Perforating pilomatricoma: transepithelial elimination or not

We present a 56-year-old woman with a perforating pilomatricoma in the left eyebrow region. Histologically, the tumor consisted mainly of basophilic cells and shadow cells, and the tumor components were being eliminated through an ulcer with damage to the epithelial structures. In past reports of perforating pilomatricoma, this elimination pattern has often been described as transepithelial elimination. In many patients with perforating pilomatricoma, elimination is accompanied by ulceration and epithelial damage. Mehregan recently stated that elimination accompanied by epidermal necrosis and superficial ulceration constituted one form of transepithelial elimination. Epidermal necrosis and ulceration generally constitute severe damage. However, when Mehregan first proposed the concept of transepithelial elimination, it was defined as a phenomenon with relatively little or no damage to the epithelial structures, differentiating it from other types of elimination. This original definition makes transepithelial elimination a unique and interesting phenomenon, and its most important feature is that there is relatively little or no damage to the epithelial structures. Therefore, the terms "epidermal necrosis" and "ulceration" should not be used in association with transepithelial elimination. Hence, in patients with perforating pilomatricoma, the elimination of tumor components from ulcers with damage to the epithelial structures, as seen in the present case, should not be described as transepithelial elimination.     

儿童穿通型毛母质瘤29例临床病理特点分析

目的:分析儿童穿通型毛母质瘤的临床及病理特点,探讨其发生机制。方法:回顾2014—2020年就诊于北京儿童医院皮肤科的29例穿通型毛母质瘤患儿资料,分析其临床及组织病理学特点。结果:29例中男11例,女18例,男女比例为1∶1.64。发病年龄3个月至14岁10个月,中位发病年龄4.58岁。病程2个月至2年,平均8.72...     

基质金属蛋白酶-9及其组织抑制物-1在皮肤鳞状细胞癌中的表达

目的探讨基质金属蛋白酶-9(MMP-9)及其组织抑制物-1(TIMP-1)在皮肤鳞状细胞癌(SCC)中的表达及其与肿瘤浸润转移的关系。方法免疫组化SP法检测MMP-9和TIMP-1蛋白在65例皮肤SCC(Bowen病17例,SCC48例)和5例正常表皮石蜡切片的表达,采用图像分析技术对免疫组化结果进行定量分析。结果MMP-9和TIMP-1蛋白均弥漫表达于皮肤SCC,分布于SCC癌巢及癌巢周围间质细胞,而在正常人皮肤仅见MMP-9和TIMP-1的弱阳性表达。SCC组MMP-9蛋白的表达水平及MMP-9/TIMP1比值高于Bowen病组(t值分别为2.33、2.36,P<0.05),SCC中淋巴结转移组MMP-9/TIMP1的比值高于无淋巴结转移组(t=2.46,P<0.05)。结论MMP-9、TIMP-1蛋白的表达与SCC的侵袭性有关,MMP-9/TIMP1比值升高(MMP-TIMP失衡)预示了SCC肿瘤细胞较高的侵袭转移潜能。     

Perforating pilomatricoma

A case of perforating pilomatricoma is described. A few published cases have shared the following features: rapid development, reddish exophytic clinical appearance with surface alterations suggestive of perforation, relatively shallow location making contact with the epidermis, and the occurrence of transepithelial elimination phenomena.     

Epidermal-dermal interactions regulate gelatinase activity in Apligraf, a tissue-engineered human skin equivalent

