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The Spectrum of Oral Lesions Presenting Clinically With Papillary-Verrucous Features
Accepted Manuscript The Spectrum Of Oral Lesions Presenting Clinically With Papillary- Verrucous Features Whitefield Sara, Dr BDS – Resident in Oral Medicine and Private practitioner, Raiser Vadim, Dr DMD – Head of Maxillofacial Unit, Shuster Amir, Dr DMD PhD – Attending Surgeon, Kleinman Shlomi, Dr Senior Surgeon, Shlomi Benjamin, Dr DMD Former Head of Maxillofacial Unit (Retired), Kaplan Ilana, Professor Ilana Kaplan- Oral Pathologist PII:
S0278-2391(17)31153-9
DOI:
10.1016/j.joms.2017.08.030
Reference:
YJOMS 57965
To appear in:
Journal of Oral and Maxillofacial Surgery
Received Date: 0278-2391 0278-2391 Revised Date:
0278-2391 0278-2391
Accepted Date: 0278-2391 0278-2391
Please cite this article as: Sara W, Vadim R, Amir S, Shlomi K, Benjamin S, Ilana K, The Spectrum Of Oral Lesions Presenting Clinically With Papillary- Verrucous Features, Journal of Oral and Maxillofacial Surgery (2017), doi: 10.1016/j.joms.2017.08.030. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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THE SPECTRUM OF ORAL LESIONS PRESENTING CLINICALLY WITH PAPILLARYVERRUCOUS FEATURES
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WHITEFIELD SARA1, RAISER VADIM2, SHUSTER AMIR 1,2, KLEINMAN SHLOMI2, SHLOMI BENJAMIN1,2, KAPLAN ILANA1,2,3
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GOLDSCHLEGER SCHOOL OF DENTAL MEDICINE, TEL-AVIV UNIVERSITY, ISRAEL TEL-AVIV SOURASKY MEDICAL CENTER, TEL-AVIV, ISRAEL 3 SACKLER SCHOOL OF MEDICINE, TEL-AVIV UNIVERSITY, ISRAEL 2
Corresponding author;
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Key words Oral, verrucous, papillary, HPV, malignant
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Dr Sara Whitefield BDS – Resident in Oral Medicine and Private practitioner Dr Vadim Raiser DMD – Head of Maxillofacial Unit Dr Amir Shuster DMD PhD – Attending Surgeon Dr Shlomi Kleinman- Senior Surgeon Dr Benjamin Shlomi- DMD Former Head of Maxillofacial Unit (Retired) Professor Ilana Kaplan- Oral Pathologist
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Dr Sara Whitefield Department of oral Pathology and Medicine Goldschleger School of Dental Medicine, Tel Aviv University Tel Aviv, Israel Tel: 00 97254 6399810 Email address: [email protected]
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THE SPECTRUM OF ORAL LESIONS PRESENTING CLINICALLY WITH PAPILLARYVERRUCOUS FEATURES
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WHITEFIELD SARA1, RAISER VADIM2, SHUSTER AMIR 1,2, KLEINMAN SHLOMI2, SHLOMI BENJAMIN1,2, KAPLAN ILANA1,2,3
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GOLDSCHLEGER SCHOOL OF DENTAL MEDICINE, TEL-AVIV UNIVERSITY, ISRAEL TEL-AVIV SOURASKY MEDICAL CENTER, TEL-AVIV, ISRAEL 3 SACKLER SCHOOL OF MEDICINE, TEL-AVIV UNIVERSITY, ISRAEL
Key words Oral, verrucous, papillary, HPV, malignant
Corresponding author;
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Dr Sara Whitefield Department of oral Pathology and Medicine Goldschleger School of Dental Medicine, Tel Aviv University Tel Aviv, Israel Tel: 00 97254 6399810 Email address: [email protected]
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Abstract
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Purpose: To study the spectrum of oral pathologies presenting clinically with papillary-verrucous features. Materials and Methods: 10-year retrospective study (2007 to 2016) of oral papillary lesions was undertaken. All biopsies which included a clinical description of papillary or verrucous architecture were retrieved. The data collected included clinical features, size, color, location, histopathological diagnosis age and gender. Results: The study included 137 patients, with a total of 151 lesions. The ages ranged from 10 weeks to 84 years (mean 49). Histopathologically, 60% of cases were HPV related, 19% showed hyperplasia, 11% hyperplastic candidiasis, 7% dysplastic or malignant and 3% benign of unknown etiology. Of the 7% diagnosed with dysplasia or malignancy, only 60% were suspected for malignancy at the time of biopsy. HPV-related lesions and hyperplasia were most frequently found on the tongue (38% and 41%) and soft palate (21 and 14%), respectively. Hyperplastic candidiasis was most frequent on the buccal mucosa and tongue (35 and 24%, respectively). 1.3% of total lesions were found to be squamous cell carcinoma (SCC) and 1.3% verrucous carcinoma. 50% of the verrucous/papillary malignant lesions were found on the gingiva. Most malignant lesions occurred in the 40-60 age group. Conclusion: The results of this study suggest, that due to the wide spectrum of entities presenting clinically as papillary-verrucous architecture, biopsy is necessary for diagnosis. The clinical presentations allowed for overall accurate diagnosis in only 47% of cases and 60% accuracy in dysplastic or malignant cases. It is of significant importance to correctly identify those lesions which are HPV-related, but at the same time to rule-out those lesions which are unrelated to HPV, to help alleviate a patient’s anxiety. Most importantly, biopsy is mandatory for recognition of the malignant lesions with a papillary verrucous architecture, which may mimic other benign entities in the group of papillary verrucous lesions.
