Mucocutaneous paraneoplastic syndromes in hematologic malignancies

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1 Oxford, IJD International Blackwell 45 UK Publishing, Journal Ltd, of Ltd. Dermatology 2005 Review Zappasodi Review et al. paraneoplastic syndromes in hematology Mucocutaneous paraneoplastic syndromes in hematologic malignancies Patrizia Zappasodi, MD, Corrado Del Forno, MD, Alessandro Corso, MD, and Mario Lazzarino, MD From the Division of Hematology and Department of Dermatology, University of Pavia, IRCCS Policlinico San Matteo, Pavia, Italy Correspondence Patrizia Zappasodi, MD Division of Hematology, Policlinico San Matteo Pavia, Italy 14 Introduction Hematologic malignancies can be accompanied by cutaneous manifestations, known as paraneoplastic syndromes, which usually present different patterns from their idiopathic counterparts. These disorders can either precede, occur concurrently with, or follow the diagnosis of a neoplastic disease. They often represent the first clinical sign of an underlying neoplasm or the earliest symptom of relapse of a previous cancer. 1 The definitive diagnosis is achievable with an accurate differential diagnosis based on the morphology of the skin lesions, their histologic pattern, and clinical picture. The pathogenetic mechanism is complex and not fully understood for each condition. The strict association between dermatosis and cancer, such as the time of presentation, clinical course, and response to the same treatment, suggests the possibility of a common pathogenetic mechanism underlying the two entities. Some molecules may be produced directly by tumor cells, or, alternatively, a depletion by the tumor of specific substances may be responsible for the paraneoplastic manifestations. Moreover, as the occurrence of these paraneoplastic syndromes is unforeseen, it is reasonable to hypothesize an abnormal host response to the neoplasm. 1 Although the pathogenetic mechanisms are still unknown, the clinical and histologic criteria of diagnosis are well defined. Corticosteroids are used as the therapeutic approach, although some paraneoplastic lesions are more resistant than their idiopathic counterparts, and successful resolution requires the eradication of the underlying malignancy. Clinical Picture The classification of paraneoplastic syndromes associated with hematologic cancers is generally based on the predominant histologic pattern. In line with this approach, we describe the most frequent dermatoses grouped in the following categories: (i) neutrophilic dermatoses; (ii) vesiculobullous disorders; (iii) papulosquamous disorders; (iv) reactive erythemas; (v) vasculitis; and (vi) dermal depositions (Table 1). Neutrophilic dermatoses Neutrophilic dermatoses are a group of diseases characterized by a dermal infiltrate of normal polymorphonuclear leukocytes without any identifiable cause. The most frequently described are Sweet s syndrome (SS), pyoderma gangrenosum (PG), and subcorneal pustular dermatosis (SPD). Sweet s syndrome SS can be observed without any evidence of other pathologic processes or in association with malignancy. In 85% of cases, the malignancy-related form is associated with a hematologic neoplasm, 2 4 mostly acute myeloid leukemia (AML), 4,5 and less frequently Hodgkin s disease (HD), non-hodgkin s lymphoma (NHL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), and chronic myelogenous leukemia (CML). 4 The idiopathic form refers to the classical description of an acute febrile neutrophilic dermatosis by Dr Robert Sweet. 6 Fever, neutrophilia, erythematous, tender plaques or nodules with a neutrophilic dermal infiltrate without vasculitis, and a prompt response to corticosteroids are constant characteristics of the clinical picture. The morphology of the lesions and their location differ in the two forms: (i) in the paraneoplastic variety, skin lesions are more severe, often vesicular, bullous, or ulcerative (Figs 1 and 2), 7 and sometimes with a mixed aspect with other dermatoses, such as PG, 8 erythema nodosum, 9 or erythema multiforme; 10 (ii) neutrophilic infiltrates mainly occur on the lower extremities, trunk, and back, with frequent involvement, in paraneoplastic SS, of the oral mucous membranes; they are more frequent

