Overexpression In Squamous Cell Carcinoma Research Articles

821 ALK expression in metastatic cutaneous squamous cell carcinoma: A pilot study

Background: Cutaneous squamous cell carcinoma (SCC) is a common skin cancer, with over 1,000,000 cases and up to 9,000 deaths annually in the United States. Treatment options for metastatic SCC are limited, although inhibitors of PD-1 and EGFR have shown some success clinically. Our group identified ALK as a potential driver mutation in metastatic SCC through targeted sequencing. Here, we examine the role of ALK overexpression in SCC. Methods: All metastatic SCCs at our institution from 2010-2018 with tissue available were included, which yielded fifteen primary SCCs and fifteen patient-matched lymph node metastases.

Human papilloma virus infection and fascin over-expression in squamous cell carcinoma of the cervix.

Background: Human papilloma virus (HPV) is involved in development of almost all cervical cancers, mainly through the subversion of cellular mechanisms of growth control. Fascin plays central role in subsequent cell transformation events. Fascin mediates stabilization of parallel actin bundles where cellular protrusions are formed; this represents primary stages of cell migration and metastasis. Immunohistochemical assays have shown up-regulation of fascin expression in many epithelial and non-epithelial neoplasms. Therefore, the aim of this study was to investigate HPV infection and fascin expression in samples of cervical cancer. Methods: Of 66 patients with confirmed SCC, formalin-fixed specimens, embedded in paraffin blocks were evaluated for HPV infection with nested multiplex polymerase chain reaction (NM-PCR) and for fascin expression with immunohistochemical assays. Statistical analysis was performed using Wilcoxon rank-sum test and SPSS software. A p<0.05 was considered for statistical significance. Results: Of 66 samples, 52 (78.7%) were found positive for HPV infection and fascin over-expression was shown in all squamous cell carcinoma samples. Conclusion: This study showed fascin overexpression in squamous cell carcinoma of the cervix which might be involved in metastasis of cancers induced by some types of HPV, hypothetically through attenuation of inter-cellular adhesions, and induction of cell motility

Anti-oncostatin M antibody inhibits the pro-malignant effects of oncostatin M receptor overexpression in squamous cell carcinoma.

The oncostatin M (OSM) receptor (OSMR) shows frequent gene copy number gains and overexpression in cervical squamous cell carcinomas (SCCs), associated with adverse clinical outcomes. In SCC cells that overexpress OSMR, the major ligand OSM induces multiple pro-malignant effects, including invasion, secretion of angiogenic factors, and metastasis. Here, we demonstrate, for the first time, that OSMR overexpression in SCC cells activates cell-autonomous feed-forward signalling, via further expression of OSMR and OSM and sustained STAT3 activation, despite expression of the negative regulator suppressor of cytokine signalling 3 (SOCS3). The pro-malignant effects associated with OSMR overexpression are critically mediated by JAK-STAT3 activation, which is induced by exogenous OSM and also by autocrine OSM-OSMR interactions. Importantly, specific inhibition of OSM-OSMR interactions by neutralizing antibodies significantly inhibits STAT3 activation and feed-forward signalling, leading to reduced invasion, angiogenesis, and metastasis. Our findings are supported by data from 1254 clinical SCC samples, in which OSMR levels correlated with multiple cognate genes, including OSM, STAT3, and downstream targets. These data strongly support the development of OSM-OSMR-blocking antibodies as biologically targeted therapies against SCCs of the cervix and other anatomical sites. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Paraoxonase-1 (PON1) induces metastatic potential and apoptosis escape via its antioxidative function in lung cancer cells.

