An Immunohistochemical Study of BCA-225 in Various Skin Cancers

We performed an immunohistochemical study of BCA-225, which is a glycoprotein secreted by the T47D breast carcinoma cell line and recognized by monoclonal antibody BRST-1 (clone name: CU-18), in normal skin and various skin cancers. In normal skin, BCA-225 was positive only in the secretory portion of both eccrine and apocrine glands and in mature cells of the sebaceous gland. We observed 10 cases of squamous cell carcinoma of the skin, 10 cases of basal cell carcinoma without sebaceous differentiation, 3 cases of basal cell carcinoma with sebaceous differentiation, 6 cases of malignant trichilemmoma, 8 cases of eccrine porocarcinoma, 3 cases of ductal carcinoma, 1 case of malignant clear cell hidradenoma, 1 case of apocrine adenocarcinoma, 6 cases of extra-ocular sebaceous carcinoma, 5 cases of extramammary Paget's disease with underlying adenocarcinoma, and 11 cases of extramammary Paget's disease without underlying adenocarcinoma. Most of the cases of sweat gland carcinoma, basal cell carcinoma with sebaceous differentiation, sebaceous carcinoma, and extramammary Paget's disease were positive for BCA-225, while none of the cases of squamous cell carcinoma, basal cell carcinoma without sebaceous differentiation, or malignant trichilemoma were positive. Based on these findings, we believe that BCA-225 is useful in distinguishing tumors with sweat gland and sebaceous differentiation and extramammary Paget's disease from tumors without such differentiation.     

CD44 Expression in Normal Human Skin and Skin Tumors

CD44 is thought to be a principal cell surface receptor for hyaluronic acid. Although the distribution of hyalulonic acid has been studied, little is known about the distribution of the CD44 molecule in the human skin and skin tumors. This study was undertaken to investigate the distribution of the CD44 molecule in normal human skin as well as in benign and malignant skin tumors. In normal skin, CD44 was expressed on 1) keratinocyte cell surfaces throughout the epidermis except for the granular and horny layers, 2) hair follicular cells, 3) eccrine sweat gland cells, and 4) cell surfaces of dendritic cells in the dermis. In skin tumors, although CD44 was expressed on the tumor cell surface of seborreic keratosis, Bowen's disease, and squamous cell carcinoma as in normal skin, we could not detect any CD44 expression on the cell surface of the tumor cells of basal cell carcinoma. However, CD44 positive dendritic cells were observed in the tumor islands of basal cell carcinoma. Phenotypic analysis suggested that these CD44 positive cells were melanocytes.     

Differentiation-associated localization of small prolne-rich rotein in normal and diseased human skin

Summary The expression of SPRR (small proline-rich protein) was investigated in normal human skin and in diseased skin from patients with psoriasis, squamous cell carcinoma, basal cell epithelioma. Naevus pigmentosus, ichthyosis vulgaris and several inflammatory skin diseases, by immunohistochemical staining. A polyclonal antibody was raised against a synthetic peptide for a C-terminal common region for SPRR l and SPRR 3. In immunoblot analysis, a positive band of 18kDa was detected, which showed the presence of SPRR l in human epidermal keratinocytes. In normal epidermis, positive staining for SPRK was observed in keratinocytes in the granular layer and the uppermost or two spinous cell layers, with no staining of the other spinous or basal layers. The staining was obvious at the cell periphery, weak at the cytoplasm, and absent in the nucleus. Staining was observed in several outer layers of the follicular infundibulum to the isthmus. No staining was detected in the inner root sheath of the hair follicles, hair matrix, sebaceous gland, eccrine gland, eccrine duct, melanocytes. Langerhans cells or fibroblasts. The arrectores pilorum, striated muscles, muscle layers of vessels, and myoepithelia of eccrine gland, were weakly stained. In psoriatic skin, stained keratinocytes were distributed in the spinous cell layers except for the basal layer, in ichthyosis vulgaris. SPRR was barely expressed in the uppermost living cell layers of the epidermis in epidermolytic hyperkeratosis. degenerated squamous cells widely expressed SPRR. In Darier's disease, dyskeratolic cells were clearly stained. In squamous cell carcinoma, staining was observed in keratotic cells around horny pearls. In basal cell epithelioma, naevus pigmentosus, and malignant melanoma, the tumour cells or naevus cells were not stained. The distribution of SPRR was similar to that of involucrin in normal and several diseased skin, except for ichthyosis vulgaris. We conclude that SPRR is expressed in close association with epidermal differentiation in normal skin and skin diseases. The alteration of the expression of the proteins correlated to terminal differentiation, and differs from disease to disease.     

