auriculararea

andthechestw

all;subcutaneous

induratio

nswith

mild

erythemaon

thebutto

ck

Highfever

Dense,predominantly

lobularneutrophilic

infiltrate

Began

toregressbefore

induction

ofmethylprednisolone

1666/ M

MDSon

G-CSF

5×3cm

tender,firm,erythem

atousnoduleon

the

leftanterior

upperarm;1

-yearhistoryof

tender,

erythematousnodulesin

varyinglocatio

ns

Afebrile

Dense

neutrophilicinfiltratepredom

inatelyin

subcutaneous

septae;few

neutrophils

exhibitedabnorm

alsegm

entatio

n

N/A

1778/ M

MDS

Multip

lenon-tender,small,indurated,erythematous

toviolaceous

nodulesin

subm

entalregion

Recurrent

and

episodic

fevers

(>38

°C)

Neutrophilic

infiltrateinvolvingseptae

and

lobulewith

prom

inentleukocytoclasia

N/A

18;two

cases

47/ M

MDS(RCMD)on

AZA

Multip

leerythematousnoduleson

lowerextrem

ities

Fever

Markedlobularneutrophilicinfiltrate

Responded

tocorticosteroid

62/F

MDS(RCMD)on

AZA

Tender,erythem

atouslesionsatAZAinjectionsites

(abdom

en)

Fever

Markedsubcutaneous

neutrophilicinfiltrate

extendingto

thelower

derm

isProm

ptresponsetocorticosteroids

19;four

cases

53/ M

AML

Tender

subcutaneous

noduleson

thebutto

ckand

thigh

Highfever,

fatig

ue,

dyspnea

Predom

inantly

lobularneutrophilicinfiltrate

Resolvedspontaneously

53/F

AML

Multip

letender,indurated,erythem

atousand

edem

atousplaques(3–7

cm)on

allthe

extrem

ities

Fever

Predominantly

lobularneutrophilicinfiltrate

with

occasionalhypersegmentatio

nand

leukocytoclasis

Resolvedspontaneously

41/ M

AML-M

2Severaltendernoduleson

thearmsandthighs

(1–

3cm

),no

erythemaor

surfacechanges

Predom

inantly

septalneutrophilicinfiltrate

with

leukocytoclasisandfocalfatnecrosis

Resolvedspontaneously

J Hematopathol

that was exclusively or predominantly located in the subcuta-neous tissue. Although most of the cases described showed alobular distribution [8, 12–15, 18, 19], the infiltrate may alsodominate the septa [16, 19], or both [11, 17]. By definition, tobe called subcutaneous SS, there should be no associatedvasculitis or other cause of panniculitis. Clinically, the lesionmay resolve spontaneously or be successfully treated withcorticosteroids. It may also respond to chemotherapy, as inour patient. Since the cases shared similar clinical and patho-logical manifestations and all occurred in patients with mye-loid disorders, they should all be classified as subcutaneousSS [6, 19].

The etiology of subcutaneous SS is still unknown. It hasbeen postulated that uncontrolled release of pro-inflammatorymediators may contribute to the development of subcutaneousSS [11]. Indeed, increased level of granulocyte colony-stimulating factor (G-CSF) and all-trans retinoic acid(ATRA) chemotherapy have been linked to the disease[14–16]. G-CSF induces neutrophil mobilization by increas-ing the production of macrophage inflammatory protein 2(MIP-2) in the bone marrow [21]; and ATRA has been shownto induce gene expressions of a number of CXC and CCchemokines in acute promyelocytic leukemia cells [22].

