Paraneoplastic Dermatoses: A Brief General Review and an Extensive Analysis of Paraneoplastic Pemphigus and Paraneoplastic Dermatomyositis.

Skin manifestations of systemic disease and malignancy are extremely polymorphous. Clinicians should be familiarized with paraneoplastic dermatoses in order to perform an early diagnosis of the underlying neoplasm. Lack of familiarity with cutaneous clues of internal malignancy may delay diagnosis and treatment of cancer. In this review, we described several paraneoplastic dermatoses and discussed extensively two paradigmatic ones, namely paraneoplastic pemphigus and paraneoplastic dermatomyositis.

Increase of a wide range of bioactive substances in an active phase of neuro-Sweet disease.

We present the case of a patient whose skin findings and human leucocyte antigen (HLA) typing were key findings for the diagnosis of his neuro-Sweet disease. A 55-year-old Japanese man with skin rashes and high fever suddenly developed consciousness disturbance, and brain MRI showed encephalitis and leptomeningitis. Neuro-Behçet disease or microbial infection was initially suspected, but he was eventually diagnosed with neuro-Sweet disease based on his skin rashes and pathology and the presence of HLA-B54 and Cw1. He responded to glucocorticoid and recovered without neurological sequelae. The involvement of cytokines has been implicated in the pathogenesis of Sweet disease, but the number of cytokines assayed in each case report is limited. In our patient's case, the result of a 27-cytokine assay showed increases in a wide range of bioactive substances including inflammatory cytokines, growth factors and chemoattractants in the active phase, indicating the involvement of multiple cytokines in the pathogenesis of Sweet disease.

Acquired cutis laxa secondary to Sweet syndrome in a child (Marshall syndrome): A rare case report.

Sweet syndrome is rare in the pediatric population and usually responds well to treatment, resolving without sequelae. Marshall syndrome is a rare pediatric skin disease characterized by loss of elastic tissue (cutis laxa) secondary to acquired, localized neutrophilic dermatitis without any internal organ involvement. Only few cases of Marshall syndrome (acquired cutis laxa type II) have been reported. Systemic steroids and dapsone show excellent results in Sweet syndrome. Although there is no satisfactory treatment for cutis laxa, dapsone can be used in the acute phase for control of swelling.

Sweet syndrome with pseudocarcinomatous hyperplasia: A case report and review of the literature.

Pseudocarcinomatous (pseudoepitheliomatous) hyperplasia represents reactive epidermal change mimicking squamous cell carcinoma (SCC), owing to a variety of inflammatory and neoplastic phenomena, including deep fungal infections, CD30-positive lymphomas, and others. We report a case of Sweet syndrome (SS) arising in a patient with acute myelogenous leukemia, with persistent orolabial involvement which mimicked SCC both clinically and microscopically, but resolved entirely with adequate corticosteroid treatment. Clinicians should be aware that neutrophilic dermatoses such as SS and pyoderma gangrenosum may rarely exhibit pseudocarcinomatous epidermal changes similar to those seen in soft tissue infections and other inflammatory dermatoses.

Cryptococcus-like changes in the setting of vasculitis.

Cutaneous vasculitis has many underlying causes, and the clinical and histological findings often overlap. Inflammatory vasculitis can mimic infection; however, distinction is critical for the timely institution of appropriate therapy. We present two patients who had generalized polymorphous eruptions whose cutaneous pathology showed vasculitis with unusual haloed yeast-like cells within the inflammatory infiltrate, mimicking Cryptococcus. The unusual cells stained negatively with Gomori methenamine silver and periodic acid-Schiff fungal stains, but positively for CD68 and had cytoplasmic reactivity with antibody to myeloperoxidase (MPO). Both patients had positive serum anti-MPO antibodies. The first patient experienced a rapidly fatal course, whereas the second patient improved with prompt initiation of systemic corticosteroids. Interestingly, the second case had prior biopsy showing Sweet syndrome with crypotoccoid-appearing cells. Cryptococcoid cells have been described previously in association with neutrophilic dermatoses, but not in the setting of vasculitis as was seen in our patients. Our cases add to the existing literature on crypotoccoid mimickers, and are the first to be reported in association with vasculitis.

