American Journal of Hematology 32:134-137 (1 989)

Chronic Myelogenous Leukemia and Sweet Syndrome

Philip R. Cohen and Razelle Kurzrock Department of Dermatology, College of Physicians and Surgeons of Columbia University, New York (P.R.C.); Department of Clinical

Immunology and Biological Therapy, University of Texas, M.D. Anderson Cancer Center, Houston (R.K.)

We report a 64-year-old woman with chronic myelogenous leukemia of 3 years duration who developed Sweet syndrome. Improvement in her blood counts after hydroxyurea was not associated with a decrease in size of the skin lesions. However, the cutaneous lesions of Sweet syndrome quickly resolved with systemic prednisone. Sweet syndrome has only been documented in the literature for five other chronic myelogenous leukemia patients. The characteristics, treatment, and differential diagnosis of this disorder in chronic myelogenous leukemia patients are reviewed.

Key words: acute febrile neutrophilic dermatosis, malignancy, Sweet syndrome, chronic myelogenous leukemia, leukemia

INTRODUCTION

An acute febrile neutrophilic dermatosis was initially described in eight women by Dr. Robert Douglas Sweet in I964 [ I 1. The condition was characterized clinically and histologically by I ) pyrexia; 2) neutrophilia; 3 ) pain- ful , erythematous plaques; 4) a dense dermal infiltrate of mature neutrophils; and 5 ) a rapid response to cortico- steroid therapy [ 1,2]. The disease, which is commonly referred to as Sweet .sytzdrotne (SS), is associated with a hematologic malignancy or a solid tumor in approxi- mately 20% of the reported cases 131. The skin lesions of SS either preceded or coincided with the detection of a previously undiagnosed leukemia in more than 60% of patients with hematologic nialignancy-associated SS 131. In contrast to acute myelogenous leukemia (AML) (the most common underlying neoplasm), chronic niyeloge- nous leukemia (CML) has seldom been reported in pa- tients with malignancy-associated SS [3,4].

CML is a myeloproliferative disorder characterized by a profound elevation in perpheral leukocyte counts ac- companied by granulocytic hyperplasia of the bone mar- row. The disease evolves from an easily controlled chronic phase to a terminal blast transformation phase in a median period of about 4 years 151. Specific and non- specific dermatologic manifestations of CML have been described: The former are referred to as leukemia cutis or chloromus and the latter as leukemids [6]. The cutaneous lesions of malignancy-associated SS are an example of a leukemid. Whereas the appearance of a chloroma (gran-

ulocytic sarcoma) is associated with an ominous progno- sis for a patient with CML, a leukemid may present before, concurrent with, or after the diagnosis of the systemic leukemia [6].

Five reports of SS associated with CML have been previously published (Table I) [7-121. We reporl the sixth patient with SS and CML. The epidemiologic, clin- ical, and laboratory characteristics of CML-associated SS are reviewed, and the treatment, pathogenesis, and differential diagnosis of SS are discussed.

CASE REPORT

In 1982, a 61-year-old white woman was referred to our clinic because of leukocytosis. Past medical history included a diagnosis of congestive heart failure, which had been stable for several years with daily digoxin ther- apy. Physical examination revealed a palpable spleen tip at the left costal margin. The rest of the examination was unremarkable. Laboratory tests revealed an elevated white blood cell count and a hypercellular bone marrow without excess blasts. The predominant cells in both the blood and bone marrow were granulocytes; monocyte counts were normal. On the basis of these results, a

Received for publication February 1 , 1989; accepted April 13, 1989.

Address reprint requests to Dr. Philip K. Cohen, 7900 Cambridge #252C, Houston, TX 77054.

0 1989 Alan R. Liss, Inc.

