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Available online 14 November 2024
Giant Cellulitis-like Sweet Syndrome: Contribution of a New Case and Medical Literature Review
Síndrome de Sweet tipo celulitis gigante: aporte de un nuevo caso y revisión de la literatura
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K. Díez-Madueñoa, D. Buendía Castañoa, D. Roldán Cortésb, P. de la Cueva Dobaoa,
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pdelacueva@yahoo.com

Corresponding author.
a Servicio de Dermatología, Hospital Universitario Infanta Leonor, Madrid, Spain
b Servicio de Anatomía Patológica, Hospital Universitario Infanta Leonor, Madrid, Spain
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K. Díez-Madueño, D. Buendía Castaño, D. Roldán Cortés, P. de la Cueva Dobao
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Table 1. Conceptual table summarizing the epidemiological, clinical, and analytical characteristics of GCSS cases described in the current literature.
Table 2. Table summarizing the histological characteristics of GCSS cases described in the current literature.
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To the Editor,

A 53-year-old male with a past medical history of hypertension, gout, obesity, and prior endoscopic ureteral lithotripsy consulted for painful skin lesions localized over the entire left thigh, ipsilateral flank and buttock, and the lumbosacral region. He reported having a fever and general malaise. Over the past 6 years, he had experienced similar episodes in the same location lasting 3 up to 7 days. Over the past 2 years, the outbreaks recurred every 4 to 8 weeks. Although, at times, he had been treated with systemic antibiotics due to suspected infectious cellulitis, this had no impact on the course of the disease. He said he did not have any other symptoms, constitutional syndrome, relevant family history, or association with drug intake. He did not meet any other criteria for familial Mediterranean fever either.

Upon examination, a large, well-demarcated, indurated, warm and painful erythematous plaque was revealed covering the above-mentioned areas (fig. 1A and B). A blood test revealed the presence of leukocytosis (11.98 x 109/L), neutrophilia (9.6 x 109/L; 80%), and an elevation of C-reactive protein (196mg/L). Other blood tests during remission periods showed no elevation in acute phase reactants. The remaining tests (tumor markers, autoimmunity, or serologies) revealed no significant findings.

Figure 1.

A: clinical image. Left lateral view. Large erythematous plaque covering the entire left thigh and ipsilateral flank. Well-demarcated, indurated, and warm plaque. B: clinical image. Posterior view. Erythematous-edematous plaque. Left thigh, buttock, and flank involvement; confluent toward the lumbosacral region. C: histological image. Overview. Skin with superficial perivascular lymphocytic inflammation with neutrophils. Mild papillary dermal edema and preserved epidermis. No evidence of panniculitis or vasculitis. No eosinophils seen. Original Image 4X. Hematoxylin-eosin stain. D: histological image. Detail of inflammatory infiltrate. Papillary dermis with perivascular lymphocytic infiltrate. Presence of neutrophils. Original Image 20X. Hematoxylin-eosin stain. E: histological image. Detail of periadnexal infiltrate. Periadnexal inflammatory infiltrate composed of lymphocytes and neutrophils. Original Image 20X. Hematoxylin-eosin stain.

(0.4MB).

Histological examination of a biopsy taken from the affected area (fig. 1C-E) revealed the presence of skin with mild papillary edema and superficial and periadnexal perivascular lymphocytic inflammation, also with the presence of neutrophils. No vasculitis or leukocytoclastic phenomena were reported. Although histology proved atypical, the clinicopathological correlation suggested the diagnosis of giant cellulitis-like Sweet syndrome (GCSS).

Initial treatment with oral corticosteroids and colchicine proved ineffective. Dapsone at a dose of 50mg daily was then administered, resulting in excellent control of the outbreaks. After gradually tapering the dose over a 9-month period, treatment was eventually discontinued. To date, no new outbreaks have occurred, and no associated comorbidities have appeared. An endoscopic ureteral lithotripsy—laterality consistent with the lesions—performed 1-2 months before symptom onset could have acted as a trigger.

Multiple clinical and histological variants of Sweet syndrome (SS) have been described to date. Surovy et al. described a rare variant in 2013, which they called “GCSS”.1 In our review (Pubmed/other sources), we found 9 articles and 1 poster, representing an exceptional SS subtype (Table 1).1–9 The articles report on 9 women and 4 men (N=13) aged between 36 and 90 years (median, 62). Notable past medical histories include the presence of neoplasms and obesity. Possible triggers described include hematological and solid organ neoplasms, trauma, or bacterial infection.

Table 1.

Conceptual table summarizing the epidemiological, clinical, and analytical characteristics of GCSS cases described in the current literature.