Tumor Necrosis Factor-α and IL-17A Activation Induces Pericyte-Mediated Basement Membrane Remodeling in Human Neutrophilic Dermatoses.

Sweet syndrome (SS) is a prototypical neutrophilic dermatosis, a class of inflammatory diseases marked by elevated levels of tumor necrosis factor (TNF)-α and IL-17A, pathologic neutrophil recruitment, and microvascular remodeling. Histologic analyses of four matrix proteins-collagen I and IV, laminin, and fibronectin-in skin biopsies of patients with SS reveal that the basement membrane of dermal postcapillary venules undergoes changes in structure and composition. Increased neutrophil recruitment in vivo was associated with increases in collagen IV, decreases in laminin, and varied changes in fibronectin. In vitro studies using TNF-α and IL-17A were conducted to dissect basement membrane remodeling. Prolonged dual activation of cultured human pericytes with TNF-α and IL-17A augmented collagen IV production, similar to in vivo remodeling. Co-activation of pericytes with TNF-α and IL-17A also elevated fibronectin levels with little direct effect on laminin. However, the expression of fibronectin- and laminin-specific matrix metalloproteinases (MMPs), particularly MMP-3, was significantly up-regulated. Interactions between pericytes and neutrophils in culture yielded even higher levels of active MMPs, facilitating fibronectin and laminin degradation, and likely contributing to the varied levels of detectable fibronectin and the decreases in laminin observed in vivo. These data indicate that pericyte-neutrophil interactions play a role in mediating microvascular changes in SS and suggest that targeting MMP-3 may be effective in protecting vascular wall integrity.

Clinicopathologic, immunophenotyping and cytogenetic analysis of Sweet syndrome in Egyptian patients with acute myeloid leukemia.

BACKGROUND: Sweet syndrome (SS) is an uncommon dermatologic disorder that could be associated with hematologic malignancies. OBJECTIVE: To describe the clinicopathologic, immunophenotyping and cytogenetic characteristics of SS in Egyptian patients with acute myeloid leukemia (AML). METHODS: The study was conducted during the period from April 2011 to March 2015. For each patient, a clinical evaluation and histological assessment of cutaneous lesions were recorded. Diagnostic investigations, immunophenotyping and cytogenetic features of leukemia were analyzed. Therapeutic monitoring and follow up of both diseases were registered. RESULTS: The study included 13 patients (7 males and 6 females) with a mean age of 44.4±17.49years. Fever was recorded in 10 cases and most of the lesions (61.5%) appeared during the post remission period. Clinically, the lesions were more frequently located on the extremities (61.5%), presented as solitary lesion (53.8%) and mostly tender (69.2%). Atypical presentations were observed in 5 cases and included ulcerative lesion, indurated mass and a gangrenous mass. Histological assessment revealed two patterns of inflammatory reactions described as classic (dermal) form (38.5%) and deep (subcutaneous) form (61.5%). Laboratory investigations showed leukocytosis in 61.5%, neutropenia in 38.5%, anaemia in 92.3%, and thrombocytopenia in 84.6%. Bone marrow aspiration and biopsy showed suppressed trilineage hematopoesis in 84.6% and blast cell count >50% in 69.2%. The common subtypes of AML included M2 and M4 (23.1% for each). Cytogenetic studies revealed genetic abnormalities in 69.2% of cases. Most of the cases (76.9%) showed a poor response to oral prednisolone but responded well to alternative therapies, including dapsone, colchicine and cyclosporine. CONCLUSION: Sweet syndrome associated with AML may show atypical clinical forms that have an aggressive course and is mostly associated with subcutaneous involvement. Although chemotherapy of AML may play a significant role in the development of SS, the exact mechanism remains unclear. The disease is considered a steroid refractory and genetic abnormalities may have a role in altering the classic nature of the disease.

