Oral Potentially Malignant Disorders (OPMD): What is the clinical utility of dysplasia grade?

INTRODUCTION: Oral epithelial dysplasia is considered a potential histologic precursor of subsequent squamous cell cancer. As standard clinical practice, pathologists grade dysplasia to assess risk for progression to malignancy. Except for the most advanced grade, severe dysplasia, dysplasia grading has failed to correlate well with the risk to develop invasive cancer. The questions of what process dysplasia grading best represents and what clinical utility dysplasia grading may have are explored. AREAS COVERED: This narrative review is based on PubMed search with emphasis on papers since 2010. Epithelial dysplasia as a precursor lesion of cancer and dysplasia grading as a risk assessment tool for progression to cancer are discussed. The close clinical association of dysplasia with known carcinogens, alcohol, and tobacco products is presented. EXPERT OPINION: Oral epithelial dysplasia is often, associated with prolonged exposure to tobacco and alcohol products. With reduction of carcinogen exposure, dysplasia is known to regress in some cases. It is proposed that histologic dysplasia grade together with macroscopic images of dysplastic clinical lesions be used as an educational tool to incentivize patients to reduce their known carcinogen exposure. This strategy has the potential to reduce lesion progression thereby reducing the disease burden of oral cancer.

Ligneous gingivitis secondary to plasminogen deficiency: a multidisciplinary diagnostic challenge.

Plasminogen deficiency is a genetic condition resulting in deposition of extravascular fibrin within mucosal tissues. Lesions associated with plasminogen deficiency most commonly affect the eyes, while intraoral lesions, when present, affect the marginal aspects of the gingiva. We report a diagnostically challenging case of ligneous gingivitis, which developed in a young male patient in the absence of other clinical lesions. Due to the rarity of this condition, it may fall under the radar of dentists and dental specialists, leading to missed or delayed diagnosis.

Histologic and Immunopathologic Variability in Primary Intraoral Angiosarcoma: A Case Report and Review of the Literature.

Primary intraoral angiosarcoma is an exceptionally rare malignancy of vascular origin which can be challenging to diagnose due to microscopic and immunohistochemical variability. A histopathologically challenging case of primary intraoral angiosarcoma, occurring in a pediatric patient is presented. A comprehensive review of the literature reveals that primary intraoral angiosarcomas occur with nearly equal frequency in males and females, affect the gingiva and the tongue most commonly and are treated primarily with surgery. As with angiosarcoma in other sites, primary intraoral angiosarcoma behaves aggressively with the majority of patients succumbing to their disease.

Surrogate markers for high-risk human papillomavirus infection in oral epithelial dysplasia: A comparison of p16, Ki-67, and ProExC.

OBJECTIVE: The aim of this study was to determine the utility of surrogate markers of human papillomavirus (HPV) infection in the diagnosis of HPV-associated oral epithelial dysplasia (OED). STUDY DESIGN: Twelve cases of oral dysplasia with histologic features of HPV infection were stained with surrogate markers for HPV (p16, Ki-67, and ProExC) on immunohistochemistry. A second group of 12 cases of oral dysplasia without histologic features of HPV infection was used for comparison. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to confirm the presence of high-risk HPV (HR HPV) in p16-positive cases. RESULTS: All of the surrogate markers showed a statistically significant association with HPV-positive OED (P < .001). The agreement between p16 and HPV positivity was the strongest (κ = 1.00), whereas Ki-67 showed very good association with HPV (κ = 0.83), and ProExC showed good association (κ = 0.75). In each case, the agreement was statistically significant (P < .001). Overall, each of the 3 markers showed good sensitivity; however, ProExC showed the lowest specificity. CONCLUSIONS: The clinicopathologic features of 12 cases of HPV OED are reported. Diffuse p16 positivity is an accurate and reliable method for predicting HR HPV infection in both high and low grade cases of epithelial dysplasia with histopathologic features of HPV OED. The use of Ki-67 and ProExC did not demonstrate any additional diagnostic benefit in the diagnosis HPV OED.

Identifying Candidate Biomarkers for Pleomorphic Adenoma: A Case-Control Study.

