Histiocytoid neutrophilic dermatoses and panniculitides: variations on a theme

Requena et al, in their article titled "Histiocytoid Sweet syndrome," in 2005, established that the dermal infiltrate in some patients with Sweet's syndrome is composed of histiocyte-like immature myeloid cells, not polymorphonuclear leukocytes as is the norm. With this premise in mind, we report on 6 cases of inflammatory skin disease in which the common denominator was a dermal and/or subcutaneous infiltrate of histiocytoid myeloid cells in patients with new-onset cutaneous eruptions and systemic symptoms. The cases were diverse clinically and microscopically, fell short of the criteria necessary for a diagnosis of classical Sweet's syndrome, and were difficult to categorize at the outset. The systemic manifestations ranged from malaise alone to a combination of fever, chills, night sweats, and polyarthralgia. The clinical morphology of the cutaneous eruptions varied from being papulovesicular in 1 patient to mainly consisting of erythematous plaques and nodules in the remainder. The dermatologists' differential diagnoses included Sweet's syndrome in 3 cases, a drug eruption in 2, and other entities such as erythema nodosum and Well's syndrome. Biopsies in all cases revealed a dermal and/or subcutaneous infiltrate composed predominantly of mononuclear histiocytoid cells of myeloid origin. With the benefit of detailed clinicopathologic correlation, the cases were classified for the purpose of this report as follows: Sweet's-like neutrophilic dermatosis, histiocytoid (3 cases); subcutaneous Sweet's syndrome, histiocytoid (2 cases); histiocytoid neutrophilic dermatosis, unspecified (1 case). In addition, we describe a further instructive case that exhibited overlap with those in the series but proved ultimately to represent leukemia cutis. The spectrum of observations in this report supports and expands the original concept of histiocytoid Sweet's syndrome.     

52d Cologne Dermatology Meeting of the Cologne University Dermatology Clinic 24 January 1990

Patients with the following diagnoses were presented: pyoderma gangraenosum in a patient with myelodysplastic syndrome passing into an acute myelomonocytic leukemia and specific cutaneous infiltration, primary genital infection with herpes simplex virus, type 1 (HSV-1) in an adult patient, pellagroid, Sweet's syndrome with follicular involvement, Sweet's syndrome in a patient with cancer of the breast, lichen amyloidosus, angiolymphoid hyperplasia with eosinophilia, Darier's disease 1. associated with basal cell carcinoma 2. with specific cutaneous infiltrations in a patient with acute myeloid leukemia, body building, anabolic steroids and fertility, multiple trichodiscomas and perifollicular fibromas, Buschke's scleroedema adultorum, extensive necrobiosis lipoidica without diabetes mellitus, extramammary, multifocal type of Paget's disease.     

Sweet's syndrome without granulocytosis

Background Sweet's syndrome (SS), acute febrile neutrophilic dermatosis, has been linked to hematologic malignancies and presents with characteristic edematous dermal plaques. Peripheral blood neutrophilia is frequently seen in association with SS and is one of the diagnostic criteria.
Objective To report the clinical, laboratory, and hematologic data of four patients with myeloid leukemia who developed SS after chemotherapy. Three of these patients were neutropenic.
Methods A retrospective study of four patients with SS and hematologic malignancies was undertaken. Three patients had de novo acute myelogenous leukemia and one was in the acute blast crisis of chronic myelogenous leukemia.
Results Sweet's syndrome was not originally suspected in these patients because of the low peripheral white blood cell counts caused by chemotherapy. All of the patients presented with fevers, arthralgias, and an eruption. They had been treated with antibiotics because of a presumed infection. Once the correct diagnosis was made and oral prednisolone was started, a rapid response followed.
Conclusions Sweet's syndrome should be considered in the differential diagnosis when acute myeloid leukemic patients develop skin lesions and unexplained fevers regardless of the peripheral blood counts.     

Sweet's syndrome in acute myelogenous leukemia presenting as periorbital cellulitis with an infiltrate of leukemic cells

Sweet's syndrome is characterized by the abrupt onset of fever, neutrophilic leukocytosis, and erythematous, tender pseudovesiculated plaques or nodules that respond readily to corticosteroid therapy. It is usually distinguished by the presence of mature neutrophils on histopathologic examination. We describe a 38-year-old man with acute myelogenous leukemia who had an erythematous vesicular eruption of the left eye develop that resembled cellulitis. A biopsy specimen revealed a dermal infiltrate of mature neutrophils and immature myeloblastic precursors. He later had hemorrhagic pseudovesiculated plaques develop bilaterally on his hands. A biopsy specimen again revealed abundant neutrophils with immature forms. A similar eruption developed at the site of a Hickman catheter placement 4 months later. His skin lesions responded rapidly to oral corticosteroids. This case is unique in that his initial presentation of Sweet's syndrome resembled orbital cellulitis that was characterized by immature myeloid precursors on histopathology.     

