Hyperkeratosis lenticularis perstans (Flegel's disease). In situ characterization of T cell subsets and Langerhans' cells

We report a patient with hyperkeratosis lenticularis perstans (HLP) manifesting as multiple reddish-brown hyperkeratotic papules on the lower extremities. Typical histologic features of HLP include hyperkeratosis, thinning or absence of the granular layer and a band-like infiltrate in the upper dermis underlying an atrophic epidermis. In order to determine the cellular composition of the infiltrate, skin biopsy specimens were studied immunohistochemically using a series of commercially available monoclonal antibodies. The dermal infiltrate consists predominantly of helper/inducer T cells (Leu-4+, Leu-3a+). Suppressor/cytotoxic T cells (Leu-2a+) were fewer at the periphery of the infiltrate. The majority of T cells were activated as they expressed HLA-DR-antigen. Large numbers of Leu-6+ Langerhans' cells were observed at the dermo-epidermal interface. Few natural killer cells (Leu-11b+) were noted within the dermal infiltrate. These findings support the hypothesis than an active cellular immune reaction involving the epidermis is of pathogenic importance for HLP.     

Immunohistologic studies in Schamberg's disease. Evidence for cellular immune reaction in lesional skin

We studied eight cases of Schamberg's disease immunohistologically by using monoclonal antibodies. The dermal infiltrate was composed of Leu-1-reactive T cells, OKT6-reactive Langerhans' cells, and Leu-M5-reactive (Leu-M5+) macrophages. Among them, the major population consisted of T cells with the predominance of Leu-3a-reactive (Leu-3a+) T cells over Leu-2a-reactive (Leu-2a+) T cells. On the other hand, the epidermotropic mononuclear cells consisted of Leu-2a+ and Leu-3a+ T cells without any predominant pattern, and Leu-M5+ macrophages. Furthermore, note that a pemphiguslike intercellular staining pattern was observed in the epidermis in most of the cases, when the sections were stained either with anti-HLA-DR antibody or with OKT6, suggesting the HLA-DR antigen expression on the keratinocyte surface and possibly an enlargement of Langerhans' cells. Based on these immunohistologic findings, we think that Langerhans' cells play an important role in the pathomechanism of Schamberg's disease, and that cellular immune reactions are taking place in the lesional skin.     

Interstitial mycosis fungoides, a variant of mycosis fungoides resembling granuloma annulare and inflammatory morphea

BACKGROUND: Interstitial mycosis fungoides (IMF) is a rare variant of mycosis fungoides that resembles the interstitial form of granuloma annulare and inflammatory morphea. IMF has received little attention in the literature. METHODS: Clinical, histological, immunophenotypical, and genotypical findings of five cases of IMF were reviewed. The histological and immunophenotypical findings were compared with those of eight cases of interstitial granuloma annulare and six cases of inflammatory morphea. RESULTS: Five patients with IMF presented with non-indurated, erythematous macules; ill-defined erythematous plaques with slight scale; and nodules on the trunk and proximal limbs. Two of five patients had a prior diagnosis of mycosis fungoides. Skin biopsies revealed a striking dermal interstitial infiltrate of lymphocytes with rare histiocytes that resembled the interstitial form of granuloma annulare or inflammatory morphea. Epidermotropic lymphocytes were present at least focally in all cases. A band-like lymphocytic infiltrate was observed in two of five cases. In contrast, many plasma cells and histiocytes were observed in cases of inflammatory morphea and interstitial granuloma annulare, respectively. With Movat-pentachrome stains, increased dermal mucin deposition was observed in two of five IMF cases, in all cases of interstitial granuloma annulare, and in one of six cases of inflammatory morphea. There was focal loss of elastic fibers in all cases of inflammatory morphea. Immunohistochemical studies of IMF highlighted a dominant population of T cells (CD3+) in the dermis and epidermis. In contrast, moderate numbers of B cells (CD20+) were admixed with T cells and plasma cells in inflammatory morphea. Almost equal numbers of histiocytes (CD68+) and T cells comprised the infiltrate of interstitial granuloma annulare. In two of five IMF cases, a clonal T-cell population was detected by PCR T-cell gamma gene rearrangement analysis. CONCLUSION: Mycosis fungoides occasionally presents as an interstitial lymphocytic infiltrate that mimics granuloma annulare and inflammatory morphea. Hematoxylin & eosin (H&E) findings alone can sometimes distinguish the three disorders. Immunophenotyping and genotyping may be helpful in difficult cases.     