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Introduction
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Exophytic, papillary-verrucous lesions are relatively common in the oral cavity. A clinical description of verrucous or papillary architecture includes a wide spectrum of histopathological diagnoses1. Their etiology varies from reactive, local irritation, viral, fungal, premalignant to malignant. The similarity in architecture and variety in histopathological diagnoses can prove to be challenging to the clinician at initial examination .A search of the English language literature for oral papillary lesions yielded only limited information regarding the epidemiological spectrum of such lesions.
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Objectives
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To investigate the spectrum of lesions presenting clinically or histologically as verrucous or papillary and to characterize each subgroup. In addition, to analyze correlations between the histopathological diagnosis and the clinical diagnosis, with emphasis on cases with histopathological dysplasia or malignancy. Methods
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A retrospective analysis of biopsy results from the Institute of Pathology between the years 2007-2016 was undertaken. The study was conducted in accordance with ethical requirements (both Israeli and GCP-ICH standards) of clinical trials. The institute is a referral center for Oral and Maxillofacial Surgery and the biopsies were diagnosed by a certified oral pathologist (IK). All intra-oral biopsy reports with a clinical and/or histopathological description of papillary or verrucous architecture were retrieved. Data collected included demographic data and clinical features of the lesions as well as histopathological diagnosis. The histopathological diagnoses were divided into the following groups: candidal hyperplasia, papillary hyperplasia, HPV-related, epithelial hyperplasia with dysplasia, malignancy and others. Each parameter was compared between groups. Statistical analysis was performed comparing each variable between the groups. One way analysis of variants (ANOVA) was performed to assess differences in age at presentation between the groups. Pearson Chi squared analysis was used to identify differences in gender distribution between the groups. The Kruskal Wallis Test was used to evaluate the differences in lesion diameter between the groups. Results
A total of 151 lesions with verrucous or papillary architecture, were obtained from 137 patients, 67 males and 70 females, almost equal gender distribution. 12 (8.7 %) patients had more than 1 lesion, one of which had 4 lesions. The most frequent diagnoses were HPV- induced lesions, 89 (60%) and papillary hyperplasia 29 (19%). 17 (11%), were hyperplastic candidiasis, 10 (7%) dysplasia or malignancy and 5 (3%) were benign lesions of unknown etiology. (Fig 1) Of the 7% diagnosed with dysplasia or malignancy, only 60% were suspected for malignancy at the time of biopsy.
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Lesions with a histopathological diagnosis of papilloma, verruca or condyloma were grouped as HPVrelated. These were most frequently found on the tongue 34 (38%) and soft palate 19 (21%). Followed by lower lip, buccal mucosa and hard palate. (Fig 2). Hyperplastic lesions were most frequently on the tongue 12 (41%) followed by gingiva and soft palate 4 (14% each), lower lip and floor of mouth (Fig 3). Hyperplastic candidiasis was most frequent on the buccal mucosa and tongue 6 and 7 (35% and 24% respectively), followed by the commissure and soft palate (Fig 4). There were 6 lesions with dysplasia, 2 of which were in the vestibule (33%), and one in each of tongue, commissure, floor of mouth and retromolar region. (17% each) (Fig 5). 2.6% of the lesions were malignant, 1.3% Squamous cell carcinoma, 1.3% verrucous carcinoma. 50% of the verrucous/papillary malignant lesions were found on the gingiva (Fig 6). Most of these lesions were found in the 40- 60-year age group (Fig 7).
