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Case 10 Proliferative leukoplakia on a the lower lip mucosa and b the buccal mucosa. c There is atypical verrucous hyperkeratosis and epithelial atrophy (H&E, original magnification ×40). d ED is not identified (H&E, original magnification ×400)
Source publication
The current WHO histopathologic criteria for oral epithelial dysplasia (ED) are based on architectural and cytologic alterations, and do not address other histopathologic features of ED. Here we propose new diagnostic criteria including architectural, organizational, and cytologic features for oral ED. Cases of unifocal leukoplakia (UL) and prolife...
Citations
... Currently, there is no uniform standard for the pathological features and diagnostic criteria of PVL. Li et al. in 2021 described demarcated hyperkeratosis and "skip" segments in Proliferative Leukoplakia [30]. The 5th edition of the World Health Organization's head and neck tumor classification synthesized past research, indicating that early pathological manifestations in PVL additionally include premature keratinization, sharp lateral margins, and increased keratin [19]. ...
Background
Proliferative verrucous leukoplakia (PVL), distinguished by its malignant transformation rate of 43.87% to 65.8%, stands as the oral potentially malignant disorder with the highest propensity for malignancy. PVL is marked by distinctive heterogeneity regarding the clinical or histopathological characteristics as well as prognostic factors pertinent to this condition. The purpose of this study is to compile and assess the clinicopathological features, malignant transformation, and associated risk factors in patients diagnosed with PVL.
Methods
This study is a hospital-based retrospective longitudinal study of 36 patients diagnosed with PVL from 2013 to 2023. We conducted complete clinical and histopathological evaluations of the patients.
Results
The cohort comprised 16 males and 20 females, yielding a male-to-female ratio of 1:1.25. The follow-up period ranged from 8 to 125 months, with an average of 47.50 months. The most common clinical type of lesion was the verrucous form (58.33%), and the gingiva was the most common site (44.44%). Each patient had between 2 to 7 lesions, averaging 3.36 per patient. During the follow-up period, twelve patients (33.3%) developed oral cancer, with an average time to malignant transformation of 35.75 months. Kaplan–Meier survival analysis indicated that patients with complaints of pain, roughness, or a rough sensation, with diabetes, and the presence of cytologic atypia histologically showed a higher risk of malignant transformation (p < 0.05). In this study, the rate of malignant transformation in the treatment group (5/23) was lower than that in the untreated group (7/13), however, no statistically significant difference (p = 0.05).
Conclusion
The main complaints of pain, roughness, or foreign body sensation, coupled with cytologic atypia histologically are indicative of an increased risk of malignant transformation in PVL. Further research is needed to elucidate the influence of these clinicopathological parameters on the malignant progression of PVL.
... First, we need to understand how dysplastic epithelial cells initiate interactions with the subepithelial microenvironment. Changes initially manifest within the epithelium and are observable through histological features like hyperkeratosis (thickening of the keratin layer), acanthosis (increased cell layers), cell pleomorphism (various cell shapes and sizes), altered cytoplasm-to-nucleus ratio, atypical mitosis (irregular cell division), and nuclear pleomorphism (various nuclear shapes and sizes) (15). These cytological alterations may occur in the absence or with a minimal inflammatory response in the connective tissue. ...
Oral leukoplakia is the most frequent and potentially malignant lesion of the oral cavity. Although dysplasia grading remains the main factor for risk assessment, challenges persist in determining the exact risk of transformation, and the literature has focused on studying alternative biomarkers. The interaction between dysplastic epithelial cells and the microenvironment starts early, and the communication is mainly mediated by lymphocytes, inflammatory factors, fibroblasts, and the extracellular matrix, leading to dysplastic progression. Leukoplakia-infiltrating leukocytes (LILs) and leukoplakia-associated fibroblasts (LAFs) play crucial roles in the dysplastic microenvironment. The immune response is related to intraepithelial T lymphocyte infiltration, mechanisms of immunosuppression coordinated by regulatory T cells, M2 macrophage polarization, and increased numbers of Langerhans cells; in contrast, fibroblastic and extracellular matrix factors are associated with increased numbers of pro-tumorigenic myofibroblasts, increased expression of metalloproteinases vs. decreased expression of TIMPs, and increased expression of chemokines and other inflammatory mediators. The microenvironment offers insights into the progression of leukoplakia to carcinoma, and understanding the complexity of the oral microenvironment in potentially malignant diseases aids in determining the risk of malignant transformation and proposing new therapeutic alternatives.
