FADD expression is associated with regional and distant metastasis in squamous cell carcinoma of the head and neck.

AIMS: The Fas-associated death domain gene (FADD) is often overexpressed in squamous cell carcinoma of the head and neck (HNSCC), and is considered to be a driver gene in amplification of the chromosomal 11q13.3 region. Amplification of 11q13.3 is associated with increased metastasis in HNSCC and breast cancer. The aim of this study was to investigate the association between FADD protein expression in advanced-stage HNSCC and clinicopathological features and outcome. METHODS AND RESULTS: Tumour tissues of 177 HNSCC patients uniformly treated with primary surgery and postoperative radiotherapy were collected. FADD expression was assessed on pretreatment tumour biopsies using immunohistochemistry. High FADD expression was detected in 44% of the HNSCC patients. High expression was associated with an increased rate of lymph node metastasis (P = 0.001) and with a shorter distant metastasis-free interval (DMFI) (HR 2.6, 95% CI 1.0-6.7, P = 0.046) when lymph node metastases were present. CONCLUSIONS: Our data show that an increase in FADD expression is associated with a higher incidence of lymph node metastasis at presentation, and with shorter DMFI when lymph node metastases are present. High FADD expression in the primary tumour could be a useful marker to select patients for systemic treatment strategies that reduce the risk of distant metastases.

Scandinavian Fellowship for Oral Pathology and Oral Medicine: guidelines for oral pathology and oral medicine in the dental curriculum.

In Scandinavia, as in many European countries, most patients consult their general dentist once a year or more. This gives the dentist a unique opportunity and an obligation to make an early diagnosis of oral diseases, which is beneficial for both the patient and the society. Thus, the dentist must have knowledge of clinical symptoms, local and systemic signs and clinical differential diagnoses to make an accurate diagnosis. The dentist must be competent in selecting appropriate diagnostic tests, for example, tissue biopsy and microbiological samples, and conducting them correctly, as well as in interpreting test results and taking appropriate action accordingly. Furthermore, the dentist must be aware of diseases demanding multidisciplinary cooperation and be able to recognise his/her professional limitation, and to refer to other specialists when required. The dental curriculum changes over time as new approaches, treatments and diagnostic possibilities develop. Likewise, the role of the dentist in the community changes and may vary in different countries. As members of the Scandinavian Fellowship for Oral Pathology and Oral Medicine and subject representatives of oral pathology and oral medicine, we feel obliged to contribute to the discussion of how the guidelines of the dental curriculum support the highest possible standards of dental education. This article is meant to delineate a reasonable standard of oral pathology and oral medicine in the European dental curriculum and to guide subject representatives in curriculum development and planning. We have created an advisory topic list in oral pathology and oral medicine.

[A local gingival swelling which was based on a peripheral giant cell lesion]. / Lokale zwelling van de gingiva die berustte op een perifere reuscellaesie.

A 29-year-old woman consulted her dentist about a localgingival swelling which bled during tooth-brushing and had been present for 1 year. In the differential diagnosis, epulis gravidarum, a peripheral giant cell lesion, and peripheral ossifying granuloma were considered. After surgical removal, histopathological examination revealed a peripheral giant cell lesion. The presence of a peripheral giant cell lesion requires thorough excochleation of the underlying bone. If the bone is cleaned thoroughly, recurrence is rare.

The phosphatase and tensin homologue deleted on chromosome 10 mediates radiosensitivity in head and neck cancer.

BACKGROUND: For locally advanced squamous cell carcinoma of the head and neck (HNSCC), the recurrence rate after surgery and postoperative radiotherapy is between 20 and 40%, and the 5-year overall survival rate is approximately 50%. Presently, no markers exist to accurately predict treatment outcome. Expression of proteins in the human epidermal growth factor receptor (EGFR) pathway has been reported as a prognostic marker in several types of cancer. METHODS: The aim of this study was to investigate the prognostic value of proteins in the EGFR pathway in HNSCC. For this purpose, we collected surgically resected tissue of 140 locally advanced head and neck cancer patients, all treated with surgery and postoperative radiotherapy. RESULTS: In a multivariate analysis, expression of the phosphatase and tensin homologue deleted on chromosome 10 (PTEN) was significantly related to worse locoregional control (LRC; HR: 2.2, 95% CI: 1.1-4.6; P=0.03), independent of lymph node metastases (HR: 5.6, 95% CI: 1.2-27.4; P=0.03) and extranodal spread (HR: 2.7; 95% CI: 1.2-6.5; P=0.02). In vitro clonogenic radiosensitivity assays confirmed that overexpression of PTEN resulted in increased radioresistance. CONCLUSION: Our study is the first report showing that expression of PTEN mediates radiosensitivity in vitro and that increased expression in advanced HNSCC predicts worse LRC.