2 Zappasodi et al. Mucocutaneous paraneoplastic syndromes in hematology Review 15 Table 1 Morphologic and histologic characteristics of the principal cutaneous paraneoplastic syndromes associated with hematologic malignancies Paraneoplastic syndrome Morphology of lesions Histologic findings Associated hematologic malignancy Neutrophilic dermatoses Sweet s syndrome Painful cutaneous plaques or nodules Dermal infiltrate of mature neutrophils AML, NHL, MDS Pyoderma gangrenosum Deep violaceous nodules with Dermal infiltrate of mature neutrophils AML, MM centrifugal extension and necrotic and epidermal necrosis and ulcerated center Subcorneal pustular Annular grouping of pustules on the Subcorneal neutrophilic abscess MM, NHL dermatosis trunk and intertriginous areas with or without a mixed superficial perivascular infiltrate Vesiculobullous disorders Pemphigus vulgaris Blisters and painful ulcers of the Intraepithelial blisters HD, NHL, CLL skin and mucous membranes (oral lesions) Pemphigus foliaceus Superficial blisters on the skin Superficial acantholytic and HD, NHL, CLL subcorneal blisters Paraneoplastic pemphigus Polymorphous skin eruption and Intraepidermal acantholysis, HD, NHL painful mucous membrane erosions keratinocyte necrosis, vacuolar interface changes Pemphigoid Pruritic skin plaques evolving to Subepidermal blisters, NHL striking bullous eruption neutrophilic infiltrate of the basement membrane and within the blister cavity Dermatitis herpetiformis Pruritic papulovesicular skin lesions Infiltration of neutrophils in NHL the tips of dermal papillae with or without subepidermal blisters Linear IgA dermatosis Pruritic papules and vesicles Subepidermal blisters, neutrophilic NHL, MM 65 infiltrate of dermal papillae Reactive erythemas Erythroderma and Diffuse erythema and desquamation Nonspecific perivascular lymphocytic HD, NHL, AML, MDS exfoliative dermatitis infiltrate Erythema gyratum repens Concentric, erythematous lesions Nonspecific perivascular lymphocytic MPD 66 with wood-grain appearance infiltrate Erythromelalgia Burning pain, erythema, and warmth Arteriolar occlusion by platelet MPD of the extremities aggregates Papulosquamous disorders Acquired ichthyosis Scales on trunk and extremities Thinning of the granular layer of the MM, HD, NHL epidermis Acanthosis nigricans Hyperkeratotic and Hyperkeratosis and papillomatosis NHL, MM hyperpigmented papules Dermatomyositis Gottron s papules, heliotrope eruption, Epidermal acanthosis or NHL, MM and periungual telangiectasias flattening, vacuolar alteration of the basal cell layer Vasculitis Papules, cutaneous and subcutaneous Leukocytoclastic vasculitis, AL, NHL, MM nodules, palpable purpura, ulcers fibrinoid necrosis of the vessels, neutrophils in the vessels, extravasation of erythrocytes Dermal deposition diseases Amyloidosis AL Papules, nodules, periorbital purpura Amyloid deposits from tissue MM aspirate AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; HD, Hodgkin s disease; AL, acute leukemia; MDS, myelodysplastic syndrome; MM, multiple myeloma; MPD, myeloproliferative disease; NHL, non-hodgkin s lymphoma. on the upper extremities, head, and neck in idiopathic conditions. Extracutaneous involvement can be observed in idiopathic SS, but is more frequent in the cancer-associated form as musculoskeletal symptoms, conjunctivitis and episcleritis, 14 and glomerulonephritis, 15 often with proteinuria, 16 pulmonary infiltrates, 17 and mucous membrane involvement, such as oral ulcers. 4 Moreover, in the paraneoplastic variety, altered laboratory tests are generally observed: the absence of neutrophilia with or without immature myeloid cells, anemia, and abnormal platelet count are related to the natural history

3 16 Review Mucocutaneous paraneoplastic syndromes in hematology Zappasodi et al. Figure 1 Sweet s syndrome: large inflammatory plaques with hemorrhagic bullae on the legs Figure 3 Pyoderma gangrenosum: hemorrhagic pustules and purulent ulcers with irregular, undermined, and raised borders on the legs Figure 2 Sweet s syndrome: large inflammatory plaques with hemorrhagic bullae on the legs of the underlying hematologic disorder. The diagnosis is based on the evaluation of the morphologic and histologic findings and the systemic associated signs. It is also necessary to exclude the presence of any bacterial, mycobacterial, and fungal infections, or the localization of primary or metastatic tumor cells. Pyoderma gangrenosum PG initially appears as a painful papule or pustule and subsequently develops into an erythematous nodule evolving to form an ulcer with violaceous irregular borders, a sterile hemorrhagic exudate, and a boggy necrotic base (Figs 3 and 4). 