Neutrophilic dermatoses associated with hematologic disorders

Neutrophilic Dermatoses Associated with Hematologic Disorders CYNTHIA D. HENSLEY, MD S. WRIGHT CAUGHMAN, MD

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he neutrophilic dermatoses are a group of disorders characterized histologically by dermal neutrophilic infiltrates, having no infectious or other identifiable etiology. These entities include acute febrile neutrophilic dermatosis, pyoderma gangrenosum, erythema elevatum diutinum, subcorneal pustular dermatosis, and neutrophilic eccrine hidradenitis. The neutrophilic dermatoses are frequently considered to be part of a continuous spectrum because they share many features including cutaneous neutrophilic infiltrates, similar clinical eruptions, systemic involvement, association with systemic diseases, and responsiveness to immunosuppressive agents.1 When evaluating patients with the clinical lesions of a neutrophilic dermatosis, infection, leukemic cell infiltration, and allergic contact dermatitis must be excluded as causes.2 The pathogeneses for these disorders are still unclear, but they are recognized paraneoplastic phenomena.3,4 The neutrophilic dermatoses may be associated with a variety of systemic disorders including myeloproliferative disorders, monoclonal gammopathies (especially IgA), inflammatory bowel disease, and rheumatoid arthritis.4 This report discusses the neutrophilic dermatoses and their associations with hematologic disorders.

Acute Febrile Neutrophilic Dermatosis Acute febrile neutrophilic dermatosis (AFND) was described by Dr. Robert Sweet in 1964 and soon came to be known as Sweet’s syndrome.5 It is a clinically and pathologically distinct entity of unknown etiology6 and is characterized by fever, neutrophilia, erythematous plaques on the limbs, face and neck, and dense dermal neutrophilic infiltration.5 Additional criteria include absence of infection and responsiveness to corticosteroids.5 Although most cases are thought to be idiopathic,7 AFND can be associated with a variety of disorders, including malignancies, infections, autoimmune disorders, pregnancy, drugs, trauma, subacute thyroiditis, Behcet’s syndrome, acute renal failure, and human imFrom the Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia, USA. Address correspondence to S.W. Caughman, MD, Dept. of Dermatology, Emory University School of Medicine, 5001 Woodruff Memorial Bldg., Atlanta, GA 30322, USA. © 2000 by Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010

munodeficiency virus (HIV).3 The association between malignancy and AFND was first recognized in the early 1970s.8 Ten to twenty percent of cases of AFND occur in the setting of an underlying malignancy, most commonly acute myelogenous leukemia (AML).9,10 An association with solid tumors is rare, but this has been reported.11,12 One series found underlying hematologic disorders in over 50% of the study patients.13 Although idiopathic and malignancy-associated AFND cannot be differentiated by clinical features or histologic examination alone, each entity has specific clinical correlations.14 There is no sex predilection in malignancy-associated AFND, whereas idiopathic AFND is characterized by a female predominance.9 Therefore, male patients with AFND are more likely to have an underlying hematologic disorder. Both groups have similar ages of onset, with most cases occurring between 30 and 60 years of age; however, there are reports of AFND occurring in patients from 3 months to 85 years old.15,16 A prior upper respiratory tract infection is frequently associated with idiopathic AFND, but a prodrome is not typically seen in malignancy-associated AFND.9 Painful, erythematous 0.5- to 12-cm papules or plaques characterize AFND (Fig 1).17,18 The distribution of lesions is similar in patients with AFND regardless of the presence or absence of malignancy.15 Classically, the lesions localize to the upper extremities, but the head, neck, lower extremities, and trunk can also be involved.15 The cutaneous lesions in patients with underlying malignancies are frequently atypical and feature vesicular, bullous, and even ulcerative lesions, as well as the more typical plaques and nodules.9,15,19 Generalized pustular lesions have been reported to occur in association with chronic myeloid leukemia.20 Oral mucosal lesions occur more frequently in malignancy-associated AFND.2 Typical sites of involvement are the lips, the buccal mucosa and the tongue.17 Lesions occurring in a dermatomal distribution resembling herpes zoster,21 and lesions presenting as facial cellulitis, have been reported in patients with associated hematoproliferative disorders.22,23 Extracutaneous manifestations of AFND are varied and can occur in over 50% of the cases with an underlying hematologic malignancy.9 The most common sys0738-081X/00/$–see front matter PII S0738-081X(99)00127-3

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Table 1.

Figure 1. Typical erythematous plaque in acute febrile neutrophilic dermatosis.

temic symptoms are arthralgias and myalgias.18 Polyarthritis can occur, affecting the hands, wrists, ankles, knees, and shoulders.17 Joint involvement often parallels the course of the cutaneous lesions.24 Also, AFND can involve other organ systems, including the muscles, bones, kidneys, eyes, and liver.9 Lung involvement,25–28 massive swelling of the tongue,29 and cutaneous pathergy have been reported in patients with underlying hematologic disorders.14,30 Lymph node involvement is unusual but has been reported to occur in some patients.24 There has been a report of myocardial neutrophilic infiltration in a patient with myelodysplastic syndrome.31 Additional systemic findings include proteinuria, hematuria, renal insufficiency, and hepatitis.18 A skin biopsy should be considered in patients with fever and lesions suggestive of AFND as the histologic features of AFND can be very helpful diagnostically.15 Microscopic examination reveals a dense dermal infiltrate of mature neutrophils.32 The infiltrate is usually localized to the upper dermis but may extend into the subcutaneous tissue.14 A mixture of lymphocytes, histiocytes and eosinophils, vascular endothelial swelling, and erythrocyte extravasation are typically noted in AFND.17,5,33 Other features that are occasionally present include neutrophil nuclear dust, and mild acanthosis or hyperkeratosis of the epidermis.34 Idiopathic and malignancy-associated AFND are similar histologically14; however, one study found that when AFND was associated with hematologic disorders there was a greater degree of epidermal edema, neutrophil exocytosis, epidermal necrosis, and ulceration.19 The diagnosis of AFND requires an absence of bacterial and fungal organisms, metastatic tumor cells, and vasculitic changes.18 Between 10 –20% of cases of AFND are associated with an underlying malignancy, and over 85% of such malignancies are hematological.17 The hemoproliferative disorders reported to occur with AFND are summarized in Table 1. The majority of cases have occurred

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AFND-Associated Hematologic Disorders

Acute leukemias Acute myelogenous leukemia2,29,40,156–159 Acute nonlymphocytic leukemia13 Acute myelomonocytic leukemia14,23,24 Acute megakaryblastic leukemia160 Acute granulocytic leukemia30 Acute promyelocytic leukemia32 Acute lymphoblastic leukemia161 Chronic leukemias Chronic myelogenous leukemia2,10,13,24,26,162,163 Chronic lymphocytic leukemia10 Chronic neutrophilic leukemia164 Lymphomas Hodgkin’s lymphoma165 Non-Hodgkin’s lymphoma10,166 Other entities Myelodysplastic syndrome2,10,13,19,40,48,49 Myeloproliferative disorder13,19 Polycythemia vera53 Myeloid metaplasia168 Multiple myeloma10 Hairy cell leukemia2,13,169 Gammopathy10,13,155 Aplastic anemia158,170,171 Idiopathic thrombocytopenia13 Essential thrombocythemia172 Sideroblastic anemia173 Congenital neutropenia174 Myelodysplaia158

with acute leukemias, primarily of the myelogenous type.35 In a review of 79 patients with malignancyassociated AFND, researchers9 found that acute myelogneous leukemias were most common, followed by lymphomas, myelodysplastic syndromes, chronic leukemias, myeloma, and other myeloproliferative disorders. Patients with AFND have only a slightly increased incidence of monoclonal gammopathy compared with the general population.36 Generally, AFND is present at the time of diagnosis of malignancy, and the skin lesions are frequently the presenting complaints.37,38 In 60% of cases AFND occurs before or concurrently with the hematologic disorder.26 It may precede the underlying disorder for years2 and in general worsens the prognosis.9,23 The onset of the skin lesions in patients with myelodysplasia is frequently associated with the development of acute leukemia.39 In addition, AFND may occur after treatment with granulocyte colonystimulating factor (G-CSF) in patients with hematologic disorders.40 Recurrent episodes of AFND occur more frequently in patients with underlying neoplasms, and often coincides with or precedes a hematologic relapse.9 There have been reports of AFND occurring concurrently with other neutrophilic dermatoses including pyoderma gangrenosum in patients with underlying myeloid neoplasia.41 Fever and an increased erythrocyte sedimentation rate occur with equal frequency in idiopathic and ma-

