[Show abstract][Hide abstract] ABSTRACT: Background: p16 overexpression is a highly sensitive yet moderately specific biomarker for predicting human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). Nuclear β-catenin translocation has been linked to HPV-positive OPSCC. However, whether the strategy of combining β-catenin with p16 can better predict HPV-associated OPSCC remains unknown. Methods: We evaluated the expression of p16 and β-catenin (nuclear and membrane) by immunohistochemistry staining in 101 OPSCC tissues and HPV status by HPV DNA in situ hybridization. Logistic regression models were used to evaluate single or multiple biomarkers for HPV prediction. The prediction power, sensitivity, and specificity were determined by receiver operating characteristic (ROC) analyses. Results: Our data showed that upon univariate analysis, p16 and nuclear β-catenin were positively correlated with HPV status, while membrane β-catenin was inversely correlated with HPV status (P < 0.01). p16 showed the highest HPV predictive power, with area under the curve (AUC) of 0.9074 compared to 0.6762 for nuclear β-catenin and 0.7635 for membrane β-catenin, respectively, indicating differential accuracies for HPV prediction. Multivariable analysis showed that p16 was significantly correlated with HPV, while nuclear and membrane β-catenin showed marginal significance. The three-biomarker model was similarly sensitive (98.9% vs. 100%) but more specific (88.9% vs. 81%) than p16 alone, which also showed a good predictive value for overall (P = 0.0002) survival and disease-free (P = 0.0158) survival. Conclusion: Our study suggests a novel model of combining p16 and subcellular β-catenin for prediction of HPV-associatred OPSCC, and this finding deserves further validation.
Full-text · Article · Oct 2015 · Journal of Oral Pathology and Medicine
[Show abstract][Hide abstract] 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.
No preview · Article · Aug 2014 · Head and Neck Pathology
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
Full-text · Article · Jan 2013 · Cancer biology & therapy
[Show abstract][Hide abstract] 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.
No preview · Article · Jul 2012 · Clinical Cancer Research
[Show abstract][Hide abstract] 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.
Full-text · Article · Apr 2012 · Head and Neck Pathology
[Show abstract][Hide abstract] 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.
Full-text · Article · Mar 2012 · Head and Neck Pathology
[Show abstract][Hide abstract] 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.
No preview · Article · Feb 2012 · European journal of cancer (Oxford, England: 1990)
[Show abstract][Hide abstract] 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.
No preview · Article · Dec 2011 · Surgical Pathology Clinics
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
Preview · Article · Mar 2011 · Head and Neck Pathology
[Show abstract][Hide abstract] 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.
No preview · Article · May 2010 · Dermatologic Therapy
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: Several recent reports suggest an increasing incidence of oral squamous cell carcinoma (OSCC) among young persons in many regions of the world--a trend which is particularly concerning given the overall stabilization or even decline in incidence rates for head and neck cancer in general. The aim of this study is to determine whether there has been an increase in the number of cases of OSCC diagnosed in patients < 40 years old by our biopsy service from 1971 to 2006.
A retrospective review of all OSCC cases diagnosed from 1971 to 2006 by the Emory University Hospital Oral Pathology biopsy service was performed. A comparison of demographic information, frequency, location and histologic grade was made between these cases as a whole and those occurring in a subset of patients < 40 years old. Statistical procedures included chi-square analyses.
From 1971-2006, 1,919 cases of OSCC were diagnosed, and 95 (5.0%) occurred in patients < 40 years old. A total of 8 cases were diagnosed from 1971 to 1980, compared to 36 cases during the period 1981-1990, 31 during the period 1991-2000 and 21 cases from 2001 to 2006. The increase in OSCC incidence from the 1970s when compared to 1981-2000 was statistically significant (P < 0.002). A 1.7:1 male:female ratio was seen in all decades. The mobile (oral) tongue was the most common location in all decades (62.1%) in young patients. In contrast, tongue cancers accounted for 27.4% in patients > or = 40. This difference between the two groups was statistically significant (P < 0.0001). Of great surprise, however, was the significant increase in tongue cancer during the study period in patients > or = 40 which accounted for 37.1% of all OSCC diagnoses from 2001 to 2006, compared to 20.5% of OSCC cases from 1971 to 1980 (P < 0.0001).
We demonstrated a greater than fourfold increase in the incidence of oral squamous cell carcinoma (OSCC) in young patients < 40 years old beginning in 1974 and peaking in the late 1980s, then remaining stable. The mobile tongue is the most common location for cancer in this age group accounting for 62.1% of cancers. However, the mobile tongue increasingly appears to be the most common site for oral cancer in all age groups.
Full-text · Article · Jun 2008 · Head and Neck Pathology
[Show abstract][Hide abstract] ABSTRACT: Esthesioneuroblastoma (ENB) is a rare tumor of the olfactory epithelium. The objective of this study was to evaluate treatment modalities including surgery, IMRT, and chemotherapy and patient outcomes.
A retrospective analysis was performed on a total of 21 patients. Therapy included craniofacial resection (CFR), radiotherapy, chemotherapy, or a combination of these methods.
The median follow-up period was 47 months. Surgery was performed in 90.4% of cases; radiotherapy was performed adjuvantly in 15 (72.7%) patients. Surgery, radiotherapy, and chemotherapy were administered to 7 (33.3%) patients. Eight (38.3%) patients had local recurrence. The 5-year crude overall survival was 71.4% and actuarial 5-year overall survival was 58% with confidence interval (CI, 25 and 81, respectively). The 5-year crude disease-free survival rate was 59% and the 5-year actuarial disease-free survival rate was 62% (CI, 28 and 83, respectively).
Multidisciplinary therapy of ENB should be considered, especially for Kadish C and high-grade lesions. Craniofacial resection (CFR), Intensity modulated radiation therapy (IMRT), and chemotherapy should be investigated in a multi-institution trial of ENB.
No preview · Article · Jul 2007 · Otolaryngology Head and Neck Surgery