Caspase-3在皮肤鳞状细胞癌及光线性角化病中的表达

目的：检测Caspase-3在皮肤鳞状细胞癌及光线性角化病组织中的表达。方法： 应用免疫组化法检测16例皮肤鳞状细胞癌皮损、27例光线性角化病皮损及24例正常皮肤组织中Caspase-3蛋白的表达。结果：Caspase-3在皮肤鳞状细胞癌、光线性角化病及正常皮肤组织的表达率分别为37.50%,51.85%,79.17%,其表达含量在皮肤鳞状细胞癌、光线性角化病、正常皮肤组织逐渐增加。结论：Caspase-3蛋白表达下调可能参与皮肤鳞状细胞癌及光线性角化病的发病过程。     

From actinic keratosis to squamous cell carcinoma

Summary The development of actinic keratosis (AK) and squamous cell carcinoma (SCC) is the result of a complex sequence of events initiated by exposure to ultraviolet (UV) light. The application of sunscreens prior to sun exposure has been reported to reduce the incidence of AK. The initial damage takes place in the DNA and most of the UV-induced lesions in the DNA are repaired. However, mutations may occur as a result of base mispairing of the cell and its DNA replicate before the DNA lesion is repaired. The genes involved in the repair process are also potential UV targets. Mutations in the tumour suppressor gene p53 are a common feature of AK and SCC. The hairless mouse is the best available animal model, in which lesions resembling human AK (papillomas), keratoacanthomas and SCCs may be induced. This model of multistage carcinogenesis offers an excellent tool for mechanistic studies. The relative efficacy of UV wavelengths (action spectrum) that induce SCC has been determined using the hairless mouse as a model. The action spectrum has been extrapolated to humans skin and is recognised worldwide.     

Fluorescence diagnosis in actinic keratosis and squamous cell carcinoma

Background: As different tissue types have distinct capabilities to accumulate protoporphyrin IX, fluorescence diagnosis with aminolevulinic acid‐induced porphyrins (FDAP) could be used to discriminate between different types of tissue. Previous results demonstrated higher fluorescence ratios in squamous cell carcinoma (SCC) compared with actinic keratoses (AKs). Objectives: The lesional : non‐lesional fluorescence ratio of AKs was compared with the ratio of SCC. Other factors influencing macroscopic fluorescence were also assessed, including stratum corneum thickness, which has been demonstrated to account for heterogeneous fluorescence in psoriasis and in AKs. Methods: After 1 week of keratolytic pretreatment, FDAP was performed in 13 patients with 36 lesions suspected for AK or SCC. Biopsies were taken for histopathological diagnosis and measurement of stratum corneum thickness. Results: No significant differences were found in the fluorescence ratio (lesional : non‐lesional skin) between AKs and SCCs, although macroscopic fluorescence was significantly higher in Bowen's disease and micro‐invasive SCCs. Conclusions: There could be a potential applicability of FDAP to differentiate premalignant lesions with a tendency to progress into SCC and squamous cutaneous lesions already progressing into early invasive cancer from other squamous cutaneous (pre)malignancies. The amount of hyperkeratosis, invasiveness and degree of differentiation seem to be responsible for variations in fluorescence intensity.     

Comparison of facial predilection sites for cutaneous squamous cell carcinoma and actinic keratosis in Japanese patients

Cutaneous squamous cell carcinoma (cSCC) and actinic keratosis (AK) occur most often on the face. Ultraviolet light is apparently their most common cause. As AK is considered to be a precursor of cSCC, their distribution on the face should be similar. However, cSCC often occurs on the temple or mandibular area, whereas AK arises on the central forehead, cheek or nose. We retrospectively evaluated differences in affected site distribution for cSCC (n = 54) and AK (n = 95). We found AK to occur preferentially on the central facial area (63/95, 66%), which is the most sun‐exposed area, and cSCC to occur preferentially on peripheral areas such as the temple and mandibular area (24/54, 44%). Those distributions were significantly different (P = 0.011, Fisher's exact test). This result suggests that cSCC occurs preferentially in the peripheral area compared with the central facial area, which further implies that either other factors are needed to make AK progress to cSCC in peripheral areas, or that peripheral cSCC can occur without preceding AK. This is the first report to focus on geographic assessment of cSCC and AK in detail. Further studies are needed to elucidate the mechanism of our finding.     

