Top 10 Basaloid Neoplasms of the Sinonasal Tract.

BACKGROUND: Basaloid neoplasms of the sinonasal tract represent a significant group of tumors with histological overlap but often with different etiologies (i.e., viral, genetics), clinical management, and prognostic significance. METHODS: Review. RESULTS: "Basaloid" generally refers to cells with coarse chromatin in round nuclei and sparse cytoplasm, resembling cells of epithelial basal layers or imparting an "immature" appearance. Tumors with this characteristic in the sinonasal tract are represented by a spectrum of benign to high-grade malignant neoplasms, such as adenoid cystic carcinoma, NUT carcinoma, sinonasal undifferentiated carcinoma, SWI/SNF complex-deficient carcinomas, and adamantinoma-like Ewing sarcoma. CONCLUSION: In some instances, histology alone may be sufficient for diagnosis. However, limited biopsy material or fine-needle aspiration specimens may be particularly challenging. Therefore, often other diagnostic procedures, including a combination of histology, immunohistochemistry (IHC), DNA and RNA testing, and molecular genetics are necessary to establish an accurate diagnosis.

Dietary carbohydrate, particularly glucose, drives B cell lymphopoiesis and function.

While diet modulates immunity, its impact on B cell ontogeny remains unclear. Using mixture modeling, a large-scale isocaloric dietary cohort mouse study identified carbohydrate as a major driver of B cell development and function. Increasing dietary carbohydrate increased B cell proportions in spleen, mesenteric lymph node and Peyer's patches, and increased antigen-specific immunoglobulin G production after immunization. This was linked to increased B lymphopoiesis in the bone marrow. Glucose promoted early B lymphopoiesis and higher total B lymphocyte numbers than fructose. It drove B cell development through glycolysis and oxidative phosphorylation, independently of fatty acid oxidation in vitro and reduced B cell apoptosis in early development via mTOR activation, independently of interleukin-7. Ours is the first comprehensive study showing the impact of macronutrients on B cell development and function. It shows the quantitative and qualitative interplay between dietary carbohydrate and B cells and argues for dietary modulation in B cell-targeting strategies.

Investigation of foreign materials in gingival lesions: a clinicopathologic, energy-dispersive microanalysis of the lesions and in vitro confirmation of pro-inflammatory effects of the foreign materials.

OBJECTIVES: This study aimed to evaluate the clinical and histopathologic features of gingival lesions containing foreign material (GLFMs). In parallel, the composition of the foreign material and its effects in primary human gingival fibroblasts (HGFs) were investigated. STUDY DESIGN: Eighty-six GLFMs were retrieved from an oral pathology biopsy service. Clinical and microscopic data were analyzed, and the composition of the particles was identified by using energy-dispersive X-ray spectroscopy (EDX). Furthermore, HGFs were stimulated with silica (SiO2) microparticles to investigate the production of collagen type 1 (COL-1), matrix metalloproteinase 2 (MMP2), and inflammatory cytokines. RESULTS: GLFMs were most commonly found in women (60.5%) and most frequently described as white plaques. Histopathologic examination identified verrucous hyperplasia in 59% and epithelial dysplasia in 28% of the cases. EDX microanalysis revealed that Si (94%) was the most frequently detected foreign element. SiO2 microparticles induced higher COL-1 expression; higher levels of proinflammatory cytokines, such as interleukin-6 (IL-6), IL-8, and transforming growth factor-ß, and increased MMP-2 activity in HGFs. CONCLUSIONS: There was a strong association between the presence of foreign material in the gingiva and white verrucous clinical lesions. In addition, the most common element in the foreign material was Si, and our in vitro findings demonstrate the importance of silica-mediated effects on gingival fibroblasts.

Analysis of the Murine Bone Marrow Hematopoietic System Using Mass and Flow Cytometry.

