Figure 1 - available from: Head and Neck Pathology
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Examples of keratinizing and nonkeratinizing severe dysplasia/carcinoma in situ. Keratinizing severe dysplasia/carcinoma in situ (a, c, e) is composed of polygonal shaped cells with eosinophilic cytoplasm and often distinct cell borders. In contrast, nonkeratinizing carcinoma in situ (b, d, f) resembles transitional epithelium and is composed of cells with scant cytoplasm and oval to spindled hyperchromatic nuclei and indistinct cell borders
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The clinical and pathologic characteristics of human papillomavirus (HPV)-related premalignant lesions in the upper aerodigestive tract have not been adequately studied. There are a few reports of oral cavity HPV-related severe dysplasia with unique morphology (prominent apoptosis/karyorrhexis imparting a ‘bowenoid’ appearance) and a single case re...
Citations
... Premalignant lesions of oral cavity infected by HPV that may lead to HPV-induced cancer have the following histological features: full-thickness proliferation of basaloid cells with prominent apoptosis and karyorrhexis and corrugated surface parakeratosis. They have been associated with the developing of squamous cell carcinoma between the 15 % and the 70 % of the cases [141][142][143][144]. So, intercepting this squamous dysplasia could be a good way to avoid future cancer developing. ...
Human Papilloma Virus (HPV) is considered one of the most common sexually transmitted infections and has been shown to play an important role in the pathogenesis of squamous cell carcinomas (SCC) of the cervix and head and neck. Manifestations of HPV infections can be manifold, ranging from asymptomatic infections to benign or potentially malignant lesions to intraepithelial neoplasms and invasive carcinomas. The heterogeneity of clinical manifestations from HPV infection depends on the interactions between the viral agent and the host, a direct consequence of the ability on the part of HPV is to remain silent and to evade and convey the action of the host immune system. The oral mucosa represents one of the tissues for which HPV has a distinct tropism and is frequently affected by infection. While much information is available on the role that HPV infection plays in the development of SCC in the oral cavity, there is less information on asymptomatic infections and benign HPV-induced oral lesions. Therefore, the purpose of this review is to analyze, in light of current knowledge, the early clinical and bio-humoral prognostic features related to the risk of HPV malignant transformation, focusing on subclinical conditions, benign lesions, and the correlation between oral infection and infection in other districts. The data show that the main risk associated with HPV infection is related to malignant transformation of lesions. Although HPV-driven OPSCC is associated with a better prognosis than non-HPV-driven OPSCC, primary prevention and early detection of the infection and affected genotype are essential to reduce the risk of malignant neoplastic complications and improve the prognosis.
... Subsequently, the study by Zhang et al. (24) broadened the understanding of HPV-associated oral epithelial dysplasia by introducing a novel nonkeratinizing pattern of severe dysplasia/ CIS. The analysis involved 98 patients diagnosed with severe dysplasia/CIS, revealing that 3% exhibited a nonkeratinizing histological type. ...
... While most studies on HPV-OED employed DNA in situ hybridization for identifying high-risk HPV (HR-HPV) (16,19,21,24,28,29,32), others employed diverse methods such as polymerase chain reaction (PCR) (27,30), real-time PCR (RT-PCR) (26), and even DNA sequencing (22,23). Despite their high sensitivity, it's important to note that a positive test from these assays might signify sample contamination or a low-level transient infection rather than the presence of active high-risk HPV. ...
... While most studies on HPV-OED have reported typical diffuse and strong p16 positivity, recognizing this biomarker as a valuable predictor of the presence of transcriptionally active high-risk HPV infection (18,19,24,26,28,29,32), other investigations have observed lower immunoreactivity in HPV-OED cases (31) or elevated p16 levels in HPV-negative oral epithelial dysplasia samples (17). ...
Oral epithelial dysplasia associated with high-risk HPV infection has received different names since its initial description, such as oral Bowenoid lesions, HPV-associated intraepithelial neoplasia, and oral koilocytic dysplasia. Some features, identified in more or less quantity in some of the descriptions, like apoptotic keratinocytes, karyorrhexis, and mitosoid figures, are intricately connected to viral transcriptional status and, consequently, viral load. Since the variety in terminology has introduced diagnostic confusion within medical and research communities, establishing a uniform and standardized approach to diagnosing HPV-oral epithelial dysplasia is crucial for accurate and early diagnoses and holds significant implications for patient outcomes, particularly in high-risk individuals.
