Dermatology Online Journal
Subcorneal pustular dermatosis (Sneddon-Wilkinson disease) occurring in association with nodal marginal zone lymphoma: A case report
- Author(s): Ratnarathorn, Mondhipa
- Newman, Jeffrey
- et al.
Subcorneal pustular dermatosis (Sneddon-Wilkinson disease) occurring in association with nodal marginal zone lymphoma: A case
report1. UC Davis School of Medicine, Sacramento, CA. firstname.lastname@example.org
Mondhipa Ratnarathorn1, Jeffrey Newman MD PhD2
Dermatology Online Journal 14 (8): 6
2. Division of Dermatology, Department of Medicine, University of Washington School of Medicine, Seattle, WA. email@example.com
Sneddon-Wilkinson disease or subcorneal pustular dermatosis (SPD) is a rare, benign inflammatory skin disorder of unknown etiology. SPD is associated with various systemic disorders, including immunoglobinopathies and lymphoproliferative disorders. The relationship between SPD and immune dysfunction is unlikely to be incidental, although it still remains a mystery whether the associated gammopathies are primary or secondary to the pathogenesis of the disease. Herein, we report the first case of SPD in association with marginal zone lymphoma.
A 45-year-old woman presented to our university practice in November 2004 complaining of a painful, pruritic, and widespread rash for 5 months. She noted onset around her collar area and subsequent spreading to involve the inframammary folds. Aside from the painful rash, the patient was in her usual state of good health and not taking any medications save hydrocodone with acetaminophen for skin pain.
Physical exam revealed pustular, crusted, erythematous, sharply-marginated plaques concentrated in skin folds including the neck base and inframammary skin. The differential diagnosis included subcorneal pustular dermatosis (Sneddon-Wilkinson disease), pemphigus folliaceus, pustular psoriasis, and IgA-pemphigus. Biopsies were taken for light microscopic and immunofluorescent examination.
Histopathology demonstrated acantholytic subcorneal vesiculo-bullous dermatitis with neutrophils. The immunofluorescent specimen revealed only granular C3 and weak linear IgA staining at the dermal-epidermal junction. However, given the context of a subcorneal pustular morphology on light microscopy, these findings were judged to be non-specific. Based on the clinical and histopathological features, a diagnosis of subcorneal pustular dermatitis (SPD, Sneddon-Wilkinson disease) was made.
Laboratory examinations demonstrated mild anemia (hematocrit=31.2%, normal range=34-48%), thrombocytosis (platelet count=480 x 10³ cells per microliter, normal range=130-400 x 10³ cells per microliter), and mild hypoalbuminemia (albumin=3.3 g/dl, normal range=3.4-4.8 g/dl). The remainder of the complete blood count and serum chemistries was normal.
SPD is widely reported in association with plasma cell dyscrasia. Examination of the serum protein electrophoresis (SPEP) demonstrated faint banding within the immunoglobulin gamma (IgG) region. Subsequent immunofixation showed both IgG kappa and IgG lambda, mitigating against monoclonal immunoglobulin production. The urine protein electrophoresis (UPEP) was not performed because the urine tested negative for protein.
After verifying a normal level of glucose-6-phosphate dehydrogenase, our patient was started on dapsone at a dosage of 200 mg daily and fluocinonide ointment twice daily. One month later, her skin findings had worsened with pustule-studded plaques covering an estimated 50 percent of the body surface area. Moreover, the hematocrit fell to a level of 25 percent. Given the poor initial response and worsened anemia, dapsone was discontinued in favor of prednisone 60 mg daily and acetretin 25 mg daily; the topical corticosteroid was continued.
One month later, a partial response was observed with drying and desquamating of many of the previously pustular plaques. The dosage of acitretin was increased to 50 mg daily and the dosage of prednisone was reduced to 40 mg daily followed by a slow taper. Over the next 2 months, she continued to steadily improve, but not clear, on a dosage of 50 mg daily of acitretin.
Subsequently, the patient was lost to follow-up for 6 months. She decreased her acitretin dosage to 25 mg/day during this period. Her disease demonstrated moderate control with erythema and scaling on the trunk, palms and soles.
On resumption of care, the laboratory evaluation revealed a drop in the white blood cell count to 2.5 X 10³ cells per microliter (normal range 4.5 X 10³ to 11 X 10³). Furthermore, the absolute neutrophil count decreased to 0.72 X 10³ cells per microliter (normal range 1.8 X10³ to 7.7 X 10³). Previous readings had all been within the normal range. The lymphocyte count was in the normal range. After confirmation of the result, a presumptive diagnosis of drug-related neutropenia was made and acitretin was withdrawn. Colchicine therapy was instituted at a dosage of 0.6 mg 3 times daily in addition to fluocinonide ointment.
The next 3 months saw a steady worsening of our patient's SPD without rebound of the white blood cell count or the absolute neutrophil count. She was re-started on acitretin and colchicine was discontinued.
Bone marrow biopsy identified a monotypic population of B lymphocytes expressing CD19, CD5, CD20, FMC7, and lambda light chain. By morphologic criteria, the abnormal population was consistent with a lymphocytic lymphoma. The cyclin-D1 was negative, mitigating against mantle cell lymphoma. CD25 and CD103 were negative, excluding hairy cell lymphoma. Cytogenetic studies revealed trisomy at chromosome 12. The patient also underwent computerized tomography imaging of the chest, abdomen, and pelvis. Enlarged lymph nodes were identified in the bilateral axilla, mediastinum, gastrohepatic ligament, retroperitoneum, omentum, along the iliac arteries, and in the inguinal region. Fatty infiltration of the liver was suspected. The spleen appeared normal. Taken together, the findings are most consistent with the diagnosis of nodal marginal zone lymphoma.