SGK1在日光性角化病、基底细胞癌及鳞状细胞癌中的表达

目的：检测SGK1在日光性角化病（AK）、基底细胞癌（BCC）及鳞状细胞癌（SCC）中的表达。方法：采用免疫组化SABC法检测SGK1在25例正常皮肤(NS)、25例AK、28例BCC、28例皮肤鳞状细胞癌标本中的表达。结果：NS、AK、BCC和SCC标本中,SGK1阳性细胞率分别为（40.03±14.42）%,（36.63±14.28）%,（52.82±18.73）%和（52.58±20.13）%。BCC组和SCC组分别与NS组比较,差异均有统计学意义（Ps<0.05）。各组SGK1染色阳性细胞率>50%的标本分别为6例（24%）,3例（12%）,16例（57.14%）和14例（50%）,BCC组和SCC组分别与NS组比较,差异均有统计学意义（Ps<0.05）。结论：SGK1的高表达可能与基底细胞癌及鳞状细胞癌的发病有关。     

Lamin expression in normal human skin,actinic keratosis,squamous cell carcinoma and basal cell carcinoma

BACKGROUND: Aberrant expression patterns of nuclear lamins have been described in various types of cancer depending on the subtype of cancer, its aggressiveness, proliferative capacity and degree of differentiation. In general, the expression of A-type lamins (lamins A and C) has been correlated with a non-proliferating, differentiated state of cells and tissues. OBJECTIVES: To establish and compare the expression patterns of lamins in normal human skin, actinic keratosis (AK), squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). METHODS: Expression patterns of the individual lamin subtypes were studied immunohistochemically. The proliferation capacity of the tumour cells was detected using a specific antibody to Ki-67, and was related to the A-type lamin expression patterns. RESULTS: In normal skin, lamin A was expressed in the suprabasal cell compartment of the epidermis, whereas the basal cells were mostly unstained. BCCs and SCCs stained positive in most cells, while the epidermis overlying BCC and SCC and the epidermis in AK stained homogeneously and strongly in the basal cells in addition to the suprabasal cells. Lamin C was expressed in some basal cells of normal epidermis while the suprabasal cells stained strongly positive. Both BCCs and SCCs stained strongly positive for lamin C, with the difference that in BCC the staining was predominantly present in nucleolar structures with occasional staining of the nuclear envelope. The epidermis overlying SCC showed strong positivity in the lamina of virtually all cells. The expression of lamin C in the basal cells of AK resembled the expression pattern seen in the epidermis overlying BCC, i.e. a nucleolar staining next to nuclear envelope staining. Lamin B1 and B2 were found in virtually all cells in normal epidermis, AK, BCC, SCC and the epidermis overlying cancer. The percentage of Ki-67-expressing cells was highest in BCC (45%), and gradually decreased via epidermis overlying BCC, AK, SCC, and epidermis overlying SCC, to normal skin (11%). Simultaneous expression of A-type lamins and Ki-67 occurred in approximately 50% of the proliferating (Ki-67 positive) cells in BCC and SCC. CONCLUSIONS: Significant changes occur in the expression patterns of A-type lamins in both premalignant and malignant lesions of the skin. The profound overlap of lamin A and Ki-67 staining patterns indicates that the proliferating tumour cells may obtain a certain degree of differentiation. Finally, lamin A expression in the basal cell layer of the apparently normal epidermis overlying BCC may suggest its involvement in the primary process.     

