Expression of stem cell markers nestin and cytokeratin 15 and 19 in cutaneous malignancies

Background Emerging evidence is implicating stem cells in the pathogenesis of different cutaneous neoplasms. The immunohistochemical use of stem cell markers has facilitated stem cell identification. While few studies have examined the expression of cytokertatin (CK)15 and cytokeratin (CK)19 in basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), only rarely have nestin expression been examined in these two malignancies. Furthermore, stem cell marker expression, to the best of our knowledge, has not been examined in Merkel cell carcinoma (MCC). Methods In this study, we examined the expression of stem cell markers CK15, CK19 and nestin in 51 overall cases (11 cases of MCC and 20 cases each of BCC and SCC) retrieved from the pathology files of Skin Pathology Laboratory, Boston University School of Medicine. Results Cytokeratin 15 immunoreactivity was observed in 30% of BCC cases and only a single (5%) SCC case, while all MCC cases were negative. While 60% of BCC cases and 30% of SCC cases stained positively with CK19, all MCC cases showed positive immunostaining in a dot‐like pattern. While negative in BCC and MCC, nestin expression was interestingly seen in 45% of SCC cases. Conclusions Our study described the expression profiles of stem cell markers CK15, CK19 and nestin in BCC, SCC and MCC. In addition to confirming results of the previous reports, our study also showed positive nestin expression in around half of SCC cases, which adds this malignancy to the cutaneous tumours that have been so far reported to exhibit nestin expression.     

Prognostic value of Ki-67, CD31 and epidermal growth factor receptor expression in basal cell carcinoma

Recurrence of basal cell carcinoma following treatment is common, and the majority of recurrences appear in the first 3 years. We examined the original tumors of 26 basal cell carcinoma cases, 14 of whom had a recurrence after an average of 3.7 years, and 12 of whom had no recurrence during an average of 4.4 years follow-up. Using immunohistochemistry, we tested for Ki-67, CD31 and epidermal growth factor receptor expressions in the tumor tissue. The percentages of expression for Ki-67, CD31 and epidermal growth factor receptor were significantly higher in the recurrent tumors than in the non-recurrent ones. Expression of Ki-67 and CD31 was 271.57 +/- 17.91 and 58.1 +/- 9.37 for the recurrent group and 187.08 +/- 21.48 and 23.9 +/- 5.45 for non-recurrent group respectively (p<0.0001; p<0.0001). Expression of epidermal growth factor receptor was positive in all basal cell carcinoma cells. The staining intensity was strong in 57% of recurrent and 8.3% of non-recurrent tumors (p=0.014). These results show that Ki-67, CD31 and epidermal growth factor receptor expression differ between basal cell carcinomas which later recur and those that do not recur.     

CD147 expression in advanced cutaneous squamous cell carcinoma

Background: CD147 is upregulated in multiple cancer types, but its expression in advanced cutaneous squamous cell carcinoma (SCC) is unknown. Our purpose was to evaluate the expression patterns of CD147 and related monocarboxylate transporters (MCT1, MCT4) to determine their correlation with survival. Methods: This is a retrospective cohort study of patients with advanced stage cutaneous SCC of the head and neck who presented to a tertiary care center between 1998 and 2006 (n=50). CD147, MCT1 and MCT4 expression levels were assessed using immunofluorescence analysis of archived tumor samples and correlated with survival and clinicopathologic characteristics. Results: The majority of patients (92%, n = 46) were diagnosed with stage III disease, with 46% (n = 23) having positive regional lymph node metastasis and 8% (n = 4) with distant metastasis. Primary malignancies had an overexpression of CD147 (78%; n = 35), MCT1 (23%; n = 10) and MCT4 (47%; n = 20). In addition, there was a significant relationship between the overexpression of CD147 and node positive disease (p = 0.048). Two‐ and five‐year survival rates were 69 and 61%, respectively. There was a trend toward decreased survival in patients with overexpression of CD147 (p = 0.17), MCT1 (p = 0.11) and MCT4 (p = 0.15). Conclusion: CD147 may represent a biomarker or potential therapeutic target in advanced cutaneous SCC. Sweeny L. Dean NR, Frederick JW, Scott Magnuson J, Carroll WR, Desmond RA, Rosenthal EL. CD147 expression in advanced cutaneous squamous cell carcinoma.     

