David P. Fivenson

Treatment of pemphigus and linear IgA dermatosis with nicotinamide and tetracycline: A review of 13 cases

Pemphigus usually requires long-term therapy with oral corticosteroids, which can cause significant morbidity. 1, 2 Several immunomodulating drugs, such as cyclophosphamide, azathioprine, and gold have proved beneficial as steroid-sparing agents.3, 4 However, these agents also have limited long-term utility because of their potential to induce renal and hepatic dysfunction and bone marrow suppression. Nicotinamide in combination with tetracycline has been reported to be effective for bullous pemphigoid (BP) and linear IgA bullous dermatosis (LABD),S,6 This regimen has the advantage of lower toxicity compared with corticosteroids and immunosuppressant regimens. We have treated 11 cases of pemphigus and two cases of LABD with nicotinamide and tetracycline and report our experience,

p53 and apoptosis alterations in keloids and keloid fibroblasts

Keloids are the result of a dysregulated wound‐healing process and are characterized by formation of excess scar tissue that proliferates beyond the boundaries of the inciting wound. In this study, we investigated the expression of key proteins involved in regulating apoptosis in keloids. Twenty archival paraffin‐embedded keloid samples were randomly selected for an immunoperoxidase assay with antibodies against fas, p53, bcl‐2, and bcl‐x proteins using the target antigen‐retrieval technique. Apoptosis was assessed in keloids and normal skin and in keloid and normal fibroblasts by the TdT‐mediated dUTP nick‐end labeling (tunel) assay on tissue sections, fibroblast cultures, and by flow cytometry for cell suspensions. We found that 18 of 20 keloids expressed p53 protein; bcl‐2 was expressed by keloid fibroblasts in 19 of 20 keloids, and all specimens had prominent fas expression throughout the tissue. The distribution of these three antigens was regional within each lesion and followed a consistent pattern of p53 and bcl‐2 expression colocalized to the hypercellular, peripheral areas of each keloid in a perinuclear pattern (p < .001). In contrast, an inverse distribution of fas expression was shown, with staining being more diffuse across the cell surfaces and limited to the central, more hypocellular regions in 16 of 17 keloids (p < .001). There was no specific staining pattern in these keloids with antihuman bcl‐x. In vitro studies on cultured keloid fibroblasts (derived from six patients) revealed maintenance of the p53+, bcl‐2+ phenotype up to passage 10. Neither neonatal nor normal adult skin fibroblasts expressed either antigen but could be induced to express p53 by exposure to adriamycin. Keloid lesions and keloid fibroblasts were found to have lower rates of apoptosis than normal controls. Keloid fibroblasts displayed enhanced apoptosis rates in response to hydrocortisone, γ interferon and hypoxia treatment as compared with normal adult fibroblasts. Focal dysregulation of p53 combined with upregulation of bcl‐2 may help produce a combination of increased cell proliferation and decreased cell death in the younger hypercellular areas of the keloid. This phenotype is reversed in the older areas of the keloid and may prevent malignan degeneration, thus favoring normal apoptosis as evidenced by prominent fas expression.

Differential expression of factor XIIIa and CD34 in cutaneous mesenchymal tumors

The histogenetic relationship amongst various dendritic cells of the dermis which may express markers including factor XIIIa (FXIIIa) or CD34 remains unclear. In this study we utilized a sensitive indirect immunoperoxidase staining technique to identify CD34 and FXIIIa, as well the monocyte/macrophage markers KP‐1 and MAC 387 expression in a variety of cutaneous dermal tumors of mesenchymal origin to see if differentia] expression of CD34 vs FXIIIa exists. Tumors studied included dermatofibroma (DF) (N = 10), keloid (N=9), atypical fibroxanthoma (AFX) (N = 3), and dermatofibrosarcoma protuberans (DFSP) (N = 7). DF were all composed of FXIIIa + spindle‐shaped and stellate tumor cells (mean score = 4.9 or ≥ 75% FXIIIa +) as previously reported, but these cells rarely (< 10%) expressed CD34. Six of 7 DFSP were found to be > 75% CD34+ and FXIIIa negative, while one DFSP was negative for both CD34 and FXIIIa. In all DFSP, there were trapped FXIIIa+ cells which were distinct from the spindle‐shaped tumor cells. AFX showed sparse populations of FXIIIa + cells in the stroma (mean score = 1.33 or 10–25% positive), which were distinct from the atypical giant cells characteristic of these tumors. Keloid similarly contained trapped FXIIIa+ cells (mean score = 0.44 or < 5% positive) that were distinct from the spindle‐shaped fibroblasts of the tumor mass. Dendritic and spindle‐shaped cells within these tumors were consistently both KP‐1 and Mac‐387 negative, while all lesions studied were characterized by scattered round, histiocytic cells which were KP‐1 + and/or Mac‐387 + irrespective of tumor cell type. We suggest that these tumors can be delineated by their relative degrees of FXIIIa and CD34 expression and that these neoplasms may be a useful link with which to study the relationship between CD34+ cells and dermal dendrocytes.