Immunohistochemical distribution of adult T-cell leukemia-derived factor/thioredoxin in epithelial components of normal and pathologic human skin conditions.

Tissues from normal human skin and various skin diseases were studied with the immunoperoxidase technique using an antibody to adult T-cell leukemia-derived factor (ADF), a homologue of human thioredoxin. Normal human skin showed positive immunostaining for ADF/thioredoxin in the outer root sheath of hair follicle, sebaceous glands, and secreting components of apocrine and eccrine sweat units, but not in the unexposed interfollicular epidermis and other parts of both hair follicles and the sweat units. Immunoreactivity of benign skin tumors gave similar distribution to their normal counterparts; trichilemmal cyst, nevus sebaceus, senile sebaceous hyperplasia, and mixed cell tumor were positive for immunostaining, whereas epidermal cyst and pilomatricoma were not. No immunoreactivity was detected in malignant skin tumors such as basal cell carcinoma and poorly differentiated squamous cell carcinoma. Solar keratosis, well-differentiated squamous cell carcinoma, some of metastatic lesions of squamous cell carcinoma, and extramammary Paget's disease reacted with the antibody. These immunoreactivities reflected numerous functions of thioredoxin in higher organisms. Our findings suggest that the expression of ADF/thioredoxin in both normal and abnormal human skin is related to epithelial cell differentiation.     

生存素和端粒酶逆转录酶在皮肤肿瘤中的表达

目的 研究皮肤肿瘤凋亡抑制基因生存素与人端粒酶逆转录酶(hTERT)的表达及相互关系.方法 免疫组化SP法检测17例鳞状细胞癌(鳞癌)、21例基底细胞癌(基癌)、19例鲍恩病、25例脂溢性角化病和13例正常人皮肤组织中生存素表达水平;原位杂交法检测上述组织中hTERT mRNA的表达水平;分析皮肤肿瘤中生存素与hTERT mRNA表达的相关性.结果 ①在鳞癌、基癌、鲍恩病中生存素及hTERT mRNA表达的阳性率均较正常人皮肤中显著增加;②脂溢性角化病中生存素表达的阳性率与正常人皮肤组织中比较差异有统计学意义,但hTERT mRNA表达的阳性率与正常人皮肤组织中比较差异无统计学意义;③鳞癌、基癌、鲍恩病中生存素阳性率及hTERT mRNA阳性率之间均呈显著正相关,脂溢性角化病中两者阳性率之间无显著相关性.结论 生存素与皮肤肿瘤发病关系密切,在鳞癌、基癌、鲍恩病中生存素与hTERT mRNA的表达具有一定的相关性.     

水通道蛋白3在四种皮肤肿瘤中的表达

目的 探讨水通道蛋白3（AQP3）在四种皮肤肿瘤组织中的表达及意义。方法 应用免疫组织化学方法检测30例脂溢性角化病、15例Bowen病、32例鳞状细胞癌、17例恶性黑素瘤及15例正常人皮肤组织中AQP3的表达。结果 脂溢性角化病、Bowen病、鳞状细胞癌、恶性黑素瘤及正常人表皮组织中均存在AQP3蛋白的表达;脂溢性角化病皮损中AQP3表达水平与正常人对照组差异无统计学意义（P > 0.05）;Bowen病、鳞状细胞癌及恶性黑素瘤皮损中AQP3蛋白表达显著高于正常人对照组（P < 0.01）,其中鳞状细胞癌与恶性黑素瘤的表达最强,均显著高于Bowen病（P < 0.01）,但鳞状细胞癌与恶性黑素瘤比较差异无统计学意义（P > 0.05）。此外,在鳞状细胞癌中AQP3的表达与肿瘤的分化有显著相关性（P < 0.01）;在已转移恶性黑素瘤中AQP3的表达显著高于未转移恶性黑素瘤（P < 0.05）。结论 AQP3在皮肤恶性肿瘤中表达上调。     

