Calibration improves the agreement in grading oral epithelial dysplasia-Findings from a National Workshop in Malaysia.

INTRODUCTION: A major pitfall of many of the established oral epithelial dysplasia (OED) grading criteria is their lack of reproducibility and accuracy to predict malignant transformation. The main objective of this study was to determine whether calibration of practicing oral pathologists on OED grading could improve the reproducibility of the WHO 2017 and the binary OED grading systems. METHODS: A nationwide online exercise was carried out to determine the influence of calibration on the reproducibility of the WHO 2017 and the binary OED grading systems. RESULTS: A significant improvement was observed in the inter-observer agreement for the WHO 2017 OED grading system (K 0.196 vs. 0.448; Kw 0.357 vs. 0.562) after the calibration exercise. The significant difference (p = 0.027) in the level of agreement between those with five or more years and less than 5 years of experience was no more observed (p = 0.426) after the calibration exercise. The percent agreement for binary grading was significantly higher (91.8%) for buccal mucosal lesions as compared to lesions on the tongue after the calibration exercise. CONCLUSION: This study validates the significance of calibration in improving the reproducibility of OED grading. The nationwide exercise resulted in a statistically significant improvement in the inter-observer agreement for the WHO 2017 OED grading system among a large number of oral pathologists. It is highly recommended that similar exercises should be organized periodically by professional bodies responsible for continuing education among oral pathologists to improve the reliability of OED grading for optimal treatment of oral potentially malignant disorders.

CEOT Variants or Entities: Time for a Rethink? A Case Series with Review of the Literature.

The first detailed description of calcifying epithelial odontogenic tumor (CEOT) are ascribed to Jens Pindborg, but this tumor was described some years previously. Subsequently, CEOT was included in the 1971 WHO classification of odontogenic tumors and a since then number of variants have been described, which have added confusion to the diagnostic criteria. We aimed to survey the literature on the variants of CEOT, in parallel with a review of our single institution experience of CEOTs. Cases identified were collated, including available clinical, radiological and histological information and then reviewed, taking into account changes in the understanding and classifications of odontogenic tumors since initial diagnosis. We identified 26 cases from 1975 to 2017 for which histological material was available. Of these, only 13 (50%) showed the "classic" histological appearance, whilst two cases were identified as recognized variants. In 11 cases, other diagnoses or a differential diagnosis were preferred, with no agreed diagnosis in four of these. The proliferation fraction (Ki67) in the 10 cases tested was 2.1% ± 0.18. These findings illustrate the diagnostic challenges in this group of tumors and highlight the gaps in knowledge. Techniques, such as EWSR1 gene cytogenetic analysis, may be helpful in cases with clear cells. However, in other areas of controversy, including the non-calcifying and Langerhans cell rich variants, further investigation, perhaps utilizing sequencing technologies may be needed to refine the classification. Owing to the relative rarity of these lesions it would be beneficial if future work could be pursued as an international collaboration.

Impact of Histological and Molecular Parameters on Prognosis of Oral Squamous Cell Carcinoma: Analysis of 290 Cases.

BACKGROUND: Nodal metastasis is a critical factor in predicting the prognosis of oral squamous cell carcinoma (OSCC). When patients present with a clinically positive neck, the treatment of choice is radical neck dissection. However, management of a clinically negative neck is still a subject of significant controversy. AIM: This study was carried out in order to propose a model to predict regional lymph node metastasis of OSCC using histological parameters such as tumour stage, tumour size, pattern of invasion (POI), differentiation of tumour, and host immune response, together with the expression levels of six biomarkers (periostin, HIF-1α, MMP-9, ß-catenin, VEGF-C, and EGFR), and, furthermore, to compare the impact of all these parameters on recurrence and 3 yr and 5 yr survival rates. Materials and Method. Histological materials collected from the archives were used to evaluate histological parameters and immunohistochemical profiles. Standard methods were used for immunohistochemistry and for evaluation of results. Data related to recurrence and survival (3 and 5 years) was also recorded. Clinical data was collected from patients' records. RESULTS: Male to female ratio was 3 : 1. The commonest site of OSCC was the buccal mucosa, and majority of them were T3 or T4 tumours presented at stage 4. 62.5% of the tumours were well differentiated. Three-year and 5-year survival rates were significantly associated with lymph node metastasis and recurrence. POI was significantly correlated with tumour size, stage, 3-year survival, EGFR, HIF-1α, periostin, and MMP-9 (p < 0.05). Expression of EGFR showed a direct association with metastasis (p < 0.05). CONCLUSION: POI, level of differentiation, and expression of EGFR are independent prognostic markers for lymph node metastasis. Therefore, these parameters may help in treatment planning of a clinically negative neck.

