Sweet's Syndrome Associated with Pediatric Acute Myeloid Leukemia: A Case Report and Concise Review of Literature

Abstract

Sweet's syndrome (SS) is an inflammatory skin condition characterized by sudden onset of fever, painful skin lesions, and neutrophilic infiltration of affected tissues. The systemic association of SS include infections, drugs, malignancy, and autoimmune disorders. We describe a case of a 6-year-old pediatric male patient who was previously treated with conventional chemotherapy for acute myeloid leukemia (AML). He presented with prolonged fever and diffuse erythematous papules over the face, neck, trunk, arms, and legs. Further evaluation revealed relapse of AML following which he was initiated on salvage chemotherapy. Initial impression of the skin lesions was cutaneous infiltration of myeloid malignancy and hence not separately addressed treatment wise apart from chemotherapy. However, as the lesions persisted following first cycle of chemotherapy, a skin biopsy was pursued that revealed SS. The lesions responded only after initiation of systemic steroids and colchicine alongside chemotherapy. Early identification and histological confirmation aided treatment of above condition. The clinical rarity, diagnostic clues, and a brief review of published literature has been described. The case reports emphasizes the importance of histopathological evaluation of cutaneous lesions in hematologic malignancy and systematic approach to treatment. The case report emphasizes the need for strong clinical suspicion, importance of histopathological evaluation, and systematic approach to treatment.

 

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Keywords

acute neutrophilic dermatosis - leukemia cutis - case report

Introduction

Sweet's syndrome (SS) also described as acute neutrophilic dermatosis is a dermatological condition characterized by red, raised, and painful skin lesions often associated with fever and systemic symptoms.[1] SS is usually described in association with various systemic illnesses, including malignancy.[2] SS associated with acute myeloid leukemia (AML) is described; however, published literature with regard to childhood AML is sparse. It is very important to suspect and diagnose SS early, to differentiate it from other common skin manifestations of myeloid malignancy like leukemia cutis, chloroma, or infective skin lesions. We describe the management of a child presenting with SS during relapse of the AML and intend to discuss the clinical insights, management aspects, and concisely review the published literature.

 

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Case Report

A 6-year-old male pediatric patient with neurofibromatosis type-1 (NF-1), presented with symptoms of progressive pallor, fever, and mucocutaneous bleeding. He was diagnosed to have AML after bone marrow aspiration (BMA), flow cytometry-based immunophenotyping, and cytogenetic evaluation. The patient was treated with standard multidrug intensive chemotherapy (MRC-15 AML Protocol),[3] following which the child was in remission. Both the parents had certain genetic diseases, NF-1 in father and skeletal dysplasia (hereditary multiple exostosis) in mother.

Sixteen months from initial diagnosis, the child presented with prolonged fever and diffuse erythematous papules distributed over arms, legs, face, trunk, and neck. Investigations revealed leukocytosis, thrombocytopenia, and circulating blasts in peripheral smear. BMA and biopsy confirmed a relapse of AML with the immunophenotype and cytogenetics similar to the primary disease. The child was hence planned for salvage chemotherapy followed by consolidation with hematopoietic stem cell transplantation (HSCT). The skin lesions were assumed to be leukemic deposits and hence were not biopsied upfront for histological evaluation.

The child received first cycle of chemotherapy (azacytidine-based), following which there was clinical improvement in terms of disappearance of circulating blasts and defervescence of fever. Contrary to the clinical expectation, the skin lesions continued to progress with crops of blotchy papules with increased tenderness.

A biopsy of the skin lesion was hence pursued, which showed dense neutrophilic infiltration in the dermis suggestive of acute neutrophilic dermatosis also termed as SS ([Fig. 1]). The patient was initiated on oral steroids (prednisolone 2 mg/kg for 1 week followed by tapering doses over next 2 weeks) following which there was remarkable response. After 2 weeks, on tapering steroids, there was recurrence or flare of skin lesions. Oral colchicine was hence added as a steroid sparing agent following which there was complete response. The steroids could be tapered and stopped in next 1 week. Oral colchicine was used for a total of 4 weeks. The child received three cycles of salvage chemotherapy (azacytidine followed by fludarabine and high-dose cytarabine) following which the disease was in morphological remission (minimal residual disease = 1.7%). He underwent a haploidentical stem cell transplantation with mother as the stem cell donor. On follow-up, he remains disease-free and healthy at 32 months from HSCT.

Fig. 1 (A) Diffuse erythematous, raised, tender papules, and plaques distributed over arms and hands of the patient. (B) Histopathology of the biopsy showed a mildly spongiotic epidermis with an occasional necrotic keratinocyte (arrow) overlying an edematous dermis with a prominent neutrophilic infiltrate.

 

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Discussion

AML is a hematologic malignancy characterized by clonal expansion of myeloid precursors.[4] The skin manifestations in AML are variable and less well described especially in children.[5] SS or acute neutrophilic dermatosis is characterized by rapid onset of red, raised, and often painful skin nodules or plaques often accompanied by fever and neutrophilia.