The hematopoietic system produces erythrocytes (red blood cells), leukocytes (white blood cells), and thrombocytes (platelets) throughout the life of an organism. Long-lived hematopoietic stem cells give rise to early progenitors with multi-lineage potential that progressively differentiate into lineage-specific progenitors. Following lineage commitment, these progenitors proliferate and expand, before eventually differentiating into their mature forms. This process drives the up- and downregulation of a wide variety of surface and intracellular markers throughout differentiation, making cytometric analysis of this interconnected system challenging. Moreover, during inflammation, the hematopoietic system can be mobilized to re-prioritize the production of various lineages, in order to match increased demand, often at the expense of other lineages. As such, the response of the hematopoietic system in the bone marrow (BM) is a critical component of both immunity and disease. Because of the complexity of the hematopoietic system in steady state and disease, high-dimensional cytometry technologies are well suited to the exploration of these complex systems. Here we describe a protocol for the extraction of murine bone marrow, and preparation for examination using high-dimensional flow or mass cytometry. Additionally, we describe methods for performing cell cycle assays using bromodeoxyuridine (BrdU) or iododeoxyuridine (IdU). Finally, we describe an analytical method that allows for a system-level analysis of the hematopoietic system in steady state or inflammatory scenarios.

Investigation of immune cell markers in feline oral squamous cell carcinoma.

Squamous cell carcinoma is the most common oral cancer in the cat and presents as a locally aggressive lesion for which an effective therapeutic protocol remains elusive. Feline oral squamous cell carcinoma (OSCC) shares many clinical characteristics with human head and neck squamous cell carcinoma (HNSCC). Accordingly, present studies were conducted to determine similarities for immune markers shared by feline OSCC and human HNSCC. Biopsies harvested from a feline patient cohort-1 (n = 12) were analyzed for lymphoid cell infiltrates by immunohistochemistry (IHC). Results revealed unique patterns of T cell infiltration involving both neoplastic epithelium and stroma that were detected in most patient tumor biopsies (92%) examined by IHC staining for CD3. Intratumoral B cell infiltrates were detected within tumor stroma only, based on IHC staining for CD79a and CD20 for all patients within the same cohort-1. Infiltration of tumors by a regulatory CD4 T cell subset (Tregs) defined by expression of the forkhead transcription factor FoxP3, was also detected in biopsies from 57% of patients and involved infiltration of neoplastic epithelium and stroma. Patient biopsies were also examined for expression of immunomodulator cyclooxygenase (COX)-2 and revealed positive but weak staining of neoplastic epithelium in a significant proportion of cases (75%). Interestingly, COX-2 expression was detected in both neoplastic epithelium and stroma. Blood collected from a second cohort of feline OSCC patients (n = 9) revealed an increased frequency of circulating CD4+FoxP3+ T cells when compared to healthy adult controls (n = 7) (P = 0.045), although frequencies of CD4+CD25+FoxP3+ T cells were comparable between patients and healthy pet cat controls. Lastly, biopsies from feline OSCC patients were characterized for histologic subtype using a classification scheme previously described for human HNSCC. This analysis revealed the conventional subtype as the predominant variant (75%) with conventional subtypes split evenly between well differentiated and moderately differentiated carcinomas. Two cases were classified as papillary and one case as basaloid subtypes. Correlations between subtype, immune marker scores or circulating Treg frequencies and clinical characteristics or outcome were not detected, most likely due to small patient numbers within patient cohorts. However, findings from these studies provide a preliminary step in the characterization of immune and histologic markers that will be critical to defining prognostic immune markers for feline OSCC and potential targets for testing of immunotherapeutics also relevant to human HNSCC in future studies.

Advanced platelet-rich fibrin and freeze-dried bone allograft for ridge preservation: A randomized controlled clinical trial.