Epidemiological, clinical and analytical characteristics of GCSS  Gender/Age  Relevant history  Possible trigger  Skin lesions  Location  Fever, malaise, others  Leukocytes/Neutrophils and %/CRP (units as per article)  Disease duration  Episodic/Recurrent  Flare duration  Treatment  Surgical debridement 
Case #1 (Surovy et al., 2013)  Male/62  Obesity  Synchronous multiple myeloma  Large, erythematous, warm, well-demarcated plaque associated with other faint erythematous plaques  Left leg, buttocks, thighs, trunk  Yes  Leukocytes: 10,600/μL / CRP: 279 mg/L  2 years  Recurrent (8 flares)  3 weeks  Prednisone  No 
Case #2 (Surovy et al., 2013)  Female/48  Obesity  Not identifiable  Painful, warm erythematous infiltrated plaques. Some with blister-purpuric appearance  Right leg and knee, left arm, buttocks, trunk  Yes  Leukocytes: 24,000/μL / CRP: 429 mg/L  8 years  Recurrent (multiple)  Not specified  Prednisone  No 
Case #3 (Surovy et al., 2013)  Female/68  Obesity  Synchronous breast cancer  Large, well-demarcated erythematous plaques. Some with blister-purpuric appearance  Suprapubic region, right thigh, leg, and foot  Yes  Leukocytes: 11,300/μL / CRP: 235 mg/L  3 months  Recurrent (3 flares)  Not specified  Prednisone, breast cancer surgery  No 
Case #4 (Koketsu et al., 2014)  Female/60s  Not relevant  Not identifiable  Erythematous macules and indurated, painful erythemato-edematous plaques  Right thigh and flank  Yes  Leukocytes: 10,300/μL / Neutrophils: 8,755/μL  3 years  Recurrent (multiple)  Not specified  Dapsone + colchicine + prednisone  No 
Case #5 (Kaminska et al., 2014)  Female/54  Sjögren's disease, morbid obesity, PBC with liver transplant  Escherichia coli bacteremia (1 month prior)  Erythemato-edematous, indurated, confluent papules and plaques. Progression with a tendency to generalize  Buttocks, limbs, trunk, head, neck  Yes  Leukocytes: 4.1 K/μL / Neutrophil percentage: 77%  Not specified  Episodic (1)  2 days  Prednisone  No 
Case #6 (So et al., 2015)  Female/72  Gastric cancer  Synchronous unclassifiable myelodysplastic syndrome  Large, well-demarcated, warm erythematous plaque, preceded by recurrent fevers and pain in the ipsilateral foot  Left thigh and flank  Yes  Leukocytes: 73.5 cells/μL / Neutrophil percentage: 66%  2 years  Recurrent (multiple flares)  2 weeks  Clobetasol propionate cream  No 
Case #7 (Buendía et al., 2019)  Female/62  Obesity  Not identifiable  Large, warm, indurated erythematous plaque followed by flares with a tendency to generalize  Buttocks, trunk, upper limbs  Yes  Leukocytes: 10,900/mm3 / Neutrophils: 10,000/mm3 / CRP: 306.8 mg/L  Not specified  Recurrent (at least 3 flares)  10 days  Prednisone, colchicine → dapsone  No 
Case #8 (Okuyama et al.)  Female/56  Gastric cancer  Lower limb trauma or synchronous acute myeloid leukemia  Cellulitis-like erythematous plaques with pain and edema. Unilateral onset with bilateral progression  Legs  Yes  Leukocytes: 10-15×103/μL / CRP 20 mg/dl  At least 2 months  Episodic (2)  Not specified  Prednisone  Yes 
Case #9 (Mitaka et al.)  Female/90  Breast cancer  Not identifiable  Erythematous, warm, well-demarcated, pruritic plaques  Breast and axilla (postsurgical/RT area), right flank, and lower limb  Yes  Leukocytes: 29,100/μL / Neutrophil percentage: 78%  2 weeks  Episodic (1)  2 weeks  Prednisone  No 
Case #10 (Zhao et al., 2022)  Male/52  Not relevant  Bone marrow biopsy in sternum (postsurgical) or synchronous myelodysplastic syndrome  Erythema around puncture site associated with edema, heat, pain, and blister formation. Progressive local extension  Anterior chest (trauma site)  Yes  Leukocytes: 1.82×109/L / Neutrophils: 1.07×109/L / CRP: 351 IU/L  1 week  Episodic (1)  1 week  Prednisone  No 
Case #11 (Díez-Madueño et al., 2023)  Male/53  Obesity  Postsurgical ureteral endoscopic lithotripsy  Large, well-demarcated erythemato-edematous plaque associated with heat and pain  Left thigh, buttock, flank, and lumbosacral region  Yes  Leukocytes: 11.98×109/L / Neutrophils: 9.6×109/L / Neutrophil percentage: 80% / CRP: 198 mg/L  6 years  Recurrent (multiple flares)  1 week  Prednisone, colchicine → dapsone  No 
Case #12 (Hingtgen et al., 2023)  Male/36  Obesity, chronic myeloid leukemia, heart failure  Not identifiable  Large, painful erythematous plaques. Local progression  Right axilla and flank. Some discontinuous lesions on the thorax  Yes  White series: 172,000/mL / Neutrophil percentage: 64% / Band percentage: 34%  1 week  Episodic (1)  1 week  Prednisone  Yes 
Case #13 (Kyung Nam et al., 2023)  Female/69  Cervical cancer, adjuvant radiotherapy  Postsurgical saphenectomy  Erythematous, edematous plaques; tender but not very painful. Associated pseudovesicles  Right thigh (postsurgical area)  Yes  Neutrophil percentage: 88.8% / CRP: 9.14 mg/dL  2 weeks  Episodic (1)  2 weeks  Prednisone  No 