Paraoxonase-1 (PON1) gene polymorphisms have been closely associated with the development of advanced cancers while PON1 secretion to the serum is linked with inhibition of oxidized high-density lipoprotein by its antioxidative function. Our group previously demonstrated that post-translational modification of serum PON1 in form of fucosylated PON1 is a potential biomarker of small cell lung cancer. Here, we interrogated the role of PON1 in the pathobiology of lung cancer (LC) by addressing cell-autonomous mechanisms using gain-of-function and loss-of-function approaches and protein expression profiling of tissue samples in our clinical biobank. PON1 expression in LC patient tissues varied between overexpression in squamous cell carcinoma and minimal loss in adenocarcinoma sub-types. Simultaneous overexpression of PON1 both at the gene and protein stability levels induced pro-oncogenic characteristics in LC cells and xenografts. PON1 overexpression supported metastatic progression of LC by decreasing G1/S ratio and LC cell senescence involving p21Waf1/Cip1. PON1 suppressed drug- and ligand-induced cell death and protected LC cells from genotoxic damages with maintained ATP levels, requiring p53-directed signals. PON1 promoted ROS deregulation protecting the mitochondria from dysregulation. PON1 knockdown resulted in the blockage of its antioxidant function in LC cells through Akt signaling with reduced invasive signature as a consequence of scant expression. Targeted glycolysis stimulated PON1 antioxidant activity regulating phosphorylation of AMPK-α. The functional data imply that exploitation of the antioxidative function of PON1 is consequential in driving LC pathogenesis at the cell-autonomous mechanistic level with consequences on tumor growth.

Clinical effects of p53 overexpression in squamous cell carcinoma of the sinonasal tract: A systematic meta-analysis with PRISMA guidelines.

Background:The level of p53 protein expression in sinonasal squamous cell carcinoma (SNSCC) has been estimated, but the results remain inconsistent and the point of consensus has not been reached. This study was first determined to evaluate the clinical effects of p53 expression in SCC of the sinonasal tract.Methods:According to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement criteria, the potential literature was searched from diverse databases. The pooled odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated to assess the strength of association between p53 expression and SNSCC.Results:Final 17 eligible studies were included in a total of 258 cases and 748 controls. The result of p53 expression was shown to be notably higher in SNSCC than in benign sinonasal papillomas and normal sinonasal mucosa (OR = 26.93, P < 0.001; OR = 39.79, P < 0.001; respectively). Subgroup analyses of ethnicity revealed that p53 expression had significant association with SNSCC in Asian and Caucasian populations in cancer versus benign sinonasal papillomas or normal sinonasal mucosa. The expression of p53 was notably higher in moderately or poorly differentiated SNSCC than in well-differentiated SNSCC (OR = 3.51, P = 0.021), while p53 expression was not associated with histological type.Conclusion:The results suggested that p53 overexpression may be correlated with the carcinogenesis and progression of SNSCC. The p53 gene may become a novel drug target of SNSCC. Additional studies on the correlation of p53 expression with clinicopathological features are needed.

Immunohistochemical demonstration of alteration of β-catenin during tumor metastasis by different mechanisms according to histology in lung cancer.

The protein β-catenin exhibits a dual function in cells, by acting as a major structural component of cell-cell adherens junctions and as a central signaling molecule in the Wnt signaling pathway. However, how the regulation of β-catenin expression during tumor metastasis in non-small cell lung cancer (NSCLC) varies according to histological type remains unclear. To investigate the regulatory mechanism of β-catenin on tumor metastasis, the present study compared the expression of Wnt1, β-catenin and E-cadherin in 41 primary NSCLC tumors and their corresponding metastatic lesions by immunohistochemistry. Altered expression of β-catenin was more frequent in the metastatic tumors (34/41, 82.9%) than in the corresponding primary tumors (24/41, 58.5%; P<0.05). There were 12 cases [nine of adenocarcinoma (ADC) and three of squamous cell carcinoma (SqCC)] that revealed discordant β-catenin expression between the primary tumors and the corresponding metastatic lesions. Of these, 11 cases (11/12, 91.7%; nine ADCs and two SqCCs) demonstrated acquired β-catenin alterations in the metastatic lesions. Subgroup analysis of these nine ADCs revealed that six cases (6/9, 66.7%) were accompanied by E-cadherin loss but no Wnt1 overexpression. Subgroup analysis of the three SqCCs revealed discordant β-catenin expression. Two cases (2/3, 66.7%) demonstrated acquired β-catenin expression during metastatic progression with Wnt1 overexpression but no change in E-cadherin expression. One case of SqCC revealed normal β-catenin expression in the metastasis although the expression was aberrant in the primary tumor. The results of the present study revealed that the changes in β-catenin expression occurred during tumor metastasis by different mechanisms, depending on histological type. The alterations in β-catenin expression may be regulated by a cadherin-catenin system in ADCs with reduced membranous expression of E-cadherin, but mediated by Wnt1 overexpression in SqCCs with cytoplasmic or nuclear transition types.