Characterization of the expression and activation of the epidermal growth factor receptor in squamous cell carcinoma of the skin

BACKGROUND: Locally advanced skin cancers including squamous cell carcinoma (SCC) of the skin are increasing in incidence. Patients are often elderly with significant comorbidities and therapy can be difficult. New targeted therapies, such as treatment directed at the epidermal growth factor receptor (EGFR), may be effective and less toxic in these patients. However, before designing appropriate clinical trials it is necessary to characterize the expression and activation of targets such as the EGFR to evaluate the rationale of using EGFR inhibitors (EGFRIs) in the treatment of this type of cancer. OBJECTIVES: To characterize the expression and activation by phosphorylation of EGFR in SCC of the skin by quantitative Western blotting using the LiCor immunofluorescence detection system with validation by immunohistochemistry. Secondary objectives were to evaluate downstream targets of EGFR expression and activation in SCC of the skin and to examine the associations between EGFR, pathological features and clinical behaviour of these tumours. METHODS: Twenty-one mainly locally advanced skin SCCs collected in our institution and stored in our tissue bank over a 4-year period were used for the study. RESULTS: Nine of 21 (43%) tumours expressed EGFR above background. Of those nine, five expressed phosphorylated EGFR. There was no correlation with downstream activation of canonical signalling pathways, pathological features or clinical behaviour. CONCLUSIONS: EGFR is expressed in a minority of tumours and then is not always activated. These results show that, before designing a trial with a targeted agent such as an EGFRI in SCC of the skin, it is important to verify the presence of the appropriate target to maximize the best outcome.     

Hmga2 is dispensable for cutaneous squamous cell carcinoma

Hmga2 functions as a chromatin‐associated factor during development, but is not expressed in most adult tissues. Expression of Hmga2 in adult tissues has been associated with a variety of human cancers. Numerous studies have implicated Hmga2 in epithelial‐to‐mesenchymal transition (EMT) and cancer progression through gain of function studies, but it is unclear whether Hgma2 is necessary for EMT, tumor formation or tumor progression. We deleted Hmga2 in two mouse models of squamous cell carcinoma and found this gene to be dispensable. In fact, EMT, tumor initiation and progression all appeared to be mostly unaffected by the absence of Hmga2. Tumors lacking the ability to induce Hmga2 proceeded to initiate cutaneous spindle cell and squamous cell carcinomas with all the typical pathological and molecular hallmarks of these cancers.     

The density of epidermal p53 clones is higher adjacent to squamous cell carcinoma in comparison with basal cell carcinoma

BACKGROUND: It is well accepted that ultraviolet radiation from the sun can induce and promote growth of skin tumours. Skin cancer develops as a consequence of multiple genetic hits, where an initial, important step includes proliferation of cells susceptible to malignant transformation. Foci of morphologically normal epidermal keratinocytes overexpressing p53 protein are common in chronically sun-exposed skin. Such foci have previously been shown to represent expanding clones of p53-mutated keratinocytes. Although several characteristics concerning epidermal p53 clones remain to be resolved, an important role in skin carcinogenesis is anticipated. The density of epidermal p53 clones in human skin is largely unknown. OBJECTIVES: To compare the occurrence of epidermal p53 clones in skin surrounding cancers with that in skin surrounding benign melanocytic naevi. To assess the influence of age on frequency and size of epidermal p53 clones in human facial skin. METHODS: We have analysed the number and sizes of epidermal p53 clones in skin specimens from patients with squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and benign melanocytic naevi. Cases included normal facial skin from four different age groups. Tissue sections were immunohistochemically stained and the presence of p53 clones was recorded. Approximately 1.4 m of epidermis from a total of 112 biopsies was analysed. RESULTS: We found 128 epidermal p53 clones in biopsy specimens from 112 patients. The results showed that the number and size of p53 clones increase with age. In normal skin adjacent to SCC p53 clones were significantly more numerous and greater in size in comparison with those in normal skin both adjacent to benign naevi and adjacent to BCC. Interestingly, normal skin in the close vicinity of BCC and melanocytic naevi showed similar results regarding both number and size of epidermal p53 clones. CONCLUSIONS: Our findings suggest a connection between development of epidermal p53 clones and SCC.     

