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Purpose Different lesions in the fibro-osseous group share microscopic features; thus, establishing a definitive diagnosis based on microscopic features alone can be a challenge. There is a need for additional microscopic tools to aid in differentiating these lesions. This study compared parameters related to vascularity among 3 lesions in the fibro-osseous group: fibrous dysplasia (FD), central ossifying fibroma (COF), and cemento-osseous dysplasia (COD). Materials and Methods This study was a cross-sectional analysis of biopsied lesions retrieved from 3 medical centers over a 14-year period. The primary predictor variables were the vascularity parameters (number, perimeter, and area). The outcome variables were diagnoses of FD, COF, and COD. Diagnosis was based on clinical, microscopic, and radiologic correlations. From each histopathologic slide, 5 representative fields were captured with a computerized digital camera. The number of blood vessels was counted, and the surface area and vascular perimeter were measured by tracing the perimeter of each vessel. Data were statistically analyzed using analysis of variance with logarithmic transformation and a Tukey adjustment. Results Sixty-six cases were included in the study (26 in FD group, 26 in COF group, and 14 in COD group). The mean number of vessels showed only a tendency to be larger in the FD group compared with the COF and COD groups (5.4 ± 2.6, 3.7 ± 2.3, and 3.6 ± 1.7, respectively), but the results did not reach the threshold for significance. The mean vascular perimeter was 1,385.8 ± 859.2 pixels in the FD group and 742.6 ± 661.8 in COF group after logarithmic transformation (P = .012). The perimeter in the COD group was smaller (941.1 ± 502) compared with that in the FD group, but the difference did not reach the threshold for significance. The mean area was 25,061 ± 24,875.6 in the FD group and 11,773.8 ± 21,734.4 in the COF group after logarithmic transformation (P = .004). The perimeter in the COD group was smaller (13,011.1 ± 8,338.3) compared with the FD group, but the difference did not reach the threshold for significance. Conclusion The vascular content of the FD group was markedly higher than of the COF group. These vascular changes can aid in differentiating these lesions microscopically.

The 4th edition of the World Health Organization’s Classification of Head and Neck Tumours was published in January of 2017. This article provides a summary of the changes to Chapter 4 Tumours of the oral cavity and mobile tongue and Chapter 8 Odontogenic and maxillofacial bone tumours. Odontogenic cysts which were eliminated from the 3rd 2005 edition were included in the 4th edition as well as other unique allied conditons of the jaws. Many new tumors published since 2005 have been included in the 2017 classification.

Long standing, asymptomatic, well-demarcated erythema of the hard palate with a histopathological psoriasiform pattern comprises a challenging diagnosis. We present a series of patients with such clinical and histological findings and discuss the possible diagnoses. We collected all patients with palatal erythematous lesions that had well-documented clinical examination. Excluded were patients with definitive diagnosis of oral infections (e.g. candidiasis), neoplastic/pre-neoplastic lesions, auto-immune diseases, reactive lesions, blood disorders and vascular malformations. Thirteen patients (six females, seven males, age range 11–56 years) were included. Histopathologically, a psoriasiform pattern was observed in all biopsied lesions. One patient was diagnosed with hereditary mucoepithelial dysplasia (HMD) and four with cutaneous psoriasis. The remaining eight patients were otherwise healthy. A combination of persistent, asymptomatic palatal erythematous lesion with psoriasis-like histopathology may represent an oral manifestation of HMD or psoriasis, concomitant to extra-oral features. In lack of any known medical background, the term "oral psoriasiform mucositis" is suggested.

Acantholytic squamous cell carcinoma (ASCC) is an uncommon variant of squamous cell carcinoma (SCC). It is characterized by a combination of typical SCC and pseudoglandular structures, dyskeratotic cells and prominent acantholysis. The purpose of this study was to analyze the histochemical and immunohistochemical characteristics of the intraoral variant of ASCC. Cases of intraoral ASCC were retrieved from the English language literature. Four new cases from our files were added. In total, 35 cases were included and analyzed in this study. The mean age of the patients was 61.5 + 13 years (age range 38–92 years), with a male-to-female ratio of 1.7:1. According to the available data, histochemical and immunohistochemical stains for mucins were found to be consistently negative. E- cadherin, a marker of adherens junctions, was usually reported to be expressed in areas of “typical” (non acantholytic) SCC, but reduced in the acantholytic areas. We examined for the first time the expression of claudin 1, a marker of tight junctions, and found it to be reduced in the acantholytic areas, similar to E-cadherin. Several cases of oral ASCC also expressed vimentin and cytokeratin (CK) 19, markers associated with epithelial-mesenchymal transition. A wide range of non-epithelial markers yielded negative immunoreactions. In conclusion, ASCC is an uncommon variant of squamous cell carcinoma. The acantholytic process appears to involve reduced expression of molecular components of both adherens junctions and tight junctions. These findings could suggest a relation to the epithelial mesenchymal transition process and therefore further studies are needed in order to establish such a link and the subsequent possible impact on the clinical outcome of the patients.

Hundreds of minor salivary glands (MiSGs) are scattered in the oral cavity located at the submucosa layer. Beside their role in the oral cavity lubrication and immunity defence system, MiSGs are beneficial tissue source for diagnosing oral and non-oral related diseases. The advantage of MiSGs as a diagnostic tool reside on their fairly simple excisional procedure on one hand and negligible impact of the normal secretion capability of the salivary gland system on the other hand. The review focuses on pathologies related to developmental, reactive, metabolic, inflammatory and immunologic conditions, Iatrogenic causes and other undefined causes.

Objectives: To examine different immunophenotypes of cancer-associated fibroblasts (CAFs) in tongue squamous cell carcinoma (TSCC) and to investigate how they related to clinical outcomes. Methods: Serial sections from 54 cases of TSCC were immunohistochemically stained with a-smooth muscle actin (alpha SMA, CAF marker) to determine CAF density, and double-immunostained with alpha SMA combined with CD80 and CD86 (myeloid/monocytic-derived cell markers), Nanog (mesenchymal stem cell marker) and CD133 (hematopoietic/endothelial stem cell marker). Density of cells co-expressing these marker combinations was semi-quantitatively assessed in 5 randomly selected high power fields within the tumor area and scored as 1 - one-to-five stained cells in each field, 2 - more than 5 stained cells in each field; any finding less than score 1, was allocated a score of 0. Results: There were 26 CAF-poor, 16 CAF-rich and 12 CAF-intermediated cases. CD86(+) alpha SMA(+) cells were the most frequent (80.4%) followed by CD80(+) alpha SMA(+) (72%) and Nanog(+) alpha SMA(+) cells (56%). The CD133(+) alpha SMA(+) phenotype was found only in association with blood vessels. High density of aSMA CAFs was associated with disease recurrence and poor survival (p