Cytokine mRNA Changes during the Treatment of Hypertrophic Scars with Silicone and Nonsilicone Gel Dressings

background Treatment of hypertrophic scars can be difficult for both patients and physicians. Silicone‐containing gel dressings have been reported to be an effective alternative treatment for hypertrophic scars, yet the mechanism of action of these dressings is unknown. objective To determine whether silicone is an essential factor in the treatment of hypertrophic scars and investigate the effects of occlusive dressing therapy on the expression of key wound healing mediators. methods A pilot paired comparison, nonrandomized study was conducted comparing a silicone gel sheeting (Silastic [SGS]) with a hydrogel dressing (Clear Site). The effects of the dressings were compared side by side in the treatment of 15 hypertrophic scars at both the clinical and molecular levels through the use of reverse transcriptase/polymerase chain reaction to evaluate effects on the expression of interleukin 8 (IL‐8), basic fibroblast growth factor (bFGF), granulocyte‐macrophage colony‐stimulating factor (GMCSF), epidermal growth factor (EGF), transforming growth factor beta (TGF‐&bgr;), and fibronectin. results Comparable clinical improvement of the hypertrophic scars was obtained with both dressings. Treatment of hypertrophic scars resulted in increased mean levels of IL‐8, bFGF, and GMCSF mRNA; while mean TGF&bgr; and fibronectin mRNAs decreased after treatment with both dressings. Comparison between the two dressings revealed significant changes in IL‐8 and fibronectin mRNA levels after treatment with Clear Site, while only fibronectin changes were significant after treatment with SGS with respect to normal skin. Only Clear Site induced significant changes in IL‐8 and bFGF levels when untreated scars were compared with posttreatment lesions, suggesting that the hydrogel augments collagenolysis via promotion of inflammation. conclusions This study demonstrates that silicone is not a necessary component of occlusive dressings in the treatment of hypertrophic scars. The pathogenesis of hypertrophic scars is further elucidated by demonstrating that there is molecular evidence for extensive connective tissue remodeling occurring during occlusive dressing therapy.

Distinctive dendritic cell subsets expressing factor XIIIa, CD1a, CD1b and CD1c in mycosis fungoides and psoriasis

The papillary dermis of psoriasis and mycosis fungoides (MF) lesions is characterized by prominent collections of cells with dendritic morphology. Immunophenotypically distinct populations of cutaneous dendritic cells have been identified as CD1a+, FXIIIa‐Langerhans cells (LC) and CD1a‐, FXIIIa+ dermal dendritic cells (DDC). In this study, antibodies against the human GDI cluster of antigens (i.e. CD1a, CD1b and CD1c) and the DDC) marker (FXIIIa) were used to further characterize the subsets of dendritic cells in normal skin as compared to neonatal foreskin, psoriasis and MF by both immunoperoxidase and double immunofluorescence techniques. Normal skin and foreskin epidermis and dermis contained few CD1b+ or CD1c+ cells along with normal numbers of CD1a+ LC and FXIIIa+ DDC. Both MF and psoriasis were characterized by CD1a+ cells in the epidermis and dermis. FXIIIa+ cells were greatly expanded in the upper dermis of MF lesions and to a lesser degree in psoriasis as has been previously described by our group. MF contained significantly increased epidermal and dermal CD1b+ (15.7/5 high power fields [HPF] and 59.7/5 HPF respectively) and CD1c+ dendritic cells (33.8/5 HPF and 95.9/5 HPF respectively), while in psoriasis these cells were not statistically different from normal skin. Double immunofluorescence studies revealed that some (<25%) FXIIIa+ cells co‐expressed CD1b and CD1c in MF>psoriasis> foreskin, while FXIIIa+ DDC never co‐expressed CD1a. Thus, in contrast to normal skin in which epidermal or dermal dendritic cells rarely express CD1b and CD1c antigens, these members of the CD1 family are upregulated on both LC and DDC in benign and malignant inflammatory states. Upregulation of CD1b and CD1c on MF epidermal and dermal dendritic cells, as compared to psoriasis, foreskin and normal skin, may be useful in the immunophenotypic recognition of MF, as well as in helping to understand its immunobiology.

Minocycline hyperpigmentation: model for in situ phagocytic activity of factor XIIIa positive dermal dendrocytes.

Pigmentary disorders resulting from the prolonged use of the semisynthetic tetracycline derivative antibiotic, minocycline, are rare but well recognized sequelae of ingestion of this drug. We present two eases of women with billions pemphigoid who developed blue‐black pigmentation in areas of scarring on the legs after oral minocycline therapy. On histologic examination, the deposited pigment was localized within dendritic cells limited to the upper dermis. Immunohistochemical analysis revealed these cells to be factor XIIIa positive dermal dendrocytes which was confirmed by transmission electron microscopy. We believe these cases demonstrate, in‐situ, the phagocytic capabilities of this recently described cell population.

