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The objectives were to characterize clinico-pathologically a large series of peri-implant peripheral giant cell granuloma (PGCG), and investigate the role of foreign material as a possible etiological factor.The study was retrospective, conducted on peri-implant specimens submitted for histology between 2005 and 2021.Three hundred and thirty-five peri-implant biopsies were retrieved, of which 52 (15.5%) were PGCG. The study population included 28 females and 24 males, age 35-92 years, mean 61. 51.2% reported bone involvement. The lesion involved the margins of the specimen in 65.3%, recurrence was reported in 46.1%. In 58.8% the implant was removed at the same time the specimen was submitted for histopathological analysis. Small foci of black granular foreign material were observed in 53.8% of cases of which 67.8% were birefringent under polarized light. The foreign material granules were not ingested inside multinucleated giant cells, but were scattered in the stromal compartment.Peri-implant PGCG is locally aggressive, with frequent bone involvement and high recurrence rate, resulting in implant loss in the majority of cases. The high recurrence rate may be related to conservative or inadequate surgery. Foreign material although common does not seem to have a role in its development.

Compare recognized microscopic parameters, including variations in width, plaque-like thickenings, intra-epithelial microcysts, clefts, mucous, hob-nail, ciliated and clear cells, between glandular odontogenic cyst (GOC) and GOC-like cysts, investigate the extent of cyst circumference exhibiting these features, and inflammation.Archival records of cysts with histological features of GOC evaluated between 2000 and2020 were retrieved. Slides were revised, and the expression of features throughout the cyst wall was analyzed. Cysts with at least 5 features were classified as GOC, cysts with 3-4 features as GOC-like.The study included 74 cysts, 47 males M, 25 females (2 unknown gender), aged 19-81 years, 62 (83.8%) GOC, 12 (16.2%) GOC-like. Mandible was involved in 44 (59.5%), maxilla in 30 (40.5%), 18 (25%) were associated with unerupted teeth. Cyst classified as GOC had significantly higher rates of all parameters investigated, (except ciliated and clear cells), than GOC-like cysts (p ≤ 0.05). 26 (40.6%) cases showed GOC features in50% of cyst circumference, 21 (32.8%) involved 25-50%, 17 (26.6%)25%. More than 50% circumference involvement was highly and independently predictive for a diagnosis of GOC,25% was highly and independently predictive for GOC-like (p = 0.003). Hobnail cells (p = 0.008) and plaque-like thickenings (p = 0.038) were significantly more frequent in inflamed cysts.Besides the number and type of histological features, GOC can be characterized by their distribution within the cyst circumference (focal Vs diffuse), and it may serve as a new diagnostic aid. It is suggested that GOC and GOC-like may represent a single spectrum.

BACKGROUND An age-related decrease in the number of osteogenic progenitor cells may compromise bone augmentation. PURPOSE Histomorphometrical assessment of age-related new bone formation, following atrophic alveolar ridge reconstruction, using cancellous bone-block allografts. MATERIAL AND METHODS Ninety-three consecutive patients (58 females and 35 males) were referred for implant-supported restoration of 122 severe atrophic alveolar ridges. Alveolar ridge deficiency locations were classified as anterior maxilla (n = 58), posterior maxilla (n= 32), and posterior mandible (n = 32). A bony deficiency of at least 3 mm horizontally and up to 3 mm vertically according to computerized tomography (CT) in the posterior mandible and anterior maxilla, served as inclusion criteria. In the posterior maxilla, a residual alveolar ridge up to 4 mm vertically according to CT served as inclusion criteria. Augmentation was performed by the use of cancellous bone-block allografts. Bone biopsies (9-month posterior maxilla, 4 months anterior maxilla and posterior mandible) of young (≤40 years) versus older (>40 years) patients were histomorphometrically evaluated. RESULTS In the posterior maxilla, no statistically significant histomorphometric differences were noted. While at the anterior maxilla and posterior mandible, statistically significant more newly formed bone was found in young versus older individuals, respectively (38.6% vs 19.8%, P = 0.04 and 69% vs 31%, P = .05). CONCLUSION New bone formation following residual alveolar ridge bone grafting is age-related. Longer bone consolidation and healing time may be recommended for older individuals.

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

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.

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.

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)

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

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.

A case of an unusual lesion from the maxilla is presented. Macroscopically, the lesion was solid and histologically consisted of 'multiple separate keratocysts' of varying size that infiltrated into the surrounding bone and soft tissues. Panoramic image and CT scans showed a multilocular honeycomb ill-defined radiolucency with infiltration into the maxillary sinus and floor of orbit. This lesion should be differentiated from similar odontogenic lesions, such as keratoameloblastoma and papilliferous keratoameloblastoma. As there was no evidence of follicles, islands of ameloblastoma, or papilliferous structures in the entire specimen, the lesion could not be diagnosed as either a keratoameloblastoma or a papilliferous keratoameloblastoma. The invasive and destructive growth behavior, the histopathological features, and the histochemical pattern of the collagen stroma imply that this solid lesion is a neoplasia. It is suggested that the proper term for this lesion is solid variant of odontogenic keratocyst.

Background Adenoid cystic carcinoma (ACC) is a malignant tumor of salivary gland origin, which is characterized by a high rate of local recurrence and distant hematogenous metastasis. Despite aggressive surgical treatment and radiotherapy, the patient's long-term prognosis is dismal. Prompted by recent studies on the amplification of the oncogene HER2/neu in salivary gland tumors, we analyzed the immunohistochemical overexpression of HER2/neu in salivary glands ACC. If the tumor exhibits overexpression of HER2/neu, then treating it with the anti-HER2/neu therapeutic agent, Herceptin (Trastuzumab, Genentech, CA), could be considered. Methods The study comprised of 32 samples of formalin-fixed, paraffin-embedded specimens. All laboratory procedures and scoring criteria were performed according to currently approved FDA methods. Results HER2/neu overexpression was found in only five (16%) cases. Four cases (13%) scored 1+ and one case (3%) scored 2+. Conclusions The low prevalence of HER2/neu overexpression in ACC limits the clinical utility of Herceptin therapy for salivary gland ACC.

Investigation of age-related prevalence of various types of focal lymphocytic infiltration (FLI) and degrees of histomorphologic changes was conducted on 120 biopsies of palatal and labial salivary glands (PSG and LSG, respectively) obtained from autopsy subjects free of salivary gland tumors/diseases. Biopsies were divided into young ( 60 years, n=45) age groups. A modified Chisholm & Mason grading system was used to record grades of FLI and a modified Greenspan et al. system was used to evaluate the severity of histomorphologic changes. The prevalence of FLI in PSG increased significantly from 10% in the young group to 46.6% in the old group (P=0.0012). No significant changes were found with aging in LSG. FLI was significantly more prevalent in the adult and old age groups in PSG as compared with LSG (P=0.015 and P=0.003, respectively). Both glands demonstrated significant histomorphologic changes among age groups (p