Aim To perform clinico-pathological characterization of a large series of oral metastases, collected from 3 main medical centers in Israel and compare findings to data on frequency of primary cancer types in the population. Materials Pathology archives were searched for cases of metastatic tumors to the oral soft tissues and jawbones, 1990 – 2016. Metastases to the skin of face or to major salivary glands have been excluded. Demographic data and histopathological features were analyzed. Results Study population included 60 patients, 35 females and 25 males (ratio of 1.4:1). The age range was 17–87 years, mean 67.7 + 14.36 years. Only 3 (5%) patients were under 40 years, the remaining clustered predominantly in the 60–80 year age group. The mean age of females (59 + 13.84) was significantly lower than that of males (67.44 + 14) (p = 0.03). There was an almost equal distribution between the oral soft tissue and the jawbones (48.3% and 51.7%, respectively). The five most common organs from which metastases were distributed to the oral cavity and jawbones combined were kidney (20%), breast (15%), cutaneous (predominately melanoma, 13%), lung (11.7%) and soft tissue-sarcomas (8.3%). For comparison, Israel National Cancer Registry 2013 reported that the most frequent malignancies were breast (25.8%), colorectal cancer (16.3%), lung (12%) and prostate (10%). Malignant melanoma was 6th (5.4%), kidney malignancy was only 9th in frequency (4.2%). Although the gingiva and jawbones were the most frequent locations, some cases presented in unusual locations, (mandibular vestibule, lower lip, posterior dorsal tongue), without any specific clinical feature to suggest metastasis. Conclusions The most frequent primary origins for oral metastasis do not correspond to the relative frequency of the primary tumors in the population, indicating that metastatic spread is not a random process. Although the majority of metastasis involves the gingiva and jawbones, any other oral mucosal location might be involved. Thus, in adult/older patients, metastasis from a distant site should be included in the differential diagnosis of oral masses at any oral location, whether the existence of a primary tumor is reported or not.

We aimed to immunohistochemically characterize the pattern of expression of epithelial markers in rare head and neck squamous cell carcinoma (HNSCC) variants: carcinoma cuniculatum (CC) and adenosquamous carcinoma (ASC). We also present an additional variant of HNSCC with concomitant basaloid and squamous components that has overlapping morphological features with odontogenic and non-odontogenic tumors, which we termed basalo-squamous carcinoma (BSC). The selected markers included CK5/6, p40, CK19, BerEP4, p16 and SOX10. All tumors were CK5/6 and p40 positive. CK19 and BerEP4 were positive in BSC and focally in ASC but negative in CC. p16 was positive in 3 (60%) of the CCs, focally positive in ASC and negative in BSC. SOX10 was negative in all three variants. Our results highlight the plasticity of the lining epithelium revealing differential profiles of immuno-expression of the selected molecular markers, possibly reflecting their diverse histopathogenesis.

Atherosclerotic carotid plaques (ACPs) constitute the main etiological factor in about 15% of strokes. ACPs can be detected on routine dental panoramic radiographs. As these are one of the most commonly performed dental images, they can be used as a source of available data for computerized methods of automatic detection of ACPs in order to significantly increase their timely diagnosis. The aim of this study was to present the potential of applying deep learning methodology to detect ACPs on routine panoramic radiographs with the ultimate goal of preventing strokes.The Faster Region-based Convolutional Neural Network (Faster R-CNN) for deep learning was used. The operation of the algorithm was assessed on a small dataset of 65 panoramic images. As the available training data was limited, data augmentation was performed by changing the brightness and randomly flipping and rotating cropped regions of interest in multiple angles. Receiver operating characteristic (ROC) analysis was performed to calculate the accuracy of detection.ACPs were detected with a sensitivity of 75%, a specificity of 80%, and an accuracy of 83%. The ROC analysis showed a significant area under curve (AUC), different from 0.5.The novelty of the study lies in showing the efficiency of a deep learning method for the detection of ACPs on routine panoramic images based on a small dataset. Further improvement is needed as regards the application of the algorithm to the level of introducing this methodology in routine dental practice for stroke prevention.

OBJECTIVES To perform systematic review and meta-analysis on correlations between cancer-associated fibroblasts (CAFs) and the risk of death for patients with oral squamous cell carcinoma. SUBJECTS AND METHODS English literature (1966-2018) was systematically analyzed for studies that immunohistochemically assessed CAF density by alpha-smooth muscle actin and presented 5 year survival rates by Kaplan-Meier plots. Mean age of patients, proportion of male/female patients, and male/female majority (>50% male/female patients) per study were also collected. Significance level for statistical models was p

Aim: To assess expression of some markers of the pre-metastatic niche (PMN) in lymph nodes (LNs) of oral cancer patients. Methods: LNs from metastatic-free neck dissections (LN0/N0, N = 43) and metastatic-free LNs in the vicinity of metastasis-containing LNs (LN0/N+, N = 30) were immuno-histochemically stained for lysyl oxidase (LOX), fibronectin (FN), vascular-endothelial growth factor receptor (VEGFR)-1 and matrix metalloproteinase (MMP)-9. Staining was assessed as 0 (no or weak staining), 1 (strong stain in 25% cells or extracellular area), 2 (same as 1 but in up to 50%) and 3 (same as 1 but in > than 50% of cells/area). Assessment was performed in the lymph node capsule (CAP), sub-capsular sinus (SCS) and medullary sinus (MS). In addition, sections were stained with picrosirius red and examined with polarized microscopy for assessing the distribution of polarization colors of the collagen fibers in the LN capsular area. Results: All examined LNs were positive for markers of the PMN. In general, the distribution and intensity of the immunoreactivity was similar between the LN0/N0 and LN0/N+, with only a few differences regarding expression of LOX in the capsule (p = 0.002) and VEGFR1 and MMP9 in the SCS (p = 0.023 and p

Lipoid proteinosis (LP) is a rare autosomal recessive disorder characterized by deposits of hyaline material within skin and mucous membranes of the upper aerodigestive tract, especially the vocal cords. We aimed to investigate possible associations between oral LP (oLP) manifestations and demographic data and extra-oral lesions. Cases of oLP were collected following a systematic search of Medline’s PubMed and Google Scholar (1948–2014). We added four new cases. Demographic data, consanguineous marriage status, oral lesion site(s), and related symptoms were analyzed for potential associations. A total of 137 patients with oLP lesions were analyzed. Parental consanguinity status was known for 52 patients, and the parents were not related in 38 (73%) of them. The tongue was the most commonly affected oral site (68%), and it was associated with significantly more affected family members (P = 0.002). The palate and gingiva were the least involved sites (25 and 6%, respectively): the former had a tendency to be affected in younger patients and the latter in older ones. Patients with palatal and labial lesions had significantly less skin scarring (P

Background Bone block grafting may be required to restore the alveolar process prior to implant placement in Kennedy Class IV partial edentulism of the anterior mandible. Purpose Evaluate the application of allograft cancellous bone blocks for the augmentation of the anterior atrophic mandible. Materials and methods Fourteen consecutive patients underwent augmentation with cancellous bone block allografts in the anterior mandible. A bony deficiency of at least 3 mm horizontally and up to 3 mm vertically according to computerized tomography para-axial reconstruction served as inclusion criteria. Following 6 months, 26 implants were placed and a cylindrical sample core was collected. All specimens were prepared for histological and histomorphometrical examination. The rehabilitation scheme was two dental implants, placed in the lateral incisor area, supporting a 4-unit implant-supported prosthesis. Results Twenty-four blocks were placed in 14 patients. Mean follow-up was 26 ± 17 months. Mean bone gain was 5 ± 0.5 mm horizontally, and 2 ± 0.5 mm vertically. Twenty-six implants were used. Marginal bone loss at last follow up did not extend beyond the first thread. Block and implant survival rates were 91.6% and 100%, respectively. All patients but one received a fixed implant-supported prosthesis. Histomorphometrically, the mean fraction of the newly formed bone was 42%, that of the residual cancellous block-allograft 17%, and of the marrow and connective tissue 41%. Conclusions The potential of cancellous bone block allografts for reconstruction of Kennedy Class IV partial edentulism in the anterior mandible seems promising but still has to be evaluated scientifically in long-term observations.

