Jean Thivolet

Comparative epidemiologic study of premalignant and malignant epithelial cutaneous lesions developing after kidney and heart transplantation

BACKGROUND Cutaneous carcinomas are the most frequent cancers in organ transplant recipients. OBJECTIVE Our purpose was to compare the epidemiologic data of cutaneous premalignant and malignant epithelial lesions in kidney and heart transplant recipients. METHODS A total of 580 kidney and 150 heart transplant recipients were examined for the presence of premalignant and malignant epithelial lesions. RESULTS A twofold increase in incidence of premalignant and malignant epithelial lesions was found in heart compared with kidney transplant recipients. Heart transplant recipients were older at transplantation, received more intense immunosuppressive treatment, and had a shorter delay from transplantation to the development of the first lesion. The squamous cell carcinoma/basal cell carcinoma ratio was 2.37:1 in kidney and 1.08:1 in heart transplant recipients. The extracephalic location represented 60% of the premalignant and malignant epithelial lesions in kidney and 30% in heart transplant recipients. CONCLUSION Cutaneous premalignant and malignant epithelial lesions in kidney and heart transplant recipients show epidemiologic differences that can tentatively be explained by the older age and the more intense immunosuppressive treatment of heart transplant recipients.

Long-term survival and immunological tolerance of human epidermal allografts produced in culture

Human epidermal cells from a small skin specimen can be grown in culture into multilayered sheets suitable for the permanent coverage of large burn wounds when used as epidermal autografts. We report here on the long-term survival of such cultured epidermal sheets used as epidermal allografts (EAG) across a major histocompatibility barrier in three nonimmunosuppressed adult patients, suffering from large chronic grafted leg ulcers, where the EAG have been placed to cover the conventional split-thickness skin autograft donor site. The absence of rejection was based upon clinical, histological, and immunopathological observation of the allografted sites at various intervals after grafting of the EAG. The identity of the epidermal cells on the grafted area with cultured cells from allogeneic donor was then established after blood substance typing by indirect immunofluorescence. Furthermore, epidermal cells from cultured sheets, but not control human cells from freshly excised normal epidermis, failed to stimulate the recipient peripheral blood cells in the mixed epidermal cell lymphocyte culture reaction, a finding that is related to the complete absence of class-II-antigen-bearing cells in cultured epidermis. This absence of T cell stimulation was noted not only on the day of grafting but throughout the follow-up. Altogether, these findings show that Langerhans cell and other class-II-antigen-bearing cell-depleted cultured epidermal allografts, are tolerated in unrelated recipients. EAG may serve as a skin substitute in patients with large wounds or burns. Since EAG may be grown continuously, the coverage of burns may not then be limited by the availability of the donor site, or by the time necessary to produce epidermal tissue in cultures.

Treatment of nine cases of pemphigus vulgaris with cyclosporine

The effects of cyclosporine were studied in nine patients suffering from pemphigus vulgaris. Of four patients treated with cyclosporine alone, only one cleared. Of four corticosteroid-resistant pemphigus vulgaris patients, all improved after cyclosporine addition to corticosteroids. The last patient treated from the beginning with a combined treatment (cyclosporine-corticosteroids) did not respond. The main advantage of using cyclosporine is to allow a decrease in corticosteroid dosages and to permit treating corticosteroid-resistant pemphigus vulgaris patients. No detectable irreversible side effects were noted. The treatment was discontinued in two patients because of reversible side effects. Cyclosporine alone does not seem to be an adequate treatment of the acute phase of pemphigus vulgaris but could be used in addition to corticosteroids. The most important drawback of cyclosporine treatment is the occurrence of clinically silent renal dysfunction (tubular involvement and interstitial fibrosis), which may occur during long-term treatments. More studies need to be carried out to determine the effects of low doses of cyclosporine on renal function in patients who have normal renal functions.

Skin Cancers in Organ Transplant Recipients

Skin cancers especially squamous cell carcinomas (SCC) are the most frequent malignancies in organ transplant recipients; they are often preceded by viral warts and solar keratoses and represent a model of viral carcinogenesis. They appear on sun-exposed areas, tend to be multiple and may have an aggressive course. Human papillomaviruses along with other co-carcinogenic factors such as ultraviolet radiation and immunosuppressive treatment seem to be involved in their development [1, 2].