Greater expression of TC21/R-ras2 in highly aggressive malignant skin cancer

Background TC21 plays an important role in highly aggressive tumor formation, and it was overexpressed in several human cancers, including breast cancer, oral squamous cell carcinoma (SCC), and esophageal SCC. In light of this, we explored the expression of TC21 in overall skin cancers in order to evaluate the relationship between TC21 and malignant skin tumors. Methods We examined six normal skin tissues and 18 malignant skin tumor tissues, including six malignant melanomas (MM), six SCCs, and six basal cell carcinomas (BCCs) using western blotting for the expression of TC21. In another set, 16 specimens of MM, 16 SCC, and 16 BCC were analyzed for the expression of TC21 using immunohistochemical staining. To evaluate the amount of expression of TC21, the Raytest TINA software was used for western blotting and a histochemical score (HSCORE) was used for immunohistochemical evaluation. Results The western blotting and immunohistochemistry showed that TC21 was expressed in all malignant skin tumors and not in normal skin tissues. The relative protein expression was an average of 0.004 in normal skin, 1.042 in MM, 0.621 in SCC, and 0.485 in BCC. In immunohistochemistry, HSCORE for normal skin was an average of 0.05, MM was 2.42, SCC was 2.11, and BCC was 1.22. Conclusions This article is the first study demonstrating expression of TC21 in human skin malignant tumors and suggests that TC21 is more expressed in highly aggressive skin tumors.     

Jagged1蛋白在银屑病、基底细胞癌及皮肤鳞状细胞癌中的表达

目的探讨Jagged1蛋白在银屑病、基底细胞癌及皮肤鳞状细胞癌中的表达及意义。方法采用免疫组化Envision法检测Jagged1蛋白在银屑病、基底细胞癌及皮肤鳞状细胞癌皮损中的表达。结果 Jagged1蛋白在寻常性银屑病患者皮损中呈阴性表达,在基底细胞癌及皮肤鳞状细胞癌中的表达较正常人皮肤增强,差异有统计学意义(P<0.01);Jagged1蛋白在基底细胞癌及皮肤鳞状细胞癌中的表达较银屑病增强,差异有统计学意义(P<0.05)。结论 Jagged1蛋白在银屑病发病机制中与角质形成细胞异常增生及真皮乳头血管增生等组织病理变化可能不相关,提示此蛋白可能与皮肤恶性肿瘤的异常增生有关。     

Expression of transferrin receptor in normal human skin, psoriatic skin and various skin tumors

The distribution of transferrin receptor in normal human skin and its expression in psoriatic skin and various skin tumors have been investigated. Immuno-peroxidase staining was performed on biopsy specimens using monoclonal OKT 9 antibody, which reacts with transferrin receptor. Normal human skin showed positive staining with OKT 9 in eccrine glands and outer root sheaths of the hair. Sebaceous glands were also strongly positive. The basal layer stained very weakly. Psoriatic skin expressed OKT 9 strongly in the epidermis, especially in the area of the rete ridge. In squamous cell carcinoma, Bowen's disease, and malignant melanoma, a widespread and strong labelling reaction was found. Basal cell epithelioma and genital Paget's disease were partially and moderately positive in their staining pattern. No such positive staining pattern could be found in either nevus cell nevi or seborrhoic keratosis. These findings indicate that, in normal skin, transferrin receptor exists in eccrine glands, sebaceous glands, and outer root sheaths of the hair in greater amounts. High amounts of expression of this receptor in psoriatic epidermis and malignant tumors suggests that immunohistochemical demonstration of transferrin receptor parallels the proliferating activity of the tissue or tumor of the skin and may provide an useful aid for detecting such conditions.     

