Three cases of lymphomatoid papulosis with a CD56+ immunophenotype.

We report 3 cases of lymphomatoid papulosis (LyP) with a CD56+, cytotoxic immunophenotype. All 3 patients presented with clinical histories typical of LyP, with one patient having associated mycosis fungoides. Histologically, two cases were type A LyP and one was type B. All 3 cases demonstrated a T-cell receptor clone in lesional skin without evidence of blood involvement. The atypical lymphocytes in each of the 3 cases expressed cytotoxic granules (T-cell intracellular antigen-1+ and granzyme B+) and were CD8+ and CD56+. Expression of CD56 is associated with a poor prognosis in subcutaneous panniculitis-like T-cell lymphoma and blastic natural killer cell lymphoma. However, the two cases of CD56+ LyP previously reported and the 3 cases in this series all appear to be pursuing an indolent course with no evidence of systemic disease.

Mycosis fungoides with a CD56+ immunophenotype.

We report 3 cases of mycosis fungoides (MF) with a CD56+ cytotoxic immunophenotype. Each patient presented with a different clinical phenotype: one exhibited limited poikilodermatous patches (skin stage T1); one, widespread hypopigmented lesions (skin stage T2); and one, poikiloderma with a single cutaneous tumor (skin stage T3). MF was confirmed both histologically and by the presence of a T-cell receptor clone in lesional skin in all cases. CD56 and T-cell intracellular antigen-1 were expressed by the malignant lymphocytes in all patients and two expressed CD8. No sample demonstrated loss of the pan T-cell markers CD2 or CD3. None of the 3 developed systemic disease and T-cell receptor gene analysis of peripheral blood was polyclonal in all cases. Only 3 cases of CD56+ MF have been reported previously, none of which exhibited tumor-stage disease. Currently, the disease in our patients appears to be behaving in a manner similar to that predicted for MF with a normal immunophenotype but the prognosis has to be guarded in view of the rarity of this subtype.

Reduced expression of insulin-like growth factor-binding protein-3 (IGFBP-3) in Squamous cell carcinoma complicating recessive dystrophic epidermolysis bullosa.

Squamous cell carcinoma (SCC) is a common complication in individuals with recessive dystrophic epidermolysis bullosa (RDEB). For the severe Hallopeau-Siemens subtype, the mortality rate from SCC is over 55% by the age of 40 y. Currently, little is known about the molecular pathology or cell biology of SCC in RDEB. In this study, we compared gene expression in RDEB SCC (n=3) and non-EB SCC (n=3) with corresponding RDEB and non-EB peri-tumoral skin, with microarray analysis using DermArray membranes as well as semi-quantitative and real-time RT-PCR. Both tumor sets showed downregulation of epidermal differentiation markers (e.g., profilaggrin, keratins 1 and 10) as well as certain pro-apoptotic genes (e.g., death-associated kinase-3 or ZIP kinase). Likewise, in both groups there was upregulation of matrix metalloproteinase 1 and laminin 5 in the tumors. But we found that the expression of insulin-like growth factor-binding protein-3 (IGFBP-3) was lower (mean of 5.8-fold) in RDEB SCC compared with non-EB SCC. These data were verified by immunohistochemistry. IGFBP-3 has an important role in cancer cell apoptosis mediated via the nuclear retinoid X receptor alpha (RXRalpha). Reduced expression of IGFBP-3 in RDEB SCC may provide a partial explanation for the aggressive behavior and poor prognosis of these tumors in this genodermatosis.

CD30(+) cutaneous lymphoma in association with atopic eczema.