Scandinavian Fellowship for Oral Pathology and Oral Medicine: statement on oral pathology and oral medicine in the European Dental Curriculum.

BACKGROUND: For many years, dentists have migrated between the Scandinavian countries without an intentionally harmonized dental education. The free movement of the workforce in the European Union has clarified that a certain degree of standardization or harmonization of the European higher education acts, including the dental education, is required. As a result of the Bologna process, the Association for Dental Education in Europe and the thematic network DentEd have generated guidelines in the document 'Profile and Competences for the European Dentist' (PCD). This document is meant to act as the leading source in revisions of dental curricula throughout Europe converging towards a European Dental Curriculum. In order to render the best conditions for future curriculum revisions providing the best quality dentist we feel obliged to analyse and comment the outlines of oral pathology and oral medicine in the PCD. METHODS: The representatives agreed upon definitions of oral pathology and oral medicine, and competences in oral pathology and oral medicine that a contemporary European dentist should master. The competences directly related to oral pathology and oral medicine were identified, within the PCD. RESULTS: The subject representatives suggested eighteen additions and two rewordings of the PCD, which all were substantiated by thorough argumentation. PERSPECTIVES: Hopefully, this contribution will find support in future revisions of the PCD in order to secure the best quality dental education.

[An obscure anomaly: regional odontodysplasia]. / Een spookachtige afwijking: regionale odontodysplasie.

In a 3-year-old child, acute dental abscesses in combination with clinical and radiographic impressions of a number of deciduous teeth indicated regional odontodysplasia as probable diagnosis. Histological examination of the removed deciduous teeth confirmed the diagnosis. Early determination of this regional developmental anomaly in the odontogenesis is of great importance for optimal guidance of the dental care of a patient with regional odontodysplasia.

Overexpression of intrinsic hypoxia markers HIF1alpha and CA-IX predict for local recurrence in stage T1-T2 glottic laryngeal carcinoma treated with radiotherapy.

PURPOSE: To examine the prognostic value of three endogenous hypoxia markers (hypoxia inducible factor 1 alpha subunit [HIF1 alpha], carbonic anhydrase IX [CA-IX], and glucose transporter type 1 [GLUT-1]) on the clinical outcome in patients with early-stage glottic carcinoma primarily treated with radiotherapy (RT) and to determine the predictive hypoxic profile to choose the optimal treatment of early-stage laryngeal carcinoma. METHODS AND MATERIALS: Immunohistochemistry for HIF1 alpha, CA-IX, and GLUT-1 was performed on formalin-fixed, paraffin-embedded, pretreatment tissue samples of 91 glottic squamous cell carcinoma specimens. The patient group consisted only of those with early-stage (T1-T2) glottic carcinoma, and all patients were treated with RT only. Relative tumor staining was scored on the tissue samples. Receiver operating curve analysis was performed to determine the optimal cutoff value for each tumor marker. Cox regression analyses for the variables HIF1 alpha, CA-IX, GLUT-1, gender, age, hemoglobin level, T category, N category, tobacco use, and alcohol use were performed with local control and overall survival as endpoints. RESULTS: HIF1 alpha overexpression in early-stage glottic carcinoma correlated significantly with worse local control (hazard ratio [HR], 3.05; p = 0.021) and overall survival (HR, 2.92; p = 0.016). CA-IX overexpression correlated significantly with worse local control (HR, 2.93; p = 0.020). GLUT-1 overexpression did not show any correlation with the clinical outcome parameters. Tumors with a nonhypoxic profile (defined as low HIF1 alpha and low CA-IX expression) had significantly better local control (HR, 6.32; p = 0.013). CONCLUSION: The results of our study have shown that early-stage glottic laryngeal carcinomas with low HIF1 alpha and CA-IX expression are highly curable with RT. For this group, RT is a good treatment option. For tumors with HIF1 alpha or CA-IX overexpression, hypoxic modification before RT or primary surgical treatment should be considered.

Non-invasive measurement of the morphology and physiology of oral mucosa by use of optical spectroscopy.