... This feature is often present in differentiated dysplasias, where an abrupt 'clonal' change between parakeratin and orthokeratin is seen with limited or no atypia. 4,32,33 This feature must be interpreted with caution as it can appear similar in reactive processes such as traumatic (frictional) keratosis or inflammatory conditions such as lichen planus, although the change in keratinisation pattern in these reactive lesions is usually more subtle and not abrupt. Anecdotally, excessive keratinisation (in particular presence of orthokeratinisation) of the floor of the mouth is worrying, particularly when paired with atrophic epithelium. ...
... 33,44 The requirement for cytological atypia to be present is debated and most classify lesions with similar features but a verrucous architecture as distinct. 4,[32][33][34][35][36][37][38][39][40][41][42][43][44] Practically, the presence of an unusual pattern of keratin for the oral subsite being examined and an abrupt transition are incredibly useful clues for the presence of differentiated OED, even in the absence of any cytological atypia ( Supplementary Fig. 3, Appendix A). However, clinicopathological correlation is important as similar changes are seen in the early stages of PVL. ...
... However, clinicopathological correlation is important as similar changes are seen in the early stages of PVL. 1,32 Grading of these lesions is difficult as the thickness of the epithelium affected by atypia is often limited, with very few lesions having full thickness dysplasia despite undergoing malignant transformation. 33 As such, a good 'rule of thumb' is to assign the lesion one grade higher than it would be given based on traditional 'thirds' assessment, and clinical follow-up should also be recommended. ...
... But what is HkNR, histopathologically? Previous studies as reviewed here do not specify the nature of the hyperkeratosis. In recent research on both solitary and proliferative (verrucous) leukoplakia, HkNR presents as abnormal architectural changes to the epithelium including marked hyperkeratosis, papillomatosis/corrugation, sharp demarcation, epithelial atrophy, hypergranulosis and/or skip segments [14,40,41]. Cytologic features of ED, on the other hand, are either absent (Fig. 2a-f) or consist of, at most, mild nuclear hyperchromasia and atypia restricted to basal/parabasal layers (Fig. 3), which may be sufficient for some pathologists to interpret as mild ED, particularly when correlated with a clinical image. ...
The presence of epithelial dysplasia (ED) in oral leukoplakia is the single most important predictor of malignant transformation (MT). The majority of leukoplakias, however, do not show evidence of ED and yet MT of these lesions is well-recognized. These lesions have been referred to as “hyperkeratosis/hyperplasia, no dysplasia,” “keratosis of unknown significance” and “hyperkeratosis, not reactive (HkNR).” This study evaluates the MT rate of such leukoplakias. A literature review was performed to identify cohort studies on leukoplakias where (1) there was a recorded histopathologic diagnosis, (2) cases of “hyperkeratosis/hyperplasia, no dysplasia” comprised part of the cohort, and (3) follow-up information was available. There were 9,358 leukoplakias, of which 28.5% exhibited ED while 37.7% consisted of HkNR. Follow-up ranged from 15 to 73 months. The incidence of MT in leukoplakia exhibiting HkNR was 4.9%, compared to 15.3% for ED. Among oral squamous cell carcinomas (SCC) with previously biopsied, site-specific precursor lesions, 55.7% arose from ED/carcinoma in situ and 28.0% arose from HkNR. Leukoplakia exhibiting HkNR has a substantial MT rate, similar to that of mild ED, and must be recognized and managed appropriately to reduce oral SCC incidence.
... These have been referred to also as "bluntly invasive squamous cell carcinoma" 16 . Cases that showed hyper(ortho)keratosis (Hk) and/or parakeratosis (Pk) and lacked unequivocal features of epithelial dysplasia or had mild atypia were reported as "Hk not reactive (HkNR)" 15,17,18 . These were comparable to the category of "corrugated ortho(para) hyperkeratotic lesion, not reactive" as described by Thompson et al. 15 . ...
