Case report
Vital organ involvement in Sweet’s syndrome with myelodysplastic syndrome: a case report and literature review Yun Li, MD, Mi Ai, MD, Wei-bing Yang, MD, PhD, and Xin Li, MD
Department of Dermatology, 181st Hospital of the Chinese People’s Liberation Army, Guilin, China Correspondence Wei-bing Yang, MD, PhD Department of Dermatology 181st Hospital of the Chinese People’s Liberation Army Guangxi, Guilin 541002 China E-mail: [email protected] Conflicts of interest: None.
In 1964, Sweet1 described a condition resembling erythema multiforme in appearance and duration, which resulted in a distinctive and fairly severe illness featuring the onset of fever, an elevated neutrophil count, and the emergence of tender erythematous skin lesions (papules, nodules, and plaques) mainly located on the face, neck, and upper extremities. Histopathology findings indicated a diffuse infiltrate with predominantly mature neutrophils typically located in the upper dermis without involvement of the epidermis. Sweet found that systemic corticosteroids were significantly efficacious for treating this disease. Later, this disease was designated Sweet’s syndrome (SS). The bones, central nervous system, ears, eyes, kidneys, intestines, liver, heart, lung, mouth, muscles, and spleen can be involved in SS as extracutaneous manifestations.2 Investigations into the relationship between SS and malignancies have alerted physicians to the possibility that patients who develop new or recurrent lesions may have an underlying malignancy.3,4 We report a patient who developed fever and painful erythematous skin lesions with myelodysplastic syndrome (MDS) and died of multiple organ failure. Case report A 63-year-old woman without a significant past medical history presented at our hospital on May 5, 2011, with a ª 2014 The International Society of Dermatology
2-week history of pain in both knees, followed by fever and the occurrence of tender erythematous skin lesions on the face, neck, and extremities. She also had cough and purulent sputums. She denied any upper respiratory tract infection or use of medication in the three weeks preceding the pain in her knees. Physical examination showed that the patient’s face, lips, and nail beds appeared pale. Her blood pressure was 109/72 mmHg, her heart rate was 105 bpm, her respiratory rate was 22 breaths/min, and her temperature was 38.3 °C. Erythematous, well-demarcated papules and plaques ranging from 0.5 9 0.5 cm to 3.0 9 4.0 cm in size, with central clearing, were sporadically located on the face, oral mucosa, and limbs. Some lesions appeared bullous; others had become ulcerated. The patient suffered severe conjunctiva hyperemia with impaired vision in the right eye (Fig. 1). Fundus examination revealed subhyaloid hemorrhage. Physical examination of the patient’s heart, lungs, and abdomen was unremarkable except for a negligibly enlarged area of cardiac dullness to percussion. Laboratory data revealed a white blood cell count of 10.82 9 109 cells/l (neutrophils 68%), hemoglobin of 51 g/l, platelet count of 21 9 109/l, circulating blasts of 8%, and erythrocyte sedimentation rate (ESR) of 80 mm/h. Renal and liver function tests were normal. A bone marrow aspirate and biopsy revealed refractory anemia with an excess of blasts (RAEB, 9.5% blasts). A skin biopsy specimen from the International Journal of Dermatology 2015, 54, 1303–1308
1303
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Li et al.
Sweet’s syndrome with myelodysplastic syndrome
Figure 2 Histopathology shows mild subepidermal edema and a diffuse inflammatory infiltrate in the dermis. (Hematoxylin and eosin stain; original magnification 9100)
left upper limb showed mild subepidermal edema, a diffuse infiltrate of predominantly mature neutrophils, and nuclear dust. Histopathology showed no evidence of vasculitis or epidermal involvement (Figs. 2 and 3). A chest radiograph showed patchy infiltrates in the left lower lobe without pleural effusions. Autoimmune antibodies, antistreptolysin-O antibody, and rheumatoid factor were absent. Serology tests of immunoglobulins (IgG, IgA, IgM), C3, and C4 revealed no abnormality. Hence, a diagnosis of SS and MDS-RAEB was established. The patient was given transfusions of leukocytereduced blood components and platelets. Despite treatment with broad-spectrum antibiotics and oral prednisone
(a)
(60 mg/d), the patient’s clinical condition deteriorated while her fever persisted (38.5–39.3 °C). Three days after admission, the patient developed two new papules on her face and complained of fatigue and dizziness. Her current white blood cell count was 14.72 9 109 cells/l (neutrophils 75%). However, cultures of sputum and blood remained sterile. Computed tomography of the chest revealed dense areas in the right middle and lower lobes and the left lower lobe with bilateral moderate pleural effusions. Antimycotic therapy with oral fluconazole (200 mg/d) was initiated. Nine days after admission, the patient failed to urinate for 18 hours until furosemide was administered (40 mg IV). Her urinary output decreased to < 17 ml/h. The patient’s serum creatinine and blood urea nitrogen (BUN) levels showed no abnormality in this period, whereas serum cystatin C elevated from 0.6 mg/l at admittance to 1.27 mg/l (enzyme immunoassay [EIA]). We ruled out urinary tract obstruction and initiated treatment for kidney failure. Meanwhile, the patient developed orthopnea and dyspnea. The patient presented moist rales in the lungs and developed a new systolic heart murmur and symmetric pitting edema in the lower limbs. Vital signs were: blood pressure, 76/50 mmHg; heart rate, 180 bpm; respiratory rate, 30 breaths/min; and temperature 39.2 °C. Her white blood cell count and hepatic serum enzymes increased progressively (Figs. 4 and 5). Arterial blood gas analysis revealed respiratory acidosis and respiratory failure type I. Transthoracic echocardiography revealed dilated ventricles, left atria and aorta (left ventricle, 58.7 mm; right ventricle, 24.4 mm; left atria 40.7 mm; ascending aortic dimension 37.7 mm) with impaired systolic function and a small pericardial effusion. All of these clinical symptoms and auxiliary examination results suggested whole heart failure. The patient’s condition worsened, and she died of multiple organ failure. For religious reasons, no autopsy was performed.