Validity of Toluidine Blue test as a diagnostic tool for high risk oral potentially malignant disorders- a multicentre study in Sri Lanka.

INTRODUCTION: - Early detection plays a major role to reduce the mortality of oral squamous cell carcinoma (OSCC). Many adjunctive techniques have emerged with claims of differentiating high risk oral potentially malignant disorders (OPMDs) from benign lesions. Toluidine blue (TB) test has been established as a diagnostic adjunct in detecting high risk OPMDs and early asymptomatic OSCCs. As majority of OSCC are preceded by OPMDs, recognition of them at an early stage is important in the management of this devastating disease. METHODS: -This study was conducted as a multi-center study prospectively for a period of 2 years. Sixty five patients presented with OPMDs were selected and TB test was performed followed by a biopsy for histopathological confirmation. Criterion validity was assessed with histological diagnosis of the incisional biopsy of the OPMD as a gold standard test verses TB test results. RESULTS: The sensitivity of the TB test was 68.3% and the specificity 63.1% with a false positive rate of 36.8% and false negative rate of 31.7%. However, the predictive value of the positive test was 80%. CONCLUSION: - TB testing might be a potential adjunct diagnostic aid in identifying high risk OPMDs. Further studies with extensive sample size and different demographics are needed to validate our findings.

Odontogenic tumors and lesions treated in a single specialist oral and maxillofacial pathology unit in the United Kingdom in 1992-2016.

OBJECTIVES: Odontogenic tumors (ODTs) are a heterogeneous group of lesions derived from elements of tooth-forming tissues. No detailed data on the incidence of odontogenic tumors in the United Kingdom have been published. The aim of this study was to retrospectively describe the range and incidence of odontogenic tumors from 1992 to 2016 in a single specialist unit and to compare this population with others. STUDY DESIGN: By using the Oral and Maxillofacial Pathology database, Sheffield (UK), we included both local and referred consultation cases. A proportion of diagnoses were reclassified in accordance with the 2017 World Health Organization classification. RESULTS: In total, 559 odontogenic tumors were diagnosed. Overall, the most common lesions were ameloblastoma (196 [33.8%]), odontoma (148 [25.5%]), and odontogenic myxoma (37 [6.3%]), but this varied between local and referral case populations, with odontomas being most common in the local population (43%). The sites affected and the gender and age of patients were similar to other Western populations. Malignant ODTs comprised 33 cases (5.7%), of which 9 (27.3%) were ameloblastic carcinoma. The majority of the malignant ODTs comprised referral cases. CONCLUSIONS: Here, we present the first detailed data on ODTs within a UK population, and the pattern of incidence from the local population is similar to other Western populations. The exceptional rarity of malignant ODTs emphasizes the need for specialist centers for their treatment to gain diagnostic experience.

An Evaluation of Clinical and Histopathological Aspects of Patients with Oral Submucous Fibrosis in the Background of Oral Squamous Cell Carcinoma.

BACKGROUND: The behavior and prognosis of oral squamous cell carcinoma (OSCC) is presumably different in patients with oral submucous fibrosis (OSF). The objective of this study was to assess the effects of demographic features, habits, and histopathological features in the transformation of OSF to OSCC. METHODS: Data were extracted from the archives and histopathological evaluation and presence of nodal metastasis were recorded. RESULTS: OSF was detected in 130 (48%) out of 273 OSCC patients. The mean age of presentation among OSF-positive patients was 57.7 years, while patients diagnosed only with OSCC had a comparatively higher age, 59.5 years. In the below 50 years of age group, presence of OSF with OSCC was less (40%). In the OSF-positive group, male to female ratio was 3.2:1. The common primary sites were buccal mucosa and tongue in both groups. Betel quid chewing was present in more than 95% of the sample. Betel chewing, smoking, and alcohol consumption were present in 26.15% of OSF-positive patients. Degree of fibrosis was neither associated with the level of histological differentiation of the tumor (p= 0.195) nor associated with the malignant transformation (p =0.373). Lymph node metastasis was not seen in 76.63% and 68.54% of the patients with and without OSF, respectively. CONCLUSIONS: High degree of prevalence of OSF was observed among the OSCC patients. There were also a male predilection and younger age at presentation in these patients. However, a significant association was not observed in the degree of fibrosis with malignant transformation or the level of histopathological differentiation of the tumor. Lymph node metastasis also failed to express a significant relationship with the presence of OSF.