Immunohistochemical localization of cathepsin L and cystatin A in normal skin and skin tumors

Cathepsin L, a cysteine proteinase, and cystatin A, an inhibitor of cysteine proteinases, are thought to regulate the invasion and metastasis of malignant cells. In this study, the expression of cathepsin L and cystatin A in skin tumors was investigated immunohistochemically in order to examine the relationship between these two enzymes in the pathophysiology of malignant cells. Formalin-fixed and paraffin embedded specimens from normal skin, seborrheic keratoses, and squamous cell carcinomas were reacted with polyclonal antibodies against rat cathepsin L or cystatin a which cross-react to human cathepsin L and cystatin A, respectively. The consequent immunostaining of these enzymes was observed to be strong in normal skin (4 cases) and seborrheic keratosis (6 cases). In well-differentiated squamous cell carcinoma (SCC) (9 cases), staining for cathepsin L and cystatin A was moderately positive in differentiated tumor cells and negative in undifferentiated SCC (5 cases). The degree of staining of these enzymes was inversely correlated with the differentiation of the malignant cells. These results suggest that the immunohistochemical analysis of cathepsin L and cystatin A is a useful indicator for an aspect of malignancy in human epidermal keratinocytes.     

An Immunohistochemical Study of Sebaceous Carcinoma with Anti-Keratin Monoclonal Antibodies: Comparison with Other Skin Cancers

Formalin-fixed and paraffin-embedded tissue specimens of six cases of extraocular sebaceous carcinoma were studied immunohistochemically with eight anti-keratin monoclonal antibodies, 34βB4, 35βH11, Ks13.1, Ks19.1, PKK1, LP34, KL1 and AE1. The staining patterns of sebaceous carcinoma were compared with those of normal sebaceous glands and other skin cancers which should be distinguished from sebaceous carcinoma histopathologically. The other skin cancers compared were eccrine porocarcinoma, malignant clear cell hidradenoma, extramammary Paget's disease with underlying adenocarcinoma, malignant trichilemmoma, and squamous cell carcinoma. Most cases of sebaceous carcinoma were stained with 35βH11, Ks19.1, LP34, KL1 and AE1, while normal sebaceous glands were positive only with 35βH11, LP34, KL1 and AE1. By immunostaining, sebaceous carcinoma was distinguishable from extramammary Paget's disease with underlying adenocarcinoma, squamous cell carcinoma, malignant trichilemmoma, and eccrine porocarcinoma, but was not clearly distinguishable from malignant clear cell hidradenoma. These findings demonstrate that sebaceous carcinoma shows positive reactions with antibodies to simple epithelial keratin, probably as a result of neoplastic transformation, and that immunohistochemical examination using anti-keratin monoclonal antibodies is useful in distinguishing sebaceous carcinoma from several other skin cancers.     

Immunohistochemical comparison of beta-catenin expression by human normal epidermis and epidermal tumors

beta-Catenin, a cytoplasmic protein that binds directly to the intracellular domain of cadherin, controls various functions such as cell adhesion. In many human carcinomas, E-cadherin-mediated cell-cell adhesion is lost or disturbed and related to metastasis. The purpose of this study was to compare the expression of beta-catenin in the normal epidermal keratinocytes and samples from cutaneous benign and malignant epidermal tumors in 140 patients. Our study population consisted of 140 patients with benign or malignant epidermal tumors. Using immunohistochemical methods, we compared the expression of beta-catenin in their normal epidermal keratinocytes, and in samples from 61 benign (seborrheic keratosis, n = 33; verruca vulgaris, n = 14; keratoacanthoma, n = 14), and 79 malignant (Bowen's disease, n = 18; basal cell carcinoma, n = 33; squamous cell carcinoma, n = 28) epidermal tumors. beta-Catenin was found to be expressed in the cell membrane of normal keratinocytes. Compared to other cell components of the normal epidermis, basal cells showed the strongest beta-catenin expression in all 140 patients. While absent in three of 61 benign tumors, compared to normal basal cells, the expression of beta-catenin in the other 58 tumors was not significantly different; it was reduced in 71 of 79 malignant tumors (P < 0.0001). In Bowen's disease, the expression of beta-catenin on the tumor cell membrane was reduced, however, strong expression was seen in the nuclei and cytoplasm. Our results suggest that beta-catenin expression on the membrane of keratinocytes is associated with the differentiation of normal keratinocytes but not with their stage of differentiation, nor with the proliferation ability of epidermal tumor cells.     