... Approximately 150 cases of HPV-OED have been reported in the English-language literature to date, with all reported series originating from North America and Europe (Table 1); [2][3][4][5][6][7][8][9][10][11]. HPV-OED usually appears clinically as well-demarcated, flat or slightly raised red/ white plaques that affect the ventral/lateral tongue, floor of mouth and buccal mucosa of middle-aged, tobacco smokers or immunosuppressed male patients [1]. ...
... Since then, only 3 additional studies have provided information on the HIV status of their affected patients, ranging from 0 to 25% [3,5,6]. HPV-OED has been associated in limited series with tobacco use [5,6,[8][9][10], a well-established etiologic factor for developing OED and OSCC [18,19]. In the present study, 40% of the patients reported smoking tobacco and one patient (20%) was an ex-smoker. ...
... Interestingly, HPV-OED usually appear as flat or slightly elevated white plaques, indistinguishable from conventional leukoplakias, but may occasionally mimic benign HPV-related oral lesions, showing papillary, verrucous or cobblestone surface [2,5], a feature observed in 60% of the present cases. Like conventional leukoplakia, the ventral/lateral border of tongue and floor of mouth are the most common sites for HPV-OED [1,[5][6][7][8]. Interestingly, the buccal mucosa and commissure were the most affected sites in the present study, a location that has been surpassed by tongue and floor of mouth lesions in previous studies [5][6][7][8]. ...
Human papillomavirus-associated oral epithelial dysplasia (HPV-OED) is a distinct oral epithelial disorder characterized by viral cytopathic changes caused by transcriptionally active high-risk HPV. The aim of the present study was to report 5 additional cases from Latin America.
Clinical data from five patients with HPV-OED were obtained from the archives of three oral pathology services from Brazil and Chile. All cases were submitted to morphological, p16 expression and in situ hybridization (ISH) for HPV analyses.
Four patients were male and one patient was female, with a mean age of 55.4 years. Four patients were HIV seropositive and two were smokers. Three cases affected the buccal mucosa and commissure, one of which had an additional plaque in the soft palate, and one case each occurred on the floor of mouth and lower labial mucosa. Most cases presented as well-demarcated white plaques with a verrucous surface. One case presented multiple lesions ranging from normal to white-colored slightly elevated plaques with a cobblestone surface. Peripheral mucosal pigmentation was observed in two cases. All five cases presented with the characteristic microscopic features of HPV-OED, including severe dysplasia with numerous karyorrhectic and apoptotic cells, full-thickness “block positivity” for p16 and high Ki-67 index (> 90%) sharply demarcated from the adjacent non-dysplastic epithelium. Wide-spectrum DNA ISH–HPV was positive in 4 cases. All patients were treated with conservative surgical excision with no signs of recurrence after a mean of 39-month follow-up.
This represents the first series of HPV-OED from Latin America; most cases presented as well-demarcated papillary white plaques affecting the buccal mucosa and commissure of HIV-positive middle-aged men, two of them exhibiting peripheral pigmentation caused by reactive melanocytes. The typical microscopic findings of HPV-OED were observed in all cases, which also showed strong p16 positivity in a continuous band through the full thickness of the epithelium and high Ki67.
... These authors are of opinion that non-keratinizing morphology is a strong predictor of transcriptionally-active HPV in severe dysplasia/carcinoma in situ. [51]. ...
We present the historical review and current state of the histopathological classifications and terminology of laryngeal precursor lesions. Attention to recent genetic findings is also presented; although in need of additional confirmation, these raise possibility for early detection of patients at risk of dysplasia progression. Although a number of identified genetic alterations with a promising diagnostic and prognostic value are emerging, none of the known genetic alterations can be currently implemented in clinical practice as a completely reliable diagnostic and/or prognostic marker. Regarding the terminology of precursor lesions, dysplasia remains the most frequently used term, but squamous intraepithelial lesion can be used as a synonym as well. Histological findings, in spite of certain degree of subjectivity, remain at present the most reliable method for an accurate diagnosis. The current 2017 WHO classification seems to successfully stratify risk of malignant progression, with a significantly different risk of malignant progression between low-grade dysplasia and high-grade dysplasia. In case of pronounced architectural disorders, severe cellular and nuclear atypias, and an increased number of mitoses, also atypical form, the high-grade dysplasia and carcinoma in situ can be separated. The Slovenian tertiary centers have a policy of surgical removal of high-grade SILs and life-long close follow-up. Radiotherapy is reserved for more pronounced intraepithelial lesions classified as carcinoma in situ and invasive cancer. Such a distinction can facilitate clinical decision to use radiotherapy if complete surgical removal is not possible.
