Do dental implants facilitate bone invasion in patients with oral squamous cell carcinoma? A case series.

Osseointegrated dental implants in the vicinity of oral squamous cell carcinoma (OSCC) will become more common given the increasing popularity of dental implants. Reports and studies of OSCC around dental implants are rare, as is the topic of how to handle OSCC surgically when implants are in contact with the tumour. In view of this uncertainty, a histological study was performed to assess tumour behaviour around implants. The aim was to determine whether an implant facilitates inward growth of the tumour and how this should be taken into account during staging and treatment planning. A total of 20 specimens were collected. The implants were macroscopically in contact with OSCC in 13 of the 20 specimens. Histologically, tumour tissue near the implant was indeed confirmed in nine of these cases. In seven cases, tumour invasion had led to resorption of the underlying jaw bone; tumour between the bone-implant interface was identified in only two of these cases, but without downward growth along the implant. In conclusion, no proof was found to confirm that the bone-implant interface is a preferred route for invasion. Therefore, dental implants in the vicinity of OSCC should not influence staging and treatment planning in this regard.

Clinicopathological characteristics and outcome of 31 patients with ETV6-NTRK3 fusion gene confirmed (mammary analogue) secretory carcinoma of salivary glands.

OBJECTIVES: In 2010, a new subtype of salivary gland cancer (SGC), (mammary analogue) secretory carcinoma (SC), was defined, characterized by the ETV6-NTRK3 fusion gene. As clinical behavior and outcome data of this histological subtype tumor are still sparse, we aimed to describe the clinicopathological course and outcome of a series of translocation positive SC patients. PATIENT AND METHODS: We re-evaluated the pathological diagnosis of a subset of SGCs, diagnosed in 4 of 8 Dutch head and neck centers. Subsequently, tumors with a morphological resemblance to SC were tested for the ETV6-NTRK3 fusion gene using RT-PCR. Furthermore, patients prospectively diagnosed with SC were included. The clinical characteristics and outcomes were retrieved from the patient files. RESULTS: Thirty-one patients with ETV6-NTRK3 fusion gene positive SC were included. The median age was 49 years, 17 patients (55%) were male. Eighteen tumors (58%) arose in the parotid gland. One patient presented with lymph node metastasis. All patients underwent tumor resection and 4 patients had a neck dissection. Four patients had re-resection and 15 patients (48%) received postoperative radiotherapy. One patient developed a local recurrence, no regional recurrences or distant metastases were observed. After a median follow-up of 49 months the 5- and 10-year overall survival were 95%, the 5- and 10-year disease free survival were 89%. CONCLUSION: The clinical course of SC is favorable with a low rate of locoregional recurrence and excellent survival. Given the low incidence of nodal metastases, elective neck treatment, i.e. surgery and/or radiotherapy, does not seem to be indicated.

Role of ancillary techniques in profiling unclassified laryngeal malignancies.

Laryngeal biopsies, contrary to biopsies from many other sites of the body, very often contain minute amounts of tumour tissue that may consist of morphologically undifferentiated tumour only. In haematoxylin- and eosin-stained sections, there may be no indicative features of what specific tumour entity that is present. In the larynx, particularly small round cell neoplasms, primary or metastatic, often cause a diagnostic dilemma and where an incorrect diagnosis can induce substantial clinical consequences for the patient (e.g., primary neuroendocrine carcinomas vs metastatic variants, certain sarcomas). If sufficient/representative material has been obtained, the application of immunohistochemistry and/or molecular techniques should in virtually every case reveal the true nature of the malignancy. In cases with sparse amount of material, and therefore a limited number of sections to be cut, a careful and thoughtful stepwise approach is necessary to ascertain a reliable diagnosis, or at least guide the clinician to the most likely diagnoses. With today's advanced and widely available technology with an abundance of markers to discriminate different tumours, the use of the term "undifferentiated" should be largely unnecessary. In the exceptional, and indeed exceedingly rare cases, when a classification is not possible, even after repeat biopsy, we suggest that the laryngeal neoplasm is better termed "unclassified malignant neoplasm" rather than "undifferentiated malignant neoplasm".

Periosteal fasciitis in a 7-year old girl: a diagnostic dilemma.