1,18 The pathologic findings include endothelial swelling of the edge of the lesion, fibrinoid necrosis, thrombosis, extravasation of erythrocytes, a neutrophilic infiltrate of the undermined borders with a central epidermal necrosis. In about 50% of cases, PG is diagnosed in association with systemic diseases. 19 These include ulcerative colitis, Crohn s disease, inflammatory arthritis, and, in 7% of cases, hematologic malignancies, most commonly AML, CML, and multiple Figure 4 Pyoderma gangrenosum: hemorrhagic pustules and purulent ulcers with irregular, undermined, and raised borders on the legs myeloma (MM). 20 It often precedes or accompanies a malignant transformation or a relapse of a hematologic disorder and, for these reasons, it is considered an adverse prognostic factor. In cancer-associated PG, the lesions are often more superficial and have atypical vesiculobullous aspects. 7,18 A distinct entity, called bullous PG, has been described in association with myeloproliferative diseases. It can be distinguished from classic PG by its atypical bullous morphology and by the unusual histologic finding of intraepidermal or subepidermal bullae. 21 The sites usually involved are the lower extremities, particularly the anterior tibial surface, buttocks, abdomen, and face. 18 Similar to SS, PG can also affect the meninges or internal organs, such as the liver, kidneys, and lungs. 7 For a correct diagnosis of PG, infections should be ruled out through appropriate cultures. Moreover, a search for a possible associated systemic disease is recommended because effective therapy of the associated disorder can potentially cure the PG lesions. 21

4 Zappasodi et al. Mucocutaneous paraneoplastic syndromes in hematology Review 17 Figure 6 Subcorneal pustular dermatosis: coalescent pustular lesions on an erythematous base forming polycyclic eroded patches on the trunk and axilla Figure 5 Subcorneal pustular dermatosis: coalescent pustular lesions on an erythematous base forming polycyclic eroded patches on the trunk and axilla Subcorneal pustular dermatosis SPD, also known as Sneddon Wilkinson disease, is defined by the following diagnostic criteria: (i) pustular eruption without systemic symptoms; (ii) absence of existing psoriasis; (iii) subcorneal neutrophilic pustules without spongiosis; and (iv) responsiveness to dapsone. 22 SPD lesions are usually present on the trunk and in intertriginous areas (Figs 5 and 6), and are characterized by a subcorneal neutrophilic abscess with or without a mixed superficial perivascular infiltrate (Fig. 7). 23 It is often described during the course of lymphoproliferative diseases, mainly MM, that are usually of the IgA type. The first-choice treatment is dapsone, which can yield good results in combination with corticosteroids, methotrexate, and psoralen plus UV-A (PUVA). 7 Pathogenesis and therapy of neutrophilic dermatoses The pathogenesis of these disorders is still undefined. Most of the studies reported have been performed in SS patients, whereas very few data are available for the other neutrophilic Figure 7 Subcorneal pustular dermatosis: histologic picture with typical subcorneal pustules filled with neutrophils diseases. There is no evidence that bacterial infection has a causative role and, indeed, antibiotics usually do not influence the course of the disease. The frequent association with systemic diseases, such as autoimmune disorders, inflammatory bowel diseases, and neoplasms, suggests that multiple antigen stimulation may have an important role in their development. 24 The presence of neutrophilia and dermal neutrophilic infiltration has driven many authors to study the function of neutrophils, but with conflicting results. 25,26 The neutrophil chemotactic activity, studied in the acute phase of SS, was decreased in some studies 27 and enhanced in others; 28 the phagocytic function has also been reported to be enhanced 28 or normal. 26 Circulating autoantibodies do not seem to be important in the pathogenesis, nor do those against components of the neutrophil cytoplasm, which are considered to be only an epiphenomenon. 29 The development of neutrophilic dermatoses in patients treated with growth factors, the evidence of enhanced endogenous serum levels, and the tissue detection of some cytokines have led to the consideration of the following

