Oral Lesions Associated with Systemic Disease.

Oral manifestations may be the first sign of a systemic disease, or represent lesions associated with an established or recurrent disease. Oral health care providers are often the first to recognize these signs. Some lesions have characteristic features that allow for early detection and intervention. On the contrary, clinical manifestations may be diverse and require a comprehensive evaluation to establish a definitive diagnosis. This article reviews the oral manifestations of select systemic diseases to help clinicians develop a differential diagnosis that leads to early diagnosis and timely intervention.

Proliferative Verrucous Leukoplakia: An Expert Consensus Guideline for Standardized Assessment and Reporting.

The many diverse terms used to describe the wide spectrum of changes seen in proliferative verrucous leukoplakia (PVL) have resulted in disparate clinical management. The objective of this study was to produce an expert consensus guideline for standardized assessment and reporting by pathologists diagnosing PVL related lesions. 299 biopsies from 84 PVL patients from six institutions were selected from patients who had multifocal oral leukoplakic lesions identified over several years (a minimum follow-up period of 36 months). The lesions demonstrated the spectrum of histologic features described in PVL, and in some cases, patients developed oral cavity squamous cell carcinoma (SCC). An expert working group of oral and maxillofacial and head and neck pathologists reviewed microscopic features in a rigorous fashion, in combination with review of clinical photographs when available. The working group then selected 43 single slide biopsy cases for whole slide digital imaging (WSI) review by members of the consensus conference. The digital images were then reviewed in two surveys separated by a washout period of at least 90 days. Five non-PVL histologic mimics were included as controls. Cases were re-evaluated during a consensus conference with 19 members reporting on the cases. The best inter-observer diagnostic agreement relative to PVL lesions were classified as "corrugated ortho(para)hyperkeratotic lesion, not reactive" and "SCC" (chi-square p = 0.015). There was less than moderate agreement (kappa < 0.60) for lesions in the "Bulky hyperkeratotic epithelial proliferation, not reactive" category. There was ≥ moderate agreement (> 0.41 kappa) for 35 of 48 cases. This expert consensus guideline has been developed with support and endorsement from the leadership of the American Academy of Oral and Maxillofacial Pathology and the North American Society of Head and Neck Pathologists to recommend the use of standardized histopathologic criteria and descriptive terminology to indicate three categories of lesions within PVL: (1) "corrugated ortho(para)hyperkeratotic lesion, not reactive;" (2) "bulky hyperkeratotic epithelial proliferation, not reactive;" and (3) "suspicious for," or "squamous cell carcinoma." Classification of PVL lesions based on a combination of clinical findings and these histologic descriptive categories is encouraged in order to standardize reporting, aid in future research and potentially guide clinical management.

Marginal linear gingival leukoplakia progressing to "ring around the collar"-An ominous sign of proliferative verrucous leukoplakia.

BACKGROUND: Potentially malignant lesions of the gingiva may frequently present as well-demarcated white lesions confined to the marginal gingiva. These lesions often become thick and verrucoid and spread along the marginal gingiva to encircle the tooth. Some cases of marginal gingival leukoplakia, over time, progress to extensively involve the gingiva fulfilling the criteria for proliferative verrucous leukoplakia (PVL). The objective of this study is to raise awareness of this pattern of leukoplakia by reporting a series of cases of marginal gingival leukoplakia. METHODS: An Institutional Review Board approved retrospective search of University of Florida and University of Nebraska Medical Center oral biopsy services was performed for all gingival biopsies. Inclusion criteria included cases exhibiting marginal gingival leukoplakia, and with accompanying clinical images. RESULTS: A total of 30 cases of marginal gingival leukoplakia were included. All cases presented as well-demarcated leukoplakias, either on the buccal or lingual gingival margin, or circumferentially forming a "ring around the collar" of single or multiple teeth. Eight patients had recurrent lesions and 12 had multifocal involvement. Six of the 12 patients with multifocal involvement presented with a "ring around the collar." The histopathologic diagnoses were representative of benign lesions in seven cases, premalignant in 13, and malignant or suggestive of malignancy in 10 cases. Seven patients had carcinoma at the time of first biopsy, whereas 6 cases showed progression at time of follow-up. CONCLUSION: This study aims to raise awareness that marginal gingival leukoplakia may represent potentially malignant lesions, and if circumferential and/or thick, may be the first manifestation of PVL.

Squamous Odontogenic Tumor: Review of the Literature and Report of a New Case.

