原发性皮肤淀粉样变淀粉样蛋白组织来源的研究

对30份原发性皮肤淀粉样变标本石腊切片进行抗角蛋白抗体免疫组化及复染荧光刚果红的对比观察,发现淀粉样蛋白的沉积非常广泛,而角蛋白的沉积仅发生在病变中期及后期少数标本的个别乳头内。在大多数有淀粉样蛋白沉积处并不存在角蛋白成分,电镜下也未见表皮角朊细胞破坏变性,而真皮乳头内有角蛋白沉积的部位均有淀粉样蛋白的沉积及基底细胞破坏。说明乳头内角蛋白的沉积是在淀粉样蛋白沉积之后发生的,是后果而不是原因。     

Immunohistochemical studies on fibrillin in amyloidosis, lichen ruber planus and porphyria.

The pathogenesis of macular amyloidosis and lichen amyloidosis remains unsolved and the primary amyloid fibril protein(s) has not yet been identified. Ultrastructural association of skin amyloid with elastin associated microfibrils has been noted earlier. The presence of fibrillin in conjunction with such microfibrils was recently demonstrated immunohistochemically. The presence of fibrillin immunoreactivity in the amyloid deposits in skin biopsies from 3 patients with macular amyloidosis and 3 patients with lichen amyloidosis was studied, using monoclonal anti-fibrillin antibodies. For comparison, skin specimens were studied from five patients with lichen ruber planus, four patients with erythropoietic protoporphyria and from a patient with myeloma-associated cutaneous amyloidosis. Renal specimens from two cases of the amyloid A type of renal amyloidosis also were investigated. There was no immunostaining either of the keratin bodies in specimens of lichen ruber planus, the cutaneous PAS-positive vascular deposits in patients with erythropoietic protoporphyria, or the amyloid deposits in specimens of systemic amyloidosis and it was faint or absent in amyloid deposits in the specimens from patients with lichen amyloidosis. In contrast, distinct fibrillin immunoreactivity could be demonstrated in amyloid deposits in specimens from patients with macular amyloidosis. It was sometimes absent in deposits located in the upper part of the papillary dermis, close to the dermal epidermal junction zone, while consistently strong in deposits located lower down in the dermis. The results suggest that fibrillin or part of the fibrillin molecule may be present in some of the amyloid deposits in specimens of macular amyloidosis.     

Age-related changes in the cutaneous basal lamina: scanning electron microscopic study

Scanning electron microscopy of human epidermal-dermal basal lamina demonstrated striking age-related changes. The basal lamina from abdominal skin was exposed in specimens from 26 humans by separation of epidermis and dermis after treatment with sodium bromide solutions. Transmission electron micrographs demonstrated the split to be in the lamina lucida. Scanning electron microscopy of mature epidermal-dermal junction and basal lamina showed distinct dermal valleys; tall, dome-shaped dermal papillae; and basal lamina arranged in prominent corrugations that tended to be oriented vertically on papillae and irregularly on interpapillary zones. Skin from subjects in their 7th through 10th decades demonstrated progressive loss of dermal valleys, flattening and widening of dermal papillae, and loss of basal lamina corrugations.     

Primary cutaneous amyloidosis of the external ear: a clinicopathological and immunohistochemical study of 17 cases

Primary cutaneous amyloidosis includes several forms of localized amyloidosis characterized by superficial amyloid deposits occurring at or near the dermal–epidermal junction in the absence of systemic involvement. Primary cutaneous amyloidosis of the auricular concha and external ear represents a rarely described variant. There have been 27 cases reported in the English language literature, and herein we report 17 additional cases. This article demonstrates that the amyloid observed in this context is generally positive for Congo red, crystal violet and thioflavin T. It also expresses cytokeratin 34ßE12 via immunohistochemistry. Our immunohistochemical results and review of the literature suggest that the amyloid in amyloidosis of the external ear is the result of basal keratinocyte degeneration and does not signify deposition from a systemic or generalized process. Wenson SF, Jessup CJ, Johnson MM, Cohen LM, Mahmoodi M. Primary cutaneous amyloidosis of the external ear: a clinicopathological and immunohistochemical study of 17 cases.     

