Susan Müller

Emory University, Atlanta, Georgia, United States

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Publications (16)45.88 Total impact

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    ABSTRACT: BACKGROUND To understand the mechanism of frequent and early lymph node metastasis in high-risk human papillomavirus (HPV)–associated oropharyngeal squamous cell carcinoma (OPSCC), this study investigated whether β-catenin is regulated by the HPV oncoprotein and contributes to OPSCC metastasis.METHODS Expression levels of p16, β-catenin, and epidermal growth factor receptor (EGFR) were examined in OPSCC samples (n = 208) by immunohistochemistry. The expression and subcellular localization of β-catenin and EGFR activation were also studied in HPV-positive and HPV-negative head and neck squamous cell carcinoma cell lines with western blot analysis. HPV16 E6 small interfering RNA was used to elucidate the effect of the HPV oncoprotein on β-catenin translocation. The involvement of EGFR in β-catenin translocation was confirmed by treatment with erlotinib. Moreover, the invasive capacity was evaluated after HPV16 E6/E7 repression.RESULTSThe results showed that the membrane weighted index of β-catenin was inversely correlated with p16 positivity (P < .001) and lymph node metastasis (P = .026), whereas nuclear staining of β-catenin was associated with p16-positive OPSCC (P < .001). A low level of membrane β-catenin expression was significantly associated with disease-free and overall survival (P < .0001 in both cases). Furthermore, the membrane weighted index of EGFR was inversely correlated with p16 positivity (P < .001) and positively correlated with membrane β-catenin (P < .001). The in vitro study showed that HPV16 E6 repression led to reductions of phospho-EGFR and nuclear β-catenin, which were also observed after erlotinib treatment, and inhibition of invasion.CONCLUSIONS The findings suggest that HPV16 E6 mediates the translocation of β-catenin to the nucleus, which may be regulated by activated EGFR. Cancer 2014. © 2014 American Cancer Society.
    Cancer 09/2014; 121(2). DOI:10.1002/cncr.29039 · 4.90 Impact Factor
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    ABSTRACT: There is a lack of a comprehensive immunohistochemical (IHC) analysis of canalicular adenoma (CanAd), especially when combined with a description of the unique histologic features. Given the usual small biopsies, IHC may be useful in distinguishing CanAd from other tumors in the differential diagnosis. Retrospective. The patients included 54 females and 13 males (4.2:1), aged 43-90 years, with a mean age at presentation of 69.9 years. Clinical presentation was generally a mass (n = 61) slowly increasing in size (mean 38.5 months), affecting the upper lip (n = 46), buccal mucosa (n = 17) or palate (n = 4), involving the right (n = 29), left (n = 24) or midline (n = 9), without any major salivary gland tumors. The tumors ranged in size from 0.2 to 3 cm (mean 1.2 cm). Most tumors were multilobular or bosselated (76 %), often surrounded by a capsule. Histologically, the tumors were characterized by cystic spaces, tumor cords with beading, tubule formation, and by the presence of luminal squamous balls (n = 41). The cells were cuboidal to columnar with stippled chromatin. Mitoses were inconspicuous. A myxoid stroma (n = 64), sclerosis (n = 42), luminal hemorrhage (n = 51), and luminal microliths (calcifications) (n = 33) were characteristic. Nine (13.4 %) were multifocal. CanAd showed the following characteristic immunohistochemistry findings: CK-pan and S100 protein (strong, diffuse reaction); peripheral or luminal GFAP reaction; CK5/6 and p16 luminal squamous ball reaction; SOX10 nuclear reaction; cytoplasmic p63 reaction. CanAd are unique minor salivary gland tumors showing a distinct architecture and phenotype. They predilect to older women, with the majority multilobulated and affecting the upper lip, multifocal in 13 %; no major salivary gland tumors were identified. S100 protein, CK-pan, GFAP and SOX10 are positive, with luminal squamous balls highlighted by CK5/6 or p16.