ExoQuick-TCTM (EQ), a chemical-based agent designed to precipitate exosomes, was calibrated for use on saliva collected from healthy individuals. The morphological and molecular features of the precipitations were compared with those obtained using the classical, physical-based method of ultracentrifugation (UC). Electron microscopy and immunoelectron microscopy with anti-CD63 showed vesicular nanoparticles surrounded by bi-layered membrane, compatible with exosomes in EQ, similar to that observed with UC. Atomic force microscopy highlighted larger, irregularly shaped/aggregated EQ nanoparticles that contrasted with the single, round-shaped UC nanoparticles. ELISA (performed on 0.5 ml of saliva) revealed a tendency for a higher expression of the specific exosomal markers (CD63, CD9, CD81) in EQ than in UC ( p>0.05). ELISA for epithelial growth factor receptor, a non-exosomal-related marker, showed a significantly higher concentration in EQ than in UC ( p=0.04). Western blotting of equal total-protein concentrations revealed bands of CD63, CD9 and CD81 in both types of preparations, although they were less pronounced in EQ compared with UC. This may be related to a higher fraction of non-exosomal proteins in EQ. In conclusion, EQ is suitable and efficient for precipitation of salivary exosomes from small volumes of saliva; however, EQ tends to be associated with considerably more biological impurities (non-exosomal-related proteins/microvesicles) as compared with UC.

The research on oral cancer has focused mainly on the cancer cells, their genetic changes and consequent phenotypic modifications. However, it is increasingly clear that the tumor microenvironment (TME) has been shown to be in a dynamic state of inter-relations with the cancer cells. The TME contains a variety of components including the non-cancerous cells (i.e., immune cells, resident fibroblasts and angiogenic vascular cells) and the ECM milieu [including fibers (mainly collagen and fibronectin) and soluble factors (i.e., enzymes, growth factors, cytokines and chemokines)]. Thus, it is currently assumed that TME is considered a part of the cancerous tissue and the functionality of its key components constitutes the setting on which the hallmarks of the cancer cells can evolve. Therefore, in terms of controlling a malignancy, one should control the growth, invasion and spread of the cancer cells through modifications in the TME components. This mini review focuses on the TME as a diagnostic approach and reports the recent insights into the role of different TME key components [such as carcinoma-associated fibroblasts (CAFs) and inflammation (CAI) cells, angiogenesis, stromal matrix molecules and proteases] in the molecular biology of oral carcinoma. Furthermore, the impact of TME components on clinical outcomes and the concomitant need for development of new therapeutic approaches will be discussed.

Early or late post-implant placement complications are usually localized infectious/inflammatory processes and treated accordingly. If the healing process does not take place within a reasonable timeframe, the possibility of a pathologic process beyond localized infection/inflammation should be suspected. We describe a radiological/histopathological spectrum of bony lesions ranging from inflammatory to malignant lesions surrounding failed dental implants. Five cases of mandibular dental implant failure that clinically, radiologically and histopathologically appeared to be inflammatory processes are presented. The failure of the dental implants was immediate in two cases and late in the remaining three. The radiological features were essentially similar for all five, and they included radiolucent or mixed radiolucent–radiopaque lesions with poorly defined borders. Three lesions were limited to the area of the failed implant, while the other two extended to a large part of the mandible. The histopathological findings ranged from acute osteomyelitis and chronic osteomyelitis with features of a fibro-osseous-like lesion and occasional rimming of atypical osteoblasts to osteogenic sarcoma that was admixed with a component of osteomyelitis (diagnosis of the latter was achieved only after a series of biopsies). In-depth investigative procedures are imperative in order to establish an accurate diagnosis whenever the histopathological diagnosis is inconsistent with persisting clinical signs and symptoms in bone lesions associated with failed dental implants.

Objectives Tetraspanins, cell surface proteins that mediate cell-cell and cell-extracellular matrix interactions, are capable to modify cell motility, thus being potential diagnostic markers in pre-malignant conditions. We examined the immunohistochemical expression of tetraspanins CD9, CD81 and CD63 in normal oral mucosa as well as in inflamed, dysplastic and neoplastic epithelial lesions. Findings Included were cases of normal oral mucosa (NOR, N=15), oral lichen planus (OLP, N=51), hyperkeratosismild dysplasia (HK, N=29), moderate-severe dysplasia (DYSP, N=22), oral squamous cell carcinoma (OSCC, N=31), and normal-looking mucosa nearby OSCC (N-OSCC, N=18). Staining, assessed as percent of stained cells multiplied by staining intensity (1=weak, 2=strong), was evaluated per epithelial thirds (basal, middle and upper) and then as total staining score (sum of all thirds). Statistical analysis was performed using One-way ANOVA. Receiver operating characteristic (ROC) curve was used for diagnostic sensitivity. Statistical significance was set at P Conclusions CD9 could accurately discriminate between normal (high expression) and all other types of pathologies (lower expression) with high diagnostic sensitivity. In addition, expression of CD9 in neoplasia and the nearby histologically “normal-looking” epithelium was similar but significantly lower than in dysplasia and OLP. Therefore, the expression of CD9 could aid in defining the nature of equivocal histopathological changes in oral epithelial lesions.

Oral squamous cell carcinoma (OSCC) is a growing global public health problem for which standard therapeutic strategies have failed to contribute significantly to improve the survival rates that have remained around 50% over the past three decades. Therefore, there is a pressing need for new therapeutic strategies. Curcumin is a natural dietary compound with known anti-neoplastic activities, hence its classification as a nutraceutical agent. This review presents the current in vitro and in vivo studies in which curcumin has been examined for its anti-cancer potential in treating OSCC. Its mechanisms of action are also beginning to become unveiled. The available studies have been focusing on the impact of curcumin on epithelial malignant cells, but overlooking the components of the tumor microenvironment. Curcumin has been emerging as a promising therapeutic agent in oral cancer, either alone or in combination with standard therapeutic agents, and will probably become of practical use once its route of administration has overcome its poor bioavailability.

Invasion is an important hallmark of cancer involving interactions between the tumor microenvironment and the cancer cells. Hypoxia, low oxygen level, is related to increased invasion and metastasis in many cancers. The aim was to elucidate the effect of hypoxia on invasion of oral squamous cell carcinoma cells (OSCCs), and the applicability of a novel 3-dimentional myoma organotypic invasion model in hypoxia experiments. OSCC cell lines (primary oral carcinoma derived cells UT-SCC-43A, recurrent oral carcinoma cells UT-SCC-43B and aggressive tongue carcinoma cells HSC-3) were studied for their migration and invasion capabilities under normoxia, hypoxia, and in the presence a hypoxia-mimicker cobalt chloride. As expected, the recurrent UT-SCC-43B cells were significantly more aggressive than the primary tumor derived cells. In contrast to tongue carcinoma HSC-3 cells, they only mildly responded to hypoxia in the migration or invasion assays, indicating a cell line specific response of hypoxia on the invasive potential. The modification of the organotypic human tissue-derived matrix via the removal of various yet unidentified soluble factors by rinsing the tissue resulting in stripped matrix substantially changed the invasion pattern of HSC-3 cells and the outcomes of hypoxic treatments. Only in the stripped tissue hypoxia significantly increased invasion, whereas in native intact tissue the induced invasion was not observed. This demonstrates the importance of the soluble factors to the invasion pattern and to the hypoxia response. A metastasis and poor prognosis marker, hypoxia-regulated lysyl oxidase (LOX), was present in the myoma tissue, but could be removed by rinsing. The inhibition of LOX resulted in a decrease in invasion area, but only very mildly in invasion depth. Thus, it may have a role in the modulation of the invasion pattern. Another hypoxia-related poor prognosis marker carbonic anhydrase 9 (CAIX) was induced in HSC-3 cells both by the hypoxic exposure and interestingly in invading HSC-3 cells inside the tissue even in normoxic conditions. In conclusion, this suggests that the intact myoma organotypic model offers optimally hypoxic surroundings, thus being an excellent human tumor microenvironment mimicker.

