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

Abstract

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.

Keywords: Classification; Consensus; Pathology criteria; Proliferative verrucous leukoplakia; Standardized criteria.

Fig. 1

Corrugated ortho(para)hyperkeratosis, not reactive. a A clinical photograph of a gingival verruciform leukoplakia (white arrow), adjacent to teeth. b Marked orthohyperkeratosis and epithelial corrugation, with the thickness of the hyperkeratosis > 1/2 of the total biopsy thickness. c Marked orthohyperkeratosis, about twice the thickness of the epithelium below. d Corrugated keratosis and corrugated (undulating) epithelium, showing an abrupt (black arrow) transition to the adjacent epithelium showing limited epithelial dysplasia. e Abrupt, sharp transitions and skip zones of orthokeratosis (black arrows) are a common finding

Fig. 2

Bulky hyperkeratotic epithelial proliferation, not reactive. a Diffuse and bulky, heterogeneous white plaque affecting the mandibular anterior segment (attached gingiva, alveolar mucosa, lower labial vestibular, and labial mucosa), contiguous with the posterior buccal vestibule and buccal mucosa. Note the dry, fissured appearance of the lower left buccal vestibular mucosa. b Low power view of a mucosal wedge showing the bulky, endophytic proliferative epithelial pattern of cytologically bland cells with broad, blunted, downwardly directed rete pegs that markedly increase the top-to-bottom width of the epithelium. The rete pegs appear to merge toward one another as they attain a uniform depth. The epithelial surface is slightly undulating with a surface crypt filled with parakeratin. c The epithelium is bulky and thickened with easily identified hyperkeratosis plus expanded, blunt rete pegs. d Low power view of undulating surface epithelial proliferation with exophytic foci covered by parakeratin. The rete pegs are uniform in depth, blunt, and broad. e As a biopsy sample, the tangential sectioning artifacts affect interpretation of the endo-exophytic bulky epithelial proliferation showing an undulating surface. The rete pegs are elongated and rounded at their tips, and together they reach a uniform depth. However, comparison to the adjacent epithelium cannot be achieved and so carcinoma cannot be diagnosed

Fig. 3

Squamous cell carcinoma. a A clinical photograph of a gingival mass enveloping several teeth, with a pebbly configuration. b A substantial, convoluted and complex epithelial proliferation much thicker than the uninvolved adjacent epithelium (black arrow), but lacking an invasive pattern below the level of the epithelium. c Broad, pushing border of infiltration displacing muscle and extending below the adjacent epithelium (black arrow). There are thick, clubby projections with a complex architecture. d The rete pegs are notably thickened and elongated; there is surface hyperkeratosis with a verrucous pattern. The rete pegs are 5x the thickness of the adjacent epithelium, but there is absence of cytologic atypia. e Conventional SCC showing broad islands and nests of destructive infiltration into the stroma. There are microabscesses present within the deep portions of the epithelium (black arrow)

Fig. 4

Normal histology by oral cavity subsite. a Gingiva: Stratified highly keratinized squamous epithelium with well-formed rete pegs that extensively interdigitate with the lamina propria to increase the surface area for epithelial attachment to the connective tissue. b Palate: Stratified keratinized squamous epithelium with elongate rete pegs that are composed of 4–8 cells wide that also allow for connective tissue attachment (fixed epithelium). c Buccal mucosa: A relatively thick stratified squamous non-keratinized epithelium lines the buccal mucosa and lips, with relatively broad rete (free epithelium). d Floor of mouth: A relatively thin non-keratinizing squamous epithelium without well-formed rete. e Tongue: Lateral tongue with a keratinized stratified squamous epithelium. f Dorsal Tongue: a complex epithelium containing papillae (filiform) with narrow bases and a well keratinizing surface

Fig. 5

Clinical and histologic mimics of PVL. a Clinical photo of delicate buccal lace-like striations (black arrow) in a case of lichen planus. b A dense, band-like lymphocytic infiltrate associated with vacuolar degeneration of the basal keratinocytes (inset). There is acanthosis and hyperkeratosis in this case of lichen planus. c A clinical photograph of lateral tongue keratosis with a shaggy appearance in traumatic hyperkeratosis. d Traumatic hyperkeratosis showing shaggy keratin with hyperkeratosis and thickened squamous epithelium. e A clinical photograph of retromolar pad white plaque clinically consistent with benign alveolar ridge keratosis (BARK). f This example of BARK shows moderate hyperkeratosis with a prominent granular layer and elongated, tapered rete pegs, focally coalescing at the base with scant inflammation. g A clinical photograph of fissured, gray-white leukoplakia along the sulcus in tobacco pouch keratosis. h There is epithelial thickening with thin hyperkeratosis, but neither significant atypia nor significant hyperkeratosis is seen in this example of tobacco pouch keratosis. i A clinical photograph of lateral tongue leukoplakia. j The histology shows focal hyperkeratosis with a thickened epithelium showing at least low grade dysplasia, with architectural as well as cellular atypia

Fig. 6

Features of barnaculate squamous cell carcinoma. a Low power shows acanthotic epithelium with both an exophytic and endophytic proliferation of complex foldings and invaginations of the epithelium. The epithelial rete pegs are bulbous, with variable keratosis extending deep into the epithelial folds. b The basement membrane is poorly demarcated. Other findings include an intraepithelial microabscess (white arrow), dyskeratosis, and inflammatory cell exocytosis. c This barnaculate carcinoma shows wide bulbous rete with associated hyperkeratosis, but is at the level of the adjacent epithelium, appearing “stuck on.” Inflammation is noted at the advancing edge. d The “stuck-on” appearance is easily identified, with a substantial endo- and exophytic appearance, but nearly all of the base of the lesion is at the same level without a significant “invasive” front. There is no church-spire keratosis, no significant keratosis, and no parakeratotic crypting. e This is an example of verrucous carcinoma, showing a predominantly exophytic growth pattern. The keratin plunges down into the epithelial crypts. This histology correlates well with the clinical presentation of a carpet-like proliferation of verrucous epithelium with fissuring. f This barnaculate carcinoma is characterized by a substantial and significant epithelial proliferation showing a nearly flat surface (rounded) with elongated and bulbous rete that all reach the same level, and does not show a significant or destructive invasion. In this case, the bulk of the proliferation is exophytic into the lumen