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lignancy-associated AFND.9 Neutrophilia is more common in idiopathic AFND,42 whereas the typical lesions of AFND may occur during neutropenia when there is an underlying hematologic disorder.7,42,43 Anemia, giant platelets, and thrombocytopenia are more frequently observed in malignancy-associated AFND.10,19 These laboratory abnormalities seen in patients with hematologic malignancies may be secondary to the natural history of the underlying disorder and to bone marrow suppression from chemotherapy.15 Untreated skin lesions of AFND tend to last 1 to 2 months and heal without scarring; those associated with malignancy may last longer.3 Antibiotics are ineffective in the treatment of AFND, although they are frequently used initially because the clinical appearance of AFND may mimic infection.15 The manifestations of AFND are extremely responsive to corticosteroid therapy, regardless of the presence or absence of an associated malignancy.9 Symptomatic relief usually occurs within hours, and substantial improvement in the skin lesions is seen within several days. Because recurrences are common when steroids are rapidly decreased or abruptly discontinued, steroid therapy should be tapered over a 4- to 6-week period.18 Alternative treatment modalities for AFND include aspirin, indomethacin, colchicine, chlorambucil, dapsone, potassium iodide, doxycycline, and cyclosporine.44 – 47 In summary, AFND occurring in patients with hematologic malignancies is characterized by an equal frequency in men and women; by more severe cutaneous lesions, which may be vesicular, bullous or ulcerative; by frequent extracutaneous involvement; by anemia and abnormal platelet counts; and by a high rate of recurrence, which often heralds a tumor relapse.26 The possibility of an underlying myeloproliferative disorder should be considered in all patients with AFND.48 Identification of a leukemic process is of considerable practical importance as it is relevant to both prognosis and therapy.49 Because of the association between AFND and malignancies, a new diagnosis of AFND warrants a comprehensive search for hematopoietic, plasma cell or lymphoid disorder, as well as additional age-appropriate studies recommended by the American Cancer Society.50

Pyoderma Gangrenosum Pyoderma gangrenosum (PG) was first described in 1930.51 Active lesions are characterized by chronic ulcerations with violaceous, undermined borders (Fig 2). The diagnosis of PG is generally made clinically as the histologic findings are not diagnostic.18 More than 50% of patients with PG have an associated systemic disease,52 including ulcerative colitis, Crohn’s disease, inflammatory arthritis, and hematologic malignancies.53 It has been determined from reviews of the literature

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Figure 2. Ulcer in pyoderma gangrenosum with undermined, dusky border.

that approximately 7% of cases of PG are associated with malignancy, most commonly acute myelogenous leukemia.54 The association between PG and hematologic disorders is poorly understood; PG may be the presenting feature of a hematologic disorder and may even signify malignant transformation of a hematologic disease.55 When associated with leukemia, PG often foreshadows a poor prognosis6 and may herald a more aggressive stage or a relapse of the underlying disease.56 Characteristically, PG presents with papules, pustules, or nodules that progress to ulcers with central necrosis.57 The lesions are typically violaceous with undermined, dusky borders and are surrounded by bright erythematous haloes.51 There may be multiple lesions that coalesce into large ulcerations. The lesions are exquisitely tender58 and heal with cribiform scarring.3 In contrast to the lesions of PG seen in gastrointestinal disorders, those in myelodysplasia are often more superficial and have vesiculobullous borders.59 Pyoderma gangrenosum has a propensity to develop on the lower extremities, particularly on the anterior tibial surfaces.18 Other sites of involvement include the trunk, perineum, abdomen, head, neck, orbit, scrotum, vulva, and lung.3 Lesions may be single or multiple, and pathergy is common.18 Systemic involvement affecting the liver, lungs, and meninges have been described, and rapidly progressive renal failure associated with monoclonal gammopathies has been reported.60 The differential diagnosis of PG includes bacterial cellulitis, herpes simplex phagedena, atypical mycobacterial infections, and deep fungal mycoses including blastomycosis, sporotrichosis, and cryptococcosis.58 There is a female predominance in nonmalignancyassociated PG.61 Men are more commonly affected in malignancy-associated PG and have a worse prognosis.62 Also, PG primarily affects adults, although its occurrence in children has been reported.63 The average

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age of onset of the disease is 40 years, and only 4% of patients are younger than 15 years.3 Diagnosis of PG essentially depends on the recognition of the clinical features as the histologic and other laboratory findings associated with PG are relatively nonspecific.18 Histology is determined by the type of lesion biopsied (ulcerative, vegetative), the stage of the lesion, and the portion of the lesion sampled.63 The stages of histologic evolution have been described as beginning with findings associated with folliculitis and early changes suggestive of emerging vasculitis, progressing to a suppurative granulomatous dermatitis, and then regressing to prominent fibroplasia.57 Findings at various stages of lesion progression include necrosis and ulceration, with accentuation in the parafollicular zones, and a dense infiltration of acute inflammatory cells at the margins of lesions, with a chronic inflammatory infiltrate in the central regions.58 Lesions of PG are typically sterile, although they may become secondarily infected.18,58 Pyoderma gangrenosum occurs in association with several systemic disorders.58 It has been reported after the administration of interferon-␣2b in a patient with chronic granulocytic leukemia,64 and after the administration G-CSF in a patient with myelodysplastic syndrome.65 Approximately 7% of patients with PG have an associated hematologic malignancy,66 most commonly AML and CML.67 Other associated hematologic disorders include polycythemia vera,55,68 monoclonal gammopathy, which is usually IgA, Waldenstrom’s macroglobulinemia, large granular lymphocytic leukemia,69 myelofibrosis,70 and non-Hodgkin’s lymphoma.71 Also, PG may be antecedent to the diagnosis of a hemoproliferative disorder or be present at the time of initial presentation.58 Patients with PG who go on to develop AML generally do so within 1 year.58 In a review of 44 patients with PG,62 it was found that 55% had an associated disease, and a hematologic disease or abnormality in the serum (eg, paraproteinemia or cryoglobulinemia) was present in 20% of the patients. Most cases of PG-associated leukemia develop within 12 months of the first PG lesions, and the occurrence of otherwise unexplained PG prior to the emergence of leukemia is generally associated with an overall poorer outcome.69 Hematological disorders may even play a role in the etiology of PG.62 Considerable variation exists between studies about the incidence of monoclonal gammopathies in patients with PG.36 A study at the Mayo Clinic reported that 10% of 86 patients with PG had an associated monoclonal gammopathy, most commonly IgA.72 Most of the patients had a benign course, and the onset of the PG preceded the detection of the monoclonal gammopathy.72 This IgA association is significant, as IgA gammopathies comprise only 10% of all monoclonal gammopathies.73

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A new diagnosis of PG mandates a search for possible associated systemic diseases, as successful therapy of these associated disorders may potentially lead to resolution of the PG lesions.63 Appropriate cultures should be taken and infection should be ruled out.18 Corticosteroids are the treatment of choice for PG, and initial therapy may consist of prednisone in doses of 60 to 80 mg daily.18 Other therapeutic modalities used in PG include dapsone, sulfasalazine, clofazimine, minocycline, GM-CSF and, more recently, immunosuppressive agents such as azathioprine, mercaptopurine, cyclophosphamide, tacrolimus, thalidomide, and cyclosporine.56,58,74 –76 Prolonged therapy is often required to prevent recurrences.62 Skin grafting is not recommended because of the recurrent nature of the ulcers and the propensity of lesions to develop at sites of trauma.3 Therapy of PG occurring in association with hematologic malignancy can be difficult. Cytotoxic chemotherapy administered to treat acute leukemia may interfere with the healing of skin lesions; as a complicating feature in immunosuppressed patients, the loss of epidermal integrity in these ulcerative lesions can be a source of sepsis.18

