Javier Fraga

Identification of Genes Involved in Resistance to Interferon-α in Cutaneous T-Cell Lymphoma

Interferon-α therapy has been shown to be active in the treatment of mycosis fungoides although the individual response to this therapy is unpredictable and dependent on essentially unknown factors. In an effort to better understand the molecular mechanisms of interferon-α resistance we have developed an interferon-α resistant variant from a sensitive cutaneous T-cell lymphoma cell line. We have performed expression analysis to detect genes differentially expressed between both variants using a cDNA microarray including 6386 cancer-implicated genes. The experiments showed that resistance to interferon-α is consistently associated with changes in the expression of a set of 39 genes, involved in signal transduction, apoptosis, transcription regulation, and cell growth. Additional studies performed confirm that STAT1 and STAT3 expression and interferon-α induction and activation are not altered between both variants. The gene MAL, highly overexpressed by resistant cells, was also found to be expressed by tumoral cells in a series of cutaneous T-cell lymphoma patients treated with interferon-α and/or photochemotherapy. MAL expression was associated with longer time to complete remission. Time-course experiments of the sensitive and resistant cells showed a differential expression of a subset of genes involved in interferon-response (1 to 4 hours), cell growth and apoptosis (24 to 48 hours.), and signal transduction.

Leishmaniasis presenting as a dermatomyositis-like eruption in AIDS.

Three patients are described with leishmaniasis and AIDS, with cutaneous lesions mimicking dermatomyositis. Leishmania organisms were observed in great numbers in the dermis of lesional skin biopsy specimens. They were also present inside keratinocytes in all layers of the epidermis in one patient. Skin cultures from all patients and bone marrow culture in patients 1 and 3 revealed Leishmania infantum. Leishmania organisms were also found in nonlesional skin. The absence of proximal symmetric muscle weakness, elevated muscle enzymes, myopathic electromyograms, or characteristic histopathologic and immunologic features of dermatomyositis, and the rapid and complete clearance or marked improvement of the cutaneous lesions after treatment for leishmaniasis, make us consider true dermatomyositis unlikely. We suggest that leishmaniasis be included in the list of diseases capable of inducing a dermatomyositis-like eruption.

Giant cell lichenoid dermatitis within herpes zoster scars in a bone marrow recipient

Cutaneous lesions arising in herpes zoster (HZ) scars are rare. We report a 34‐year‐old woman with acute lymphoblastic leukemia underwent allogenic bone marrow transplant (BMT). Ten days after the BMT, she developed clusters of vesicles over the right neck, scapula, shoulder and chest. She was treated with intravenous acyclovir and foscarnet. One month after the vesiculous episode of HZ she showed 5 mm to 2 cm clustered flat violaceous lichenoid papules and confluent plaques within the HZ scars. Histopathologic examination revealed a inflammatory infiltrate present in the papillary dermis with granulomatous agregated formed by histiocytes, multinucleated giant cells and lymphocytes. She was treated with topic steroids with significant improvement. Pathologic findings are similar to those of an unusual lichenoid reaction named “giant cell lichenoid dermatitis”. We present the first reported case of giant cell lichenoid dermatitis at the sites of HZ scars.

Superficial mucoceles and lichenoid graft versus host disease: report of three cases.

Superficial mucoceles are subepithelial extravasations of sialomucin that occur at the epithelial-connective tissue interface and are directly related to minor salivary glands. They have been described in association with oral lichen planus and, exceptionally, with chronic graft versus host disease. Three patients who underwent an allogeneic bone marrow transplantation for a chronic myelogenous leukaemia presented multiple superficial mucoceles and an oral lichenoid graft versus host disease.

Herpetic syringitis associated with eccrine squamous syringometaplasia in HIV‐positive patients

Herpetic syringitis has been described as a rare manifestation of herpes virus infection in patients with an immunodeficiency, usually secondary to human immunodeficiency virus (HIV) infection. Eccrine squamous syringometaplasia (ESS) is an infrequent alteration of the eccrine duct epithelium reported in association with several conditions, including chronic ulcers, inflammatory processes, and patients receiving chemotherapy. The association of herpetic syringitis with ESS has not been reported before. We identified 3 cases of herpetic syringitis associated with ESS in patients with the acquired immunodeficiency syndrome. In 2 of 3 cases the signs of herpetic syringitis were limited to the meta‐plastic duct epithelium, but in 1 case there were also herpetic alterations without ESS.

Dermal infiltrate of enlarged macrophages in patients receiving chemotherapy

A histologically distinct maculopapular eruption has heen associated with the use of recombinant forms of granulocyte and gran‐ulocytte‐inacrophage colony‐stimulating factors (GCSF and GMCSF). One of the most distinctive features was an increase in the number and the size of dermal maerophages, which was proposed as a clue to diagnosis of these cytokine‐induced dermatoses.