(b)
Figure 1 Clinical examination showed erythematous, well-demarcated papules and plaques with central clearing on the (a) face and (b) left elbow of a 63-year-old woman. The patient demonstrated severe conjunctiva hyperemia in the right eye and an ulcer on the oral mucosa International Journal of Dermatology 2015, 54, 1303–1308
ª 2014 The International Society of Dermatology
Li et al.
Figure 3 Histopathology shows neutrophils and nuclear dust in the dermis, with no evidence of vasculitis. (Hematoxylin and eosin stain; original magnification 9400)
Discussion Nowadays, SS is considered to present in three major different types: classical (or idiopathic) SS; malignancyassociated SS (MASS); and drug-induced SS.2 In 1986, Su and Liu5 proposed the original diagnostic criteria for classical SS. In 1994, von den Driesch6 modified these criteria to include: (i) abrupt onset of painful erythematous plaques or nodules; (ii) histopathologic evidence of a
Sweet’s syndrome with myelodysplastic syndrome
Case report
dense neutrophilic infiltrate without evidence of leukocytoclastic vasculitis; (iii) pyrexia of > 38 °C; (iv) association with an underlying hematologic or visceral malignancy, inflammatory disease, or pregnancy, or a prior upper respiratory or gastrointestinal infection or vaccination; (v) an excellent response to treatment with systemic corticosteroids or potassium iodide; and (vi) abnormal laboratory values at presentation to include three of: ESR of > 20 mm/h; positive C-reactive protein; > 8000 leukocytes; and > 70% neutrophils. Both of the major (i and ii) and two of the four minor (iii–vi) criteria are required to be present in order to establish a diagnosis of classical SS. Classical SS and MASS share the same diagnostic criteria. In 1996, Walker and Cohen7 established diagnostic criteria for drug-induced SS. The basic pathogenesis of SS is unclear. The following points show close associations. (i) Bacterial infection: most patients with classic SS develop skin lesions 1–3 weeks after a febrile upper respiratory tract infection or tonsillitis. The symptoms and lesions of some patients with inflammatory disorders resolve after treatment with antibiotics. (ii) A hypersensitivity reaction to bacterial, viral, or tumor antigens for treatment of systemic corticosteroids is efficacious. (iii) Circulating autoantibodies, cytokines, dermal dendrocytes, human leukocyte antigen serotypes, immune complexes, and leukotactic mechanisms have all been postulated to partially contribute to the pathogenesis and development of SS.2 Studies by Cohen and Kurzrock3,8 show that 21% of cases represent MASS, there is no difference in morbidity between male and female patients, and 85% of cases represent hematologic malignancy and 15% represent solid tumor malignancy. In this setting, the most common hematologic malignancy is acute myelogenous leukemia
Figure 4 White blood cell counts and neutrophil levels in the present 63-year-old female patient at and after admission ª 2014 The International Society of Dermatology
International Journal of Dermatology 2015, 54, 1303–1308
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Li et al.