5 18 Review Mucocutaneous paraneoplastic syndromes in hematology Zappasodi et al. molecules as potential causative factors: granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), interleukin-6 (IL-6), interleukin-8 (IL-8), and α-interferon (α- IFN) Indeed, an abnormal production of these cytokines could be responsible for unwanted recruitment and activation of leukocytes and for subsequent tissue toxicity. Moreover, recent investigations have postulated a role for the T-helper-1 (Th-1) cell cytokines (γ-ifn and IL-2) in the pathogenesis of SS. 37 Although the pathogenetic mechanisms of the neutrophilic diseases have not yet been defined, the therapy is well established with satisfactory results. Steroids are the therapeutic gold standard in both idiopathic and paraneoplastic dermatoses, although, in the latter group, a high rate of recurrence forces clinicians to prolong therapy, to taper slowly, and, importantly, to treat the underlying neoplasm contemporaneously. 7 Other therapeutic options include either potassium iodide or colchicine, which rapidly improve Sweet s lesions; moreover, in cases with a potential systemic infection, corticosteroids are contraindicated, and potassium iodide and colchicine represent first-line treatment. 38 In addition, dapsone, chlorambucil, cyclophosphamide, cyclosporine, tacrolimus, and thalidomide have been proposed in the therapy of neutrophilic dermatoses, but the results are anecdotal or preliminary. 21,38 40 Vesiculobullous disorders Vesiculobullous disorders include pemphigoid, the group of different types of pemphigus (vulgaris, foliaceus, and paraneoplastic), dermatitis herpetiformis, and linear IgA dermatosis. Pemphigus lesions are usually characterized by flaccid bullae and superficial crusted erosions with intraepidermal blisters. By contrast, paraneoplastic forms start with small papules that later form vesicles and bullae, painful mucous membrane ulcerations, and lichenoid skin lesions (Figs 8 and 9). Intraepithelial blister formation is due to the loss of normal cell-to-cell adhesion, which, on histologic examination, is evidenced by intraepidermal acantholysis. 18 The pathogenesis is related to the action of IgG autoantibodies directed against epithelial cell surface proteins and identified by direct and indirect immunofluorescence. Furthermore, specific antibodies (IgG antidesmogleins 1 and 3) in sera from all paraneoplastic pemphigus patients have recently been detected by enzyme-linked immunosorbent assay (ELISA). 41 Some cases of pemphigus vulgaris and foliaceus, and all cases of paraneoplastic pemphigus, have been reported to be associated with malignancy, such as thymomas, or lymphoproliferative disorders [HD, NHL, chronic lymphocytic leukemia (CLL)]. In contrast with the other forms of pemphigus, paraneoplastic pemphigus does not usually respond to corticosteroids or plasmapheresis, and a rapid worsening of the clinical condition is frequently observed. Recent in vitro studies have suggested a central role of IL-8 in the pathogenesis of epidermal neutrophil recruitment via IgG autoantibodies that are able to Figure 8 Pemphigus vulgaris: crusted erosions and erythematous sequelae on the back and scalp Figure 9 Pemphigus vulgaris: crusted erosions and erythematous sequelae on the face activate IL-8 cytoplasmic expression and secretion in normal human keratinocytes. 42 Pemphigoid is a dermatosis included in the group of vesiculobullous disorders and sometimes associated with