Expression of neural-tissue markers (S-100 protein and Leu-7 antigen) by sweat gland tumors of the skin: An immunohistochemical study

The expression of two immunohistochemical markers of neural tissue and of cutaneous sweat glands (S-100 protein and Leu-7 antigen) was studied in a group of cutaneous epithelial, mostly glandular, tumors. These antigens were detected only on sweat gland neoplasms showing both types (eccrine and apocrine) of differentiation. These results suggest that antibodies to S-100 protein and to Leu-7 antigen have a limited value in the distinction between eccrine and apocrine tumours, but they may serve as a useful adjunct for the confirmation of the glandular differentiation of cutaneous epithelial tumors.

Langerhans Cells of Human Mucosa

The ontogeny of human LC and their presence in all Malpighian epithelia underline their important role in immunoregulation of the skin and mucous membranes.

Localized cutaneous cryptococcosis successfully treated with ketoconazole

A 27-year-old female recipient of a renal allograft, treated with systemic steroids and azathioprine, developed progressive cutaneous lesions (an ulcer, a nodule, and an abscess). Histopathologic and tissue-culture examination of the skin lesions led to the diagnosis of cutaneous cryptococcosis. A description of the light and electron microscopic features of the cutaneous lesions is reported. A thorough visceral investigation failed to detect systemic involvement. The patient was treated with oral ketoconazole (400 mg daily) for 6 months. A gradual healing of the lesions was obtained, and cultures performed 3 months after the onset of treatment failed to show Cryptococcus neoformans. No relapse or dissemination has so far been observed.

A surface glycoprotein complex related to the adhesive receptors of the VLA family, shared by epidermal Langerhans cells and basal keratinocytes.

A murine monoclonal antibody, designated K20, was raised by immunization with a human malignant T-cell line. It reacted specifically with membrane glycoprotein complexes on early haematopoietic cells, T cells, and monocytes. In epidermis, K20 specifically reacted with Langerhans cells and basal keratinocytes, as demonstrated by double labeling experiments. Membrane immunoprecipitation analysis demonstrated that the antigen identified by K20 on lymphoid cells and epidermal cells was different. While on lymphoid cells, K20 recognized glycoprotein complexes made of a constant 130-kD subunit associated with subunits of higher molecular weight ranging from 150 to 200 kD, a complex of 105-145 kD was precipitated from Langerhans and basal cells. Metabolic labeling studies demonstrated that these proteins were synthesized by the basal cells. The antigen identified by K20 was thought to belong to the integrins, a family of cell surface receptors that play a role in cell adhesion, cell interactions, wound healing, and immune defense mechanisms. K20 is the first monoclonal antibody that specifically recognizes a membrane antigen common to Langerhans and basal cells. Additionally, K20 is the first of five reported monoclonal antibodies to have been characterized on the epidermal cells that detect antigens shared by lymphoid subpopulations and normal basal keratinocytes.

A sequential study of histological and immunological changes in the skin after allogenic bone marrow transplantation.

Histological and immunopathological studies were performed on serial skin biopsies from thirteen recipients of aullogenic and two recipients of autologous bone marrow transplants. Marked dermoepidermal infiltration with Leu 2a+ (OKT8+) phenotype cells was found in two patients with severe graft-versus-host disease, but the infiltration did not precede clinical onset of the graft-versus-host disease. Absence of Langerhans cells was noted during the early posttransplant period in recipients of both allogenic and autologous transplantation. Intercellular epidermal staining with anti-DR was observed in three cases, without relation to graft versus-host disease.

Immunogold labeling of keratin filaments in normal human epidermal cells with two anti-keratin monoclonal antibodies.

We report on application of the highly sensitive and specific immunogold labeling method for ultrastructural investigation of keratin intermediate filament antigens in human epidermal cell suspensions. Triton X-100 pretreated cells proved accessible to the colloidal gold conjugate, thus enabling keratin filament bundles to be labeled. Anti-keratin KL1 and KL2 monoclonal antibodies were raised in mice after immunization with either human stratum corneum-isolated keratins or keratins extracted from human epidermal cells suspensions, respectively. Immunoelectron microscopy confirmed immunofluorescence and immunoperoxidase results of epidermal keratinocyte staining, and revealed two different antibody reactivity patterns: KL2 reacted with keratin filaments in keratinocytes of all epidermal layers, whereas antigen to KL1 was detected only on keratin of the suprabasal layers, not on the basal keratinocyte tonofilaments. The monoclonal antibody-recognized epitopes were specific for the keratin filaments. Vimentin-rich cells (melanocytes) were not stained in the same epidermal cell suspensions. Additionally, two distinct ultrastructural patterns of keratin filament epitope labeling were observed. KL1 and KL2 monoclonal antibodies react with two different antigenic determinants, depending on the stage of keratinocyte differentiation, and may therefore be used for immunohistochemical studies of various keratin-containing cells in normal and pathologic conditions.