Aldo-keto reductase 1C3 is overexpressed in skin squamous cell carcinoma (SCC) and affects SCC growth via prostaglandin metabolism.

Aldo-keto reductase 1C3 (AKR1C3) is an enzyme involved in metabolizing prostaglandins (PGs) and sex hormones. It metabolizes PGD2 to 9α11β-PGF2 , diverting the spontaneous conversion of PGD2 to the PPARγ agonist, 15-Deoxy-Delta-12, 14-prostaglandin J2 (15d-PGJ2 ). AKR1C3 is overexpressed in various malignancies, suggesting a tumor promoting function. This work investigates AKR1C3 expression in human non-melanoma skin cancers, revealing overexpression in squamous cell carcinoma (SCC). Effects of AKR1C3 overexpression were then evaluated using three SCC cell lines. AKR1C3 was detected in all SCC cell lines and its expression was upregulated in response to its substrate, PGD2 . Although attenuating AKR1C3 expression in SCC cells by siRNA did not affect growth, treatment with PGD2 and its dehydration metabolite, 15d-PGJ2 , decreased SCC proliferation in a PPARγ-dependent manner. In addition, treatment with the PPARγ agonist pioglitazone profoundly inhibited SCC proliferation. Finally, we generated an SCC cell line that stably overexpressed AKR1C3 (SCC-AKR1C3). SCC-AKR1C3 metabolized PGD2 to 9α11β-PGF2 12-fold faster than the parent cell line and was protected from the antiproliferative effect mediated by PGD2 . This work suggests that PGD2 and its metabolite 15d-PGJ2 attenuate SCC proliferation in a PPARγ-dependent manner, therefore activation of PPARγ by agonists such as pioglitazone may benefit those at high risk of SCC.

Highlights of This Issue

The epidermal growth factor receptor (EGFR) is a validated therapeutic target in many human cancers. In spite of the frequent EGFR overexpression in squamous cell carcinoma (SCC), the anti-EGFR antibody, cetuximab, as a single agent exhibits marginal efficacy. Our study shows an impressive efficacy of cetuximab/namitecan combination, which reflects a complete abrogation of EGFR expression, in SCC preclinical models characterized by high EGFR gene copy number. The study provides a molecular basis for a rational combination to be exploited for possible therapeutic applications in the clinical setting and suggests EGFR gene copy number as a possible marker for patient selection.Shortened constitutional telomere length is a well-established risk factor for the development of primary malignancies, related to genomic instability that may result from excessive telomere shortening. However, the relationship between telomere length and risk for second malignancies has not been explored. Gramatges and colleagues performed a matched case-control analysis of telomere length between survivors with and without second malignancies within the Childhood Cancer Survivor Study. A relationship was observed with shortened telomeres, driven by a highly significant association with thyroid second cancers. These results suggest cancer predisposition related to genetic or therapy-related telomere shortening, or other factors affecting telomere homeostasis.Both protein kinase C (PKC) and Twist1 play an important role in cancer pathology, including epithelial-mesenchymal transition as well as treatment resistance. Shiota and colleagues have explored the signaling pathway evoked by androgen-deprivation therapy (ADT) for prostate cancer. ADT induced PKC activation and Twist1 induction. On the other hand, an inhibition of PKC, especially PKCβ and PKCϵ, suppressed Twist1 expression, indicating the novel relationship between PKC and Twist1. Accordingly, PKC inhibition combined with ADT such as novel antiandrogen enzalutamide exerted excellent synergistic anticancer effects, suggesting that PKC inhibition as an alternative of Twist1 inhibition might be a promising therapeutic strategy.The uptake transporter SLC22A1 (OCT1) has been suggested to contribute to imatinib resistance; however, its role for imatinib transport into cells is controversial. Nies and colleagues applied an array of in vitro and in vivo model systems to systematically elucidate the contribution of OCT1 to imatinib transport. Using various OCT1-overexpressing cells, leukemic cells being devoid of OCT1 mRNA and protein, and Oct1-deficient mice the authors demonstrate that cellular uptake of imatinib is independent of OCT1. Therefore, OCT1 is apparently not a valid biomarker for imatinib resistance.