    Head and Neck Pathology 08/2014; 9(2). DOI:10.1007/s12105-014-0560-6
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    ABSTRACT: Human pituitary adenomas express folate receptors (FR); therefore, we hypothesized that parathyroid (PT) tumors also might express FR, whereas normal human thyroids might not. The purpose of our study was to characterize the functionality of FRs on human PT tumors, with the goal of developing an imaging tool that would concentrate in PT more than in the thyroid. Human PTs and thyroids were evaluated for FR expression by immunohistochemistry. Expression of genes for FRα and FRβ was measured with the Illumina Human HT-12 Expression Bead Chips and verified by quantitative reverse-transcription polymerase chain reaction. Folate incorporation by PT cells versus normal thyroid cells was determined by incubation with (99m)Technetium ((99m)Tc)(CO)3-folate and (99m)Tc-Etarfolatide, and uptake was determined by gamma counting. Specific targeting of FRs was demonstrated by blocking with cold folate. A549 cells and Jurkat cells served as FR-negative controls, and KB cells and HeLa cells were FR-positive controls. On immunohistochemistry and Western blotting, human PT cells expressed FRs, whereas human thyroid cells did not. The FRα gene was expressed in all PTs analyzed, and the FRβ gene was expressed by most. Uptake of (99m)Tc(CO)3-folate was increased in PT cells versus thyroid cells. There was dose-dependent uptake of (99m)Tc-etarfolatide, and uptake was inhibited by preincubation with cold folate, confirming FR-mediated binding. This is the first report of the expression and functionality of FRs on human PT cells. These findings suggest that (99m)Tc-folate holds potential for localization of PT tumors preoperatively and their treatment.
    Surgery 10/2013; 154(6). DOI:10.1016/j.surg.2013.06.045 · 3.11 Impact Factor
  • Susan Müller, Lester D R Thompson
    Head and Neck Pathology 07/2013; 7(S1). DOI:10.1007/s12105-013-0463-y
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    ABSTRACT: We investigated the efficacy and underlying molecular mechanism of a novel chemopreventive strategy combining EGF receptor (EGFR) tyrosine kinase inhibitor (TKI) with cyclooxygenase-2 inhibitor (COX-2I). We examined the inhibition of tumor cell growth by combined EGFR-TKI (erlotinib) and COX-2I (celecoxib) treatment using head and neck cancer cell lines and a preventive xenograft model. We studied the antiangiogenic activity of these agents and examined the affected signaling pathways by immunoblotting analysis in tumor cell lysates and immunohistochemistry (IHC) and enzyme immunoassay (EIA) analyses on the mouse xenograft tissues and blood, respectively. Biomarkers in these signaling pathways were studied by IHC, EIA, and an antibody array analysis in samples collected from participants in a phase I chemoprevention trial of erlotinib and celecoxib. The combined treatment inhibited head and neck cancer cell growth significantly more potently than either single agent alone in cell line and xenograft models, and resulted in greater inhibition of cell-cycle progression at G phase than either single drug. The combined treatment modulated the EGFR and mTOR signaling pathways. A phase I chemoprevention trial of combined erlotinib and celecoxib revealed an overall pathologic response rate of 71% at time of data analysis. Analysis of tissue samples from participants consistently showed downregulation of EGFR, pERK, and pS6 levels after treatment, which correlated with clinical response. Treatment with erlotinib combined with celecoxib offers an effective chemopreventive approach through inhibition of EGFR and mTOR pathways, which may serve as potential biomarkers to monitor the intervention of this combination in the clinic. Clin Cancer Res; 19(5); 1244-56. ©2013 AACR.
    Clinical Cancer Research 03/2013; 19(5):1244-56. DOI:10.1158/1078-0432.CCR-12-3149 · 8.19 Impact Factor
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    ABSTRACT: FAS-associated death domain (FADD) is a key adaptor protein that bridges a death receptor (e.g., death receptor 5; DR5) to caspase-8 to form the death-inducing signaling complex during apoptosis. The expression and prognostic impact of FADD in head and neck squamous cell carcinoma (HNSCC) have not been well studied. This study focuses on detecting FADD expression and analyzing its prognostic impact in primary and metastatic HNSCCs. We found a significant increase in FADD expression in primary tumors with lymph node metastasis (LNM) in comparison with primary tumors with no LNM. This increase was significantly less in the matched LNM tissues. Both univariate and multivariable analyses indicated that lower FADD expression was significantly associated with better disease-free survival and overall survival in HNSCC patients with LNM although FADD expression did not significantly affect survival of HNSCC patients without LNM . When combined with DR5 or caspase-8 expression, patients with LNM expressing both low FADD and DR5 or both low FADD and caspase-8 had significantly better prognosis than those expressing both high FADD and DR5 or both high FADD and caspase-8. However, the expression of both low FADD and caspase-8 was significantly linked to worse overall survival compared with both high FADD and caspase-8 expression in HNSCC patients without LNM. Hence, we suggest that FADD alone or together with DR5 and caspase-8 participates in metastatic process of HNSCC.
