Effects of Krestin (PSK) on Tumorigenesis Induced by Two-stage and Complete Chemical Carcinogenesis

The effects of PSK on tumorigenesis in mouse skin were investigated either when mouse skins were initiated by benzo(a)pyrene and promoted by 12-O-tetradecanoyl-phorbol-13-acetate (Group I, two-stage carcinogenesis) or when both initiated and promoted by benzo(a)pyrene (Group II, complete carcinogenesis). Twelve mice in each group were fed chow with or without 0.4% PSK. This concentration of PSK was determined by calculation to give mice enough PSK to exert antitumorigenic activity without cytotoxicity. By the end of the experimental periods (26 weeks), two carcinoma-burdened mice in Group I without PSK were dead, but no carcinomas at all were identified in the mice fed with PSK, although considerable numbers of papillomas developed in both groups. In Group II, carcinomas started to evolve at the 15th week of the experiment regardless of PSK feeding. The number of carcinomas observed in the mice fed with PSK in Group II was statistically significantly lower than that in the mice fed without PSK. Histologically, mild inflammatory infiltrations were seen around the papillomas, and moderate to dense infiltrations, mainly composed of neutrophils, T lymphocytes, and macrophages, were observed in squamous cell carcinomas. There were apparently no significant differences in the number of the infiltrating cells around carcinomas in PSK (+) and PSK (?) groups in both early and fully developed lesions. However, considerable numbers of cells infiltrating into the nests were observed in the early lesions of elicited carcinomas in the mice fed with PSK, while such cells were rarely seen in carcinoma nests in the group without PSK at that stage. The multi-stage carcinogenesis regimen which evokes both benign and malignant epidermal tumors in mouse skin should provide insights into the function of the specific infiltration of immuno-competent cells and should also be a valid system for the quantitative and qualitative analysis of the anti-tumor effects of immunopotentiators such as PSK.     

Basal cell carcinomas are populated by melanocytes and Langerhans [correction of Langerhan's] cells

Several reports have documented the coexistence of basal cell carcinoma (BCC) with other lesions, including melanoma. This study was performed to determine whether nests of BCC contain benign melanocytes and Langerhans [corrected] cells. Ten cases of BCC were investigated to determine whether benign melanocytes and Langerhans [corrected] cells populate tumor nests. The BCCs were stained with antibodies to cytokeratin AEI/AE3, S-100, HMB-45, Melan-A, and CD1a proteins. We report that all 10 BCCs were populated by dendritic melanocytes distributed at the periphery (5/10 cases) or evenly throughout tumor nests (5/10 cases). Clusters of melanocytes were not identified in any of the BCCs. A total of 9 of 10 tumors showed staining of dendritic Langerhans cells with CD1a. A total of 8 of 10 tumors stained with cytokeratin AEI/AE3; in 6 of the 8 tumors, the staining was focal. We compared these findings with a single example of a BCC and melanoma in situ (MIS) collision tumor in which the cytokeratin AE1/AE3-positive epithelial nests of BCC were populated by a high density of malignant melanocytes that stained with S-100 and HMB-45. Melanocytes were disposed singly and in clusters of two or more cells within BCC tumor nests. We conclude from this study that BCCs are regularly populated by benign melanocytes and Langerhans [corrected] cells. Furthermore, when BCC is infiltrated with malignant melanocytes of MIS, the melanocyte density is higher and clusters of melanocytes can be observed. The significance of these two findings is unclear, as additional cases of BCC MIS collision tumor need to be studied.     

Immunophenotyping and morphometry of inflammatory infiltrates in variants of basalioma

The inflammatory infiltrate of 5 histologically different types of basal cell carcinoma (BCC) (n = 22) was characterized by means of the alkaline phosphatase monoclonal antialkaline phosphatase technique (APAAP). We proved a distinct stromal pattern of infiltration, which was focally accentuated; in some cases, the cells infiltrated the tumor itself. On phenotyping these cells, we found clear predominance of T cells (75%), which mostly consisted of T helper/inducer cells (45%) and suppressor/cytotoxic cells (32%); in addition, we found B cells (6%) as well as monocytes and macrophages (15%). Morphea-like and adenoid types of BCC showed some tendency to a less pronounced infiltration. Chronic exposure to sunlight and ulceration did not significantly influence the quality or quantity of the inflammatory infiltrate--except for polymorphonuclear leucocytes and macrophages.     