Sweet’s syndrome with myelodysplastic syndrome
Figure 5 Results of liver function tests, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), c-glutamyl transpeptidase (c-GT) and direct bilirubin (DBIL), in the present patient at and after admission
(42%), followed by lymphoma (11%) and MDS (9%). Chronic lymphocytic leukemia, hairy cell leukemia, and myeloproliferative disorders are relatively rare. The most common solid tumor in MASS is genitourinary tumor (37%), followed by breast tumor (23%) and gastrointestinal organs tumor (17%). Tumors in the lung, thyroid, and larynx are relatively rare. Malignancy-associated SS can precede, follow, or appear concurrently with the diagnosis of the patient’s malignancy. Hence, MASS may represent a clue to either an undiagnosed malignancy in a previously healthy individual or an unsuspected recurrence of malignancy in an oncology patient. In patients with MASS, the elevation of granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-c (IFN-c), interleukin-1 (IL-1), IL-3, IL-6, and IL-8 is common.2–4, 9–11 At present, G-CSF is considered to be most closely related to the pathogenesis of SS in cytokines. The exogenous administration of G-CSF may induce SS. However, Kawakami et al.12 found that the suppression of neutrophil apoptosis induced by G-CSF and serum G-CSF levels were both higher in patients with active SS compared with those with inactive SS and healthy controls. These findings partially explained the accumulation of neutrophil in tissues. In addition, the suppression of neutrophil apoptosis may be deeply involved in the pathogenesis of SS. The skin lesions and extracutaneous manifestations of SS present as sterile neutrophilic infiltrates. Patients with MASS are more likely to develop extracutaneous manifestations. Although involvement of the heart and lung is relatively rare, prognoses tend to be poor. The aortic valve, atrioventricular valves, endocardium, myocardium, and great cardiac vessels (aorta, bracheocephalic trunk, International Journal of Dermatology 2015, 54, 1303–1308
and coronary arteries) can be involved, which may cause aortic stenosis, aortitis, coronary artery occlusion, valvular regurgitation, valvular perforation, cardiomegaly, and heart failure.2,13–16 Shimizu16 reported a patient with SS and MDS who died of cardiac arrest. During hospitalization, the patient’s MDS refractory anemia seemed to have evolved to MDS-RAEB. Antibiotics and corticosteroid therapy did not alter the patient’s worsening condition. The autopsy revealed a perivascular and myocardial infiltration by neutrophils, which was considered responsible for the cardiomegaly. In addition, the lung was infiltrated by neutrophils.16 Patients with lung involvement may present with neutrophilic inflammation in pulmonary tissue, pleural effusions containing abundant neutrophils without microorganisms, or even progressive pharyngeal mucosal infiltration and edema resulting in upper airway obstruction.2 Peters et al.17 reported a patient with SS and MDS with lung involvement. The skin lesions and lung involvement kept worsening during broad-spectrum antibiotics and corticosteroid therapy. However, although the patient’s condition improved after treatment with chemotherapy for myelodysplasia, the patient died within a period of months. Takimoto et al.18 reported another patient with SS and MDS with lung involvement. Having initially shown an excellent response to corticosteroids, the patient became resistant to the previous therapy within a short time and died of respiratory failure. Although treatment with corticosteroids is efficacious in most instances of classical SS and MASS, patients with MASS are more likely to be secondarily infected and resistant to corticosteroids. In addition, corticosteroid therapy may expand the infection. Patients with SS often have fever, and their skin lesions may appear as pustules and ulcers. Patients ª 2014 The International Society of Dermatology
Li et al.
with lung involvement may have pleural effusions and manifestations of pneumonia. Therefore, if there is no definite evidence of infection or there is a contraindication for corticosteroid therapy, potassium iodide or colchicine may be the best alternative choice. Some case reports19,20 have suggested that patients’ conditions might improve greatly with treatment with corticosteroids and antibiotics for specific microorganisms. Malignancy-associated SS is not rare. Patients may develop additional complications, such as secondary infection, resistance to corticosteroids, immune dysfunction, immunosuppression as a result of chemotherapy, and a poor general condition. All of these clinical data13,16,18 suggest that it is difficult to treat patients for complicated SS. In most cases, patients either had malignancy or developed vital organ dysfunctions and became resistant to corticosteroids. In addition, even in patients who respond positively to corticosteroids, recurrence of the dermatosis is noted in approximately one-third of individuals.2 The present patient demonstrated a more severe and progressive clinical course than those reported by Peters et al.17 and Takimoto et al.18 Our patient presented with arthralgia before the onset of skin lesions. However, although the patient did not undergo blood tests prior