PURPOSE: Squamous odontogenic tumor (SOT) is a rare, benign, locally infiltrative odontogenic tumor of the gnathic bones. It is composed of islands of bland, well-differentiated squamous epithelium of varying shape and size. Because of histologic overlap, SOT has often been overdiagnosed as ameloblastoma and squamous cell carcinoma. It thus becomes important to understand the clinical, radiologic, histopathologic, and treatment characteristics of this tumor. MATERIALS AND METHODS: Using the PubMed and Google Scholar databases, we searched for reported cases of SOT published in the English-language literature. We were able to retrieve 49 acceptable cases and perform a comprehensive literature review of the intraosseous SOTs, with emphasis on their clinical, radiographic, and pathologic characteristics, as well as treatment strategies. In addition, we present an additional case of SOT affecting the posterior mandible in a 44-year-old female patient. RESULTS: The tumor in the posterior mandible in our patient was accompanied by acute pain and treated by enucleation. Histopathologic evaluation showed variably sized islands of benign squamous epithelium scattered in a fibrous stroma, consistent with the diagnosis of an SOT. Uneventful healing was noted at the 1-month postoperative appointment. However, the patient was lost to long-term follow-up. Our literature review showed that the average age at the time of diagnosis of SOT is 34.2 years. Men and women are equally affected, and the tumor does not show a predilection for either jaw bone. The most common locations are the anterior maxilla and posterior mandible. Most SOTs are treated conservatively by enucleation or curettage, whereas aggressive or recurrent tumors require radical resection. CONCLUSIONS: Careful evaluation of the excised specimen, with immunohistochemical investigations, may prove rewarding in differentiating an SOT from other odontogenic neoplasms and thus minimize the patient's chances of undergoing an unnecessary aggressive intervention.

Inter-observer Variability in the Diagnosis of Proliferative Verrucous Leukoplakia: Clinical Implications for Oral and Maxillofacial Surgeon Understanding: A Collaborative Pilot Study.

The use of diverse terminology may lead to inconsistent diagnosis and subsequent mistreatment of lesions within the proliferative verrucous leukoplakia (PVL) spectrum. The objectives of this study were: (a) to measure inter-observer variability between a variety of pathologists diagnosing PVL lesions; and (b) to evaluate the impact of diverse terminologies on understanding, interpretation, and subsequent treatment planning by oral and maxillofacial surgeons (OMFS). Six oral pathologists (OP) and six head and neck pathologists (HNP) reviewed 40 digitally scanned slides of PVL-type lesions. Inter-observer agreement on diagnoses was evaluated by Fleiss' kappa analysis. The most commonly used diagnostic terminologies were sent to ten OMFS to evaluate their resulting interpretations and potential follow-up treatment approaches. The overall means of the surgeons' responses were compared by Student t test. There was poor inter-observer agreement between pathologists on the diagnosis of PVL lesions (κ = 0.270), although there was good agreement (κ = 0.650) when diagnosing frankly malignant lesions. The lowest agreement was in diagnosing verrucous hyperplasia (VH) with/without dysplasia, atypical epithelial proliferation (AEP), and verrucous carcinoma (VC). The OMFS showed the lowest agreement on identical categories of non-malignant diagnoses, specifically VH and AEP. This study demonstrates a lack of standardized terminology and diagnostic criteria for the spectrum of PVL lesions. We recommend adopting standardized criteria and terminology, proposed and established by an expert panel white paper, to assist pathologists and clinicians in uniformly diagnosing and managing PVL spectrum lesions.

A Retrospective 20-Year Analysis of Proliferative Verrucous Leukoplakia and Its Progression to Malignancy and Association with High-risk Human Papillomavirus.

Proliferative verrucous leukoplakia (PVL) is defined as an aggressive, relentless and recalcitrant form of leukoplakia that has a high propensity for malignant transformation. The aim of this study was to evaluate the malignant potential of PVL and determine its possible association with high-risk human papillomavirus (HPV). Twenty cases with a clinical and biopsy proven diagnosis of PVL were collected from the University of Florida Oral Medicine clinic database. Immunohistochemistry was performed to evaluate the expression of p16INK4A and p53 genes in the PVL lesions. The lesions were also tested for high-risk HPV by DNA in-situ hybridization. The average age of the patients at the time of first biopsy was 62.7 years. Most patients had multiple sites of involvement, gingiva being the most common location. The lesions progressed to malignancy in approximately 50% of patients. The expression of p16INK4A gene was considered negative, with at least a 50-65% immunoreactivity observed in only three cases that progressed to malignancy. No expression of high-risk HPV was detected, whereas p53 staining was positive in less than 25% of the cells demonstrating gene expression. No definite association between PVL and high-risk HPV infection could be established. Due to the high transformation potential of PVL, early recognition with aggressive treatment, including multiple biopsies, and continued close clinical follow-up, remain the mainstay of favorable management of this condition.

