Diagnostic delay in autoimmune oral diseases.

Autoimmune diseases (ADs) affect about 5% of the general population, causing various systemic and/or topical clinical manifestations. The oral mucosa is often affected, sometimes as the only involved site. The misdiagnosis of oral ADs is an underreported issue. This narrative review focuses on diagnostic delay (DD) in oral ADs (oral lichen planus [OLP], oral Pemphigus Vulgaris, mucous membrane pemphigoid, oral lupus erythematosus, orofacial granulomatosis, oral erythema multiforme [EM], and Sjogren syndrome). Extensive literature research was conducted via MEDLINE, Embase and Google Scholar databases for articles reporting the time spent to achieve the correct diagnosis of oral ADs. Only 16 studies reported DD in oral ADs. Oral autoimmune vesiculobullous diseases are usually diagnosed after 8 months from the initial signs/symptoms, the Sjogren Syndrome diagnosis usually requires about 73 months. No data exist about the DD in OLP, oral lupus erythematosus, orofacial granulomatosis, and oral EM. The diagnosis of oral ADs can be difficult due to the non-specificity of their manifestations and the unawareness of dentists, physicians, and dental and medical specialists about these diseases. This can lead to a professional DD and a consequential treatment delay. The delay can be attributed to the physicians or/and the healthcare system (Professional Delay) or the patient (Patient's Delay).

Oral leukoplakia, the ongoing discussion on definition and terminology.

In the past decades several definitions of oral leukoplakia have been proposed, the last one, being authorized by the World Health Organization (WHO), dating from 2005. In the present treatise an adjustment of that definition and the 1978 WHO definition is suggested, being : "A predominantly white patch or plaque that cannot be characterized clinically or pathologically as any other disorder; oral leukoplakia carries an increased risk of cancer development either in or close to the area of the leukoplakia or elsewhere in the oral cavity or the head-and-neck region". Furthermore, the use of strict diagnostic criteria is recommended for predominantly white lesions for which a causative factor has been identified, e.g. smokers' lesion, frictional lesion and dental restoration associated lesion. A final diagnosis of such leukoplakic lesions can only be made in retrospect after successful elimination of the causative factor within a somewhat arbitrarily chosen period of 4-8 weeks. It seems questionable to exclude "frictional keratosis" and "alveolar ridge keratosis" from the category of leukoplakia as has been suggested in the literature. Finally, brief attention has been paid to some histopathological issues that may cause confusion in establishing a final diagnosis of leukoplakia.

Disease scoring systems for oral lichen planus; a critical appraisal.

The aim of the present study has been to critically review 22 disease scoring systems (DSSs) on oral lichen planus (OLP) that have been reported in the literature during the past decades. Although the presently available DSSs may all have some merit, particularly for research purposes, the diversity of both the objective and subjective parameters used in these systems and the lack of acceptance of one of these systems for uniform use, there is a need for an international, authorized consensus meeting on this subject. Because of the natural course of OLP characterized by remissions and exacerbations and also due to the varying distribution pattern and the varying clinical types, e.g. reticular and erosive, the relevance of a DSS based on morphologic parameters is somewhat questionable. Instead, one may consider to only look for a quality of life scoring system adapted for use in OLP patients.

Granular cell tumor of the oral cavity; a case series including a case of metachronous occurrence in the tongue and the lung.

The granular cell tumor (GCT) is a rare, benign tumor that most commonly occurs in the oral cavity, particularly in the anterior part of the tongue. In this study the experience with 16 patients with a GCT observed in a single Institution will be discussed. Although no radicality has been obtained in most cases, recurrences are rare. In one patient, a recurrence was noted four years after excision of the primary. In the same patient a pulmonary lesion occurred five years after excision of the recurrence in the oral cavity, most likely representing an example of metachronous occurrence and not a distant metastasis. Since recurrences and metachronous lesions are rare, as are distant metastases, routine follow-up does not seem warranted in patients treated for a granular cell tumor of the oral cavity.