to admission, we assumed that her MDS preceded the skin lesions because her initial blood tests revealed substantial abnormalities. The patient exhibited fever and the clinical symptoms of pneumonia, but her condition was not improved by the administration of broadspectrum antibiotics. During hospitalization, her white blood cell count elevated progressively. Her hepatic and renal function decreased, the dense areas in her lung enlarged, and the aorta, valves, and myocardium became involved. The patient died just 10 days after admission. This suggests that patients with MASS may be subject to a progressive clinical course of disease, especially when vital organs, such as the heart, lung, kidney, and liver, are involved. The present patient presented multiorgan involvement indicated by conjunctivitis, oral ulcer, arthralgia, dense areas in the lungs with pleural effusions, cardiomegaly with pericardial effusions, liver dysfunction, and renal failure. To our knowledge, this is the first case involving this number of organs to be reported. Blood tests in the present patient revealed severe decreases in the red blood cell count and blood platelet count and a dramatic increase in the white blood cell count. This may suggest that the patient’s MDS was evolving to leukemia. Some case reports of SS with vital organ involvement have been published.13–15,17–19,21,22 All of the patients reported were treated with corticosteroids; however, their prognoses differed dramatically. This suggests that the clinical features ª 2014 The International Society of Dermatology
Sweet’s syndrome with myelodysplastic syndrome
Case report
of these patients differ from those of patients with common SS. It is unfortunate that specific treatment protocols have yet to be developed for these patients. References 1 Sweet RD. An acute febrile neutrophilic dermatosis. Br J Dermatol 1964; 76: 349–356. 2 Cohen PR. Sweet’s syndrome – a comprehensive review of an acute febrile neutrophilic dermatosis. Orphanet J Rare Dis 2007; 2: 34. 3 Cohen PR, Kurzrock R. Sweet’s syndrome and cancer. Clin Dermatol 1993; 11: 149–157. 4 Cohen PR, Kurzrock R. Sweet’s syndrome and malignancy. Am J Med 1987; 82: 1220–1226. 5 Su WP, Liu HN. Diagnostic criteria for Sweet’s syndrome. Cutis 1986; 37: 167–174. 6 von den Driesch P. Sweet’s syndrome (acute febrile neutrophilic dermatosis). J Am Acad Dermatol 1994; 31: 535–556; quiz 557–560. 7 Walker DC, Cohen PR. Trimethoprim-sulfamethoxazoleassociated acute febrile neutrophilic dermatosis: case report and review of drug-induced Sweet’s syndrome. J Am Acad Dermatol 1996; 34: 918–923. 8 Cohen PR, Kurzrock R. Sweet’s syndrome: a neutrophilic dermatosis classically associated with acute onset and fever. Clin Dermatol 2000; 18: 265–282. 9 Choi HJ, Chang SE, Lee MW, et al. A case of recurrent Sweet’s syndrome in an 80-year-old man: a clue to an underlying malignancy. Int J Dermatol 2006; 45: 457–459. 10 van Hirtum PV, Prins M, ten Oever J, et al. Sweet syndrome in underlying malignancy. Ned Tijdschr Geneeskd 2010; 154: A2112. 11 Shinojima Y, Toma Y, Terui T. Sweet syndrome associated with intrahepatic cholangiocarcinoma producing granulocyte colony-stimulating factor. Br J Dermatol 2006; 155: 1103–1104. 12 Kawakami T, Ohashi S, Kawa Y, et al. Elevated serum granulocyte colony-stimulating factor levels in patients with active phase of Sweet syndrome and patients with active Behcßet disease: implication in neutrophil apoptosis dysfunction. Arch Dermatol 2004; 140: 570– 574. 13 Dorenkamp M, Weikert U, Meyer R, et al. Heart failure in acute febrile neutrophilic dermatosis. Lancet 2003; 362: 1374. 14 Guia JM, Frias J, Castro FJ, et al. Cardiovascular involvement in a boy with Sweet’s syndrome. Pediatr Cardiol 1999; 20: 295–297. 15 Hayashi I, Hosoda Y, Kawasaki S, et al. Aortic and mitral valve replacement in a patient with acute febrile neutrophilic dermatosis (Sweet’s syndrome): report of a case. Surg Today 2001; 31: 810–813. 16 Shimizu K. Neutrophilic infiltration of the myocardium in a patient with myelodysplastic syndrome. Am J Hematol 1998; 58: 337–338. International Journal of Dermatology 2015, 54, 1303–1308
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Sweet’s syndrome with myelodysplastic syndrome
17 Peters FP, Drent M, Verhaegh M, et al. Myelodysplasia presenting with pulmonary manifestations associated with neutrophilic dermatosis. Ann Hematol 1998; 77: 135–138. 18 Takimoto CH, Warnock M, Golden JA. Sweet’s syndrome with lung involvement. Am Rev Respir Dis 1991; 143: 177–179. 19 DiCaudo DJ, Ortiz KJ, Mengden SJ, et al. Sweet syndrome (acute febrile neutrophilic dermatosis) associated with pulmonary coccidioidomycosis. Arch Dermatol 2005; 141: 881–884. 20 Neau D, Monlun E, Delmas M, et al. Sweet syndrome and Yersinia enterocolitica infection Two cases. Rev Med Interne 1995; 16: 919–922.
International Journal of Dermatology 2015, 54, 1303–1308
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21 Garg R, Soud Y, Lal R, et al. Myelodysplastic syndrome manifesting as Sweet’s syndrome and bronchiolitis obliterative organizing pneumonia. Am J Med 2006; 119: 5– 7. 22 Imanaga T, Hayashi T, Yoshii C, et al. Pulmonary involvement in acute febrile neutrophilic dermatosis (Sweet’s syndrome). Nihon Kokyuki Gakkai Zasshi 2000; 38: 206–210.
