Sweet syndrome as an adverse reaction to tyrosine kinase inhibitors: A review

Tyrosine kinase inhibitors are a class of targeted anticancer drugs that inhibit cancer cell proliferation by inactivating proteins involved in signal transduction cascades. Various cutaneous adverse events have been observed after tyrosine kinase inhibitor administration, including Sweet syndrome. We queried the PubMed database to identify 14 cases of Sweet syndrome thought to be secondary to tyrosine kinase inhibitors. Tyrosine kinase inhibitor‐induced Sweet syndrome had a median of 2 months latency following drug administration. All cases but one had morphologic features classic for Sweet syndrome (erythematous and tender papules, plaques, or nodules). All cases also had classic histopathologic findings (dermal neutrophilic infiltrate without vasculitis or necrosis). Using diagnostic criteria for drug‐induced Sweet syndrome and the Naranjo Drug Reaction Probability Scale for a drug‐induced cutaneous eruption, we found that six cases favored a drug‐induced etiology over malignancy, two cases favored a malignancy‐associated Sweet syndrome, and the remaining eight met drug‐induced Sweet syndrome criteria but had low Naranjo scores. Nine cases resulted in medication discontinuation, while five cases continued anticancer therapy and were treated only with corticosteroids with quick resolution of skin lesions. Dermatologists should be aware of this adverse cutaneous reaction to tyrosine kinase inhibitors and should treat on a case‐by‐case basis, though limited evidence in this review suggests that oncologic therapy may safely be continued with prompt corticosteroid treatment.     

Potassium iodide in refractory,recurrent pediatric Sweet syndrome: Guidance in dosing and monitoring

We describe a 5‐month‐old boy with clinical and histopathologic presentation of Sweet syndrome. He responded to systemic corticosteroids, with multiple flares on tapering; potassium iodide was added, which provided complete resolution of Sweet syndrome. Potassium iodide has been used in only a few cases, and no standard dosage has been established in children. We discuss calculation of a pediatric dosage for potassium iodide in Sweet syndrome.     

Cutaneous histiocytoid Sweet syndrome and its relationship to hematological diseases

Sweet syndrome (SS) was described over 50 years ago as a distinctive form of neutrophilic dermatosis. It may be idiopathic, drug‐induced or paraneoplastic, and in the last of those subtypes, myeloproliferative diseases are prominently represented. A peculiar variant of SS is termed ‘histiocytoid’ SS (HSS), and early accounts of that condition asserted that it showed no linkage to hematological disorders. We herein report two additional cases of HSS – both of which were associated with myeloid dyscrasias – together with a review of the pertinent literature. Along with our observations, the latter process appears to contradict the contention that HSS has no relationship to hematopoietic diseases; between 35 and 55% of reported cases have indeed shown such an association, usually with myelogenous leukemia or myelodysplastic syndromes.     

Sweet综合征的临床相关进展

Sweet综合征又称急性发热性嗜中性皮病,是一种少见的、病因尚未完全阐明的反应性疾病。临床上分为经典型/特发型、恶性肿瘤相关型和药物诱导型三个类型,以发热、疼痛性红色斑块、血中嗜中性粒细胞升高和真皮内中性粒细胞浸润为特征,可与多种炎症性疾病或肿瘤伴发。组织学上主要表现为真皮弥漫性成熟中性粒细胞浸润、白细胞核碎裂、真皮乳头水肿,通常缺乏表皮和原发性白细胞破碎性血管炎的改变。系统性糖皮质激素可快速缓解皮肤和系统症状。本文对Sweet综合征的相关进展作综述。     

Facial Sweet syndrome mimicking photoallergic contact dermatitis

Sweet syndrome (acute febrile neutrophilic dermatosis) usually presents with painful erythematous plaques, malaise, and fever. Histologically skin infiltration with neutrophils is characteristic. The etiology of the disease is unknown. Sweet syndrome can be subdivided into the classical form, which is usually idiopathic and is associated with some kind of inflammation, the paraneoplastic form and the drug‐induced one. We present the unusual case of an 83‐year‐old woman who appeared to have facial photoallergic contact dermatitis but turned out to have facial Sweet syndrome.     