Purpose Central giant cell granulomas (CGCGs) are clinically classified as nonaggressive (nA-CGCGs) and aggressive (A-CGCGs). However, histopathologically, all lesions feature spindle mononuclear cells (MCs) and multinuclear giant cells (GCs) in a hemorrhage-rich stroma. We aimed to investigate the presence of cells with a monocyte- or macrophage-related phenotype and, together with clinical variables, to examine their predictive potential for the biological behavior of CGCGs. Patients and Methods For our investigation, we implemented a retrospective cohort study. Sections were immunohistochemically stained for colony-stimulating factor 1 receptor (CSF-1R) (CD115), CD163, CD68, and nuclear factor κB. The clinical variables included age, gender, and location of lesions. Associations between immunostains, clinical variables, and CGCG aggressiveness were analyzed by the Wilcoxon (Mann-Whitney) exact test and t test. Significant variables were further analyzed by a logistic regression model followed by receiver operating characteristic (ROC) curve analysis for diagnostic sensitivity. Significance was set at P < .05. Results Patients with A-CGCGs (n = 36) were younger than those with nA-CGCGs (n = 31) (P = .002). Logistic regression showed that CD163-GC (β = –0.870, P = .031) and CD115-MC (β = –0.783, P = .027) had a significant protection effect (odds ratio, 0.419 [95% confidence interval, 0.190 to 0.925], and odds ratio, 0.457 [95% confidence interval, 0.229 to 0.913], respectively). ROC curve analysis showed that CD163-GC and CSF-1R (CD115)–MC combined were the best predictor in distinguishing nA-CGCGs from A-CGCGs (area under ROC curve, 0.814; P < .001). At the optimal cutoff value (0.408), sensitivity was 87% and specificity, 65%. Conclusions Increasing age and high expression of CD163-GC and CSF-1R (CD115)–MC can serve as significant predictors of nA-CGCGs. A functional link between CD163-GC and the characteristic areas of extravasation of erythrocytes is discussed.

Background Cancer associated fibroblasts (CAFs) are generally associated with negative prognostic factors. This study compares the clinicopathologic impact of CAFs in oral squamous cell carcinoma in patients with a history of proliferative verrucous leukoplakia (p-scca) and patients with conventional squamous cell carcinoma of the buccal mucosa, gingiva and palate (c-scca). Methods A retrospective clinicopathologic and immunohistochemical analysis of 97 tumor specimens from 78 patients (13 patients with PVL-associated squamous cell carcinoma (n=32) and conventional squamous cell carcinoma from the buccal mucosa, gingiva and palate (n=65) was conducted. Immunostaining with anti- alpha smooth muscle actin (α-SMA) antibody was used to evaluate the presence of CAFs. Results α-SMA expression was an infrequent finding in p-scca and seen in only 6% of p-scca compared to 40% of c-scca (p

Background This study was aimed to evaluate the prevalence of metaplastic changes in the epithelium of radicular cysts and to investigate how they relate to the clinical and radiographic characteristics of the cysts, based on a large series of radicular cysts. Material and Methods Biopsies of cysts of endodontic origin that were examined at the Department of Oral Pathology between 2004 and 2011 have been re-evaluated for this study. Only cases that were re-confirmed with clinical and histological diagnoses of a radicular or residual radicular cyst were included. The included cases were evaluated for the prevalence of metaplastic changes in the form of mucous secreting cells (MSC) or ciliated cells (CC). The relations between the metaplastic changes and the cyst type (radicular or residual radicular), as well as demographic, clinical and radiographic parameters, were statistically evaluated using Fischer and chi-square tests. Significance was set at p

We characterized tumor microenvironment (TME) components of mobile tongue (MT) cancer patients in terms of overall inflammatory infiltrate, focusing on the protumorigenic/anti-inflammatory phenotypes and on cancer-associated fibroblasts (CAFs) in order to determine their interrelations and associations with clinical outcomes. In addition, by culturing tongue carcinoma cells (HSC-3) on a three-dimensional myoma organotypic model that mimics TME, we attempted to investigate the possible existence of a molecular crosstalk between cancer cells and TME components. Analysis of 64 cases of MT cancer patients revealed that the overall density of the inflammatory infiltrate was inversely correlated to the density of CAFs (P = 0.01), but that the cumulative density of the protumorigenic/anti-inflammatory phenotypes, including regulatory T cells (Tregs, Foxp3+), tumor-associated macrophages (TAM2, CD163+), and potentially Tregs-inducing immune cells (CD80+), was directly correlated with the density of CAFs (P = 0.01). The hazard ratio (HR) for recurrence in a TME rich in CD163+ Foxp3+ CD80+ was 2.9 (95% CI 1.03–8.6, P = 0.043 compared with low in CD163+ Foxp3+ CD80+). The HR for recurrence in a TME rich in CAFs was 4.1 (95% confidence interval [CI] 1.3–12.8, P = 0.012 compared with low in CAFs). In vitro studies showed cancer-derived exosomes, epithelial–mesenchymal transition process, fibroblast-to-CAF-like cell transdifferentiation, and reciprocal interrelations between different cytokines suggesting the presence of molecular crosstalk between cancer cells and TME components. Collectively, these results highlighted the emerging need of new therapies targeting this crosstalk between the cancer cells and TME components in MT cancer. publishedVersion

We sought to investigate the expression of cells with immunosuppressive/protumorigenic phenotypes in oral lichen planus (OLP), such as M2-tumor-associated macrophages (TAM2), myeloid-derived suppressive cells (MDSCs), and regulatory T cells (Tregs) in association with clinical parameters.Cases of hyperkeratotic (HK)-OLP (n = 23) and erosive (E)-OLP (n = 26) were immunohistochemically stained to determine the percentages of CD163-TAM2, CD80-MDSCs, and FOXP3-Tregs of proinflammatory CD121a-Th17, CD4 and CD8 lymphocytes, and of cells positive for nuclear factor kappa B (NF-κB) and transforming growth factor beta. Clinical parameters included symptoms, treatment approach, treatment response, and others.The inflammatory infiltrate in HK-OLP and E-OLP contained immunosuppressive cells; however, their pattern of expression was compatible with a proinflammatory response [membranous CD163-TAM2 staining (not extracellular), CD80+ lymphocytes (not macrophages), and a few Tregs]. The presence of CD4+, CD8+, and CD121a+ T lymphocytes was extensive. TAM2 were more frequent in E-OLP than in HK-OLP (P = 0.017). A higher frequency of CD80+ lymphocytes was associated with partial to no response to treatment (P = 0.028). Nuclear expression of NF-κB in the inflammatory cells was absent.The pattern of expression of the immunosuppressive cells, together with numerous CD4+, CD8+, and Th17-CD121a+ lymphocytes, suggest an extensive proinflammatory response rather than an immunosuppressive/protumorigenic response.The frequency of selective types of inflammatory cells calls for individual profile analyses of inflammatory infiltrates and individually adjusted treatment.