Editorial Comment

Epidermal growth factor receptor (EGFR) is expressed in nonsmall cell lung cancer, head and neck squamous cell carcinoma, colorectal cancer, and breast cancer. In each of these diseases, there are EGFR inhibitors that are approved for these conditions. EGFR is expressed in squamous cell penile cancer.1Barnholtz-Sloan J.S. Maldonado J.L. Pow-sang J. Giuliano A.R. Incidence trends in primary malignant penile cancer.Urol Oncol. 2007; 25: 361-367Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar, 2Bahl A.K. Sohail M. Johnson D. et al.EGFR overexpression in invasive squamous cell carcinoma of the penis.J Clin Onc. 2010; 28 (ASCO proceedings): e15078Google Scholar, 3Gou H.-F. Li X. Qiu M. et al.Epidermal growth factor receptor (EGFR)-RAS signaling pathway in penile squamous cell carcinoma.PLoS ONE. 2013; 8: e62175Crossref PubMed Scopus (39) Google Scholar The question: is it potentially useful in patients with squamous cell penile cancer? There are important parameters whether a target for treatment is important or not. Is the target over expressed, could it be inhibited, is it the predominant target, is it an important factor for growth for this cancer, and could it be given safely. There are more questions than answers. Gou et al3Gou H.-F. Li X. Qiu M. et al.Epidermal growth factor receptor (EGFR)-RAS signaling pathway in penile squamous cell carcinoma.PLoS ONE. 2013; 8: e62175Crossref PubMed Scopus (39) Google Scholar in a study of 150 patients in China with penile cancer showed EGFR expression was positive in all the 150 cases. Five cases (3.3%) were 1+, 7 (4.7%) were 2+, 21 (14%) were 3+, and 117 (78%) were 4+. The rate of EGFR over expression was 92%. No significant correlation was observed between the EGFR expression and tumor grade (P = .215), pT stage (P = .053), or lymph node metastases (P = .685). In a study by Lavens et al4Lavens N. Gupta R. Wood L.A. EGFR overexpression in squamous cell carcinoma of the penis.Curr Oncol. 2010 February; 17: 4-6PubMed Google Scholar from a selected 8-year time period, 17 cases were obtained and studied. The median age of all patients was 66 years (range, 46-95). All 17 cases over expressed EGFR. Expression was 3+ in 14 cases and 2+ in 3 cases. The case series highlights the importance of reviewing the biology of the disease and the importance of identifying markers that are expressed. Two of the 3 patients responded to the treatment, and 1 had a response lasting 42 months. Several investigators have shown that patients with EGFR expression in small case series also did respond to EGFR inhibitors. On the basis of these preliminary data, I agree with the authors that a clinical trial should be done. In addition, it is important to develop less toxic oral therapy for penile cancer because chemotherapy can be toxic especially for patient with advanced cancer, and additionally there are no options after tumor progression on cisplatin-based treatment. To test the question whether EGFR inhibitors are effective in the treatment of this cancer, there is an ongoing trial of Dacomitinib (PF-00299804 pan HER inhibitor/EGFR) in advanced/metastatic squamous cell carcinoma of the penis with the primary endpoint of response rate. NCT01728233 was based on early results from Tumori Milan and the University of Texas MD Anderson.5Clinical Trials.gov 2013 NCT identifier number 01728233.Google Scholar This might be the next step big for this cancer. Epidermal Growth Factor Receptor-targeted Therapy in Squamous Cell Carcinoma of the Penis: A Report of 3 CasesUrologyVol. 83Issue 1PreviewTo describe 3 cases of advanced refractory penile cancer treated with targeted therapy against the epidermal growth factor receptor (EGFR). Full-Text PDF ReplyUrologyVol. 83Issue 1PreviewAs the editorial comment points out, the gap between our knowledge of which markers are expressed on tumor cells and which of these markers will provide a successful therapeutic target has become increasingly apparent. Furthermore, the complexities of signaling pathways have complicated attempts to target receptors identified on tumor tissue: for example, K-ras mutations affect response to epidermal growth factor receptor (EGFR)–targeted therapy. In penile cancer, with nearly ubiquitous EGFR expression and low incidence of K-ras mutation, we might expect some response to EGFR-targeted therapy but will need to interrogate the pathway more comprehensively to understand why some patients benefit and others do not. Full-Text PDF