盘状红斑狼疮继发口唇鳞状细胞癌1例

报告1例盘状红斑狼疮继发口唇鳞状细胞癌。患者女,62岁。面部、右侧手背盘状红斑30年,上唇菜花状增生物1年,迅速增大3月。皮肤组织病理检查:盘状红斑处皮损示角化过度,棘层萎缩,表皮突变平,基底细胞液化变性,真皮层有淋巴细胞灶性浸润。菜花状增生物皮损示:真皮内广泛分布由表皮细胞形成的癌细胞巢,癌巢内表皮细胞轻度异形性改变,可见病理性核分裂,有大量角化珠形成。癌细胞团周围少许炎症细胞浸润。诊断盘状红斑狼疮继发口唇鳞状细胞癌。     

Melanotrichoblastoma: immunohistochemical study of a variant of pigmented trichoblastoma

Trichoblastomas (TBs) are benign skin tumors recapitulating the differentiation of hair follicles. Several pathologic variants have been described, including the rare pigmented TB. We report a deeply pigmented nodular tumor excised on the scalp of a 32-year-old African woman, which was clinically suggestive of blue nevus or melanoma. Histologically, the tumor presented features of TB, remarkable by virtue of heavy melanin deposits found within and around tumor nests. By immunohistochemistry, abundant dendritic melanocytes with features of hair follicle melanocytes (expression of S100 protein, tyrosinase, and, most importantly, gp100/HMB-45) were found within the tumor masses. By analogy with melanoacanthoma, a tumor consisting of a combined proliferation of epidermal keratinocytes and melanocytes, we called this tumor "melanotrichoblastoma" and view it as a peculiar variant of (pigmented) TB.     

Psoriasis vulgaris - an inflammatory skin disease and/or benign epidermal hyperplasia

Psoriasis vulgaris (PV) is a systemic inflammatory disease in which immune and genetic factors are involved in the pathogenesis. Some treatment approaches in PV patients have been similar to therapy of some tumors. This fact has led to a new scientific approach to PV not only as an inflammatory disease, but also as a benign epidermal hyperplasia or a benign tumor. In this article, we hypothesize that there has been a parallel between some benign tumors and neoplasms and PV. The aim of this article is to present the approach to PV as an inflammatory disease as well as benign epidermal hyperplasia or tumor, and to introduce a new meaning.     

Ultraviolet light exposure stimulates HMGB1 release by keratinocytes

The primary cause of non-melanoma skin cancer is ultraviolet (UV) light from the sun. Many studies have demonstrated that cutaneous inflammation resulting from UV exposure is important for the development of skin cancer. In fact, anti-inflammatory drugs have been shown to be effective in preventing skin cancer in animal models and in clinical trials. One new class of inflammatory mediators that could regulate UV-induced inflammation and skin carcinogenesis is alarmins. Alarmins are endogenous molecules that act as potent pro-inflammatory mediators when they are released by cells or accumulate extracellularly. The purpose of the current studies was to examine the expression and release of the alarmin high mobility group box 1 (HMGB1) after acute and chronic UV irradiation. Acute UV exposure stimulated the release of HMGB1 in cultured human keratinocytes and epidermal keratinocytes in murine skin. HMGB1 release correlated with pro-inflammatory cytokine production in vitro and inflammatory cell infiltration in vivo. HMGB1 was also examined in tumors arising in chronically irradiated murine skin. HMGB1 protein expression in low grade, benign papillomas was similar to adjacent skin. However, HMGB1 staining was more widespread with a higher number of HMGB1-positive cells observed in high grade papillomas and malignant tumors. Overall, the data suggest that HMGB1 may be an important regulator of UV-induced cutaneous inflammation and tumor formation. Additional studies are needed to assess whether targeting HMGB1 would be a useful strategy to prevent tumors from developing in response to chronic UV exposure.     