尖锐湿疣、鲍恩样丘疹病、Bowen病及外阴鳞状细胞癌皮损中端粒酶的表达

目的 探讨端粒酶在正常组织、良性增殖性疾病及恶性肿瘤中的表达情况及其临床意义。方法 采用免疫组化方法检测皮损中端粒酶逆转录酶(hTERT)蛋白的表达情况,并对所有鲍恩样丘疹病和Bowen病病例进行组织病理分析。结果 正常人对照组、尖锐湿疣组及外阴鳞状细胞癌组中任两组间hTERT表达强度差异均有统计学意义,其阳性率依次增高。鲍恩样丘疹病组较尖锐湿疣组hTERT表达强度高,两组差异有统计学意义;虽与Bowen病组比较差异无统计学意义,但较外阴鳞状细胞癌组表达强度低,差异有统计学意义。组织病理上,Bowen病比鲍恩样丘疹病细胞异形性更明显。结论 端粒酶在正常组织、良性增殖性疾病及恶性肿瘤中的表达强度呈梯度升高,提示端粒酶激活在细胞增生及永生化中均发挥重要作用。     

端粒酶逆转录酶在皮肤肿瘤原位表达水平的比较

目的　研究端粒酶在皮肤恶性肿瘤发病机制中的作用。方法　采用人端粒酶逆转录酶 (hTERT)cRNA探针与石蜡标本进行原位杂交的方法检测 3 0例皮肤基底细胞癌、15例皮肤鳞状细胞癌、19例脂溢性角化、14例正常皮肤中hTERTmRNA的表达水平 ,并进行比较。结果　hTERT阳性率基底细胞癌为 73 .3 5 %(2 2 /3 0 ) ,鳞状细胞癌为80 .0 0 %(12 /15 ) ,均明显高于脂溢性角化 3 6.84%(7/19)和正常皮肤 2 8.5 7%(4 /14 ) ,并具有统计学意义。结论　hTERT在恶性皮肤肿瘤中的阳性表达率明显高于良性肿瘤和正常皮肤 ,提示端粒酶在皮肤恶性肿瘤发病机制中起着重要作用。原位杂交检测hTERT表达水平的方法有可能成为鉴别皮肤良恶性肿瘤的辅助检查手段。     

Carcinoma erysipeloides associated with anaplastic thyroid carcinoma

Cutaneous metastases from carcinoma of the thyroid gland are rare and carcinoma erysipeloides is even rarer. We present the clinical, histological, and immunohistochemical features of inflammatory erysipeloid metastases arising from an anaplastic carcinoma of the thyroid gland. In this case the anaplastic carcinoma probably transformed from a pre-existing, long-standing papillary carcinoma of the thyroid gland. Although visible inflammation is a hallmark of many benign skin disorders, it is not commonly present in cutaneous malignant metastases. As a result, the significance of a marked inflammatory changes in association with metastatic skin disease may not be recognized. Dermatologists need to be aware of the potential for inflammatory manifestations in cutaneous metastases from a thyroid carcinoma.     

Expression of α subunit of guanine nucleotide-binding protein Go in Merkel cell carcinoma

The α subunit of guanine nucleotide-binding protein G_o(G_oα), which was initially isolated from bovine brain, interacts with muscarinic cholinergic receptors and regulates neuronal calcium channels. G_oα is known to be localized in neural tissues, some endocrine cells, and neuroendocrine tumors. We have immunohistochemically investigated the expression of G_oα in 4 cases of Merkel cell carcinoma using the method of microwave treatment. In all cases of Merkel cell carcinoma, G_oα was consistently detected on the plasma membrane and cytoplasm of the tumor cells. Nerve fibers in the skin were also positive for G_oα, but other epidermal or dermal components such as keratinocytes, melanocytes, fibroblasts, or lymphoid cells were negative. Tumor cells of squamous cell carcinoma, cutaneous lymphoma, sweat gland carcinoma, and malignant melanoma were negative for G_o4aL. The present study indicates that G_oα may be a useful immunohistochemical marker of Merkel cell carcinoma.     