Lichen amyloidosus with subepidermal blister formation

We report a 74-year-old man who presented with multiple, itchy keratotic papules or plaques on the trunk and extremities. Erosions and vesicles were also intermingled on keratotic lesions. Histopathologic examination of biopsy specimens taken from three different lesions showed a subepidermal blister with amyloid deposits in the dermal papillae. No systemic disease or involvement of other organs was detected. The clinical and histological findings were compatible with a bullous variant of lichen amyloidosus. Although bullous amyloidosis has been reported in systemic amyloidosis, bullous lesions associated with lichen amyloidosus are very rare.     

Lichenoid skin lesions as a sign of β2-microglobulin-induced amyloidosis in a long-term haemodialysis patient

We report a case of β₂-microglobulin-induced amyloidosis. The patient was a 40-year-old man suffering from non-amyloid nephropathy, who had been treated by haemodialysis for 20 years. Lichenoid skin lesions, consisting of groups of pin-head-sized shiny papules, were present on the arms and trunk. On histological examination, amyloid deposits were present, principally in the dermal papillae, hut also around the sweat ducts and hair follicles. The amyloid displayed potassium-permanganate-resistant Congo red affinity, and green birefringence under polarized light, Immuno-histochemically, β₂-microglobulin was demonstrated in the lesions, confirming that they were a manifestation of β₂-microglobulin-associated amyloidosis. Skin lesions of this type have not been reported previously in β₂-microglobulin-associated amyloidosis.     

细胞角蛋白和波形蛋白在皮肤淀粉样变淀粉样蛋白中表达的研究

目的:探讨皮肤淀粉样变淀粉样蛋白的生物学来源.方法:应用免疫组化染色技术检测4种角蛋白(cytokeratins,CKs)及波形蛋白在20例斑状或苔藓样型皮肤淀粉样变淀粉样蛋白中的表达情况.结果:①CK3413E12和CK5/6在20例标本的淀粉样蛋白团块中均呈阳性表达:而AE1/AE3、CK10/13和波形蛋白在淀粉样蛋白团块中均呈阴性表达;②淀粉样蛋白团块中波形蛋白表达阳性的成纤维细胞明显增生.结论:淀粉样蛋白主要来源于凋亡的表皮基底细胞而非真皮组织.     

Primary cutaneous amyloidosis of the auricular concha: case report and review of published work

A 70-year-old Japanese female developed tiny papules on her bilateral ears 2 years previously. A histological study of a biopsy specimen revealed that amorphous materials were present in the widened dermal papillae. Because these materials were positive for both Congo red and Dylon, we diagnosed the lesion as primary cutaneous amyloidosis of the auricular concha. Immunohistochemically, the amyloid substance stained positively with 34betaE12 (cytokeratin 1/5/10/14), suggesting that it had an epidermal origin. Seven reported cases of this unique disorder were also reviewed.     

Microscopic in vivo description of cellular architecture of dermoscopic pigment network in nevi and melanomas

OBJECTIVE: To characterize the microscopic aspects of the dermoscopic pigment network in vivo, by means of confocal scanning laser microscopy. DESIGN: Confocal imaging was performed on melanocytic lesions characterized by pigment network at dermoscopy. Some confocal architectural and cytologic features, as observed at the dermoepidermal junction, were morphologically described and quantified by means of a dedicated program. SETTING: University medical department. STUDY POPULATION: We studied confocal images of 15 melanomas, 15 dermoscopic atypical nevi, and 15 common nevi. MAIN OUTCOME MEASURES: Features referring to aspect, size, regularity, homogeneity, and infiltration of dermal papillae and to cellular size, regularity, and atypia were described by 2 observers on confocal images. Mean dermal papillary diameter, mean cell area, and shape irregularity were quantified by drawing papillae and cell contours on confocal images and measured with the use of a computer program. RESULTS: Pigment network in melanomas consisted of large basal cells that circumscribed small to medium-sized dermal papillae with marked cellular atypia, sometimes infiltrating dermal papillae. On the other hand, common acquired nevi were characterized by lack of atypical cells and edged dermal papillae. Atypical nevi presented intermediate characteristics between clearly benign and malignant lesions. CONCLUSION: Cellular atypia was the most sensitive feature for melanoma diagnosis, whereas the presence of nucleated cells infiltrating dermal papillae was the most specific one.     