Case Report: CML-Associated Sweet Syndrome 135

TABLE I. Characteristics of Five Patients With Sweet Syndrome and Chronic Myelogenous Leukemia*

Epidemiologic Laboratory

Neutrophilia Clinical Interval Recurrence from CML Fever (neutrophil Anemia

Case Age (years) Sex (No. ) (months) (temp. ,“C) Site of lesions countimm’) (hemoglobin, gidl) Reference

I 67 M None 0 + U Ext + + 7

2 19 F Yes 24 + U Ext + + 8

(38.0) H&N (7,200) (10.9)

(>3) (38.9) H&N (8,000) (8.7) L Ext Trunk

3 32 F Yes 32 + U Ext + NR 9 (1) (39.0) L Ext ( 1 0,600)

10, 4 78 F Yes 0 + U Ext + (1) (NR) H&N (7,995) (12.8) 11

5 64 F Yes 36 - U Ext + + CR

-

( 1 ) (37.2) (30,000) (10.5)

T M L , chronic myelogenous leukemia; CR, present case report; F, female; H&N, head and neck; L Ext, lower extremities; M, male; NR, not reported; U Ext, upper extremities; -, characteristic absent; +, characteristic present. Definitions: Anemia: hemoglobin level of 13.0 gidl or less in men and 12.0 gidl or less in women; fever: temperature of 38°C or more; interval from CML: time duration by which the diagnosis of Sweet syndrome followed the diagnosis of CML; neutrophilia: neutrophil count of 6,000 cellsimm’ or more. An afebrile female patient who presented with lesions of Sweet syndrome and subsequently developed CML is also cited in the Spanish literature [12], yet additional characteristics form the original description of this sixth case of CML-associated Sweet syndrome are currently unavailable

diagnosis of chronic myelogenous leukemia was made. The patient was treated with intermittent hydroxyurea for the next 3 years with good control of her disease.

In August 1985, she complained of skin lesions on her hands, which had steadily worsened over the preceding 3 months. There was no previous history of skin problems. She had not had any recent respiratory tract infections, joint pain, eye problems, or fever. The patient had taken several courses of oral antibiotics for these lesions with- out any improvement. Physical examination revealed a thin woman in no distress. Temperature was 37.2”C. Examination of the hands and fingers revealed multiple, bilateral, nonsymmetrical, erythematous, ulcerating, painful nodules and plaques. Her spleen extended 14 cm below the left costal margin. Cardiovascular and chest examination were completely normal. There was no pe- ripheral edema. Laboratory tests were as follows: white blood cells, 57.0 x lo3 cells/mm3 with 64% neutrophils; hemoglobin, 10.5 g/dl; hematocrit, 29%; platelet count, 307 x 103/mm’; bone marrow cellularity, 100%; and bone marrow blasts, 4.7%. Urinalysis showed no evi- dence of infection or proteinuria. Roentgenogram of the chest revealed bilateral interstitial infiltrates that had not been seen on previous examinations. Cardiac size was normal. Sputum gram and acid fast stains and cultures were negative for bacteria and mycobacterial organisms.

The patient’s leukemia was treated with hydroxyurea, and a repeat course of antibiotics was initiated. After 2

weeks, her white blood count had decreased to 15.0 X 10’ cells/mm3 and her spleen size was smaller. However, her skin lesions continued to worsen. At this time, bi- opsy of one of the skin lesions was performed and showed extensive neutrophilic infiltration of the dermis, edema of the upper dermis, and hyperplasia of the epi- dermis. Minimal nuclear dust and endothelial swelling were present. There was no fibrinoid necrosis of, cellular infiltration into, or extravasation of erythrocytes from the blood vessels. Special stains for bacteria, acid fast ba- cilli, and fungi were negative, as were bacterial, myco- bacterial, and fungal cultures. These findings suggested a diagnosis of Sweet syndrome. Chest roentgenogram was unchanged. The etiology of the pulmonary infiltrates remained unclear, and the patient refused lung biopsy. The patient was treated with 60 mg of prednisone, ad- ministered orally, daily. A dramatic improvement in the skin lesions was noted within 5 days. Surprisingly, re- peat chest roentgenogram on day 5 showed resolution of the pulmonary infiltrates. The prednisone was tapered gradually and completely discontinued after a total of 6 weeks. Although the skin lesions had completely re- solved, leaving only residual hyperpigmentation in af- fected areas, recurrent plaques were noted 1 week after discontinuation of prednisone. A repeat 6 week course of tapering prednisone doses was given with complete res- olution of skin lesions. Since then, there have been no further recurrences of Sweet syndrome.