Bullous Pyoderma Gangrenosum In 1972, researchers77 described an atypical bullous form of PG characterized by inflammatory bullae. Hallmarks of this eruption include concentric, painful bullae that are more superficial and less destructive of tissue.53,77 These lesions progress to ulcerations with violaceous, undermined borders,78 and they are reported to occur more frequently over the face and extremities.40 Neutrophilic infiltration of internal organs has been reported with bullous PG and may contribute to the high mortality rate.78 The bullous PG variant is closely related to the vesiculopustular variant of AFND in its association with myeloproliferative disease, but the typical lesions of each may not be clinically similar.14 (See Figs 3 and 4.) Histologic examination of bullous PG reveals a massive neutrophilic epidermal and dermal infiltration resulting in inflammatory erosions and necrosis that spread peripherally.53 Associated findings include intraepidermal or subepidermal bullae, features not typical for classic PG.63 Bullous PG is often associated with myeloproliferative disorders, particularly leukemias and preleukemias.78 The appearance and the course of the PG in many cases parallels that of the hematologic disorder. The skin lesions frequently appear within a month of the onset of the systemic disease.78 Premalignant conditions may transform into acute leukemia soon after the appearance of the skin leisons.69 Bullous PG may occur during treatment with G-CSF.65 Bullous PG is often severe and refractory to treat-

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Figure 3. Bullous lesions in pyoderma gangrenosum.

ment,78 and its appearance almost always signifies a poor prognosis. Aggressive treatment with high-dose corticosteroids and consideration of systemic chemotherapy may prolong survival, but no reported treatment consistently alters the outcome.3,78 Many patients die within 12 months of the appearance of skin lesions.5,27

Figure 4. Same patient as in Fig 2, 2 weeks later.

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Figure 5. Characteristic brownish red papules in erythema elevatum diutinum.

Erythema Elevatum Diutinum In 1894, investigators79 coined the name “erythema elevatum diutinum” (EED) for a condition first described in 1878,80 and again in 1889.81 The condition is a rare, chronic inflammatory dermatosis characterized by brownish, red, elevated lesions occurring symmetrically over extensor surfaces.82 It is considered to be a chronic, localized variant of leukocytoclastic vasculitis.83 Both the etiology and pathogenesis of the disease are unknown, but an immune-complex–mediated disorder has been proposed.29,83 Because EED is a chronic disease, it waxes and wanes in severity; typically, it spontaneously involutes after 5 to 10 years.84 (See Fig 5.) The disease is characterized by the insidious development of symmetrical nodules and plaques on the extensor surfaces of the interphalangeal joints, elbows, ankles, and knees.83,85 The skin lesions are brownish, red (erythema), raised (elevatum), and persistent (diutinum).82 On clinical examination, the lesions are initially soft but later become hard as a result of fibrosis.83 Small, crusted papules evolve into erythematous nodules that are often depressed centrally.85 Lesions have a purple tinge and resolve with orange-brown pigmentation and sometimes scarring.86 A predominantly acral distribution with truncal sparing is characteristic.82 Additionally, EED may have varied clinical presentations, including symmetric erythematous plaques,87 hemorrhagic bullae,88 livedo reticularis,89 and purpura.90 Lesions that are pedunculated,91 that occur on the fingertips,83 or that resemble porphyria cutanea

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tarda have been reported.92 The lesions of EED are occasionally painful or pruritic.88 Most cases begin in middle age, but the age at onset can vary from 6 months to 75 years.82 There is no sex predilection or familial association, apart from a single case involving a mother and daughter.83 The skin is the primary site of involvement.82 Constitutional symptoms can occur and can be severe.82 Arthralgia and constitutional symptoms are common, but the patient’s general health is unaffected.81 The lesions may fluctuate and become more raised after exposure to extremes of temperature and are more pronounced at the time of menses.93 Cold exposure may be painful and can aggravate the eruption. The course of EED is unpredictable94; the nodules may persist for many years or regress spontaneously.3 Once a lesion has resolved, residual hyperpigmentation is common, and slight atrophy may occur.82 The microscopic findings in EED correlate with the age of the lesion at the time of biopsy.87 The etiology of EED is unknown, but the dermatopathologic process begins with a leukocytoclastic angiitis.82 The leukocytoclastic vasculitis may be accompanied by bullae formed secondary to epidermal necrosis.88 Later lesions show nodules with vasculitis, dermal aggregates of neutrophils, and granulation tissue formation.95,96 Newly formed vessels in the granulation tissue may be susceptible to further damage by immune complexes. The final stage of EED is a nodule with fibrosis and infiltration by histiocytes and macrophages.95 Results of direct immunofluorescence studies have occasionally revealed perivascular deposits of immunoglobulins, fibrin, and complement. In a few cases granular IgA deposits have been demonstrated at the dermoepidermal junction, but this is only an occasional finding.83 The degree of blood vessel destruction and leukocytoclasia does not predict associated medical disorders.87 The disease may be associated with a variety of underlying processes, including hepatitis B, streptococcal infections,3 ulcerative colitis,85 Crohn’s disease,97 rheumatoid arthritis,98 recurrent bacterial infections,87 collagen vascular diseases,87 polycythemia vera,87,99 myelodysplastic syndrome,100 hairy cell leukemia,101 mixed cryoglobulins,93 hypereosinophilic syndrome,102 HIV infection,103,104 and IgA gammopathy.87,105–108 The association between EED and paraproteinemia, particularly IgA, is well described.109 There have been multiple isolated reports of immunoglobulin abnormalities in patients with EED. Abnormalities have included elevated IgD,110 IgA and IgG, IgA and IgG kappa paraproteinemia and IgA paraproteinemia progressing to myeloma, as well as myeloma alone.88 In addition, EED has been described in a patient with both polycythemia vera and an IgA gammopathy.99 A retrospective study87 of 13 patients revealed that 6 had hematologic abnormalities including IgA monoclo-

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nal gammopathy, multiple myeloma, myelodysplasia, and polycythemia. The EED preceded the hematologic disease by an average of 7.8 years. Immunoelectrophoresis (IEP) was required to identify the gammopathies as there were no abnormalities on serum protein electrophoresis (SPEP).87 Other hematologic abnormalities that have been reported in association with EED include hairy cell leukemia, mixed cryoglobulins (IgG/IgM), polycythemia vera, and hypereosinophilic syndrome.87,93 There has also been a patient described with having both EED and a monoclonal gammopathy who developed PG.111 In many of these cases, EED preceded the hematologic disorder.87 A review of eight patients with EED96 revealed no associated hematologic disorders. The association of IgA paraproteinemia and EED is well established, and it has been suggested that the excess antibody levels may play a pathogenic role in EED.97 Paraproteins produce vessel damage by a variety of mechanisms, but most commonly as a result of complement-mediated inflammatory processes.112 Further studies are needed to clarify whether IgA or other gammopathies play a causal role by initiating immune complexes with the activation of complement and other mediators of inflammation or whether these immunoglobulins are simply markers for the disease.87 As there is a high frequency of hematologic abnormalities in patients with EED, it is recommended that all patients with EED undergo laboratory evaluation, including immunoelectrophoresis or immunofixation.36 The disease is very responsive to dapsone.86 Maintenance therapy may be required to suppress recurrences as dapsone is suppressive rather than curative.83,82 Dapsone may work by stabilizing the neutrophilic lysosomes or by interfering with the deposition of complement (C3), but its exact mode of action is not yet known.83 Plasma exchange has been reported to be an effective therapy for severe EED associated with IgA paraproteinemia that is refractory to other treatment.113 Intralesional triamcinolone,114 colchicine,115 chloroquine,82 clofazimine,116 and niacinamide in combination with tetracycline hydrochloride may also be useful.117 Pregnancy may improve EED.82 Protecting lesions from minor trauma is also very important.118

Subcorneal Pustular Dermatosis Subcorneal pustular dermatosis (SCPD) is a unique clinical and histologic entity.119 It is characterized by a chronic, relapsing vesiculopustular eruption that typically affects the trunk and intertriginous areas.120 Criteria for the diagnosis of SCPD include a new onset of pustular eruptions without systemic symptoms, absence of existing psoriasis, subcorneal neutrophilic pustules without spongiosis, and responsiveness to dapsone.119 The condition has been associated with

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Figure 6. Annular grouping of pustules in a patient with subcorneal pustular dermatosis.

