Dermatology

Acute febrile neutrophilic dermatosis

Are You Confident of the Diagnosis?

  • Characteristic findings on physical examination

The diagnosis of acute febrile neutrophilic dermatosis, commonly referred to as Sweet's syndrome, can be made with confidence on the basis of its distinctive clinical and histopathologic features. Patients classically present abruptly with one or more tender, erythematous or violaceous edematous plaques, which favor the face, neck, and upper extremities (Figure 1).The appearance of superficial vesicles overlying the plaques is common, as a result of intense dermal edema. Bullae and pustules may appear as well.

Figure 1.

Multiple edematous pink plaques on the forehead, with areas of overlying vesiculation present.

Necrotic and/or ulcerated lesions are sometimes found in cases of Sweet's syndrome associated with underlying malignancies. Pathergy may be observed.

Several forms of Sweet's syndrome have been described. The classic form of Sweet's is linked to infections of the upper respiratory or gastrointestinal tract, pregnancy, and inflammatory conditions (most commonly inflammatory bowel disease). It may also be idiopathic.

Another form of Sweet's is associated with malignancies, particularly acute myelogenous leukemia (AML). Lastly, drug-induced Sweet's syndrome has been observed to occur, most often in patients receiving granulocyte-colony stimulating factor (G-CSF). Other medications associated with this form of Sweet's syndrome include all-trans-retinoic acid, bortezomib, trimethoprim-sulfamethoxazole, minocycline, and oral contraceptives.

Over 75% of patients present with one or more of the following systemic symptoms: fever, arthralgias, arthritis, and myalgias. Fever is the most common associated finding, and may either precede the skin eruption or occur concurrently. Ocular involvement, often manifesting as conjunctivitis or episcleritis, may occur in classic Sweet's syndrome, but is less common in the forms associated with malignancy and medications. Oral ulcers, on the other hand, are observed more frequently in malignancy-related Sweet's (about 10% of cases) than in the classic type.

Pulmonary manifestations are not unusual, and chest imaging may reveal infiltrates and effusions. Rarely, Sweet's affects the gastrointestinal, renal, cardiac, musculoskeletal, and central nervous systems.

  • Expected results of diagnostic studies

Classically, the histopathology of Sweet's syndrome is characterized by a dense dermal infiltrate of neutrophils and dermal edema (Figure 2). Occasional eosinophils, histiocytes, and lymphocytes may be present. Karyorrhexis and endothelial swelling are often observed, but in most cases frank vasculitis is not seen.

Figure 2.

Dense dermal neutrophil-predominant infiltrate, with rare eosinophils and lymphocytes present. (H&E, X100)

In older lesions, leukocytoclastic vasculitis may be present focally, although this is thought to be a secondary rather than a primary (immune-mediated) process. A deep neutrophilic infiltrate involving the fat is observed in subcutaneous Sweet's syndrome.

A histologic variant of Sweet's, the so-called histiocytoid type, is marked by the presence of a dermal infiltrate composed of immature myeloid cells which appear as mononuclear cells. The cells are positive for markers indicative of a monocyte-macrophage lineage (CD15, CD43, CD45, CD68, MAC-386, HAM56, and lysozyme), but also react strongly to myeloperoxidase.

To date, it appears that the histiocytoid type of Sweet's syndrome only differs from the conventional form of Sweet's syndrome on the basis of histology. If the diagnosis of histiocytoid Sweet's syndrome is given on a biopsy report, the clinician should take care to establish that this is indeed the correct diagnosis through clinical-pathologic correlation, keeping in mind that leukemia cutis may closely resemble histiocytoid Sweet's histologically.

  • Diagnosis confirmation

Neutrophilic dermatosis of the dorsal hand is often considered to be a variant of Sweet's syndrome. Clinically, edematous papules, plaques, and pustules appear on the dorsal hands. Its clinical course and histologic features closely resemble those of classic Sweet's syndrome.

The diagnostic criteria for Sweet's syndrome are presented in Table I.

Table I.

Diagnostic criteria for Sweet's syndrome
Major criteria
   1. Abrupt onset of tender, erythematous or violaceous          plaques and nodules, sometimes with vesicles, bullae, and       pustules
   2. Histopathology typical for Sweet's syndrome
Minor criteria
   1. Preceded by infection or vaccination, or associated with an          inflammatory condition, myeloproliferative disease or malignancy,        pregnancy, and/or drug exposure
   2. Fever and constitutional symptoms
   3. Leukocytosis, left shift, neutrophilia, elevated CRP, and/or elevated       ESR
   4. Excellent response to systemic corticosteroids
Abbreviations: CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.