BACKGROUND: Advanced platelet-rich fibrin (A-PRF) is an autogenous blood product with applications in dento-alveolar surgery. However, there is minimal information regarding its optimal clinical application or efficacy. The aim of this multi-arm parallel randomized controlled clinical trial was to evaluate the efficacy of A-PRF alone or with freeze-dried bone allograft (FDBA) in improving vital bone formation and alveolar dimensional stability during ridge preservation. METHODS: Forty patients requiring extraction of non-molar teeth and replacement with dental implants were randomized into one of four ridge preservation approaches: A-PRF, A-PRF+FDBA, FDBA, or blood clot. A-PRF was prepared at 1,300 rpm for 8 minutes. Non-traumatic extractions and ridge preservation was performed. After an average of 15 weeks healing, bone core samples were harvested at the time of implant placement for micro-CT and histomorphometric analysis. Ridge dimensions were measured immediately after extraction and before implant placement. RESULTS: Significantly greater loss of ridge height was noted in the blood clot group (3.8 ± 2.0 mm) compared to A-PRF (1.8 ± 2.1 mm) and A-PRF+FDBA (1.0 ± 2.3 mm) groups (P < 0.05). No significant differences in ridge width reduction were noted between groups. Significantly more vital bone was present in the A-PRF group (46% ± 18%) compared to the FDBA group (29% ± 14%) (P < 0.05). Bone mineral density was significantly greater in the FDBA group (551 ± 58 mg/cm3 ) compared to blood clot (487 ± 64 mg/cm3 ) (P < 0.05). CONCLUSIONS: This study demonstrates A-PRF alone or augmented with FDBA is a suitable biomaterial for ridge preservation. This study represents the first randomized controlled clinical trial comparing A-PRF with and without FDBA to FDBA alone for ridge preservation.

The Oral Effects of Inhalation Corticosteroid Therapy: An Update.

Inhaled corticosteroids (IC) are commonly used for the treatment of respiratory diseases. Although these medications are generally considered safer when compared to oral systemic corticosteroids, there is evidence for potential systemic and local adverse effects with their use. Therefore, dentists should be aware of these adverse effects, especially the commonest local effects that can involve the oral mucosa. This article reviews the literature on the complications of IC therapy with emphasis on its potential oral effects.

An intravaginal ring for real-time evaluation of adherence to therapy.

Two recent Phase III clinical trials to investigate an intravaginal ring for preventing HIV infection demonstrated that adherence to prescribed device use was a primary driver of efficacy. Surrogate methods for determining adherence in the studies were limited in their inability to monitor temporal patterns of use and allow deconvolution of the effects of adherence and device efficacy on HIV infection rates. To address this issue, we have developed functionality in an intravaginal ring to continuously monitor when the device is being used and maintain a log of adherence that can be accessed by clinicians after it is removed. An electronic module fabricated with common, inexpensive electronic components was encapsulated in a silicone intravaginal ring. The device uses temperature as a surrogate measure of periods of device insertion and removal, and stores a record of the data for subsequent retrieval. The adherence-monitoring intravaginal ring accurately recorded the device status over 33 simulated IN-OUT cycles and more than 1000 measurement cycles in vitro. Following initial in vitro testing in a temperature-controlled chamber, the device was evaluated in vivo in sheep using a predetermined insertion/removal pattern to simulate intravaginal ring use. After insertion into the vaginal cavity of a sheep, the logged data correctly indicated the device status over 29 hours of continuous measurement including three cycles of insertion and removal. The device described here is a promising, low-cost method for real-time adherence assessment in clinical trials involving medicated intravaginal rings or other intravaginal devices.

Oral Squamous Cell Carcinoma Mimicking Peri-Implantitis.