monoclonal gammopathies and multiple myeloma.119 In addition, SCPD may be clinically and histologically difficult to differentiate from impetigo, pemphigus foliaceous, pustular psoriasis, necrolytic migratory erythema, and other neutrophilic dermatoses.121 Clinically, SCPD presents as annular groupings of pustules (Fig 6) occurring on the trunk and in intertriginous areas.121 Even though the pustules are sterile, secondary infection may occur.121 Classically, SCPD occurs in women between the ages of 40 and 70.73,122 It clinically presents with superficial pustules that coalesce to form circinate patterns and is typically located in the axilla, groin, and abdomen.73 It tends to be chronic, and the lesions are moderately pruritic.73 New waves of pustules spread in an annular or gyrate pattern, leaving collarettes of scale.119 Palmar-plantar involvement is rare but has been reported.123 Residual hyperpigmentation is common.119 The condition can last many years with multiple recurrences.122 The histologic features of SCPD may be indistinguishable from those of pustular psoriasis.122 The hallmark of SCPD is a subcorneal neutrophilic abscess.73 Neutrophilic spongiform pustules are occasionally seen in the spinous and granular layers.122 Acantholytic clefts and eosinophils are rarely present within the blister. There is often as associated mixed superficial perivascular infiltrate.121 Direct and indirect immunofluorescence studies reveal no positive staining.73 In addition, SCPD may be associated with many systemic disorders, including monoclonal gammopathies, lymphomas, and multiple myelomas. The para-

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proteins in SCPD are usually of the IgA type, whereas the most common type of paraproteinemia in the general population is IgG.119 IgG-cryoglobulinemia, IgA myeloma, and IgG myeloma have also been described with SCPD.124 –127 It is difficult to determine the true incidence of paraproteinemia in SCPD because of the low incidence of this disorder.36 This association between SCPD and paraproteinemia is unlikely to be coincidental. The latency period between the diagnosis of SCPD and associated myeloma is often variable, and the associated gammopathies are often antecedent to the diagnosis of SCPD. The associated gammopathy may be a primary event resulting in the typical skin findings. Another theory is that the resultant monoclonal spike is secondary to an unknown chronic antigenic stimulus within the epidermis.121 Also, SCPD has been reported to occur in association with aplastic anemia.120 In consideration of the reported relationship between SCPD and myeloma, it is imperative to rule out underlying myeloma by screening urine and serum for paraproteins.125 There may be a long latency between the diagnosis of a myeloma and the onset of cutaneous lesions.123,128 As for treatment, SCPD usually responds well to oral dapsone therapy.73 Other treatments include PUVA, UVB, prednisone, etretinate, and methotrexate.129 The cutaneous lesions of SCPD may improve when the underlying IgA myeloma has been treated.127

Intraepidermal IgA Pustulosis In 1985, investigators130 described a blistering disease characterized by neutrophilic collections in the epidermis and extensive intraepidermal IgA deposits. Wallach131 later coined the term “intraepidermal IgA pustulosis” (IEAP) for this dermatosis associated with intraepidermal IgA. There is some debate about whether these cases should be classified as SCPD, as a form of IgA pemphigus, or in a separate category of IgA pustulosis.73 The IEAP features intraepidermal deposits of IgA on the intercellular substance of the epidermis in a pemphigus-like pattern. This disorder is distinguished by sterile subcorneal pustules and can be classified with the group of neutrophilic disorders.131 The condition is characterized by a slight female predominance and can begin at any age. It has reported in patients as young as 5 and as old as 92 years, and patients with IEAP have been described worldwide.131 Many of the cases have been given the diagnosis of SCPD, as the clinical pictures may be identical.125 Cutaneous features include pustules arising on a slightly erythematous base coalescing to form annular, circinate patterns. The axillae and groin are most frequently involved, although lesions may also occur on the trunk and proximal limbs. The disorder usually runs a chronic, benign course featuring intermittent acute flares.131 Dapsone is generally the first line of therapy.

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Etretinate, colchicine, PUVA, topical steroids, and systemic steroids have been used with varying success.131 Subcorneal pustules, resembling SCPD, characterize the histology of IEAP. The pustules may be located intraepidermally or subepidermally depending on the age or appearance of the lesion. There is also infrequent acantholysis. Intraepidermal IgA deposits are by definition always present in IEAP. Deposition of IgA in an intercellular pattern and often restricted to the upper epidermis, and linear, subcorneal staining have been described.131 In 20% of reported cases of IEAP, an associated monoclonal gammopathy, which may be benign or malignant, is present. This gammopathy is typically of the IgA class, frequently with kappa light chains.131 Patients with B-cell lymphoma, myeloma, and CD30⫹ anaplastic large cell lymphoma125 have also been described. Associated systemic disorders in patients with IEAP include cryoprecipitate IgG, acute polyarthritis, colitis, Crohn’s disease, and gluten-sensitive enteropathy.131

Neutrophilic Eccrine Hidradenitis Neutrophilic eccrine hidradenitis (NEH) was originally described in 198228 in a patient with acute myelogenous leukemia who developed tender, erythematous plaques of the neck and shoulders after receiving induction chemotherapy. It is an acute inflammatory reaction that presents with localized Sweet’s syndrome-like lesions and occurs most commonly in patients receiving chemotherapy for acute myelogenous leukemia.28,132 It has a wide variation in clinical presentation. The usual presentation of red nodules and plaques must be differentiated from cutaneous lesions associated with sepsis, leukemia cutis, PG, bullous pyoderma, or AFND.133 Whether NEH is a variant presentation of AFND or PG, or a toxic effect of commonly used chemotherapeutic agents, remains unclear.134 The eruption of NEH is polymorphic and is characterized by erythematous and edematous papules, pustules, and plaques that can also be purpuric and painful.135 The onset is often associated with neutropenia and fever.136 These lesions develop approximately 8 to 10 days after the institution of chemotherapy, and they spontaneously resolve without scarring over a 10-day period.137 Lesions can recur with subsequent courses of chemotherapy.132 The sites affected are the extremities, trunk, periorbital region, neck, face, ears, and palms.136 The phenomenon of pathergy has been reported. When NEH is associated with acute myelogenous leukemia (AML), the patients are more frequently male.138 Both children and adults can be affected, with patients ranging in age from 3 years to 79 years.139,140 The histologic picture of NEH is distinctive and reveals neutrophils in and around the eccrine coil.133

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There is variable cellular damage, with some eccrine glands and ducts exhibiting mild vacuolar alteration, while others demonstrate total necrosis.141 Variable findings in NEH include dermal hemorrhage, edema, and mucinous degeneration of the adipose tissue cuff and periadnexal dermis. In addition, perivascular infiltrates have been reported in some cases, usually composed of a mixture of lymphocytes, histiocytes, and occasionally neutrophils.136 Neutrophils may invade the apocrine glands,142 as well as the ductal lamina, forming microabscesses.136 There have even been two cases of NEH reported in neutropenic patents with AML leukemia in which a neutrophil infiltrate was lacking.143 Underlying malignancies are almost always present in patients with NEH as NEH typically occurs in the setting of induction chemotherapy.139 The most common malignancy occurring with NEH is acute myelogenous leukemia (64% patients).136 Also, NEH may be associated with lymphocytic leukemia, monocytic leukemia, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, and various solid tumors.139,144,145 The condition has developed in patients receiving many different chemotherapeutic treatments, although cytarabine and bleomycin are most frequently associated with NEH.146,147 The pathogenesis of NEH remains unclear, but it has been speculated to be associated with the toxic effects of a chemotherapeutic agent concentrated in the eccrine glands.133 Researchers148 injected intradermal bleomycin in healthy volunteers and produced the histologic findings of NEH, suggesting a link to chemotherapy as the causative agent in NEH. Often, NEH recurs with subsequent courses of chemotherapy,137 and it has been reported to occur in the same patient after different chemotherapeutic regimens.149 Although the temporal relationship to induction chemotherapy suggests that NEH is a reaction to a chemotherapeutic agent, a neutrophilic dermatosis associated with leukemia cannot be excluded28; NEH has been reported to occur in patients not receiving chemotherapy,150 and there has even been a case of NEH heralding the diagnosis of AML.151 In addition, NEH and the paraneoplastic neutrophilic dermatoses may have a similar pathogenesis,138 and in the original report of NEH, researchers28 speculated that NEH may be part of the spectrum of neutrophilic dermatoses. In summary, the etiology NEH may be related to a toxic effect of chemotherapy, or NEH may be a cutaneous manifestation of leukemia or it may be a neutrophilic dermatosis.133 Because NEH is usually self-limited and resolves without any change in drug therapy, medical intervention is usually unnecessary.152–154 Agents that have been reported to cause symptomatic improvement, however,