人类原始抗原（CD34）在毛发上皮瘤和基底细胞癌中的表达

毛发上皮瘤是一种向毛囊分化的良性肿瘤，常与基底细胞癌混淆。应用人类原始抗原（ＣＤ３４）检测７例毛发上皮瘤和１２例基底细胞瘤中表达，结果：在正常皮肤血 皮细胞、血管周围和真皮内梭形细胞、毛囊、小汗腺周围梭形细胞阳性。毛发上皮瘤瘤团周围梭形细胞阳性，而基底细胞癌外周间质阴性，说明ＣＤ３４染色有助于临别这两种肿瘤。     

皮肤镜表现为红色均质模式的Spitz痣一例

19岁女性患者,右乳下缘红棕色斑块10余年,逐渐增大。皮肤镜检查:中央均质暗红色区域,可见白色晶状体结构,周边对称分布网状色素沉着和色素条纹向四周呈放射状排列。皮损组织病理示:表皮和真皮可见大量梭形细胞和上皮样黑素细胞组成的瘤细胞巢,具有典型收缩间隙,周围炎性细胞浸润。诊断:Spitz痣。     

Basement membrane laminin and type IV collagen in various benign and malignant adnexal tumors of the skin: an immunohistochemical study

Thirty benign and seven malignant adnexal tumors of the skin and one lymph node metastasis were stained for laminin and type IV collagen with rabbit antibodies against the human basement membrane (BM) proteins using the immunoperoxidase technique. Fifteen of the benign sweat gland, sebaceous gland, and hair follicle tumors showed a continuous and distinct BM around the tumor aggregates. The cylindromas and eccrine spiradenomas seemed to produce excessive amounts of BM material, part of which was seen as amorphic patches within the tumor cell clusters, whereas the trichofolliculomas, trichoepitheliomas, and pilomatrixomas showed an absence of BM from many areas. In syringomas, in addition to the tubular structures surrounded by a continuous BM, undifferentiated cell nests containing granular BM material were present. They probably represent primitive structures obtaining during early development into tubules. The seven malignant tumors and the only metastasis studied here all contained small, narrow strips of BM material extracellularly between the infiltrating tumor clusters. Only in two cases was faint staining for laminin found within the cells. The pepsin pretreatment of the formalin-fixed, paraffin-embedded samples had most probably degraded the intracytoplasmic BM material in most cases. The BM defects were found to be associated with malignancy and low differentiation of the adnexal skin tumors, as reported previously for other tumor types, but a partial loss of BM was also associated with high differentiation in some benign adnexal tumors.     

Six cases of perforating pilomatricoma: Anetodermic changes with expression of matrix metalloproteinases

Perforating pilomatricoma (PP) is a rare clinical variant of pilomatricoma presenting as a crusted or ulcerated nodule. Previous reports have suggested that the tumor cells perforate the epidermis through a process of transepithelial elimination. Here, we report six cases of PP and examine the mechanism of transepithelial elimination in PP. Histologically, the dermis above or around the tumor nest exhibited edema, dilated vascular spaces, sparse collagen bundles and absence of elastic fibers, suggesting anetodermic changes in all cases. Immunohistochemistry demonstrated many CD68-positive macrophages around the tumor nests. Matrix metallopeptidase (MMP)-9 and MMP-12 were expressed in the inflammatory cells and tumor cells, and were also present in the epidermis and fibroblasts in all cases. We speculate that in PP anetodermic change caused by MMP and elastases including MMP-9 and MMP-12 may precede elimination of the tumor.     

Nevoid malignant melanoma

Summary Primary cutaneous malignant melanomas with histological features suggestive of benign nevocytic nevi were studied. From a total of about 3,500 cases, 33 patients with sufficient records, histological slides, and follow-up (at least 5 years for disease-free cases) were found; 15 of them had developed metastases, and 8 had died of disseminated melanoma. Some of the following histological characteristics were always observed: cellular atypia, mitoses, infiltration of adnexa, and in the deeper dermis, infiltrative growth, pigmented tumor cells, sharply demarcated tumor nests, and the absence of maturation. Tumor thickness was the most important prognostic criterion. Clinically, the tumors corresponded to nodular and superficial spreading melanomas. It is concluded that, in rare instances, malignant melanomas strongly resemble benign melanocytic/nevocytic nevi. Such cases do not appear to have a lower degree of malignancy and should be treated as normal malignant melanomas.     

