Papuloerythroderma of Ofuji
Papuloerythroderma of Ofuji (PEO) is a rare skin disorder most commonly found in Japan, which is characterized by polygonal, flat-topped erythematous-brown papules coalescing into sheets which often cover the entire skin surface but spare the skin folds. PEO was first discovered in Japan in 1984 by Ofuji, Furukawa, Miyachi, and Ohno. It is a rare entity that is commonly accompanied by pruritus, peripheral eosinophilia, and elevated IgE. The basis of the disease and initial diagnosis stem from an initial meta-analysis comprised of 170 patients via Torchia et al. who placed fourth a preliminary set of five major and five minor criteria which define PEO. These major and minor criteria help aid in determining etiology and allow for categorization into four sub-types which include primary, secondary, papuloerythroderma imitating lymphoma, and a non-papular form of PEO.
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While the underlying etiology of papuloerythroderma of Ofuji has not been elucidated, a clear connection between underlying malignancy, infectious processes, and pharmacological agents preceding the presentation of PEO has been a consistent theme. The range of oncotic disorders found in association with PEO includes gastric carcinomas, hepatocellular carcinoma, adenocarcinoma of the colon, cutaneous T-cell lymphoma, prostate cancer, and chronic lymphocytic leukemia. This fact leads to the possibility of PEO being a paraneoplastic syndrome with screening for underlying malignancy being a crucial component in the work-up of patients with PEO. In addition to oncotic processes, the hepatitis C virus has also been found to cause PEO with complete resolution of all lesions after levels of HCV antigen became undetectable . Drug-induced papuloerythroderma is a distinct Th2 cell-mediated drug hypersensitivity. Pharmacological agents associated with this phenomenon include nicardipine, aspirin, isoniazid, furosemide, etretinate, ranitidine, leuprorelin, and diltiazem.
The most common subset of the population affected by papuloerythroderma of Ofuji consists of the following demographic; 55 years of age or older, Asian or Caucasian descent, and a predilection for males to females with a ratio of 4 to 1. Epidemiologic factors including age and gender comprise two of the five minor criteria used in diagnosing PEO. PEO is also found commonly in individuals with underlying cutaneous T-cell lymphoma (CTCL). This close correlation between the two diseases is a common theme and plays a significant role in the evaluation of PEO.
Histopathological examination of the tissue reveals focal hyperkeratosis and an acanthotic epidermis with minimal spongiotic change. Inflammatory infiltration is present in a perivascular distribution with a non-specific collection of plasma cells, eosinophils, Langerhans cells, lymphocytes, and Th2 cells. These findings are not pathognomonic; however, they do aid in the diagnosis and evaluation of PEO.
History and Physical
Included in the history and physical in a patient with suspected papuloerythroderma of Ofuji, the provider should elucidate the presence of pruritus, establish the status of atopy, and exclude all external triggering factors including infectious processes, malignancy, and drug-induced lesions. Minor criteria for the diagnosis of PEO include age over 55, male gender, eosinophilia, elevated IgE, and reduced lymphocyte count. A full-body skin examination will likely reveal erythematous lesions comprised of flat, confluent, reddish-brown papules with distribution on the trunk, extremities, and extensor surfaces. In addition to these lesions, a positive deck-chair sign which is defined by exclusion of inframammary folds, axillary folds, inguinal creases, and popliteal fossae should be present. Dermoscopy of PEO reveals multiple erythematous pin-point papules with surrounding whitish halos on an erythematous-pinkish background.
Laboratory, histopathological, and clinical features are the hallmark of evaluation of papuloerythroderma of Ofuji. Laboratory tests including complete blood count, comprehensive metabolic panel, serum IgE, viral titers for Epstein-Barr virus, cytomegalovirus, hepatitis B virus, hepatitis C virus, and HIV, RPR, VDRL should be performed. Presence of lymphopenia elevated serum IgE, and peripheral eosinophilia are all consistent with the diagnosis of PEO. Histological evaluation of a punch biopsy should be performed in patients and reveals a perivascular infiltration of inflammatory cells including histiocytes, lymphocytes, and granulocytes. As a result of the similarity in clinical presentation of cutaneous T-cell lymphoma (CTCL) and that of PEO, patients should undergo flow cytometry and T-cell receptor clonality studies to rule out the possibility of misdiagnosis and to prevent further delay of treatment in patients with CTCL.
Treatment / Management
Treatment of papuloerythroderma of Ofuji consists of initially finding the underlying etiology and treating the secondary disease; this may include the treatment of infectious processes or removal of pharmacological agents. Those with idiopathic disease currently have no gold standard of therapy; however previous cases have received treatment with photochemotherapy (PUVA - psoralen and ultraviolet A), oral steroid courses, and cyclosporine. A 9-month course of cyclosporine at 3mg/kg was noted to lead to complete resolution of skin-lesions with some residual post-inflammatory change.
Differential diagnosis of papuloerythroderma of Ofuji should include the following: cutaneous T-cell lymphoma, secondary syphilis, and drug reaction with eosinophilia and systemic symptoms (DRESS). Differentiation of cutaneous T-cell lymphoma and PEO is by flow cytometry and evaluation of clonal t-cell samples, secondary syphilis may be ruled out via VDRL and RPR testing, and DRESS can be differentiated via its acute presentation versus the more gradual, chronic course of PEO.
The course of papuloerythroderma of Ofuji is generally indolent with remission occurring many years after the initial onset in idiopathic cases. Those with secondary etiology leading to PEO may experience rapid clearance of lesions upon removal of the offending agents, or with the treatment of the underlying causes. In the absence of secondary bacterial super-infection, the overall disease progression is non-acute and consists of resolving pruritus which generally leads to complete resolution.
A significant complication of papuloerythroderma of Ofuji is secondary bacterial super-infection of the polygonal papular lesions likely due to excoriation. These secondary infections may lead to erysipelas or cellulitis and significantly impact patients overall well-being. These complications are manageable with brief oral courses of clindamycin or cefuroxime. In addition to bacterial superinfection, delay of diagnosis of CTCL can also occur if there is a diagnosis of PEO without proper evaluation to rule out CTCL. Missing this critical diagnosis can lead to a deterioration of the clinical picture.
Deterrence and Patient Education
Patients suffering from papuloerythroderma of Ofuji should receive proper education on the correlations that exist between PEO and multiple internal malignancies, as well as its similarity and possible association with CTCL. Proper screening and evaluation to rule out these internal malignancies is a crucial component in the management of PEO and informing patients regarding the types of screening they should undergo will aid in adequate the evaluation of possible underlying disease processes.
Enhancing Healthcare Team Outcomes
Management of papuloerythroderma of Ofuji requires the participation of an interprofessional healthcare team approach. Besides the primary care provider, nurse practitioner and internist, the involvement of specialists in multiple fields to aid in the diagnosis of underlying malignancy should have participation at an early stage in the disease process. Pharmacists can be integral in helping determine when the condition is drug-induced as well as recommendations for pharmaceutical therapy, and nursing is often the primary point of contact for patients and families, providing education. [Level V] Patients with PEO should undergo evaluation via a gastroenterologist to perform upper endoscopy and colonoscopy to rule out gastric carcinoma and adenocarcinoma of the colon. In addition to proper gastroenterological work-up patients should be evaluated for any hematological abnormalities and referred to hematology/oncology specialists if any cell line abnormalities, flow-cytometry abnormalities, or clinical features of malignancy are present.
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