Acute febrile neutrophilic dermatosis associated with JAK-2 positive myeloproliferative disorder.

We present a case of a 77-year-old man with a history of myeloproliferative disorder. He was admitted with a 2-week history of erythaema, swelling and significant pain of the right forearm following a mechanical fall at home, which had caused a skin laceration. During his admission, he developed ongoing intermittent fever and persistently elevated C reactive protein, and total white cell count. Initially, he was treated with antibiotics for suspected cellulitis. However, symptoms continued to progress, making a suitable management plan challenging. Wound swabs, blood cultures and viral PCR did not confirm infection. A punch biopsy of a skin lesion on the forearm was performed. The histology demonstrated a dense infiltrate of neutrophils and neutrophilic debris in keeping with acute febrile neutrophilic dermatosis (Sweet's syndrome). He was treated with oral steroids and after that he had a complete resolution of symptoms. However, he required a period of rehabilitation before returning home.

Sweet's syndrome complicating ulcerative colitis: a rare association.

Sweet's syndrome (SS) is a neutrophilic dermatosis disorder of unknown aetiology, characterised by acute fever, neutrophilia, painful erythematous papules, nodules and plaques, and an infiltrate consisting predominantly of mature neutrophils in the upper dermis. Classical SS is a rare extra-intestinal manifestation of inflammatory bowel disease (IBD). It is more common in Crohn's disease than in ulcerative colitis (UC). There is a predilection for women, and for patients with colonic disease and active IBD. We report the case of a 39-year-old woman with a flare of moderate severity UC treated with mesalazine who presented with a 5-day history of acute fever, painful papules and plaques on forearms and legs, episcleritis and cervical pain. Skin biopsies showed papillary dermis inflammatory cell infiltration composed mainly of neutrophils, without evidence of leukocytoclastic vasculitis or panniculitis, compatible with SS. The patient had an excellent response to systemic corticosteroids. Symptoms promptly improved and skin lesions resolved after 7 weeks.

Neutrophilic dermatoses and autoinflammatory diseases with skin involvement--innate immune disorders.

Neutrophilic dermatoses (NDs) such as Sweet's syndrome and pyoderma gangrenosum were first described more than 50 years ago and grouped based on their clinical features combined with the typical, neutrophil-rich cutaneous inflammation. In contrast, the recently identified autoinflammatory diseases (ADs) that are also associated with neutrophil granulocyte infiltration of the skin were first characterized based on their genetic architecture. Though both the older ND and the newer AD encompass distinct conditions, they can be seen as parts of a spectrum of innate inflammation. Both groups of diseases show so many overlapping clinical, pathogenetic, histologic, and genetic features that together they should likely be considered as innate immune disorders.

Severe Sweet's Syndrome with Elevated Cutaneous Interleukin-1ß after Azathioprine Exposure: Case Report and Review of the Literature.

Sweet's syndrome (SS) is a dermatosis with systemic symptoms characterized by tender, red nodules or papules, occasionally covered with vesicles, pustules or bullae, usually affecting the upper limbs, face and neck. SS is frequently observed in patients with leukemia or connective tissue diseases, while it is rather seldom in patients with inflammatory bowel disease. The exact pathogenesis of SS is only partially understood. We report the case of a 50-year-old patient with indeterminate colitis, presenting with a febrile diffuse papulopustular and necrotizing skin eruption that healed with significant scarring and appeared 14 days after onset of treatment with azathioprine. Histological examination revealed the presence of features typical of SS, gene expression analysis very high levels of interleukin-1ß (IL-1ß) mRNA in lesional skin, and immunohistochemistry high levels of IL-1ß at the protein level. SS associated with azathioprine is being increasingly reported and is reviewed herein.

Neutrophilic dermatosis: disease mechanism and treatment.