INTRODUCTION: Peri-implantitis is inflammation and alveolar bone loss around a dental implant. Published case reports have described squamous cell carcinoma (SCC) development around dental implants. CASE PRESENTATION: A 60-year-old female presented with two small fistulas on the alveolar ridge of missing tooth #18. The mucosa around the fistulas appeared normal otherwise, with no hyperplasia, erythema, or keratotic changes. The patient had a 14-year history of recurrent erythroleukoplakia (with microscopic dysplasia) on the left tongue that had been managed by surgical removal (scalpel and carbon dioxide laser), biopsies, and close follow-up. She had no other medical conditions. She reported that she had an implant placed to replace tooth #18 4 years ago that had been removed without flap reflection, curettage, or biopsy 1 year previously as a result of peri-implantitis. Periapical radiographs showed that the peri-implant radiolucency in the region of tooth #18 was unchanged in dimensions from the time of implant removal 1 year ago. Curettage and biopsy of the area were performed and showed the presence of a well-differentiated SCC. CONCLUSIONS: This is a case of peri-implant SCC development in a patient at high risk for oral SCC. The carcinoma was present within the alveolar defect in the area of a failed implant that had been removed 1 year previously. The overlying surface mucosa did not show the clinical changes typically seen in carcinoma. This case and others demonstrate the importance of periodic oral and radiographic examination after implant placement. Although rare, neoplasia must be considered in the evaluation of peri-implant pathology.

Lymphangioma-like Kaposi sarcoma of the oral mucosa.

With the epidemic of acquired immunodeficiency syndrome, the clinical and histopathological features of Kaposi sarcoma (KS) became routine for most practicing surgical pathologists. The histological spectrum of KS broadened significantly over time and today a wide variety of rare histological variants are reported, but not widely recognized. Lymphangioma-like KS (LLKS) is a rare histological variant of KS occurring in skin, with banal histological features that can lead to misdiagnosis and inappropriate therapy. We report a series of intra-oral cases of LLKS and review the literature regarding this lesion.

Rare diagnosis of IgG4-related systemic disease by lip biopsy in an international Sjögren syndrome registry.

IgG4-related disease has been recently defined as a distinct clinic-pathologic entity, characterized by dense IgG-4 plasmacytic infiltration of diverse organs, fibrosis, and tumefactive lesions. Salivary and lacrimal glands are a target of this disease and, when affected, may clinically resemble Küttner tumor, Mikulicz disease, or orbital inflammatory pseudotumor. In some patients, the disease is systemic, with metachronous involvement of multiple organs, including the pancreas, aorta, kidneys, and biliary tract. We report a 66-year-old man who presented with salivary gland enlargement and severe salivary hypofunction and was diagnosed with IgG4-related disease on the basis of a labial salivary gland biopsy. Additional features of his illness included a marked peripheral eosinophilia, obstructive pulmonary disease, and lymphoplasmacytic aortitis. He was evaluated in the context of a research registry for Sjögren syndrome and was the only 1 of 2594 registrants with minor salivary gland histopathologic findings supportive of this diagnosis.

p53 expression and mutation analysis of odontogenic cysts with and without dysplasia.

OBJECTIVE: Overexpression of p53 protein is well described in odontogenic cystic lesions (OCLs), including those with epithelial dysplasia; however, most p53 antibodies stain both wild-type and mutated p53 protein and may not reflect genotype. Direct sequencing of the p53 gene has not identified mutations in OCLs with dysplasia. The purpose of this study was to determine the molecular basis of p53 expression in several types of OCLs with and without dysplasia. METHODS: The study material comprised 13 OCLs: odontogenic keratocyst (n = 5), orthokeratinized odontogenic cyst (n = 5), dentigerous cyst (n = 2), lateral periodontal cyst (n = 1), and unspecified developmental odontogenic cyst (UDOC) (n = 1). Five of these had features of mild or moderate epithelial dysplasia. One intraosseous squamous cell carcinoma (SCC) that was believed to have arisen from an antecedent dysplastic orthokeratinized OC was also included. Immunohistochemistry was performed using the DO7 monoclonal antibody that recognizes wild-type and mutated p53. DNA was extracted from microdissected tissue for all samples and exons 4 to 8 of the p53 gene direct sequenced. RESULTS: In 4 of 5 OCLs with dysplasia there was strong nuclear staining of basal and suprabasal cells. In all cases without dysplasia, nuclear expression in basal cells was either negative or weak and was absent in suprabasal cell nuclei. A mutation in exon 6 of the p53 gene (E224D) was identified in both the dysplastic orthokeratinized OC and the subsequent intraosseous SCC. CONCLUSIONS: OCLs with features of dysplasia show increased expression of p53 protein that does not reflect p53 mutational status. One dysplastic OC shared the same p53 mutation with a subsequent intraosseous SCC, indicating that p53 mutation may be associated with malignant transformation in this case.