Oral potentially malignant disorders: is malignant transformation predictable and preventable?

Leukoplakia is the most common potentially malignant disorder of the oral mucosa. The prevalence is approximately 1% while the annual malignant transformation ranges from 2% to 3%. At present, there are no reliable clinicopathological or molecular predicting factors of malignant transformation that can be used in an individual patient and such event can not truly be prevented. Furthermore, follow-up programs are of questionable value in this respect. Cessation of smoking habits may result in regression or even disappearance of the leukoplakia and will diminish the risk of cancer development either at the site of the leukoplakia or elsewhere in the mouth or the upper aerodigestive tract. The debate on the allegedly potentially malignant character of oral lichen planus is going on already for several decades. At present, there is a tendency to accept its potentially malignant behaviour, the annual malignant transformation rate amounting less than 0.5%. As in leukoplakia, there are no reliable predicting factors of malignant transformation that can be used in an individual patient and such event can not truly be prevented either. Follow-up visits, e.g twice a year, may be of some value. It is probably beyond the scope of most dentists to manage patients with these lesions in their own office. Timely referral to a specialist seems most appropriate, indeed.

Epidemiology of ameloblastomas of the jaws; a report from the Netherlands.

OBJECTIVES: To provide epidemiological data of ameloblastomas of the jaws in the Netherlands over a 25-year time period (1985-2010) and to compare these data with data from other parts of the world. MATERIAL AND METHODS: The data of all patients diagnosed with a primary ameloblastoma of the jaws in the Netherlands in the period 1985-2010 have been retrieved from the nationwide histopathology and cytopathology network and registry in the Netherlands (PALGA). The pathology reports were screened and only those cases were included in which a distinct diagnosis of primary, histopathologically benign, intraosseous ameloblastoma was rendered. The average population in The Netherlands during this period amounted approximately 15 million people. RESULTS: An annual incidence rate was approximately 1,5 per million population, the male-female ratio being 1.4: 1. The age at the time of diagnosis was 44.1 years. The average age in males was 46.3 years compared to an average age in females of 41.3 years, the difference being significant (p≤ 0.05). The results were compared with those available in only a small number of publications worldwide. CONCLUSIONS: There is no strong evidence for significant differences of the true incidence of ameloblastomas worldwide, neither for a gender predilection. The diagnosis is generally made at a somewhat lower age in women; this phenomenon is even much stronger in the Black population, irrespective of gender. No proper explanation for this finding can be provided.

Proposal for a new staging system for osteoradionecrosis of the mandible.

A new staging system for osteoradionecrosis of the mandible has been retrospectively applied to a group of 31 patients. In this system clinicoradiographic signs and symptoms are incorporated in a simplified manner. For imaging purposes the use of plain radiographs such as periapical films and panoramic radiographs is recommended, mainly because of their readily availability. The presented staging system seems well reproducible, facilitating the comparison of study groups dealing with the various issues of osteoradionecrosis of the mandible. It is yet to be evaluated whether the presently proposed staging system is useful for management purposes.

The role of a labial salivary gland biopsy in the diagnostic procedure for Sjögren's syndrome; a study of 94 cases.