Papillomavirus-induced changes in the topography of the epidermal-dermal junction: a scanning electron microscopic study of basal lamina

Papillomavirus infects human epidermal cells and causes verruca vulgaris, which is characterized by altered epidermal growth rates and differentiation patterns. There is also a prominent induced dermal proliferative response. Ten formalin-fixed skin specimens from 10 patients, each with histologically characteristic verruca vulgaris, were excised from paraffin blocks, deparaffinized in xylene, and rehydrated in graded ethanol solutions. Hydrated specimens were incubated in 90% formic acid at 45 degrees C for 18 h. Using a dissecting microscope the epidermis was gently separated from the dermis, which then was fixed in 3% glutaraldehyde and processed for scanning electron microscopy. Scanning electron microscopy showed a well-preserved epidermal-dermal junction (EDJ) covered by basal lamina. In comparison with normal EDJ, the EDJ of verruca vulgaris showed markedly elongated dermal papillae. Some papillae were broad and thin, and others were broad and thick. Irregularly shaped and branching secondary papillae were common. Also, there were changes in the basal lamina: the normal corrugation pattern was replaced by relatively smooth undulations or coarse, vertically oriented ridges on papillae. Papillary tips were often smooth. This study shows that there were prominent alterations in the topography of the EDJ and basal lamina in verruca vulgaris. This technique should be useful in evaluating epithelial-connective tissue morphologic interactions in formalin fixed archival tissue in other diseases characterized by alterations in epidermal growth rates and differentiation patterns.     

Ultrastructural abnormalities in the dermal papillae of both lesional and clinically normal follicles from alopecia areata scalps

Summary Alopecia areala is a form of balding whose aetiology is uncertain. Although the dermal papilla in the hair bulb regulates the iollicie and may play a part in the pathogenesis of alopecia areata. Its ultrastructure has not been well described. As clinically normal, i.e. non-balding, follicles from alopecia areata scalps show abnormalities at the light microscope level, it would be expected that they should exhibit the earliest pathological changes involved in the dysfunction of the follicle. This study was designed to investigate the ultrastructure of normal human scalp follicular dermal pap-illae and to see if changes occurred in the ultrastructure of dermal papillae from either lesional or non-balding regions of alopecia areata. Normal dermal papillae contained well formed fibroblast-like cells with large, oval nuclei and well-developed endoplasmic reticulum; the cells were separated from each other by extracellular matrix containing small pieces of collagen and basal lamina-like material. Dermal papille from both clinically normal and lesional alopecia areata follicles were less well organized and the dermal papilla cells exhibited signs of cell injury and contained abnormal amounts of pigment; an increased concentration of fibrous material in the extracellular matrix and thickening of the dermal papilla-epithelial junction were also seen. Follicles from lesional areas showed more pronounced changes than clinically normal ones. Ultrastructural abnormalities in the dermal papillae of clinically normal scalp follicles support the study of these follicles as a prime research target. The changes detected suggest that dermal papilla cells in alopecia areata would be less able to synthesize regulatory factors and that these may have more difficulty crossing into the epithelial compartment. They are consistent with an early pathological role for the dermal papilla in alopecia areata, but do not distinguish whether this is a primary aetiological role or a secondary response to an insult elsewhere in the follicle.     

盘状红斑狼疮和扁平苔藓在表皮真皮连接处的扫描电镜观察

用扫描电镜观察盘状红斑狼疮、扁平苔藓及正常皮肤的表皮真皮连接处及基底膜.正常皮肤真皮乳头呈圆柱形,乳头表面及乳头间峡谷区有波纹状基底膜覆盖.盘状红斑狼疮真皮乳头平坦,有的呈尖顶形,乳头高低悬殊,基底膜粗糙不平,方向杂乱;真皮乳头间区域可见较多孔穴,为淋巴细胞通道.而扁平苔藓真皮乳头圆柱形或不规则形基底膜粗糙,有的乳头顶部光滑,有较少的孔穴.在表皮真皮连接处,这两种病有明显区别.     

Amyloidogenesis in organ-limited cutaneous amyloidosis: an antigenic identity between epidermal keratin and skin amyloid

Epidermal keratin was extracted and antibody against this protein was produced in rabbits. Various forms of organ-limited cutaneous amyloidosis (lichenoid, macular, and nodular amyloidosis, and basal cell epithelioma) and primary systemic amyloidosis were immunohistochemically examined to test the identity between epidermal keratin and skin amyloid. Amyloids in lichenoid and macular amyloidoses, and in basal cell epithelioma had an identical antigenicity with epidermal keratin, whereas amyloids in nodular amyloidosis and systemic amyloidosis did not have this identity. In addition, amyloid in lichen amyloidosis contained disulfide bonds as in keratin. Connective tissue components including filaments of fibroblasts and vascular endothelial cells did not react with this antikeratin antibody. It was concluded that at least some of the amyloid substance in organ-limited cutaneous amyloidosis is derived from degenerated epidermal keratinocytes through filamentous degeneration or apoptosis.     