Interestingly, subcutaneous SS may occur prior to the acutetransformation of the underlying myeloid disorders. Cooperet al. reported a patient with MDS and subcutaneous SS whodeveloped AML 11 weeks after the skin lesion appeared [8].Cullity et al. described a case of “Sweet’s panniculitis” occur-ring on a patient with MDS transforming to AML [10]. Thepresent case demonstrated a clear association between thecourse of the skin lesion and the underlying CML, in whichthe nodules occurred prior to the patient entering a presumedaccelerated phase and regressed after starting chemotherapy. Ithas been shown that high expression of CXC chemokineligand 4 (CXCR4) and activation of the CXCR4-CXCL12axis can promote leukemogenesis and the progression ofAML [23]. On the other hand, increased cytokines/chemokines will lead to the activation or recruitment ofmacrophages/neutrophils which may play a role in the patho-genesis of subcutaneous SS.

A diagnosis of subcutaneous SS should be made only afterruling out other possible conditions [24]. Leukemia cutis is animportant differential, as both entities may occur in a similarclinical setting. Microscopically, leukemia cutis typicallyshows a perivascular and/or periadnexal leukemic infiltrateor a dense interstitial/nodular infiltrate involving the dermisand subcutis. Immunohistochemistry, in most cases, is veryhelpful in confirming a diagnosis of leukemia cutis [25].Erythema nodosum (EN) may be indistinguishable from sub-cutaneous SS, both clinically and histologically. EN is themost common form of panniculitis. EN is a hypersensitivityreaction with a spectrum of histologic features that is related tothe morphologic chronology of the disease [26]. TheT

able1

(contin

ued)

Reference

Age/

sex

Myeloid

disorder

Clin

icalmanifestatio

nsof

thelesion

General

symptom

sHistopathologicfindings

ofthelesion

Clin

icalcourse

Fever,diffuse

swellin

gof

the

extrem

ities

62/F

MDS

Violaceousplaqueson

thelegs

N/A

Dense

neutrophilicinfiltratewith

inthe

superficialsubcutis,som

eneutrophils

appeared

hyposegm

ented

Resolvedafteroralprednisone

Present

case

43/F

CML

Five

subcutaneous

firm

,tender,erythematous

noduleson

medialright

thighandarms(upto

4cm

)

Fever,fatig

ue,

pain

inabdomen

and

extrem

ities

organizing

fatn

ecrosisanddenselobular

neutrophilicinfiltrateassociated

with

fibrinoidnecrosisandnumerous

macrophages

Responded

tochem

otherapy

with

idarubicin

andcytarabine

AMLacutemyeloid

leukem

ia,A

PMLacuteprom

yelocytic

leukem

ia,A

TRAall-trans-retin

oicacid,A

ZAazacitidine,C

MLchronicmyelogenous

leukem

ia,G

-CSF

granulocytecolony-stim

ulatingfactor,

MDSmyelodysplasticsyndrome,N/A

notavailable,RAEBrefractory

anem

iawith

excessblasts,R

ARSrefractory

anem

iawith

ringed

sideroblasts,R

CMDrefractory

cytopeniawith

multilineage

dysplasia,

SSSweet’s

syndrome

J Hematopathol

prototypical lesions present as a septal panniculitis with amixed cellular infiltrate comprising lymphocytes, neutrophils,histiocytes, giant cells, and variable eosinophils. Occasionally,EN may demonstrate a predominant neutrophilic component[27]. The presence of Miescher radial granulomas is thoughtto be relatively specific for EN [7, 19]. However, it has alsobeen reported in SS, Behcet’s disease, and necrobiosislipoidica [28]. Additionally, several other conditions that canlead to subcutaneous neutrophilic inflammation should beexcluded, including infection, pancreatic panniculitis, alpha-1 antitrypsin deficiency, rheumatoid arthritis, with inflamma-tory bowel disease, and local reaction secondary to injection[6, 19, 24].

In conclusion, we report the first case of subcutaneous SSoccurring in the setting of CML. Subcutaneous SS is a rareentity associated with MDS, AML, and CML. In our opinion,it is important to recognize and differentiate subcutaneous SSfrom other diseases and conditions, as subcutaneous SS maybe a warning sign of progression of the underlying myeloiddisorder.

Conflict of interest The authors declare that they have no conflict ofinterest.

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