OBJECTIVES: The purpose of the present study is to examine the role of the outcome of the labial salivary gland biopsy (LSGB) in the diagnostic procedure of patients suspected of suffering from Sjögren's syndrome (SS). MATERIAL AND METHODS: In a retrospective study the result of histopathological assessment of 94 consecutively taken labial salivary gland biopsies has been examined. For the diagnosis of SS the American-European Consensus Group classification (AECG, 2002) have been used. The outcome of the assessment has been discussed in relation to a recently reported classification provided by the American College of Rheumatology (ACR, 2012). RESULTS: In the 94 LSGBs support for a diagnosis of SS has been encountered in 24 out of 26 patients with SS. In the 68 patients with a negative diagnosis of SS only six positive LSGBs were observed. The sensitivity of the labial biopsy amounted 0.92; the specificity was 0.91, while the positive predictive value and the negative predictive value amounted 0.80 and 0.97 respectively. LSGBs taken by or on the request of the departments of Rheumatology or Internal Medicine had a significant higher yield compared to LSGBs taken in other clinical departments. CONCLUSIONS: The LSGB may play a role in the diagnostic procedure of Sjögren's syndrome when using either the AECG classification or the ACR classification. A LSGB should preferably taken after counseling for the possible presence of SS by a department of Rheumatology or Internal Medicine since the yield of such biopsies is much higher than in patients who have not been counseled by these departments prior to the taking of a LSGB. When using the ACR classification, a positive serologic result and a positive ocular test make the taking of a LSGB redundant. Only in case of a negative serologic outcome or a negative result of the ocular test a LSGB is indicated. Since both the serologic test and the ocular test carry hardly any morbidity, these tests should, indeed, be performed first before considering to take a LSGB.

Are we able to reduce the mortality and morbidity of oral cancer; some considerations.

Oral cancer makes up 1%-2% of all cancers that may arise in the body. The majority of oral cancers consists of squamous cell carcinomas. Oral cancer carries a considerable mortality rate, being mainly dependent on the stage of the disease at admission. Worldwide some 50% of the patients with oral cancer present with advanced disease. There are several ways of trying to diagnose oral cancer in a lower tumor stage, being 1) mass screening or screening in selected patients, 2) reduction of patients' delay, and 3) reduction of doctors' delay. Oral cancer population-based screening ("mass screening") programs do not meet the guidelines for a successful outcome. There may be some benefit when focusing on high-risk groups, such as heavy smokers and heavy drinkers. Reported reasons for patients' delay range from fear of a diagnosis of cancer, limited accessibility of primary health care, to unawareness of the possibility of malignant oral diseases. Apparently, information campaigns in news programs and TV have little effect on patients' delay. Mouth self-examination may have some value in reducing patients'delay. Doctors' delay includes dentists' delay and diagnostic delay caused by other medical and dental health care professionals. Doctors' delay may vary from almost zero days up to more than six months. Usually, morbidity of cancer treatment is measured by quality of life (QoL) questionnaires. In the past decades this topic has drawn a lot of attention worldwide. It is a challenge to decrease the morbidity that is associated with the various treatment modalities that are used in oral cancer without substantially compromising the survival rate. Smoking cessation contributes to reducing the risk of oral cancers, with a 50% reduction in risk within five years. Indeed, risk factor reduction seems to be the most effective tool in an attempt to decrease the morbidity and mortality of oral cancer.

Clinicopathological evaluation of 164 dental follicles and dentigerous cysts with emphasis on the presence of odontogenic epithelium in the connective tissue. The hypothesis of "focal ameloblastoma".

OBJECTIVES: Some ameloblastomas presumably originate from odontogenic epithelium within the connective tissue of dental follicles and dentigerous cysts. Therefore, it would seem reasonable to discuss as whether odontogenic epithelium proliferations, frankly displaying ameloblastomatous features ("focal ameloblastoma"), should be considered as an "early" ameloblastoma. STUDY DESIGN: Histopathological reports from 164 dental follicles and dentigerous cysts from the Department of Oral and Maxillofacial Surgery/Oral Pathology of the VU Free University medical center in Amsterdam, The Netherlands, were reviewed. Histopathological slides from 39 cases reporting the presence of odontogenic epithelium within the connective tissue were re-evaluated in order to assess the possible presence of focal ameloblastomas. RESULTS: Focal ameloblastomas were detected in one dental follicle and in two dentigerous cysts. During a follow-up period of 6, 8 and 22 years, respectively, no clinical signs of (recurrent) ameloblastoma have occurred in these patients. CONCLUSIONS: Focal ameloblastoma possibly represents the early stage of ameloblastoma development.