... These diagnostic terms could just as well represent chronic frictional keratoses including benign alveolar ridge keratoses and that is why the diagnostic term HkNR or "corrugated ortho (para)keratotic lesion, not reactive" is favored to indicate these are not reactive lesions. This has been proposed by Thompson et al. 15 and others for uniform reporting of these entities 14,17,18 . In this series of 86 initial/early biopsies from 3 centers, 31.4% showed hyperkeratosis and/or parakeratosis with epithelial atrophy or acanthosis, but without overt evidence of OED. ...
The aim of this multicenter retrospective study is to characterize the histopathologic features of initial/early biopsies of proliferative leukoplakia (PL; also known as proliferative verrucous leukoplakia), and to analyze the correlation between histopathologic features and malignant transformation (MT). Patients with a clinical diagnosis of PL who have at least one biopsy and one follow-up visit were included in this study. Initial/early biopsy specimens were reviewed. The biopsies were evaluated for the presence of squamous cell carcinoma (SCCa), oral epithelial dysplasia (OED), and atypical verrucous hyperplasia (AVH). Cases that lacked unequivocal features of dysplasia were termed “hyperkeratosis/parakeratosis not reactive (HkNR)”. Pearson chi-square test and Wilcoxon test were used for statistical analysis. There were 86 early/initial biopsies from 59 patients; 74.6% were females. Most of the cases had a smooth/homogenous (34.8%) or fissured appearance (32.6%), and only 13.0% had a verrucous appearance. The most common biopsy site was the gingiva/alveolar mucosa (40.8%) and buccal mucosa (25.0%). The most common histologic diagnosis was OED (53.5%) followed by HkNR (31.4%). Of note, two-thirds of HkNR cases showed only hyperkeratosis and epithelial atrophy. A lymphocytic band was seen in 34.8% of OED cases and 29.6% of HkNR cases, mostly associated with epithelial atrophy. Twenty-eight patients (47.5%) developed carcinoma and 28.9% of early/initial biopsy sites underwent MT. The mortality rate was 11.9%. Our findings show that one-third of cases of PL do not show OED with most exhibiting hyperkeratosis and epithelial atrophy, but MT nevertheless occurred at such sites in 3.7% of cases.
... The most common sites for oral leukoplakia are the tongue (36-50%), buccal mucosa (18-26%), floor of mouth (8-22%), gingiva (6-22%), and hard palatal mucosa (7%) [5][6][7]. The spectrum of histopathologic diagnoses of oral leukoplakia includes oral epithelial dysplasia (OED), atypical verrucous hyperplasia, squamous cell carcinoma, and the so-called 'simple' or 'benign' hyperkeratosis (Hk) that lacks features of dysplasia as defined by the World Health Organization (WHO) [1,8]. Oral epithelial dysplasia is present in 15-79% [6,7,[9][10][11][12][13][14][15] of all leukoplakias and the malignant transformation rate of oral leukoplakia ranges from 6 to 24% [1]. ...
... This is characterized by marked papillary or verruciform architecture with or without OED and has a high association with malignant transformation [20]. More recently, other architectural features of OED have been proposed besides papillary/verrucous morphology and these include Hk with epithelial atrophy, bulky squamous proliferation, and demarcated Hk with or without "skip segments" [4,8]. ...
... The remaining cases that were not reactive were then evaluated for the presence of squamous cell carcinoma, atypical verrucous hyperplasia which is now widely accepted as a dysplastic lesion [20], and OED by WHO criteria [1]. The rest of the non-reactive nondysplastic cases were then evaluated by the architectural criteria of corrugated/verrucous/papillary morphology, Hk with epithelial atrophy (less than 15 cells thick), demarcated keratosis with skip segments, and atypical bulky squamous proliferation [4,8,27]. These were broadly designated as "Hk/Pk not reactive (HkNR)" (Fig. 1). ...