ª 2014 The International Society of Dermatology
Vital organ involvement in Sweet’s syndrome with myelodysplastic syndrome: a case report and literature review Yun Li, MD, Mi Ai, MD, Wei-bing Yang, MD, PhD, and Xin Li, MD
Department of Dermatology, 181st Hospital of the Chinese People’s Liberation Army, Guilin, China Correspondence Wei-bing Yang, MD, PhD Department of Dermatology 181st Hospital of the Chinese People’s Liberation Army Guangxi, Guilin 541002 China E-mail: [email protected] Conflicts of interest: None.
In 1964, Sweet1 described a condition resembling erythema multiforme in appearance and duration, which resulted in a distinctive and fairly severe illness featuring the onset of fever, an elevated neutrophil count, and the emergence of tender erythematous skin lesions (papules, nodules, and plaques) mainly located on the face, neck, and upper extremities. Histopathology findings indicated a diffuse infiltrate with predominantly mature neutrophils typically located in the upper dermis without involvement of the epidermis. Sweet found that systemic corticosteroids were significantly efficacious for treating this disease. Later, this disease was designated Sweet’s syndrome (SS). The bones, central nervous system, ears, eyes, kidneys, intestines, liver, heart, lung, mouth, muscles, and spleen can be involved in SS as extracutaneous manifestations.2 Investigations into the relationship between SS and malignancies have alerted physicians to the possibility that patients who develop new or recurrent lesions may have an underlying malignancy.3,4 We report a patient who developed fever and painful erythematous skin lesions with myelodysplastic syndrome (MDS) and died of multiple organ failure. Case report A 63-year-old woman without a significant past medical history presented at our hospital on May 5, 2011, with a ª 2014 The International Society of Dermatology
2-week history of pain in both knees, followed by fever and the occurrence of tender erythematous skin lesions on the face, neck, and extremities. She also had cough and purulent sputums. She denied any upper respiratory tract infection or use of medication in the three weeks preceding the pain in her knees. Physical examination showed that the patient’s face, lips, and nail beds appeared pale. Her blood pressure was 109/72 mmHg, her heart rate was 105 bpm, her respiratory rate was 22 breaths/min, and her temperature was 38.3 °C. Erythematous, well-demarcated papules and plaques ranging from 0.5 9 0.5 cm to 3.0 9 4.0 cm in size, with central clearing, were sporadically located on the face, oral mucosa, and limbs. Some lesions appeared bullous; others had become ulcerated. The patient suffered severe conjunctiva hyperemia with impaired vision in the right eye (Fig. 1). Fundus examination revealed subhyaloid hemorrhage. Physical examination of the patient’s heart, lungs, and abdomen was unremarkable except for a negligibly enlarged area of cardiac dullness to percussion. Laboratory data revealed a white blood cell count of 10.82 9 109 cells/l (neutrophils 68%), hemoglobin of 51 g/l, platelet count of 21 9 109/l, circulating blasts of 8%, and erythrocyte sedimentation rate (ESR) of 80 mm/h. Renal and liver function tests were normal. A bone marrow aspirate and biopsy revealed refractory anemia with an excess of blasts (RAEB, 9.5% blasts). A skin biopsy specimen from the International Journal of Dermatology 2015, 54, 1303–1308
1303
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Li et al.
Sweet’s syndrome with myelodysplastic syndrome
Figure 2 Histopathology shows mild subepidermal edema and a diffuse inflammatory infiltrate in the dermis. (Hematoxylin and eosin stain; original magnification 9100)
left upper limb showed mild subepidermal edema, a diffuse infiltrate of predominantly mature neutrophils, and nuclear dust. Histopathology showed no evidence of vasculitis or epidermal involvement (Figs. 2 and 3). A chest radiograph showed patchy infiltrates in the left lower lobe without pleural effusions. Autoimmune antibodies, antistreptolysin-O antibody, and rheumatoid factor were absent. Serology tests of immunoglobulins (IgG, IgA, IgM), C3, and C4 revealed no abnormality. Hence, a diagnosis of SS and MDS-RAEB was established. The patient was given transfusions of leukocytereduced blood components and platelets. Despite treatment with broad-spectrum antibiotics and oral prednisone
(a)
(60 mg/d), the patient’s clinical condition deteriorated while her fever persisted (38.5–39.3 °C). Three days after admission, the patient developed two new papules on her face and complained of fatigue and dizziness. Her current white blood cell count was 14.72 9 109 cells/l (neutrophils 75%). However, cultures of sputum and blood remained sterile. Computed tomography of the chest revealed dense areas in the right middle and lower lobes and the left lower lobe with bilateral moderate pleural effusions. Antimycotic therapy with oral fluconazole (200 mg/d) was initiated. Nine days after admission, the patient failed to urinate for 18 hours until furosemide was administered (40 mg IV). Her urinary output decreased to < 17 ml/h. The patient’s serum creatinine and blood urea nitrogen (BUN) levels showed no abnormality in this period, whereas serum cystatin C elevated from 0.6 mg/l at admittance to 1.27 mg/l (enzyme immunoassay [EIA]). We ruled out urinary tract obstruction and initiated treatment for kidney failure. Meanwhile, the patient developed orthopnea and dyspnea. The patient presented moist rales in the lungs and developed a new systolic heart murmur and symmetric pitting edema in the lower limbs. Vital signs were: blood pressure, 76/50 mmHg; heart rate, 180 bpm; respiratory rate, 30 breaths/min; and temperature 39.2 °C. Her white blood cell count and hepatic serum enzymes increased progressively (Figs. 4 and 5). Arterial blood gas analysis revealed respiratory acidosis and respiratory failure type I. Transthoracic echocardiography revealed dilated ventricles, left atria and aorta (left ventricle, 58.7 mm; right ventricle, 24.4 mm; left atria 40.7 mm; ascending aortic dimension 37.7 mm) with impaired systolic function and a small pericardial effusion. All of these clinical symptoms and auxiliary examination results suggested whole heart failure. The patient’s condition worsened, and she died of multiple organ failure. For religious reasons, no autopsy was performed.