Proliferative verrucous leukoplakia; a critical appraisal of the diagnostic criteria.

Since its introduction in the literature in 1985, the term proliferative verrucous leukoplakia (PVL) has been the subject of an ongoing discussion with regard to its definition. Widespread or multifocal occurrence of oral leukoplakia is not just synonymous to PVL. In the present treatise the proposal is made to require the involvement of more than two oral oral subsites, a total added seizeof the leukoplakic areas of at least 3 centimeters, and a well documented period of at least five years of disease evolution being characterized by spreading and the occurrence of one or more recurrences in a previously treated area.

The relevance of uniform reporting in oral leukoplakia: definition, certainty factor and staging based on experience with 275 patients.

The aim of the present study was to evaluate the definition of oral leukoplakia, proposed by the WHO in 2005 and taking into account a previously reported classification and staging system, including the use of a Certainty factor of four levels with which the diagnosis of leukoplakia can be established. In the period 1997-2012 a hospital-based population of 275 consecutive patients with a provisional diagnosis of oral leukoplakia has been examined. In only 176 patients of these 275 patients a firm diagnosis of leukoplakia has been established based on strict clinicopathological criteria. The 176 patients have subsequently been staged using a classification and staging system based on size and histopathologic features. For use in epidemiological studies it seems acceptable to accept a diagnosis of leukoplakia based on a single oral examination (Certainty level 1). For studies on management and malignant transformation rate the recommendation is made to include the requirement of histopathologic examination of an incisional or excisional biopsy, representing Certainty level 3 and 4, respectively. This recommendation results in the following definition of oral leukoplakia: "A predominantly white lesion or plaque of questionable behaviour having excluded, clinically and histopathologically, any other definable white disease or disorder". Furthermore, we recommend the use of strict diagnostic criteria for predominantly white lesions for which a causative factor has been identified, e.g. smokers' lesion, frictional lesion and dental restoration associated lesion.

Histopathology of ameloblastoma of the jaws; some critical observations based on a 40 years single institution experience.

The aim of the present study is to examine all cases of intraosseous benign ameloblastomas treated between 1970 and 2010 in a single institution and to look for a possible correlation between the histopathological aspects and the demographical and clinical parameters, as well as the treatment outcome. The data of a total number of 44 patients were retrieved from the records. Nine patients were excluded because of doubt about the correct diagnosis (8 patients) or because of an extra-osseous presentation (1 patient). No statistically significant differences were found between the histopathological (sub)types of ameloblastomas and the demographical and clinical parameters, nor between the histopathological (sub)types and treatment outcome. Of the 28 patients treated by enucleation, in 17 patients one or more recurrences occurred, with no significant predilection for any histopathological (sub)type, including the unicystic type. There were no significant differences in the recurrence rate after enucleation in patients below and above the age of 20 years either. In six out of 17 patients with a recurrence, the recurrent lesion showed a different histopathological subtype than was encountered in the primary. In two cases a change from solid/multicystic to desmoplastic ameloblastomas was noticed. In conclusion, the current histopathological classification of benign intraosseous ameloblastoma does not seem to have clinical relevance with the possible exception of the luminal unicystic ameloblastoma that has been removed in toto, unfragmented. Since no primary desmoplastic ameloblastomas were encountered in the present study no further comments can be made on this apparently rare entity.

Oral lichen planus and the p53 family: what do we know?

Oral lichen planus (OLP) is a relatively common chronic disease of the oral mucosa for which the aetiopathogenesis is not fully understood. It mainly affects middle aged and elderly. The finding of autoantibodies against p63, a member of the p53 family, is a strong indication of autoimmunity as a causative or contributing factor. The WHO classified OLP as a potentially malignant disorder, but still there is an ongoing debate in the literature on this subject. The TP53 gene encodes a tumour suppressor protein that is involved in induction of cell-cycle arrest or apoptosis of DNA-damaged cells. The p63 gene encodes six different proteins that are crucial for formation of the oral mucosa and skin. The coordinated stabilization of p53 and decreased expression of p63 seen in OLP cause induction of apoptosis enabling removal of DNA-damaged cells. In view of the complexity of cancerogenesis, no firm statement can at present be made about the relevance of the observed relationship between p53 and p63 and the possible malignant transformation of OLP.