MYC gene numerical aberrations in actinic keratosis and cutaneous squamous cell carcinoma

Background  The genetic alterations that drive the transition from actinic keratoses (AKs) to cutaneous squamous cell carcinomas (SCCs) have not been defined precisely. Amplification and/or overexpression of the MYC proto-oncogene have been demonstrated in several human, malignant tumours including head and neck SCCs.
Objectives  To evaluate the presence of MYC genomic aberrations in both AKs and SCCs.
Methods  Skin biopsy specimens corresponding to AKs, SCCs and control samples were included in two paraffin-embedded tissue microarrays. MYC cytogenetic profile was evaluated by fluorescence in situ hybridization (FISH). The results obtained were compared with MYC immunohistochemical expression.
Results  Twenty-three AKs and 30 SCCs were evaluated. MYC numerical aberrations were observed in eight of 23 (35%) AKs and 19 of 30 (63%) SCCs ( P  = 0·05). MYC numerical aberrations were more frequent in moderately to poorly differentiated SCCs (77%) when compared with well-differentiated SCCs (25%; P  = 0·027). A significant association between copy number gains of MYC by FISH analysis and MYC protein expression was demonstrated.
Conclusions  MYC gains and amplifications are frequent cytogenetic abnormalities in SCCs and may play a relevant role in promoting SCC undifferentiation and tumoral progression.     

Inflammation is associated with progression of actinic keratoses to squamous cell carcinomas in humans

BACKGROUND: Squamous cell carcinoma (SCC) is a common skin tumour that may metastasize and lead to death. We have observed that before actinic keratoses (AK) progress to SCCs they may become tender and inflamed. In some of these, histological examination shows that they are, in fact, SCCs. OBJECTIVES: To study the progression of AK to SCCs. METHODS: We studied skin tumours from 50 patients with either asymptomatic AK, inflamed AK or SCCs, using immunocytochemistry. The diagnosis of each tumour was confirmed by histological examination. RESULTS: Studies of differentiation using heat shock protein 27 showed a stepwise loss of differentiation as the tumours progressed from asymptomatic AK, through inflamed AK to SCCs. During the inflamed AK phase, there was a marked increase in T lymphocytes and Langerhans cells: the number of infiltrating cells diminished as progression to SCC occurred. There was an increase in immunoreactive p53 and the apoptosis inhibitor bcl-2 as tumours progressed from AK to SCCs, and a decrease in Fas and Fas ligand. CONCLUSIONS: These studies have shown that progression from benign to malignant tumours may be associated with an inflammatory response, which appears to drive malignant conversion, but subsides rapidly following this conversion.     

Caveolin-1、Met蛋白在日光性角化病、鲍温病和皮肤鳞状细胞癌中的表达

目的：检测Caveolin-1、Met蛋白在肿瘤边缘正常皮肤、日光性角化病、鲍温病和皮肤鳞状细胞癌组织中的表达情况。方法：通过免疫组化SP法，对肿瘤边缘正常皮肤、日光性角化病(Actinic keratosis，AK)、鲍温病(Bowen's Disease，BD)、皮肤鳞状细胞癌(cutaneous squamous cell carcinoma，cSCC)标本中Caveolin-1、Met进行检测。结果：Caveolin-1在正常皮肤、AK、BD、SCC中阳性率依次为16.7%、36.8%、52.9%、78.9%，四组间采用Kruskal-wallis H秩和检验，差异具有统计学意义(P<0.05)。Met在正常皮肤、AK、BD、SCC中阳性率依次为8.3%、26.3%、58.8%、84.2%，四组间采用Kruskal-wallis H秩和检验，P<0.05，差异具有统计学意义。在cSCC组中，Caveolin-1、Met阳性表达之间呈现正相关(r=0.484,P=0.036)。结论：Caveolin-1、Met在AK、BD和cSCC细胞中表达强度与恶性程度相关，且Caveolin-1、Met可能在cSCC发生、发展中具有协同作用。     

Cyclin A and beta-catenin expression in actinic keratosis, Bowen's disease and invasive squamous cell carcinoma of the skin