136

DISCUSSION

Case Report: Cohen and Kurzrock

Idiopathic SS predominantly occurs in middle-aged women with a prior upper respiratory tract infection and represents the classical description of an acute febrile neutrophilic dermatosis [ 1 I . Fever, neutrophilia, an ele- vated erythrocyte sedimentation rate, and a characteristic neutrophilic dermal infiltrate are cardinal features. The skin lesions, most frequently located on the upper ex- tremities, head, and neck, typically appear as red, pseudovesicular plaques and nodules [ 2 ] . Musculoskel- etal, ocular, and/or renal manifestations of SS may also be present 141. The disorder promptly responds to corti- costeroid thcrapy but may recur in approximately one- third of patients 131.

Nearly one-fifth of the reported cases of SS are asso- ciated with a hematologic malignancy (most frequently AML) or B solid tumor (usually a carcinoma of the gen- itourinary organs) [3]. In contrast to idiopathic SS, SS in patients with hematologic malignancies is characterized by 1 ) no sexual predilection; 2) typical and/or more se- vere (vesicular, bullous, and/or ulcerative) cutaneous lesions; 3) extracutaneous involvement in nearly S O per- cent of patients; 4) absence of neutrophilia in over one- half of the patients; 5 ) frequent anemia and abnormal platelet counts; and 6 ) a high rate of recurrence (about 70%), which often heralds a tumor relapse [3]. Similar to the situation in idiopathic SS, a dramatic response to corticosteroid therapy is observed-even when the asso- ciated malignancy remains untreated or progresses [4]. Importantly, the onset of SS occurred prior to or coinci- dent with that of the associated malignancy in nearly two-thirds of these patients [ 3 ] . Thus, the absence of neutrophilia does not rule out the diagnosis of SS in a patient with a hematologic malignancy, and the presence of atypical skin lesions, anemia, and/or an abnormal platelet count in an SS patient should prompt a diligent evaluation for an underlying or relapsing hematologic disorder [2-41.

In addition to our patient, malignancy-associated SS has been reported in five other individuals with CML (Table I) [7-12]. CML-associated SS is characterized by a male to female ratio of 1 5 and a median onset age of 64 years. None of the patients had a preceding upper respiratory tract infection, and lesions of SS appeared either concurrent with or subsequent to the diagnosis of leukemia. More than one episode of SS occurred in four patients with CML; the recurrence was associated with the transformation into blast crisis for one patient [9]. Similar to our patient, lowering or discontinuing the cor- ticosteroid therapy too rapidly also prompted skin lesions of SS to recur in a CML patient [ l O , l I ] . The multiple recurrent episodes of SS in another CML patient were related to neither an exaccerbation of her leukemia nor

the corticosteroid management of her cutaneous SS le- sions [S].

Clinical and laboratory characteristics of CML-asso- ciated SS revealed neutrophilia, fever, and anemia in five, four, and three individuals, respectively (Table I) [7-121. Only one patient had thrombocytopenia [ X I ; three individuals (including our patient) had normal platelet counts [7,10,1 I ] . The erythrocyte sedimentation rate was elevated (greater than 100 mm/hr) in the two CML patients with reported values [7,8]. All patients had cutaneous lesions on the upper extremities. Three patients also had lesions on their head and neck; in ad- dition, either the lower extremities or the trunk was in- volved in one patient.