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include naproxen, ibuprofen, prednisone, and dapsone.3,132

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Conclusions The neutrophilic dermatoses are a group of disorders characterized by massive dermal infiltration of neutrophils.154 They share many common features, such as the association with systemic diseases and the possible occurrence of extracutaneous neutrophilic infiltrates.155 It is important to recognize the neutrophilic dermatoses as they may occur in association with hemoproliferative disorders. Although the neutrophilic dermatoses are clinically and histologically distinct entities, they may on occasion display overlapping features.53 Some patients may present with clinicopathological symptoms overlapping the above well-defined entities.155 Neutrophilic dermatoses may be important clinical signs of underlying systemic disorders. The most common hematologic associations are with leukemias, lymphomas, myeloproliferative disorders, and monoclonal gammopathies. Any patient with a neutrophilic dermatosis and unexplained anemia should undergo appropriate investigation to rule out leukemia or myelodysplasia.14 It is important to recognize the variable clinical and histologic patterns of the neutrophilic dermatoses and to appreciate the importance of accurate diagnoses and their associations with systemic disorders.53

References 1. Vignon-Pennamen MD, Wallach D. Cutaneous manifestations of neutrophilic disease. Dermatologica 1991;183; 9:751– 8. 2. Clemmensen OJ, Menne T, Brandrup F, et al. Acute febrile neutrophilic dermatosis—a marker of malignancy? Acta Derm Venereol (Stockh) 1989;69:52– 8. 3. Huang W, McNeely MC. Neutrophilic tissue reactions. Adv Dermatol 1997;13:33– 64. 4. Johnson ML, Grimwood RE. Leukocyte colony-stimulating factors. A review of associated neutrophilic dermatoses and vasculitides. Arch Dermatol 1994;130:77– 81. 5. Sweet RD. An acute febrile neutrophilic dermatosis. Br J Dermatol 1964;74:349 –56. 6. Reuss-Borst MA, Pawelec G, Saal JG, et al. Sweet’s syndrome associated with myelodysplasia: Possible role of cytokines in the pathogenesis of the disease. Br J Haematol 1993;84:356 – 8. 7. Heer-Sonderhoff AH, Arning M, Wehmeier A, et al. Neutrophilic dermal infiltrates in granulocytopenic patients with acute leukemia. Ann Hematol 1995;71: 257– 61. 8. Matta M, Malak J, Tabet E, et al. Sweet’s syndrome: Systemic associations. Cutis 1973;12:561– 6. 9. Cohen PR, Talpaz M, Kurzrock R. Malignancy-associated Sweet’s syndrome: review of the world literature. J Clin Oncol 1988;6:1887–97. 10. Bourke JF, Keohane S, Long CC, et al. Sweet’s syndrome

12.

13.

14.

15. 16.

17.

18. 19.

20.

21.

22.

23.

24.

25. 26. 27.

28.

29.

363

and malignancy in the U.K. Br J Dermatol 1997;137: 609 –13. Sandlund JT, Miser JS, Miser AW. Sweet syndrome in a patient with osteosarcoma. Am J Clin Oncol 1996;19: 349 –50. Gimenez-Arnau A, Carles J, Pla-Ferrer C, et al. Sweet’s syndrome and malignancy: A case associated with multiple oral squamous-cell carcinoma. Dermatology 1996; 193:154 –5. Fett DL, Gibson LE, Su WP. Sweet’s syndrome: Systemic signs and symptoms and associated disorders. Mayo Clin Proc 1995;70:234 – 40. Cooper PH, Innes DJ, Greer KE. Acute febrile neutrophilic dermatosis and myeloproliferative disorders. Cancer 1983;51:1518 –26. Cohen PR, Kurzrock R. Sweet’s syndrome and malignancy. Am J Med 1987;82:1220 – 6. Bajwa RP, Marwaha RK, Garewal G, et al. Acute febrile neutrophilic dermatosis (Sweet’s syndrome) in myelodysplastic syndrome. Ped Hematol Oncol 1993;10:343– 6. Von den Driesch P. Sweet’s syndrome (acute febrile neutrophilic dermatosis). J Am Acad Dermatol 1994;31: 535–56. Baer MR. Management of unusual presentations of acute leukemia. Hematol Oncol Clin North Am 1993;7:275–92. Chan HL, Lee YS, Kuo TT. Sweet’s syndrome: Clinicopathologic study of eleven cases. Int J Dermatol 1994;33: 425–32. Feliu E, Cervantes F, Ferrando J, et al. Neutrophilic pustulosis associated with chronic myeloid leukemia: A special form of Sweet’s syndrome. Report of two cases. Acta Haematol 1992;88:154 –7. Chiang CT, Chan HL, Kuo TT, et al. Herpes zoster-like Sweet’s syndrome in acute myelogenous leukemia. Int J Dermatol 1997;36:717– 8. Krilov LR, Jacobson M, Shende A. Acute febrile neutrophilic dermatosis (Sweet’s syndrome) presenting as facial cellulitis in a child with juvenile chronic myelogenous leukemia. Pediatr Infect Dis J 1987;6:77–9. Dompmartin A, Troussard X, Lorier E, et al. Sweet syndrome associated with acute myelogenous leukemia. Atypical form simulating facial erysipelas. Int J Dermatol 1991;30:644 –7. Sitjas D, Puig L, Cuatrecasas M, et al. Acute febrile neutrophilic dermatosis (Sweet’s syndrome). Int J Dermatol 1993;32:261– 8. Bourke SJ, Quinn AG, Farr PM. Neutrophilic alveolitis in Sweet’s syndrome. Thorax 1992;47:572–3. Cohen PR, Kurzrock R. Chronic myelogenous leukemia and Sweet’s syndrome. Am J Hematol 1989;32:134 –7. Takimoto CH, Warnock M, Golden JA. Sweet’s syndrome with lung involvement. Am Rev Respir Dis 1991; 143:177–9. Harrist TJ, Fine JD, Berman RS, et al. Neutrophilic eccrine hidradenitis. A distinctive type of neutrophilic dermatosis associated with myelogenous leukemia and chemotherapy. Arch Dermatol 1982;118:263– 6. Bamelis M, Boyden B, Sente F, et al. Sweet’s syndrome and acute myelogenous leukemia in a patient who presented with a sudden massive swelling of the tongue. Dermatology 1995;190:335–7.

