A critical analysis of textbooks of dermatopathology in historical perspective. Part 9.
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Biomedical subjects
Publications and source records attributed to P Milde.
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We report a case of a 3-year-old boy who developed crops of papules and ulcerating nodules on the limbs in April 1992. Periodically, new lesions continue to erupt, while others resolve spontaneously. This course is characteristic for rhythmic paradoxical eruptions. This course and the clinical picture, supported by the histopathological and immunohistochemical findings, led to the diagnosis of lymphomatoid papulosis. Lymphomatoid papulosis is extremely rare in childhood. All published cases of lymphomatoid papulosis in children under 10 years of age are reviewed. The differential diagnosis of lymphomatoid papulosis in childhood includes arthropod assaults, pityriasis lichenoides et varioliformis acuta, primary cutaneous Hodgkin's disease, Ki-1 large cell anaplastic lymphoma and other lymphomas and pseudolymphomas in children.
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We report on a 32-year-old woman with chronic relapsing papular and papulopustular lesions in the area of the hairlines and on the scalp. The diagnosis of acne necrotica (varioliformis) was made on the basis of the typical clinical picture and the histopathology, which showed necrotizing lymphocytic folliculitis. This rare disease must be differentiated from other pustular diseases of the scalp. Acne necrotica has been known as an entity since the beginning of the last century. In recent literature, however, it has received little attention.
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Acquired melanocytic nevi are among the commonest neoplasms in man, yet classification of them has proven elusive and elucidation unsatisfactory. From "active junctional nevus" to "dysplastic nevus," the brains of clinicians and histopathologists have been boggled and the psyches and skin of patients have been served badly. This essay advocates eponymic designations for acquired melanocytic nevi, all of which are common, as the surest route to comprehensive classification of them.
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We report on two women with pigmented lesions of the vulva. The histopathology (filiform downgrowth of pigmented epithelial strands two to four cells wide, extending from the interfollicular epidermis and from follicular infundibula; no increased numbers of melanocytes; horn pseudocysts) was specific for Dowling-Degos disease. One patient also had acne inversa, and the other patient had been treated surgically for a pilonidal sinus some years before. The spectrum of conditions that should be considered in the differential diagnosis of genital pigmented lesions is discussed. Vulvar melanosis, genital lentigo, malignant melanoma, acanthosis nigricans maligna and benigna and syndromes occurring concomitantly with pigmentation of the mucosa need to be excluded. The association of Dowling-Degos disease with acne inversa, which was recently described for the first time, is discussed.
Disturbed calcification of the growth plate and stunting is a frequent finding in vitamin D-deficiency rickets, vitamin D-dependency rickets and renal osteodystrophy, illustrating that chondrocytes are a target for vitamin D. This observation prompted an investigation of Ic, 25-dihydroxy vitamin D3 [1,25(OH)2D3] receptor expression and action of vitamin D metabolites on chondrocyte proliferation. In tibial growth plates and in primary cultures of tibial growth cartilage of male Sprague-Dawley rats (80 g) specific binding of [3H]-1,25(OH)2D3 was noted. Scatchard analysis revealed the presence of a single class of non-interacting binding sites. Kd was 10(-11) M irrespective of growth phase. The binding macromolecule had a sedimentation coefficient of 3.5 S. Interaction with DNA was demonstrated by DNA-cellulose affinity chromatography. By immunohistology, growth cartilage cells (rabbit tibia) were shown to express nuclear 1,25(OH)2D3 receptors, most prominently in the proliferative and early hypertrophic zone. This corresponds to binding data which showed highest binding of 1,25(OH)2D3 in the logarithmic growth phase (12,780 molecules/cell versus 4,538 molecules/cell in confluent cells) in primary cultures of growth plate chondrocytes. In the presence of delipidated fetal calf serum 1,25(OH)2D3 had a biphasic effect on cell proliferation and density, i.e. stimulation at 10(-12) M and dose-dependent inhibition at 10(-10) M and below. Inhibition was specific and not seen with 24 (R), 25-dihydroxy-vitamin D3 or dexamethasone. Growth phase-dependent 1,25(OH)2D3 receptor expression and specific effects of 1,25(OH)2D3 on chondrocyte proliferation in vitro point to a role for vitamin D in the homeostasis of growth cartilage of the rat.