Stereographic analysis of syringomas

Summary To investigate biological characteristics of syringomas, three-dimensional (3-D) architectures of epithelial tumor nests and luminal structures of syringomas, hair follicles, and epidermal basement membrane in skin lesions were reconstructed using a computer stereographic analysis. Each lesion was composed of many spherical- to ovoid-shaped tumor nests, which interconnected with each other by narrow tumor strands, showing features of ginger roots or budding fungi. Small discrete tumor nests were often present in the peripheral areas of the lesions. Tumor nests developed around hair follicles and beneath epidermis, but they were never connected with hair follicles or epidermal basement membrane, although occasionally such structures were slightly bent by a pressure from the developing tumor nests. There was no relationship between tumor nests and normal sweat glands. Many tumor nests formed luminal structures; however, some small tumor nests did not. Most of the luminal structures were disconnectedly present. These findings suggest that in each lesion syringoma may occur in a single focus in the upper dermis without a relationship to the surrounding normal epithelial tissues, develop and partly swell forming lumina, and then the peripheral parts of the tumor may become discrete. The ratio of [lumen volume/ tumor nest volume] measured by computer stereometry was 0.275±0.037 (n=5); this indicates a constant ability to form luminal structures by syringoma cells.This work has been partly presented at the XVII World Congress of Dermatology, Berlin, 24–29 May, 1987     

Pagetoid Merkel cell carcinoma: epidermal origin of the tumor

We report a case of intraepidermal Merkel cell carcinoma which occurred on the face of a 76-year-old white male. This slow-growing tumor was mostly confined in the epidermis and pilosebaceous apparatus where tumor cells spread in a pagetoid fashion forming tumor cell nests. Histologically it resembled a superficial spreading melanoma. A heavy lymphocytic infiltration was seen beneath the epidermal lesion as is often seen in pagetoid melanomas. Histochemical and ultrastructural features such as the presence of cytokeratin 20, synaptophysin, neuron specific enolase, desmosomes, and dense cored granules confirmed the diagnosis of Merkel cell carcinoma. Occasional mitotic cells and many apoptotic cells were found in the tumor. Dylon positive, amyloid depositions were seen in the lower epidermis and papillary dermis; they were probably derived from apoptotic tumor cells. It was thought that apoptosis limited the speed of growth of this tumor. We believe that this is probably the most convincing case of intraepidermal Merkel cell carcinoma originating from epidermal Merkel cells or its precursors (stem cells).     

Strong anti-tumor effect of monosialoganglioside specific monoclonal antibody 202: a clinical trial in a cancer patient with melanoma

Mab 202, a mouse monoclonal IgM antibody which recognizes sialic acid alpha 2----3 galactosyl residue in monosialogangliosides and reacts with human melanoma cells but not with normal cells, was administered to a melanoma patient by either intralesional injection or intravenous infusion. Mab 202 induced regressions of the metastatic tumors without side effects. Histopathologic examination showed remarkable degenerative and necrotic changes in the tumor, around which lymphocytes, eosinophils, plasma cells and macrophages infiltrated. Immunoperoxidase staining revealed Mab 202 binding to melanoma cells. Clinical and pathologic evidence suggested that Mab 202 has cytotoxic effects against melanoma cells. Mab 202 may therefore be useful in the treatment of human malignant melanoma.     

Distribution of fibronectin and laminin in basal cell epitheliomas

The distribution of fibronectin (FN) and laminin (LM) in basal cell epithelioma was evaluated by indirect immunofluorescence. FN is a glycoprotein which promotes interaction between cells and the extracellular matrix, and is present at the dermal-epidermal junction (DEJ) and throughout the dermis, but absent in the normal epidermis. LM, a noncollagenous basement membrane protein, plays a role in epithelial adhesion to type IV collagen, and is normally present in the DEJ, but absent in the epidermis. The role of FN and LM in epithelial differentiation has not been established. Therefore, the distribution of FN and LM in a tumor of epithelial origin was studied by indirect immunofluorescence. Using affinity-purified antibodies to FN and LM, and the appropriate fluorescein-conjugated second antibodies, normal skin and 7 basal cell tumors were examined. By immunofluorescence, nests of malignant basal cells were surrounded by linear LM staining. FN immunofluorescence was intense throughout the connective tissue stroma of all tumors. Five tumors also showed FN staining within the nests of neoplastic cells, and 4 of these were also LM-positive in the tumor bulk. These immunofluorescent findings suggest that epidermal neoplasia can be associated with alterations in the distribution of FN and LM.     