364 HENSLEY AND CAUGHMAN

30. Su WPD, Liu H-NH. Diagnostic criteria for Sweet’s syndrome. Cutis 1986;137:167–74. 31. Shimizu K. Neutrophilic infiltration of the myocardium in a patient with myelodysplastic syndrome. Am J Hematol 1998;58:337– 8. 32. Piette WW, Trapp JF, O’Donnell MJ, et al. Acute neutrophilic dermatosis with myeloblastic infiltrate in a leukemia patient receiving all-trans-retinoic acid therapy. J Am Acad Dermatol 1994;30:293–7. 33. Jordaan HF. Acute febrile neutrophilic dermatosis. A histopathological study of 37 patients and a review of the literature. Am J Dermatopathol 1989;11:99 –111. 34. Su WP, Fett DL, Gibson LE, et al. Sweet syndrome: Acute febrile neutrophilic dermatosis. Semin Dermatol 1995;14: 173– 8. 35. Horan MP, Redmond J, Gehle D, et al. Postpolycythemic myeloid metaplasia, Sweet’s syndrome, and acute myeloid leukemia. J Am Acad Dermatol 1987;16:458 – 62. 36. Daoud MS, Lust JA, Kyle RA, et al. Monoclonal gammopathies and associated skin disorders. J Am Acad Dermatol 1999;40:507–35. 37. Behm FG, Kay S, Aportela R. Febrile neutrophilic dermatosis associated with acute leukemia. Am J Clin Pathol 1981;76:344 –7. 38. Klock JC, Oken RL. Febrile neutrophilic dermatosis in acute myelogenous leukemia. Cancer 1976;37:922–7. 39. Soppi E, Nousiainen T, Seppa A, et al. Acute febrile neutrophilic dermatosis (Sweet’s syndrome) in association with myelodysplastic syndromes: A report of three cases and a review of the literature. Br J Haematol 1989; 73:43–7. 40. Paydas S, Sahin B, Seyrek E, et al. Sweet’s syndrome associated with G-CSF. Br J Haematol 1993;85:191–2. 41. Caughman W, Stern R, Haynes H. Neutrophilic dermatosis of myeloproliferative disorders. Atypical forms of pyoderma gangrenosum and Sweet’s syndrome associated with myeloproliferative disorders. J Am Acad Dermatol 1983;9:751– 8. 42. Ferrandiz C, Ribera M, Flores A, et al. Sweet’s syndrome and acute myelogenous leukemia. Int J Dermatol 1990; 29:209 –10. 43. Probert C, Ehmann WC, al-Mondhiry H, et al. Sweet’s syndrome without granulocytosis. Int J Dermatol 1998; 37:108 –12. 44. Jeanfils S, Joly P, Young P, et al. Indomethacin treatment of eighteen patients with Sweet’s syndrome. J Am Acad Dermatol 1997;36:436 –9. 45. Sharpe GR, Leggat HM. A case of Sweet’s syndrome and myelodysplasia: Response to cyclosporin. Br J Dermatol 1992;127:538 –9. 46. von den Driesh P, Steffan C, Zobe A, et al. Sweet’s syndrome—therapy with cyclosporin. Clin Exp Dermatol 1994;19:274 –7. 47. Joshi RK, Atukorala DN, Abanmi A, et al. Successful treatment of Sweet’s syndrome with doxycycline. Br J Dermatol 1993;128:584 – 6. 48. Trau H, Mozes B, Pines A, et al. Neutrophilic dermatosis and myelodysplastic syndrome. Isr J Med Sci 1987;23: 1145–7. 49. Knight DK, Layton DM, Mufti GJ, et al. Sweet’s syndrome and myelodysplasia. Blut 1988;56:47– 8.

Clinics in Dermatology

Y

2000;18:355–367

50. Hamblin J, Connor PD. An overview of the American Cancer Society screening guidelines. J Tenn Med Assoc 1995;88:10 – 6. 51. Brunsting LA, Goeckerman WH, O’Leary PA. Pyoderma (ecthyma) gangrenosum: Clinical and experimental observation in five cases occurring in adults. Arch Dermatol Syph 1930;22:655. 52. Callen JP, Woo TY. Vesiculopustular eruption in a patient with ulcerative colitis. Pyoderma gangrenosum. Arch Dermatol 1985;121:399 – 403. 53. Wong TY, Suster S, Bouffard D, et al. Histologic spectrum of cutaneous involvement in patients with myelogenous leukemia including the neutrophilic dermatoses. Int J Dermatol 1995;34:323–9. 54. Lear JT, Atherton MT, Byrne JP. Neutrophilic dermatoses: Pyoderma gangrenosum and Sweet’s syndrome. Postgrad Med J 1997;73:65– 8. 55. Cox NH, White SI, Walton S, et al. Pyoderma gangrenosum associated with polycythemia rubra vera. Clin Exp Dermatol 1987;12:375–7. 56. Takvorian T, Skarin A, Johnson R. Pyoderma gangrenosum. J Clin Oncol 1997;15:407. 57. Hurwitz RM, Haseman JH. The evolution of pyoderma gangrenosum. A clinicopathologic correlation. Am J Dermatopathol 1993;15:28 –33. 58. Schwaegerle SM, Bergfeld WF, Senitzer D. Pyoderma gangrenosum: A review. J Am Acad Dermatol 1988; 18:559 – 68. 59. Savige JA, Chang L, Smith CL, et al. Myelodysplasia, vasculitis and anti-neutrophil cytoplasm antibodies. Leuk Lymphoma 1993;9:49 –54. 60. Akatsuka T, Kawata T, Hashimoto S, et al. Rapidly progressive renal failure occurring in the course of pyoderma gangrenosum and IgA (lambda) monoclonal gammopathy. Intern Med 1997;36:40 –3. 61. Ko CB, Walton S, Wyatt EH. Pyoderma gangrenosum: Associations revisited. Int J Dermatol 1992;31:574 –7. 62. Von den Driesch P. Pyoderma gangrenosum: A report of 44 cases with follow-up. Br J Dermatol 1997;137:1000 –5. 63. Powell FC, Su WP, Perry HO. Pyoderma gangrenosum: Classification and management. J Am Acad Dermatol 1996;34:395– 409. 64. Montoto S, Bosch F, Estrach T, et al. Pyoderma gangrenosum triggered by alpha2b-interferon in a patient with chronic granulocytic leukemia. Leuk Lymphoma 1998; 30:199 –202. 65. Lewerin C, Mobacken H, Nilsson-Ehle H, et al. Bullous pyoderma gangrenosum in a patient with myelodysplastic syndrome during granulocyte colony-stimulating factor therapy. Leuk Lymphoma 1997;26:629 –32. 66. Duguid CM, O’Loughlin S, Otridge B, et al. Paraneoplastic pyoderma gangrenosum. Australas J Dermatol 1993; 34:17–22. 67. Powell C, Schroeter AL, Su WPD. Pyoderma gangrenosum: A review of 86 patients. QJM 1985;173:173– 86. 68. Ho KK, Otridge BW, Vandenberg E, et al. Pyoderma gangrenosum, polycythemia rubra vera, and the development of leukemia. J Am Acad Dermatol 1992;27: 804 – 8. 69. Helm KF, Peters MS, Tefferi A, et al. Pyoderma gangre-

Clinics in Dermatology

70.

71.

72.

73.

74.

75.

76.

77. 78.

79. 80.

81.

82. 83.

84. 85.

86.

87.

88.

89.

90.

Y

2000;18:355–367

nosum-like ulcer in a patient with large granular lymphocytic leukemia. J Am Acad Dermatol 1992;27:868 –71. Sgarabotto D, Vianello F, Valeri P, et al. Pyoderma gangrenosum associated with idiopathic myelofibrosis. Case history. Haematologica 1993;25:249 –52. Hedeyati H, Zuzga JJ Jr, Faber DB. Rheumatoid arthritis, relapsing polychondritis, and pyoderma gangrenosum evolving into non-Hodgkin’s lymphoma. J Am Osteopath Assoc 1993;93:240 –2. Powell C, Schroeter AL, Su WPD. Pyoderma gangrenosum and monoclonal gammopathy. Arch Dermatol 1983; 119:468 –72. Stone MS, Lyckholm LJ. Pyoderma gangrenosum and subcorneal pustular dermatosis: Clues to underlying immunoglobulin A myeloma. Am J Med 1996;100:663– 4. Cooley HM, Castelino D, McNair P, et al. Resolution of pyoderma gangrenosum using tacrolimus (FK-506). Aust N Z J Med 1996;26:238 –9. Hecker MS, Lebwohl MG. Recalcitrant pyoderma gangrenosum: Treatment with thalidomide. J Am Acad Dermatol 1998;38:490 –1. Bulvik S, Jacobs P. Pyoderma gangrenosum in myelodysplasia responding to granulocyte macrophage-colony stimulating factor (GM-CSF). Br J Dermatol 1997;136: 637– 8. Perry HO, Winkelmann RK. Bullous pyoderma gangrenosum and leukemia. Arch Dermatol 1972;106:901–5. Koester G, Tarnower A, Levisohn D, et al. Bullous pyoderma gangrenosum. J Am Acad Dermatol 1993;29: 875– 8. Radcliffe-Crocker HW, Williams C. Erythema elevatum diutinum. Br J Dermatol 1894;6:1–9. Hutchinson J. On two remarkable cases of symmetrical purple congestion of the skin in patches, with induration. Br J Dermatol 1888;1:10 –5. Bury JS. A case of erythema with remarkable thickening and induration of the skin, associated with intermittent albuminuria. Illustr Med News 1889;3:145–9. Fort SL, Rodman G. Erythema elevatum diutinum. Arch Dermatol 1977;113:819 –22. Hansen U, Haerslev T, Jacobsen GK, et al. Erythema elevatum diutinum: Case report showing an unusual distribution. Cutis 1994;53:124 – 6. Haber H. Erythema elevatum diutinum. Br J Dermatol 1955;67:121– 45. Buahene K, Hudson M, Ormerod AD, et al. Erythema elevatum diutinum: An unusual association with ulcerative colitis. Clin Exp Dermatol 1991;16:203– 6. Vollum DI. Erythema elevatum diutinum: Vesicular lesions and sulfone response. Br J Dermatol 1968;80: 178 – 83. Yiannias JA, El-Azhary RA, Gibson LE. Erythema elevatum diutinum: A clinical and histopathologic study of 13 patients. J Am Acad Dermatol 1992;26:38 – 44. Wilkinson S, English JSC, Smith NP, et al. Erythema elevatum diutinum: A clinicopathologic study. Clin Exp Dermatol 1992;17:87–93. Planaguma M, Puig L, Alomar A, et al. Pyoderma gangrenosum in association with erythema elevatum diutinum: Report of two cases. Cutis 1992;49:201– 6. Kovary PM, Dhonau H, Happle R. Paraproteinemia in

DERMATOSES AND HEMATOLOGIC DISORDERS

91.