Localization of clonal T cells to the epidermis in cutaneous T-cell lymphoma

BACKGROUNDnMycosis fungoides (MF) is a form of cutaneous T-cell lymphoma (CTCL) characterized by progression of clonal, epidermotropic T cells with the proliferative (Ki-67+) T-cell fraction primarily confined to the epidermis in early CTCL.nnnOBJECTIVEnOur purpose was to determine whether the malignant clone (recognized by its clonal T-cell receptor [TCR] rearrangement) might also be localized to the epidermal compartment by differential Southern blot analysis.nnnMETHODSnA rapid heat-saline technique was used to separately isolate epidermal and dermal DNA from 11 patients with CTCL (1 with disease in the pre-MF stage, 4 with patch-stage MF, 3 with plaque-stage MF, 1 with tumor-stage MF, 1 with Sézary syndrome, and 1 with non-MF peripheral T-cell lymphoma). Whole and heat-saline separated 6 mm biopsy specimens (obtained from the same lesion) were analyzed by standard Southern blotting with 5 to 10 micrograms of DNA digested with BamHI, HindIII, or EcoRI in each case. Filters were probed with a 32P-labeled TCR-C beta complementary DNA. Skin compartment localization of TCR-C beta rearrangement was compared with results of diagnostic immunophenotyping and expression of proliferating cell nuclear antigen.nnnRESULTSnDNA yields were as follows: from the whole specimens, 14.5 to 62.5 micrograms; from epidermal sheets, 2 to 42.5 micrograms; and from the dermis specimens, 2.5 to 25.5 micrograms. Whole and separated specimens from one patient with plaque-stage disease, three with patch-stage disease, and one patient with pre-MF disease revealed no rearrangement. Six patients had detectable gene rearrangements in the whole specimen by Southern blot; four of six had identical rearrangements in only the epidermal fragment (including the Sézary syndrome biopsy specimen) and not the dermis. The other two patients had only dermal TCR-C beta rearrangement. No relation was seen between immunophenotype or proliferating cell nuclear antigen expression and the localization of TCR-C beta rearrangements. However, the degree of epidermotropism significantly correlated with the presence of TCR-C beta rearrangements in the epidermal sheets.nnnCONCLUSIONnThis study demonstrates that the malignant clone in CTCL can be localized to the epidermal compartment in most cases in which a TCR rearrangement is detectable and that these clones are associated with epidermal proliferation of lymphocytes. This technique of differential epidermal versus dermal Southern analysis for TCR rearrangement may improve sensitivity by helping to distinguish reactive from malignant T-cell populations in future studies of the pathogenesis of CTCL.

308-nm Excimer laser for the treatment of lymphomatoid papulosis and stage IA mycosis fungoides

To the Editor, Lymphomatoid papulosis (LyP) is a chronic, recurrent, self-healing, papulonecrotic and papulonodular cutaneous disorder. This disorder can affect individuals of all ages and is considered a low-grade malignant cutaneous T-cell lymphoma (CTCL). The treatment of LyP is often unsatisfactory and lesions may recur weeks to months after the discontinuation of therapy. Mycosis fungoides (MF) is a malignancy of clonal skin homing CD4 T-lymphocytes and is the most common form of CTCL. In its earliest stages, it manifests as patches and/or plaques. Treatment options for early stage MF include various topical agents and phototherapy, including narrowband ultraviolet B phototherapy (NB-UVB; 311–312 nm) (1–3). To our knowledge, there are no reports using targeted UVB phototherapy for the treatment of LyP; only one case series showing the beneficial use of the excimer laser for the treatment of early stage MF has been published (4). Based on this series and the reported efficacy of NB-UVB in the treatment of MF, we propose that the 308-nm excimer laser can be beneficial for the treatment of LyP and stage IA mycosis fungoides and present preliminary results in support of this concept.

Dermal dendrocytes and T-cells in canine mycosis fungoides. Support for an animal model of human cutaneous T-cell lymphoma.

Background. An extensive upper dermal network of human Thy‐1+/Factor XIIIa+ dermal dendrocytes (DD) exists in human mycosis fungoides (MF).

Lepromatous phlebitis of the external jugular vein

Mycobacterium leprae (M leprae), the causative agent of Hansens disease, is endemic in many areas of Asia, sub-Saharan Africa, South and Central America, the Pacific Islands, and the Philippines. The spectrum of clinical disease is dependent on the patients cell-mediated immunity and might range from localized anesthetic patches or plaques to disseminated disease. If undiagnosed, progression with damage to the involved sensory and motor nerves might occur. Lepromatous vasculitis occurs most commonly in patients with severe disseminated disease. Vascular disease, as the initial presenting sign of tuberculoid leprosy, is, however, rare. We present one patient in whom the development of Hansens disease was associated with involvement of the external jugular vein and was initially seen as external jugular vein fibrosis.