The distribution of these lesions is characteristic with involvement of limbs, head, and neck, less frequently the trunk and rarely mucosal surfaces.[2] The important and close clinical differentials include pyoderma gangrenosum, erysipelas, erythema multiforme, erythema nodosum, leukemia cutis, acute generalized exanthem pustulosis, and chloroma.

Our case had SS in the background of a relapsed AML, which was initially unrecognized due to its clinical rarity. However, with no response to conventional chemotherapy, a histological evaluation was undertaken that prompted the diagnosis of SS.

SS is classified based on underlying clinical illness as classical/idiopathic SS, malignancy-associated SS, and drug-induced SS.[6] Malignancy-associated SS may present prior to, at the onset, after the diagnosis, or at recurrence of malignancy. SS has also been associated rarely with immunodeficiency with published reports mainly in chronic granulomatous disease common variable immunodeficiency, hypogammaglobulinemia, and T cell lymphopenia.[7] Myeloid malignancy is one of the common cancers associated with SS.[8] [9] In addition, treatment modalities utilized in hematologic malignancies including granulocyte colony-stimulating factor, granulocyte–macrophage colony-stimulating factor, hypomethylating agents including azacytidine or decitabine are implicated in drug-induced SS.[10] Our case presented with the skin lesions at the relapse of AML. However, the child received azacytidine, which is a hypomethylating agent in the salvage chemotherapy, which may have contributed to persistence of lesions post the salvage chemotherapy. Our case hence best describes a combination of paraneoplastic SS and drug-induced SS. Understanding the inciting agent for SS is hence critical in treatment, as it would define natural course of SS.

The etiopathogenesis of malignancy-associated SS is not well known. It is hypothesized that the alteration in various pro- and anti-inflammatory cytokine (interleukin [IL], tumor necrosis factor alpha, interferon) drives the neutrophilic infiltration of dermis.[2] The dysfunctional immune mediators with increased TH1 response, reduced TH2 response, and increased cytokine milieu especially IL-1, IL-2, and IFN-γ have been postulated to be responsible for neutrophil maturation and localization.[11]

SS associated with pediatric hematologic malignancy is less well described. A concise review of the published literature of malignancy-associated SS has been presented in [Table 1]. In most of the studies, early identification, histological confirmation, and prompt treatment has resulted in good initial response with variable degree of recurrence.

Table 1 Concise review of published literature of myeloid malignancy associated with Sweet's syndrome

Country, year of publication, (reference number)	Sample size (n)	Median age (years)	Primary diagnosis	Treatment of malignancy	Treatment of Sweets syndrome	Outcome
United States, 2015[2]	21	56	AML (20), APML (1)	Conventional chemotherapy	Glucocorticoids and antibiotics	Resolved in 13, recurrent in 3, which required multiple courses of steroids
United States, 2013[10]	4	52	AML (3), MDS (1)	Conventional chemotherapy	Glucocorticoids, antibiotics	Relapse in 2 patient, who both ultimately died with the disease. Other 2 had complete resolution of SS, and eventually the primary disease
France, 2020[11]	10	55	AML (6), MDS (2), MPN (1), MDS/MPN (1)	Conventional chemotherapy, hypomethylating agents, quizartinib	Not specified	Not specified
United States, 2020[9]	4	68	AML (2) and MDS (2)	Conventional chemotherapy, hypomethylating agents	Glucocorticoids, antibiotics	Refractory in 1, ultimately died with the disease. Rest resolved
Egypt, 2017[7]	13	44	AML (13)	Conventional chemotherapy, hypomethylating agents	Steroids, dapsone, colchicine	Resolved in all. Two died and 1 had relapse in the course
United States, 1980[1]	2	48	AML (1), myelofibrosis (1)	Conventional chemotherapy	Oral prednisolone	Both patients succumbed to illness. One had refractory course
Spain, 2017[8]	8	46	MDS (3), AML (2), chronic myelomonocytic leukemia (2), and chronic myelogenous leukemia (1)	Not specified	Oral corticosteroids (mentioned only for two patients)	SS resolved in both patients. Outcome of other patients not specified
Austria, 1999[12]	26	53	AML (17) and CML (9)	Conventional chemotherapy, Resection in 2 of the CML cases, Radiation for 1 of the AML cases	(This article talks about all specific skin infiltrates in myelogenous leukemia, and not SS specifically) Small solitary lesions surgically removed. Two patients received radiation	Follow up data available for 22 patients (17 AML and 5 CML) Recurrences of skin lesions were observed in 7 patients (5 AML and 2 CML) All 22 patients died of their disease withing 24 mo after onset of skin lesions
United States, 1981[13]	1	73	Dysmyelopoiesis syndrome	Conventional chemotherapy	Antibiotics and erythrocyte transfusion	SS resolved in 2 wk, Disease outcome of patient is not specified
United States, 2020[14]	3	57	AML (2), and MDS (1)	Conventional Chemotherapy, Patient with MDS required allogenic stem cell transplant	Glucocorticoids, IVIG, dapsone	2 patients had relapses, but eventually all 3 patients had resolution of SS All 3 patients disease resolved
UK, 2009[6]	1	1.5	No evidence of hematologic malignancy	–	Oral prednisolone	Complete resolution, no recurrence
United States, 1988[15]	69	52	AML(42), MPD(15), MDS (6), CLL (3), HCL (3), Myeloma (3), AL-Unclassified (3), HL (1), NHL-B cell (4) and NHL- T cell (2)	Tumor-directed therapy	Corticosteroids, indomethacin, clofazimine, dapsone, Potassium iodide, colchicine	Almost 70% of the patients had relapses of SS All manifestations of SS improved dramatically with corticosteroid therapy