92.

93.

94.

95.

96.

97.

98.

99.

100.

101.

102.

103.

104.

105.

106. 107.

108. 109.

365

erythema elevatum diutinum. Arch Dermatol Res 1977; 260:155– 8. English JSC, Smith NP, Kersy PJW, et al. Erythema elevatum diutinum—an unusual case. Clin Exp Dermatol 1985;10:577– 80. Requena L, Barat A, Hasson A, et al. Erythema elevatum diutinum mimicking porphyria cutanea tarda. Br J Dermatol 1991;124:89 –91. Morrison JGL, Hull PR, Fourie E. Erythema elevatum diutinum, cryoglobulinemia, and fixed urticaria on cooling. Br J Dermatol 1977;97:99 –104. Porneuf M, Duterque M, Sotto A, et al. Unusual erythema elevatum diutinum with fibrohistiocytic proliferation. Br J Dermatol 1996;134:1131– 4. Leboit PE, Yen TSB, Wintroub B. The evolution of lesions in erythema elevatum diutinum. Am J Dermatopathol 1986;8:392– 402. Sangueza OP, Pilcher B, Martin Sangueza J. Erythema elevatum diutinum: A clinicopathological study of eight cases. Am J Dermatopathol 1997;19:214 –22. Walker KD, Badame AJ. Erythema elevatum diutinuum in a patient with Crohn’s disease. J Am Acad Dermatol 1990;22:948 –52. Collier PM, Neill SM, Branfoot AC, et al. Erythema elevatum diutinum—a solitary lesion in a patient with rheumatoid arthritis. Clin Exp Dermatol 1990;15:394 –5. Stathum BN, Greenwood R, Tring FC, et al. Erythema elevatum diutinum—a report of two unusual patients. Clin Exp Dermatol 1983;8:549 –52. Aractingi S, Bachmeyer C, Dombret D. Simultaneous occurrence of two rare cutaneous markers of poor prognosis in myelodysplastic syndrome: Erythema elevatum diutinum and specific lesions. Br J Dermatol 1995;131: 112–7. Dorsey JK, Penick GD. The association of hairy cell leukemia with unusual immunologic disorders. Arch Intern Med 1982;142:902–3. Cordier JF, Faure M, Hermier C, et al. Pleural effusions in an overlap syndrome of idiopathic hypereosinophilic syndrome and erythema elevatum diutinum. Eur Respir J 1990;3:115–7. Leboit PE, Cockerell CJ. Nodular lesions of erythema elevatum diutinum in patients infected with the human immunodeficiency virus. J Am Acad Dermatol 1993;28: 919 –22. Requena L, Yus ES, Martin L, et al. Erythema elevatum diutinum in a patient with acquired immunodeficiency syndrome. Arch Dermatol 1991;127:1819 –22. Archimandritis AJ, Fertakis A, Alegakis G, et al. Erythema elevatum diutinum and IgA myeloma: An interesting association. BMJ 1977;2:613– 4. Dowd PM, Munro DD. Erythema elevatum diutinum. J R Soc Med 1983;76:310 –3. Katz SI, Gallin JI, Hertz KC, et al. Erythema elevatum diutinum: Skin and systemic manifestations, immunologic studies and successful treatment with dapsone. Medicine 1977;56:443–55. Lotti T, Difonzo EM, Panconesi EX. Erythema elevatum diutinum. Int J Dermatol 1994;33:638 – 40. Chow RK, Benny WB, Coupe RL, et al. Erythema elevatum diutinum associated with IgA paraproteinemia suc-

366 HENSLEY AND CAUGHMAN

110.

111.

112. 113.

114. 115.

116. 117.

118.

119.

120.

121.

122.

123.

124. 125.

126.

127.

128. 129.

cessfully controlled with intermittent plasma exchange. Arch Dermatol 1996;132:1360 – 4. Miyagawa S, Kitamura W, Morita K, et al. Association of hyperimmunoglobulinaemia D syndrome with erythema elevatum diutinum. Br J Dermatol 1993;128:572– 4. Wayte JA, Rogers S, Powell FC. Pyoderma gangrenosum, erythema elevatum diutinum and IgA monoclonal gammopathy. Australas J Dermatol 1995;36:21–3. Russell JR. The cutaneous manifestations of paraproteinemia. Br J Dermatol 1980;103:335– 42. Chow RK, Benny WB, Coupe RL, et al. Erythema elevatum diutinum associated with IgA paraproteinemia successfully controlled with intermittent plasma exchange. Arch Dermatol 1996;132:1360 – 4. Ramsey ML, Gibson B, Tschen JA, et al. Erythema elevatum diutinum. Cutis 1984;34:41–3. Henriksoson R, Hofer P-A, Hornqvist R. Erythema elevatum diutinum—a case successfully treated with colchicine. Clin Exp Dermatol 1989;14:451–3. Farella V, Lotti T, Difonzo EM, et al. Erythema elevatum diutinum. Int J Dermatol 1994;33:638 – 40. Kohler IK, Lorincz AL. Erythema elevatum diutinum treated with niacinamide and tetracycline. Arch Dermatol 1980;116:693–5. Schumacher HR, Carroll E, Taylor F, et al. Erythema elevatum diutinum: Cutaneous vasculitis, impaired clot lysis, and response to phenformin. J Rheumatol 1977;4: 103–12. Lutz ME, Daoud MS, McEvoy MT, et al. Subcorneal pustular dermatosis: A clinical study of ten patients. Cutis 1998;61:203– 8. Park BS, Cho KH, Eun HC, et al. Subcorneal pustular dermatosis in a patient with aplastic anemia. J Am Acad Dermatol 1998;39:287–9. Kasha EE Jr, Epinette WW. Subcorneal pustular dermatosis (Sneddon-Wilkinson disease) in association with a monoclonal IgA gammopathy: A report and review of the literature. J Am Acad Dermatol 1988;19:854 – 8. Chimenti S, Ackerman AB. Is subcorneal pustular dermatosis of Sneddon and Wilkinson an entity sui generis? Am J Dermatopathol 1981;3:363–76. Dal Tio R, Di Vito F, Salvi F. Subcorneal pustular dermatosis and IgA myeloma. Dermatologica 1985;170: 240 –3. Murphy GM, Griffiths WA. Subcorneal pustular dermatosis Clin Exp Dermatol 1989;14:165–7. Guggisberg D, Hohl D. Intraepidermal IgA pustplosis preceding a CD30⫹ anaplastic large T-cell lymphoma. Dermatology 1995;191:352– 4. Guggisberg D, Hohl D. Intraepidermal pustulosis preceding a CD30⫹ anaplastic large T-cell lymphoma. Dermatology 1995;191:352– 4. Takata M, Inaoki M, Shodo M, et al. Subcorneal pustular dermatosis associated with IgA myeloma and intraepidermal IgA deposits. Dermatology 1994;189(Suppl 1): 111– 4. Tio RD, Di Vito F, Salvi F. Subcorneal pustular dermatosis and IgA myeloma. Dermatologica 1985;170:240 –3. Todd DJ, Bingham EA, Walsh M, et al. Subcorneal pustular dermatosis and IgA paraproteinemia: Response to both etretinate and PUVA. Br J Dermatol 1991;125:387–9.