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The mean age of patients with HPV induced lesion was 48 years, malignant or dysplastic lesions - 67 years and hyperplastic lesions - 43 years. Lesions with dysplasia and malignancy were seen in an older age group than HPV induced lesions and hyperplastic lesions (found to be statistically significantANOVA, p<0.05). The average clinical size for each group of lesions was as follows: dysplasia 20mm, HPV induced lesions 5.7mm, hyperplastic lesions 5.4 mm, hyperplastic candidiasis 4.3 mm, malignancy 22 mm and others 5mm. The dysplastic and malignant lesions were larger than the remainder of the lesions (Kruskal Wallis Test). Analysis of the clinical diagnoses submitted with the biopsy showed that overall, 47% of cases included the correct diagnosis in the differential. 61% of HPV induced lesions and 31% of candida involved lesions were suspected as such in the differential diagnosis. 60% of malignancies were suspected at the time of biopsy.
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Discussion
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The purpose of this study was to investigate the spectrum of pathologies of lesions which present clinically with a papillary-verrucous architecture. A deeper understanding of the types of lesions in this group as well as their relative frequencies may aid the clinician to more effectively devise a differential diagnosis and a treatment plan. For analysis lesions were grouped into six subgroups. HPV-induced lesions were the most frequent diagnosis; however, they account for only 60% of cases in the present series, oral squamous papilloma (Fig8A) being the most common in that group. In a study2 of 464 lesions, squamous papilloma was defined as an “exophytic arrangement of multiple papillary projections of stratified squamous epithelium arranged around a central fibrovascular connective tissue core”. The squamous papilloma has since been clearly associated with Human Papilloma Virus (HPV), most frequently types 6 and 113. Verruca vulgaris (the common wart) (Fig9C) is an additional lesion induced by HPV, most frequently HPV type 2. It has been described in the literature as "pebbly". The clinicians in our group most frequently described these lesions as papillary and exophytic. Verruca vulgaris is a relatively common lesion in children4, but, in the present cohort, verruca have been observed in a wide age range- children and adults alike. Condyloma is also associated with HPV types 6 and 11, although additional HPV types, 16 and 18 have been described in condyloma. Condyloma is also characterized by a proliferation of squamous epithelium, with short blunt surface projections, which in contrast to papilloma, has a sessile base. In the present study, most papilloma presented as white lesions, and measured 5-6 mm in diameter. Condylomas were described as pink and larger in size and broad based. Condylomas are considered sexually transmitted diseases5, and are not uncommon in the
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oral cavity. For the majority of the cases in the present study there is no clinical information regarding genital lesions in the same patients. Verruca and papilloma are macroscopically very similar, making the differentiation between the two challenging. If properly sectioned during lab processing prior to embedding, papilloma will present a central stalk around which the papillary projections are arranged, whereas verruca will have a broad base with the epithelial extensions at the base of the lesion converging towards the center. However, distinction between the two may not be possible on a microscopic basis due to orientation of the tissue and final diagnosis relies on the clinical description of sessile or pedunculated lesions. In a majority of these lesions focal koilocytes can be observed.