Periosteal fasciitis, considered a subtype of nodular fasciitis, is a rare benign soft tissue mass often misdiagnosed as a malignant lesion due to its fast and infiltrative growth pattern and histological features. Nodular fasciitis is usually found in the upper extremities in adults and in the head and neck region in children. Incorrect diagnosis may lead to overtreatment, potentially causing disturbed orofacial development in growing children. A rapidly growing asymptomatic mass, initially suspected to be a malignant bone tumour, was found in the left angle area of the mandible in a healthy 7-year-old girl. Radiographic examination revealed an exophytic, expansile and destructive nodule arising from the periosteal region. A diagnosis of periosteal fasciitis was established based on histological findings in an open biopsy specimen and the lesion was subsequently enucleated. Fluorescence in situ hybridization analysis revealed a USP6 gene rearrangement and confirmed the diagnosis molecularly. Due to the aggressive growth pattern without external trauma and the results of the gene rearrangement test, it is suggested that nodular fasciitis be regarded as a benign neoplasm rather than as a reactive process. The patient remains free of disease at 3 years after surgery.

Using a semi-conductor sequencing-based panel for genotyping of HPV-positive and HPV-negative oropharyngeal cancer: a retrospective pilot study.

OBJECTIVES: The aim of this study was to assess the feasibility of testing actionable mutations in small amounts of formalin-fixed paraffin-embedded material in multiple genes of the receptor tyrosine kinase pathway and to determine the frequency of these mutations in human papillomavirus (HPV)-positive and HPV-negative oropharyngeal cancer (OPC). DESIGN: A retrospective pilot study was performed. SETTING: In OPC, no predictive markers for response to epidermal growth factor receptor inhibition are known. Therefore, identifying predictive biomarkers is of utmost importance, but is often hampered by the small amount of tumour material available. PARTICIPANTS: We included the archival material of 45 OPC, all treated with concomitant chemoradiotherapy between 2003 and 2010. MAIN OUTCOME MEASURES: Besides the HPV status, we assessed mutations using a gene panel that targets 16 genes in the receptor tyrosine kinase pathway and six other genes. The polymerase chain reaction required only 10 ng DNA. RESULTS: In total, 42 of the 45 biopsies have been successfully analysed. In total 20 of 42 samples were HPV-positive and 22 of 42 were HPV-negative. In the receptor tyrosine kinase pathway, mutations in PIK3CA were most frequently identified. A TP53 mutation was identified in one HPV-positive sample and in 13 HPV-negative samples. Additionally, three mutations in three different genes were found. CONCLUSIONS: We evaluated an assay to identify mutations in the receptor tyrosine kinase pathway. As only small amounts of formalin-fixed paraffin-embedded material are sufficient for reliable analysis, this test opens up new possibilities for personalised medicine.

Chromosome instability predicts the progression of premalignant oral lesions.

OBJECTIVES: One of the main problems in reducing the incidence of oral squamous cell carcinoma (OSCC) is the inability to appropriately deal with leukoplakia. Accurately identifying lesions which will progress to malignancy is currently not possible. The present study aims to establish the value of chromosome instability (CI) detection by DNA image cytometry and FISH analysis for prognosis and monitoring of oral leukoplakia. MATERIALS AND METHODS: For this purpose, we included from our archives 102 oral leukoplakia cases, which had been diagnosed between 1991 and 2008. Patient follow-up data were collected and the histopathological diagnosis was revised. CI assessment was carried out on paraffin-embedded tissue sections using both DNA image cytometry (ICM) and dual target FISH for chromosomes 1 and 7. RESULTS: 16 of 102 Patients developed carcinoma in situ or OSCC. Both detection methods were found to yield prognostic information independent of the histopathological diagnosis. CI was a strong individual marker of progression, with hazard ratios (HRs) of 7.2 and 6.8 for ICM and FISH respectively. Moreover, this approach seems suitable for monitoring lesions over time (especially ICM). Combining histopathology and CI enables subdivision of patients into three risk groups, with different probabilities of malignant progression. CONCLUSION: CI detection seems a reliable method for risk assessment of oral premalignancies and its application may contribute to a better risk-counselling and appropriate treatment regimen or watchfull-waiting approach of patients.

[Contemplations on responsibility for oral healthcare]. / Bespiegelingen over verantwoordelijkheid in de mondzorg.

The academic dental education in The Netherlands has been extended to 6 years, among other reasons in order to make it possible for responsibility for oral healthcare to be borne in a wide medical context. It is the job of the 3 national dental schools to make this happen. The new dentist should know and recognize all (peri-)oral disorders and oral symptoms of systemic diseases, and he should be able to deliver oral healthcare to medically compromised patients. Accepting this responsibility is required for dentistry to be transformed into medical oral healthcare and for dentists to be upgraded to oral physicians.

