An adenoid cystic carcinoma (AdCC) of the ceruminous glands is very rare; its diagnosis is most often challenging, and simple biopsies may be misleading. Our paper describes a case of a circumferential mass of the left ear canal that was initially reported as a basal cell carcinoma on biopsies in the clinic and on frozen sections intraoperatively. The final pathology was an AdCC of the ceruminous glands of the external auditory canal. Our case reflects the difficulty in the diagnosis of an AdCC of the ceruminous gland and the importance of keeping broad differential diagnoses in mind when counseling patients with masses in the ear canals until final pathology is obtained.

Lung cancer carries a poor prognosis and is the most common cause of cancer-related death worldwide. The integrin α6β4, a laminin receptor, promotes carcinoma progression in part by cooperating with various growth factor receptors to facilitate invasion and metastasis. In carcinoma cells with mutant TP53, the integrin α6β4 promotes cell survival. TP53 mutations and integrin α6β4 overexpression co-occur in many aggressive malignancies. Because of the high frequency of TP53 mutations in lung squamous cell carcinoma (SCC), we sought to investigate the association of integrin β4 expression with clinicopathologic features and survival in non–small cell lung cancer (NSCLC). We constructed a lung cancer tissue microarray and stained sections for integrin β4 subunit expression using immunohistochemistry. We found that integrin β4 expression is elevated in SCC compared with adenocarcinoma (P<.0001), which was confirmed in external gene expression data sets (P<.0001). We also determined that integrin β4 overexpression associates with the presence of venous invasion (P=.0048) and with reduced overall patient survival (hazard ratio, 1.46; 95% confidence interval, 1.01-2.09; P=.0422). Elevated integrin β4 expression was also shown to associate with reduced overall survival in lung cancer gene expression data sets (hazard ratio, 1.49; 95% confidence interval, 1.31-1.69; P<.0001). Using cBioPortal, we generated a network map demonstrating the 50 most highly altered genes neighboring ITGB4 in SCC, which included laminins, collagens, CD151, genes in the EGFR and PI3K pathways, and other known signaling partners. In conclusion, we demonstrate that integrin β4 is overexpressed in NSCLC where it is an adverse prognostic marker.

S100A4 (metastasin-1), a metastasis-associated protein and marker of the epithelial to mesenchymal transition, contributes to several hallmarks of cancer and has been implicated in the progression of several types of cancer. However, the impacts of S100A4 signaling in lung cancer progression and its potential use as a target for therapy in lung cancer have not been properly explored. Using established lung cancer cell lines, we demonstrate that S100A4 knockdown reduces cell proliferation, invasion and three-dimensional invasive growth, while overexpression of S100A4 increases invasive potential. In patient-derived tissues, S100A4 is preferentially elevated in lung adenocarcinoma. This elevation is associated with lymphovascular invasion and decreased overall survival. In addition, depletion of S100A4 by shRNA inhibits NF-κB activity and decreases TNFα-induced MMP9 expression. Furthermore, inhibition of the NF-κB/MMP9 axis decreases lung carcinoma invasive potential. Niclosamide, a reported inhibitor of S100A4, blocks expression and function of S100A4 with a reduction in proliferation, invasion and NF-κB-mediated MMP9 expression. Collectively, this study highlights the importance of the S100A4/NF-κB/MMP9 axis in lung cancer invasion and provides a rationale for targeting S100A4 to combat lung cancer.

Objectives. Prospectively validate an intraoperative surgical staging algorithm to stratify patients with early endometrial cancer by risk of lymph node metastasis.Methods. Subjects with endometrial cancer clinically confined to the uterus were prospectively enrolled at an academic cancer center between Jan 2012 and Jun 2015. Study participants were stratified intraoperatively into two groups based on risk of nodal involvement using cell type, tumor grade, myometrial invasion, and tumor size in accordance with an established protocol from the Mayo Clinic. Low risk (LR) subjects received extrafascial hysterectomy with bilateral salpingo-oophorectomy; high risk (HR) patients received complete surgical staging including bilateral pelvic and para-aortic lymphadenectomy.Results. Of the 200 subjects enrolled, 194 were eligible for analysis. The algorithm identified 132 (68%) HR and 62 (32%) LR cancers. Of the HR subjects, 126 had lymphadenectomy performed with 14 (11%) positive for nodal metastases. Five HR subjects experienced disease recurrence. Of the 62 LR cancers, two patients developed disease recurrence. Ten LR cancers were upgraded to HR on final pathology due to lesion size (6) and grade (4). None of these patients experienced disease recurrence. The algorithm demonstrated 90% sensitivity (18/20) and 36% specificity (62/174) as determined by positive lymph nodes and/or disease recurrence.Conclusions. Intraoperative assessment of early endometrial cancer can be used to determine the extent of surgical staging. The studied algorithm has low specificity and modifications are necessary to better match the surgical procedure to the risk of metastatic cancer. Published by Elsevier Inc.