(b)
Figure 1 Clinical examination showed erythematous, well-demarcated papules and plaques with central clearing on the (a) face and (b) left elbow of a 63-year-old woman. The patient demonstrated severe conjunctiva hyperemia in the right eye and an ulcer on the oral mucosa International Journal of Dermatology 2015, 54, 1303–1308
ª 2014 The International Society of Dermatology
Li et al.
Figure 3 Histopathology shows neutrophils and nuclear dust in the dermis, with no evidence of vasculitis. (Hematoxylin and eosin stain; original magnification 9400)
Discussion Nowadays, SS is considered to present in three major different types: classical (or idiopathic) SS; malignancyassociated SS (MASS); and drug-induced SS.2 In 1986, Su and Liu5 proposed the original diagnostic criteria for classical SS. In 1994, von den Driesch6 modified these criteria to include: (i) abrupt onset of painful erythematous plaques or nodules; (ii) histopathologic evidence of a
Sweet’s syndrome with myelodysplastic syndrome
Case report
dense neutrophilic infiltrate without evidence of leukocytoclastic vasculitis; (iii) pyrexia of > 38 °C; (iv) association with an underlying hematologic or visceral malignancy, inflammatory disease, or pregnancy, or a prior upper respiratory or gastrointestinal infection or vaccination; (v) an excellent response to treatment with systemic corticosteroids or potassium iodide; and (vi) abnormal laboratory values at presentation to include three of: ESR of > 20 mm/h; positive C-reactive protein; > 8000 leukocytes; and > 70% neutrophils. Both of the major (i and ii) and two of the four minor (iii–vi) criteria are required to be present in order to establish a diagnosis of classical SS. Classical SS and MASS share the same diagnostic criteria. In 1996, Walker and Cohen7 established diagnostic criteria for drug-induced SS. The basic pathogenesis of SS is unclear. The following points show close associations. (i) Bacterial infection: most patients with classic SS develop skin lesions 1–3 weeks after a febrile upper respiratory tract infection or tonsillitis. The symptoms and lesions of some patients with inflammatory disorders resolve after treatment with antibiotics. (ii) A hypersensitivity reaction to bacterial, viral, or tumor antigens for treatment of systemic corticosteroids is efficacious. (iii) Circulating autoantibodies, cytokines, dermal dendrocytes, human leukocyte antigen serotypes, immune complexes, and leukotactic mechanisms have all been postulated to partially contribute to the pathogenesis and development of SS.2 Studies by Cohen and Kurzrock3,8 show that 21% of cases represent MASS, there is no difference in morbidity between male and female patients, and 85% of cases represent hematologic malignancy and 15% represent solid tumor malignancy. In this setting, the most common hematologic malignancy is acute myelogenous leukemia
Figure 4 White blood cell counts and neutrophil levels in the present 63-year-old female patient at and after admission ª 2014 The International Society of Dermatology
International Journal of Dermatology 2015, 54, 1303–1308
1305
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Case report
Li et al.