A gene expression profile for non-smoking and non-drinking patients with head and neck cancer.

OBJECTIVE: A small subset of patients with head and neck squamous cell carcinoma are non-smoking and non-drinking and have distinct clinical characteristics. We aimed to identify a possible different genetic profile for these patients when compared with their smoking and drinking counterparts. MATERIALS AND METHODS: The gene expression data previously detected from primary tumors located in the oral cavity and oropharynx, using DNA microarray was analyzed for their differential expression between non-smoking and non-drinking patients (n = 15) and smoking and drinking patients (n = 89). Student's T-test (P < 0.05) and 10-fold cross-validation procedure (100 times repeated) were performed to determine differentially expressed genes. RESULTS: Non-smoking and non-drinking patients were older, mostly female and had oral cavity-localized tumors, whereas smoking and drinking patients were younger male patients with 81% oral cavity and 19% oropharynx tumors. A set of 49 differentially expressed genes were detected. Among others, seven genes related to interferon-γ were upregulated and two genes linked to NFKB pathway were downregulated. CONCLUSIONS: Differentially expressed genes in non-smoking and non-drinking patients possibly indicate the presence of a different cellular response to carcinogenic events in these patients. Further studies are warranted to validate this gene set and explore possible therapeutic implications to improve prognosis for these patients.

Human Papillomavirus and Oropharyngeal Squamous Cell Carcinoma: A Case-Control Study regarding Tobacco and Alcohol Consumption.

We aimed to determine the role of HPV in the pathogenesis and outcome of oropharyngeal squamous cell carcinoma (OSCC) in lifelong nonsmoking and nondrinking patients. A case-case analysis was performed to compare the presence of HPV-DNA in tumor cells of 16 nonsmoking and nondrinking with 16 matched smoking and drinking patients (matching criteria: age at incidence, gender, tumor sublocation, tumor stage). HPV was detected using 2 PCR tests, FISH analysis, and p16(INK4A) immunostaining. Nonsmoking and nondrinking patients had more HPV-positive tumors than smoking and drinking patients (n = 12; 75% versus n = 2; 13%; P < 0.001). All HPV-positive tumors showed p16(INK4A) overexpression, and 1 HPV-negative tumor had p16(INK4A) overexpression, (P < 0.001). Overall survival and disease-specific survival were higher for HPV-positive compared to HPV-negative cases (P = 0.027, P = 0.039, resp.). In conclusion, HPV is strongly associated with OSCC of nonsmoking and nondrinking patients. Specific diagnostic and therapeutic actions should be considered for these patients to achieve a better prognosis.

Targeted therapy for Ewing's sarcoma: significance of heterogeneity.

BACKGROUND: Survival in Ewing's sarcoma (ES) is limited. Experience with insulin-like growth factor targeting drugs, which require specific molecular tumour alterations, herald a major breakthrough. We screened for tumour heterogeneity within patients by DNA quantification. MATERIALS AND METHODS: DNA image cytometry (IC) was performed on 41 samples from 21 patients, evaluating if ploidy state remained constant over time and between different lesions within patients and the prognostic value of ploidy was assessed. RESULTS: DNA content varied over time and different ploidy states were found to coexist at a single timepoint. Non-diploid DNA content was associated with shorter overall survival (median, 19 vs. 84 months, p=0.047). CONCLUSION: We encountered a change and heterogeneity of ploidy state. This implies that screening for targets on a single tumour sample is insufficient and may lead to under- or overtreatment. The fact that non-diploid DNA content was associated with an adverse outcome confirms that this technique discriminates biologically different tumour clones.

The prediction of mandibular invasion by squamous cell carcinomas with the expression of osteoclast-related cytokines in biopsy specimens.

Destruction of bone by tumour is caused by osteoclasts rather than by tumour cells directly. Tumour cells of invasive oral squamous cell carcinomas (SCC) release osteoclast-related cytokines and cytokines activate osteoclasts. The purpose of this study was to investigate the possibility of predicting mandibular invasion by SCC by analysis of the expression of osteoclast-related cytokines in biopsy specimens of SCC, adjacent or fixed to the mandible. Thirty-five biopsy specimens from the pathology archives were examined from patients who had been treated for SCC, adjacent or fixed to the mandible. The patients were divided into those with and without medullary invasion. The expression of tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-11 was studied by immunohistochemical analysis. No significant differences were found in expression of TNF-alpha, IL-6 and IL-11 between biopsy specimens with or without medullary invasion. Quantification of the density of tumour-infiltrating lymphocytes was not reproducible. In conclusion, the expression of TNF-alpha, IL-6 and IL-11 in biopsy specimens of SCC, adjacent or fixed to the mandible, is not an appropriate method for predicting the presence of medullary invasion of the mandible.