Pleomorphic adenoma (PA) is the most common benign salivary gland tumor. Kallikrein-related peptidases have been identified as biomarkers in many human tumors and may influence tumor behavior. We investigated KLK1-15 messenger ribonucleic acid and proteins in PA specimens to determine a KLK expression profile for this tumor. Fresh frozen PA tissue specimens (n = 26) and matched controls were subjected to quantitative real-time reverse transcription polymerase chain reaction to detect KLK1-15 mRNA. Expression of KLK1, KLK12, KLK13, and KLK8 proteins were then evaluated via immunostaining techniques. Statistical analyses were performed with the level of significance set at P < .05. We observed downregulation of KLK1, KLK12, and KLK13 mRNA expression, and immunostaining studies revealed downregulation of the corresponding proteins. Histologic evidence of capsular perforation was associated with increased KLK1 protein expression. Tumor size was not associated with capsular invasion and/or perforation. This study is the first to detail a KLK expression profile for PA at both the transcriptional level and the protein level. Future work is required to develop clinical applications of these findings.

Central xanthoma of the jaws: a clinicopathologic entity?

OBJECTIVE: To investigate central lesions of the jaws dominated by foamy macrophages (foam cells), which are interpreted to be "central xanthomas of the jaws" and to differentiate this condition from reported cases of jaw nonossifying fibroma/fibrous cortical defect and benign fibrous histiocytoma of bone. STUDY DESIGN: The study is a literature review and a retrospective analysis of clinical, radiographic, microscopic, and immunohistochemical features of five new cases of this condition. RESULTS: The lesion has a predilection for the mandible in adults of variable ages, with the potential to become very large and destructive; however, it has a very low recurrence rate, if any, following surgical curettage. CONCLUSION: We suggest that the "central xanthoma of the jaws" be considered a unique, although rare, clinicopathologic entity. It is unclear whether this lesion is a benign neoplastic process or a persistent reactive process.

Loss of P2X7 nucleotide receptor function leads to abnormal fat distribution in mice.

The P2X7 receptor is an ATP-gated cation channel expressed by a number of cell types. We have shown previously that disruption of P2X7 receptor function results in downregulation of osteogenic markers and upregulation of adipogenic markers in calvarial cell cultures. In the present study, we assessed whether loss of P2X7 receptor function results in changes to adipocyte distribution and lipid accumulation in vivo. Male P2X7 loss-of-function (KO) mice exhibited significantly greater body weight and epididymal fat pad mass than wild-type (WT) mice at 9 months of age. Fat pad adipocytes did not differ in size, consistent with adipocyte hyperplasia rather than hypertrophy. Histological examination revealed ectopic lipid accumulation in the form of adipocytes and/or lipid droplets in several non-adipose tissues of older male KO mice (9-12 months of age). Ectopic lipid was observed in kidney, extraorbital lacrimal gland and pancreas, but not in liver, heart or skeletal muscle. Specifically, lacrimal gland and pancreas from 12-month-old male KO mice had greater numbers of adipocytes in perivascular, periductal and acinar regions. As well, lipid droplets accumulated in the renal tubular epithelium and lacrimal acinar cells. Blood plasma analyses revealed diminished total cholesterol levels in 9- and 12-month-old male KO mice compared with WT controls. Interestingly, no differences were observed in female mice. Moreover, there were no significant differences in food consumption between male KO and WT mice. Taken together, these data establish novel in vivo roles for the P2X7 receptor in regulating adipogenesis and lipid metabolism in an age- and sex-dependent manner.

Kallikrein-related peptidase 10 expression in salivary gland tissues and tumours.

OBJECTIVES: Kallikrein-related peptidase 10 (KLK10) has been implicated in the development of several types of cancer. The purpose of this study was to analyze the expression of KLK10 in 3 types of salivary gland tumour and normal salivary glands. MATERIALS AND METHODS: A standard immunoperoxidase staining technique was used to assess the immunoexpression profile of KLK10 in normal salivary glands and 3 types of salivary gland tumour: pleomorphic adenoma, adenoid cystic carcinoma and mucoepidermoid carcinoma. RESULTS: Pleomorphic adenomas showed significantly lower KLK10 levels than control tissues. Neither of the malignant tumours (adenoid cystic carcinoma and mucoepidermoid carcinoma) showed a significant alteration in the immunoreactive scores of KLK10 in comparison with the normal salivary gland tissues. KLK10 immunoreactive scores were comparable in adenoid cystic carcinoma and mucoepidermoid carcinoma. Pleomorphic adenoma had significantly lower levels of KLK10 than mucoepidermoid carcinoma. CONCLUSIONS: The finding of lower KLK10 levels in pleomorphic adenoma suggests aberrant expression in a tumour that develops primarily from myoepithelial cells. A kallikrein cascade may play a role in the development and/or outcome of some salivary gland tumours.