Identification of T-cell subpopulations in granuloma annulare

Granuloma annulare is a lymphohistiocytic process of unknown cause characterized by necrobiotic dermal papules. Acetone-fixed frozen sections of eight granuloma annulare lesions were studied for the presence of T-cell subsets, using monoclonal antibodies to T-cell surface antigens. The palisading and perivascular lymphocytic infiltrate shows that most of the mononuclear cells are reactive with LEU-1 antibody, which characterizes peripheral T cells and activated T cells. Numerous cells were reactive with LEU-3a antibody, which identifies the helper-inducer T-cell subset. Some cells were positive with LEU-2a antibody, which detects suppressor-cytotoxic cell populations. Masses of histiocytes were identified infiltrating between the collagen fibers and surrounding the central necrobiosis area; the histiocytes showed a very strong diffuse acid phosphatase and nonspecific esterase activity. These findings suggest that a cell-mediated immune response may be the dominant pathogenic event in granuloma annulare.     

Oral lichen planus: an immunoperoxidase study using monoclonal antibodies to lymphocyte subsets

Sixteen biopsies from patients with oral lichen planus (10), simple keratosis (3) and lichenoid reactions (3) were studied using monoclonal antibodies directed against lymphocyte markers. T lymphocytes predominated in the cellular infiltrates of the epithelium and lamina propria of all biopsies, and cells positive with Leu 3a and Leu 2a antibodies were also present at both sites in all specimens. However, many of the Leu 3a positive intraepithelial cells had a dendritic appearance and distribution consistent with their being Langerhans cells. Limited results from cell counts on three lichen planus specimens suggested that the majority of intraepithelial T cells were of the cytotoxic/suppressor phenotype (OKT3 and Leu 2a positive).     

Actinic reticuloid: immunohistochemical analysis of the cutaneous infiltrate in 13 patients

An immunohistological study on cryostat sections of skin biopsies in 13 patients with actinic reticuloid has been performed using a panel of 21 monoclonal antibodies against lymphoid and non-lymphoid infiltrate cells. The infiltrate consisted of activated T cells, numerous histiocytes and macrophages, and small numbers of B cells. In 10 out of 13 patients the majority of the lymphocytes expressed the phenotype of suppressor cells. The number of Leu 8+ cells was inversely proportional to HLA-DR expression by the dermal infiltrate, which suggested a negative correlation between a state of activation and the concentration of Leu 8+ cells. There was a striking number of IgE bearing dendritic cells in the dermis associated with elevated serum IgE levels.     

单克隆抗体对异位性皮炎损害内浸润细胞免疫荧光表现型的鉴定

应用冰冻切片下间接免疫荧光技术及针对总T细胞、T辅助/诱导细胞及T抑制/杀伤细胞的单克隆抗体,对一例异位性皮炎皮损的浸润细胞进行组织内免疫荧光表现型鉴定.结果表明,该例异位性皮炎损害内的浸润细胞,大部份有T辅助细胞的表面标志.     

Parapsoriasis en plaques. Characterization of the cellular infiltrate using monoclonal antibodies

We report on a 65-year old woman suffering from parapsoriasis with large plaques. The cellular infiltrate was analysed by means of monoclonal antibodies and an immunoperoxidase technique. Our findings proved that the majority of the cellular infiltrate in the upper dermis is composed of helper-inducer T-cells (Leu 4+, Leu 3a+). A notable number of Leu-2a-reactive suppressor-cytotoxic T-cells associated with hydropic degeneration of the basal cell layer were found within the dermal infiltrate and the dermoepidermal interface. Large numbers of Leu-6-reactive dendritic Langerhans' cells were noted in the lower layers of the epidermis, in particular in areas where the epidermis showed focal exocytosis of lymphoid cells. Langerhans' cells, in contrast, were present in the upper portions of epidermis lacking exocytic T-cells. HLA-DR antigens were expressed on Langerhans' cells as well as on nearly all T-lymphocytes. Positive intercellular staining for HLA-DR antigens were only found in localized areas of the epidermis. Small numbers of both Leu-11B-reactive natural killer cells and cells expressing interleukin-2 receptors were seen within the basal cell layer and at the dermo-epidermal junction. Our findings suggest that a cell-mediated immune response which is directed against antigens expressed by keratinocytes may play an important role in the pathogenesis of parapsoriasis en plaques.     

Perforating granuloma annulare in a patient with acquired immunodeficiency syndrome. Immunohistologic evaluation of the cellular infiltrate

The inflammatory infiltrate found in the lesions of perforating granuloma annulare in a patient with acquired immunodeficiency syndrome was analyzed. Double labeling with fluorescent antibody tags fluorescein isothiocyanate-Leu 4 (peripheral T cells) and phycoerythrin-Leu 2a (cytotoxic/suppressor) revealed the infiltrate to consist predominantly of cytotoxic/suppressor T cells. This finding is a reflection of the patient's altered immune status and calls into question the role of specific T-cell subsets in the pathogenesis of granuloma annulare.     