Alpha-smooth muscle actin within epithelial islands is predictive of ameloblastic carcinoma.

Ameloblastoma is the most common clinically significant odontogenic tumor. It is considered benign but locally invasive and associated with variable clinico-pathological behavior. Ameloblastic carcinoma is a malignant tumor having features of ameloblastoma in addition to cytologic atypia with or without metastasis. It is aggressive and associated with poor prognosis. The aim of this study was to examine which epithelial and stromal markers are predictive of histologically diagnosed ameloblastic carcinoma and can sufficiently differentiate it from solid/multicystic ameloblastoma (SA). We examined immunohistochemically Ki-67, epithelial membrane antigen (EMA), alpha-smooth muscle actin (alpha-SMA), calponin, p63 and DNA content using image (ICM) and flow cytometry (FCM) in three ameloblastic carcinomas and up to 18 SAs. The important findings were that Ki-67 labeling index was significantly higher in ameloblastic carcinoma than SA while EMA, calponin, p63, ICM and FCM did not sufficiently differentiate the two groups of lesions. Expression of alpha-SMA was consistently obtained within the epithelial island cells of ameloblastic carcinoma and not in SA, although the marker was well expressed in the stroma of both lesions. We therefore conclude that the presence of alpha-SMA within the epithelial islands is highly predictive of ameloblastic carcinoma.

Lesions of the jaws.

The jaws differ in various aspects from all other bones in the skeleton. Embryologically, they are for the major part derived from migrating cells of the cranial neural crest, the so-called ectomesenchyme, and not merely from mesoderm, and they contain teeth. This latter point, especially, results in the presence of lesions that are not found in other bones, a broad variety of odontogenic cysts and tumours. They will be the major topic of this review. Other lesions, not strictly odontogenic but also mainly confined to the jaw bones, are giant cell lesions, fibro-osseous lesions, and the melanotic neuro-ectodermal tumour of infancy. They also will be included in this overview.

No high-risk HPV detected in SCC of the oral tongue in the absolute absence of tobacco and alcohol--a case study of seven patients.

INTRODUCTION: In recent years, there has been an increase in the number of patients with squamous cell carcinoma (SCC) of the mobile tongue in the absence of tobacco and alcohol. The literature suggests that human papilloma virus (HPV) may be involved in the development of SCC of the head and neck, especially in non-smoking and non-drinking patients. In the oral cavity, however, the presence of the HPV genome has been reported with various percentages. This may be due to misclassification of the oropharyngeal tongue as oral cavity subsite and the use of various detection methods. MATERIALS AND METHODS: Therefore, we evaluated the role of HPV in seven consecutive non-smoking and non-drinking patients (2003-2006) with a SCC located at the oral, mobile tongue using in situ hybridization and SPF(10)Line Blot 25 polymerase chain reaction assays. RESULTS: No HPV was detected in these specimens. To further determine whether a relationship exists between HPV and SCC in the absence of tobacco and alcohol, subsequent studies at specific locations are necessary.

Assessment of mandibular invasion of squamous cell carcinoma by various modes of imaging: constructing a diagnostic algorithm.

The aim of this study was to determine the optimal combination of preoperative examination methods to predict mandibular invasion by squamous cell carcinoma of the oral cavity. Data were gathered prospectively but evaluated retrospectively. The preoperative results of clinical examination, conventional radiography, bone single photon emission computed tomography (SPECT), computed tomography and magnetic resonance imaging were compared to the histological results of resection specimens from 67 patients with tumours, adjacent or fixed to the mandible, histologically confirmed as squamous cell carcinoma. The examination methods with acceptable sensitivity and specificity were selected and diagnostic algorithms were constructed using all possible combinations. The preferred diagnostic algorithm was found to be either computed tomography or magnetic resonance imaging, followed by a bone SPECT in cases where the first scan is negative. A negative bone SPECT rules out mandibular invasion (100% sensitivity). This algorithm accurately predicted mandibular invasion in 85% of the patients, without yielding false negative results. In this study group, application of such an algorithm would have resulted in a reduction of the number of unnecessary mandibular resections by 50%. The suggested, preferred, diagnostic algorithm shortens the preoperative screening process, avoiding unnecessary costs, as well as considerably reducing the number of unnecessary mandibular resections.