Gingival lesions of squamous hyperplasia, cystic keratinizing hyperplasia (CKH), and squamous cell carcinoma (SCC) can be induced in rats treated by chronic gavage with 10–100 mg/kg 3,3′,4,4′-tetrachloroazobenzene. We evaluated gingival squamous hyperplasia (GSH), CKH, and SCC for the immunohistochemical pattern of expression of carcinogenesis-associated markers. The 3 types of lesions and controls were stained with proliferation markers (proliferating cell nuclear antigen [PCNA] and cyclin-D1), tumor-suppressor markers (β-catenin and mammary serine protease inhibitor [maspin]) and stroma-related markers (α-smooth muscle actin [SMA] and osteonectin/SPARC). The lesions had common immunohistochemical characteristics that differed in their expression patterns among the various diagnoses. PCNA and cyclin-D1 expression was higher in GSH, CKH, and SCC than in controls. The normal membranous expression of β-catenin was lower in GSH, and almost absent in CKH and SCC. Maspin expression was similar in GSH and controls, whereas both CKH and SCC showed decreased expression. SMA and/or osteonectin/SPARC were seen in stromal cells in CKH and SCC. Collectively, there appears to be a progression from hyperplastic and cystic lesions toward malignancy based on the morphological changes, supported by the expression of carcinogenesis-associated proteins. The exact sequence of events leading to SCC remains to be defined in a time-dependent manner.

Salivary gland tumors (SGTs) of epithelial origin are relatively rare, and worldwide reports show considerable variations in their epidemiology. The aim of this study was to examine, for the first time, the records of SGTs from two very distant geographical locations, Finland (two medical centers) and Israel (one medical center) between 1999 and 2008, based exclusively on the 2005 WHO classification of head and neck tumors, and to compare those data to the other available (single-center) studies that used the same classification. A total of 2,218 benign and malignant tumors diagnosed in the three centers were analyzed. Differences in classification of the tumors were found between the two geographical locations as well as between the two centers from Finland. There was a higher ratio of benign-to-malignant SGTs in the Finnish centers (5.4:1 and 7:1) compared to the Israeli center (2:1), a higher frequency of tumors of minor salivary glands in the Israeli center (34%) than in the Finnish centers (4 and 11%), and a higher frequency of malignant SGTs in the minor salivary glands in Israel (64.5%) than in Finland (10.9 and 27%). The diversity of these multicenter data are compatible with reports from different parts of the world. We conclude that conducting epidemiologic surveys based on the latest WHO classification provides clinicopathologic correlations on SGTs that seem to be characteristic even in small geographical regions.

Mobile tongue squamous cell carcinoma (MTSCC) is known for its strong propensity for regional metastasis and poor patient survival despite aggressive treatment, thus calling for new and reliable markers for predicting prognosis and guiding therapeutic management. Towards this end, three classes of markers were investigated: cancer-associated fibroblasts (CAFs; α-SMA positivity) as a representative of the tumor microenvironment, maspin (mammary serine protease inhibitor) as a tumor marker likely to be modulated by factors within the tumor microenvironment, and DNA content and Ki-67 labeling index as inbuilt tumor markers in 128 cases of MTSCC using immunohistochemistry and image cytometry. Of these markers, only CAF density was independently and relatively strongly associated with elevated mortality from MTSCC. The hazard ratio in the CAF-rich type of tumor microenvironment was 4.85 (95% CI 1.41-16.6, versus the CAF-poor) when adjusted by proportional hazards modeling for the center where the patient was managed, gender, tumor stage, presence of neck metastasis and age at diagnosis. CAF density was unrelated to non-MTSSC mortality. Given the strong association between increased CAF density and higher mortality in MTSCC, routine assessment of CAF density for disease course prognosis and inclusion as an integral part of treatment protocols are recommended.

Oral Diseases (2011) 17, 335–339 Objectives: To present a combination of clinical and histopathological criteria for diagnosing cheilitis glandularis (CG), and to evaluate the association between CG and squamous cell carcinoma (SCC). Materials and Methods: The medical literature in English was searched from 1950 to 2010 and selected demographic data, and clinical and histopathological features of CG were retrieved and analysed. Results: A total of 77 cases have been published and four new cases were added to the collective data. The clinical criteria applied included the coexistence of multiple lesions and mucoid/purulent discharge, while the histopathological criteria included two or more of the following findings: sialectasia, chronic inflammation, mucous/oncocytic metaplasia and mucin in ducts. Only 47 (58.0%) cases involving patients with a mean age of 48.5 ± 20.3 years and a male-to-female ratio of 2.9:1 fulfilled the criteria. The lower lip alone was most commonly affected (70.2%). CG was associated with SCC in only three cases (3.5%) for which there was a clear aetiological factor for the malignancy. Conclusions: The proposed diagnostic criteria can assist in delineating true CG from a variety of lesions with a comparable clinical/histopathological presentation. CG in association with premalignant/malignant epithelial changes of the lower lip may represent secondary, reactive changes of the salivary glands.

J Oral Pathol Med (2011) 40: 174–180 Background: Classic neurothekeoma (nerve sheath myxoma) is regarded as being a true benign cutaneous tumor of nerve sheath origin. Cellular neurothekeoma was separated from the classic type by histogenesis, morphology and immunophenotype. Whether cellular neurothekeoma represents a continuum within the spectrum of classic neurothekeoma or is an independent entity is controversial. Only a small number of classic neurothekeomas of the oral mucosa have been reported and there are even fewer publications on cellular neurothekeoma. We analyzed a series of oral neurothekeomas (classic and cellular) with a panel of neural and other mesenchymal markers to enhance their diagnosis and classification. Methods: One cellular and three classic neurothekeomas were submitted to a panel of immunohistochemical stains with antibodies against S100, S100A6, NSE, NKI/C3, PGP9.5, α-SMA, HHF-35, CD68 and vimentin. Two cases of neurofibroma (plexiform type), representing a true lesion of neural origin, served as control. Results: The cellular neurothekeoma yielded a positive immunoreaction for S100A6 and NKI/C3 and a negative immunoreaction for S-100. The classic neurothekeomas demonstrated a positive reaction for S-100 and S100A6, but a negative one for NKI/C3. Other markers were non-contributory to distinguishing between these types of lesions. Conclusions: The small number of reported oral neurothekeomas (classic and cellular) could be due, in part, to the lack of recognition of their particular morphologic and immunohistochemical features. Our results indicate that testing for NKI/C3 immunoreactivity may be of value in distinguishing between cellular and classic neurothekeoma.

J Oral Pathol Med (2010) 39: 631–638 Background: The gingiva reacts to chronic irritation or trauma with localized reactive hyperplastic lesions (LRHL) that can be classified into four groups: focal fibrous hyperplasia (FFH), pyogenic granuloma (PG), peripheral ossifying fibroma (POF), and peripheral giant cell granuloma (PGCG). This study determined the frequency of LRHL in an oral pathology biopsy service and compared these data with reports from other countries. Methods: The material included the biopsies of all consecutive LRHL of the gingiva stored in the departmental database (1989–2008). Lesions were analyzed according to their location and to the patients’ age and gender. The findings were compared with those published in studies from other countries. Results: There were 1675 LRHL that comprised 6.7% of the 25 106 accessed biopsies. FFH was the most common (31.8%), followed by PG (29.1%), POF (20.4%), and PGCG (18.7%). POF tended to affect younger patients than did FFH, PG, and PGCG. FFH, PG, and POF were more common in women, while PGCG showed no gender predilection. PG and POF were more common in the maxilla, PGCG more common in the mandible and FFH was distributed equally between the jaws. The anterior region of the maxilla was the most prevalent site for FFH, PG, and POF. Conclusion: The results of this study differ somewhat from those of other countries. There is a need for further investigation to answer the question whether the differences can be attributed to geographic or ethnic factors and/or to small sample sizes of the reported studies.