Differential path-length spectroscopy (DPS) was used to non-invasively determine the superficial optical properties of oral mucosa in vivo. DPS yields information on physiological parameters such as the mucosal blood content, the microvascular blood oxygenation and the average micro-vessel diameter as well as on morphological parameters such as the scattering slope and scattering amplitude. DPS measurements were made on normal and cancerous oral mucosa using a novel fiber-optic probe, and were correlated to the histological outcome of punch biopsies taken from the same location. Our data shows that the mucosa of oral squamous cell carcinoma is characterised by a significant decrease in microvascular oxygenation and increase in mucosal blood content compared to normal oral mucosa as well as a significant decrease in scattering amplitude and increase in scattering slope.

CO2 laser evaporation of oral lichen planus.

Oral lichen planus is a relatively common disease of the oral mucosa. The buccal mucosa and lateral border of the tongue are mostly involved, although the condition can occur anywhere in the oral cavity. The erosive type in particular can cause spontaneous pain during eating. In the period from 1975 to 2003, a group of 21 patients with 39 lesions of oral lichen planus which caused pain, even after conservative therapy, were treated with CO2 laser evaporation. During a follow-up period of 1-18 years (mean 8 years) 21 patients were pain free (85%) and 6 patients (15%) experienced painful recurrence after treatment. After retreatment with CO2 laser evaporation there were no complaints of pain. Among the many treatments available, high-potency topical corticosteroids remain the most consistent and effective. In patients whose condition is unresponsive to topical corticosteroids, CO2 laser evaporation can cause long-term remission of symptoms, and may even be the treatment of first choice in patients suffering from painful oral lichen planus.

[Prophylactic thyroidectomy in children who are carriers of a multiple endocrine neoplasia type 2 mutation: description of 20 cases and recommendations based on the literature]. / Profylactische thyreoïdectomie bij kinderen die drager zijn van een mutatie van multipele endocriene neoplasie type 2: beschrijving van 20 casussen en aanbevelingen op grond van de literatuur.

OBJECTIVE: Evaluation of treatment of children who are proven carriers of a multiple endocrine neoplasia type 2 (MEN 2)-associated rearranged during transfection (RET) gene mutation. DESIGN: Retrospective case study and review of the literature. METHOD: Between 1976 and 2005, 6 boys and 14 girls with a proven RET mutation or biochemical indication of MEN 2 had thyroid surgery at the University Medical Center, Groningen, The Netherlands. The median age was 10 years (range: 0-08). Preoperative assessment, surgical procedure, pathological findings, postoperative complications and treatment results were studied and compared with data from the literature. RESULTS: All 20 children underwent total thyroidectomy. In 17 children with preoperatively abnormal basal or stimulated calcitonin levels, total thyroidectomy was combined with tracheo-oesophageal exploration (n = 6) or central compartment dissection (n = 11). C-cell hyperplasia was found in 19 cases (95%) and medullary thyroid carcinoma in 14 (70%; aged 3-18 years). Lymph-node metastases were found in 3 children (15%), all over the age of 10. They underwent additional selective lateral neck dissection, unilateral in 2 cases and bilateral in 1. Two children developed hypoparathyroidism postoperatively, no recurrent laryngeal-nerve palsy was observed. All patients are clinically free of disease after a median follow-up of 9 years (range: 0.6-27). The patients with node metastases still have biochemical evidence of disease. The literature indicates that the progression of the malignant transformation to medullary thyroid carcinoma is connected to the type of RET-mutation. The treatment plan depends on the type of mutation. CONCLUSION: Medullary thyroid cancer occurs at a very young age in carriers ofgermline RET mutations. In patients with high-risk mutations prophylactic thyroidectomy is likely to be recommended before the child reaches the age of 2. Elective central lymph-node dissection can be omitted in this instance. After this age, however, the risk of lymph-node metastases increases and, for cases with increased basal or stimulated calcitonin levels, total thyroidectomy with central compartment dissection is indicated.

The results of CO2 laser surgery in patients with oral leukoplakia: a 25 year follow up.

Oral leukoplakia is an important premalignant lesion of the oral mucosa. We treat this lesion prophylactically with CO2 laser evaporation. In the period from 1976 to 2001, a group of 200 patients with 282 oral leukoplakias were treated by CO2 laser evaporation. In a follow up period of 1-219 months (mean 52), 251 treated leukoplakias (89.0%) did not show a recurrence. Twenty eight (9.9%) local recurrences were observed in 5 to 168 months after treatment. Three (1.1%) squamous cell carcinoma, occurred in the treated area respectively 7, 17 and 19 month after CO2 laser evaporation. This large study with a long follow up shows that laser treatment is a good prophylactic treatment for oral leukoplakia.