Head and neck squamous cell carcinoma in non-smoking and non-drinking patients with multiple tumors: etiologic significance of p53 and Ki-67 in non-tumorous epithelium.

BACKGROUND: Non-smoking and non-drinking patients with head and neck squamous cell carcinoma have different clinical characteristics than their smoking and drinking counterparts. They are predominantly older female patients with oral cavity tumors, however, both groups show the same percentage of second primary tumors. Expression of tumor suppressor gene p53 and proliferation marker Ki-67 in mucosal epithelial cells was analyzed to study whether biomarker expression is associated with a history of smoking and drinking and with single and multiple tumors. METHODS: Non-smoking and non-drinking patients with multiple (n = 18) and single tumors (n = 15), smoking and drinking patients with multiple (n = 15) and single tumors (n = 14) were selected. For all groups, p53 and Ki-67 expression patterns in non-tumorous (tumor-adjacent) mucosa including positivity of dispersed single cells and clusters for p53 and for suprabasal expression of Ki-67 were immunohistochemically analyzed and compared. RESULTS: p53 expression was significantly higher in users of tobacco and alcohol than in non-users. Ki-67 expression was not affected by tobacco and alcohol usage. Both Ki-67 and p53 were similarly expressed in the groups with single and multiple tumors and hence not significantly related to the number of tumors. CONCLUSIONS: Non-smoking and non-drinking patients with squamous cell carcinoma have the same risk for developing multiple tumors as their smoking and drinking counterparts. As this occurs without an increased expression of p53 or Ki-67, the significance of these proteins as biomarkers indicating pre-malignant mucosal alterations is doubtful. Further research is needed to clarify this predisposition for developing multiple head and neck cancer.

Case-report: metastasizing pleomorphic adenoma of the parotid gland.

CASE-REPORT: Metastasizing pleomorphic adenoma of the parotid gland. We present a case of metastasizing pleomorphic adenoma (MPA). The patient died in 2002 at the age of 64 years, following on an initial diagnosis of a pleomorphic adenoma of the right parotid gland at the age of nineteen, multiple local recurrences and finally rib metastases. Histological examination of the excised tissue from the parotid gland and the metastases showed it to be a pleomorphic adenoma without any signs of malignancy, although the metastatic deposits consisted mostly of a myoepithelial component. Both in our case as in most of the literature, MPA follows a probable incomplete removal of the first tumour. We conclude that the first operation is of great importance for the prevention of late recurrences and metastatic spread.

Non-smoking and non-drinking patients with head and neck squamous cell carcinoma: a distinct population.

OBJECTIVE: To recognize specific clinicopathological characteristics of non-smoking and non-drinking (NSND) head and neck squamous cell carcinoma (HNSCC) patients. This can increase our knowledge regarding a potentially different carcinogenesis in these patients. STUDY DESIGN/METHODS: Retrospective analysis of data for 195 NSND patients with HNSCC and comparison with data for patients with HNSCC obtained from the Netherlands Cancer Registry. RESULTS: Compared with all HNSCC patients in the Netherlands, our NSND patients with HNSCC were typically female (n = 142; 73%vs 26%), old at disease presentation (mean 73 years vs 64 years), and had tumors mainly of the oral cavity (n = 130; 66%vs 25%). Most tumors were stage I (n = 67; 34%) and stage IVA (n = 59; 30%). The incidence of second primary tumors (SPTs) was high (n = 32; 16%), mainly occurring in the oral cavity (n = 26; 13%). DISCUSSION/CONCLUSION: Our study confirms that NSND HNSCC patients have different clinicopathological characteristics from those of the overall HNSCC population; however, the frequency of SPTs is as high in NSND patients as in patients who smoke and drink alcohol. More research, and particularly molecular data are needed to obtain a better understanding of head and neck cancer in NSND patients.

Neurofibromatosis presenting with a cherubism phenotype.

We report on a child who presented clinical manifestations of both neurofibromatosis type 1 (NF1) and cherubism. With genetic testing, we found a mutation in the NF-1 gene, confirming the neurocutaneous disorder. Histology when correlated with radiological evaluation of a mandibular biopsy was consistent with cherubism. This is the first report in the literature of a child with proven neurofibromatosis type 1 and cherubism without extragnathic lesions. This emphasises that cherubism is a clinical phenotype that can be associated with a number of germline mutations involving SH3BP2, PTPN11 and NF1.