Immunohistochemical demonstration of amyloid P component in skin of normal subjects and patients with cutaneous amyloidosis

The presence of amyloid P component (AP) in dermal deposits of cutaneous atnyloidosis was demonstrated by a direct immunofluorescence technique using an antibody to serum amyloid P component (SAP). AP was also shown, for the first time, to be a constituent of normal human skin. It was present at the periphery of dermal elastic tissue fibres, in basement membranes of dermal blood vessels and surrounding eccrine sweat glands but was absent from the dermo-epidermal basement membrane. The staining pattern in cutaneous amyloidosis was morphologically distinctive and readily distinguishable from staining of thickened vascular basement membranes in porphyria. Itnmunofluorescence with anti-SAP is simple and specific and may become the procedure of choice in the differential diagnosis of amyloidosis.     

Therapeutic removal of amyloid deposits in cutaneous amyloidosis by localised intra‐lesional injections of anti‐amyloid antibodies

Please cite this paper as: Therapeutic removal of amyloid deposits in cutaneous amyloidosis by localised intra‐lesional injections of anti‐amyloid antibodies. Experimental Dermatology 2010; 19 : 904–911. Abstract: In the skin, amyloidosis can be found with or without systemic disease. Primary cutaneous amyloidosis defines those amyloidoses restricted to the skin without involvement of other systems. Here, we used conformation‐specific antibodies to characterise both fibrillar and oligomeric amyloid aggregates in the skin from patients with cutaneous amyloidosis. Localised cutaneous amyloidosis with different morphology was reproduced in mice by intra‐dermal (i.d.) and subdermal administration of amyloid‐enhancing factor. Moreover, we demonstrated that conformational antibodies were effective in clearing amyloid deposits caused by localised intra‐lesional injections without the necessity of an immune response. Given the accessibility and amyloid localization in this disease, direct i.d. injections of conformational antibodies could be a convenient and direct method for treatment.     

In vivo quantification of epidermis pigmentation and dermis papilla density with reflectance confocal microscopy: variations with age and skin phototype

Reflectance confocal microscopy (RCM) may help to quantify variations of skin pigmentation induced by different stimuli such as UV radiation or therapeutic intervention. The objective of our work was to identify RCM parameters able to quantify in vivo dermis papilla density and epidermis pigmentation potentially applicable in clinical studies. The study included 111 healthy female volunteers with phototypes I-VI. Photo-exposed and photo-protected anatomical sites were imaged. The effect of age was also assessed. Four epidermis components were specifically investigated: stratum corneum, stratum spinosum, basal epidermal layer and dermo-epidermal junction. Laser power, diameter of corneocytes and upper spinous keratinocytes, brightness of upper spinous and interpapillary spinous keratinocytes, number of dermal papillae and papillary contrast were systematically assessed. Papillary contrast measured at the dermo-epidermal junction appeared to be a reliable marker of epidermis pigmentation and showed a strong correlation with skin pigmentation assessed clinically using the Fitzpatrick's classification. Brightness of upper spinous and interpapillary spinous keratinocytes was not influenced by the skin phototype. The number of dermal papillae was significantly lower in subjects with phototypes I-II as compared with darker skin subjects. A dramatic reduction in the number of dermal papillae was noticed with age, particularly in subjects with fair skin. The method presented here provides a new in vivo investigation tool for quantification of dermis papilla density and epidermal pigmentation. Papillary contrast measured at the dermo-epidermal junction may be selected as a marker of skin pigmentation for evaluation in clinical studies.     

Two different pathogenetic pathways in lichen amyloidosus and macular amyloidosis

Summary In lichen amyloidosus (LA) and macular amyloidosis (MA), small amyloid deposits occur in the upper papillary dermis. Previous electron-microscopic studies have indicated an epidermal origin of the amyloid, where degenerating keratinocytes drop into the dermis and undergo transformation to amyloid. While this mechanism seems possible at least in MA, we suggest an alternative pathogenetic pathway in LA, in which amyloid fibrils seem to form on the dermal surface of living basal keratinocytes. It is possible that the different morphology of the amyloid in LA and MA is explained by partially different pathogenetic mechanisms although the amyloid in both conditions may be chemically closely related.     