Hybrid Central Odontogenic Fibroma with Giant Cell Granuloma like Lesion: A Report of Three Additional Cases and Review of the Literature.

Central odontogenic fibroma (COF) is an uncommon intraosseous neoplasm of the gnathic bones which is composed of fibrous connective tissue, with or without calcifications, and variable amounts of inactive odontogenic epithelium. It makes up less than 5% of odontogenic tumors and is more commonly seen in females. Central giant cell granuloma (CGCG) is a locally destructive but benign lesion of the jaws containing osteoclast-like multinucleated giant cells in a fibrovascular stroma. CGCG makes up approximately 10% of all benign jaw tumors and typically occurs in females younger than 30 years of age. A hybrid lesion with histologic features of both COF and CGCG is very rare and was first described in 1992. To date, fewer than 50 cases of this lesion have been reported. In this study, we present three additional cases of COF developing in conjunction with giant cell granuloma-like lesion, as well as provide a comprehensive literature review. Two of the lesions presented in our study were located in the posterior mandible and one occurred in the anterior mandible. Buccal and/or lingual expansion was noted in two patients and no recurrence was reported. Histologically, all three lesions demonstrated a blend of odontogenic epithelial islands with numerous multinucleated giant cells in a highly cellular connective tissue stroma. Immunohistochemical staining with CK19 and CD68 highlighted the odontogenic epithelium and multinucleated giant cells respectively. The precise nature of these hybrid lesions remains obscure and additional molecular studies may be of help in understanding their pathogenesis.

Peripheral Ameloblastoma: A Study of 18 Cases and Usage of Ber-EP4 Immunohistochemistry to Rule out a Diagnosis of Intraoral Basal Cell Carcinoma.

PURPOSE: Peripheral ameloblastoma (PA) is a rare odontogenic tumor arising in the mucosa of tooth-bearing areas of the jaws that typically shows no radiographic evidence of bone involvement. It bears close histologic resemblance to intraoral basal cell carcinoma (IOBCC), an extremely rare entity. In our experience from previous published data, 3 cases of IOBCC were initially misdiagnosed as PA and were later differentiated from PA on the basis of Ber-EP4 protein expression. This unusual but significant experience set the premise for us to rule out a diagnosis of IOBCC by evaluating Ber-EP4 expression in all previously diagnosed cases of PA from the University of Florida Oral Pathology (UFOP) biopsy service archives. MATERIALS AND METHODS: With institutional review board approval, 18 cases of PA were retrieved from the UFOP biopsy service archives. We describe the clinicopathologic features of these cases and discuss the Ber-EP4 immunohistochemical staining performed to rule out a potential diagnosis of IOBCC. In addition, we conducted calretinin and epithelial membrane antigen staining for 1 case of PA. RESULTS: Most PAs presented in the lingual gingiva of the posterior mandible. Men were affected twice as often as women, and the average age at the diagnosis was 59 ± 21.5 years. Of the 18 lesions, 13 showed no reactivity to Ber-EP4, 4 displayed patchy membranous immunoreactivity, and 1 demonstrated nonspecific reactivity. CONCLUSIONS: We have concluded that all cases of PA that present with histologic overlap with basal cell carcinoma, especially those from incisional biopsies, those that appear significantly infiltrative, and those that appear ulcerated and/or demonstrate recurrence should be evaluated with Ber-EP4 to rule out IOBCC.

Papillon-Lefèvre syndrome: A series of three cases in the same family and a literature review.

Papillon-Lefèvre syndrome (PLS) is a rare autosomal recessive disorder that exhibits palmoplantar keratosis and early severe periodontitis. The oral disease affects both the primary and permanent dentitions leading to premature exfoliation of teeth. Various etiologic factors, such as genetic mutations, immunologic alterations, and bacteria have been implicated in PLS. Genetic mutations leading to the loss of function of cathepsin C (CTSC) gene, located on chromosome 11q14, is considered pivotal in this condition. The present case series describes PLS in three siblings, with consanguineously married parents, who live in a remote area of Yemen. The affected children presented with prominent palmoplantar keratosis and early periodontitis with only a few remaining teeth. The severity of skin lesions in all patients exhibited seasonal variations. Based on their clinical findings, a diagnosis of PLS was made. Dentists have a significant role in the early diagnosis and management of PLS patients.