6 Zappasodi et al. Mucocutaneous paraneoplastic syndromes in hematology Review 19 lymphoproliferative diseases, mainly in its bullous variety. 43 The skin lesions are typically very pruritic, and may first present as urticarial plaques on the trunk and extremities. Subsequently, tense blisters arise, sometimes producing an extensive and striking bullous eruption. In pemphigoid, the pathogenesis is related to the presence of autoantibodies which prime a cascade of inflammatory events causing blister formation. This mechanism is different from that of pemphigus in which direct cell detachment after antibody binding to the cell adhesion molecules is responsible for blistering. 44 The main diagnostic criterion is represented by the identification, using immunoblotting analysis, of specific antigens (bullous pemphigoid antigen (BPAG)1, BPAG2) recognized by patients sera. In addition, four clinical criteria have recently been proposed for a rapid diagnosis of bullous pemphigoid: (i) age greater than 70 years; (ii) absence of atrophic scars; (iii) absence of mucosal involvement; and (iv) absence of predominant bullous lesions on the neck and head. 45 For a long time, bullous pemphigoid has been considered, in most cases, as a paraneoplastic feature; currently, some authors have opposed this theory and consider the association between pemphigoid and cancer as fortuitous. 46 Recent classifications still include pemphigoid as a cutaneous manifestation of neoplasia. 47 Some studies have revealed a higher risk of cancer in patients with pemphigoid, in particular when an immunofluorescence test is negative. 48 Further studies are necessary to clarify this problem, but, at present, it is advisable to look for an occult neoplasm in all patients with a new diagnosis of pemphigoid and to follow them carefully during the course of the disease. Dermatitis herpetiformis is characterized by pruritic papular or vesicular lesions symmetrically distributed over the extensor surfaces of the extremities, the buttocks, the posterior neck, and the scalp (Fig. 10). Histology shows neutrophilic microabscesses in dermal papillae with or without subepidermal blisters, and direct immunofluorescence of perilesional regions reveals granular deposits of IgA antibodies at the dermal epidermal junction. 1 It is frequently associated with glutensensitive enteropathy and, amongst hematologic neoplasms, with non-hodgkin s T-cell lymphomas of the small intestine. 49 Papulosquamous disorders Papulosquamous disorders are characterized by small (papules) or large (plaques) raised skin lesions. The prototype paraneoplastic papulosquamous disorder is acanthosis nigricans, which is frequently associated with solid tumors, such as gastric carcinoma, but has also been reported in association with lymphoproliferative diseases. 50,51 It is a dermatosis that presents with confluent small hyperkeratotic and hyperpigmented papules, mainly in flexural areas (axillae, posterior neck), intertriginous areas (groin and submammary region) (Figs 11 and 12), or the palmar region (lesions of palmar skin similar to the surface of bovine foregut and, for this Figure 10 Dermatitis herpetiformis: small grouped vesicles and crusts on an erythematous base on the arm Figure 11 Acanthosis nigricans: hyperkeratotic and hyperpigmented patches with velvety surface and papillomatosis on the groin reason, named tripe palms ). It has also been described as mucosal involvement (lips, anus, periocular areas), typical of the paraneoplastic form. 1,52 Acquired ichthyosis (AI) is the papulosquamous disorder most frequently associated with hematologic malignancies. It presents as small white to brown rhomboid scales with free edges, mainly on the trunk and extensor surface of the limbs. 1 The pathologic findings consist of an increase in the stratum corneum, thinning to absence of the granular layer, and mild acanthosis of the epidermis. 18 AI has been reported in 30% of cases in association with systemic diseases, such as immunodeficiency syndromes, endocrinopathies, sarcoidosis, or malignancy, mostly HD. The skin lesions are itchy, but pruritus may also be present in normal-appearing skin areas; excoriations secondary to pruritus are frequently associated. 1 The pathogenesis is unknown, but reduced dermal lipid synthesis and cholesterol deficiency seem to be frequent in these patients and are possibly involved in the pathogenesis. 53 Once a diagnosis of AI is made through the evaluation of clinical

