Delay in diagnosis: trauma- and coinfection-related cutaneous leishmaniasis because of Leishmania guyanensis infection.

Trauma can trigger the onset of some lesions of cutaneous leishmaniasis (CL). In this study, we present the case of a 65-year-old man who developed persistent, ulcerative, nodular lymphangiitis at the site of elbow abrasions from a fall during a trip to northeastern Brazil. Skin and lymph node biopsy showed tuberculoid granulomatous inflammation and Grocott-methamine silver-positive yeast forms consistent with Sporothrix and Staphylococcus lugdunensis was identified from tissue culture. Antibacterial and antifungal treatment produced short-term healing. Crusted papules recurred at the sites of injury 3 months later and persisted despite therapy. After 15 months, two punch biopsies showed scarring and granulomatous inflammation; cultures and histochemical stains were negative for microorganisms. Because of refractory disease, multiple polymerase chain reaction (PCR) assays for infectious agents on DNA extracted from the biopsy specimens were performed, and Leishmania guyanensis was detected in all specimens. The patient refused pentavalent antimonial therapy and elected for excision of the CL lesions. After 2 years of follow up, he is without disease. CL should be considered in the differential diagnosis in patients who present with ulcerative, nodular lymphangiitis; have a history of travel to endemic regions; and describe a traumatic insult to the affected region. PCR methods for infectious agents increase the sensitivity and specificity of detecting causative agents in these patients who are negative by routine methods. In some, leishmaniasis may be an occult infection whose presence is heralded by trauma. Coinfection, by altering the immune response, may have facilitated the clinical acquisition of CL.

Varicella-zoster-virus folliculitis promoted clonal cutaneous lymphoid hyperplasia.

Post herpes zoster (HZ) reactions have been associated with panoply of neoplastic, inflammatory, and fibro-inflammatory cutaneous disorders. Varicella zoster virus (VZV) DNA has not been identified in most of these reports. After an episode of HZ, a healthy, active 90-year-old female developed ulcerative nodules in the affected trigeminal V1 dermatome and the contra-lateral trigeminal region over a 1-year period. Excision and/or biopsy of all these lesions showed similar pathologic changes that consisted of herpetic folliculitis, adjacent dense mixed nodular lymphocytic infiltrates with germinal centers (cutaneous lymphoid hyperplasia (CLH)), and in the deeper excision specimens, an obliterative vasculitis of a vessel with smooth muscle in its wall. Immunophenotype analysis revealed a mixed, predominate T- and B-cell population without loss of pan-T cell antigens or aberrant expression by B cells of T-cell antigens. Polymerase chain reaction for herpetic DNA was positive for VZV DNA. Lymphocyte gene rearrangement analysis revealed 2 distinct, anatomically and chronologically, monoclonal B-cell populations and a monoclonal T-cell population in one nodule. Treatment with valacyclovir has lead to almost complete resolution of her cutaneous nodules after 6 months of therapy. In this case, it can be surmised that persistence of VZV infection and lack of effective cell-mediated immunity lead to development of both immunopathology (vasculitis) and excessive lymphoid cell proliferation (CLH).

Adhesion control of cyclin D1 and p27Kip1 levels is deregulated in melanoma cells through BRAF-MEK-ERK signaling.

Mutations in BRAF, a component of extracellular signal-regulated kinases 1 and 2 (ERK) cascade, are frequent in melanoma. It is important to understand how BRAF mutations contribute to malignant traits including anchorage- and growth factor-independence. We have previously shown that efficient activation of ERK in normal human epidermal melanocytes (NHEM) requires both adhesion to the extracellular matrix and growth factors. Mutant V599E BRAF is sufficient to promote ERK activation independent of adhesion and growth factors. Here, we analysed regulation of G1 cell cycle events in NHEM and human melanoma cells. We show that S phase entry in NHEM requires both adhesion and growth factor signaling through the MEK-ERK pathway. This control correlates with induction of cyclin D1 and downregulation of p27Kip1, two key G1 cell cycle events. In melanoma cells expressing V599E BRAF, cyclin D1 was constitutively expressed independent of adhesion but dependent upon MEK activation and nuclear accumulation of ERK. Reduction of cyclin D1 levels by RNA interference inhibited S phase entry in melanoma cells. Importantly, expression of V599E BRAF in NHEM was sufficient to promote cyclin D1 promoter activity in the absence of adhesion. Additionally, p27Kip1 levels were downregulated in V599E BRAF-expressing melanoma cells and active BRAF was sufficient to downregulate p27Kip1 in serum-starved NHEM. Thus, adhesion-growth factor cooperation, leading to efficient activation of ERK, regulates cyclin D1 and p27Kip1 levels in human melanocytes and mutant BRAF overrides adhesion-growth factor control of these two G1 cell cycle proteins in melanomas. These findings provide important insight into how BRAF mutations contribute to aberrant human melanocyte proliferation.