PURPOSE OF REVIEW: The purpose of this review is to describe the physiopathological and therapeutic aspects of neutrophilic dermatosis, taking into account their most frequent associated conditions. RECENT FINDINGS: In autoinflammatory syndromes featuring neutrophilic dermatosis, the role of interleukin-1 and tumor necrosis factor (TNF)-α cytokines in the immunopathogenesis of neutrophilic dermatosis has supported their classification as autoinflammatory diseases. In malignancy-associated neutrophilic dermatosis, the role of the malignant clone in myeloid neoplasms and the role of the monoclonal gammopathy and/or of the malignant plasmocyte clone in myeloma have been underlined. SUMMARY: Recent insights into neutrophilic dermatosis' pathophysiology have encouraged the use of targeted biological therapies for their treatment. Although systemic glucocorticoids remain the mainstay of treatment for Sweet's syndrome and pyoderma gangrenosum, anti-TNF-α is becoming the preferred treatment when pyoderma gangrenosum is accompanied by inflammatory bowel disease or rheumatoid arthritis. Interleukin-1 receptor inhibitor anakinra is a promising therapeutic alternative for refractory Sweet's syndrome.

Sweet's syndrome complicated by Kikuchi's disease and hemophagocytic syndrome which presented with retinoic acid-inducible gene-I in both the skin epidermal basal layer and the cervical lymph nodes.

A 21-year-old man was admitted to our hospital with a fever, erythema, cervical lymphadenopathy and pancytopenia. A diagnosis of Sweet's syndrome (SS) with Kikuchi's disease (KD) and hemophagocytic syndrome (HPS) was made based on the results of a bone marrow aspiration along with the results from biopsy specimens of the brachial skin and a cervical lymph node. The expression of retinoic acid-inducible gene-I (RIG-I) in the skin epidermal basal layer as well as in a cervical lymph node was revealed through immunohistochemistry. He successfully entered remission through treatment with prednisolone. This findings of this case indicate that when SS with KD presents as HPS, it may suggest an association with an RIG-I-related innate immunity.

On the potential involvement of CD11d in co-stimulating the production of interferon-γ by natural killer cells upon interaction with neutrophils via intercellular adhesion molecule-3.

Interaction between neutrophils and other leukocytes plays a variety of important roles in regulating innate and adaptive immune responses. Recently, we have shown that neu-trophils amplify NK cell/6-sulfo LacNAc(+) dendritic cells (slanDC)-mediated cytokine production, by potentiating IL-12p70 release by slanDC via CD18/ICAM-1 and directly co-stimulating IFNγ production by NK cells via ICAM-3. Herein, we have identified additional molecules involved in the interactions among neutrophils, NK cells and slanDC. More specifically, we provide evidence that: i) the cross-talk between neutrophils and NK cells is mediated by ICAM-3 and CD11d/CD18, respectively; ii) slanDC potentiate the production of IFNγ by NK cells via CD11a/CD18. Altogether, our studies shed more light on the role that adhesion molecules play within the neutrophil/NK cell/slanDC network. Our data also have potential implications in the pathogenesis of diseases driven by hyperactivated leukocytes, such as Sweet's syndrome, in which a neutrophil/NK cell co-localization is frequently observed.

Role of inflammatory cells, cytokines and matrix metalloproteinases in neutrophil-mediated skin diseases.