Sweet's syndrome from an Indian perspective: a report of four cases and review of the literature

BACKGROUND: Sweet's syndrome or acute febrile neutrophilic dermatosis is not frequently reported from India. Four patients fulfilling clinico-pathologic criteria for Sweet's syndrome seen during May-August 2002 prompted us to review reports on Indian patients from the indexed literature. METHODS: A PubMed and IndMed search for Sweet's syndrome revealed 11 reports appearing between 1985-2002 documenting 12 patients. The clinico-pathologic features, clinical course and treatment of all these 16 patients (including four new cases) were studied. RESULTS: The study comprised 12 females and four males between 35 days to 57 years of age. There were four children of < 12 years. Ulcerated, crusted lesions in one and typical, erythematous, tender, papulo-nodulo-plaques and targetoid lesions with pseudovesiculation were observed in 13 other patients particularly involving head, neck and upper limbs. Extracutaneous Sweet's syndrome manifesting as gingival hyperplasia and myositis was seen in one patient each. All had simultaneous onset of cutaneous lesions, fever, headache and malaise. Ocular involvement was observed in four patients only. Associated hematoligic disorders recorded were myelodysplasia in three, polycythemia vera in one and leukemia in three patients respectively. Two of these patients had treatment with all-transretinoic acid and low-dose cytosine-arbinoside before onset of Sweet's syndrome. One patient each had symptoms of upper respiratory tract infection and history of minor injury prior to cutaneous lesions. Another patient had pregnancy induced self-limiting Sweet's syndrome. Leukocytosis was present in 11 patients. Three of four new patients had positive tests for antistreptolysin-O and C-reactive protein. Characteristics histologic features were recorded in specimens of all patients. Eleven patients responded to systemic corticosteroids. Colchicin or potassium iodide were effective in one patient each. CONCLUSION: The overall clinico-pathologic and therapeutic spectrum of Sweet's syndrome in Indian patients does not appear to be different from its established picture.     

Sweet's syndrome with neurologic manifestations in a patient with esophageal adenocarcinoma: case report and review of the literature

Background  Sweet's syndrome, also known as febrile neutrophilic dermatosis, can occur in patients with an underlying malignancy and can present with extracutaneous manifestations, including neurologic symptoms.
Methods  This report describes a 62-year-old man with adenocarcinoma of the esophagus who developed Sweet's syndrome and whose postoperative course was complicated by encephalitis.
Results  A diagnosis of Sweet's syndrome with neurologic manifestations was made, and the patient was treated with oral corticosteroids. His symptoms improved markedly within 12 h.
Conclusion  Neurologic symptoms in Sweet's syndrome are infrequently reported and have not been described previously in a patient with adenocarcinoma of the esophagus.     

Acute febrile neutrophilic dermatosis (Sweet's syndrome) in a patient with hairy-cell leukemia

A case of hairy-cell leukemia that started with cutaneous lesions similar to those of acute febrile neutrophilic dermatosis (Sweet's syndrome) is reported. The patient had leukopenia and a recurrent eruption for a year prior to the diagnosis of the hematologic disorder. Bone marrow examination eventually demonstrated characteristic "hairy" cells with tartrate-resistant, acid-phosphatase activity. Biopsy of a cutaneous lesion suggested an abscess showing a dense neutrophilic dermal infiltrate with perivascular predilection. The findings of IgA, IgM, C3, and fibrinogen in vessel walls by immunofluorescence and vascular disruption by electron microscopy contribute additional evidence for an immunologic determinant in this instance of Sweet's syndrome. It is known that neutrophilic infiltrates of Sweet's syndrome may have a variety of clinical presentations. This is the second case of hairy-cell leukemia with which Sweet's syndrome was associated.     