Matrix metalloproteinase‐7 activates heparin‐binding epidermal growth factor‐like growth factor in cutaneous squamous cell carcinoma

Background Tumour‐specific expression of matrix metalloproteinase (MMP)‐7 has been noted in cutaneous squamous cell carcinomas (SCCs) in patients with recessive dystrophic epidermolysis bullosa (RDEB). Objectives To examine the potential role of MMP‐7 in shedding of heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF) in RDEB‐associated and sporadic SCCs. Methods Tissue microarrays of RDEB‐associated SCC (n = 20), non‐EB SCC (n = 60) and Bowen disease (n = 28) were immunostained for MMP‐7, CD44 variant 3 (CD44v3) and HB‐EGF. Shedding of HB‐EGF was studied in vitro using two cutaneous SCC cell lines. Results Immunohistochemical analysis showed that HB‐EGF was absent in tumour cells when MMP‐7 and CD44v3 colocalized, and that the absence of HB‐EGF was more pronounced in RDEB‐associated SCCs than in non‐EB SCCs. The loss of HB‐EGF in MMP‐7–CD44v3 double‐positive areas was interpreted to indicate shedding and activation of HB‐EGF; this was also detected in Bowen disease indicating its importance in the early phase of SCC development. Specific knockdown of MMP‐7 expression in human cutaneous SCC cells by small interfering RNA inhibited shedding of HB‐EGF and resulted in diminished activation of the EGF receptor (EGFR) and ERK1/2, and in reduced proliferation of SCC cells. Conclusions These findings provide evidence for the role of MMP‐7 in promoting the growth of cutaneous SCCs by shedding HB‐EGF, and identify EGFR signalling as a potential therapeutic target in RDEB‐associated SCC and unresectable sporadic cutaneous SCC.     

An unusual presentation of primary cutaneous squamous cell carcinoma

The cutaneous squamous cell carcinoma is a malignant epithelial tumour that usually arises from an underlying precursor skin lesion. We report the case of a 65-year-old woman with multiple de novo squamous cell carcinomas in an unusual presentation.     

抗增殖蛋白2在皮肤鳞状细胞癌中的表达及其对A431细胞增殖的影响

目的: 观察抗增殖蛋白2在皮肤鳞状细胞癌、鲍温病、日光性角化病组织中的表达情况及其对A431细胞增殖作用的影响.方法: 采用免疫组织化学方法检测抗增殖蛋白2在40例皮肤鳞状细胞癌、18例鲍温病、17例日光性角化病组织以及9例正常皮肤组织中的表达水平.采用CRISPR-Cas9法构建两组靶向敲除抗增殖蛋白2的皮肤鳞状细胞...     

The epidermal growth factor receptor in squamous cell carcinoma: An emerging drug target

Squamous cell carcinoma (SCC) of the skin is an increasingly common diagnosis worldwide. Together with precursor lesions, SCC carry a significant morbidity, particularly in regions with high solar UV radiation levels. Advanced lesions are locally or sometimes widely metastatic and may be resistant to treatment. Drugs targeting the epidermal growth factor receptor (EGFR) are currently the only significant non‐surgical option for advanced SCC beyond radiotherapy and conventional chemotherapy. The role of the EGFR in skin cancer is described and the outcomes of targeted anti‐EGFR therapy published to date are summarised. The future of anti‐EGFR targeted therapies in the treatment of skin cancer is discussed. Targeted molecular therapies are becoming increasingly widespread and an understanding of the evidence for their use as well as their side effect profile is important in order to offer patients informed and current advice.     