Abstract The metastatic nature of advanced non-small cell lung cancer (NSCLC) is associated with therapeutic resistance, quick time to progression, and poor prognosis. This dismal outcome remains until we gain a better understanding of the crucial drivers of the metastatic process and the power to effectively target them. S100A4 (metastasin-1) is a tumor metastasis associated protein and an epithelial to mesenchymal transition (EMT) marker. S100A4 contributes to several hallmarks of cancer such as anti-apoptosis, proliferation, and therapeutic resistance. This protein has been implicated in the progression of different types of cancer, including breast, colon and pancreas. However, the impacts of S100A4 signaling in lung cancer progression and its potential use as a target for therapy have not been properly explored. Here, using established lung cancer cell lines, we demonstrate that S100A4 is overexpressed in about 45% of lung cancer cell lines tested, both at the mRNA and protein levels. To address the biological action of S100A4 overexpression in lung cancer cells, loss-of function and gain-of function experiments were performed. We found that inhibition of S100A4 by shRNA in A549 and H460 lung cancer cell lines reduced cell proliferation and invasion and decreased 3D invasive growth, while exogenous overexpression of S100A4 in H1299 cells increased invasive potential. In order to examine S100A4 expression in patient-derived tissues, we constructed a lung cancer tissue microarray (TMAs, N = 212) and analyzed it using immunohistochemistry. We found that S100A4 is preferentially overexpressed in lung adenocarcinoma (P = 0.0007) when compared to squamous cell carcinoma, which was confirmed using publicly available gene expression datasets (TCGA). Furthermore, we found that S100A4 overexpression is associated with the presence of lymphovascular invasion (P = 0.0189) and with decreased overall survival (Hazard ratio 2.14, 95% confidence interval 1.08-4.22, P = 0.0243) among patients with lung adenocarcinoma. To elucidate the mechanisms by which S100A4 promotes lung cancer invasive capacity, we focused on the NF-κB pathway. We observed that depletion of S100A4 by shRNA inhibited NF-κB activity and decreased TNFα-induced MMP9 expression. Furthermore, inhibition of the NF-κB/MMP9 axis decreased lung cancer cell invasive potential. Collectively, this study highlights the importance of the S100A4/NF-κB/MMP9 axis in lung cancer invasion and metastasis and provides rationale for targeting S100A4 to combat lung cancer. Citation Format: Rachel L. Stewart, Brittany L. Carpenter, Dava S. West, Teresa Knifley, Chi Wang, Heidi L. Weiss, Tamas S. Gal, Kathleen L. O'Connor, Min Chen. S100A4/metastasin-1 promotes lung cancer cell invasion and associates with decreased overall survival among patients with adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2275. doi:10.1158/1538-7445.AM2015-2275

Human ovarian cancer is diagnosed in the late, metastatic stages but the underlying mechanisms remain poorly understood. We report a surprising functional link between CD151-α3β1 integrin complexes and the malignancy of serous-type ovarian cancer. Analyses of clinical specimens indicate that CD151 expression is significantly reduced or diminished in 90% of metastatic lesions, while it remains detectable in 58% of primary tumors. These observations suggest a putative tumorsuppressing role of CD151 in ovarian cancer. Indeed, our analyses show that knocking down CD151 or α3 integrin enhances tumor cell proliferation, growth and ascites production in nude mice. These changes are accompanied by impaired cell-cell contacts and aberrant expression of E-cadherin, Mucin 5AC and fibronectin, largely reminiscent of an epithelial to mesenchymal transition (EMT)-like change. Importantly, Slug, a master regulator of EMT, is markedly elevated. Knocking down Slug partially restores CD151-α3β1 integrin complex-dependent suppression of cell proliferation. Moreover, disruption of these adhesion protein complexes is accompanied by a concomitant activation of canonical Wnt signaling, including elevated levels of β-catenin and Axin-2 as well as resistance to the inhibition in β-catenin-dependent transcriptional complexes. Together, our study demonstrates that CD151-α3β1 integrin complexes regulate ovarian tumor growth by repressing Slug-mediated EMT and Wnt signaling.

We report a case of a 56-year-old woman with endobronchial breast cancer metastasis of unusual histology. The patient presented with persistent cough, and a lesion was noted in the left mainstem bronchus on bronchoscopic examination. Biopsy revealed extensive squamous metaplasia of bronchial epithelium along with large, atypical cells exhibiting pagetoid intraepithelial spread within squamous mucosa. Immunohistochemical stains were compatible with a diagnosis of metastatic breast adenocarcinoma with pagetoid spread. To our knowledge, this is the first reported case of endobronchial breast cancer metastasis with this histologic presentation. In this report, we describe the clinical, radiographic, bronchoscopic, histologic, and immunohistochemical characteristics of this case. We provide a brief review of existing literature on endobronchial breast cancer metastasis. In addition, we discuss the principal differential diagnosis of bronchial pagetoid lesions. This report raises awareness of this uncommon manifestation of metastatic breast cancer.