Vitamin D deficiency leads to disturbed calcification of growth cartilage and enlargement of growth plate, illustrating that chondrocytes are a target for vitamin D. This observation prompted an investigation of 1,25(OH)2D3 receptor expression and action of vitamin D metabolites on chondrocyte proliferation. In primary cultures of tibial growth cartilage of male SD rats (80 g), specific binding of [3H]-1,25(OH)2D3 is noted in both the logarithmic growth phase and at confluence (Nmax 12780 molecules/cell versus 4368 molecules/cell). Scatchard analysis revealed the presence of a single class of noninteracting binding sites. KD was 10(-11) M irrespective of growth phase. The binding macromolecule had a sedimentation coefficient of 3.5 S. Interaction with DNA was demonstrated by DNA cellulose affinity chromatography. In immunohistology, growth cartilage cells (rabbit tibia) expressed nuclear 1,25(OH)2D3 receptors most prominently in the proliferative and hypertrophic zone. This corresponds to binding data which showed highest Nmax in the proliferating cartilage. 1,25(OH)2D3 in the presence of delipidated fetal calf serum (FCS) had a biphasic effect on cell proliferation and density, i.e., stimulation at 10(-12) M and dose-dependent inhibition at 10(-10) M and below. Inhibition was specific and not seen with 24,25(OH)2D3 or dexamethasone. Growth phase-dependent 1,25(OH)2D3 receptor expression and effects of 1,25(OH)2D3 on chondrocyte proliferation point to a role of vitamin D in the homeostasis of growth cartilage.
Increasing evidence suggests an immunoregulatory function of the potent steroid hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) which has been successfully applied for treatment of psoriasis. The skin is both a site of production and a target of 1,25(OH)2D3. In vitro, 1,25(OH)2D3 inhibits proliferation and stimulates differentiation of keratinocytes. We investigated the in situ expression of vitamin D-receptors (VDR) in normal and psoriatic skin by immunochemical methods. The VDR were visualized using the monoclonal antibody (MoAb) 9A7g to the VDR and the labeled avidinbiotin technique. Immunoreactivity was consistently confined to nuclei in all skin biopsies. In normal skin specimens (n = 10) VDR antigens were expressed in keratinocytes of all epidermal layers (except those of the stratum corneum) and in cells of the epidermal appendages. Double labeling experiments with MoAb to cluster-defined antigens indicated that melanocytes and approximately 75% of Langerhans cells exhibit 1,25(OH)2D3 receptors in normal skin biopsies (n = 5). Depending on their localization in skin compartments 42-62% of CD11b+ positive macrophages and 45-75% of CD3+ T lymphocytes expressed VDR. Non-lesional psoriatic skin specimens (n = 8) revealed nearly identical staining patterns. Lesional psoriatic skin specimens (n = 8) exhibited a significant increase of VDR expression both in basal and suprabasal epidermal layers as measured by computer-assisted morphometry and showed a remarkable change of the immune cell pattern: the densitity and proportion of VDR positive T lymphocytes and macrophages were higher in the epidermal and the perivascular papillary loop compartment. These in vivo findings strongly support the hypothesis that 1,25(OH)2D3 modulates immune response and cell proliferation/differentiation in human skin.
Vitamin D (calciferol) is under clinical investigation for the treatment of psoriasis. Vitamin D was previously solely regarded as a key substance in hormonal calcium homeostasis, a view that is no longer tenable. The human receptor for the biologically active metabolite 1,25-dihydroxyvitamin-D3 was cloned in 1988. Sequence analyses revealed that it was a member of the nuclear steroid hormone receptor family. This family of gene-regulatory DNA-binding proteins includes the oestrogen, progesterone, glucocorticoid, mineralocorticoid, thyroxine (T-3) and retinoic acid receptors. Vitamin D receptors have been identified in a variety of tissues primarily unrelated to calcium metabolism. The skin and the immune system are some of the most interesting new targets. In vitro 1,25-dihydroxyvitamin-D3 inhibits proliferation and induces differentiation of keratinocytes. Furthermore, this hormone has potent immunomodulatory functions.