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Pathologists recognize the presence of koilocytes in a lesion as proof that it is HPV induced6; with the increased access of PCR techniques it has been shown that the presence of koilocytes in lesions is 80% accurate in proving association with HPV7. Therefore, to achieve a higher level of accuracy in diagnosing HPV lesions, PCR may be carried out in addition to histopathological analysis. In the present study, histopathological analysis alone had been performed, so approximately 80% accuracy can be expected. In clinical practice, PCR analysis and genotyping of HPV has not been accepted yet as mandatory for every case of oral HPV-related lesion, and no treatment or follow-up protocol has yet been accepted which would put into use the results of molecular studies, although this may change in the future. Following excision, which is the accepted form of treatment, there is mixed data regarding recurrence of HPV induced lesions, ranging between 0-18%8. There is accumulated evidence of the association of oropharyngeal cancers and HPV9+10, including identifying HPV viral genomes within the tumor11. An increase in HPV positive oropharyngeal (base of tongue and pharynx) carcinomas in the last 3 decades has been observed12+13. Supporting this, Gillisons14 study of individuals aged 14 to 69 years in the US (2009-2010), found the prevalence of oral HPV to be increased to 6.9%. However, the majority of oral HPV related lesions are induced by low-risk species, and not related with malignancy. Therefore, it is important for specialists in oral surgery and oral medicine to have a wider understanding of the nature and behavior of HPV induced lesions, and then to accurately diagnose, as well as relate the correct information to the anxious patient. Furthermore, only 61% of HPV-related lesions were recognized as such prior to biopsy, emphasizing limitations of clinical diagnosis.
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The second relatively common group in the present study was papillary hyperplasia. Inflammatory papillary hyperplasia, is most often seen underneath ill-fitting dentures, however, it may also be present without a denture. Usually asymptomatic, the mucosa has a pebbly, papillary appearance. Histologically, there are multiple papillary projections of the surface of the mucosa, and there is an associated chronic inflammatory component15. Papillary hyperplasia has been frequently associated with candida infection16. The microscopic features which would help in differentiating papillary hyperplasia from HPVrelated lesions would be a predominant lack of the typical hyperkeratosis, (sometimes described as "church spire keratosis") which is seen in papilloma and verruca, as well as absence of koilocytosis, common in most HPV-related lesions. Some oral malignancies may also present with papillary-verrucous surface characteristics. Verrucous carcinoma (VC) (Fig9A) is a low-grade variant of the squamous cell carcinoma, which has been associated in several reports with HPV type 6, 11, 16 and 1817. Clinically seen as a mass with a verrucous or papillary surface, VC has been known to develop from proliferative verrucous leukoplakia (PVL) in some cases18, but may also be related to chewing tobacco 19, or develop spontaneously. The most frequent type of oral malignancy (95%) is squamous cell carcinoma20. The clinical appearance of oral SCC is wide and varied, including leukoplakic, ulcerated and exophytic masses. Papillary SCC is a relatively uncommon subtype, most cases have been found in the larynx and far fewer in the oral
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cavity21. It may present a papillary exophytic component clinically, and there is a possible association with HPV. In addition, carcinoma cuniculatum, a rare form of oral cancer may also present with an exophytic papillary-verrucous component22. These lesions usually have features other than papillaryverrucous surface which may raise suspicion for malignancy, (such as a larger size, induration, or foulsmelling secretion in the case of carcinoma cuniculatum). However, as has been demonstrated in the present group, close to half of the cases of dysplasia or malignancy had not been suspected as such at the time the biopsy had been submitted. Thus, in lesions with a clinical description of verrucous or papillary surface VC and SCC cannot be excluded from the differential diagnosis list with a high degree of confidence. However, considering the relative low frequency of VC or papillary SCC, they probably need not be high on the list of DD. Since papillary- verrucous lesions which are dysplastic or frankly malignant cannot always be separated clinically from the majority of benign lesions in this groups, biopsy is mandatory.
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There are some additional lesions of unknown etiology which may present with a verrucous or papillary surface. Verruciform xanthoma (Fig8) is described as a hyperplastic proliferation of the epithelium with a sub epithelial accumulation of lipid-laden histiocytes, thought to be caused by trauma23. The accumulation of these large histiocytes underneath the surface pushes the surface into the typical pebbly architecture, which may take on a yellowish hue. These lesions are not related to HPV, a fact which may be reassuring for the patient, once the correct diagnosis has been obtained following biopsy.
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A small number of giant cell fibromas were seen in the present group. Giant cell fibromas are fibrous tumors, appearing clinically as a sessile or a pedunculated mass, which is usually asymptomatic and generally, no bigger than 1cm. Frequently, the surface of this lesion is described as papillary and so can be mistaken for a papilloma. Histologically, the giant cell fibroma is made up of a mass of dense fibrous connective tissue, with numerous, large stellate fibroblasts, sometime observed to have multiple nuclei24. Although, HPV is the etiological factor in a significant proportion of lesions, it is by no means the unique cause of verrucous-papillary lesions. In the present study 40% of lesions had another diagnosis, including candida induced, dysplastic and even malignancy.