Sweet's syndrome in the setting of CD34-positive acute myelogenous leukemia treated with granulocyte colony stimulating factor: evidence for a clonal neutrophilic dermatosis

BACKGROUND: Sweet's syndrome in the setting of hematologic dyscrasias can be categorized into paraneoplastic-associated SS, drug-induced SS, and SS with leukemia cutis. Apart from those cases demonstrating concomitant leukemic infiltrates, it has been surmised that SS is a reactive phenomenon induced by a specific cytokine milieu. METHODS: The authors present a patient with CD34+ acute myelogenous leukemia (AAML) who developed SS in the setting granulocyte colony stimulating factor (GCSF) therapy. Routine light microscopy and molecular studies were carried on the patient's skin biopsy specimen and post-treatment marrow. An X inactivation assay for clonality was employed. RESULTS: Routine light microscopic examination revealed differentiated myeloid precursors including myelocytes and metamyelocytes within the subcutis; myeloblasts were not identified. In addition, in the overlying skin, features typical of SS were observed. The neutrophils demonstrated dysplastic features including hypolobation compatible with a Pseudo Pelger-Huet anomaly. X inactivation studies showed clonality both within her post-treatment marrow and skin biopsy specimen. CONCLUSIONS: Sweet's syndrome developing in CD34+ AML patients following GCSF therapy likely reflects therapy induced differentiation of sequestered leukemic cells, hence indicative of a clonal neutrophilic dermatosis.     

Sweet’s Syndrome

Sweet's syndrome was originally described in 1964 by Dr Robert Douglas Sweet as an 'acute febrile neutrophilic dermatosis'. The syndrome is characterized by pyrexia, elevated neutrophil count, painful red papules, nodules, plaques (which may be recurrent) and an infiltrate consisting predominantly of mature neutrophils that are diffusely distributed in the upper dermis. In addition to skin and mucosal lesions, Sweet's syndrome can also present with extra-cutaneous manifestations. Sweet's syndrome can be classified based upon the clinical setting in which it occurs: classical or idiopathic Sweet's syndrome, malignancy-associated Sweet's syndrome and drug-induced Sweet's syndrome. Systemic corticosteroids have been considered the 'gold standard' for the treatment of patients with Sweet's syndrome; in addition, treatment with topical and/or intralesional corticosteroids may be effective as either monotherapy or adjuvant therapy. However, spontaneous resolution of the symptoms and lesions has occurred in several patients with Sweet's syndrome for whom disease-specific therapeutic intervention was not initiated and in some of the patients with drug-induced Sweet's syndrome after withdrawal of the dermatosis-causing medication. Oral therapy with either potassium iodide or colchicine typically results in rapid resolution of Sweet's syndrome symptoms and lesions; therefore, in patients with Sweet's syndrome who have a potential systemic infection or in whom corticosteroids are contraindicated, it is reasonable to initiate treatment with these agents as a first-line therapy. Indomethacin, clofazimine, dapsone, and cyclosporine have also been effective therapeutic agents for managing Sweet's syndrome. However, indomethacin and clofazimine appear less effective than corticosteroids, potassium iodide, and colchicine. Appropriate initial and follow-up laboratory monitoring is necessary when treating with either dapsone or cyclosporine because of the potential for severe adverse drug-associated effects. Systemic antibacterials with activity against Staphylococcus aureus frequently result in partial improvement of Sweet's syndrome lesions when they are impetiginized or secondarily infected. In some patients with dermatosis-associated bacterial infections, organism-sensitive specific systemic antibacterials have been helpful in the management of their Sweet's syndrome. Although patients with hematologic malignancy-associated Sweet's syndrome often receive cytotoxic chemotherapy agents and antimetabolic drugs for the treatment of their underlying disorder, these agents are seldom used solely for the management of the symptoms and lesions of Sweet's syndrome. The treatment of patients with Sweet's syndrome with either etretinate or interferon-alpha have been reported as single case reports; both patients had improvement of not only their Sweet's syndrome lesions, but also their associated hematologic disorder.     

Diagnostic criteria for Sweet's syndrome

Five patients with Sweet's syndrome with typical clinical and histologic features were reviewed. Attention is drawn to the possible association of drug use, venipuncture and insect bite, resection of colon, exacerbation of sinusitis, and acute myelocytic leukemia with the onset of the skin eruptions in our patients. The question of whether Sweet's syndrome is just a reactive phenomenon or a specific entity is raised. Our opinion is that Sweet's syndrome is a reaction to many different antigens. However, characteristic clinical and histologic features are present to allow a definite diagnosis of Sweet's syndrome. We propose two major criteria and four minor criteria for the diagnosis of Sweet's syndrome. Findings in patients must fulfill both of the major criteria and at least two of the minor criteria to allow a diagnosis of Sweet's syndrome.     