Disease is characterized by outbreaks—lasting days to weeks—featuring large, confluent, well-demarcated erythematous-edematous plaques, associated with fever and general malaise. Lesions can be warm, painful, and pruritic. They may begin in a localized area and then spread locally or affect multiple areas. Initially, lesions can mimic bacterial cellulitis, so patients are sometimes hospitalized and treated with antibiotics, or surgical treatment. The most widely affected areas are the lower limbs, buttocks, and trunk. Regarding the duration and frequency of the outbreaks, 2 forms of presentation seem to emerge. One shows a recurrent pattern,7 with multiple episodes over months or even years. The second form has an episodic pattern,6 with 1 or 2 self-limited episodes over a period of weeks to months.

Blood tests during outbreaks show leukocytosis, neutrophilia, or elevated acute phase reactants. Histological features are shown in Table 2.

Table 2.

Table summarizing the histological characteristics of GCSS cases described in the current literature.

Sweet syndrome resembling giant cellulitis  Histopathological examination
Case #1 (Surovy et al., 2013)  Edema in the papillary dermis with an inflammatory infiltrate in the upper dermis composed mainly of mature neutrophils. No vasculitis.
Case #2 (Surovy et al., 2013)  Edema of the papillary dermis with a dense inflammatory infiltrate in the upper dermis consisting of mature neutrophils. No vasculitis.
Case #3 (Surovy et al., 2013)  Prominent edema of the papillary dermis with a dense inflammatory infiltrate of mature neutrophils in the papillary dermis. No vasculitis.
Case #4 (Koketsu et al., 2014)  Papillary dermal edema. Superficial and mid-dermal inflammatory infiltrate, perivascular and interstitial, composed of lymphocytes and numerous neutrophils. No vasculitis.
Case #5 (Kaminska et al., 2014)  Prominent papillary dermal edema with a mixed inflammatory infiltrate composed of abundant neutrophils intermingled with lymphocytes, histiocytes, and eosinophils.
Case #6 (So et al., 2015)  Superficial dermal edema with a perivascular and interstitial inflammatory infiltrate of predominantly histiocytoid and immature granulocytic cells, along with neutrophils, eosinophils, and lymphocytes. Staining with CD68 and myeloperoxidase highlighted most interstitial cells (histiocytoid).
Case #7 (Buendía et al., 2019)  Polymorphonuclear-predominant infiltrate in the dermis, with perivascular accentuation and slight edema of the dermal papillae. No vasculitis.
Case #8 (Okuyama et al., 2019)  Neutrophil infiltration in the dermis and adipose tissue, with superficial dermal edema. No vasculitis.  Neutrophil infiltration in the dermis and adipose tissue, superficial dermal edema, intact epidermis, and absence of vasculitis or massive necrotic changes. 
Case #9 (Mitaka et al., 2020)  Dense neutrophilic infiltration in the dermis. No vasculitis.
Case #10 (Zhao et al., 2022)  Edema in the papillary dermis and dense inflammatory infiltration in the dermis composed of myeloperoxidase-positive and CD163-negative mononuclear cells with twisted vesicular nuclei and scant eosinophilic cytoplasm. No vasculitis (histiocytoid).
Case #11 (Díez-Madueño et al., 2023)  Superficial perivascular and perianexial lymphocytic infiltration with presence of neutrophils. Mild edema in the papillary dermis. Intact epidermis. No vasculitis.
Case #12 (Hingtgen et al.)  Dermal edema with a perivascular and interstitial neutrophilic infiltration spreading towards the subcutaneous tissue.
Case #13 (Kyung Nam et al., 2023)  Prominent upper dermal edema and diffuse neutrophilic infiltrates with histiocytoid mononuclear cells. No vasculitis.