Potential relevance of cyclooxygenase-2 expression in keratocystic odontogenic tumours - an immunohistochemical study.

There is increasing evidence that overexpression of cyclooxygenase-2 (COX-2) plays an important role in tumour growth and spread of tumours by interfering with cell proliferation, cellular adhesion, immune surveillance, apoptosis, and angiogenesis. COX-2 levels are increased in various tumours. In this study, the expression of COX-2 in 116 specimens of keratocystic odontogenic tumours (KCOT) has been analyzed. KCOT is a benign neoplasm of odontogenic origin with an occasionally aggressive behavior leading to high recurrence rates. Formalin-fixed, paraffin-embedded blocks were sectioned and used for hematoxylin-eosin (H&E) staining and incubated with an anti-COX-2 monoclonal antibody for immunohistochemical examination. Detection of the COX-2 antibody was performed with the EnVision kit. Cellular staining pattern for COX-2 was cytoplasmatic, and the staining intensities were semi-quantitatively evaluated as follows: negative (-), mild (±) or strong (+). Mild to strong expression of COX-2 was observed in 83 (71.6%) cases; 34 (29.3%) of which were mild positive and 49 (42.2%) were strong positive. COX-2 stain was detected mainly in the epithelial lining. The expression of COX-2 in KCOT and the current knowledge of the role played by COX-2 in tumorigenesis further strengthen the current concept that the KCOT should be regarded as a neoplasm. Furthermore, the multitude of markers known to be overexpressed in KCOTs is suggestive of what could be called a 'network addiction' pattern, rather than a pathological mechanism dependant on a specific activated/suppressed gene, thus explaining its aggressive behavior.

Primary intraosseous squamous cell carcinoma arising in an odontogenic cyst: a clinicopathologic analysis of 116 reported cases.

PURPOSE: To review the literature on primary intraosseous squamous cell carcinoma (PIOSCC) associated with odontogenic cyst. METHODS: All well-documented cases of PIOSCC published between 1938 and 2010 were collected. Only cases of PIOSCC arising from the lining of an odontogenic cyst, including the keratocystic odontogenic tumor, were selected. Age, sex, signs and symptoms, affected jaw, cyst type, treatment, histopathology, and outcome were recorded. RESULTS: The mean age was 60.2 years (range 1.3-90). There were 80 (69%) men and 36 (31%) women. Mass and pain were the most common presenting symptoms. The mandible was affected in 92 (79%) patients and the maxilla in 24 (21%). It was a residual/radicular cyst in 70 (60%) patients and a dentigerous cyst or a keratocystic odontogenic tumor in the remaining 40%. The histopathology was well-differentiated SCC in 53 (46%) patients and moderately differentiated SCC in 47 (40%) patients. Fifty-three (46%) patients were treated with surgery alone and 44 (38%) with surgery and radiotherapy. Fifty-eight (62%) patients survived 2 years and 36 (38%) survived 5 years. CONCLUSION: PIOSCC has a predilection for men (M/F ratio of 2.22:1), affects mainly adults in their 6-8th decades, occurs most frequently (79%) in the mandible, and is associated mainly with a residual/radicular cyst. Histologically, the well-to-moderately differentiated SCC was the most common. Surgery alone or combined therapy of surgery and radiation was the most common approach. The prognosis is 62% surviving 2 years and 38% 5 years.

Early diagnosis in primary oral cancer: is it possible?