Hodgkin lymphoma of the oral mucosa.

In this report, we describe a rare case of relapsed nodular sclerosing Hodgkin lymphoma presenting as a lesion of the oral mucosa. Although this is an uncommon clinical scenario, health care professionals should be aware of this possibility. A brief differential diagnosis and review of Hodgkin lymphoma is discussed.

Markers of potential malignancy in chronic hyperplastic candidiasis.

AIM: To examine the presence of markers associated with malignancy, including p53, p21 cyclin-dependent kinase inhibitor 1A, murine double minutes-2, and others, in chronic hyperplastic candidiasis. METHODS: Immunohistochemical methods were used to examine the expression of p53, murine double minutes-2, p21 cyclin-dependent kinase inhibitor 1A, metallothionein, and proliferating cell nuclear antigen in 42 chronic hyperplastic candidiasis lesions and 11 non-infected control tissues. Terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP nick-end labeling was used to examine apoptosis, which was correlated with p53 expression. These markers were measured in lesions of chronic hyperplastic candidiasis that did not show any epithelial dysplasia or histological signs of malignancy. RESULTS: p53 scores were higher in chronic hyperplastic candidiasis than in controls (P = 0.0046). Murine double-minutes 2 levels were not elevated. p21 cyclin-dependent kinase inhibitor 1A was increased in parabasal (P < 0.0001) and basal epithelial cells. Chronic hyperplastic candidiasis lesions showed a similar basal/parabasal metallothionein staining pattern to that seen in normal squamous epithelium. Proliferating cell nuclear antigen was increased (P = 0.0007), as was apoptosis (P = 0.0033). CONCLUSION: Increased p53 in oral chronic hyperplastic candidiasis suggests an increased potential for malignant change in the epithelium, above that of normal tissues. Further functional investigation is required, as well as clinical follow-up studies.

Oral elastofibromatous lesions: a review and case series.

Elastofibromas of the oral cavity are rare, with only 5 cases reported. In this paper, we present a series of five new cases of oral elastofibromatous lesions, occurring in 4 males and 1 female, with ages ranging from 33 to 76 years. The clinical differential diagnosis includes fibroepithelial polyp or fibroma, among other connective tissue tumours. Elastofibromas probably develop as reactive lesions, for which surgical treatment is definitive.

Metastases to the mouth and jaws: a contemporary Canadian experience.

BACKGROUND AND OBJECTIVE: The types of cancers that most frequently metastasize to the mouth and jaws reflect, for the most part, the relative incidence of cancers in a given population at a given time. We report a retrospective, but relatively contemporary study of 38 cases of metastatic oral tumours in a Canadian population to compare the Canadian experience with that of nearby and distant countries. METHODS: Thirty-eight cases of metastatic disease to the mouth and jaws in a Canadian population were analyzed. Data about patients' age, sex, site of metastatic deposits, clinical history, including the presence of a known primary cancer, and radiographic features were collected from the files (1992-2010) of the oral pathology diagnostic service at the University of Western Ontario, and the hospital archives (2002-2010) of the department of pathology, London Health Sciences Centre, London, Ontario. RESULTS: Most metastases were to the mandible, although oral soft tissues were also involved, most frequently, the gingiva and mucosa of the alveolar ridge. Prostate, lung and breast cancers were the most common primary sites, but a variety of cancer types were found. CONCLUSIONS: The relative frequency of types of metastatic cancer to the oral region is similar in Canada, the United States and Northern Europe, but differs significantly from those reported in South East Asia and Japan. The relative frequency of types of cancer that metastasize to the mouth and jaws reflects the relative incidence of cancers in the population.

Oral metastatic hepatocellular carcinoma: a changing demographic in Europe and North America. Immunohistochemical advances in the microscopic diagnosis.