Differentiation syndrome during ivosidenib treatment with immunohistochemistry showing isocitrate dehydrogenase R132H mutation

We report a case of differentiation syndrome in a patient receiving the IDH1 inhibitor ivosidenib, with skin biopsy showing isocitrate dehydrogenase (IDH) R132H-mutated leukemia cutis. A 72-year-old man with IDH1-mutated acute myeloid leukemia (AML), status-post allogeneic cell transplantation, on ivosidenib for 6 months, was admitted for culture-negative neutropenic fever, pink and purpuric plaques and patches on the legs, abdomen and back, edema, hypotension, and shortness of breath. Skin biopsy revealed an infiltrate of atypical, immature, myeloperoxidase-positive mononuclear cells compatible with leukemia cutis or Sweet syndrome. Although dermal edema and interstitial neutrophilic infiltrate with karyorrhexis characteristic of Sweet syndrome were not seen, the atypical cells lacked expression of CD117 and CD34, which were expressed in the original leukemia. Additional immunohistochemical staining of suspected blasts was strongly positive for IDH1 R132H, suggesting a diagnosis of leukemia cutis. As the immunophenotype of blasts in skin infiltrates can significantly differ from the immunophenotype seen in blood and bone marrow, this case shows that mutation-specific antibodies such as anti-IDH1 R132H may be useful to help distinguish malignant from non-malignant infiltrates in the skin. Furthermore, differentiation syndrome may show histopathologic features of leukemia cutis on skin biopsy.     

Sweet syndrome associated with malignancies: A retrospective analysis of 25 patients from West China hospital

Sweet syndrome (SS), also known as acute febrile neutrophilic dermatosis, is a rare inflammatory disorder characterized by sudden onset of variably tender brightly erythematous‐to‐violaceous papules, plaques, or nodules. To clarify the frequency, clinical course, therapeutic response, and outcome of Sweet syndrome with malignancy. We conducted a retrospective review of patients diagnosed with SS between 2009 and 2019 with a diagnosis of Sweet syndrome in West China hospital. Records were analyzed for variables, clinical features, etiological factors, laboratory results, and treatment outcomes. The 25 cases under study consisted of 14 (56%) females and 11 (44%) males. Mean age was 52.2 years (range: 4‐76 years). Nodules were the commonest lesion presentation (48%), involving mostly the lower limbs (52%). Pain of lesion was identified as the most common symptom (88%), followed by fever (76%) and cough (44%). Among the patients, 52% exhibited the classic form, 48% showed the malignancy‐associated form, and 4% exhibited the drug‐induced form in the setting of malignancy. Acute myeloid leukemia was the most common malignancy, observed in 5 of 12 patients (41.6%). Anemia (P = .002) was associated with malignancy (Chi‐square test).     

Typically atypical: histiocytoid Sweet syndrome, associated with malignancy

Sweet syndrome (acute febrile neutrophilic dermatosis) is characterized by a dramatic onset of high fever, neutrophilia and typical skin lesions. About 20 % of patients have an associated malignancy, most commonly hematologic diseases. Chronic and paucisymptomatic manifestations of Sweet syndrome may be misdiagnosed or misinterpreted as harmless, resulting in delayed diagnosis. "Atypical" manifestations are especially suspicious for associated malignancies. This is demonstrated by a 39-year old patient with chronic and afebrile disease who was referred to our clinic only after symptoms had persisted for several months. By that point, an underlying nodular lymphocyte predominant Hodgkin's lymphoma had already reached an advanced stage. Skin biopsies revealed dermal infiltrates of histiocytoid cells of myelogenous origin, supporting a diagnosis of histiocytoid Sweet syndrome. Specific cutaneous infiltrates associated with myelogenous leukemia were ruled out.     

Acquired cutis laxa secondary to Sweet syndrome in a child (Marshall syndrome): A rare case report

Sweet syndrome is rare in the pediatric population and usually responds well to treatment, resolving without sequelae. Marshall syndrome is a rare pediatric skin disease characterized by loss of elastic tissue (cutis laxa) secondary to acquired, localized neutrophilic dermatitis without any internal organ involvement. Only few cases of Marshall syndrome (acquired cutis laxa type II) have been reported. Systemic steroids and dapsone show excellent results in Sweet syndrome. Although there is no satisfactory treatment for cutis laxa, dapsone can be used in the acute phase for control of swelling.     