Marginal zone lymphoma was diagnosed in April 2006 and rituximab (anti-CD20, a B lymphocyte marker) therapy was initiated. Rituximab is a chimeric monoclonal antibody that targets the B cell antigen CD20. CD20 is expressed on all stages of normal B lymphocytes, as well as most B cell lymphomas. The lymphotoxic effects of rituximab, which include direct signaling of apoptosis, complement activation, and cell-mediated cytotoxicity , prevents the differentiation of B lymphocytes into plasma cells and the subsequent generation of antibodies, such as IgA.
After 1 year of treatment, although the patient's lymphoma demonstrated little radiographic response, the cutaneous eruption became more tractable. While the improvement of her SPD could represent a waning in the natural history of the disorder, it is tempting to speculate that the rituximab played a role. Since the bulk of our patient's tumor responded poorly to therapy, it is unlikely that the observed improvements relate to the drug's anti-tumor effects. Instead, we postulate anti-CD20 targeting of a non-neoplastic B cell clone mediated the improvement of the skin disease.
Currently, the patient continues to be followed in clinic. Her chronic skin condition is stable and controlled with 50 mg acitretin per day, alternating with 25 mg acitretin per day. Simvistatin at a dose of 20 mg per day was recently added to her medication regimen to treat the hypercholesterolemia and hypertriglyceridemia secondary to her acitretin use. Treatment of the nodal marginal zone lymphoma continues to be managed with rituximab by her oncologist at another hospital.
Sneddon-Wilkinson or subcorneal pustular dermatosis (SPD) is a rare, benign inflammatory skin disorder of unknown etiology. Originally described in 1956 , SPD occurs in people of all ethnic backgrounds and more often in middle-aged and elderly women.
SPD is classified as a neutrophilic dermatosis . It presents with chronic, recurrent vesiculopustular eruptions. The lesions coalesce into annular, circinate or serpinginous patterns, preferring the trunk and intertriginous areas, including the axillae, groin, and submammary regions. Histopathologically, the hallmark of SPD is a strictly subcorneal pustule filled with polymorphonuclear leukocytes. The underlying epidermis is generally spared, demonstrating minimal spongiosis or acantholysis.
It is generally accepted that SPD results from an abnormal cytokine profile secondary to immunological dysfunction. Increased levels of the neutrophil chemoattractants interleukin-8 and leukotriene B4, along with the complement fragment C5a and its metabolite C5a des Arg  have been isolated in pustular extracts from cases of SPD. Exaggerated activation of leukocytes, likely through normal signaling pathways, leads to neutrophilic infiltration followed by tissue destruction. Despite many attempts, no infectious agent or other immunogenic trigger has yet been identified in SPD patients.
Immunofluorescence is classically negative in SPD. However, cases presenting with clinical features of SPD and positive immunofluorescence of IgA restricted to the upper epidermis have been reported. The target of these IgA autoantibodies is desmocollin 1 . Characterized by intraepidermal neutrophilic pustules and intercellular IgA deposition, this condition resembles IgA pemphigus. The distribution of subcorneal lesions can be widespread and involve the scalp and face, locations usually spared in classic SPD . These cases constitute a subgroup and have been referred to both as subcorneal pustular dermatosis type IgA pemphigus and IgA pemphigus: type SPD. Our patient demonstrated no intraepidermal staining. The IgA and C3 reactivity, observed only at the dermo-epidermal junction, was judged to be at background intensity. Thus, by immunofluorescent criteria, our patient manifested classic SPD.
SPD frequently presents with various systemic disorders, including immunoglobinopathies and lymphoproliferative disorders, such as IgA multiple myeloma. Other reported associations include CD30+ anaplastic large-cell lymphoma, non-small-cell lung cancer, apudoma, rheumatoid arthritis, hyperthyroidism, and mycoplasma pneumoniae infection . The relationship between SPD and immune dysfunction is unlikely to be incidental, although it remains a mystery whether the associated gammopathies are primary or secondary to the pathogenesis of the disease. Herein, we report the first case of SPD in association with marginal zone lymphoma. Although our patient failed to demonstrate serological evidence of the plasma cell dyscrasias commonly associated with SPD, closer analysis of her laboratory workup revealed persistent neutropenia. Once medications were ruled out as causative, further evaluation revealed the underlying disease. Thus, although a negative immunoelectrophoresis test may be reassuring to the clinician, the possibility of an underlying lymphoproliferative disease is not ruled out and vigilance should be maintained.
There is no cure for SPD; palliative treatment centers on the anti-neutrophilic sulfone, dapsone. Other therapies include etretinate, acitretin, PUVA, narrow-band UVB, and prednisone. Our patient did not have a favorable response to dapsone but did improve on acetretin and high-potency topical steroids.
Further study of the etiology and pathogenesis of this neutrophilic dermatosis will contribute valuable insights into the mechanisms of the autoimmune paraneoplastic syndromes. An understanding of the clinical profile of SPD and its systemic associations will potentially allow for the early diagnosis of immune dysfunctions through their dermatological manifestations and enhance the selection and treatment of these systemic disorders.
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