Identification of methylation markers for the prediction of nodal metastasis in oral and oropharyngeal squamous cell carcinoma.

Hypermethylation is an important mechanism for the dynamic regulation of gene expression, necessary for metastasizing tumour cells. Our aim is to identify methylation tumour markers that have a predictive value for the presence of regional lymph node metastases in patients with oral and oropharyngeal squamous cell carcinoma (OOSCC). Significantly differentially expressed genes were retrieved from four reported microarray expression profiles comparing pN0 and pN+ head-neck tumours, and one expression array identifying functionally hypermethylated genes. Additional metastasis-associated genes were included from the literature. Thus genes were selected that influence the development of nodal metastases and might be regulated by methylation. Methylation-specific PCR (MSP) primers were designed and tested on 8 head-neck squamous cell carcinoma cell lines and technically validated on 10 formalin-fixed paraffin-embedded (FFPE) OOSCC cases. Predictive value was assessed in a clinical series of 70 FFPE OOSCC with pathologically determined nodal status. Five out of 28 methylation markers (OCLN, CDKN2A, MGMT, MLH1 and DAPK1) were frequently differentially methylated in OOSCC. Of these, MGMT methylation was associated with pN0 status (P = 0.02) and with lower immunoexpression (P = 0.02). DAPK1 methylation was associated with pN+ status (P = 0.008) but did not associate with protein expression. In conclusion, out of 28 candidate genes, two (7%) showed a predictive value for the pN status. Both genes, DAPK1 and MGMT, have predictive value for nodal metastasis in a clinical group of OOSCC. Therefore DNA methylation markers are capable of contributing to diagnosis and treatment selection in OOSCC. To efficiently identify additional new methylation markers, genome-wide methods are needed.

Clinical imaging of head and neck cancer with technetium-99m-labeled monoclonal antibody E48 IgG or F(ab')2.

METHODS: In 32 patients who were suspected of having a neck lymph node metastasis from a histologically proven squamous-cell carcinoma of the head and neck (HNSCC), the diagnostic value of 99mTc-labeled (750 MBq) monoclonal antibody (1-2 mg) E48 IgG (n = 17) and its F(ab')2 fragment (n = 15) was evaluated and compared. Preoperative findings on lymph node status obtained by radioimmunoscintigraphy (RIS), computerized tomography (CT), magnetic resonance imaging (MRI) and palpation were defined per side (left and/or right side of the neck) as well as per lymph node level (I through V) and compared to the histopathological outcome of the neck dissection specimen. RESULTS: All 31 tumors at the primary site were visualized. RIS was correct in 201 of 221 levels (accuracy 91%) and in 38 of 47 sides (accuracy 81%). Fifteen levels and seven sides with limited tumor load were scored false-negative and five levels and two sides were scored false-positive. Sensitivity and specificity of RIS were similar to those of palpation, CT and MRI. The diagnostic value of RIS with E48 F(ab')2 or E48 IgG appeared to be similar. CONCLUSIONS: The present study shows that RIS with either E48 F(ab')2 or E48 IgG is as valuable as the other imaging techniques. The selective accumulation of radioactivity in tumor tissues, in combination with the known intrinsic radiosensitivity of HNSCC, justifies the development of radioimmunoconjugates for radioimmunotherapy.

Histological reclassification of 101 intraoral salivary gland tumours (new WHO classification).

The epithelial salivary gland tumours have for many years been categorised according to the 1972 World Health Organisation (WHO) classification. In 1990 a proposed revision of this classification was elaborated. In this study 101 intraoral salivary gland tumours were reclassified accordingly. In 29 of the cases the original histological diagnosis was changed, which in most cases, occurred in the benign or malignant tumour groups. In seven cases the diagnosis was changed from benign to malignant or vice versa. The results of this study show that the histological classification of intraoral salivary gland tumours remains difficult, even when applying the new WHO classification.

Comparative genomic hybridisation divides retinoblastomas into a high and a low level chromosomal instability group.