BACKGROUND: Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) have important functions during skin development, repair and maintenance. MMP-2 and MMP-9 (gelatinase A and gelatinase B) are involved in regulating keratinocyte migration. OBJECTIVES: To analyse whether Apligraf, a bilayered tissue-engineered human skin equivalent (HSE), produces gelatinases and TIMPs and whether or not epidermal-dermal interactions regulate MMP activity. METHODS: The tissue distribution of MMP-2, MMP-9, TIMP-1, TIMP-2 and fibronectin was analysed by immunohistochemistry. Secreted MMP activity was quantified by a fluorimetric assay and gelatin zymography was used to monitor gelatinases in tissue culture supernatants. RESULTS: Apligraf expressed MMP-2 and MMP-9 and contained immunohistochemically detectable amounts of TIMP-1 and TIMP-2. The gelatinases were predominantly produced in the epidermis, whereas immunostaining of TIMP-1 and TIMP-2 was largely confined to the dermal component of the HSE. Fibronectin was expressed only in the dermis. Gelatin zymography demonstrated that intact Apligraf produced both MMP-2 and MMP-9, the latter predominantly in its latent form. Separation of the dermis from the epidermis resulted in an enhanced production and activation of MMP-9 by the epidermal layer, and secretion of latent and active MMP-2 by the dermal layer. Moreover, the incubation media of the separated epidermis demonstrated significantly stronger MMP activity than did intact Apligraf or its dermal component. CONCLUSIONS: These observations provide evidence that epidermal-dermal interactions suppress epidermal gelatinase activity. In addition, coexpression of TIMPs and fibronectin in the Apligraf dermis suggests that the product has the potential to counteract the imbalance between matrix production and degradation in chronic wounds and thus may support wound re-epithelialization.     

Perforating pilomatricoma

A case of "perforating pilomatricoma" is reported. A cutaneous horn-like tumor, the size of a grain of rice, developed on the left upper arm of a 51-year-old man. Histological examination revealed typical microscopic features of pilomatricoma. In addition, however, an interesting phenomenon was observed: a small portion of the mass had extruded from the upper dermis to the skin surface through the perforated epidermal channel. It might have been possible in this case for all of the tumor mass to be extruded by transepithelial elimination.     

Topical synthetic inhibitor of matrix metalloproteinases delays epidermal regeneration of human wounds

Matrix metalloproteinases (MMPs) degrade extracellular proteins during epithelialization of wounds. To evaluate the biological significance of MMPs in epidermal healing, the synthetic broad-spectrum MMP inhibitor GM 6001 (also called Galardin and Ilomastat) was applied topically to standardized human wounds. GM 6001 (10 microg/microl) or vehicle alone was applied every second day onto 4 de-roofed 6 mm suction blister wounds on the volar forearm of healthy male volunteers for 12 days. GM 6001 delayed healing by 2-4 days as assessed macroscopically and microscopically. In situ hybridization or immunohistochemistry showed that MMP-1 (interstitial collagenase) was present in and MMP-2 (gelatinase A) close to laterally migrating keratinocytes whereas MMP-9 (gelatinase B) was seen during maturation of new epidermis. MMP-1 was undetectable in blister roofs (normal epidermis) and found in low levels in normal skin. Total MMP-1 activities increased about 100-fold in wounds, independent of treatment, compared to normal skin as analyzed by specific ELISA-based activity assay. By gelatin zymography, MMP-2, but not MMP-9, was detected in blister roofs and wound healing was associated with increased active MMP-2 and latent MMP-9 levels. GM 6001 prevented activation of MMP-2 and increased latent MMP-9 levels. GM 6001 delayed re-appearance of laminin-5, the synthesis of which correlated with epidermal regeneration. Restoration of stratum corneum, measured indirectly by transepidermal water loss, was also impaired (P<0.05) in the GM 6001 group. In conclusion, pharmacological MMP inhibition delayed epidermal regeneration in vivo, suggesting that MMPs are required to restore epidermis after epidermal ablation in humans.     

Transformation-specific matrix metalloproteinases (MMP)-7 and MMP-13 are expressed by tumour cells in epidermolysis bullosa-associated squamous cell carcinomas