BACKGROUND: Actinic keratosis (AK) has been defined as a precancerous lesion or an early phase in the evolution of squamous cell carcinoma (SCC) and histological changes seen in the individual cells of an AK are indistinguishable from those seen in SCC, which invade the dermis. Cyclin A is an increasingly utilized proliferation marker that has functions in both S phase (DNA replication) and initiation of mitosis, whereas alterations of beta-catenin, the molecule involved in cell-cell adhesion and in signalling transduction, could promote invasive and proliferative capacities of malignant tumours. OBJECTIVES: To determine cyclin A and beta-catenin expression pattern in cutaneous SCC and in in situ lesions classified as keratinocytic intraepidermal neoplasia (KIN) and, using traditional terms, as AK and Bowen's disease (BD), and to analyse it in relation to SCC differentiation, diameter and thickness. METHODS: Immunohistochemical staining was performed on 110 formalin-fixed paraffin-embedded tissue samples with the streptavidin-biotin technique using antibodies to cyclin A and beta-catenin. On histological examination, 53 lesions were diagnosed as AK, 16 as BD and 41 as SCC-11 well differentiated (WD), 16 moderately differentiated (MD) and 14 poorly differentiated (PD). Using KIN classification, 22 lesions were KIN1, 23 were KIN2 and 24 were KIN3. For cyclin A, distribution and labelling index (LI), and for beta-catenin, level of membranous staining and presence of aberrant (nuclear/cytoplasmic) localization were examined. RESULTS: Diffuse cyclin A presence was observed more frequently in BD than in AK (P < 0.0001) or SCC (P = 0.0002), and in SCC-PD compared with SCC-WD (P < 0.0001) or SCC-MD (P = 0.0003). Differences between KIN3 and KIN2, as well as KIN3 and KIN1 lesions, were statistically significant (P < 0.0001), and the same result appeared when KIN1 and KIN2 cases were grouped and compared with those of KIN3 (P < 0.0001). Cyclin A LI was significantly lower (P < 0.05) in AK than in BD or SCC, but no difference between BD and SCC was found, and LI in BD was even higher than in SCC-WD or SCC-MD, while analysis regarding SCC differentiation and KIN classification revealed the same correlation as for the cyclin A distribution. Reduced or absent beta-catenin membranous staining was found in 90 cases (81.8%), more often in SCC than in AK (P = 0.03) or in AK and BD grouped together (P = 0.02). There was no statistical difference between SCCs of various level of differentiation, or between different KIN grades. Diffuse loss of membranous beta-catenin staining showed 36 lesions (32.7%), more frequently SCC than AK (P = 0.003) or AK and BD grouped (P = 0.006), as well as SCC-PD compared with SCC-WD (P = 0.01) and SCC-MD (P = 0.03), whereas all KIN comparisons remained nonsignificant. Aberrant beta-catenin cellular localization demonstrated 28 lesions (25.5%), most often in the basal or peripheral parts and in the lesions with diffuse beta-catenin loss (P = 0.009), but revealed no correlation with the histological type, SCC level of differentiation or KIN grades. Diffuse loss of membranous beta-catenin staining was found to be significantly more frequent in SCC thicker than 4 mm (P = 0.03), while all other comparisons between cyclin A or beta-catenin with the tumour size remained nonsignificant. Cyclin A LI was higher in cases with diffuse loss of membranous staining (P = 0.001) or with aberrant cellular localization of beta-catenin (P = 0.002). CONCLUSIONS: Cyclin A LI showed greater difference between AK and BD than between BD and SCC, suggesting that increased proliferation (measured by cyclin A LI) characterizes progression of in situ lesions from AK to BD, whereas reduced beta-catenin expression separates more clearly SCC from the in situ lesions. Diffuse pattern of loss of membranous beta-catenin staining correlated better with the type of lesion, SCC differentiation and tumour size than reduced expression in general or aberrant cellular localization of beta-catenin. KIN classification does not seem to be supported by our findings, except when KIN1 and KIN2 lesions (in situ, partial thickness) are grouped.     

Smad7在脂溢性角化病、日光性角化病及基底细胞癌中的表达

目的： 检测Smad7在脂溢性角化病、日光性角化病以及基底细胞癌中的表达。方法：对脂溢性角化病、日光性角化病及基底细胞癌标本（各30例）和30例正常标本进行免疫组化染色。结果：23例脂溢性角化病标本、23例日光性角化病标本和28例基底细胞癌标本中Smad7染色阳性,阳性细胞率分别为（31.0±23.0）%,（32.7±26.3）%和（62.6±32.1）%,均显著高于正常组织的（6.7±5.0%）。结论： Samd7可能与脂溢性角化病、日光性角化病以及基底细胞癌的发病有关。     