A model to predict nodal metastasis in patients with oral squamous cell carcinoma.

Difficulty in precise decision making on necessity of surgery is a major problem when managing oral squamous cell carcinomas (OSCCs) with clinically negative neck. Therefore, use of clinical and histopathological parameters in combination would be important to improve patient management. The main objective is to develop a model that predicts the presence of nodal metastasis in patients with OSCC.623 patients faced neck dissections with buccal mucosal or tongue squamous cell carcinoma (SCC) were selected from patients' records. Demographic data, clinical information, nodal status, Depth of invasion (DOI) and pattern of invasion (POI) were recorded. The parameters which showed a significant association with nodal metastasis were used to develop a multivariable predictive model (PM). Univariate logistic regression was used to estimate the strengths of those associations in terms of odds ratios (OR). This showed statistically significant associations between status of the nodal metastasis and each of the following 4 histopathological parameters individually: size of the tumour (T), site, POI, and DOI. Specifically, OR of nodal metastasis for tongue cancers relative to buccal mucosal cancers was 1.89, P-value < 0.001. Similarly, ORs for POI type 3 and 4 relative to type 2 were 1.99 and 5.83 respectively. A similar relationship was found with tumour size; ORs for T2, T3, and T4 compared to T1 were 2.79, 8.27 and 8.75 respectively. These four histopathological parameters were then used to develop a predictive model for nodal metastasis. This model showed that probability of nodal metastasis is higher among tongue cancers with increasing POI, with increasing T, and with larger depths while other characteristics remained unchanged. The proposed model provides a way of using combinations of histopathological parameters to identify patients with higher risks of nodal metastasis for surgical management.

A Predictive Model to Determine the Pattern of Nodal Metastasis in Oral Squamous Cell Carcinoma.

BACKGROUND: Developing histological prediction models that estimate the probability of developing metastatic deposit will help clinicians to identify individuals who need either radical or prophylactic neck dissection, which leads to better prognosis. Identification of accurate predictive models in oral cancer is important to overcome extensive prophylactic surgical management for neck nodes. Therefore, accurate prediction of metastasis in oral cancer would have an immediate clinical impact, especially to avoid unnecessary radical treatment of patients who are at a low risk of metastasis. METHODS: Histologically confirmed OSCC cases with neck dissection were used. Interrelation of demographic, clinical, and histological data was done using univariate and multivariate analysis. RESULTS: 465 cases were used and presence of metastasis and extracapsular invasion were statistically well correlated with level of differentiation (p < 0.001) and pattern of invasion (p < 0.001). Multivariate analysis showed level of differentiation, pattern of invasion, and stage as predictors of metastasis. CONCLUSIONS: The proposed predictive model may provide some guidance for maxillofacial surgeons to decide the appropriate treatment plan for OSCC, especially in developing countries. This model appears to be reliable and simple and may guide surgeons in planning surgical management of neck nodes.

Oropharyngeal epignathus with partial facial duplication: report of a rare case.

Foetal oral teratoma or epignathus is a rare benign condition that originates in the oropharyngeal region. The term 'teratoma' refers to a mass composed of poorly organized tissues derived from each of the three germ layers. Epignathus may occur when one twin ceases development during gestation and becomes vestigial to the fully formed dominant twin. The reported incidence of epignathus is approximately 1:35,000 to 1:200,000 live births. A unique case of partial facial duplication with gross histological and radiological evidence of partial duplication of the facial elements and organs is presented herein. The affected newborn baby underwent urgent surgery due to breathing difficulties. The mass was excised successfully and the infant made an uneventful recovery. The resected specimen included two developing faces, each composed of a developing mandible and maxilla with developing tooth buds. Tissues from all three germ layers were present. In such cases, the treatment option is exclusively surgical, and complete resection is curative in most cases during the early neonatal period.

Unilateral Cervical Lymphadenopathy due to Cladosporium oxysporum: A Case Report and Review of the Literature.

Phaeohyphomycosis is a fungal infection caused by Dermatiacae group of fungi, by Cladosporium spp. The term phaeohyphomycosis was introduced by Ajello et al. in 1974 to designate infections by brown pigmented filamentous fungi. Cladosporium oxysporum is a very rare etiological agent in humans. Phaeohyphomycosis of the cervical lymph node in an immunocompetent individual is a very rare clinical entity. To the best of our knowledge we report the first case of phaeohyphomycosis caused by Cladosporium oxysporum in the absence of other systemic manifestations in a 16-year-old male.