Two women patients with chronic eczematous dermatitis, who also developed extremely severe, persistent photosensitivity during a course of 10 and over 40 years, are presented. Both patients had an atopic history with positive immediate skin reactions. Patch and photopatch tests revealed sensitization to several contact allergens, and in one case also a photocontact allergy. The action spectrum of the photosensitivity was confined to UV-B; it was possible to provoke eczematous skin reactions with doses smaller than 1 mJ/cm2 UV-B. Both patients were successfully treated with PUVA therapy. These case reports demonstrate the difficulty of nosological classification of chronic eczematous photosensitive dermatoses under the traditional terms persistent light reaction, photosensitive eczema, photosensitivity dermatitis, and actinic reticuloid. Chronic actinic dermatitis is defined clinically by chronic dermatitis on skin exposed to sun, histologically by spongiotic dermatitis, and photobiologically by experimental provocation of spongiotic dermatitis with UV-B and often also longer wavelengths in the absence of a photoallergen. Chronic actinic dermatitis should be used as a general term in addition to the more specific terms listed above.
Because 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) has been shown to play roles in both proliferation and differentiation of novel target cells, the potential expression of 1,25(OH)2D3 receptor (VDR) activity was investigated in cultured bovine aortic endothelial cells (BAEC). Receptor binding assays performed on nuclear extracts of BAEC revealed a single class of specific, high-affinity VDR that displayed a 4.5-fold increase in maximal ligand binding (Nmax) in rapidly proliferating BAEC compared with confluent, density-arrested cells. When confluent BAEC were incubated with activators of protein kinase C (PKC), Nmax increased 2.5-fold within 6-24 h and this upregulation was prevented by sphingosine, an inhibitor of PKC, as well as by actinomycin D or cycloheximide. Immunohistochemical visualization using a specific MAb disclosed nuclear localized VDR in venular and capillary endothelial cells of human skin biopsies, documenting the expression of VDR, in vivo, and validating the BAEC model. Finally, additional experiments indicated that BAEC formed the 1,25(OH)2D3 hormonal metabolite from 25(OH)D3 substrate, in vitro, and growth curves of BAEC maintained in the presence of 10(-8) M 1,25(OH)2D3 showed a 36% decrease in saturation density. These data provide evidence for the presence of a vitamin D microendocrine system in endothelial cells, consisting of the VDR and a 1 alpha-hydroxylase enzyme capable of producing 1,25(OH)2D3. That both components of this system are coordinately regulated, and that BAEC respond to the 1,25(OH)2D3 hormone by modulating growth kinetics, suggests the existence of a vitamin D autocrine loop in endothelium that may play a role in the development and/or functions of this pathophysiologically significant cell population.
We developed an immunohistochemical method for visualization of vitamin D (VDR) and estrogen receptors (ER) in cryostat sections, using monoclonal antibodies (MAb) to the vitamin D receptor and estrogen receptor, respectively. This method is based on an avidin-biotin labeling technique (LAB). To establish a reliable and sensitive method which can be used easily as a routine diagnostic procedure, we systematically compared four different immunoenzymatic methods with respect to their efficiency in detecting vitamin D and estrogen receptors. Compared to the indirect bridged avidin-biotin (IBRAB), the peroxidase- anti-peroxidase (PAP), and the avidin-biotin complex (ABC) methods, the LAB method produced stronger staining intensities and had higher detection efficiency for both vitamin D and estrogen receptors. In addition, the LAB method had a higher spatial resolution compared to the ABC technique in detection of VDR in normal human skin biopsies. In the case of steroid receptors, i.e., nuclear antigens, immunohistochemistry must deal with a relatively low number of antigenic sites per cell, restricted accessibility of the antigens, and slight differences in antigen concentrations among cells. Under these particular conditions, the chemical properties of the conjugates used in the LAB method may explain why it is superior to the other methods. Consequently, the LAB method is recommended for visualization of ER and VDR.