White lesions on the gingiva and palatal mucosa may represent reactive keratoses, including specific diseases such as benign alveolar ridge keratosis, or nonreactive keratoses, such as true leukoplakia, the latter being associated with a high recurrence rate at this site. The aim of this study is to determine the histopathologic features of gingival keratoses. Hyperkeratotic lesions from the gingiva, palatal mucosa, and alveolar ridge mucosa were available for evaluation after excluding specific keratotic lesions such as candidiasis. There were 321 biopsies from 296 patients and approximately half of the cases (159/321, 49.5%) were reactive keratoses. The rest of the 162 biopsies from 149 patients (76 females; 51.0%) represented true leukoaplakias. The most common location was the gingiva (73.2%) followed by the palatal mucosa (17.0%). Hyperkeratosis/parakeratosis not reactive (HkNR) represented 43.8% of cases; 45.7% were dysplasia or carcinoma, and the rest were not readily classifiable as reactive or non-reactive keratoses. Histopathologic features commonly noted in the HkNR lesions include sharp demarcation (72.7%), corrugated surface (53.5%), and epithelial atrophy (48.1%). A lymphocytic band was noted in 8.5% of the cases, mostly associated with epithelial atrophy (5/6 cases). Seven patients with 17 biopsies from noncontiguous sites likely had proliferative leukoplakia; the most common location was the gingiva (88.2%) and the most common diagnosis was HkNR (52.9%). HkNR is a common histopathologic diagnosis for leukoplakias on the gingiva, and these lesions frequently exhibit thick hyperkeratosis, epithelial atrophy and a lymphocytic band at the interface.
... Then, their titles and abstracts were screened and 45 papers selected for full-text reading (22 of them did not meet our eligibility criteria and were excluded; their references and exclusion reasons are listed in the Supplementary Materials, pp.[32][33][34]. Finally, 23 studies were included in the systematic review's final sample-23 for qualitative evaluation and 21 for quantitative meta-analysis-[5][6][7]22,[37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55]. ...
Proliferative verrucous leukoplakia (PVL) is contemplated by the World Health Organization (WHO) as an oral potentially malignant disorder (OPMD) with a high the highest malignant transformation ratio among all OPMD (approximately 50%). Our aim was to evaluate the current evidence in relation to the prognosis of oral carcinoma developed in patients with proliferative verrucous leukoplakia (PVL-OC). We searched PubMed, Embase, Web of Science and Scopus for published studies (upper date limit = June 2021). We evaluated the quality of studies (QUIPS tool). We carried out meta-analyses, examined inter-study heterogeneity through subgroup and meta-regression analyses, and performed sensitivity and small-study effects analyses to test the stability and reliability of results. 23 studies met inclusion criteria (505 patients with PVL, of which 288 developed a total of 504 carcinomas). The meta-analyzed overall mortality rate was 21.29% (pooled proportions [PP] = 95% confidence intervals [CI] = 8.77–36.36) for PVL-OC, clearly lower than the 34.7–50% mortality rate for conventional oral cancer reported in previous studies. In comparison with a single study reporting on conventional oral cancers, mortality was significantly lower for PVL-OC (hazard ratio = 0.29 [95%CI = 0.10–0.89], p = 0.03). Univariable meta-regression verified that case series that presented higher proportions of verrucous carcinomas showed a better survival of PVL-OC (p = 0.05), but not with higher proportion of oral squamous cell carcinomas (p = 0.74). Significant differences were not found for other relevant variables such as follow up period (p = 0.44) or multiple tumor development (p = 0.74). In conclusion, PVL-OC show favorable prognostic parameters, especially with regard to the mortality rate.
... After duplicates removal, 341 records were considered potentially eligible and screened according to titles and abstracts, leaving a sample of 49 studies for full text evaluation. Finally, 24 studies meeting all eligibility criteria were included for critical analysis and evidence synthesis in our scoping review [4,[6][7][8][9][10]13,[21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37]. Table 3 summarizes the characteristics of the 24 selected studies, which reported on a total of 631 patients with PVL. ...