BACKGROUND: Retinoblastoma is the most common intraocular malignancy in childhood and is responsible for approximately 1% of all deaths caused by childhood cancer. AIMS/METHODS: Comparative genomic hybridisation was performed on 13 consecutive, histologically confirmed retinoblastomas to analyse patterns of chromosomal changes and correlate these to clinicopathological variables. Six cases were hereditary and seven cases were sporadic. RESULTS: In 11 of the 13 tumours chromosomal abnormalities were detected, most frequently gains. Frequent chromosomal gains concerned 6p (46%), 1q (38%), 2p, 9q (30%), 5p, 7q, 10q, 17q, and 20q (23%). Frequent losses occurred at Xq (46%), 13q14, 16q, and 4q (23%). High level copy number gains were found at 5p15 and 6p11-12. A loss at 13q14 occurred in three cases only. Relatively few events occurred in the hereditary cases (27) compared with the non-hereditary cases (70 events). The number of chromosomal aberrations in these 13 retinoblastomas showed a bimodal distribution. Seven tumours showed less than four chromosomal aberrations, falling into a low level chromosomal instability (CIN) group, and six tumours showed at least eight aberrations, falling into a high level CIN group. In the low level CIN group the mean age was half that seen in the high level CIN group, there were less male patients, and there were more hereditary and bilateral cases. Microsatellite instability was not detected in either of the two groups. CONCLUSION: Despite the complex pattern of genetic changes in retinoblastomas, certain chromosomal regions appear to be affected preferentially. On the basis of the number of genetic events, retinoblastomas can be divided in low and a high level chromosomal instability groups, which have striking differences in clinical presentation.

Salivary agglutinin/DMBT1SAG expression is up-regulated in the presence of salivary gland tumors.

Salivary agglutinin (SAG) is encoded by the gene Deleted in Malignant Brain Tumors 1 (DMBT1) and represents the salivary variant of DMBT1 (DMBT1(SAG)). While SAG is a bona fide anti-caries factor, DMBT1 was proposed as a candidate tumor-suppressor for brain, digestive tract, and lung cancer. Though DMBT1(SAG) is expressed in the salivary glands, its expression in salivary gland tumors is unknown. Here we analyzed DMBT1(SAG) expression in 20 salivary gland tumors and 14 tumor-flanking tissues by immunohistochemistry. DMBT1(SAG) in salivary gland tumors resembles the changes of expression levels known from DMBT1 in tumors in other cancer types. Particularly, DMBT1(SAG) was up-regulated in 10/14 tumor-flanking tissues, and a strong staining of the luminal content in the tumor and/or the tumor-flanking tissue was observed in 14/20 cases. This suggests that, in addition to its role in caries defense, SAG may serve as a potential tumor indicator and/or tumor suppressor in salivary gland tissue.

Immunohistochemical detection of salivary agglutinin/gp-340 in human parotid, submandibular, and labial salivary glands.

Salivary agglutinin is a Streptococcus mutans binding protein and a member of the scavenger receptor cysteine-rich superfamily. It is identical to lung gp-340 and brain DMBT1, which possibly play a role in innate immunity and tumor suppression, respectively. The goal of this study was to localize salivary agglutinin in human salivary glands. Two monoclonal antibodies, directed against gp-340, were characterized. mAb 213-1 reacted with sialic acid epitopes and cross-reacted with MUC7. The reaction with mAb 213-6 disappeared after reduction, suggesting that a protein epitope was recognized. In the parotid gland, immunohistochemical labeling with mAb 213-6 was found in the duct cells. In the submandibular gland and labial gland, both serous acini and demilune cells were labeled. In the labial gland, labeling was found at the luminal side of the duct cells. Salivary agglutinin was distinctly localized in salivary glands, but in distinct glandular secretions, no differences in electrophoretic behavior were observed.

The rare sialadenoma papilliferum. Report of a case and review of the literature.

Sialadenoma papilliferum is a rare benign tumor of salivary gland origin. A case is described of a 46-year-old man with an exophytic lesion at the junction of the hard and soft palate. The literature is briefly discussed.

Regional odontodysplasia: report of three cases.

Regional odontodysplasia is a developmental anomaly of dental tissues with characteristic clinical, radiographic, and histologic appearances. It most commonly affects the maxillary anterior teeth of both the primary and permanent dentition, and occurs in females twice as often as in males. The pathogenesis is unknown. The clinical and histopathologic findings of regional odontodysplasia in three patients are discussed.

Oncologic aspects of vermilionectomy in microinvasive squamous cell carcinoma of the lower lip.

Twelve patients with microinvasive squamous cell carcinoma of the lower lip were studied in order to determine whether vermilionectomy was justifiable. The maximum tumor thickness (MTT) varied between 1.1 and 3.1 mm. In none of the patients was there local recurrence during a mean follow-up period of 4.4 years (range 4-8). In view of these results and of what has been reported in the literature, it seems warranted to conclude that vermilionectomy is an appropriate procedure in microinvasive carcinoma of the lower lip with a MTT of up to 3 mm.