... A meta-analysis found that p16 expression was associated with better clinical outcome and good prognostic factors including low risk of nodal metastasis [21]. Among other histologic parameters, p16 expression was noted to be associated with non-keratinizing phenotype [22], however, we did not find any such association in our study. ...
Background
p16 is a tumor suppressor gene, over expression of which is considered as a surrogate marker of oncogenic human papillomavirus (HPV) infection. Moreover, p16 over expression correlates with good prognosis in head and neck squamous cell carcinoma (HNSCC). In the present study, we aimed to evaluate the frequency of p16 overexpression in HNSCC in our setup and its association with clinicopathologic parameters.
Methods
We performed p16 immunohistochemistry (IHC) on 144 cases of HNSCC. Association of p16 overexpression with various clinicopathologic parameters including T-stage, N-stage, grade,recurrence status, and risk factors was evaluated.
Results
p16 over expression was noted in 22.9% (33 cases), while 21.5% (31 cases) were focal positive and 55.6% (80 cases) were negative for p16 over expression. On the basis of percentage of expression; > 70% p16 expression was noted in 4.9% (7 cases), 9% (13 cases) showed 51% - 70% p16 expression, 9% (13 cases) revealed 11%-50% p16 expression, while 77.1% cases revealed no expression or < 10% p16 expression. Significant association of p16 expression was noted with nodal metastasis and extranodal spread while no significant association of p16 was noted with other prognostic parameters and risk factors.
Conclusion
Our data revealed that high expression (> 50%) of p16 is low in oropharyngeal squamous cell carcinoma in our setup. These finding suggest a low prevalence of HPV as a cause of HNSCC in our population. Moreover, p16 expression was found to be associated with some good prognostic parameters like lack of nodal metastasis, however, no significant association was noted with overall disease-free survival.
... The dysplastic cells in these sites had oval to fusiform nuclear morphology, many times hyperchromatic, scarce cytoplasm, and indistinct edges of cell with little or no squamous maturation. However, biopsies of patients do not show oropharynx cancer with frank invasion; while dysplasia in soft epithelium (without keratinization) with conjunctive invasion [10]. On the basis of this context, we inferred that the keratinization can be protective fact or natural barrier that minimizes the cellular infection to HPV. ...
Introduction: For a long time, the literature has established that HPV may be associated to pharynx cancer. Objective: To verify the number of publications in three different databases on the prevalence of oral, esophageal, penile, and cervical-vaginal cancer associated with HPV. Material and methods: The publications were verified in Pubmed, Lilacs, and Bireme databases; the keywords “mouth cancer”, “esophageal cancer”, “penile cancer”, and “cervical vaginal cancer”were associated with HPV. Data were tabulated in absolute numbers. Results: In all databases, the number of cervical carcinoma was much larger than that of other cancers. Conclusion: The number of cervical cancer was the most found associated with HPV because of the histological and specific functional conditions of this site.
The chapter provides historical context and biological understanding of precancerous changes, and describes disorders that predispose to squamous carcinoma. It discusses grading systems for use at different head and neck sites, with no single grading system being applicable to all, and those developed for cervix, colon, and other sites being inappropriate. Oral lesions are more diverse than laryngeal lesions, with a different approach required for dysplasia grading at the two sites because of the restricted opportunities for intervention in the larynx. The current World Health Organization classifications are included, together with newly described conditions such as human papillomavirus–associated dysplasia in the mouth. Terminology is updated and the normal microscopic anatomy of the sites reviewed.