7 20 Review Mucocutaneous paraneoplastic syndromes in hematology Zappasodi et al. Figure 12 Acanthosis nigricans: hyperkeratotic and hyperpigmented patches with velvety surface and papillomatosis on the axilla Figure 13 Dermatomyositis: periungual telangiectasias and violaceous flat papules and plaques on the fingers, particularly over the interphalangeal joints (Gottron s papules) characteristics and skin biopsy, it is recommended to screen for an underlying cancer. 54 The treatment of the associated neoplasm is the only curative approach for paraneoplastic AI. Dermatomyositis is an inflammatory myopathy defined by the following diagnostic criteria: proximal and symmetrical muscle weakness; evidence of myositis at muscle biopsy; elevation of serum muscle enzyme levels; typical electromyographic abnormalities; and cutaneous signs. 55 Pathognomonic cutaneous signs of dermatomyositis include erythematous dermal papules overlying the phalangeal joints, known as Gottron s papules, heliotrope eruption involving a violaceous and edematous eruption in periorbital areas, pruritic scalp eruption, and periungual telangiectasias 56 (Fig. 13). The characteristic pathologic finding is vacuolar alteration of the basal cell layer, with acanthosis or flattening of the epidermis, respectively, in Gottron s papules and heliotrope eruption. 56 About 30% of cases of dermatomyositis are associated with a neoplasm, including NHL, and the majority of cases precede cancer discovery. 57 Reactive erythemas These consist of a nonspecific cutaneous response to an underlying primary systemic cause with its antigenic burden. They can be associated with solid cancers or hematologic malignancies. The main variants are erythroderma, exfoliative dermatitis, erythromelalgia, and erythema gyratum repens. Erythroderma and exfoliative dermatitis present with generalized pruritic redness and inflammation of the skin with or without exfoliation. 58 Systemic symptoms, such as malaise, adenopathy, leukocytosis, and eosinophilia, can accompany the eruption. Histologic findings are nonspecific and include acanthosis, hyperkeratosis, and perivascular lymphocytic dermal infiltrates. Lymphomas, leukemias, and MDS are associated in more than 50% of cases, sometimes discovered years after the onset of dermatosis. 59 In cutaneous T-cell lymphoma, erythroderma can be the result of tumor invasion of the skin rather than a paraneoplastic phenomenon. Erythromelalgia is characterized by attacks of burning pain, erythema, and warmth of the extremities with arterial occlusions by aggregates of platelets. 1 The adult-onset variety is associated with systemic diseases, such as diabetes mellitus, autoimmune diseases, vasculitis, and, in about 20% of cases, myeloproliferative disorders, mostly polycythemia vera. 60 Acetylsalicylic acid, through an inactivation of platelet aggregation, significantly reduces the intravascular occlusion, resulting in a relief of symptoms. Vasculitis Vasculitis, a heterogeneous group of diseases characterized by the necrosis of blood vessels, is associated with cancer in about 5% of cases. 61 It is most commonly detected in patients with hematologic malignancies, such as hairy cell leukemia, hairy cell leukemia (HCL) lympnomas, CML, and MDS. 62 Those reported most often in association with hematologic neoplasms include leukocytoclastic vasculitis and polyarteritis nodosa. The former is a vasculitis of the small vessels of the skin and presents with palpable purpura, especially on the lower extremities. By contrast, polyarteritis nodosa involves medium- and small-sized arteries and presents with linear subcutaneous nodules, erythematous papules, livedo reticularis, ulcerations, distal digit necrosis, and systemic manifestations, including abdominal pain, asymmetric polyarteritis, and peripheral neuropathy. The pathogenesis is unknown and the therapy consists of systemic steroid administration and cure of the underlying neoplasm. 1 Dermal depositions Primary amyloidosis (amyloidosis AL) is a systemic disease associated in 90% of cases with monoclonal gammopathies. 63 It is characterized by tissue deposits of an amorphous hyaline material, called amyloid. This material, consisting of monoclonal light chains, is insoluble and ultimately leads to a disorganization of tissue architecture. It can be evidenced