EGFR and MYC gene copy number aberrations are more common in squamous cell carcinoma than keratoacanthoma: a FISH study

Epidermal growth factor receptor (EGFR) and MYC genomic aberrations have been described in cutaneous squamous cell carcinoma (SCC) but have not been widely investigated in keratoacanthoma (KA). EGFR and MYC were evaluated by fluorescence in situ hybridization and immunohistochemistry in 8 verrucae, 19 involuting KA (IKA), 23 classic KA (CKA), 6 atypical KA (AKA) and 19 SCC. Increased EGFR gene copy number was seen in 9 of 23 CKA and 14 of 19 SCC (p = 0.03). Increased MYC gene copy number was observed in 7 of 23 CKA and 17 of 19 SCC (p = 0.0001). MYC gene amplification was more common in SCC than CKA (p = 0.005), while EGFR gene amplification was rare and not significant. MYC protein overexpression was identified in 6 of 23 CKA and 14 of 19 SCC (p = 0.005). There was no statistical difference in EGFR protein overexpression in SCC and CKA (p = 0.06). EGFR and MYC aberrations were rare in IKA. AKA showed EGFR and MYC anomalies at an incidence intermediate between CKA and SCC. EGFR and MYC gene copy number aberrations are more common in SCC than KA. The incidence of aberrations parallels the degree of cytologic atypia in KA.

CCR10 and CCL27 are overexpressed in cutaneous squamous cell carcinoma

C–C chemokine receptor (CCR)10 is a specific receptor for chemokine ligand (CCL)27, a selective chemoattractant for skin-associated memory T cells to cutaneous sites. In melanoma, CCR10 increases the ability of neoplastic cells to grow, invade tissues, disseminate to lymph nodes, and escape the host immune responses. In this study, we investigated the expression of CCR10 and its ligand CCL27 in squamous cell carcinoma (SCC). CCR10 and CCL27 were expressed in SCC, actinic keratosis (AK), Bowen's disease, and seborrheic keratosis (predominantly prickle cell type), but not in seborrheic keratosis (predominantly basal cell type) and basal cell carcinoma. Furthermore, CCR10 and CCL27 were overexpressed in SCC relative to Bowen's disease, an early stage of SCC. Consistently, a human SCC cell line, A253 cells, and HaCaT cells exhibited CCL27 production that was strongly induced by tumor necrosis factor-α and interleukin-1β. Finally, A253 cells expressed stronger intracellular CCR10 compared to HaCaT cells by flow cytometry. These results suggest that CCR10 and CCL27 overexpression in SCC is related to the progression of SCC and is useful for the diagnosis of SCC.

Results of a randomized, phase III trial of nab-paclitaxel (nab-P) and carboplatin (C) compared with cremophor-based paclitaxel (P) and carboplatin as first-line therapy in advanced non-small cell lung cancer (NSCLC).