The diagnosis of GCSS is one of exclusion, and differential diagnosis should include the following entities: bacterial cellulitis, eosinophilic cellulitis, thrombophlebitis, autoinflammatory syndromes, or atypical SS subtypes (e.g., necrotizing fasciitis-type SS).10 The presentation of large plaques with atypical characteristics, asymmetrical distribution affecting multiple areas, negative cultures, and the lack of response to antibiotics help distinguish it from bacterial cellulitis.

Treatment is similar to that used to treat classic SS, often responding to corticosteroids. In non-responsive cases, dapsone is considered an effective drug.

Localized neutrophilic dermatosis triggered by tissue injury (LNDT) is a recently described umbrella term used to unify cases of SS triggered by trauma, surgery, lymphedema, or chronic venous insufficiency (whether primary or secondary).11 In our opinion, both GCSS and LNDT share traits that suggest they could be presentations of the same autoinflammatory syndrome. The 2 entities exhibit skin lesions, fever, and general malaise occurring in episodic or recurrent outbreaks, which can affect a localized area or become generalized. Differently, in LNDT, the lesions are predominantly limited to the affected tissue or area—usually the lower limb or postoperative region—with multi-territory involvement being less frequent. GCSS, therefore, remains a concept still under definition. New publications are necessary to properly define this entity.

Understanding GCSS helps in the early suspicion of the disease, distinguishing it from bacterial cellulitis, thus avoiding multiple hospital admissions, prolonged antibiotic use, and unnecessary surgical interventions.

Conflicts of interest

None declared.

References
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A.M. Surovy, N. Pelivani, I. Hegyi, U. Buettiker, H. Beltraminelli, L. Borradori.
Giant cellulitis-like Sweet Syndrome, a new variant of neutrophilic dermatosis.
JAMA Dermatol. enero de, 149 (2013), pp. 79-83
[2]
H. Koketsu, C. Ricotti, F.A. Kerdel.
Treatment of giant cellulitis-like Sweet syndrome with dapsone.
JAMA Dermatol., 150 (2014), pp. 457-459
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E.C.N. Kaminska, A.I. Nwaneshiudu, A. Ruiz de Luzuriaga, M. Tsoukas, D. Bolotin.
Giant cellulitis-like Sweet syndrome in the setting of autoimmune disease.
J Am Acad Dermatol., 71 (2014), pp. e94-e95
[4]
J.K. So, C.A. Carlos, C.S. Frucht, P.R. Cohen.
Histiocytoid giant cellulitis-like Sweet's syndrome: Case report and review of the literature.
Dermatol Online J., 21 (2015),
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S. Okuyama, T. Nito, N. Yanagawa, K. Tajima.
Giant cellulitis-like Sweet syndrome as an initial clinical presentation of acute myeloblastic leukemia with t(6;9)(p23;q34): DEK-CAN and internal duplications of FMS-like tyrosine kinase 3.
Ann Hematol., 98 (2019), pp. 787-788
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D.W. Zhao, J. Ni, X.L. Sun.
Histiocytoid giant cellulitis-like Sweet syndrome at the site of sternal aspiration: A case report and review of literature.
WJCC., 10 (2022), pp. 9768-9775
[7]
D. Buendía Castaño, M. Molins Ruiz, D. Fernandez-Nieto, Pindado Ortega, P. Fernández-González, M. Fernández Guarino, P. Jaén Osasolo.
Libro de Resúmenes de Comunicaciones Orales y Pósteres del 47 Congreso Nacional de Dermatología y Venereología, Barcelona.
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[8]
K.N. Bae, K. Shin, H.S. Kim, H.C. Ko, B.S. Kim, M.B. Kim.
Giant cellulitis-like Sweet syndrome following varicose vein surgery: A rare variant of sweet syndrome mimicking cellulitis.
Ann Dermatol., 35 (2023), pp. 151
[9]
G. Hingtgen, R. Mojica, K. Motaparthi.
Giant cellulitis-like Sweet syndrome in association with chronic myeloid leukemia.
JAAD Case Rep., 34 (2023), pp. 1-4
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D. Kroshinsky, A. Alloo, B. Rothschild, J. Cummins, J. Tan, R. Montecino, et al.
Necrotizing Sweet syndrome: A new variant of neutrophilic dermatosis mimicking necrotizing fasciitis.
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V.A. Imstepf, C. Schlapbach, M. Benzaquen, L. Feldmeyer, D. Lipsker, L. Borradori.
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Copyright © 2023. AEDV
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