Acute disseminated histiocytosis-X: in situ immunophenotyping with monoclonal antibodies

The proliferating skin cells in a case of acute disseminated histiocytosis-X (Abt-Letterer-Siwe disease) confirmed by electron microscopy, were characterized by a panel of monoclonal antibodies using an immunoperoxidase technique. The "histiocytes" were found to stain with OKT-6 (anti-T6) and anti-HLA-DR antibodies. Unexpectedly, slight staining was also observed with Leu 3a (anti-T4) and OKM-1. A proliferative process of T4, T6, HLA-DR, OKM-1 positive Langerhans' cells has not yet been described and may be specific for histiocytosis-X.     

Epidermal dendritic S100 positive cells in necrobiosis lipoidica and granuloma annulare

Using an antibody to S100 protein, the number of dendritic cells above the basal layer in the epidermis was assessed in necrobiosis lipoidica and granuloma annulare. A statistically significantly higher number of these cells was found within the epidermis in necrobiosis lipoidica compared with granuloma annulare and normal skin. The numbers were similar to those seen in sarcoidosis and tuberculous reactions in the skin, which raises the possibility of an immune pathogenesis for necrobiosis lipoidica.     

Interstitial granulomatous lesions as part of the spectrum of presenting cutaneous signs in pediatric sarcoidosis

Abstract:  Skin findings in childhood sarcoidosis vary greatly, but only a few occurrences have been published in which the histopathology has been characterized well. We describe a child with sarcoidosis in whom the cutaneous findings were atypical, resembling granuloma annulare. Histologic examination of these cutaneous lesions, however, revealed areas of sarcoid-like epithelioid cell granulomas, a palisading granulomatous process with features of granuloma annulare, as well as palisading neutrophilic and granulomatous dermatitis and interstitial granulomatous dermatitis. This underscores the variability of skin findings in childhood sarcoidosis—even within the same patient—and suggests that sarcoidosis should be considered in the differential diagnosis of children initially diagnosed with granulomatous skin lesions, such as granuloma annulare, palisading neutrophilic, and granulomatous dermatitis or interstitial granulomatous dermatitis, who demonstrate associated signs of systemic disease.     

Rod-shaped bodies resembling birbeck granule-like structures in endothelial cells of dermal capillaries in generalized granuloma annulare

A previous study demonstrated that, in generalized granuloma annulare in the epidermis, the Langerhans' cell section area and the number of Langerhans' cell granules or Birbeck granules per cell section were increased, suggesting an active state of these Langerhans' cells. Reexamination by transmission electron microscopy of the same tissue, but in samples also containing dermal tissue, from the same subjects revealed endothelial cells with rod-shaped bodies resembling Birbeck granules or Birbeck granule-like structures. This finding has not been previously described in blood vessels of human skin and is described here.     

Granuloma annulare: An immunohistochemical study

The monocyte/histiocytic response in granuloma annulare has not been extensively studied. We studied the immunohistochemical staining pattern in granuloma annulare by using a panel of markers for "histiocytic" cells including Ham 56, KP1, factor XIIIa, Mac 387, vimentin, and lysozyme. The infiltrate failed to stain with the histiocytic markers, except with antibodies against vimentin and lysozyme. Commonly used histiocytic markers for infectious, immunogenic, and foreign body granulomas fail to stain the infiltrate in granuloma annulare. We hypothesize that a locally derived, immunologically distinct population of histiocytes produces the reaction pattern of granuloma annulare.     

Biochemical and immunohistochemical comparison of collagen in granuloma annulare and skin sarcoidosis

Collagen was studied by biochemical and immunohistochemical means in 5 patients with granuloma annulare (GA) and 3 with cutaneous sarcoidosis (SA). The solubility of collagen from the lesional skin in acetic acid was higher than that of collagen from unaffected skin from both patients and control subjects. Collagen concentration in the skin lesions, measured in terms of hydroxyproline content, was reduced in 3 patients with granuloma annulare and one with sarcoidosis, but the ratio of type III/I collagen was unchanged vis-à-vis non-affected skin. The collagen concentration in non-affected skin of both GA and SA-patients was also lower than in controls. The most typical immunohistochemical finding was the association of type III procollagen and fibronectin with granulomas in the lesional skin of both GA and SA cases. The activity of prolyl hydroxylase, a key enzyme in collagen biosynthesis, was markedly increased in the lesional skin, indicating that collagen synthesis in vivo was also increased. Surprisingly, collagen synthesis was not increased in cell culture studies. This could be due to cell selection as observed previously in scleroderma. Another possibility could be that various mediators released in vivo from inflammatory cells activate fibroblasts. However, when cells are subcultivated, this effect is not maintained. In conclusion, marked changes in collagen could be observed in granuloma annulare and skin sarcoidosis, reflecting increased turnover of collagen in vivo.     