LBA7511 Background: Platinum-based doublet therapy in NSCLC, regardless of the combination used, reached a therapeutic plateau. PC produced 15-25% overall response (ORR, Kelly 2001; Sandler 2006; Schiller 2002). Albumin-bound paclitaxel, nab-P, utilizes the albumin receptor (gp60)/caveolin-1 (CAV1) pathway achieving high intratumoral paclitaxel accumulation (Desai 2006), which may have contributed to a 48% ORR observed with nab-PC in NSCLC (Stroyakovsky, 2009). This phase III trial studied the efficacy of nab-PC vs. PC in advanced NSCLC of all histologic types. Methods: First-line stage IIIB or IV NSCLC pts (ECOG 0/1) were randomized to C AUC6 q3w and either nab-P 100 mg/m2 qw w/o premed (n = 521) or P 200 mg/m2 q3w with premed (n = 531). Primary endpoint: ORR by independent radiologic review (IRR). Results: Baseline and histologic characteristics were well balanced. Dose intensity of paclitaxel was higher in nab-PC vs. PC (82 vs. 65 mg/m2/wk). nab-PC was superior to PC both by IRR (33 vs. 25%, p=0.005), a 31% improvement (1.31 response ratio [RR], 95% CI: 1.08, 1.59), and by investigator review (37 vs. 30%, p=0.008), a 26% improvement (1.26 RR, CI: 1.06, 1.50). Histologic analysis showed significantly improved ORR for nab-PC (n = 228) vs. PC (n = 221) in squamous cell carcinoma (SQC) pts (41 vs. 24%, p&lt;0.001, IRR), a 67% improvement (1.67 RR, CI: 1.26, 2.21). nab-PC was as effective as PC in nonSQC pts (ORR 26 vs. 25%). nab-PC was well tolerated, with significantly improved safety profile vs. PC despite higher paclitaxel dose delivered (1,338 vs. 1,100 mg/m2). Conclusions: The primary endpoint was met, with significantly improved ORR and safety profile of nab-PC vs. PC as first-line therapy for advanced NSCLC. nab-PC was highly active in the SQC subset, which may in part be attributed to the aberrant CAV1 overexpression in SQC (Yoo 2003) and the high intratumoral accumulation of nab-P via the gp60-CAV1 pathway. [Table: see text] [Table: see text]

Egfr Overexpression in Squamous Cell Carcinoma of the Penis

Penile cancer is a rare cancer in developed countries, but it has a higher incidence in developing countries such as Asia, Africa, and South America [...]

Prostaglandin E2 receptor 2 overexpression in squamous cell carcinoma of the lung correlates with p16INK4A methylation and an unfavorable prognosis

Several studies have described p16INK4A and prostaglandin E2 (PGE2) co-alterations in various solid tumors, including non-small cell lung cancer (NSCLC). In this study, we examined the correlation between PGE2 receptor 2 (EP2) expression and p16INK4A methylation in NSCLC, and the association with clinicopathological features and prognostic significance. We retrospectively reviewed 88 NSCLC patients who underwent resection from July 1993 to May 1997. The tumors included 43 adenocarcinomas, 39 squamous cell carcinomas, and 6 large cell carcinomas. EP2 expression was determined by immunostaining, and p16INK4A methylation was analyzed by methylation specific PCR. EP2 was overexpressed in 44% of NSCLC patients, 61% of adenocarcinoma cases, 28% of squamous cell carcinoma cases, and 33% of large cell carcinoma cases. EP2 expression positively correlated with lymph node metastasis (P=0.034), especially in patients with squamous cell carcinoma (P<0.009). Methylation of p16INK4A was detected in 34% of NSCLC patients, 23% of adenocarcinoma cases, 44% of squamous cell carcinoma cases, and 50% of large cell carcinoma cases. In patients with squamous cell carcinoma, EP2 overexpression correlated with poor prognosis with a relative risk of 2.4 (confidence interval 2.1-51.8, P<0.003), and positively correlated with p16INK4A methylation (P<0.024). Adenocarcinoma patients with p16INK4A methylation had poor prognosis with a relative risk of 2.4 (confidence interval 1.8-69.7, P<0.009), but this was not correlated with EP2 expression. In conclusion, EP2 overexpression was common in NSCLCs, especially in adenocarcinomas. Synchronous alteration of p16INK4A and EP2 may accelerate progression of squamous cell carcinomas. These two alterations may differentially affect pathogenesis among subtypes of NSCLC.