Utility of myeloperoxidase stain in the differential diagnosis of leukemia cutis vs. hystiocitoid Sweet syndrome

Leukemia cutis is defined as a skin infiltration by leukemic cells. The diagnosis of myeloid leukemia cutis (MLC) can represent a challenge, especially in those cases without symptoms of systemic disease. The clinical appearance, histopathological analysis and immunohistochemical profile can be indistinguishable from those observed in cases of hystiocitoid Sweet syndrome (HSS). We present a case of MLC in which the cutaneous affectation was the first sign of the systemic leukemia. In this setting, the myeloperoxidase stain was the clue to rule out the possibility of HSS. We discuss the role and the utility of the myeloperoxidase stain in the differentiation of these two entities.     

Sweet syndrome in children

The objective of this study was to describe the clinical features of Sweet syndrome in children. Our study population consisted of seven children diagnosed with Sweet syndrome over a 22-year period. Age, sex, appearance and location of lesions, associated signs and symptoms, past medical history, pathology, and subsequent disease course were documented for each patient. Fever and typical lesions were reported in most of patients in our study. The majority of patients presented with less-typical findings, such as pustules, vesicles, bullae, oral ulcerations, atrophic scars, and evidence of pathergy. Of the seven children in our study, four were found to have a preceding nonspecific upper respiratory or gastrointestinal infection, and two were diagnosed with an underlying hematologic malignancy. Our results suggest that atypical lesions are relatively common in children with Sweet syndrome and that underlying malignancy is associated with a minority of cases of pediatric Sweet syndrome.     

Sweet syndrome associated with secondary nodular syphilis in an immunocompetent patient

Sweet syndrome is an inflammatory disease characterized by fever, neutrophilia, papules and erythematous plaques, and a skin neutrophilic infiltrate. Syphilis has been reported among the infectious causes of Sweet syndrome. Syphilis can present atypical manifestations; a rare presentation is nodular syphilis, characterized by nodules with granulomas and plasma cells at histopathology. This case report presents a 20-year-old woman patient, with plaques and nodules, and systemic symptoms. The histopathological exam revealed both non-tuberculoid granulomas and a dense infiltration of polymorphonuclear neutrophils in the dermis. These findings, plus laboratory abnormalities, characteristic of both conditions, were conclusive for Sweet syndrome and nodular syphilis association.     

Infantile Sweet syndrome following MMRV vaccine

Sweet syndrome (SS), also called acute febrile neutrophilic dermatosis, is rare in the pediatric population, especially in infants and neonates. We present a case of infantile SS that developed 1 day after the MMRV vaccine; we suggest a possible causal relationship between the MMRV vaccine and SS.     

Treatment of Sweet's syndrome in pregnancy

Pregnancy‐associated Sweet's syndrome is a rare occurrence (2%), with good prognosis, spontaneous resolution after delivery, and not increased infant morbidity and mortality. However, differential diagnosis is not easy for physician not familiar with skin lesions. Systemic involvement, even though unusual, might occur in nearly every organ of the body, including pericardium, myocardium, and placenta, as well as one report of early fetal miscarriage, questioning the possibility of risks underestimation. We present two further cases, one occurred in a 31‐year‐old woman at 26 weeks of gestation and the other on a 26‐year‐old woman at 24 weeks of gestation, primigravidae. Both presented with tender papules and nodules on their face and upper body parts. Laboratory examinations and skin biopsy histology were pathognomonic. Monitoring of general maternal and fetal conditions showed no signs of sufferance, but the decision to accelerate skin symptoms release, being time to delivery quite distant, challenge the treatment options. There are no recommended treatments for Sweet syndrome and the choice is very limited during pregnancy. A short course of oral steroids was very effective, with lesions healing in few days, no relapses or fetal complications. When pregnant patients exhibit fever, neutrophilia, arthralgia or myalgia, and tender erythematous plaques or nodules, Sweet syndrome should be considered. The trained dermatologist is in the leading position to address the differential diagnosis, reassure the patient, and avoid complications, even if they are rare.     