Odontogenic osteomyelitis or bisphosphonate-related osteonecrosis of mandible of patient with autoimmune disease: clinical dilemma.

The key to appropriate treatment of odontogenic osteomyelitis or bisphosphonate-related osteonecrosis of the mandible in patients with autoimmune diseases lies in making the correct diagnosis based on meticulous review of signs and symptoms. As this complex case involving a patient with multiple comorbidities illustrates, diagnosis can be difficult, because these conditions may overlap or be mistaken for other conditions. However, prompt treatment is essential to limit the progression, which can be devastating for these medically complex patients. It is, therefore, important to understand local and systemic conditions that can weaken the immune system and predispose patients to chronic bone infection, meticulously go through signs and symptoms, and have a complete medical history, including patient medications.

Clinical signs and histologic findings in dogs with odontogenic cysts: 41 cases (1995-2010).

OBJECTIVE: To characterize clinical signs and histologic findings in dogs with odontogenic cysts and determine whether histologic findings were associated with clinical features. DESIGN: Retrospective case series. ANIMALS: 41 dogs. PROCEDURES: Medical records were reviewed to obtain clinical data, including breed, age, sex, and lesion location. Microscopic sections and results of diagnostic imaging were reviewed. RESULTS: Odontogenic cysts were identified in 41 dogs between 1995 and 2010. There were 29 dogs with dentigerous cysts, 1 with a radicular cyst, 1 with a lateral periodontal cyst, and 1 with a gingival inclusion cyst. In addition, 9 dogs with odontogenic cysts that had clinical and histologic features suggestive of, but not diagnostic for, odontogenic keratocysts seen in people were identified. In all 9 dogs, these cysts were located in the maxilla and surrounded the roots of normally erupted teeth. Of the 29 dogs with dentigerous cysts, 23 had a single cyst, 5 had 2 cysts, and 1 had 3 cysts. Six cysts were associated with an unerupted canine tooth, and 30 were associated with an unerupted first premolar tooth (1 cyst was associated both with an unerupted canine tooth and with an unerupted first premolar tooth). Dentigerous cysts were identified in a variety of breeds, but several brachycephalic breeds were overrepresented, compared with the hospital population during the study period. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that a variety of odontogenic cysts can occur in dogs. In addition, cysts that resembled odontogenic keratocysts reported in people were identified. We propose the term canine odontogenic parakeratinized cyst for this condition.

Associations between salivary gland histopathologic diagnoses and phenotypic features of Sjögren's syndrome among 1,726 registry participants.

OBJECTIVE: To examine associations between labial salivary gland (LSG) histopathology and other phenotypic features of Sjögren's syndrome (SS). METHODS: The database of the Sjögren's International Collaborative Clinical Alliance (SICCA), a registry of patients with symptoms of possible SS as well as those with obvious disease, was used for the present study. LSG biopsy specimens from SICCA participants were subjected to protocol-directed histopathologic assessments. Among the 1,726 LSG specimens exhibiting any pattern of sialadenitis, we compared biopsy diagnoses against concurrent salivary, ocular, and serologic features. RESULTS: LSG specimens included 61% with focal lymphocytic sialadenitis (FLS; 69% of which had focus scores of ≥1 per 4 mm²) and 37% with nonspecific or sclerosing chronic sialadenitis (NS/SCS). Focus scores of ≥1 were strongly associated with serum anti-SSA/SSB positivity, rheumatoid factor, and the ocular component of SS, but not with symptoms of dry mouth or dry eyes. Those with positive anti-SSA/SSB were 9 times (95% confidence interval [95% CI] 7.4-11.9) more likely to have a focus score of ≥1 than were those without anti-SSA/SSB, and those with an unstimulated whole salivary flow rate of <0.1 ml/minute were 2 times (95% CI 1.7-2.8) more likely to have a focus score of ≥1 than were those with a higher flow rate, after controlling for other phenotypic features of SS. CONCLUSION: Distinguishing FLS from NS/SCS is essential in assessing LSG biopsies, before determining focus score. A diagnosis of FLS with a focus score of ≥1 per 4 mm², as compared to FLS with a focus score of <1 or NS/SCS, is strongly associated with the ocular and serologic components of SS and reflects SS autoimmunity.