The incidence of hepatocellular carcinoma has shown an alarming increase in North America and Europe since 1980, as has the incidence of reported metastases to the oral region. Consequently, it is important that head and neck health care specialists be familiar with recent epidemiological trends and the histologic and recent immunohistochemical advances in the diagnosis of this deadly malignancy. Histologic features are reviewed, and recent advances in the immunohistochemical differential diagnosis are detailed and illustrated in two cases. A panel of immunohistochemical stains is recommended, some or all of which may be useful to differentiate poorly differentiated or pseudoglandular hepatocellular carcinoma from other metastatic adenocarcinomas to the oral and maxillofacial region.

Human kallikrein 14 (KLK14) expression in salivary gland tumors.

OBJECTIVE: To analyze the expression of human kallikrein 14 (KLK14) in salivary gland tumors. METHODS: A standard immunoperoxidase staining technique was used to assess the expression profile of KLK14 in normal salivary glands and tumors including pleomorphic adenoma (PA; n=17), adenoid cystic carcinoma (ACC; n=13) and mucoepidermoid carcinoma (MEC; n=9). Tumor stage, grade, patient age and gender, and site of occurrence were recorded. These clinical parameters were correlated with KLK14 levels in malignant tumors. The expression profiles for KLK3, 5, 6, 8 and 13 were also retrieved. RESULTS: Normal salivary glands, PA, ACC and MEC showed strong expression of KLK14 in ductal and non-ductal cells. Both PA and ACC showed higher KLK14 levels than normal glands and MEC tissues. There were no statistically significant associations between levels of KLK14 and clinical parameters. CONCLUSIONS: The differences in the levels of KLK14 suggest that KLKs may aid in the differential diagnosis of salivary gland tumors. The coexpression of KLKs suggests their possible involvement in an enzymatic pathway activated in salivary gland. KLK14 may be a promising new biomarker in salivary gland tumors.

Benign Triton tumor of the tongue.

A case of the extremely rare benign Triton tumor of the tongue is presented. This article presents new observations concerning associated hyperelastosis, the recognition of 2 distinct clinicopathological variants, and a new theory concerning pathogenesis that more closely fits current clinical and histopathological observations.

Human kallikrein 8 expression in salivary gland tumors.

The human kallikrein 8 protein (KLK8) is expressed in many normal tissues including esophagus, skin, testis, tonsil, kidney, breast, and salivary gland, and is found in biological fluids including breast milk, amniotic fluid, seminal fluid and serum. It has also been shown to be a biomarker and prognostic factor for breast cancer. The aim of this study was to determine whether KLK8 is expressed in salivary gland tissues and salivary gland tumors (both benign and malignant), in order to compare normal with tumor tissues. Pleomorphic adenomas, adenoid cystic carcinomas, polymorphous low grade adenocarcinomas, acinic cell carcinomas, mucoepidermoid carcinomas, and adenocarcinomas NOS of both minor and major salivary glands were examined. The results of this study indicate that most salivary gland tumors show high levels of expression of KLK8.

Juvenile spongiotic gingivitis.

BACKGROUND: This article recognizes the microscopic diagnosis of acute spongiotic mucositis as an analog to acute spongiotic dermatitis of the skin and defines a specific clinicopathological entity "juvenile spongiotic gingivitis" within this microscopic spectrum. METHODS: Twenty-four patients, usually juveniles, with patches of bright red, often slightly thickened, painless, and persistent lesions of the attached gingiva, which may or may not involve the marginal gingiva, were identified by clinical and microscopic features. Immunohistochemical studies for cytokeratins 5/6 and 19, estrogen receptors, and progesterone receptors were completed on 10 of these cases. A comparison to puberty gingivitis, which occurs in the same age group, was done. RESULTS: Microscopically, the epithelium exhibited hyperplasia, significant spongiosis, loss of keratinization, and a neutrophilic infiltrate, sometimes with microabscess formation, whereas the underlying connective tissue exhibited an acute on chronic inflammatory infiltrate. Full-thickness epithelial immunostaining for cytokeratins 5/6 and 19 was found, whereas no reactivity was seen for estrogen receptors or progesterone receptors in the specimens. CONCLUSIONS: Juvenile spongiotic gingivitis differs from puberty gingivitis by not needing to show continuity with plaque-related marginal gingivitis, by a lack of response to hygiene procedures, by an occasional occurrence at ages not related to puberty, and by the absence of sex hormone receptors investigated immunohistochemically in 10 of the cases. We propose juvenile spongiotic gingivitis as a distinct clinicopathological entity.