8 Zappasodi et al. Mucocutaneous paraneoplastic syndromes in hematology Review 21 from tissue aspirate (abdominal fat, rectal mucosa, normalappearing skin) because of its apple-green birefringence when viewed with a polarized light source. It usually involves the internal organs (kidneys, heart, liver), causing progressive deterioration of their function. The prognosis is poor, with a mean survival of about 1 year. 64 The cutaneous involvement is polymorphic, presenting with papules, nodules, plaques, bullae, and purpura. Mucocutaneous lesions are observed in periorbital areas, flexural areas, eyelids, nasolabial folds, lips, tongue, and oral mucosa. 64 Conclusions Mucocutaneous paraneoplastic syndromes are a heterogeneous group of cutaneous manifestations, sometimes accompanied by systemic symptoms and abnormal laboratory tests, whose natural history is strictly linked to the underlying neoplasm. The paraneoplastic dermatosis can precede, be concomitant with, or follow cancer development. Moreover, it may be the first sign of cancer relapse. Because of the known association of these dermatoses with malignancy, when a diagnosis of paraneoplastic dermatosis is made, it is mandatory to search for an underlying neoplasm. Even in the case of the idiopathic form, the patient must be strictly followed as, in some cases, malignancy can develop subsequently. The pathogenesis of each form is not fully understood: an aberrant production of a variety of cytokines or a dysfunction of immune surveillance seem to represent the most likely hypotheses. Therapy with steroid administration usually gives encouraging results. Nevertheless, the most important therapy of the paraneoplastic forms is treatment of the underlying malignancy. References 1 Cohen PR, Kurzrock R. Mucocutaneous paraneoplastic syndromes. Semin Oncol 1997; 24: Cooper PH, Innes DJ, Greer KE. Acute febrile neutrophilic dermatosis (Sweet s syndrome) and myeloproliferative disorders. Cancer 1983; 51: Klock JC, Oken RL. Febrile neutrophilic dermatosis in acute myelogenous leukemia. Cancer 1976; 37: Cohen PR, Talpaz M, Kurzrock R. Malignancy-associated Sweet s syndrome: review of the world literature. J Clin Oncol 1988; 6: Cohen PR, Kurzrock R. Sweet s syndrome revisited: a review of disease concepts. Int J Dermatol 2003; 42: Sweet RD. An acute febrile neutrophilic dermatosis. Br J Dermatol 1964; 76: Hensley CD, Caughman SW. Neutrophilic dermatoses associated with hematologic disorders. Clin Dermatol 2000; 18: Zappasodi P, Corso A, Del Forno C. Sweet s syndrome and myelodysplasia: two entities with a common pathogenetic mechanism? Haematologica 2000; 85: Suzuki Y, Kuroda K, Kojima T, et al. Unusual cutaneous manifestations of myelodysplastic syndrome. Br J Dermatol 1995; 133: Cohen PR, Kurzrock R. Sweet s syndrome: a neutrophilic dermatosis classically associated with acute onset and fever. Clin Dermatol 2000; 18: Krauser RE, Schumacher HR. The arthritis of Sweet syndrome. Arthritis Rheum 1975; 18: Greer KE, Cooper PH. Sweet s syndrome (acute febrile neutrophilic dermatosis). Clin Rheumatol Dis 1982; 8: Su WPD, Liu HN. Diagnostic criteria for Sweet s syndrome. Cutis 1986; 37: Cohen PR. Sweet s syndrome. Orphanet Encyclopedia, October Sweet.pdf. 15 Unis ME, Hill GS. Sweet s syndrome associated with acute renal failure. Cutis 1987; 40: Matta M, Malak J, Tabet E, et al. Sweet s syndrome: systemic association. Cutis 1973; 12: Lazarus AA, McMillan M, Miramadi A. Pulmonary involvement in Sweet s syndrome (acute febrile neutrophilic dermatosis). Preleukemic and leukemic phases of acute myelogenous leukemia. Chest 1986; 90: Kurzrock R, Cohen PR. Mucocutaneous paraneoplastic manifestations in hematologic malignancy. Am J Med 1995; 99: Callen JP, Woo TY. Vesiculopustular eruption in a patient with ulcerative colitis. Pyoderma gangrenosum. Arch Dermatol 1985; 121: Lear JT, Atherton MT, Byrne LP. Neutrophilic dermatoses. Pyoderma gangrenosum and Sweet s syndrome. Postgrad Med J 1997; 73: Powell FC, Su WP, Perry HO. Pyoderma gangrenosum: classification and management. J Am Acad Dermatol 1996; 34: Lutz ME, Daoud MS, McEvoy MT, et al. Subcorneal pustular dermatosis: a clinical study of ten patients. Cutis 1998; 61: 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: Cohen PR, Kurzrock R. Sweet s syndrome and cancer. Clin Dermatol 1993; 11: Fett DL, Gibson LE, Su WPD. Sweet s syndrome. Systemic signs and symptoms and associated disorders. Mayo Clin Proc 1995; 70: Aram H. Acute febrile neutrophilic dermatosis (Sweet s syndrome). Response to dapsone. Arch Dermatol 1984; 120: Nunzi E, Crovato F, Dallegri F, et al. Immunopathological studies on a case of Sweet s syndrome. Dermatologica 1981; 163: Kaplan SS, Wechsler HL, Basford RE, et al. Increased plasma chemoattractant in Sweet s syndrome. J Am Acad Dermatol 1985; 12:

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