Acute febrile neutrophilic dermatosis--a marker of malignancy?

A retrospective survey during a 2-year period disclosed 18 patients with acute febrile neutrophilic dermatosis (Sweet's syndrome). An associated lympho- or myeloproliferative malignancy was found in 6 patients. Attacks of Sweet's syndrome preceded the diagnosis of neoplasia in 4 patients (3 months to 6 years). Some differences in symptoms and signs were found in the group of patients with associated malignancy compared with the group without, that is, male predominance, mucosal symptoms, anemia, and frequent recurrence of skin symptoms. The onset of Sweet's syndrome indicates an acute infectious disease, and the patients are frequently referred to departments of internal medicine and infectious diseases. In addition, the skin lesions may mimic those which often accompany a generalized infection (erythema multiforme, erythema nodosum, vasculitis, pustular eruptions and urticaria). Since Sweet's syndrome may precede the possibly associated malignant disease, the initial diagnosis of the syndrome is important and should be made with confidence with increasing awareness of the characteristic symptoms.     

Sweet's syndrome masquerading as facial cellulitis

Sweet's syndrome, or acute febrile neutrophilic dermatosis, is a cutaneous condition that typically occurs as tender red plaques or nodules. However, atypical presentations may occur and, in our case, Sweet's syndrome masqueraded as facial cellulitis and soft tissue infections of the extremities in a sporotrichoid pattern. Despite treatment with broad-spectrum antibiotics, the cutaneous lesions progressed. Results of skin biopsy specimens of the facial plaque and a nodule on the right upper extremity were diagnostic of Sweet's syndrome. Simultaneous to diagnosis, the patient also was found to have acute myelogenous leukemia (AML).     

Lymphocytic infiltrate of the dermis preceding typical Sweet's syndrome

BACKGROUND: The histologic criteria for Sweet's syndrome consist in prominent oedema of the dermis and a diffuse infiltrate of numerous neutrophils with leukocytoclasis without vasculitis in the superficial and the deep dermis. Several comorbidities have been observed in patients with Sweet's syndrome, particularly hemo-proliferative diseases. PATIENTS: We report the cases of two men aged 60 and 75 years with Sweet's syndrome associated in one case with myelodysplasia and in the other with chronic lymphocytic leukemia. These two patients had typical edematous plaques highly evocative of Sweet's syndrome. However, histological examination revealed superficial and deep perivascular lymphocytic infiltrate in the dermis on 5 occasions before the typical neutrophilic dermatosis of Sweet's could be diagnosed after respectively 2 and 4 years of progression. DISCUSSION: Histological findings in Sweet's syndrome are characteristic and constitute a major diagnostic factor. However, these two cases show that a lymphocytic infiltrate can occur months or even years before the appearance of typical neutrophilic infiltrate in patients with Sweet's syndrome.     

Facial Sweet's syndrome mimicking rosacea fulminans

A 36-year-old man presented with a non-pruritic, erythematous facial rash with peri-oral and peri-orbital sparing. The initial clinicopathological diagnosis was rosacea fulminans, which was treated with 25 mg oral prednisolone and cephalexin. The patient re-presented 1 week later with exacerbation of his rash in addition to constitutional symptoms of fever and malaise. A further skin biopsy was taken and the marked neutrophilic infiltrate in the absence of vasculitis made the diagnosis of Sweet's syndrome (acute febrile neutrophilic dermatosis). High-dose prednisolone (50 mg daily), topical hydrocortisone cream and ichthammol in zinc ointment were commenced with rapid clinical improvement. This case highlights the importance of considering Sweet's syndrome as a differential diagnosis when presented with a facial eruption.     

Elastophagocytosis: a feature of resolving Sweet''s syndrome

We report the case of a patient with atypical Sweet's syndrome characterized by an annular erythema that showed consumption of elastic fibres by giant cells and histiocytes. Although the lesions were found on sun-exposed sites and the first biopsy demonstrated extensive elastophagocytosis, our patient did not have photodamaged skin clinically. A repeat biopsy 5 weeks later demonstrated an abundant collection of neutrophils supporting the diagnosis of Sweet's syndrome. To our knowledge, an elastolytic granulomatous reaction pattern has not been previously reported in Sweet's syndrome.     