Extracutaneous manifestations of SS were present in three CML patients. Musculoskeletal symptoms of either myalgias [ X I or arthralgias [ 10,l I ] were described in two individuals. Pulmonary involvement of SS, which ap- peared as a new onset (sputum culture negative) lung infiltrate on chest roentgenogram whose clinical course paralleled that of the concurrent skin lesions, occurred in our patient. The lung lesions responded to corticosteroid, and the pulmonary infiltrates were not present on subse- quent chest roentgenograms. Similar pulmonary stigmata of SS have also been reported in three other patients with malignancy-associated SS [ 13-15]. In addition, open lung biopsy specimens from two of these patients re- vealed an extensive neutrophilic infiltrate of their pul- monary parenchyma reminiscent of that observed on their corresponding skin biopsies [ 14,151. In one of these patients, when corticosteroid therapy was tapered, the pulmonary infiltrate recurred on five separate occasions [IS].

Corticosteroids are the treatment of choice for both idiopathic and malignancy-associated SS. The CML pa- tients with SS were treated with systemic prednisone. The skin lesions and extracutaneous manifestations of SS promptly responded and subsequently resolved in all of these patients-even in those individuals with progres- sive leukemia [7,9].

The pathogenesis of SS is unknown. Several immu- nologic mechanisms have been proposed. A primary eti- ologic role of the neutrophil has been postulated. Also, the possibility that the skin lesions represent a specific isomorphic response (similar to a Koebner phenomenon) to various nonspecific external stimuli has been consid- ered.

Individually, none of the above theories are able to account for many of the characteristic features of SS, specifically, the pyrexia, the neutrophilia, and the in- creased erythrocyte sedimentation rate. These biologic effects can be mediated by certain endogenous cyto- kines. It is possible that inappropriate secretion of one or several of these cytokines, such as granulocyte colony-

Case Report: CML-Associated Sweet Syndrome 137

stimulating factor (G-CSF), epidermal cell thymocyte- activating factor, and/or interleukin-1, might have a role in the pathogenesis of SS [2,3]. Presently, no experi- ments exploring this intriguing hypothesis have been per- formed. However, Glaspy and colleagues [16] have re- cently described skin lesions compatible with those of Sweet syndrome in a hairy cell leukemia patient treated with G-CSF. Unfortunately, the diagnosis of SS was not confirmed by skin biopsy [17]. Additional clinical and laboratory investigation are necessary and warranted to determine whether endogenous cytokines directly and/or indirectly mediate the clinicopathologic manifestations of ss.

The clinical differential diagnosis of SS includes sev- eral inflammatory and infectious disorders, certain sys- temic diseases (Behqet disease, familial mediterranean fever, lupus erythematosus, dermatomyositis, and bowel bypass syndrome), reactive erythemas, vasculitis, neo- plastic processes (leukemia cutis, lymphoma, and meta- static tumor), and other miscellaneous conditions (hala- genoderma, granuloma faciale, and drug eruptions) [2,3]. Importantly, in a febrile CML patient, an infec- tious disease and a chloroma should be seriously consid- ered in the evaluation of a new erythematous plaque. In contrast to lesions of infectious etiology, cutaneous le- sions of SS have negative results after special stains and/ or bacterial and fungal cultures and do not improve with antibiotic therapy [4]. Chloromas (granulocytic sarco- mas) may be differentiated from SS skin lesions histo- logically: The former contains a dermal infiltrate of im- mature myeloid cells, and the latter is composed of mature neutrophils [6]. Therefore, when the diagnosis of SS is being considered in a patient with CML, it is es- sential to obtain a lesional skin biopsy specimen for his- tologic evaluation, special staining, and culture of bac- terial and fungal organisms.

CONCLUSIONS

In CML patients, SS was often the presenting sign of their hematologic disease. CML-associated SS was typ- ically characterized by pyrexia, neutrophilia, painful cu- taneous lesions of the upper extremities with pathogno- monic histologic features occurring in elderly women. Anemia was often present, and the platelet count was frequently normal. Musculoskeletal and pulmonary ex- tracutaneous manifestations were described in these pa- tients. Infectious diseases and chloromas should espe-

cially be considered in the differential diagnosis of SS in patients with CML and a lesional skin biopsy to be eval- uated histologically and cultured is strongly recom- mended. Both the skin lesions and extracutaneous man- ifestations of CML-associated SS were effectively treated with corticosteroid therapy.

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