Pyoderma gangrenosum (PG) is a rare, immune-mediated inflammatory skin disease presenting with painful ulcers having undermined edges. Less commonly, bullous and vegetative variants exist. Histology consists of a neutrophil-rich dermal infiltrate. We characterized immunohistochemically the infiltrate in different variants of PG and in another neutrophilic dermatosis as Sweet's syndrome. We studied 21 patients with PG, eight with Sweet's syndrome and 20 controls, evaluating skin immunoreactivity for inflammatory cell markers (CD3, CD163 and myeloperoxidase), cytokines [tumour necrosis factor (TNF)-α, interleukin (IL)-8 and IL-17], metalloproteinases (MMP-2 and MMP-9) and vascular endothelial growth factor (VEGF). Immunoreactivities of CD3, CD163, myeloperoxidase, TNF-α, IL-8, IL-17, MMP-2, MMP-9 and VEGF were significantly higher in both PG and Sweet's syndrome than in controls (P=0·0001). Myeloperoxidase (neutrophil marker), IL-8 (cytokine chemotactic for neutrophils) and MMP-9 (proteinase-mediating tissue damage) were expressed more significantly in both ulcerative and bullous PG than in vegetative PG as well as in Sweet's syndrome (P=0·008-P=0·0001). In ulcerative PG, the expression of CD3 (panT cell marker) and CD163 (macrophage marker) were significantly higher in wound edge than wound bed (P=0·0001). In contrast, the neutrophil marker myeloperoxidase was expressed more significantly in wound bed than wound edge (P=0·0001). Our study identifies PG as a paradigm of neutrophil-mediated inflammation, with proinflammatory cytokines/chemokines and MMPs acting as important effectors for the tissue damage, particularly in ulcerative and bullous PG where damage is stronger. In ulcerative PG, the wound bed is the site of neutrophil-recruitment, whereas in the wound edge activated T lymphocytes and macrophages pave the way to ulcer formation.

Sweet's syndrome: a retrospective clinical, histopathological and immunohistochemical analysis of 11 cases.

The aim of this paper is to report our clinical experience of Sweet's syndrome, a severe dermatological disease which may be extremely important to recognize for the early diagnosis of a neoplastic disorder. Eleven patients affected by Sweet's syndrome, treated at the Department of Dermatology, University of Ferrara, Ferrara, Italy, during 1998 to 2004, were evaluated. A retrospective analysis was performed. Data on age, sex distribution, clinical data, histopathological and immunohistochemical findings and therapy were collected. We observed one patient with idiopathic form, 5 patients affected by the para-inflammatory variant and 5 para-neoplastic cases (with haemoproliferative diseases). The cases with the para-inflammatory form were affected by minor infectious manifestations. Prolonged follow-up is necessary to verify that a case of idiopathic variant is not really a paraneoplastic form. Based on immunohistochemical analysis, we cannot exclude that true histiocytes, immunoreactive for CD68/PGM, infiltrate the dermis in Sweet's syndrome lesions.

Neutrophilic dermatoses with acute myeloid leukemia associated with an increase of serum colony-stimulating factor.

We report a case of acute myeloid leukemia with folliculitis, Sweet's syndrome, and neutrophilic panniculitis after remission induction chemotherapy for acute myeloid leukemia. The level of endogenous granulocyte colony-stimulating factor was closely associated with disease activity.

Acute febrile neutrophilic dermatosis: a histopathologic study of 31 cases with review of literature.

Sweet syndrome is a neutrophilic dermatosis defined by diagnostic criteria that include the lack of evidence for leukocytoclastic vasculitis. Because of the clinicopathological similarities on the one hand and the strict exclusion on the other hand, we were interested in a systematic evaluation of the relationship between these two diseases. We investigated the clinical and histopathological characteristics of 31 patients with Sweet syndrome, comparing our cases with 32 cases of leukocytoclastic vasculitis (including seven cases of urticarial vasculitis) and tried to place them in the background of published cases. There is a close relationship between Sweet syndrome and leukocytoclastic vasculitis in terms of clinical appearance, histopathological pattern, triggers, disease course, and response to treatment. The majority of the cases (23/31; 74%) showed histologic evidence of vasculitis, including nuclear dust, extravasation of erythrocytes, fibrin in and around vessel walls, and degeneration of collagen. Although one original criterion for Sweet syndrome is the absence of vasculitis, we propose that vasculitic changes should not exclude the diagnosis of Sweet syndrome. In contrast, Sweet syndrome can demonstrate vasculitis and may, similarly to urticarial vasculitis, be regarded a variant of leukocytoclastic vasculitis. Clinicopathologic characteristics with acute onset of juicy papules, plaques mostly on the face, shoulder, and trunk, and prominent edema probably reflect modifications of the pathogenetic process based on location and disease acuity.