Introduction Extracellular vesicles (EVs), like exosomes, are attributed crucial paracrine and endocrine effects, which are of utmost importance in cancer. EVs carry markers that characterise their parental cells, and as such they also have a central diagnostic value. EVs are found in all body fluids, including saliva. EVs from oral cancerous cells are expected to concentrate in saliva. Our aim was to determine whether the infrared (IR) spectra of salivary EVs from oral cancer (OC) patients were significantly different from IR spectra of healthy individuals (HI). Material and methods Whole saliva samples were collected from 9°C patients and 8 HI. Saliva was further collected from additional 12°C patients and pooled together to one sample. In parallel, saliva was pooled from 5 additional HI. EVs were pelleted from samples of saliva (17 individual samples and 2 pools) using differential centrifugation (12,000 × g followed by 120,000 × g). The mid-IR absorbance spectra were measured in the range of 700cm-1 to 5,000cm-1, using MIR8025 Oriel Fourier transformation infrared (FTIR) equipped with a PIKE MIRacle ZnSe attenuated total reflectance (ATR) attachment. Results and discussions Individual and pooled pellets from OC patients showed a similar pattern of spectroscopy which was different from that of the HI (individual and pooled). The IR spectra of cancer versus healthy was consistently different in the 1025 (cancer peak) and 1080 (healthy peak) cm-1 region, 1,745 cm-1, 2,855 cm-1 and 2,925 cm-1 (low-to-absent in cancer), and in the region of 1,540 cm-1 (higher peak in cancer). A linear discriminant analysis (LDA) model showed a sensitivity of 90% and specificity of 100%. Conclusion A specific IR spectral signature for OC salivary EVs was shown for the first time in this pilot study. The high sensitivity and specificity of the outcomes warrant further analysis that may yield an efficient, reproducible and non-invasive clinical tool for the diagnosis of oral cancer at its very early stages or in oral lesions with potential for malignant transformation.

Background: Intrasocket reactive soft tissue can be used for primary closure during augmentation of infected extraction sites exhibiting severe bone loss prior to implant placement. The present study evaluated the histological characteristics of the initially used intrasocket reactive soft tissue, the overlying soft tissue, and the histomorphometry of the newly formed bone during implant placement. Materials and Methods: Thirty-six consecutive patients (43 sites) were included in the study. Extraction sites demonstrating extensive bone loss on preoperative periapical and panoramic radiographs served as inclusion criteria. Forty-three implants were inserted after a healing period of 6 months. Porous bovine xenograft bone mineral was used as a single bone substitute. The intrasocket reactive soft tissue was sutured over the grafting material to seal the coronal portion of the socket. Biopsies of the intrasocket reactive soft tissue at augmentation, healed mucosa, and bone cores at implant placement were retrieved and evaluated. Results: The intrasocket reactive soft tissue demonstrated features compatible with granulation tissue and long junctional epithelium. The mucosal samples at implant placement demonstrated histopathological characteristics of keratinized mucosa with no residual elements of granulation tissue. Histomorphometrically, the mean composition of the bone cores was – vital bone 40 ± 19% (13.7–74.8%); bone substitute 25.7 ± 13% (0.6–51%); connective tissue 34.3 ± 15% (13.8–71.9%). Conclusions: Intrasocket reactive soft tissue used for primary closure following ridge augmentation is composed of granulation tissue and long junctional epithelium. At implant placement, clinical and histological results demonstrate its replacement by keratinized gingiva. The histomorphometrical results reveal considerable bone formation. Fresh extraction sites of hopeless teeth demonstrating chronic infection and severe bone loss may be grafted simultaneously with their removal.

We examined cancer-associated fibroblasts (CAFs) and a panel of immunohistochemical markers of epithelial-mesenchymal transition (EMT) in 19 pair-matched oral tongue squamous cell carcinoma (SCC) and metastatic tumors to regional lymph nodes (RLNs). alpha-Smooth muscle actin (alpha-SMA) was studied to identify CAFs. EMT was studied with syndecan-1, Cadherin-11, fibroblast-specific protein (FSP)-1, secreted protein acidic and rich in cysteine (SPARC) and Twist. Triple immunostaining in RLNs was used to highlight the carcinoma cells (E-cadherin and Ki-67) and their relationship to the CAFs (alpha-SMA). We found that metastatic RLNs hosted CAFs similarly as in pair-matched primary tumors. Expression of EMT markers is common in both primary and metastatic tumors. We demonstrate that metastatic carcinoma cells (Ki-67 positive) downregulate E-cadherin expression at the periphery of cancer islands, where they are in direct contact with CAFs. The supporting connective tissue microenvironment also commonly expresses syndecan-1, Cadherin-11, FSP-1, and SPARC. In conclusion, CAFs are common to both primary and metastatic SCC. We hypothesize that CAFs not only promote tumor invasion but also facilitate metastases, either by cometastasizing and/or being recruited to lymph nodes. Evidence of EMT is common within primary tumors and metastatic SCC and may be further modulated by CAFs.

Mucoepidermoid carcinoma (MEC) of the salivary glands has a low-grade variant (LGMEC), which may be found within the jawbones. LGMEC shares a number of histopathological similarities with glandular odontogenic cysts (GOC) of the jawbones. Maspin has been identified in several benign and malignant salivary gland neoplasms. We investigated the immunolocalization of maspin in LGMEC and GOC and evaluated its potential to distinguish between these two entities. Cases of LGMEC (n=6), GOC (n=8) and various odontogenic cysts with marked mucous metaplasia (OCMM, n=7), which served as controls, were immunohistochemically labeled for the binding of an antibody directed against maspin. Immunomorphometry was performed separately for maspin-immunopositive epithelial cells and epithelial-mucous cells in either their nuclear or cytoplasmic compartments. Results were presented as the volume fraction (Vv) of each element. The Vv of the maspin-immunopositive epithelial-mucous cytoplasm and nuclei was significantly higher in LGMEC than in GOC and OCMM (p0.001 and p=0.026, respectively). In the epithelial cells, no significant differences were observed among the lesions (p0.05). It is suggested that the high levels of maspin in the epithelial-mucous cells (in both cytoplasm and nuclei) in LGMEC may serve as a tool to distinguish it from GOC. This may be useful especially in equivocal cases and in small incisional biopsy samples.