Human papillomavirus (HPV) is a principal driver for most oropharyngeal squamous cell carcinomas (OPSCCs), where it is strongly associated with improved survival. HPV is much less frequently detected in squamous cell carcinomas arising in nonoropharyngeal sites (non-OPSCCs), and its pathogenic role and prognostic value in these tumors is unclear. We evaluated the clinicopathologic features of 52 non-OPSCCs considered HPV-positive based upon p16 immunohistochemistry and direct HPV detection using RNA in situ hybridization (ISH), DNA ISH, or real-time DNA polymerase chain reaction. The HPV-positive non-OPSCCs were from the larynx (n=27), oral cavity (n=21), and hypopharynx (n=4). While most cases (n=34, 65%) showed classic histologic features of HPV-positive OPSCC, including endophytic growth, minimal keratinization, and hyperchromatic nuclei without koilocytic changes, a subset (n=13, 25%) were characterized by exophytic growth, exuberant surface hyperkeratosis and parakeratosis, marked nuclear pleomorphism, and prominent koilocytic atypia. These antithetical features were highly reminiscent of the warty variant of HPV-positive squamous cell carcinoma described in anogenital sites. Compared with tumors without warty features, the warty tumors presented at lower stage and were not associated with lymph node metastasis, local recurrence, or distant spread (4 y disease-free survival of 100% vs. 66%, P=0.069). The presence of transcriptionally active HPV as detected by RNA ISH suggests a pathogenic role for HPV in these nonoropharyngeal sites. While most HPV-positive non-OPSCCs are morphologically similar to their tonsillar counterparts, this study highlights a previously unrecognized warty variant that may be associated with a highly favorable clinical outcome.
Objective:
The aim of this study was to determine the utility of surrogate markers of human papillomavirus (HPV) infection in the diagnosis of HPV-associated oral epithelial dysplasia (OED).
Study design:
Twelve cases of oral dysplasia with histologic features of HPV infection were stained with surrogate markers for HPV (p16, Ki-67, and ProExC) on immunohistochemistry. A second group of 12 cases of oral dysplasia without histologic features of HPV infection was used for comparison. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to confirm the presence of high-risk HPV (HR HPV) in p16-positive cases.
Results:
All of the surrogate markers showed a statistically significant association with HPV-positive OED (P < .001). The agreement between p16 and HPV positivity was the strongest (κ = 1.00), whereas Ki-67 showed very good association with HPV (κ = 0.83), and ProExC showed good association (κ = 0.75). In each case, the agreement was statistically significant (P < .001). Overall, each of the 3 markers showed good sensitivity; however, ProExC showed the lowest specificity.
Conclusions:
The clinicopathologic features of 12 cases of HPV OED are reported. Diffuse p16 positivity is an accurate and reliable method for predicting HR HPV infection in both high and low grade cases of epithelial dysplasia with histopathologic features of HPV OED. The use of Ki-67 and ProExC did not demonstrate any additional diagnostic benefit in the diagnosis HPV OED.
The RNAscope utilizes in situ hybridization (RISH) technology to detect single RNA molecules in a variety of tissue samples, including formalin fixed paraffin embedded (FFPE) tissues. Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are found in association with neoplastic tissues and inflammatory lesions, and immunohistochemistry (IHC) or other techniques (ISH) are utilized to identify them. We compared the RNAscope RISH to ISH and IHC in the detection of EBV and CMV respectively to determine RNAscope utility in a clinical setting. Thirty-one FFPE tissues were stained by RISH to detect EBV and 24 samples of tissue for CMV. The RISH used the RNAscope (Leica BioSystems, Buffalo Grove, IL), the Bond III autostainer (Leica), and probes V-EBV and V-CMV (Advanced Cell Diagnostics, Newark, CA) as well as negative (DapB) and positive probe (PPIB) for RNA. Results were compared with those by ISH (Leica, EBV RNA probe), and IHC (CMV Dako, 1/160), respectively. RISH and ISH were concordant in 100% of cases positive for EBV by ISH (19/19). Of the cases negative for EBV by ISH, RISH showed positivity in an additional 25% of the samples (3/12). Overall concordance was 90.3% (28/31). RISH and IHC were concordant in 100% of cases positive for CMV by IHC (8/8). Of the cases negative for CMV by IHC, RISH detected positivity in an additional 50% of the samples (8/16). Overall concordance was 66.7% (16/24). RISH demonstrates increased sensitivity in the clinical setting, especially for CMV, detecting positive cells not stained by EBV ISH and CMV IHC.