A retrospective analysis to determine factors contributing to the survival of patients with oral squamous cell carcinoma.

The clinical outcome of patients with OSCC is assessed based on TNM system and currently it is the most reliable indicator on which therapeutic decisions are made. The patients with advanced disease are managed with combined treatment modalities. The aim of this retrospective study was to identify the factors which influence survival of patients with OSCC in Sri Lanka. Four hundred and thirty patients who have been managed surgically using either (1) local excision, (2) local excision+supraomohyoid neck dissection, (3) local excision+modified radical neck dissection, (4) local excision+radical neck dissection, (5) local excision+contra-lateral neck dissection depending on TNM stage, with or without post-operative radiotherapy. Patients with incompletely excised tumours showed statistically significant poor survival which improved with radiotherapy (stage II P=0.002, stage III P=0.017). With reference to TNM stage IV tumours, the patients who had received surgical option 4, showed poor survival compared to surgical options 2, 3, and 5 (P=0.001). However, within the group of patients who had received surgical option 4, those who had nodal metastasis showed poorer survival compared to patients without nodal metastasis. In addition, survival improved in patients who had been treated with surgical option 4, with radiotherapy. Furthermore, margin status was also found to significantly influence the survival of patients with TNM stage IV tumours (P=0.003). The main factors that had significant impact on the survival were TNM stage, nodal metastasis and the state of excision margins.

Pigmented mucoepidermoid carcinoma with spindle cell differentiation.

Mucoepidermoid carcinoma is the most common malignant salivary gland tumor of children and adults, showing diverse histopathologic features. Mucoepidermoid carcinoma with both melanin pigmentation and spindle cell differentiation has not been previously reported. We report the first documented case of pigmented mucoepidermoid carcinoma with spindle cell differentiation in a 34-year-old woman who presented with a swelling of the floor of the mouth.

Relative frequency of odontogenic tumors in Sri Lanka: Analysis of 1677 cases.

Odontogenic tumors (OTs) constitute a heterogeneous group of lesions with diverse histopathological features and clinical manifestations. The present study is to determine the frequency of odontogenic tumors (OTs) in Sri Lankan population. A total of 1677 cases of OTs were retrieved and analyzed for age, gender and primary site of the tumors. Cases were re-classified according to the 2005 WHO classification of OTs. The relative frequency of different types of tumors was also analyzed and compared with the literature. OTs represent 3.75% of all cases received during a period of 30 years. Ninety-eight percent of these tumors were benign and the rest malignant. Mandible to maxilla ratio is 2.8:1. The posterior part, the molar region, is the most frequently affected site for the mandible whilst it is the anterior region for the maxilla. The age ranges from 1 to 80 years, with a mean age of 30.6 years. Ameloblastoma of solid/multicystic and unicystic types showed a high preponderance for the mandible (>90%) with a ratio of 12.9:1 and 10.8:1, respectively. Out of 1677 cases, 48.7% were ameloblastoma, and other tumors, such as keratocystic odontogenic tumor (KCOT) and odontoma, were 25.7% and 10.1%, respectively. There is a significant change in the frequency of OTs after the inclusion of odontogenic keratocyst as a tumor. Although odontoma is said to be the commonest in western countries, our results showed ameloblastoma as the commonest followed by KCOT, and the relative frequencies of different tumors have changed significantly as a result of inclusion of KCOT in the new classification.

A Rare Clinical Presentation of Intraoral Darier's Disease.

Darier's disease, also known as keratosis follicularis or dyskeratosis follicularis, is a rare disorder of keratinization. It is an autosomal dominant genodermatosis with high penetrance and variable expressivity. Its manifestation appears as hyperkeratotic papules primarily affecting seborrheic areas on the head, neck, thorax, and less frequently the oral mucosa. When oral manifestations are present, the palatal and alveolar mucosae are primarily affected. They usually asymptomatic and are discovered in routine dental examination. Histologically, the lesions present as suprabasal clefts in the epithelium with acantholytic and dyskeratotic cells represented by "corps ronds and grains." This paper reports a case of an adult male patient who presented with painful whitish lesions on buccal mucosa with crusty lips as the only clinical sign of Darier's disease. As this patient did not have skin lesions or family history, an intraoral biopsy confirmed the diagnosis of Darier's disease by a multidisciplinary team.