BACKGROUND: Patients with recessive dystrophic epidermolysis bullosa (RDEB) have an increased risk of developing rapidly progressive and metastatic cutaneous squamous cell carcinomas (SCC). It is unclear why these SCC behave more aggressively than sporadic SCC. Matrix metalloproteinases (MMP) are a family of endopeptidases that contribute to growth, invasion and metastasis of SCC. The role of MMP in RDEB-associated SCC is not known. OBJECTIVES: To investigate the expression of MMP-7, MMP-13 and MMP-9 in RDEB-associated SCC in comparison with sporadic SCC and Bowen's disease. METHODS: Immunohistochemical analysis of 25 RDEB-associated SCC, 61 sporadic SCC and 28 sporadic lesions of Bowen's disease was carried out using monoclonal antibodies for MMP-7, MMP-9, MMP-13 and E-cadherin and syndecan-1. RESULTS: MMP-7 was detected in all RDEB-associated SCC, in tumour cells within the invasive edge, where E-cadherin and syndecan-1 were markedly diminished or absent. MMP-7 expression was also observed in 98% of sporadic SCC and in 68% of Bowen's diseases. MMP-7 staining was significantly stronger in RDEB-associated SCC than in sporadic SCC, and was most abundant in poorly differentiated tumours. MMP-13 was detected in tumour cells in 96% of RDEB-associated SCC and in all sporadic cutaneous SCC. MMP-9 was detected in the inflammatory cells in all SCC examined. CONCLUSIONS: These results identify MMP-7 and MMP-13 as tumour cell-specific markers for SCC progression and as potential therapeutic targets in RDEB-associated SCC. The pattern of immunolabelling suggests that MMP-7 may shed E-cadherin and syndecan-1 from the SCC cell surface.     

Nuclear localization of beta-catenin in the hair matrix cells and differentiated keratinocytes

Beta-catenin is a structural component of adherens junctions and also a downstream effector of Wnt signaling pathway. Beta-catenin has been detected in the adherens junctions in almost all normal tissues including the epidermis. Only in some malignant tumor cells was it found in the cytoplasm and nuclei. Recently pilomatricoma was found to be caused by mutations of amino-terminal segment of beta-catenin, normally involved in phosphorylation-dependent ubiquitin-mediated degradation of the protein. Since nuclear beta-catenin has not been detected in pilomatricoma or any other benign follicular tumors, we investigated localization of beta-catenin in the normal hair follicle, follicular tumor cells, normal and psoriatic epidermis by using immunohistochemical method with a high temperature antigen unmasking technique. The nuclear localization of beta-catenin was detected not only in the matrix cells of follicular tumors including pilomatricoma but also in the normal hair matrix cells and the differentiated keratinocytes of the upper layers of the epidermis. Cell membrane staining of beta-catenin and E-cadherin was decreased in these differentiated keratinocytes. This coincided with the emergence of nuclear beta-catenin. The present immunohistochemical method has revealed hitherto unproven nuclear localization of beta-catenin in hair matrix cells. Our results also provided evidence suggesting that beta-catenin plays an important role in keratinocyte differentiation.     

Expression of matrix metalloproteinase (MMP)-7 and MMP-13 and loss of MMP-19 and p16 are associated with malignant progression in chronic wounds

BACKGROUND: The risk of squamous cell carcinoma (SCC) is significantly increased in chronic leg ulcers. Very little is known about the molecular pathogenesis of these tumours, which are often undiagnosed for a long time. As matrix metalloproteinases (MMPs) are implicated at all stages of tumorigenesis, we investigated whether the pattern of epithelial MMP expression can predict development of SCC from pseudoepitheliomatous hyperplasia of chronic wounds. METHODS: Samples from nine patients with SCCs that had arisen in chronic wounds and 31 with venous leg ulcers were studied using immunohistochemistry for MMP-7, MMP-8, MMP-9, MMP-13, MMP-19 and the tumour suppressor p16. In situ hybridization was performed for MMP-1, MMP-3, MMP-7, MMP-12 and MMP-13. RESULTS: MMP-7 was expressed by malignantly transformed epithelium, while it was absent from chronic wounds. MMP-9 was detected in the epithelium in both SCCs and chronic wounds. Epithelial MMP-13 expression was strong in SCC, but was absent in chronic wounds. MMP-12 was expressed in the epithelium in two SCCs, while macrophages were positive in chronic wounds. MMP-19 was induced in proliferating epithelium of wounds, but was absent from invasive areas of SCC. p16 was expressed by keratinocytes in half of the chronic wounds and at superficial margins of SCCs, while invasive areas were negative. CONCLUSIONS: Our results suggest that epithelial expression of MMP-7, MMP-12 and MMP-13, but not that of MMP-1, MMP-3, MMP-8, MMP-9 and MMP-10, in chronic wounds provides a diagnostic clue for distinguishing SCCs from nonmalignant wounds. The loss of MMP-19 and p16 from the epithelium could aid in making the differential diagnosis between well-differentiated SCCs and nonmalignant chronic wounds.     