Acute febrile neutrophilic dermatosis is a diagnosis of exclusion. It is necessary to exclude infectious processes by skin biopsy and culture, particularly in patients who are immunocompromised.

Besides infection, the differential diagnosis for Sweet's syndrome includes the other neutrophilic dermatoses, such as pyoderma gangrenosum, bowel-bypass syndrome, and neutrophilic eccrine hidradenitis (NEH). Early lesions of pyoderma gangrenosum and Sweet's may have very similar clinical and histopathologic features, making them difficult to distinguish from one another. In addition, both are associated with systemic conditions including inflammatory bowel disease and malignancies. However, lesions of pyoderma gangrenosum are typically more likely to be ulcerative and chronic in nature than those of Sweet's.

Bowel-bypass syndrome is caused by bacterial overgrowth of a blind loop of bowel as a result of gastrointestinal surgery, and similar to Sweet's, occurs in patients with inflammatory bowel disease. Cutaneous findings in bowel-bypass syndrome resemble those in Sweet's, and histopathologic findings may be indistinguishable.

As in Sweet's syndrome, NEH occurs in patients with AML, although NEH is strongly associated with chemotherapy medications such as cytarabine. NEH is histologically distinct from Sweet's, demonstrating a neutrophilic infiltrate around and within eccrine coils.

Who is at Risk for Developing Acute febrile neutrophilic dermatosis?

The classic or idiopathic form of Sweet's syndrome is much more common in women than men. Affected patients are typically between 30 and 70 years old, although cases in children and young adults have been reported. Patients with myeloproliferative disorders, particularly AML and myelodysplastic syndrome (MDS), are at risk of developing Sweet's syndrome. In malignancy-associated Sweet's, women and men are equally affected.

What is the Cause of Acute febrile neutrophilic dermatosis?

  • Etiology

The etiology of Sweet's syndrome is not known. However, it appears to be a reactive process, which presents in response to infection, inflammation, hematologic disease and/or malignancy, and medication exposure. The concept of Sweet's as a hypersensitivity reaction is supported by its quick response to systemic corticosteroids.

  • Pathophysiology

Cytokines appear to play a role in the development of Sweet's syndrome, directly or indirectly. The most commonly implicated cytokines are G-CSF and granulocyte macrophage colony stimulating factor (GM-CSF); exogenous administration of both agents to neutropenic patients is closely linked to development of Sweet's syndrome.

Tumors are capable of producing G-CSF as well, which may explain the occurrence of Sweet's in cancer patients. Serum G-CSF levels may be normal or elevated in Sweet's patients; one study demonstrated the presence of higher levels in patients with active compared to inactive Sweet's-related skin disease. Elevated Th1-associated cytokines, namely interleukin-2 and interferon-gamma, were detected in the serum of Sweet's patients in another study. Other cytokines which have been implicated in the pathogenesis of Sweet's syndrome include interleukin-1, -3, -6, and -8, and TNF-alpha.

Systemic Implications and Complications

As mentioned above, a number of systemic disorders have been associated with Sweet's syndrome. Infections, particularly upper respiratory and gastrointestinal infections, may precede the development of Sweet's. Ten to twenty percent of patients with Sweet's syndrome have an underlying hematologic or solid malignancy. The condition tends to occur in the early stages of the cancer, and may sometimes appear before the malignancy has been diagnosed.

Inflammatory bowel disease (both ulcerative colitis and Crohn's) has been strongly associated with the development of Sweet's syndrome. In addition, a number of other inflammatory diseases have been linked to Sweet's, including relapsing polychondritis, rheumatoid arthritis, Behçet's, sarcoidosis, and thyroid disease.

Treatment Options

Treatment options are summarized in Table II.

Table II.

Treatment options for acute febrile neutrophilic dermatosis
Medical Treatment
Systemic corticosteroids
Topical or intralesional corticosteroids (for localized cases)
Potassium iodide
Colchicine
Indomethacin
Doxycycline
Metronidazole
Clofazamine
Dapsone
Cyclosporine
TNF-alpha inhibitors (etanercept, infliximab, adalimumab)
Interferon-alpha
Thalidomide
Anakinra
Abbreviation: TNF, tumor necrosis factor.

Optimal Therapeutic Approach for Acute febrile neutrophilic dermatosis

Treatment of an underlying cause of Sweet's syndrome (such as malignancy) or withdrawal of the suspected inciting medication will sometimes lead to spontaneous resolution of the skin lesions.