    Cancer biology & therapy 01/2013; 14(4). DOI:10.4161/cbt.23636 · 3.63 Impact Factor
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    ABSTRACT: This study aimed to understand the prognostic value of integrin β1 expression in head and neck squamous cell carcinoma (HNSCC) and the mechanism underlying its association with metastatic HNSCC. Archival HNSCC tissues including 99 nonmetastatic primary tumors and 101 metastatic primary tumors were examined for the association of integrin β1 expression with metastasis and disease prognosis by appropriate statistical methods. Fluorescence-activated cell sorting was used to separate the integrin β1(high/+) cell population from the integrin β1(low/-) population in HNSCC cell lines. These two populations and integrin β1 shRNA knockdown HNSCC cells were examined for the effect of integrin β1 on invasion in vitro and on lymph node and lung metastases in a xenograft mouse model. Expression and activation of matrix metalloproteinases (MMP) were examined by zymography. Statistical analysis showed that integrin β1 expression was significantly higher in the metastatic primary tumors than in the nonmetastatic tumors (42.6% vs. 24.8%, P < 0.0001 and P < 0.0001 by univariate and multivariate analyses, respectively). In patients with lymph node metastasis, integrin β1 expression was inversely correlated with overall survival (P = 0.035). The integrin β1 knockdown or integrin β1(low/-) HNSCC cells showed a significant reduction in lymph node and lung metastases in vivo (P < 0.001 and P < 0.05, respectively). Significantly reduced Matrigel invasion capability was also found in integrin β1 knockdown or integrin β1(low/-) HNSCC cells (P < 0.01). Finally, zymography results showed integrin β1-affected HNSCC invasion by regulating MMP-2 activation. These findings indicate that integrin β1 has a major impact on HNSCC prognosis through its regulation of metastasis.
    Clinical Cancer Research 07/2012; 18(17):4589-99. DOI:10.1158/1078-0432.CCR-11-3127 · 8.19 Impact Factor
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    ABSTRACT: To describe the clinical, histopathologic, immunohistochemical and molecular features of human papilloma virus (HPV)+ squamous cell carcinomas of the oropharynx that had an atypical clinical course. Methods and Results: Four patients with HPV+ oropharyngeal squamous cell carcinoma (OPSCC) were identified retrospectively based on unanticipated clinical behavior. The histopathology, immunohistochemistry and molecular studies of both the primary tumor and the metastases were analyzed to look for any predictors to explain the clinical course. The four patients were all male (average age 55) who presented initially with a neck mass and had stage IVA disease. Three of the primary tumors were nonkeratinizing squamous cell carcinoma and one case was a hybrid tumor of both high-grade squamous cell carcinoma and nonkeratinizing type, and all were p16 and HPV 16/18 positive. All patients received concurrent chemoradiation as primary therapy and had a complete response. Disease-free survival ranged from 7 to 15 months and metastases in 3 patients occurred only in bone, including the sternum, humerus, clavicle, and vertebrae. In one patient, distant metastases were identified in the pancreas, liver, lung and skull base. All metastatic lesions were nonkeratinizing morphology and were p16 and/or HPV positive. Two patients died of their disease, one patient is alive with disease and one patient is disease-free. Although infrequent, unanticipated clinical outcomes can occur in HPV-related OPSCC including distant metastases and bone-only metastases. The tumor morphology of the metastases was comparable to the primary and retained p16 and HPV expression.