Increased plasma chemoattractant in Sweet''s syndrome

The neutrophil function and plasma leukotactic activity of a patient with Sweet's syndrome and cystonodular acne were evaluated during a 2 1/2-year period. These studies demonstrated that chemotaxis was frequently slightly increased, especially during an exacerbation of Sweet's syndrome, but showed some decrease during isotretinoin therapy. Other functions, such as phagocytosis, metabolic activation, and bacterial killing, also were slightly increased. In addition, the patient's serum contained a heat-stable, nonlipid chemoattractant that was present at all times except during a course of isotretinoin. Although his symptoms responded to aspirin, the plasma continued to show this chemoattractant. These findings are consistent with the hypothesis that excess chemoattractant in Sweet's syndrome attracts neutrophils, which then mediate an inflammatory response. In addition, aspirin may be used to control Sweet's syndrome symptoms, although it does not suppress the plasma chemoattractant.     

Nitrofurantoin-associated Sweet's syndrome

A 53-year-old woman was seen for arthralgias, fever, and a painful rash developing at the end of a 7-day course of nitrofurantoin for a urinary tract infection. Her only other medication was naproxen, which was started after the onset of symptoms. Initial biopsy showed microscopic changes suggestive of a toxic eruption, but within 3 days the clinical signs and symptoms typical of Sweet's syndrome evolved. A repeat biopsy showed microscopic features characteristic of that diagnosis. The patient subsequently cleared with prednisone therapy. We report this patient as a case consistent with drug-induced Sweet's syndrome induced by nitrofurantoin.     

Clonality in the setting of Sweet's syndrome and pyoderma gangrenosum is not limited to underlying myeloproliferative disease

BACKGROUND: The neutrophilic dermatoses encompass, among others, Sweet's syndrome (SS) and pyoderma gangrenosum (PG), which are associated with underlying systemic diseases including myeloid dyscrasias. METHODS: On skin biopsies from 16 patients with biopsy-proven SS and/or PG, we performed an X-inactivation assay to detect clonal restriction of neutrophils. There were two patient categories based on known diseases at the time of diagnosis: patients with myeloproliferative disease and patients without myeloproliferative disease. RESULTS: Among seven patients with acute myelogenous leukemia and two with myelodysplastic syndrome, clonal restriction was found in five; three were homozygous, precluding analysis. Among the seven control patients, infiltrates were clonally restricted in five; one was polyclonal and the other was homozygous for the allele, precluding analysis. Of the five patients with clonally restricted infiltrates, one was subsequently diagnosed with myelodysplasia, one had unexplained neutropenia and an additional patient developed breast cancer. Overall, the incidence of clonality in both groups was the same, averaging 81%. CONCLUSION: These findings suggest that clonality in neutrophilic dermatoses, while characteristic of underlying myeloid dyscrasia, is not observed exclusively in the setting of myeloproliferative diseases. The significance of clonal neutrophilic infiltrates unassociated with myeloproliferative disease is unclear, but it may have some implications regarding the pathogenesis of sterile neutrophilic infiltrates. Clonality is well described in the setting of lymphomatoid hypersensitivity, reflecting an overzealous response to antigenic stimuli. One could speculate a similar mechanism operational in cases of apparently reactive SS/PG associated with monoclonality; a localized form of cutaneous neutrophilic dyscrasia is also possible.     

Sweet's syndrome revisited: a review of disease concepts

Sweet's syndrome, also referred to as acute febrile neutrophilic dermatosis, is characterized by a constellation of symptoms and findings: fever, neutrophilia, erythematous and tender skin lesions that typically show an upper dermal infiltrate of mature neutrophils, and prompt improvement of both symptoms and lesions after the initiation of treatment with systemic corticosteroids. Hundreds of patients with this dermatosis have been reported. The manifestations of Sweet's syndrome in these individuals have not only confirmed those originally described by Dr Robert Douglas Sweet in 1964, but have also introduced new features that have expanded the clinical and pathologic concepts of this condition. The history, clinical characteristics, laboratory findings, associated diseases, pathology, and treatment options of Sweet's syndrome are reviewed. The evolving and new concepts of this dermatosis that are discussed include: (i) Sweet's syndrome occurring in the clinical setting of a disease-related malignancy, or medication, or both; (ii) detection of additional sites of extracutaneous Sweet's syndrome manifestations; (iii) discovery of additional Sweet's syndrome-associated diseases; (iv) variability of the composition and/or location of the cutaneous inflammatory infiltrate in Sweet's syndrome lesions; and (v) additional efficacious treatments for Sweet's syndrome.