Raptor、Rictor和磷酸化Akt在日光性角化病、Bowen病及鳞状细胞癌中的表达

目的:检测Raptor、Rictor和磷酸化Akt(p-Akt)在日光性角化病、Bowen病和鳞状细胞癌中的表达。方法:采用免疫组化法检测Raptor、Rictor及p-Akt(Ser473)在20例正常皮肤、20例日光性角化病、20例Bowen病及40例鳞状细胞癌中的表达。结果:Raptor在鳞状细胞癌、Bowen病和日光性角化病中的阳性表达率分别为87.50%、70.00%和60.00%,均高于正常皮肤的25.00%(均P0.05);其中低分化鳞状细胞癌中Raptor的阳性表达率为100%,高于高分化鳞状细胞癌的阳性表达率75%(P0.05)。Rictor在鳞状细胞癌、Bowen病和日光性角化病中的阳性表达率分别为80.00%、70.00%及55.00%,均高于正常皮肤阳性表达率的20%(均P0.05);p-Akt(Ser473)在鳞状细胞癌、Bowen病和日光性角化病中的阳性表达率分别为77.50%、65.00%及50.00%,而正常皮肤阳性表达率为0。鳞状细胞癌、Bowen病和日光性角化病中Rictor的阳性表达水平和p-Akt(Ser473)的阳性表达水平均呈正相关(均P0.05)。结论:Raptor、Rictor和p-Akt(Ser473)的高表达可能与日光性角化病、Bowen病和鳞状细胞癌的发生发展有关。     

Cutaneous undifferentiated small (Merkel) cell carcinoma,that developed synchronously with multiple actinic keratoses,squamous cell carcinomas and basal cell carcinoma

Merkel Cell Carcinoma (MCC) is an uncommon undifferentiated neuroendocrine tumor, arising in skin mainly on sun-exposed areas. We present an unusual case of primary cutaneous undifferentiated small cell carcinoma that co-existed with six other lesions; 2 actinic keratoses, 3 squamous-cell carcinomas and a basal-cell carcinoma. HE stained sections revealed MCC located in the mid-dermis, co-existing with severe actinic keratosis. Immunohistochemically, the tumor cells reacted to cytokeratin 20, epithelial membrane antigen, chromogranin and neuron specific enolase. This is an unusual case of cutaneous MCC co-existing with six other different lesions. The concurrent development of MCC, squamous-cell and basal-cell carcinoma in the same patient indicates the pluripotent epidermal stem cell origin of these tumors. Further research is needed to enlighten the factors inducing this divergent differentiation.     

Successful treatment of actinic keratosis with imiquimod cream 5%: a report of six cases

BACKGROUND: Actinic keratoses (AK) are premalignant lesions, which are routinely treated by destructive procedures such as cryotherapy, electrodessication or topical 5-fluorouracil. OBJECTIVES: The aim of this study is to report six cases of AK treated with a potential new topical therapy, imiquimod. METHODS: Subjects included in this study had suffered with recurrent AK for between 5 and 16 years. All six men were treated with imiquimod 5% cream three times a week for 6-8 weeks. In the event of a local skin reaction treatment was modified to two times per week. RESULTS: All the AK lesions were successfully cleared after treatment with imiquimod cream 5% for 6-8 weeks. Histologically, no apparent signs of persisting AK could be detected, and no recurrences were reported during follow up. CONCLUSIONS: This study suggests that imiquimod may be useful as a new therapy for the treatment of actinic keratoses.     

光线性角化病向鳞状细胞癌转化的分子机制研究进展

光线性角化病（AK）是皮肤鳞状细胞癌（SCC）的癌前病变,AK向SCC转化的分子机制一直是研究热点,但尚未完全清楚。围绕染色体变异、基因突变、信号通路和其他因子机制4个部分,概述了染色体3p、9p、9q、13q、17p和17q基因选择性突变、18q杂合性缺失,p53、p16和Ras基因突变,转化生长因子β1信号通路、Fas/FasL信号通路活性异常,及基质金属蛋白酶因子异常表达在AK向SCC进展中的机制研究进展,为进一步研究提供参考。