EGFR over-expression in squamous cell carcinoma of the penis

16029 Background: Squamous cell carcinoma of the penis (SCCP) can be an aggressive, disabling disease and a limited body of published literature exists in this area. Furthermore, standard chemotherapy drug combinations have been poorly studied and there have been no recent advances in systemic therapy. The use of targeted agents in SCCP has not been reported. Although EGFR expression is seen in normal squamous epithelium, it is typically confined to the basal cell layer. SCC from other sites overexpress EGFR and respond to EGFR targeted therapy, which leads one to consider whether the same is true for SCCP. This study was designed to examine whether EGFR is overexpressed in SCCP and could serve as a potential target for treatment. Objective: To examine EGFR expression in SCC of the penis. Materials and Methods: 17 consecutive cases of invasive SCCP (biopsy or surgical resection) collected over an 8-year period (1997 to 2004) were analyzed. Specimens were obtained from the QEII HSC pathology database after REB approval. EGFR expression was evaluated and graded (0, 1+, 2+, 3+) by a trained pathologist using guidelines outlined in the commercially available immunohistochemical system kit EGFR pharmDxTM (DakoCytomation, Carpinteria, CA). EGFR pharmDx monoclonal mouse antibody (clone 2–18C9) with controls consisting of human cell lines CAMA-1 (negative control) and HT29 (positive control) were used. Overexpression of EGFR was defined as any immunohistologic staining of tumor cell membranes above background level whether complete or incomplete circumferential staining. Results: All 17 cases overexpressed EGFR (14 cases 3+, 3 cases 2+). Of the specimens examined, 4 cases were also associated with CIS. In 2, the CIS also overexpressed EGFR, however to a lesser degree (1+) compared to the invasive component and in 2 cases, the CIS did not overexpress EGFR. In all cases, adjacent normal squamous epithelium demonstrated normal background EGFR expression. Conclusions: EGFR was overexpressed in all cases of invasive penile SCC in this study. Given this high rate of overexpression and that other SCC (eg. Head and Neck) benefit from EGFR targeted therapy, it is very reasonable that EGFR targeted agents warrant investigation in penile SCC. No significant financial relationships to disclose.

Comparative analysis of c‐erbB‐2 (HER‐2/neu) in squamous cell carcinoma of the tongue: does over‐expression exist? And what is its correlation with traditional diagnostic parameters?

Over-expression of the proto-oncogene c-erbB-2 (HER-2/neu) has been shown to be a prognostic marker in many kinds of cancer, whereas conflicting data exist about the prevalence of HER-2/neu over-expression in squamous cell carcinoma (SCC) of the tongue. The status of Her-2/neu was evaluated in a series of SCC of the tongue to verify the frequency of over-expression of HER-2/neu and evaluate the correlation with traditional diagnostic parameters of this neoplasm. Fourty patients with SCC of the tongue were investigated for over-expression of the protein through immunohistochemistry using CB11 antibody, the Hercep Test kit and FISH. Data obtained using the Hercep Test differ from published reports concerning the over-expression of Her-2/neu and there was no correlation between levels of expression of Her-2/neu and other clinico-pathological and/or prognostic parameters. Of the 40 specimens, using CB11 we obtained results in line with published reports; however, with the Hercep Test we found only 1 positive case (2.5%) (score 3+). These data, confirmed by FISH, suggest that Her-2/neu is not a suitable marker that could play a primary role in the clinical-therapeutic management of SCC of the tongue.

Phase II study of gefitinib in patients with metastatic/recurrent squamous cell carcinoma of the skin

5531 Background: Interrupting the epidermal growth factor receptor (EGFR) signaling pathway has shown promise in a variety of cancers. Skin squamous cell cancer (SCC) has been increasing in incidence at the rate of 4% to 8% per year since the 1960s, with especially increased rates (up to 10% annually) in recent years. Treatment options for advanced or recurrent skin SCC are extremely limited. Patients (pts) who fail surgery, radiation and/or chemotherapy have a very poor prognosis. Because of the importance of EGFR in tumorigenesis, and its overexpression in squamous cell carcinoma of the skin, it is an interesting target for treatment intervention. Gefitinib, an EGFR tyrosine kinase inhibitor, had a 11% response rate in HNSCC. Because of the possible efficacy, we proposed to study gefitinib in advanced skin SCC. Methods: Pts were required to have pathologically confirmed skin SCC adequate performance status, measurable disease, no prior EGFR therapy, and may have received prior chemotherapy. Pts must not have been amenable for curative intenet therapy with surgery or radiation. Treatment included gefitinib 250mg orally daily for 4 weeks. Results: 18 pts have been enrolled and 17 are evaluable. Median age is 68 years (range 37–84). Median ECOG PS is 1 (range 1–2). 12 pts are men and 5 women. 15 pts are currently evaluable for response. No objective partial responses were observed per WHO criteria. 4 pts (27%) have stable disease. Clinical responses were noted in 2 pts via photographs and clinical inspection. 17 pts are evaluable for toxicity. 2 pts had grade 3 rash and 1 pt had grade 3 keratitis. The most common grade 1–2 toxicities were diarrhea and fatigue. Conclusions: Gefitinib is well tolerated and has modest activity in advanced skin SCC. These pts have very few options for therapy. Data collection for response rate, duration of response and survival is ongoing as several patients are still receiving treatment. [Table: see text]