In this treatise oral carcinogenesis is briefly discussed, particularly with regard to the number of cell divisions that is required before cancer reaches a measurable size. At that stage, metastatic spread may have already taken place. Therefore, the term "early diagnosis" is somewhat misleading. The delay in diagnosis of oral cancer is caused both by patients' delay and doctors' delay. The total delay, including scheduling delay, work-up delay and treatment planning delay, varies in different studies, but averages some six months. The total delay is more or less evenly distributed between patients' and doctors' delay and is partly due to the unawareness of oral cancer among the public and professionals, and partly to barriers in the health care system that may prevent patients from seeking dental and medical care. Due to the relatively low incidence of oral cancer it will be difficult to increase the awareness of this cancer type among the public, thereby reducing patients' delay. However, it should be possible to considerably reduce doctors' delay by increasing the awareness of oral cancer among professionals and by improving their diagnostic ability. Population-based annual or semi-annual screening for oral cancer is not cost-effective, high-risk groups such as heavy smokers and drinkers perhaps excluded. Dentists and physicians, and also oral hygienists and nurse practitioners, may play a valuable role in such screening programs.

Oral cancer trends in a single head-and-neck cancer center in the Netherlands; decline in T-stage at the time of admission.

OBJECTIVES: In this study we evaluated the possible epidemiologic changes of oral cancer patients in the Netherlands between the years 1980-1984 and 2000-2004. We specifically studied the differences in male-female ratio, age, TNM-stage, site distribution, and alcohol and tobacco use. MATERIALS AND METHODS: Patients from the VU University Medical Center with an oral squamous cell carcinoma of the oral cavity registered in 1980-1984 (n=200), group 1, were compared to patients registered in 2000-2004 (n=184), group 2. Trends in prevalence, site distribution, TNM-stage, alcohol and tobacco use, age and gender were studied. RESULTS: The male-female ratio has decreased from 1.8 to 1.2. There were no differences in age between the two groups of patients. The site distribution was similar in both groups. The most commonly involved sites were the tongue and the floor of mouth. In group 2 more patients were diagnosed with a T1 tumour. There were no differences in tobacco use between the two different groups. There were much more light drinkers (0-2 drinks per day) in group 2 than in group 1, whereas there were more heavy drinkers (>4 per day) in group 1 than in group 2 (p<0.001). This was observed in both male and female patients. CONCLUSION: In our study there were no significant differences between the patients registered in the years 1980-1984 and 2000-2004 regarding the mean age of the patients, site distribution and smoking habits. The male-female ratio has decreased. In the recent group more patients were staged T1N0 and there was a strong decrease of the patients who were heavy drinkers.

Unilateral condylar hyperactivity: a histopathologic analysis of 47 patients.

PURPOSE: To perform a histopathologic analysis of condyles that were resected because of unilateral condylar hyperactivity and compare the results of the bone scan with the histopathologic findings. PATIENTS AND METHODS: A total of 47 resected condyles were histopathologically examined. In 29 cases, a single photon emission computed tomography (SPECT) bone scan was available. For all condylar specimens, a standardized histologic scoring system was used to assess the number of cartilage islands and the thickness of the cartilage layer. The SPECT scans were analyzed by calculating the difference in bone activity between the hyperactive and contralateral condyles. RESULTS: The number of cartilage islands was highly variable, ranging from almost absent in 37% of the patients to abundant in 35%. Furthermore, the relative thickness of the cartilage layer exhibited considerable variation, from less than one quarter of the total thickness of the condylar articular layer in 22% of the patients to one half of the total thickness in 35%. We found no significant relationship between the number of cartilage islands and bone activity using SPECT (P = .11) or between the relative thickness of the cartilage layer and bone activity using SPECT (P = .82). CONCLUSIONS: Unilateral condylar bone growth can occur without large numbers of cartilage islands and without abundant cartilage formation. The bone activity measured by bone scintigraphy was not related to the histologic results. The histopathologic findings of resected condyles in unilateral condylar hyperactivity cannot, therefore, be used as a reference standard. Nevertheless, histopathologic examination should always be performed to rule out other diseases.