Multicellular origin of tenascin in skin tumors – an in situ hybridization study

Tenascin mRNA expression was studied by an in situ hybridization method in 27 skin tumors. Tenascin synthesis was increased in all skin tumors when compared to uninvolved skin but there was variation in the site of cellular synthesis between different types of tumors. In melanocytic nevi and precancerous keratinocyte lesions, tenascin seemed to be of epidermal or stromal origin. In basal cell carcinoma, squamous cell carcinoma and malignant melanoma, there was tenascin synthesis also in tumor cells. These findings are in concordance with earlier studies which suggest a role of tenascin as an anti-adhesive and motility-promoting factor in malignant skin tumors.     

角质形成细胞增生行为与p16INK4a蛋白表达和基因失活的相关性研究

目的：探讨角质形成细胞(KC)增生行为与p16^INK4a蛋白表达及其基因失活的相关性。方法：对20例皮肤鳞状细胞癌、24例基底细胞癌、18例Bowen病、12例光线性角化病以及8例脂溢性角化病共计82例患者中具不同增生行为的KC,分别应用免疫组化检测其p16^INK4a蛋白表达：应用聚合酶链反应(PCR)、PCR-单链构象多态性以及PCR-限制性内切酶分析方法分别检测p16^INK4a基因外显子1和外显子2的缺失、突变和甲基化。结果：p16^INK4a蛋白表达的阳性率和表达强度随着KC恶性程度的增加而降低,基因缺失和甲基化是皮肤癌p16^INK4a基因失活的主要方式,p16^INK4a蛋白失表达与其基因失活是一致的。结论：p16^INK4a基因失活在KC恶性转化中起重要作用;p16^INK4a基因有可能成为皮肤癌诊断与治疗的一种新靶位。     

基因工程抗角蛋白抗体在正常皮肤和几种表皮增生性皮肤病皮损中的反应定位

目的　探索一株基因工程人源性抗角蛋白Fab抗体在正常皮肤及几种表皮增生性皮肤病皮损中的反应定位。方法　利用从噬菌体抗体库中筛选到的特异表达抗角蛋白Fab片段的质粒转化大肠杆菌 ,IPTG诱导表达出Fab抗体 ,纯化鉴定后用此抗体对正常皮肤及银屑病、鳞癌、基底细胞癌和脂溢性角化病皮损进行免疫组化染色。结果　正常皮肤表皮呈阴性染色 ,毛囊呈阳性染色 ,银屑病、鳞癌、基底细胞癌和脂溢性角化病皮损均呈现明显的阳性着色 ,其中银屑病皮损基底细胞层为强阳性。所有细胞染色部位均位于胞质 ,胞核未见着色 ,真皮为阴性。结论　该株人源性抗角蛋白Fab抗体主要与表皮组织结合 ,对银屑病等表皮增生性皮肤病的损害具有较高特异性。     

Hautkrebs und Berufserkrankung

Although it is universally accepted that UV light exposure can cause malignant skin tumors, UV-induced skin cancers are not recognized as an occupational disease in Germany. Exposure to natural or artificial UV light occurs in many work places, so that the induction of occupational skin cancers is certainly plausible. In recent years, a special clause in the occupational disability rules has recognized some cases of UV-induced skin cancers. We discuss the nature of occupational UV exposure, explore preventative measures and review the data regarding occupational UV-induced skin tumors. After evaluating recent publications, we conclude that for squamous cell carcinoma the epidemiological proof of an at least doubled risk (RR >2) due to occupational UV radiation can be given. The clear dose response relationship supports these epidemiological findings. For the individual risk assessment, an attributive UV radiation >40% due to occupational factors must exist. Under those circumstances, squamous cell carcinoma should be recognized and compensated as an occupational disease.