BACKGROUND: Chronic atopic eczema is not regarded as a precursor of malignancy, and, to our knowledge, there has been only one previous case report of CD30(+) cutaneous lymphoma in association with atopic dermatitis. OBSERVATIONS: We report 4 cases of CD30(+) lymphoproliferative disease in young adult patients with active atopic eczema dating from early childhood. Three patients developed primary cutaneous anaplastic large cell lymphoma, of whom 2 developed systemic disease and 1 died. The other patient developed lymphomatoid papulosis type A, which resolved after withdrawal of cyclosporine therapy. No other patient had received immunosuppressive therapy. Three had been treated with phototherapy, and 2 of these patients exhibited positive immunostaining for p53 within a proportion of the tumor cell population. CONCLUSIONS: Although we have not been able to establish a causative link, we believe that the association of these 2 conditions has not occurred by chance. Biopsies of lesional skin from subjects with atopic eczema exhibit a proportion of CD30 cells, and clonal transformation of this subpopulation might account for the CD30(+) lymphomas in our patients.

Outcome in 34 patients with juvenile-onset mycosis fungoides: a clinical, immunophenotypic, and molecular study.

BACKGROUND: Mycosis fungoides (MF) is predominantly a disease of older patients, but occasionally occurs in children. The aims of the current study were to describe the clinical presentation, pathologic features, and disease progression (DP) in patients who developed MF before age 16 years. METHODS: A retrospective study was performed. Patients with juvenile-onset MF were identified from our databases. Clinical features were determined from the medical records and patient interviews. Histologic, immunohistochemical, and T-cell receptor (TCR) gene analysis was performed. RESULTS: Thirty-four patients were identified: 50% had Stage IA disease, 47% had Stage IB disease, and 3% had Stage IIA disease. The male-to-female ratio was 2:1. Clinical features included hypopigmented lesions (24%), poikiloderma (26%), pilotropic disease (9%), and disease associated with lymphomatoid papulosis (18%). Twenty-eight patients had diagnostic histology, and six patients were included on the basis of compatible histology and a TCR clone in lesional skin. A cytotoxic immunophenotype was observed in 38%, including 71% of patients with hypopigmented lesions. Overall disease-specific survival (DSS) rates at 5 and 10 years were 95% and 93%, respectively. DP rates were 5% at 5 years and 29% at 10 years. Subgroup analysis demonstrated improved DSS and reduced DP in patients with Stage IA disease, those with hypopigmented or poikilodermatous lesions, and those with associated lymphomatoid papulosis. CONCLUSIONS: The prognosis for juvenile-onset MF is similar to that of adult-onset disease. There was an overrepresentation of a cytotoxic phenotype, which was most marked in hypopigmented variants. Widespread cutaneous disease (Stage IB) indicated a less favorable outcome.

Lipoid proteinosis maps to 1q21 and is caused by mutations in the extracellular matrix protein 1 gene (ECM1).

Lipoid proteinosis (LP), also known as hyalinosis cutis et mucosae or Urbach-Wiethe disease (OMIM 247100) is a rare, autosomal recessive disorder typified by generalized thickening of skin, mucosae and certain viscera. Classical features include beaded eyelid papules and laryngeal infiltration leading to hoarseness. Histologically, there is widespread deposition of hyaline (glycoprotein) material and disruption/reduplication of basement membrane. The aetiology of LP is currently unknown. Using DNA from three affected siblings in a consanguineous Saudi Arabian family we performed genome-wide linkage and mapped the disorder to 1q21 (marker D1S498) with a two-point LOD score of 3.45 at theta = 0. A further 28 affected individuals from five other unrelated consanguineous family groups from different geographical regions also showed complete linkage and resulted in a maximum two-point LOD score of 21.85 at theta = 0. Using available markers in the interval between D1S442 and D1S305, the observed recombinants placed the gene in a 2.3 cM critical interval between D1S2344 and D1S2343 (Marshfield genetic map) corresponding to an approximately 6.5 Mb region on the UCSC physical map. Using a candidate gene approach (comparison of control versus LP gene expression in cultured fibroblasts) and subsequent direct sequencing of genomic DNA, we identified six different homozygous loss-of-function mutations in the extracellular matrix protein 1 gene (ECM1). Although the precise function of ECM1 is not known, our findings provide the first clinical indication of its relevance to skin adhesion, epidermal differentiation, wound healing, scarring, angiogenesis/angiopathy and basement membrane physiology, as well as defining the molecular basis of this inherited disorder.