Lichen sclerosus et atrophicus in sclerodermatous chronic graft-versus-host disease

In May 1994, a 40‐year‐old woman with chronic myeloid leukemia received an allogeneic bone marrow transplant (BMT) from her human leukocyte antigen (HLA) identical sister, after a conditioning regimen with cyclophosphamide and busulfan. Graft‐versus‐host disease (GVHD) prophylaxis consisted of cyclosporine (CsA) and methotrexate. Facial and palmoplantar erythema and moderate cholestasis developed on day 14 after the BMT. A diagnosis of acute GVHD was made and she was successfully treated with low doses of corticosteroids. On day 150 after the BMT, despite the prophylactic treatment of GVHD with CsA (150u2003mg/12u2003h), she developed several burning white plaque‐like striae over the buccal mucosa and numerous itching violaceous lichenoid papules on the fingertips. Biopsy specimens obtained from both the skin of the fingertips and the oral mucosa ( Fig.u20031 ) revealed patchy to diffuse subepithelial lymphocytic inflammation and necrosis of individual squamous cells, consistent with a diagnosis of chronic lichenoid GVHD. Despite therapy with CsA, topical and systemic corticosteroids (prednisone 60u2003mg/24u2003h), the oral lichenoid lesions persisted. On day 750 after the BMT, 2u2003months after withdrawal of immunosuppressive therapy, she developed several erythematous, pruriginous, and slight indurated lesions over the neck. These lesions coalesced into plaques, adopting a white atrophic‐like appearance with follicular plugs similar to lichen sclerosus et atrophicus ( Fig.u20032 ). Histopathologic examination showed hyperkeratosis with follicular plugging, atrophy of the stratum Malpighii with hydropic degeneration of the basal cells, homogenization of the collagen, incontinence of the pigment, and a discrete lymphoplasmocytic inflammatory infiltrate in the upper dermis ( Fig.u20033 ). Systemic corticosteroid therapy was re‐introduced. On day 850 after the BMT, physical examination revealed patchy hyperpigmentation affecting the back and limbs, and diffuse thickening and hardening of the skin of the legs, forearms, and dorsa of the hands, resulting in

Cutaneous metaplastic synovial cyst in an Ehlers-Danlos patient

Metaplastic synovial cyst is a recently reorganized entity characterized by a cystic space lined by polygonal cells and villous structures resembling synovium pointing toward the lumen. It usually develops following trauma. We report a 15-year-old girl with Ehlers-Danlos syndrome who developed a nodular lesion of her elbow without previous trauma. Histopathological and immunohistochemical studies yielded results similar to those reported in cases of cutaneous metaplastic synovial cyst. This case appears to be the first one reported of cutaneous metaplastic synovial cyst associated with an Ehlers-Danlos syndrome. Cutaneous fragility and anomalous scarring typical of Ehlers-Danlos syndrome may be related to the development of this pseudocyst. If so, other connective-tissue diseases with increased skin fragility could be susceptible to development of such lesions.

CUTANEOUS ALTERNARIOSIS DUE TO ALTERNARIA CHLAMYDOSPORA AFTER BONE MARROW TRANSPLANTATION

In June 1994, a 33-year-old man was diagnosed with chronic myelogenous leukaemia. In November 1995, he underwent an allogeneic BMT from an unrelated donor. Three months later, a slightly itchy erythematous papule appeared on his left leg. During the following days, 2 similar lesions developed on his left thigh and right arm (Fig. 1). The lesions increased a little in size and the centre of the lesions became necrotic and ulcerated. A biopsy specimen was obtained from the left leg and showed epidermal hyperplasia with discrete parakeratosis. In the reticular dermis a mixed acute and chronic interstitial, in£ammatory in¢ltrate was observed with several foci of necrosis. These areas of necrosis contained multiple branching septate hyphae, which formed acute angles, and multiple round and oval spores, both of which stained heavily with periodic acid-Schi¡ (PAS) and Gomori-Grocott stain. Some of the fungal elements invaded the vessel walls. In the subcutaneous tissue several foci of ¢brosis with similar fungal structures were present. A biopsy culture was performed on Sabouraud agar with chloramphenicol and was identi¢ed as A. chlamydospora (colonies growing rapidly, olivaceous-black, £u¡y conidiophores up to 150 mm long, 3 ^ 6 mm wide, pale brown). No alterations were found on the rays of the chest and paranasal sinuses. The patient was treated intravenously with amphotericin B at a dose of 1 mg/kg/day for 4 days, followed by a lipidic complex of amphotericin B (Abelcet1) for another 18 days at a dose of 5 mg/kg/day, with complete resolution of the lesions.

Epidermodysplasia verruciformis-like lesions in a patient with systemic lupus erythematosus

Sir, Epidermodysplasia verruciformis (EV) is a rare, frequently familial disease, caused by chronic infection with human papillomavirus (HPV). EV is characterized by numerous flat warts and red and brownish macules, which sometimes strongly resemble pityriasis versicolor. A high percentage of these lesions develop into squamous cell carcinomas. Lesions similar to those present in EV have been clinically and histologically reported in patients with immunosuppression. We present here a patient with systemic lupus erythematosus (SLE) and EV-like lesions associated with HPV-17 and HPV-20.