Margin status, a major prognostic parameter in oral cancer, was analyzed vis-a-vis the histopathologic parameters of risk scores and stromal myofibroblasts. Specimens of tongue carcinoma (n = 50) were submitted to a risk score assignment consisting of the worst pattern of invasion, lymphocytic infiltration, and perineural invasion. Frequency of stromal myofibroblasts (alpha-smooth muscle actin stain) was assessed. A triple immunostaining assay with E-cadherin, Ki-67 and alpha-smooth muscle actin was used to identify carcinoma cells undergoing epithelial–mesenchymal transition. Margins were considered ‘clean’ if the tumor was ≥5 mm away from them. Patients ≤60 years were considered as ‘young’. Kaplan–Meier survival analysis with univariate and Cox multivariate regression model with stepwise forward selection, and Fisher’s exact tests were used. Abundant myofibroblasts were found in 27 (54%) cases. Carcinoma cells devoid of E-cadherin but amalgamated with the stromal myofibroblasts were identified in 18 (36%) cases. Local recurrence and overall survival were negatively influenced by abundance of stromal myofibroblasts (P = 0.004 and P = 0.008, respectively). High-risk scores (P = 0.011), positive margins, and ‘young’ age (P = 0.027, each) had an unfavorable impact on recurrence. Multivariate analysis revealed that only abundance of stromal myofibroblasts had an independent adverse effect on local recurrence (hazard ratio [HR] 4.369; P = 0.014; 95% confidence interval [CI], 1.356–14.074). It seems that abundant stromal myofibroblasts (camouflaging some malignant cells) and high-risk scores have an unfavorable impact on the risk of recurrence in particular in ‘young’ patients. Therefore, the treatment concept should be adjusted accordingly and target concomitantly the epithelial malignancy and its allied stroma. (Cancer Sci 2009)

Stromal myofibroblasts (SMF) associated with various types of carcinomas are believed to emerge under the influence of the tumor cells. Recent studies have shown that SMF may originate from fibroblasts within the tumor stroma or even from carcinoma cells by the process of epithelial-mesenchymal transition. The aim of this study was to investigate the concomitant expression of epithelial membrane antigen and alpha-smooth muscle actin in cells at the tumor-connective tissue interface in human tongue carcinoma, as a possible reflection of epithelial-mesenchymal transition. Given its key role in this process, expression of transforming growth factor-beta in the malignant cells was assessed as well. Immunostaining with alpha-smooth muscle actin was performed on cases of hyperplasia (n = 16), mild dysplasia (n = 12), moderate-to-severe dysplasia (n = 11) and carcinoma (n = 22). Transforming growth factor-beta assessment and double immunostaining with epithelial membrane antigen and alpha-smooth muscle actin were performed only in cases of carcinoma. SMF were significantly associated with carcinomas, while their number in pre-malignant lesions (hyperplasia and dysplasia) was significantly lower (P0.001). Although SMF were found in all carcinomas, they were heterogeneous in their frequency and patterns of distribution. In addition, 95% of the carcinomas expressed transforming growth factor-beta and 41% exhibited cells positive for both epithelial membrane antigen and alpha-smooth muscle actin. SMF were almost exclusively associated with established carcinomas and not with pre-malignant lesions. Cells that co-expressed epithelial membrane antigen and alpha-smooth muscle actin can be a manifestation of epithelial-mesenchymal transition and, as such, may serve as a source for SMF in these tumors. These findings appear to be linked to the frequent expression of transforming growth factor-beta by the malignant cells.

Background: Granular cell tumor (GCT) is a benign lesion that occurs at different body sites with preponderance to the oral cavity. It is generally believed to be of schwann cell/neural cell origin. We used a large panel of both traditional and recently developed antibodies in an attempt to trace the origin of GCTs on the basis of their immunoprofile. Methods: The patients’ demographic data and the cytological and architectural features of the lesions were analyzed in a large series of oral GCTs (n = 68). Forty-two lesions were also submitted to a panel of immunohistochemical stains with antibodies against S-100, CD-68 (KP-1 and PG-M1), vimentin, calretinin, NKI/C3, PGP9.5, p75/NGFR and inhibin-α. Results: The tongue was the most common location of oral GCTs (81%). The granular cells demonstrated a wide array of cytological features in terms of cell shape and position of the nucleus. In addition, the lesions showed different architectural patterns, including ‘infiltration’ with satellite nodules. Interestingly, no recurrences were reported, even in lesions that were not completely excised. Granular cells were usually found to be strongly and diffusely positive for p75, vimentin, calretinin and NKI/C3, inhibin-α, PGP9.5, and S-100. Conclusions: Immunoreactivity of the granular cells to a broad panel of antibodies that characterize different tissues does not confirm any particular cell type for the histogenetic origin of GCTs. Furthermore, GCTs could be regarded as lesions that reflect a local metabolic or reactive change rather than a true neoplasm.

Background: The pattern of changes in the expression of mammary serine protease inhibitor (maspin) tumor suppressor protein in tongue epithelial lesions [hyperplasia (HP), mild dysplasia (MD), moderate-to-severe dysplasia (MSD) and squamous cell carcinoma (SCC)] was investigated and correlated to the expression of maspin-regulating factors p53 and p63, and the proliferation marker Ki-67. Methods: Cases of HP (n = 16), MD (n = 12), MSD (n = 11), and SCC (n = 22) were immunostained for maspin, p53, p63, and Ki-67. Maspin expression was scored separately for the basal, middle, and upper thirds of the epithelial width, and as the total sum of all ‘thirds’ (maspin-total). p53, p63, and Ki-67 were immuno-morphometrically assessed for the entire epithelial width. Results: Maspin expression was differential and progressive extending to higher epithelial layers as dysplastic changes aggravated and culminated in carcinoma. Strong expression was related to MSD in the middle third and to carcinoma in the upper third. It was frequently lost at the invasion front, where the tumor was less differentiated. The changes in mean scores of maspin-total in the different study groups were positively correlated to the mean scores of p63 (r = 0.5, P

The 4-nitroquinoline 1-oxide (4NQO)-induced rat tongue carcinoma, in which the carcinogen is administered systemically in drinking water, is the most comparable animal model to the development of human oral carcinoma. This is the first study to report the ultrastructural changes in this model. The most significant changes were observed in the carcinoma cells at the invasion front and included unique modifications in the basal lamina, presence of micropinocytotic vesicles (plasmalemmal caveolae), and emergence of cytoplasmic microfilaments featuring a parallel arrangement. The microfilaments, in both appearance and organization, were consistent with contractile microfilaments. These observations may be the morphological reflection of the phenotypic modifications occurring within the carcinoma cells, approaching smooth muscle differentiation.

Aim: To characterize the immunohistochemical profile of the inflammatory cells included in the focal lymphocytic infiltration in the minor salivary glands of healthy individuals. Materials and Methods: Tissue samples of the labial and palatal salivary glands from 46 postmortem subjects, demonstrating the presence of focal lymphocytic infiltration were quantitatively evaluated for the presence of T- and B-cell lymphocytes, plasma cells and macrophages by immunohistochemical and morphometric methods. Results: B-cell lymphocytes, the predominant cell population in labial (67.5%) and palatal salivary glands (60.8%), were more frequent than T-cell lymphocytes in both glands (P

Objective: To investigate correlations between myofibroblast density (MFD) and biological behavior of a large series of non-aggressive and aggressive central giant cell granuloma lesions (CGCGs). Methods: Twenty-four non-aggressive and 17 aggressive lesions were immunohistochemically stained with alpha smooth muscle actin. MFD was assessed using the point counting method in the lesions’ core tissue and in control areas that consisted of non-involved, connective tissue surrounding the lesion. Results: All CGCGs contained myofibroblasts among the stromal cells. No significant differences were found in the mean percentage of MFD (%MFD) of non-aggressive (20.8 ± 15.7%) and aggressive (23.7 ± 22.9%) lesions (P > 0.05) or in the mean %MFD of the respective control areas (1.4 ± 2.2% and 1.7 ± 4.1%; P > 0.05). The mean core tissue %MFD of both lesion types was significantly higher than that of the control areas (P