PRIMARY LOCALIZED CUTANEOUS AMYLOIDOSIS

Fifty-seven patients with primary localized cutaneous amyloidosis (PLCA) were clinically and histopathologically reviewed. Two-thirds of patients had macular amyloidosis (MA). Intermediate cases having macular lesions with micropapules and/or lichens were identified. A spectrum for the disease is proposed, in which the less itchy classical macular variant occurs at one end and the very pruritic traditional lichen variant at the other. The salient histopathologic findings were similar in the macules, micropapules, and lichens, but were more prominent in the lichens. These consisted of hyperkeratosis, keratinocyte degeneration, satellite cell necrosis, and basal cell destruction. Amyloid deposition in the dermal papillae with transepidermal elimination, dermal melanophages, and superficial perivascular inflammation were also present. These changes represent an interface dermatitis of the vacuolar type. PLCA may be categorized under the group of dermatoses characterized by a lichenoid tissue reaction; inflammation may play a key role in mediating these disorders.     

Cutis laxa in hereditary gelsolin amyloidosis

BACKGROUND: Hereditary gelsolin amyloidosis (AGel amyloidosis) is an age-associated systemic disease with global distribution, caused by a G654A or G654T gelsolin gene mutation. Cutis laxa is a principal clinical manifestation of this disease. However, only few data on the dermatological involvement are available, and the pathogenesis of this amyloidosis-associated form of cutis laxa has remained unknown. OBJECTIVES: To elucidate the pathomechanism of this less well-known genodermatosis. METHODS: We performed systematic clinical, histological, immunohistochemical and ultrastructural skin biopsy studies in 12 patients with a G654A gelsolin gene mutation. For comparison, skin specimens from 10 control subjects were analysed. RESULTS: All patients had clinically characteristic cutis laxa, and frequently other signs of symptomatic skin disease such as increased fragility and risk for intracutaneous bleeding. All patients showed cutaneous deposition of gelsolin amyloid (AGel), mainly attached to basement membranes or basal laminae of various cutaneous structures, dermal nerves and blood vessel walls, and elastic fibres, particularly in the lower reticular dermis. AGel often encircled the elastic fibres, and colocalized with amyloid P component (AP), an elastic fibre microfibrillar sheath-associated protein. Fragmentation and loss of elastic fibres, epidermal atrophy, and reduction of dermal appendages were also common. Antibodies to wild-type gelsolin bound to S-100-positive epidermal dendritic cells, a previously unrecognized immunoreaction. Patients had fewer gelsolin-positive dendritic cells than controls. CONCLUSIONS: Widespread skin involvement with AGel deposition and elastic fibre involvement are essential pathological features in AGel amyloidosis, and contribute to the characteristic cutis laxa, dramatic in old age. Codistribution of AGel and AP, with demonstrated specific binding affinity for amyloid fibrils, suggests that elastic fibre-associated AP acts as a matrix for cutaneous amyloid deposition in AGel amyloidosis.     

Alitretinoin treatment of lichen amyloidosis

Lichen amyloidosis (LA) is characterized by the deposition of amyloid that may respond to chronic scratching that may be secondary to atopic dermatitis, stasis dermatitis, or interface dermatitis. Despite the development of several therapeutic strategies, including topical steroids, oral antihistamines, cyclosporine, and retinoids, an effective treatment for LA has not been established. A 49‐year‐old woman who has been treated irregularly for atopic dermatitis for 7 years presented with localized brownish papules on the left forearm and right elbow. They developed 3 months prior and were becoming more prominent despite of treatment with cyclosporine, oral antihistamines, and topical steroids for 5 months prior to presentation. A skin biopsy revealed amyloid deposition in the dermal papillae and the patient was diagnosed with LA associated with atopic dermatitis. A 6‐month course of daily oral alitretinoin 30 mg produced marked improvement in the thickness and color of the hyperkeratotic papules without aggravation of the patient's atopic dermatitis. Histologic evaluation showed clearance of amyloid deposition and almost normalization of the epidermal changes. Herein, we report a case of LA treated with alitretinoin and suggest that it could be a potential treatment option for LA, especially in patients with inflammatory skin diseases including atopic dermatitis.