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

Abstract

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.

Keywords: Atypical epithelial proliferation; Inter-observer variability; Papillary squamous cell carcinoma; Proliferative verrucous leukoplakia; Verrucous hyperplasia.

Fig. 1

Classic examples of proliferative verrucous leukoplakia cases belonging to the five major categories. a Category 1—hyperkeratosis and mild lichenoid mucositis. b Category 2—verrucous hyperplasia. c Category 3—acanthosis and moderate to severe epithelial dysplasia. d Category 4—verrucous carcinoma. e Category 5—well-differentiated squamous cell carcinoma

Fig. 2

a Biopsy of a proliferative verrucous leukoplakia (PVL) lesion demonstrating papillary proliferation (H&E, × 2). b Papillary epithelial proliferation exhibiting prominent keratosis and keratin clefts (H&E, × 4). c Multiple foci of epithelial swirls (red arrow) and cells demonstrating hyperchromatic nuclei and pleomorphism (blue arrows, H&E, × 10). d Higher magnification of epithelial swirls (red arrows) and pleomorphic cells (blue arrows) noted in the papillary epithelial proliferation (H&E, × 20)

Fig. 3

a Histologic features of biopsy of PVL lesion exhibiting hyperplastic elongated epithelial rete ridges and a prominent band of lymphocytic infiltrate beneath the rete ridges. Red arrow marks the area magnified in (b) (H&E, × 2.5). b Cytologic features demonstrating keratin clefting and keratin pearls marked by red arrows (H&E, × 20). c Histologic appearance of the additional section of tissue on the same slide as part A (H&E, × 2.5). d Hyperplastic elongated rete ridges showing a glassy cytoplasm and cells exhibiting dyskeratosis (blue arrows) (H&E, × 7)

Fig. 4

a Histologic findings of a PVL lesion displaying verrucous architecture and prominent keratosis (H&E, × 2). b Verrucous hyperplasia demonstrating keratin clefting (H&E, × 4). c Prominent hyperkeratosis with cells exhibiting premature keratinization in lower third of the epithelium (red arrows, H&E, × 20). d Dyskeratosis (red arrows) and pleomorphic cells (blue arrows) (H&E, × 20)

Fig. 5

a PVL lesion demonstrating an atypical verrucoid architecture and elongated epithelial rete ridges (H&E, × 2). b Higher magnification showing significant keratosis and hyperchromatic nuclei in lower third of the epithelium (H&E, × 5)

Fig. 6

Overall agreement between the ten OMFS on treatment options for the most commonly used histologic terminologies. The total responses received for treatment of each diagnosis are displayed as percentage. HK hyperkeratosis, VPHK verrucopapillary hyperkeratosis, VH verrucous hyperplasia, LG low-grade, HG high-grade, AEP atypical epithelial proliferation