Subcutaneous sweet syndrome

Neutrophilic panniculitis encompasses a heterogeneous group of diseases histopathologically characterized by an inflammatory infiltrate in the subcutaneous fat mainly composed of mature neutrophils. This group of panniculitides includes alpha(1)-antitrypsin deficiency, infectious panniculitis, factitious panniculitis, subcutaneous Sweet syndrome, neutrophilic/pustular panniculitis associated with rheumatoid arthritis, erythema nodosum-like lesions of Beh?et disease, bowel bypass panniculitis, and iatrogenic panniculitis. This article reviews subcutaneous Sweet syndrome, which is a rare idiopathic panniculitis characterized by a dense neutrophilic infiltrate in the subcutis and is often related to hematologic malignancies. The relationship of subcutaneous Sweet syndrome and erythema nodosum is discussed as well as the differential diagnosis with other neutrophilic panniculitis.     

抗γ干扰素自身抗体阳性伴Sweet综合征的马尔尼菲篮状菌病九例临床分析

【摘要】 目的 报道9例HIV阴性伴Sweet综合征的马尔尼菲篮状菌病（TSM），及其与抗γ干扰素自身抗体的关系。方法 回顾分析广西医科大学第一附属医院2013—2018年确诊的HIV阴性伴Sweet综合征TSM患者的临床资料。以19例HIV阳性TSM患者及107例健康人为对照，检测外周血抗γ干扰素自身抗体。结果 9例中男5例，女4例，TSM发病年龄38 ~ 60岁。患者均呈播散性感染，临床表现为长期不规则发热、多部位淋巴结肿大、咳嗽、消瘦、贫血。9例均符合经典型Sweet综合征的诊断标准，Sweet综合征皮疹微生物学检查阴性。除马尔尼菲篮状菌感染之外，还合并非结核分支杆菌（6例）、水痘-带状疱疹病毒（4例）、沙门氏菌（2例）感染。患者组9例外周血抗γ干扰素自身抗体检测结果均阳性，而107例健康人及19例HIV阳性TSM患者均阴性。结论 抗γ干扰素自身抗体阳性可能与HIV阴性伴Sweet综合征的TSM相关。     

Sweet syndrome (acute febrile neutrophilic dermatosis) associated with pulmonary coccidioidomycosis

BACKGROUND: Sweet syndrome (acute febrile neutrophilic dermatosis) may arise in association with a variety of underlying systemic diseases. Only 1 case of coccidioidomycosis-associated Sweet syndrome has previously been reported. OBSERVATIONS: We describe 2 patients who developed Sweet syndrome during the onset of acute pulmonary coccidioidomycosis. Systemic antifungal therapy was given in both cases. Respiratory symptoms and skin lesions resolved within 5 weeks. CONCLUSIONS: Sweet syndrome may be a presenting feature of coccidioidomycosis. Recognition of the underlying pulmonary infection is important so that inappropriate treatment with systemic corticosteroids can be avoided.     

Sweet syndrome with pseudocarcinomatous hyperplasia: A case report and review of the literature

Pseudocarcinomatous (pseudoepitheliomatous) hyperplasia represents reactive epidermal change mimicking squamous cell carcinoma (SCC), owing to a variety of inflammatory and neoplastic phenomena, including deep fungal infections, CD30‐positive lymphomas, and others. We report a case of Sweet syndrome (SS) arising in a patient with acute myelogenous leukemia, with persistent orolabial involvement which mimicked SCC both clinically and microscopically, but resolved entirely with adequate corticosteroid treatment. Clinicians should be aware that neutrophilic dermatoses such as SS and pyoderma gangrenosum may rarely exhibit pseudocarcinomatous epidermal changes similar to those seen in soft tissue infections and other inflammatory dermatoses.     

Sweet syndrome in two children

We report a 9-month-old girl and a 4-year-old boy with acute febrile neutrophilic dermatosis (Sweet syndrome). Both children were febrile, had leukocytosis, and exhibited lesions characteristic of Sweet syndrome. Both had an antecedent infection. Our evaluation and long-term follow-up of these children failed to reveal evidence of underlying malignancy or a chronic systemic illness typically encountered in Sweet syndrome. Of interest, the 4-year-old boy responded to systemic corticosteroids with remission, whereas the 9-month-old infant experienced flaring of the disease on successive attempts to taper the systemic corticosteroids. Systemic corticosteroid usage was associated with alteration in behavior in the 4-year-old and transient growth retardation in the 9-month-old. In both patients, the adverse effects resolved after discontinuation of the corticosteroids.