P16 ink4a overexpression and human papillomavirus infection in small cell carcinoma of the uterine cervix

Carcinogenesis of cervical cancer has been investigated, and p16 INK4a overexpression in squamous cell carcinoma of the cervix has been reported as a result of infection by human papillomavirus (HPV) (eg, HPV 16), and the consequence of the retinoblastoma (Rb) protein inactivation by HPV E7 protein. However, to our knowledge, there have been no studies on the relation between p16 INK4a overexpression associated with HPV and small cell carcinoma of the cervix, which behaves more aggressively clinically than squamous cell carcinoma. The purpose of this study was to determine whether p16 INK4a is overexpressed in small cell carcinoma, and if p16 INK4a is overexpressed, the types of HPV that are related to this cancer. We reviewed 10 cases of small cell carcinoma and examined them for p16 INK4a overexpression by immunohistochemistry. We also performed HPV typing with polymerase chain reaction (PCR)-sequencing analysis and in situ hybridization and found that p16 INK4a was overexpressed in every case. PCR-sequencing analyses revealed that all cases were HPV-positive and that 9 cases were positive for HPV 18. Five of the 9 cases positive for HPV 18 were also positive by in situ hybridization and yielded a punctate signal, considered to represent the integrated form. In conclusion, p16 INK4a was overexpressed and HPV 18 was frequently detected in an integrated form in small cell carcinoma. Therefore, inactivation of Rb protein by HPV 18 E7 protein may be associated with carcinogenesis of small cell carcinoma the same as inactivation of Rb protein by HPV 16 E7 protein is associated with carcinogenesis of squamous cell carcinoma.

Chromosomal translocations involving 11q13 contribute to cyclin D1 overexpression in squamous cell carcinoma of the head and neck

CCND1 amplification results in cyclin D1 overexpression. However, other unidentified genetic mechanisms contribute to enhanced gene expression. In the present study, 32 squamous cell carcinoma of the head and neck (SCCHN) were investigated regarding chromosomal abnormalities involving 11q13 by cytogenetic analysis, genomic CCND1 amplification by differential PCR and FISH, and cyclin D1 expression on the mRNA and protein level by differential RT-PCR and immunohistochemistry, respectively. CCND1 amplification, observed in 11 of 32 (34%) tumours, resulted in overexpression of cyclin D1 on the mRNA and/or protein level, in 3 cases in association with chromosomal translocations. In cytogenetic analysis, 4 tumours had hsr(11)(q13), all of which showed CCND1 amplification and cyclin D1 overexpression. Overexpression of cyclin D1 was detected at the mRNA level in 23 tumours (72%) and on the protein level in 25 tumours (78%). In one case a translocation was seen together with cyclin D1 overexpression on the mRNA level, without any cytogenetic or molecular signs of amplification. Furthermore, cases with cyclin D1 overexpression were frequently observed in the absence of any genomic rearrangement. We conclude that, besides amplifications, chromosomal translocations and other transcriptional or translational regulatory mechanisms are involved in CCND1 deregulation.

High incidence of p53 overexpression in squamous cell carcinoma of the tongue in young patients with no known tisk factors

High incidence of p53 overexpression in squamous cell carcinoma of the tongue in young patients with no known tisk factors