Sweet’s syndrome with myelodysplastic syndrome
Figure 5 Results of liver function tests, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), c-glutamyl transpeptidase (c-GT) and direct bilirubin (DBIL), in the present patient at and after admission
(42%), followed by lymphoma (11%) and MDS (9%). Chronic lymphocytic leukemia, hairy cell leukemia, and myeloproliferative disorders are relatively rare. The most common solid tumor in MASS is genitourinary tumor (37%), followed by breast tumor (23%) and gastrointestinal organs tumor (17%). Tumors in the lung, thyroid, and larynx are relatively rare. Malignancy-associated SS can precede, follow, or appear concurrently with the diagnosis of the patient’s malignancy. Hence, MASS may represent a clue to either an undiagnosed malignancy in a previously healthy individual or an unsuspected recurrence of malignancy in an oncology patient. In patients with MASS, the elevation of granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-c (IFN-c), interleukin-1 (IL-1), IL-3, IL-6, and IL-8 is common.2–4, 9–11 At present, G-CSF is considered to be most closely related to the pathogenesis of SS in cytokines. The exogenous administration of G-CSF may induce SS. However, Kawakami et al.12 found that the suppression of neutrophil apoptosis induced by G-CSF and serum G-CSF levels were both higher in patients with active SS compared with those with inactive SS and healthy controls. These findings partially explained the accumulation of neutrophil in tissues. In addition, the suppression of neutrophil apoptosis may be deeply involved in the pathogenesis of SS. The skin lesions and extracutaneous manifestations of SS present as sterile neutrophilic infiltrates. Patients with MASS are more likely to develop extracutaneous manifestations. Although involvement of the heart and lung is relatively rare, prognoses tend to be poor. The aortic valve, atrioventricular valves, endocardium, myocardium, and great cardiac vessels (aorta, bracheocephalic trunk, International Journal of Dermatology 2015, 54, 1303–1308
and coronary arteries) can be involved, which may cause aortic stenosis, aortitis, coronary artery occlusion, valvular regurgitation, valvular perforation, cardiomegaly, and heart failure.2,13–16 Shimizu16 reported a patient with SS and MDS who died of cardiac arrest. During hospitalization, the patient’s MDS refractory anemia seemed to have evolved to MDS-RAEB. Antibiotics and corticosteroid therapy did not alter the patient’s worsening condition. The autopsy revealed a perivascular and myocardial infiltration by neutrophils, which was considered responsible for the cardiomegaly. In addition, the lung was infiltrated by neutrophils.16 Patients with lung involvement may present with neutrophilic inflammation in pulmonary tissue, pleural effusions containing abundant neutrophils without microorganisms, or even progressive pharyngeal mucosal infiltration and edema resulting in upper airway obstruction.2 Peters et al.17 reported a patient with SS and MDS with lung involvement. The skin lesions and lung involvement kept worsening during broad-spectrum antibiotics and corticosteroid therapy. However, although the patient’s condition improved after treatment with chemotherapy for myelodysplasia, the patient died within a period of months. Takimoto et al.18 reported another patient with SS and MDS with lung involvement. Having initially shown an excellent response to corticosteroids, the patient became resistant to the previous therapy within a short time and died of respiratory failure. Although treatment with corticosteroids is efficacious in most instances of classical SS and MASS, patients with MASS are more likely to be secondarily infected and resistant to corticosteroids. In addition, corticosteroid therapy may expand the infection. Patients with SS often have fever, and their skin lesions may appear as pustules and ulcers. Patients ª 2014 The International Society of Dermatology
Li et al.
with lung involvement may have pleural effusions and manifestations of pneumonia. Therefore, if there is no definite evidence of infection or there is a contraindication for corticosteroid therapy, potassium iodide or colchicine may be the best alternative choice. Some case reports19,20 have suggested that patients’ conditions might improve greatly with treatment with corticosteroids and antibiotics for specific microorganisms. Malignancy-associated SS is not rare. Patients may develop additional complications, such as secondary infection, resistance to corticosteroids, immune dysfunction, immunosuppression as a result of chemotherapy, and a poor general condition. All of these clinical data13,16,18 suggest that it is difficult to treat patients for complicated SS. In most cases, patients either had malignancy or developed vital organ dysfunctions and became resistant to corticosteroids. In addition, even in patients who respond positively to corticosteroids, recurrence of the dermatosis is noted in approximately one-third of individuals.2 The present patient demonstrated a more severe and progressive clinical course than those reported by Peters et al.17 and Takimoto et al.18 Our patient presented with arthralgia before the onset of skin lesions. However, although the patient did