Matrilysin-1 (MMP-7) and MMP-19 are expressed by Paget's cells in extramammary Paget's disease

BACKGROUND: Extramammary Paget's disease (EMPD) is a rare malignant neoplasm of apocrine gland bearing skin characterized by intraepidermal proliferation of adenocarcinoma cells. Tumor growth depends on the ability of tumor cells to migrate by proteolysis and on angiogenesis. The matrix metalloproteinase (MMP) enzymes have been implicated in both of these processes in other types of skin cancer. METHODS: The expression of MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-13, and MMP-19 was analyzed by immuno- histochemistry and/or in situ hybridization in 27 EMPD and five mammary PD (MMPD) specimens. The distribution of laminin-5 (LN-5) and tenascin-C, two extracellular matrix proteins associated with tumor invasion, was studied by immunohistochemistry. RESULTS: MMP-7 (matrilysin-1) and MMP-19 were the most frequently expressed MMPs in Paget's cells. Overexpression of MMP-2, MMP-9, or MMP-13, which is seen in many cancers, was not evident in EMPD. LN-5 and tenascin-C positivity did not correlate with the level of invasion. MMP-7, MMP-13, and MMP-19 were detected abundantly in MMPD, while MMP-9 was absent. CONCLUSIONS: MMP expression did not generally associate with the level of invasion of EMPD. In three samples positive for MMP-7 and four samples positive for MMP-19, an underlying carcinoma was detected, suggesting the importance of these two MMPs as predictors of secondary EMPD or the putative origin of Paget's cells from the dermal adenocarcinoma cells of apocrine duct origin.     

皮肤恶性黑素瘤中基质金属蛋白酶-9及其组织抑制物-1的表达及意义

目的:探讨基质金属蛋白酶-9(MMP-9)及其组织抑制物-1(TIMP-1)在皮肤恶性黑素瘤中的表达及其临床、病理学意义。方法:采用免疫组织化学S-P方法观察MMP-9和TIMP-1在51例皮肤黑素瘤及15例色素痣石蜡切片中的表达,使用图像分析技术对免疫组化结果进行定量分析。结果:与色素痣比较,皮肤恶性黑素瘤中MMP-9表达较强(P<0.05),MMP-9/TIMP-1比值较高(P<0.05)。MMP-9和TIMP-1的表达及MMP-9/TIMP-1比值与黑素瘤浸润深度有关(P<0.05)。有淋巴结转移者MMP-9表达较强(P<0.05),MMP-9/TIMP-1比值较高(P<0.05)。结论:MMP-9、TIMP-1蛋白的表达与皮肤恶性黑素瘤的侵袭性有关,MMP-9/TIMP-1比值增高提示肿瘤具有较高侵袭转移能力。     

结节性红斑与硬结性红斑皮损原位抗原研究

采用ＰＡＰ法对结节性红斑、慢性游走性结节性红斑、硬红斑及结节性血管炎４种疾病共３５例的原位抗原进行检测。结果在血管的检出例数分别为１１／１２，８／８，８／８，６／７；在胶原纤维表面的检出例数分别为１１／１２，７／８，８／８，６／７；所有病例表皮角朊细胞内均能检出；在血管腔内与血管腔外的红细胞表面的检出例数除慢性游走性结节性红斑为５／８外，其余病种均能检出。提示结节性红斑等４种疾病均为存在免疫复合物     

Pilomatricomal horn: a new superficial variant of pilomatricoma

We describe a pilomatricomal horn on the right arm of a 39-year-old man. Although initially the tumor was clinically thought to be a verruca vulgaris, the microscopic features were similar to those found in classic pilomatricoma, except for the epidermal location and the presence of a cutaneous horn. Light microscopy showed replacement of the epidermis by basaloid cells, with masses of cornified material containing shadow cells that formed a cutaneous horn. Whereas classic pilomatricoma is confined to the deep reticular dermis or subcutis, the present case represents a unique heretofore unreported epidermal variant of pilomatricoma that pathologists should be aware of to differentiate it from malignant epidermal tumors.     