Occurrence of Langerhans cells and expression of class II antigens on keratinocytes in malignant and benign epithelial tumors of the skin: an immunohistopathologic study with monoclonal antibodies

We used an avidin-biotin complex immunoperoxidase technique with various monoclonal antibodies to determine Langerhans cell densities, class II antigen expression on keratinocytes, and phenotypes of other infiltrating cells in several malignant and benign epithelial tumors of the skin. Our observations indicate (1) there are few Langerhans cells in nests of basal cell carcinoma and squamous cell carcinoma; (2) there are increased Langerhans cell densities in seborrheic keratoses, verrucous epidermal nevus, and Bowen's disease; (3) there is an expression of class II molecules on the keratinocytes and cancer cells of basal cell carcinoma, squamous cell carcinoma, Bowen's disease, seborrheic keratosis, and verrucous epidermal nevus; and (4) there is a netlike staining of the keratinocyte surface with OKM5 in the epidermal lesion of seborrheic keratosis, verrucous epidermal nevus, and Bowen's disease, as well as in the epidermis adjacent to the basal cell carcinoma and squamous cell carcinoma nests.     

皮肤纤维瘤与隆突性皮肤纤维肉瘤的临床病理比较

对皮肤纤维瘤（DF）与隆突性皮肤纤维肉瘤（DFSP）在临床、组织形态及免疫组化等方面进行了比较。DF20例,平均年龄37.75岁,好发于四肢,平均直径0.8cm。瘤细胞呈束状或旋涡状排列,局部可见车辐结构。平均每50个高倍视野核分裂为0.75个。常伴组织细胞和炎细胞浸润、胶原增生、表皮增生及黑色素增多,CD34（－）。瘤细胞密度与胶原增生及炎细胞浸润呈负相关,提示DF可能为反应性病变。DFSP10例,平均年龄49.1岁,好发于躯干,平均年龄49.1岁,好发于躯干,平均直径3.23cm。瘤细胞呈典型的车辐状排列,平均每50个高倍视野核分裂为5.5个。肿瘤背景清晰,少数可见炎细胞浸润及表皮增生,无胶原增生及黑色素增多,CD34（＋）。这些临床及病理特征有助于两者的鉴别诊断。     

A Case of Eccrine Poroma with Multiple Transepidermal Elimination

The skin functions to eliminate foreign substances through the epidermis to the epidermal surface; this process is called transepidermal elimination (TEE). TEE has been observed in various skin tumors. We encountered a 64-year-old male patient with eccrine poroma with marked TEE. A dark brown nodular papule appeared on the anterior aspect of his right leg about 20 years ago and gradually expanded. Histopathologically, cell nests of poroma were extruded to the epidermal surface at several sites. No erosion was noted, and mild to moderate inflammatory cell infiltration was observed in the upper layer of the dermis. According to Mehregan's classification, the TEE phenomenon observed in our case may correspond to types 2 and 3.     

Is epidermal cell proliferation in psoriatic skin grafts on nude mice driven by T-cell derived cytokines?

Plasminogen activity and DNA synthesis by epidermal cells have been reported to be doubled in psoriatic skin grafts compared with grafts of normal skin 6 weeks after transplantation to nude mice. In our study human lymphocytes disappeared from such grafts within 48 h whilst some DR-positive human dendritic cells were retained in the grafts for up to 4 weeks. However, the grafts were infiltrated by Thy 1.2+ mouse lymphocytes within 6 days and this infiltration persisted at a moderate level throughout the observation period. It consisted of perivascular aggregates, scattered dermal and papillary T cells, and some mouse T cells were also found in the epidermal compartment. Grafts of psoriatic and non-psoriatic control skin were infiltrated to a similar extent, suggesting a low-grade rejection response against the human xenografts. These findings raise the possibility that psoriatic keratinocytes are responding abnormally to inflammatory cytokines released by mouse lymphocytes reacting against the skin grafts.