Aberrant beta-catenin expression and adenomatous polyposis coli gene mutation in ameloblastoma and odontogenic carcinoma.

The Wnt pathway is involved in carcinogenesis and three regulatory genes of the Wnt pathway, APC (adenomatous polyposis coli), beta-catenin and Axin are frequently mutated in some primary human cancers. This study was conducted to clarify the relation of beta-catenin accumulation and the mutation of the CTNNB1 (beta-catenin) gene with the mutation of APC gene in the process of development of odontogenic tumors including ameloblastoma and odontogenic carcinoma (OC). beta-Catenin accumulation was examined by immunohistochemistry in formalin-fixed, paraffin-embedded samples of six ameloblastomas and eight OCs. We also performed a mutation analysis of CTNNB1 and APC to examine the cause of beta-catenin accumulation. All ameloblastoma cases and six out of eight (75%) OC cases exhibited beta-catenin accumulation in the nucleus. CTNNB1 mutation was only found in one OC case, whereas three of six (50%) ameloblastoma cases and two out of eight (25%) OC cases had APC mutations within the mutational cluster region. Our findings suggest that aberrant beta-catenin expression and APC missense mutation may play an important role for the pathogenesis of epithelial odontogenic tumors.

VEGF-C is associated with lymphatic status and invasion in oral cancer.

BACKGROUND: Nodal metastasis is a major prognostic indicator for oral squamous cell carcinoma (OSCC) progression. Recently, it has been revealed that lymphangiogenic growth factor VEGF-C and its receptor Flt-4 play an important role for invasion and metastasis in cancer cells. AIM: To examine VEGF-C expression and its correlation with lymphatic status, including the number of lymph vessels and lymphatic invasion, tumour invasion and metastasis in OSCC. METHODS: Intratumoural and peritumoural lymphatic vessels were examined using D2-40 in 54 OSCC cases and correlated with VEGF-C expression and clinicopathological findings. The histological pattern of invasion and pathological findings were compared. RESULTS: High expression of VEGF-C was frequently observed in OSCC and was associated with increased number of lymph vessels and lymphatic invasion. VEGF-C was well correlated with invasion pattern and metastasis. CONCLUSIONS: Results suggest that VEGF-C may play an important role for lymphangiogenesis and invasion in the metastatic process and can be a strong predicting factor for metastasis of OSCC.

Periostin: novel diagnostic and therapeutic target for cancer.

Periostin is a secreted protein that shares a structural homology to the axon guidance protein fasciclin I (FAS1) in insects and was originally named as osteoblast-specific factor-2 (Osf2). Periostin is particularly highly homologus to Betaig-h3, which promotes cell adhesion and spreading of fibroblasts. It has recently been reported that Periostin was frequently overexpressed in various types of human cancers. Although the detailed function of Periostin is still unclear, Periostin-integrin interaction through FAS1 domain is thought to be involved in tumor development. In addition, Periostin stimulates metastatic growth by promoting cancer cell survival, invasion and angiogenesis. Therefore, Periostin can be a useful marker to predict the behavior of cancer. This review summarizes the recent understanding of Periostin roles in tumor development and speculates on the usefulness of Periostin as a therapeutic and diagnostic target for cancer.

Analysis of histopathological and immunohistochemical differences of oral squamous cell carcinoma in young and old patients in Sri Lanka.

BACKGROUND: Oral squamous cell carcinoma (OSCC) most commonly occurs in the middle-aged and older individuals. The purpose of the present study was to evaluate the histopathological and immunohistochemical differences of the younger (<40 years) and the older (more than 50 years) groups. METHODS: The histopathological parameters of 112 patients (younger 56 and older 56) were compared according to three grading systems (Broder JAMA 1920; 74: 656, Anneroth et al. Scand J Dent Res 1987; 95: 229, Bryne et al. J Pathol 1992; 166: 375) and as individual histopathological parameters. Further, the expression of p53 and Proliferative Cell Nuclear Antigen (PCNA) index was also compared. RESULTS: Although there was no significant difference between two groups regarding the three grading systems, a significantly higher number of nuclear aberrations was found in younger group (P<0.001). Interestingly, higher number of mitoses (P<0.05) and lymph node metastasis (P<0.05) were observed in the older group (P<0.05). Furthermore, significantly a higher PCNA index was found in the older group (P<0.005). CONCLUSIONS: Although tumours of the young patients showed more nuclear aberrations, OSCC of the older patients is proliferative and showed higher metastatic rate.