Association of Generalized Granuloma Annulare with Autoantibodies

Granuloma annulare is a degenerative disease of the skin histopathologically characterized by focal degeneration of collagen with a surrounding infiltrate of lymphoid cells, histiocytic cells, and multinucleated giant cells. Immunological abnormalities such as delayed-type hypersensitivity and vasculitic origin are suspected in the pathogenesis. We describe three patients with generalized granuloma annulare, in whom autoantibodies, including antinuclear antibody, antithyroid stimulating hormone receptor antibody, and immune complex, were detected.     

Localization of angiotensin converting enzyme (ACE) in granulomas of sarcoidosis cutaneous lesions

Using an immunofluorescent technique, the localization of angiotensin converting enzyme (ACE) was investigated in granuloma lesions from the skin of three sarcoidosis cases. Specific fluorescence was observed in epithelioid cells in the sarcoidosis granulomas examined. However, it was not found in any other granulomatous diseases observed as controls, which included granuloma annulare, foreign body granuloma and lupus miliaris disseminatus faciei. These results indicate that ACE is specifically localized in the epithelioid cells in cutaneous granuloma lesions of sarcoidosis; in one case, it was also observed in Langhans giant cells. Therefore, it is suggested that examination for ACE in cutaneous lesions using an immunofluorescent technique is very useful for the diagnosis of sarcoidosis in the skin. We suggest that epithelioid cells of granulomas in sarcoidosis cutaneous lesions may play an important role in the increase of serum ACE activity.     

Actinic granuloma. A clinical, histopathologic, and immunocytochemical study

Two cases of actinic granuloma are described with emphasis on distinctive clinical and histopathologic features, including immunoperoxidase staining for lysozyme and immunophenotyping of mononuclear leukocytes. Actinic granuloma presents in chronically sun-damaged skin as normally colored to erythematous papules that coalesce to form centrifugally enlarging annular patterns. By light microscopy, a granulomatous infiltrate of giant cells and histiocytes is seen to be intimately related to the presence of elastotic fibers in the upper dermis. Selective localization of lysozyme in the giant cells of the granuloma is apparent by a tertiary antibody immunoperoxidase technique. Determination of mononuclear leukocyte subsets with monoclonal antibodies reveals a predominance of helper T cells in the lymphocytic infiltrate associated with the granuloma. It is postulated that actinic granuloma represents a cell-mediated immune response to weakly antigenic determinants on actinically altered elastotic fibers.     

Elastic tissue changes in generalized granuloma annulare

The histological picture in granuloma annulare (GA) is well defined. The types of infiltrate and the changes in collagen and elastic tissue have been repeatedly described. This is a preliminary study focused on the elastic tissue changes in lesions of generalized GA. Biopsies from four patients were studied. Specimens of involved and uninvolved skin from both exposed and unexposed parts of the body were compared. Changes of actinic elastosis in the papillary dermis in each patient in different stages were observed only in the exposed skin. The typical GA infiltrate was located beneath, in the upper mid-dermis. In the zone of the infiltrate in all specimens--exposed and unexposed--with no regard to the severity of actinic elastotic changes, absence or a marked reduction of elastic material was noted with engulfment of elastic remnants in giant cells. Giant cells with phagocytosis of elastotic material were mostly located on the periphery of the granuloma in the upper as well as in the deeper portion, where elastic fibers were still present. This might support the suggestion that degenerating elastic fibers promote the granulomatous reaction that leads to the formation of granuloma annulare.     

Clonality in sarcoidosis, granuloma annulare, and granulomatous mycosis fungoides

The histological discrimination of granulomatous cutaneous T-cell lymphomas (CTCLs) from reactive granulomatous disorders such as sarcoidosis and granuloma annulare (GA) may be difficult due to overlapping histological features. We analyzed the T-cell receptor gene rearrangement in sarcoidosis and GA to investigate the value of the detection of clonal T cells as an adjunctive diagnostic marker in the differentiation between sarcoidosis and GA versus granulomatous CTCLs. Rearrangement of T-cell receptor γ genes was examined by the use of automated high-resolution polymerase chain reaction fragment analysis in 35 cases of sarcoidosis and 15 cases of GA and compared with a series of 19 cases of granulomatous CTCLs. A monoclonal T-cell population was found in none of the cases of sarcoidosis and in 2 of 15 cases of GA (13%). In granulomatous CTCLs, a neoplastic T-cell clone was detected in 94%. Presence of clonal T cells argues in favour of a granulomatous CTCL, while a polyclonal T-cell population makes the presence of a sarcoidosis or a GA more likely. The analysis of T-cell clonality is a useful diagnostic adjunct in the differentiation between sarcoidosis and GA from granulomatous CTCLs.