    Head and Neck Pathology 04/2012; 6(3):336-44. DOI:10.1007/s12105-012-0355-6
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    ABSTRACT: Ectopic sphenoid sinus pituitary adenoma (ESSPA) may arise from a remnant of Rathke's pouch. These tumors are frequently misdiagnosed as other neuroendocrine or epithelial neoplasms which may develop in this site (olfactory neuroblastoma, neuroendocrine carcinoma, sinonasal undifferentiated carcinoma, paraganglioma, melanoma). Thirty-two patients with ESSPA identified in patients with normal pituitary glands (intact sella turcica) were retrospectively retrieved from the consultation files of the authors' institutions. Clinical records were reviewed with follow-up obtained. An immunohistochemical panel was performed on available material. Sixteen males and 16 females, aged 2-84 years (mean, 57.1 years), presented with chronic sinusitis, headache, obstructive symptoms, and visual field defects, although several were asymptomatic (n = 6). By definition, the tumors were centered within the sphenoid sinus and demonstrated, by imaging studies or intraoperative examination, a normal sella turcica without a concurrent pituitary adenoma. A subset of tumors showed extension into the nasal cavity (n = 5) or nasopharynx (n = 9). Mean tumor size was 3.4 cm. The majority of tumors were beneath an intact respiratory epithelium (n = 22), arranged in many different patterns (solid, packets, organoid, pseudorosette-rosette, pseudopapillary, single file, glandular, trabecular, insular). Bone involvement was frequently seen (n = 21). Secretions were present (n = 16). Necrosis was noted in 8 tumors. The tumors showed a variable cellularity, with polygonal, plasmacytoid, granular, and oncocytic tumor cells. Severe pleomorphism was uncommon (n = 5). A delicate, salt-and-pepper chromatin distribution was seen. In addition, there were intranuclear cytoplasmic inclusions (n = 25) and multinucleated tumor cells (n = 18). Mitotic figures were infrequent, with a mean of 1 per 10 HPFs and a <1% proliferation index (Ki-67). There was a vascularized to sclerotic or calcified stroma. Immunohistochemistry highlighted the endocrine nature of the tumors, with synaptophysin (97%), CD56 (91%), NSE (76%) and chromogranin (71%); while pan-cytokeratin was positive in 79%, frequently with a dot-like Golgi accentuation (50%). Reactivity with pituitary hormones included 48% reactive for 2 or more hormones (plurihormonal), and 33% reactive for a single hormone, with prolactin seen most frequently (59%); 19% of cases were non-reactive. The principle differential diagnosis includes olfactory neuroblastoma, neuroendocrine carcinoma, melanoma, and meningioma. All patients were treated with surgery. No patients died from disease, although one patient died with persistent disease (0.8 months). Surgery is curative in the majority of cases, although recurrence/persistence was seen in 4 patients (13.8%). In conclusion, ESSPAs are rare, affecting middle aged patients with non-specific symptoms, showing characteristic light microscopy and immunohistochemical features of their intrasellar counterparts. When encountering a tumor within the sphenoid sinus, ectopic pituitary adenoma must be considered, and pertinent imaging, clinical, and immunohistochemical evaluation undertaken to exclude tumors within the differential diagnosis. This will result in accurate classification, helping to prevent the potentially untoward side effects or complications of incorrect therapy.
    Head and Neck Pathology 03/2012; 6(1):75-100. DOI:10.1007/s12105-012-0336-9
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    ABSTRACT: This study explored whether the expression of aldehyde dehydrogenase 1 (ALDH1A1) in the primary tumour correlated with lymph node metastasis (LNM) of squamous cell carcinoma of the head and neck (HNSCC). We used both quantum dot (QD)-based immunohistofluorescence (IHF) and conventional immunohistochemistry (IHC) to quantify ALDH1A1 expression in primary tumour samples taken from 96 HNSCC patients, 50 with disease in the lymph nodes and 46 without. The correlation between the quantified level of ALDH1A1 expression and LNM in HNSCC patients was evaluated with univariate and multivariate analysis. The prognostic value of ALDH1A1 was examined by Kaplan-Meier analysis and Wald test. ALDH1A1 was highly correlated with LNM in HNSCC patients (p<0.0001 by QD-based IHF and 0.039 by IHC). The two methods (QD-based IHF and conventional IHC) for quantification of ALDH1A1 were found to be comparable (R=0.75, p<0.0001), but QD-IHF was more sensitive and objective than IHC. The HNSCC patients with low ALDH1A1 expression had a higher 5-year survival rate than those with high ALDH1A1 level (p=0.025). Our study suggests that ALDH1A1 is a potential biomarker for predicting LNM in HNSCC patients, though it is not an independent prognostic factor for survival of HNSCC patients. Furthermore, QD-IHF has advantages over IHC in quantification of ALDH1A1 expression in HNSCC tissues.
    European journal of cancer (Oxford, England: 1990) 02/2012; 48(11):1682-91. DOI:10.1016/j.ejca.2011.12.029 · 4.82 Impact Factor
  • Susan Müller
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    ABSTRACT: Lichenoid changes in the oral mucosa can be encountered in a wide range of lesions and can have varied etiologies. Immune-mediated disorders, including lichen planus, mucous membrane pemphigoid, discoid lupus erythematosus, and graft-versus-host disease, can have clinical and histologic overlaps. Lichenoid reactions to dental materials, such as amalgam, or to many systemic drugs are also well documented. Dysplasia of the oral cavity at times can also express a lichenoid histology, which may mask the potentially cancerous component. Proliferative verrucous leukoplakia, an unusual clinical disease, mimics oral lichen planus clinically and requires careful correlation of the clinical and pathologic features.
