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Predicting malignancies in Sweet syndrome has become sweeter

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By Warren R. Heymann, MD
Feb. 8, 2018

sweet syndrome
Histiocytoid Sweet syndrome. A, Multiple round erythematous papules and plaques on trunk and upper limbs. B, Multiple erythematous papules and plaques grouped in figurate pattern on the right thigh of a pediatric patient. C, Erythematous figurate annular plaques with erythematous elevated borders and depressed pale-pink center on the upper aspect of left arm and shoulder. D, Large erythematous plaque with pseudobullous features and some purpuric areas on the right thigh.
Credit: JAAD

For a disease that was described more than half a century ago, I find it humbling that controversy still swirls around Sweet syndrome (SS), especially for malignancy-associated cases.

The modified Su and Liu criteria for SS include major criteria (1. Rapid onset of characteristic tender cutaneous plaques and nodules; 2. Histology of dense neutrophilic infiltration without leukocytoclastic vasculitis) and minor criteria (1. Fever > 38 degrees C; 2. Association of a malignancy [hematologic or visceral cancer], inflammatory disease, or preceded by an upper respiratory infection, gastrointestinal infection, or vaccination, or pregnancy; 3. An excellent response to therapy with systemic corticosteroids or other agent such as potassium iodide; 4. Abnormal laboratory values of 3 of the following at presentation: a. ESR > 20 mm/h; b. high CRP; c. WBC > 8K; d. neutrophil count > 70% of WBC total). The presence of both major criteria (1 and 2) and two of the four minor criteria confirms the diagnosis. (1)

SS is classified as classic (associated with the inflammatory disorders, infections, or pregnancy listed in criterion 2), malignancy-associated, or drug-induced. The literature typically states that about 20% of SS patients have an associated malignancy, with acute myeloid leukemia (AML) being the most frequent, followed by myelodysplastic disorders (MDS). (2) The onset of SS can precede, follow, or appear concurrently with the diagnosis of the patient’s cancer. (3)

In drug-induced SS a temporal relationship between drug administration and clinical presentation is readily apparent. The most common culprit is granulocyte-colony stimulating factor; other implicated medications include bortezomib, hypomethylating agents (azacitidine, decatibine), imatinib, lenalidomide, and all-trans retinoic acid. (1)

While it is reasonably straightforward to categorize patients with SS, it is essential to hone in on those who are at risk of malignancy.

Marcoval et al retrospectively studied 138 patients with SS (66 male, 72 female, mean ± SD age 51.24 ± 14.11 years). SS was associated with hematological malignancy in 31 cases, infection in 23, inflammatory bowel disease in 12, inflammatory systemic disease in 8, and solid tumors in 4. It was drug-induced in 5 cases and idiopathic in 54. In 4 patients, an underlying hematological disease that was considered related to SS was diagnosed between 4 and 16 months after SS presentation. Variables significantly associated with malignancy in multivariate logistic regression analysis were age (OR = 1.08 for each increasing year), anemia (OR = 9.38), thrombocytopenia (OR = 16.10) and absence of arthralgia (OR = 11.13). The authors concluded that patients with advanced age, anemia or thrombocytopenia, and without arthralgia are more likely to have malignancy-associated SS. They recommended that patients with SS without a clear etiology be followed up for at least 16 months to exclude a possible underlying hematological malignancy. (2)
Several of these conclusions were confirmed by Misha Rosenbach’s group at Penn. Nelson et al identified 83 patients (mean age, 57 years; 51% male) with SS: 30% with the classic form, 44% with the malignancy-associated form, 24% with the drug-induced form in the setting of malignancy, and 2% with the drug-induced form. AML was the most common malignancy (in 24 of 83 patients [29%]). Filgrastim was the most common medication (used in 8 of 83 patients [10%]). Leukopenia, anemia , thrombocytopenia, absence of arthralgia, and histiocytoid or subcutaneous histopathology were all associated significantly associated with malignancy. (4)

The issue of whether histiocytoid SS (HSS) is associated with hematopoietic disorders remains unsettled. HSS is characterized histologically by a dense infiltrate of histiocytoid cells that stain with myeloperoxidase. Bush and Wick state that between 35 and 55% of reported cases of HSS have demonstrated such an association, usually with myelogenous leukemia or MDS, in their report of two additional cases associated with myeloid dyscrasias. (5) Despite the association of HSS with lymphoproliferative disorders, the infiltrate itself should not be interpreted as leukemia cutis. In a study of 33 patient of HSS, no cytogenetic anomalies were found in the infiltrate, except in one case in which neoplastic cells of chronic myelogenous leukemia were intermingled with the cells of HSS. (6)

What strikes me is the absence of arthralgia and presence of anemia, leukopenia, and/or thrombocytopenia in malignancy-associated SS. In the classic form, neutrophilia and arthralgias are characteristic features. This suggests that these two variants have a different pathogenesis. The interplay of genetic predisposition, HLA patterns, cytokines, autoantibodies, immune complexes, and dermal dendrocytes must differ between the variants of SS. This requires further research. Unraveling this data will help identify those at risk, and could even have therapeutic implications. Improving diagnostic accuracy and obviating malignancy in those at risk would be very sweet.

1. Raza S, et al. Insight into Sweet’s syndrome and associated-malignancy: A review of the current literature. Int J Oncol 2013; 42: 1516-22.
2. Marcoval J, et al. Sweet syndrome: Long-term follow-up of 138 patients. Clin Exp Dermatol 2016; 41: 741-6.
3. Amouri M, et al. Sweet’s syndrome: A retrospective study of 90 cases from a tertiary care center. Int J Dermatol 2016; 55: 1033-9.
4. Nelson CA, et al. Sweet syndrome in patients with and without malignancy: A retrospective analysis of 83 patients from a tertiary academic referral center. J Am Acad Dermatol 2018; 78: 303-9.
5. Bush JW, Wick MR. Cutaneous histiocytoid Sweet syndrome and its relationship to hematological disease. J Cutan Pathol 2016; 43: 394-9.
6. Alegría-Landa V, et al. Clinicopathologic, immunohistochemical, and molecular features of histiocytoid Sweet syndrome. JAMA Dermatol 2017; 153: 651-9.

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