Clinics in Dermatology

Y

2000;18:355–367

130. Huff JC, Golitz LE, Kunke KS. Intraepidermal neutrophilic IgA dermatosis. N Engl J Med 1985;313:1643–5. 131. Wallach D. Intraepidermal IgA pustulosis. J Am Acad Dermatol 1992;27:993–1000. 132. Shear NH, Knowles SR, Shapiro L, et al. Dapsone in prevention of recurrent neutrophilic eccrine hidradenitis J Am Acad Dermatol 1996;35:819 –22. 133. Flynn TC, Harrist TJ, Murphy GF, et al. Neutrophilic eccrine hidradenitis: A distinctive rash associated with cytarabine therapy and acute leukemia. J Am Acad Dermatol 1984;114:584 –90. 134. Beutner KR, Packman CH, Markowitch W. Neutrophilic eccrine hidradenitis associated with Hodgkin’s disease and chemotherapy. A case report. Arch Dermatol 1986; 122:809 –11. 135. Nikkels AF, Hansen I, Collignon J, et al. Neutrophilic eccrine hidradenitis. A case report. Acta Clin Belg 1993; 48:397– 400. 136. Wenzel FG, Horn TD. Nonneoplastic disorders of the eccrine glands. J Am Acad Dermatol 1998;38:1–17. 137. Katsanis E, Luke KH, Hsu E, et al. Neutrophilic eccrine hidradenitis in acute myelomonocytic leukemia. J Pediatr Hematol Oncol 1987;9:204 – 8. 138. Aractingi S, Mallet V, Pinquier L, et al. Neutrophilic dermatoses during granulocytopenia. Arch Dermatol 1995;131:1141–5. 139. Vion B, Alvero H. Neutrophilic eccrine hidradenitis. Dermatologica 1991;183:70 –2. 140. Bailey DL, Barron D, Lucky AW. Neutrophilic eccrine hidradenitis: A case report and review of the literature. Pediatr Dermatol 1989;6:33– 8. 141. Fitzpatrick JE, Bennion SD, Reed OM, et al. Neutrophilic eccrine hidradenitis associated with induction chemotherapy. J Cutan Pathol 1987;14:272– 8. 142. Brehler R, Reimann S, Bonsmann G, et al. Neutrophilic hidradenitis induced by chemotherapy involves eccrine and apocrine glands. Am J Dermatopathol 1997;19:73– 8. 143. Allegue F, Soria C, Rocamora A, et al. Neutrophilic eccrine hidradenitis in two neutropenic patients. J Am Acad Dermatol 1990;23:1110 –3. 144. Cancelas Perez JA, Perez de Oteyza J, Megido M, et al. Chemotherapy-induced neutrophilic eccrine hidradenitis in acute myeloid leukemia. Acta Haematol 1992;87: 167– 8. 145. Fernandez CE, Ambrojo AP, Aquilar MA, et al. Neutrophilic eccrine hidradenitis. A report of two additional cases. Clin Exp Dermatol 1989;14:341– 6. 146. Thorisdottir K, Tomecki KJ, Bergfeld WF, et al. Neutrophilic eccrine hidradenitis. J Am Acad Dermatol 1993;28: 775–7. 147. Flynn TC, Harrist TJ, Murphy GF, et al. Neutrophilic eccrine hidradenitis: A distinctive rash associated with cytarabine therapy and acute leukemia. J Am Acad Dermatol 1984;114:584 –90. 148. Templeton SF, Solomon AR, Swerlick RA. Intradermal bleomycin injections into normal human skin. Arch Dermatol 1994;130:577– 83. 149. Bernstein EF, Spielvogel RL, Topolsky DL. Recurrent neutrophilic eccrine hidradenitis. Br J Dermatol 1992;127: 529 –33. 150. Kuttner BJ, Kurban RS. Neutrophilic eccrine hidradenitis

Clinics in Dermatology

151.

152.

153. 154. 155.

156.

157.

158.

159.

160.

161. 162. 163.

Y

2000;18:355–367

in the absence of an underlying malignancy. Cutis 1988; 41:403–5. Pierson JC, Helm TN, Taylor JS, et al. Neutrophilic eccrine hidradenitis heralding the onset of acute myelogenous leukemia. Arch Dermatol 1993;129:791–2. Thorisdottir K, Tomecki KJ, Bergfeld WF, et al. Neutrophilic eccrine hidradenitis. J Am Acad Dermatol 1993;28: 775–7. Margolis DJ, Gross PR. Neutrophilic eccrine hidradenitis. Cutis 1991;48:198 –200. Burton JL. Sweet’s syndrome, pyoderma gangrenosum and acute leukemia. Br J Dermatol 1980;102:239. Vignon-Pennamen MD, Wallach D. Cutaneous manifestations of neutrophilic disease. Dermatologica 1991;183; 9:751– 8. Suzuki Y, Kuroda K, Kojima T, et al. Unusual cutaneous manifestations of myelodysplastic syndrome. Br J Dermatol 1995;133:483– 6. van Kamp H, van den Berg E, Timens W, et al. Sweet’s syndrome in myeloid malignancy: A report of two cases. Br J Haematol 1994;86:415–7. Prevost-Blank PL, Shwayder TA. Sweet’s syndrome secondary to granulocyte colony-stimulating factor. J Am Acad Dermatol 1996;35:995–7. Genet P, Pulik M, Lionnet F, et al. Sweet’s syndrome during acute myeloid leukaemia: Is there a role for hematopoietic growth factors? Am J Hematol 1995;50:64. Yokoyama K, Kojima M, Komatsumoto S, et al. Acute megakaryoblastic leukemia associated with Sweet’s syndrome, including review of the literature. Rinsho Ketsueki 1993;34:341–7. Tuncer AM. Acute lymphoblastic leukemia and Sweet’s syndrome. Acta Haematol 1988;80:224. Skarin A. Sweet’s syndrome. J Clin Oncol 1997;15:860 –1. Gonzalez-Castro U, Julia A, Pedragosa R, et al. Sweet syndrome in chronic myelogenous leukemia. Int J Dermatol 1991;30:648 –50.

DERMATOSES AND HEMATOLOGIC DISORDERS

367

164. Castanet J, Lacour JP, Garnier G, et al. Neutrophilic dermatosis associated with chronic neutrophilic leukemia. J Am Acad Dermatol 1993;29:290 –2. 165. Zamora ME, Martin ML, de Castro TA, et al. Sweet’s syndrome: A study of 10 cases and review of the literature. Rev Clin Esp 1990;186:264 –9. 166. Woodrow SL, Munn SE, Basarab T, et al. Sweet’s syndrome in association with non-Hodgkin’s lymphoma. Clin Exp Dermatol 1996;21:357–9. 167. Bajwa RP, Marwaha RK, Garewal G, et al. Acute febrile neutrophilic dermatosis (Sweet’s syndrome) in myelodysplastic syndrome. Pediatr Hematol Oncol 1993;10: 343– 6. 168. Caughman W, Stern R, Haynes H. Neutrophilic dermatosis of myeloproliferative disorders. Atypical forms of pyoderma gangrenosum and Sweet’s syndrome associated with myeloproliferative disorders. J Am Acad Dermatol 1983;9:751– 8. 169. Glaspy JA, Baldwin JC, Robertson PA, et al. Therapy for neutropenia in hairy cell leukemia with recombinant human G-CSF. Ann Intern Med 1988;109:789 –95. 170. Fukutoku M, Shimizu S, Ogawa Y, et al. Sweet’s syndrome during therapy with granulocyte colony-stimulating factor in a patient with aplastic anaemia. Br J Haematol 1994;86:645– 8. 171. Sharma PK, Schwartz RA, Janniger CK, et al. Sweet’s syndrome with acute leukemia. Cutis 1991;47:249 –52. 172. Hehlmann R, Luderschmidt C, Goebel FD, et al. Relapsing acute febrile neutrophilic dermatosis and essential thrombocythemia. Blut 1984;48:297–305. 173. Duggan CJ, Willsteed EM, McCrossin ID, et al. Sweet’s syndrome associated with sideroblastic anaemia. Aust N Z J Med 1990;20:179 – 81. 174. Richard MA, Grob JJ, Laurans R, et al. Sweet’s syndrome induced by granulocyte colony-stimulating factor in a woman with congenital neutropenia. J Am Acad Dermatol 1996;35:629 –31.