Spindle cell squamous cell carcinoma arising in Bowen's disease: Case report and review of the published work

A 79‐year‐old Japanese woman presented with an ulcerated, brown‐red nodule in the center of a sharply demarcated, tan‐brown plaque situated on the left side of her right breast. Histologically, the plaque demonstrated an acanthosis with an intraepidermal epithelioma of Borst‐Jadassohn. Small oval nests of bland‐appearing basophilic cells in the periphery gradually enlarged into nests of various sizes and irregular shapes, composed of densely cohesive, atypical basophilic cells above the central nodule. The atypical keratinocytes shifted to atypical spindle cells beneath the acanthotic epidermis, penetrating deep into the subcutaneous tissue. In addition to vimentin and p63, the spindle cells were positive for several cytokeratin (CK) markers, including AE1/AE3, 34βE12 and CK5/6, which showed more intense signals closer to the epidermis. Basophilic cells in the clonal nests were positive for p63, AE1/AE3, 34βE12 and CK5/6. The MIB‐1 index was estimated at approximately 40–50% in both the bland‐appearing and the atypical basophilic cells. We describe the first case of spindle cell squamous cell carcinoma arising in an intraepidermal epithelioma expressed by clonal Bowen's disease, which was difficult to differentiate from clonal seborrheic keratosis.     

Study of cutaneous cell carcinomas ex vivo using ultrasound biomicroscopic images

Background: The ultrasound biomicroscopy (UBM) technique generates high‐resolution echographic images using acoustic frequencies between 20 and 200 MHz. In dermatology, it enables non‐invasive visualization of cutaneous structures. In this sense, several studies are being conducted for the measurement of cutaneous tumor sizes and for the evaluation of their response to therapeutic procedures. The present work was conducted to analyze the ability of UBM to identify diverse histological structures associated with cutaneous carcinomas ex vivo regarding the evaluation of the technique as a diagnostic tool that could, eventually, improve the patient's healthcare protocol. Methods: Ex vivo human tissue samples, corresponding to basal cell carcinoma and squamous cell carcinoma cases, were studied. The ultrasonic system operated with a center frequency of 45 MHz and the histological structures were identified by comparison with the light microscopy images. Results: The histological components present in the tumors were identified by variations in the echogenicity level for several of the studied cases and particular characteristics were observed for the different tumor types. Conclusion: The possibility of differentiating the histological components associated with cutaneous carcinomas indicates the potential use of UBM for diagnostic applications. However, a larger number of specimens must be studied.     

PD-L1在皮肤鳞状细胞癌及角化棘皮瘤中的表达

目的：检测PD-L1在皮肤鳞状细胞癌（cSCC）及角化棘皮瘤（KA）中的表达,分析PD-L1与cSCC分化程度的相关性。方法：免疫组化染色检测PD-L1在cSCC及KA中表达水平。结果：共检测56例cSCC患者和32例KA患者标本，PD-L1在cSCC组和KA组中的阳性率分别为66.07%和62.50%，均显著高于正常对照组（9.38%）（Ps＜0.01）。PD-L1阳性率在cSCC与KA组的差异没有统计学意义（P＞0.05）。PD-L1的表达强度与cSCC的分化程度呈负相关（P＜0.05）。结论：PD-L1不能作为区分cSCC与KA的指标。PD-L1的表达强度与cSCC分化程度呈负相关。     

角化棘皮瘤和皮肤鳞状细胞癌bcl—2和Nm23癌基因蛋白表达的比较研究

目的：通过研究分析bcl-2和Nm23蛋白在角化棘皮瘤（KA）和皮肤鳞状细胞癌（SCC）中的表达和临床意义。探寻两病的鉴别标志。方法：应用免疫组化技术（SABC）对11例KA，28例SCC进行了检测。结果：bcl-2和Nm23蛋白在KA和SCC中的表达经统计学分析无显著性意义。结论：bcl-2和Nm23癌基因均参与了KA和SCC的发病过程，但都不能作为KA和SCC的鉴别标志。