    Surgical Pathology Clinics 12/2011; 4(4):1005-1026. DOI:10.1016/j.path.2011.07.001
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    Susan Müller, Siema Eljack, John M DelGaudio
    Head and Neck Pathology 08/2011; 5(3):268-72. DOI:10.1007/s12105-011-0291-x
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    ABSTRACT: Epithelial-mesenchymal transition (EMT) is a crucial mechanism for the acquisition of migratory and invasive capabilities by epithelial cancer cells. By conducting quantitative proteomics in experimental models of human prostate cancer (PCa) metastasis, we observed strikingly decreased expression of EPLIN (epithelial protein lost in neoplasm; or LIM domain and actin binding 1, LIMA-1) upon EMT. Biochemical and functional analyses demonstrated that EPLIN is a negative regulator of EMT and invasiveness in PCa cells. EPLIN depletion resulted in the disassembly of adherens junctions, structurally distinct actin remodeling and activation of β-catenin signaling. Microarray expression analysis identified a subset of putative EPLIN target genes associated with EMT, invasion and metastasis. By immunohistochemistry, EPLIN downregulation was also demonstrated in lymph node metastases of human solid tumors including PCa, breast cancer, colorectal cancer and squamous cell carcinoma of the head and neck. This study reveals a novel molecular mechanism for converting cancer cells into a highly invasive and malignant form, and has important implications in prognosis and treating metastasis at early stages.
    Oncogene 05/2011; 30(50):4941-52. DOI:10.1038/onc.2011.199 · 8.56 Impact Factor
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    Susan Müller
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    ABSTRACT: Lichenoid changes in the oral mucosa can be encountered in a wide range of lesions with varied etiologies including immune-mediated disorders, reactions to systemic medications and to dental materials. Dysplasia of the oral cavity can exhibit a lichenoid histology, which may mask the potentially cancerous component. Another unusual clinical disease, proliferative verrucous leukoplakia, can often mimic oral lichen planus clinically requiring careful correlation of the clinical and pathologic features.
    Head and Neck Pathology 03/2011; 5(1):36-40. DOI:10.1007/s12105-010-0237-8
  • Susan Müller
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    ABSTRACT: Intraoral pigmentation is quite common and has numerous etiologies, ranging from exogenous to physiological to neoplastic. Many pigmented lesions of the oral cavity are associated with melanin pigment. The differential diagnosis of mucosal pigmented lesions includes hematomas, varices, and petechiae which may appear to be pigmented. Unlike cutaneous melanomas, oral melanomas are diagnosed late and have a poor prognosis regardless of depth of invasion. As such, the clinical presentation and treatment of intraoral melanoma will be discussed. Developing a differential diagnosis is imperative for a clinician faced with these lesions in order to appropriately treat the patient. This article will focus on the most common oral melanocytic lesions, along with mimics.
    Dermatologic Therapy 05/2010; 23(3):220-9. DOI:10.1111/j.1529-8019.2010.01319.x · 1.48 Impact Factor
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    ABSTRACT: Nanotechnology-based drug delivery approaches may help increase therapeutic efficacy and decrease side effects of chemotherapeutics. We investigated expression levels of folate receptor in squamous cell carcinoma of the head and neck (SCCHN) to evaluate folate receptor as a target for nanotherapy. Folate receptor expression levels in archival SCCHN tissues were analyzed by immunohistochemistry and correlated with clinical parameters. Folate receptor was detected in 45% of primary tumors and 40% of corresponding lymph node metastases. Folate receptor expression in primary tumors of the metastatic group strongly correlated with the corresponding lymph node metastases (p = .0002). Folate receptor expression was inversely correlated with disease-free survival in nonmetastatic (p = .0048), metastatic (p = .0127), and lymph node metastases (p <.001) groups, and with overall survival in the lymph node metastases group (p <.0001). Folate receptor is expressed in a significant proportion of primary SCCHN and corresponding lymph node metastases tissues, and correlates with worse clinical outcome. These findings provide support for folate receptor-mediated nanotherapeutics in SCCHN.
    Head & Neck 12/2008; 31(4):475-81. DOI:10.1002/hed.21003 · 3.01 Impact Factor