The most effective treatment for Sweet's syndrome is systemic steroids, at a dose of approximately 1mg/kg day to be tapered over 4-6 weeks. Treatment is expected to lead to significant improvement of cutaneous lesions and fever (if it is present) within a few days. Intralesional steroids and short courses of high potency topical steroids may be employed for limited disease.

Potassium iodide has also been shown to be effective for treatment of Sweet's syndrome, starting at an oral dose of 40-60mg three times a day. Oral dosing may be increased to up to 300mg three times a day (a total of 900mg daily).

Alternatively, a supersaturated solution of potassium iodide (SSKI) is available, for which the usual starting dose is 3 drops three times a day. The dose should be increased by 1 drop three times a day, to a final dose of 10 drops three times a day (500mg three times a day). Therapy should be continued until the skin lesions clear, then tapered. Improvement of skin findings is typically seen after 1-5 days.

Use of potassium iodide should be avoided in pregnant patients given the risk of thyroid suppression in fetuses. Potassium iodide is absolutely contraindicated in patients with known iodine hypersensitivity reactions, and relatively contraindicated in those with renal and cardiac disease, pre-existing thyroid dysfunction, and Addison's disease. Reported side effects of potassium iodide therapy include hypo- and hyperthyroidism, iododerma, nausea, vomiting, potassium toxicity, and "iodism" (metallic taste, sore mouth and gums, headache).

In several case reports and larger studies, colchicine (starting dose 0.5mg three times a day by mouth) has been used successfully for treatment of Sweet's syndrome, with improvement of skin lesions within 5 days of starting therapy. Length of therapy ranged between 7 and 21 days. The major side effects are nausea, vomiting, and diarrhea, which improve with dose reduction.

Indomethacin has been used with benefit and relatively few side effects, starting at a dose of 150mg daily by mouth for 7 days, and then 100mg daily for another 14 days. Courses of tetracycline family antibiotics (tetracycline, doxycycline, and minocycline) were found to be helpful in patients with and without known infection (Yersinia, Chlamydia) associated with Sweet's syndrome, although it should be noted that minocycline is also a potential cause of Sweet's. Sweet's syndrome in two patients with underlying inflammatory bowel disease has been documented to resolve with metronidazole treatment.

Treatment with clofazamine (200mg daily for 4 weeks, and then 100mg daily for 4 weeks) led to near remission of Sweet's syndrome in six patients in one study. Cyclosporine (between 2 and 10mg/kg/day) and dapsone (100-200mg daily) have been used successfully both in the initial management of Sweet's syndrome, and also after other agents have failed. Both have been used alone and in combination with other medications. Cyclosporine should only be used for a limited period of time given the risk of renal disease.

Patients receiving dapsone must be monitored closely for signs of hemolytic anemia; a complete blood count (CBC) should be checked weekly for the first month of therapy, and then monthly for the next 6 months. Assessment of the patient's G6PD level is also recommended prior to initiating therapy.

Isolated case reports have documented successful use of etanercept, infliximab, adalimumab, interferon-alpha, thalidomide, and anakinra for treatment of refractory Sweet's syndrome.

Patient Management

Work-up to exclude an underlying condition should be performed if one is not already apparent. Laboratory evaluation should include CBC with differential, complete metabolic panel, thyroid function tests, and urinalysis. In women of child-bearing age, a pregnancy test should be performed. Evaluation of rheumatoid factor and angiotensin-converting enzyme (ACE) level may be added to assess for rheumatoid arthritis and sarcoidosis, respectively.

Evaluation of an underlying malignancy should strongly considered, especially in those over the age of 50 years. A complete history and detailed physical examination should be performed, including genitourinary and digital rectal examination in both sexes. Additional testing includes a stool guaiac testing, chest x-ray, Pap smear, mammography, prostate-specific antigen level, and sigmoidoscopy in those over 50 years of age.

It has been suggested that checking a CBC with differential every 6-12 months after the appearance of Sweet's syndrome is prudent, since hematologic malignancies have been reported to occur up to 11 years after initial diagnosis of Sweet's.

Sweet's syndrome is generally very responsive to treatment as outlined above, often with complete resolution of symptoms, However, patients should be counseled that relapses may occur, especially if the underlying cause is not addressed.

Unusual Clinical Scenarios to Consider in Patient Management

Histiocytoid Sweet's syndrome may be difficult to differentiate from leukemia cutis based on histopathology, especially as both entities stain positively for myeloperoxidase. However, the entities may be distinguished by examination of peripheral blood smears, fluorescent in-situ hybridization to assess for bcr/abl gene fusion, and clinical follow-up.

Once the diagnosis of histiocytoid Sweet's has been established with confidence, patients may be followed as detailed above for the conventional form of Sweet's syndrome.

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