Metaplastic changes in the epithelium of radicular cysts: A series of 711 cases

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. 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<0.05. A total of 711 cysts were included: 677 were radicular cysts (95%) and 34 (5%) were residual radicular cysts. 23 cases had histopathological diagnoses other than radicular or residual radicular cysts and were excluded from the study. MSC were present in 47 (6.6%) cysts. MSC were significantly more common in residual radicular cysts than in radicular cysts [8 (23.5%) and 39 (5.8%), respectively; p<0.001]. MSC-containing cysts were commonly found in asymptomatic patients (10.5%, p<0.001), and usually presented with well-defined radiographic borders (7.2%, p<0.05). CC were present in 34 (4.8%) cysts, with a markedly high prevalence in the maxillary molar sextant (15%, p<0.001). In the epithelium of radicular and residual radicular cysts the presence of specific metaplastic changes may be related to cyst type, symptomatology, radiographic findings and tooth location

Cancer-associated fibroblasts in the tumor microenvironment of tongue carcinoma is a heterogeneous cell population

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 <0.05). Increased density of CD86(+) alpha SMA(+) cells was significantly associated with CAF-rich tumors and with poor survival (p <0.05). Conclusion: In TSCC, CAFs demonstrate heterogeneous and overlapping phenotypes with the myeloid/monocytic type being the most frequent and having an impact on the clinical outcomes. Further studies are needed in order to further characterize CAF phenotypes in carcinomas of various oral sites, as this may open new frontiers for personalized medicine.Peer reviewe

Markers of the pre-metastatic niche "knock on the door" of metastasis-free cervical lymph nodes in patients with oral cancer

Aim: To assess expression of some markers of the pre-metastatic niche (PMN) in lymph nodes (LNs) of oral cancer patients. Materials: 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 <0.001, respectively). Picrosirius red stain and polarized microscopy revealed a disrupted arrangement and distribution of the collagen fibers in both LN0/N0 and LN0/N +. Conclusion: Markers for PMN were shown for the first time to be expressed in cervical LN0/N0 from patients with oral cancer, suggesting the increased permissive pathway remotely paved by the primary oral tumor for the incoming metastatic cells.Peer reviewe

Molecular crosstalk between cancer cells and tumor microenvironment components suggests potential targets for new therapeutic approaches in mobile tongue cancer

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.Peer reviewe

Molecular crosstalk between cancer cells and tumor microenvironment components suggests potential targets for new therapeutic approaches in mobile tongue cancer

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.publishedVersio

Fermented Lingonberry Juice Inhibits Oral Tongue Squamous Cell Carcinoma Invasion In Vitro Similarly to Curcumin

Background: Oral tongue squamous cell carcinoma (OTSCC) cells are highly proliferative and invasive. Lingonberry contains several polyphenolic compounds similar to curcumin. We hypothesize that fermented lingonberry juice (FLJ) has an anti-invasive and anti-proliferative effect on OTSCC cells similarly to curcumin, which is known to be anti-carcinogenic. Materials and Methods: FLJ, curcumin dissolved in ethanol, or curcumin loaded in Candida extracellular vesicles (EVs) were added to more (HSC-3) and less aggressive (SCC-25) OTSCC cells. Cell proliferation was measured with a 5-bromo-2'-deoxyuridine kit and invasion in the three-dimensional Myogel spheroid assay. Statistical analyses were completed with one-way ANOVA and Bonferroni post-hoc testing. Results: Both FLJ and curcumin significantly reduced the proliferation and invasion of HSC-3 and SCC-25 cells. The effects of curcumin were not improved when cells were treated with curcumin loaded within EVs. Conclusion: Our results suggest that FLJ, like curcumin, has an anti-carcinogenic effect on aggressive OTSCC cells in vitro.Peer reviewe

Conceptual changes in ameloblastoma : Suggested re-classification of a "veteran" tumor

Objectives: The merging of ameloblastoma (AM) with mural unicystic ameloblastoma (UAM-M) was suggested by the 2017 WHO based on similar treatment needs. In an international multicenter study, we investigated the characteristics of their merged product (merged-AM) and raised the possibility of unifying AM and UAM (total-AM). Materials and methods: AM and UAM (luminal/intraluminal/mural), separate and combined, were analyzed for demographic/clinical/radiological features. ANOVA and chi-square tests were followed by univariate and multivariate analyses, and significance was set at p .05). Conclusions: Merged-AM partially differed from AM, but differences appeared to diminish in an age/time-wise manner. Merged-AM and total-AM were nearly indistinguishable. Therefore, AM and UAM may be considered a continuous spectrum of one type of tumor, further necessitating revision of the treatment approaches.Peer reviewe

Caveolin-1 accumulation in the tongue cancer tumor microenvironment is significantly associated with poor prognosis : an in-vivo and in-vitro study

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Human Bone Marrow Mesenchymal Stem Cells Induce Collagen Production and Tongue Cancer Invasion

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