Chondrodermatitis nodularis helicis: epidermal hyperplasia with transepithelial elimination (author's transl)

CNH strongly resembles, both clinically and histopathologically, other lesions showing transepithelial elimination. WE studied 14 cases, only one of which was a woman. Ths lesions had either a smooth surface or a scaly one. Histological findings were rather poor in the smooth lesions; the scaly lesions, instead, which were more advanced, showed epidermal proliferation and perforation, dermal acidophilic necrosis, transepithelial elimination, granulation tissue, and perichondritis. Actinic elastic degeneration seemed to be the first alteration; it was present in all. This, together with the repeated adverse climatic factors and the fact that circulation is of the terminal type in the region affected, is followed by the acidophilic necrosis between the apex of the cartilage and the epidermis. The processes which take place in both cartilage and epidermis are secondary to the dermal lesion. The former perforates and this is followed by elimination of the altered tissues. Persistence of the lesion is to be ascribed to the fact that the diseased cartilage can not be eliminated completely. CNH is the most frequent of the conditions which show transepithelial elimination. It is less frequent in women because they protect themselves from adverse climatic factors by covering their ears with their hair.     

Depletion of cell surface CD44 in nonmelanoma skin tumours is associated with increased expression of matrix metalloproteinase 7

Background  Expression of matrix metalloproteinase (MMP)-7 and MMP-9 is low in the normal epidermis and is induced by physiological processes such as wound healing, but also malignant transformation of epidermal cells. The activity of both MMPs has been associated with the hyaluronan (HA) receptor CD44. We previously reported that the levels of CD44 and HA differ between the two types of epidermal tumours, basal (BCC) and squamous cell carcinoma (SCC), as well as between different grades of SCC.
Objectives  To investigate if the immunostaining patterns of MMP-7 and MMP-9 correlate to those of CD44 and HA in BCC and SCC.
Methods  Paraffin sections from 71 BCCs, 21 in situ SCCs and 27 SCCs were immunostained for MMP-7 and -9.
Results  Positive immunostaining for MMP-7 and MMP-9 was found in tumour cells of both BCC and SCC, while the staining intensity tended to be stronger in SCC. The staining intensity of MMP-7 was inversely correlated with that of CD44 in both tumour types. In well-differentiated SCC, the intensity of MMP-7 was generally weak, while CD44 staining was strong and homogeneously distributed. In poorly differentiated SCC, an increase in MMP-7 was seen, and the staining intensity of CD44 became weak and was locally absent. No correlation was seen between MMP-9 and CD44 or either of the two MMPs and HA.
Conclusions  Our results show that in nonmelanoma skin tumours MMP-7 and -9 are present in the tumour cells, and suggest a link between MMP-7 activity and the depletion of cell surface CD44.     

Immunohistochemical study on keratin expression in certain cutaneous epithelial neoplasms. Basal cell carcinoma, pilomatricoma, and seborrheic keratosis

We investigated immunohistochemically 20 basal cell carcinomas (BCC), five pilomatricomas, and nine seborrheic keratoses using anti-BCC keratin monoclonal antibody (BKN-1) and anti-hair keratin monoclonal antibodies (HKN-2, HKN-4- -7). The neoplastic cells in all the cases of BCC were always uniformly stained by BKN-1, HKN-2, and HKN-4, indicating that the BCC cells display a constant antigenicity of keratin, which may be different from that of the normal epidermis. Although no fluorescence by HKN-6 or HKN-7 was seen in any cases of BCC, HKN-5 partially but strongly stained the neoplastic nests in most cases of BCC; BCC may have differentiation toward the lower part of hair follicular epithelium. In pilomatricoma, all the anti-keratin monoclonal antibodies showed a similar staining pattern; the differentiating neoplastic cells undergoing transition from basaloid to eosinophilic were positively stained by each antibody in all the cases. This finding of pilomatricoma corresponds to that of the differentiating cells in the inner hair layers, especially in the hair cortex. In seborrheic keratoses, no fluorescence was recognized with HKN-5- -7, which stain the lower follicular cells in the normal human skin. The staining patterns of seborrheic keratosis by BKN-1, HKN-2, and HKN-4 were similar to those of the normal interfollicular epidermis. These anti-keratin monoclonal antibodies seem to be useful for the investigation of the direction of differentiation of skin adnexal neoplasms.     