not undergo blood tests prior to admission, we assumed that her MDS preceded the skin lesions because her initial blood tests revealed substantial abnormalities. The patient exhibited fever and the clinical symptoms of pneumonia, but her condition was not improved by the administration of broadspectrum antibiotics. During hospitalization, her white blood cell count elevated progressively. Her hepatic and renal function decreased, the dense areas in her lung enlarged, and the aorta, valves, and myocardium became involved. The patient died just 10 days after admission. This suggests that patients with MASS may be subject to a progressive clinical course of disease, especially when vital organs, such as the heart, lung, kidney, and liver, are involved. The present patient presented multiorgan involvement indicated by conjunctivitis, oral ulcer, arthralgia, dense areas in the lungs with pleural effusions, cardiomegaly with pericardial effusions, liver dysfunction, and renal failure. To our knowledge, this is the first case involving this number of organs to be reported. Blood tests in the present patient revealed severe decreases in the red blood cell count and blood platelet count and a dramatic increase in the white blood cell count. This may suggest that the patient’s MDS was evolving to leukemia. Some case reports of SS with vital organ involvement have been published.13–15,17–19,21,22 All of the patients reported were treated with corticosteroids; however, their prognoses differed dramatically. This suggests that the clinical features ª 2014 The International Society of Dermatology
Sweet’s syndrome with myelodysplastic syndrome
Case report
of these patients differ from those of patients with common SS. It is unfortunate that specific treatment protocols have yet to be developed for these patients. References 1 Sweet RD. An acute febrile neutrophilic dermatosis. Br J Dermatol 1964; 76: 349–356. 2 Cohen PR. Sweet’s syndrome – a comprehensive review of an acute febrile neutrophilic dermatosis. Orphanet J Rare Dis 2007; 2: 34. 3 Cohen PR, Kurzrock R. Sweet’s syndrome and cancer. Clin Dermatol 1993; 11: 149–157. 4 Cohen PR, Kurzrock R. Sweet’s syndrome and malignancy. Am J Med 1987; 82: 1220–1226. 5 Su WP, Liu HN. Diagnostic criteria for Sweet’s syndrome. Cutis 1986; 37: 167–174. 6 von den Driesch P. Sweet’s syndrome (acute febrile neutrophilic dermatosis). J Am Acad Dermatol 1994; 31: 535–556; quiz 557–560. 7 Walker DC, Cohen PR. Trimethoprim-sulfamethoxazoleassociated acute febrile neutrophilic dermatosis: case report and review of drug-induced Sweet’s syndrome. J Am Acad Dermatol 1996; 34: 918–923. 8 Cohen PR, Kurzrock R. Sweet’s syndrome: a neutrophilic dermatosis classically associated with acute onset and fever. Clin Dermatol 2000; 18: 265–282. 9 Choi HJ, Chang SE, Lee MW, et al. A case of recurrent Sweet’s syndrome in an 80-year-old man: a clue to an underlying malignancy. Int J Dermatol 2006; 45: 457–459. 10 van Hirtum PV, Prins M, ten Oever J, et al. Sweet syndrome in underlying malignancy. Ned Tijdschr Geneeskd 2010; 154: A2112. 11 Shinojima Y, Toma Y, Terui T. Sweet syndrome associated with intrahepatic cholangiocarcinoma producing granulocyte colony-stimulating factor. Br J Dermatol 2006; 155: 1103–1104. 12 Kawakami T, Ohashi S, Kawa Y, et al. Elevated serum granulocyte colony-stimulating factor levels in patients with active phase of Sweet syndrome and patients with active Behcßet disease: implication in neutrophil apoptosis dysfunction. Arch Dermatol 2004; 140: 570– 574. 13 Dorenkamp M, Weikert U, Meyer R, et al. Heart failure in acute febrile neutrophilic dermatosis. Lancet 2003; 362: 1374. 14 Guia JM, Frias J, Castro FJ, et al. Cardiovascular involvement in a boy with Sweet’s syndrome. Pediatr Cardiol 1999; 20: 295–297. 15 Hayashi I, Hosoda Y, Kawasaki S, et al. Aortic and mitral valve replacement in a patient with acute febrile neutrophilic dermatosis (Sweet’s syndrome): report of a case. Surg Today 2001; 31: 810–813. 16 Shimizu K. Neutrophilic infiltration of the myocardium in a patient with myelodysplastic syndrome. Am J Hematol 1998; 58: 337–338. International Journal of Dermatology 2015, 54, 1303–1308
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17 Peters FP, Drent M, Verhaegh M, et al. Myelodysplasia presenting with pulmonary manifestations associated with neutrophilic dermatosis. Ann Hematol 1998; 77: 135–138. 18 Takimoto CH, Warnock M, Golden JA. Sweet’s syndrome with lung involvement. Am Rev Respir Dis 1991; 143: 177–179. 19 DiCaudo DJ, Ortiz KJ, Mengden SJ, et al. Sweet syndrome (acute febrile neutrophilic dermatosis) associated with pulmonary coccidioidomycosis. Arch Dermatol 2005; 141: 881–884. 20 Neau D, Monlun E, Delmas M, et al. Sweet syndrome and Yersinia enterocolitica infection Two cases. Rev Med Interne 1995; 16: 919–922.
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21 Garg R, Soud Y, Lal R, et al. Myelodysplastic syndrome manifesting as Sweet’s syndrome and bronchiolitis obliterative organizing pneumonia. Am J Med 2006; 119: 5– 7. 22 Imanaga T, Hayashi T, Yoshii C, et al. Pulmonary involvement in acute febrile neutrophilic dermatosis (Sweet’s syndrome). Nihon Kokyuki Gakkai Zasshi 2000; 38: 206–210.
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