Background: Myofibroma is a solitary benign tumor of myofibroblasts. Myofibromatosis describes multiple, simultaneous myofibromas at different sites in various organs. The clinico-pathologic correlations of myofibroma/myofibromatosis confined only to oral soft tissues were analyzed. Methods: In the English language literature, 41 myofibroma and 12 myofibromatosis cases involving the oral soft tissues were found. From our files, three new myofibroma cases were added. Results: Age at time of diagnosis of oral mucosa myofibroma ranged from birth to 70 years (mean 21.7 years), considerably higher than myofibroma in other parts of the body. Lesions occurred during the first decade (44%) and in the first year of life (17%). Male:female ratio was 1:1.6, contrary to the male predominance in other parts of the body. Common sites were the tongue (32%) and buccal mucosa (18%). Treatment was local excision, either complete (n = 13) or partial (n = 3), wide excision (n = 4), surgery, and chemotherapy (n = 1). Myofibromatosis involving oral soft tissues was diagnosed at birth in nine (75%) patients, within the first year in two, and as a young adult in one. Male:female ratio was 2:1. The tongue was the most common site (50%). Half the patients died of disseminated disease within a few days from birth, three were cured by partial or complete excision, and three experienced spontaneous regression. Histologically, oral mucosa myofibroma/myofibromatosis appearance agreed with findings in the literature. Conclusions: Myofibroma should be included in the clinical differential diagnosis of masses of the oral soft tissues, especially in the tongue and buccal mucosa of children and adolescents. Histological differential diagnosis includes benign and malignant spindle-shaped lesions. Treatment of choice is local excision.

Objective Myofibroma frequently manifests as a solitary soft tissue tumor and less as simultaneous multiple tumors in both soft tissues and bones. The present study evaluated clinical, radiological, and histopathologic features of myofibroma of the jaws. Study design Nineteen cases from the literature and 4 new cases were analyzed. Results At initial diagnosis, age ranged from birth to 34 years (mean 7.2 years, median 6 years). Male/female ratio was 2.3:1. Myofibromas were radiolucent solitary lesions located solely in the mandible: 70% unilocular, 30% multilocular; 67% with well-defined borders. Conservative treatment was performed on 75% of the patients; 25% underwent partial jaw resection. Where information was provided, no lesion recurred during 6-month to 17-year follow-up. Conclusion Although rare, myofibroma of the mandible should be considered in the differential diagnosis of radiolucent lesions (particularly unilocular), especially in children. Treatment of choice is conservative surgery to minimize potential functional and/or esthetic damage.

Purpose Dentinogenic ghost cell tumor (DGCT) is a very rare odontogenic lesion, with most knowledge based on single case reports. Therefore, a comprehensive analysis was performed of the clinical and radiologic features of reported cases of DGCT with an emphasis on treatment modalities. Material and Methods This is a case series of DGCTs collected from the literature after a systematic search of Medline's PubMed and Google Scholar. Three additional cases were included from the authors' files. Demographic data of the patients, lesion site and size, and radiologic features were analyzed. Treatment approach and events of recurrence were recorded. Results Forty-five cases (42 from the literature) were included. The mean age of patients was 39.7 ± 19.3 years (range, 12 to 79 yr) and the male-to-female ratio was 1.8:1. The mandible-to-maxilla ratio was 1.14:1, with the posterior region of the jaws being the most commonly involved site. Radiographically, 78% lesions were unilocular, 67% were mixed radiolucent and radiopaque, and 68% had well-defined borders. The mean lesion size was 4.0 cm (range, 1.8 to 13.0 cm). The primary treatment for 21 patients was conservative surgery consisting of enucleation or curettage. Follow-up information for longer than 1 year (mean, 6.2 ± 8.3 yr; range, 1 to 31 yr) was known for 15 patients, of whom 11 (73%) had recurrences. The primary treatment in 19 patients was radical surgery consisting of marginal or segmental resection. Follow-up information for longer than 1 year (mean, 3.3 ± 2.6 yr; range, 1 to 10 yr) was known for 12 patients, of whom 4 (33%) had recurrences. Conclusions This study highlighted the potentially aggressive biological behavior of DGCTs that demands extensive surgery and long follow-up. However, owing to the rarity of DGCT, more well-documented cases with long follow-up periods are needed to further define the optimal treatment modalities and prognosis.

Oral cancer (OC) patients are at high risk to develop recurrent disease or secondary primary cancers with no available biomarkers to detect these events until a visible lesion is readily present and diagnosed by biopsy. Exosomes secreted by cancer cells are involved in tumor growth, invasion and metastasis. We aimed to determine morphological and molecular differences between oral fluid (OF)-derived exosomes of OC patients and those isolated from healthy individuals (HI). OF from OC patients (n = 36) and HI (n = 25) was initially assessed by nanoparticle tracking analysis (NTA). Following ultracentrifugation, exosomal pellets of OC patients and HI were morphologically examined by transmission electron microscopy and atomic force microscopy (AFM). Enzyme-linked immunosorbent assay (ELISA) and western blotting (WB) were used to analyze the expression of exosomal markers—CD9, CD81 and CD63. NTA showed that OC samples of OF had a significantly higher concentration of nanoparticles/ml (p = 0.01) and modal nanoparticle size (p = 0.002) compared to HI. The difference in size was structurally highlighted by AFM three-dimensional images applied on exosomal pellets. ELISA and WB showed differential expression of exosomal markers in OC exosomes compared to HI: lower expression of CD81 and CD9 in contrast to a higher expression of CD63 (~53 kDa). OF-derived exosomes from OC patients differ both morphologically and molecularly from exosomes present in HI. This study is a baseline that provides a starting point for finding exosomal biomarkers for early detection of malignant changes in high-risk patients without overt clinical signs/lesions.

Oral tongue squamous cell carcinoma (OTSCC) has a high mortality rate and the incidence is rising worldwide. Despite advances in treatment, the disease lacks specific prognostic markers and treatment modality. The spreading of OTSCC is dependent on the tumor microenvironment and involves tumor-associated macrophages (TAMs). Although the presence of TAMs is associated with poor prognosis in OTSCC, the specific mechanisms underlying this are still unknown. The aim here was to investigate the effect of macrophages (Mfs) on HSC-3 tongue carcinoma cells and NF-kappaB activity. We polarized THP-1 cells to M1 (inflammatory), M2 (TAM-like) and R848 (imidazoquinoline-treated) type Mfs. We then investigated the effect of Mfs on HSC-3 cell migration and NF-kappaB activity, cytokine production and invasion using several different in vitro migration models, a human 3D tissue invasion model, antibody arrays, confocal microscopy, immunohistochemistry and a mouse invasion model. We found that in co-culture studies all types of Mfs fused with HSC-3 cells, a process which was partially due to efferocytosis. HSC-3 cells induced expression of epidermal growth factor and transforming growth factor-beta in co-cultures with M2 Mfs. Direct cell-cell contact between M2 Mfs and HSC-3 cells induced migration and invasion of HSC-3 cells while M1 Mfs reduced HSC-3 cell invasion. M2 Mfs had an excess of NF-kappaB p50 subunit and a lack of p65 subunits both in the presence and absence of HSC-3 cells, indicating dysregulation and pro-tumorigenic NF-kappaB activation. TAM-like cells were abundantly present in close vicinity to carcinoma cells in OTSCC patient samples. We conclude that M2 Mfs/TAMs have an important role in OTSCC regulating adhesion, migration, invasion and cytokine production of carcinoma cells favouring tumor growth. These results demonstrate that OTSCC patients could benefit from therapies targeting TAMs, polarizing TAM-like M2 Mfs to inflammatory macrophages and modulating NF-kappaB activity.