Matrix metalloproteinases in the progression and regression of Kaposi's sarcoma

BACKGROUND: Matrix metalloproteinases (MMPs) are associated with Kaposi's sarcoma (KS) tumorigenesis. To date, only a few MMPs have been studied in KS lesions. Their role in KS regression has not been investigated. The aim of this study was to evaluate the expression of multiple MMPs in developing and pharmacologically regressed KS lesions. METHODS: Nine samples of acquired immune deficiency syndrome (AIDS)-related and classic cutaneous KS lesions at various histological stages were studied. Regressing KS lesions from three patients treated with systemic therapy were procured after one and two cycles of chemotherapy. Tissue sections from all specimens were immunostained using monoclonal antibodies to MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-13, and MMP-14. RESULTS: KS lesional cells were immunoreactive for all MMPs, except MMP-14. Admixed inflammatory cells were immunoreactive for MMP-1, MMP-2, MMP-7, MMP-9, and MMP-13. The MMP immunoprofile in residual KS lesional cells was unaltered in regressed lesions. Increased extracellular matrix (ECM) and macrophage immunoreactivity for MMPs was identified in regressed specimens. CONCLUSIONS: These data show that developing KS lesional cells express collagenases (MMP-1, MMP-13), gelatinases (MMP-2, MMP-9), stromelysin-1 (MMP-3), and matrilysin (MMP-7) but not the membrane-type MMP-14. This MMP expression profile is retained by residual KS cells and also expressed by infiltrating macrophages in regressed KS lesions. Pantanowitz L, Dezube BJ, Hernandez-Barrantes S, Tahan SR, Dabbous MK. Matrix metalloproteinases in the progression and regression of Kaposi's sarcoma.     

Heat modulation of tropoelastin, fibrillin-1, and matrix metalloproteinase-12 in human skin in vivo

Photoaged skin contains elastotic materials in the upper reticular dermis. This phenomenon is commonly known as solar elastosis. In this study, we investigated the effects of heat on the expression of tropoelastin and fibrillin-1, two main components of elastic fibers, and on matrix metalloproteinase (MMP)-12, the most active MMP against elastin, in human skin in vivo. Heat was found to increase tropoelastin mRNA and protein expression in the epidermis and in the dermis. Fibrillin-1 mRNA and protein expression were increased by heat in the epidermis, but were decreased in the dermis. We found that pre-treatment of skin with N-acetyl cysteine or genistein for 24 h prior to heat treatment inhibited the heat-induced expression of tropoelastin, but not of fibrillin-1. These data indicate that reactive oxygen species may play a role in tropoelastin expression by heat, but not in fibrillin-1 expression. We also found that heat treatment increases MMP-12 mRNA and protein expression in human skin. Our results suggest that the abnormal production of tropoelastin and fibrillin by heat in human skin and that their degradation by various MMP, such as MMP-12, may contribute to the accumulation of elastotic material in photoaged skin.     

Expression of matrix metalloproteinase (MMP)-2, MMP-9, MMP-13, and MT1-MMP in skin tumors of human papillomavirus type 8 transgenic mice

Human papillomaviruses (HPV) are small DNA viruses that induce a wide variety of hyperproliferative lesions in cutaneous and mucosal epithelia. It is proposed that HPV is involved in non-melanoma skin cancer development. We have previously shown that HPV8 transgenic mice spontaneously develop papillomatous skin tumors. Histology revealed epidermal hyperplasia, acanthosis and hypergranulosis and in some cases squamous cell carcinomas (SCC). Zymographic and immunoblot analysis of normal skin extracts identified increased amounts of matrix metalloproteinase (MMP)-9, MMP-13 and MT1-MMP in HPV8-positive mice compared with HPV8-negative animals. In situ gelatin zymography of tumor specimens displayed a strong proteolytic activity in papillomas, and SCC putatively attributed to the increased amounts of activated MMP-9 found in tissue extracts. In addition, immunoblot analysis revealed increased amounts of active MMP-13 and MT1-MMP in tumor extracts as compared with control extracts. Immunohistochemical stainings of SCC specimens depicted MMP-13 to be specifically expressed in stromal fibroblasts neighboring the tumor islands, whereas MT1-MMP was detected both in tumor cells and in stromal cells. Taken together, these results implicate a role for MMPs in the development of HPV8-induced cutaneous tumors.