... Our next research question addresses the extent to which the gingiva or palate are required to be involved in order to classify a lesion as PVL. In Cerero-Lapiedra's criteria [11], the gingiva and palate involvement is considered as a major not mandatory criterion, Carrard et al. [12] classify the location as suggested but not mandatory, while neither of the two remaining proposals [10,13] consider this question as a diagnostic criterion; 10/24 papers [8,9,21,23,24,26,28,31,33,36] analyzed in this scoping review (41.67%) offer data on the location of the lesions in 145 patients. The oral mucosal site mostly affected in patients with PVL was buccal mucosa (63/145 patients; 43.45%) followed by gingiva (58/145 patients; 40%), tongue (47/145 patients; 32.41%), and palate (29/145 patients; 13.79%). ...
... Another research question is related to what extent it is necessary to demonstrate the malignant transformation of a white lesion in order to consider it as a PVL. All of the four diagnostic criteria for PVL proposed malignant transformation as a common fact in the PVL evolution, although not required for diagnosis [10][11][12][13]; 100% of studies included in our current paper (24/24) [4,[6][7][8][9][10]13,[21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] also corroborate this proposition, i.e., no study indicates malignancy as a mandatory criterion for diagnosis. Papers published in this regard by the WHO Collaborating Center for Oral Cancer [5] describe PVL as an aggressive form of leukoplakia, among other reasons due to its tendency to become malignant and to develop multiple carcinomas. ...
Proliferative verrucous leukoplakia (PVL) is considered as an oral potentially malignant disorder (OPMD) that presents with a high tendency to recurrence after treatment and has the highest malignant transformation ratio among all OPMD (50%). Evidence-based publications have indicated that the malignant evolution reported is significantly related to the inconsistent diagnostic criteria used in primary-level studies; so, it has been hypothesized that the risk of oral cancer for this disease could even be underestimated. This is important because PVL requires specific management protocols, evidence-based, aimed at the early diagnosis of cancer developing in these lesions. We present a scoping review—a novel approach to mapping the available literature on a given topic to provide an overview of the available research evidence and to highlight possible gaps in the evidence—especially related in our study to the diagnostic aspects of PVL, and to issue a conceptual proposal and diagnostic criteria for PVL. We conclude that PVL is a white, multifocal and progressive lesion with a high malignant transformation rate which is diagnosed mainly around the age of 60 years without any specific histological characterization. We also advise a personal reflection on the level of certainty with which the clinician makes the diagnosis of a particular case of PVL.
Aims
Oral epithelial dysplasia (OED) often exhibits a lymphocytic/lichenoid immune response (LIR), imparting histological resemblance to lichenoid mucositis and rendering diagnosis challenging. The clinical appearances of OED and lichenoid inflammatory processes are generally divergent, presenting as well‐demarcated hyperkeratotic plaques and diffuse white and/or red mucosal change with variably prominent Wickham striae, respectively. To date, clinicopathological characterisation of OED with LIR, including clinical/gross appearance, has not been depicted.
Methods and results
Cases of solitary OED with LIR for which a clinical photograph was available were identified in the authors’ institutional files. Clinical and histological features were documented. In 44 identified cases, dysplasia was mild (19 of 44, 43.2%), moderate (19 of 44, 43.2%) and severe (six of 44, 13.6%). Clinically/grossly, all 44 cases (100.0%), presented as well‐demarcated hyperkeratotic plaques lacking diffuse white‐and‐red mucosal change or Wickham striae. Histologically, OED with LIR exhibited numerous ‘lichenoid’ features beyond the lymphocytic band in the superficial lamina propria, including: leucocyte transmigration (38 of 44, 86.4%), spongiosis (37 of 44, 84.1%), Civatte/colloid bodies (36 of 44, 81.8%), basal cell degeneration (29 of 45, 65.9%), sawtooth rete ridges (11 of 44, 25.0%) and subepithelial clefting (7 of 44, 15.9%).
Conclusions
Virtually any lichenoid histological feature may be seen in OED with LIR, representing a significant diagnostic pitfall. The typical clinical appearance of OED with LIR is of a well‐demarcated hyperkeratotic plaque, characteristic of keratinising dysplasia and devoid of lichenoid features. This suggests that pathologist access to clinical photographs during diagnostic interpretation of biopsied white lesions, which represents opportunity to perform gross examination of the disease process, may reduce interobserver variability and improve diagnostic accuracy in this challenging differential diagnosis.