Clinicopathologic characterization of odontogenic tumors and focal fibrous hyperplasia in dogs: 152 cases (1995-2005).

OBJECTIVE: To characterize clinicopathologic features of the most common odontogenic tumors and focal fibrous hyperplasia (FFH) in dogs. DESIGN: Retrospective case series. ANIMALS: 152 dogs evaluated for oral tumors of possible odontogenic origin at the William R. Pritchard Veterinary Medical Teaching Hospital of the University of California-Davis between 1995 and 2005. PROCEDURES: Information was collected from records, including dog breed, age, reproductive status, and location of lesion in the oral cavity. Histologic slides pertaining to each dog were reviewed by 3 investigators. Data regarding clinicopathologic features of the 3 most common lesions (canine acanthomatous ameloblastoma [CAA], peripheral odontogenic fibroma [POF], and FFH) were summarized. RESULTS: 152 dogs with odontogenic tumors or FFH were identified. Sixty-eight (45%) dogs had CAA, 47 (31 %) had POF, 24 (16%) had FFH, and 13 (9%) had other odontogenic tumors. Canine acanthomatous ameloblastoma was present most commonly in the rostral aspect of the mandible, with POF and FFH more common in the rostral aspect of the maxilla. Males and females were equally represented among dogs with CAA and FFH. Castrated males were overrepresented among dogs with POF. Golden Retrievers, Akitas, Cocker Spaniels, and Shetland Sheepdogs were overrepresented among dogs with CAA. No breed predisposition was detected for FFH or POF. Dogs with FFH had a greater mean age at initial evaluation than did dogs with CAA or POF. CONCLUSIONS AND CLINICAL RELEVANCE: CAA, POF, and FFH have distinct clinical patterns that may help clinicians and pathologists identify such lesions more readily.

Mutations in the c-Kit gene disrupt mitogen-activated protein kinase signaling during tumor development in adenoid cystic carcinoma of the salivary glands.

The Ras/mitogen-activated protein kinase (MAPK) pathway is considered to be a positive regulator of tumor initiation, progression, and maintenance. This study reports an opposite finding: we have found strong evidence that the MAPK pathway is inhibited in a subset of adenoid cystic carcinomas (ACCs) of the salivary glands. ACC tumors consistently overexpress the receptor tyrosine kinase (RTK) c-Kit, which has been considered a therapeutic target. We performed mutational analysis of the c-Kit gene (KIT in 17 cases of ACC and found that 2 cases of ACC had distinct missense mutations in KIT at both the genomic DNA and messenger RNA levels. These mutations caused G664R and R796G amino acid substitutions in the kinase domains. Surprisingly, the mutations were functionally inactive in cultured cells. We observed a significant reduction of MAPK (ERK1/2) activity in tumor cells, as assessed by immunohistochemistry. We performed further mutational analysis of the downstream effectors in the c-Kit pathway in the genes HRAS, KRAS, NRAS, BRAF, PIK3CA, and PTEN. This analysis revealed that two ACC tumors without KIT mutations had missense mutations in either KRAS or BRAF, causing S17N K-Ras and V590I B-Raf mutants, respectively. Our functional analysis showed that proteins with these mutations were also inactive in cultured cells. This is the first time that MAPK activity from the RTK signaling has been shown to be inhibited by gene mutations during tumor development. Because ACC seems to proliferate despite inactivation of the c-Kit signaling pathway, we suggest that selective inhibition of c-Kit is probably not a suitable treatment strategy for ACC.