Abbreviations: AML, acute myeloid leukemia; APML, acute promyelocytic leukemia; CML, chronic myelogenous leukemia; IVIG, intravenous immunoglobulin; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm; SS, Sweet's syndrome.

A study from United States reported 21 cases of SS associated with myeloid malignancy. Conventional chemotherapy, glucocorticoids, and antibiotics were utilized in management. There was complete resolution of SS in 13 patients, relapse of SS in 3 patients, and 5 patients were lost to follow-up.[2] Further, another six studies reported a total of 83 cases predominantly in adult malignancy setting and with variable resolution of symptoms. Glucocorticoids and dapsone were the most common agents used in treatment of SS.[1] [4] [10] A study from Egypt, reported 13 cases of SS with AML, of which 10 patients had complete resolution, 1 patient had relapse of symptoms, and 2 patients died of refractory disease.[9] Reports from France and Spain documented 18 cases of SS following myeloid malignancy with variable outcome. Conventional chemotherapy and hypomethylating agents were used for treatment of malignancy, and systemic steroids were mainstay in treatment of SS.[8] [12]

Another study, done in the United Kingdom presented a case of SS without any evidence of hematologic malignancy. Oral corticosteroids were given as treatment, and there was complete resolution, with no recurrence.[5] A study from Austria looked at various cutaneous manifestations in AML (26 patients) and reported SS in few of them.[13] A study from India published a series of 4 cases of SS and reviewed 12 older cases. Five out of 16 cases were associated with myeloid malignancy. Systemic glucocorticoids were used in majority, with a few required addition of potassium iodide and colchicine.[14] Although, various studies describe the course of SS with AML, there is no clear evidence to suggest association of SS to have any prognostic implication in the outcome of malignancy. The diagnosis of SS does not affect the median survival of myeloid malignancy, and the prognosis depends purely on the severity and risk stratification of myeloid malignancy.[2]

The primary management of SS is treatment of underlying condition. However, systemic glucocorticoids are the most common first-line agent recommended at a dose of 1 to 2 mg/kg prednisolone for 1 to 2 weeks and slow taper over 4 to 6 weeks.[10] Potassium iodide and colchicine are other first-line agents, sometimes shown to be more efficacious than steroids.[10] Cyclosporine, indomethacin, doxycycline, and dapsone have also been tried in management of SS often as second-line agents when nonresponsive to steroids or colchicine.[5] [9] [10] In our case, there was rapid clinical response to glucocorticoids initially but skin lesions flared on tapering steroids. Colchicine was used for a total of 4 weeks following which there was complete resolution of lesions. More importantly, the child received a haploidentical bone marrow transplantation, which effectively ensured remission of AML and thereby preventing relapse of SS.

The strength in our case report is presentation of a rare instance of SS in a pediatric patient with AML, emphasizing the critical role of thorough clinical evaluation, histopathological confirmation, and a systematic treatment approach. Given that SS is uncommon in children and its association with AML is even rarer, this case adds valuable insight into the spectrum of malignancy-associated SS in the pediatric population.

We acknowledge the limitation of reporting a single case, which restricts the generalizability of our findings. However, the rarity of such presentations underscores the need for more extensive research. Prospective studies and multicenter collaborations with pooled analyses are essential to better understand the incidence, treatment outcomes, and prognostic implications of SS in pediatric AML. Such efforts will aid in developing standardized treatment protocols and improving patient care outcomes.

 

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Conclusion

To conclude, our case highlights a rare cutaneous manifestation associated with AML. Lack of response to conventional chemotherapy prompted us to do a skin biopsy, which helped in diagnosis. Astute clinical suspicion along with pursual of histological evaluation is the cornerstone for diagnosis of SS. It is prudent to have high degree of suspicion and recognize the difference between SS and other dermatological conditions associated with childhood leukemias such as leukemia cutis. Early identification aids treatment and helps achieve complete clinical response.

 

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Conflict of Interest

None declared.

Patient's Consent

Written consent was acquired from the patient after explanation of case report in the patient's native language.

• References

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Publikationsverlauf

Artikel online veröffentlicht:
03. Juli 2025