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The age of the patient definitely plays a role in guiding the clinician towards a differential diagnosis, which in the over 60-year age group, should include malignancy or dysplasia. Although the biopsies were carried out by trained specialists or residents of the Oral-Maxillofacial and ENT departments, the ability to provide an accurate provisional diagnosis, based solely on clinical examination had limitations, with an overall accuracy below 50% of cases, and only 60% in malignant or dysplastic lesions. A similar level of accuracy was seen previously in a study by Kondori et.al. of excised oral lesions25. These results indicate that there is a need to excise and submit for histopathological diagnosis all oral papillary lesions, for accurate diagnosis and treatment planning. Due to recent media coverage on the papilloma virus and its association with both cancer and sexually transmitted disease, it is of growing importance to correctly identify those lesions which are HPV-related, but at the same time to rule-out those lesions which are unrelated to HPV, to help in alleviating patients, and their partners' anxieties. Although only a relatively small fraction of the papillary-verrucous lesions was dysplastic or malignant, they could not all be identified clinically as such, again emphasizing the need for biopsy and histopathological evaluation. Conclusion
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Lesions with a clinical papillary- verrucous architecture present a wide spectrum of entities, benign in the majority but not all cases, with various etiologies, which include HPV as well as candida, and some lesions of undetermined etiology. Although the size of the lesions and patients age may help in developing a more accurate differential diagnosis, the clinical presentations allowed for overall accurate diagnosis in only 47% of cases, 60% in dysplastic or malignant cases. This indicates there is a need to biopsy all papillary-verrucous lesions, since it is of significant importance to correctly identify those lesions which are HPV-related, but at the same time to rule-out those lesions which are unrelated to HPV, to help in alleviating a patient’s anxiety. Most importantly, biopsy is mandatory for recognition of the malignant lesions with a papillary verrucous architecture, which may mimic other benign entities in the group of papillary verrucous lesions.
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Kallarakkal. T.G, Ramanathan A, Rosnah Binti Zain. Verrucous Papillary Lesions: Dilemmas in Diagnosis and Terminology. Int j Dent. 2013. 2 Abbey LM, Page DG, Sawyer DR: The clinical and histopathologic features of a series of 464 oral squamous cell papillomas. Oral Surgery, Oral Med Oral Pathol 49: 419, 1980. 3 th Neville B, Damm DD, Allen CM, Bouquot J. Oral and Maxillofacial Pathology. 4 ed. St Louis: Saunders-Elsevier; 2016. 332. 4 Castro TP, Bussoloti Filho I: Prevalence of human papillomavirus (HPV) in oral cavity and oropharynx . Braz J Otorhinolaryngol 72: 272, 2006. 5 Anderson KM, Perez-Montiel D, Miles L, Allen CM, Nuovo GJ: The histologic differentiation of oral condyloma acuminatum from its mimics. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 96: 420, 2003. 6 Aggarwal S, Arora VK, Gupta S, Singh N, Bhatia A. Koilocytosis: correlations with high-risk HPV and its comparison on tissue sections and cytology, urothelial carcinoma. Diagn Cytopathol 37: 174-177, 2009. 7 Miyahara GI, Simonato LE, Mattar NJ, Camilo DJ, Biasoli ER: Correlation between koilocytes and human papillomavirus detection by PCR in oral and oropharynx squamous cell carcinoma biopsies. Mem Inst Oswaldo Cruz 106: 166, 2011. 8 Bouquot JE, Wrobleski GJ. Papillary (pebbled) masses of the oral mucosa: more than simple papillomas. Pract Periodontics Aesthet Dent. 8(6):533-43, 1996 9 Smith EM, Hoffman HT, Summersgill KS, Kirchner HL, Turek LP, Haugen TH. Human papillomavirus and risk of head and neck cancer. Laryngoscope; 108:1098-103, 1998 10 Franceschi S, Munoz N, Snijders PJ. How strong and wide is the link between HPV and oropharyngeal cancer? Lancet; 356:871-2, 2000 11 Smith EM, Ritchie JM, Summersgill KF, Klussman JP, Lee JH, Wang D, Haugen TH, Turek LP. Age, sexual behavior and human papillomavirus infection in oral cavity and oropharyngeal cancers. Int. J. Cancer: 108 766-772, 2004. 12 Bayer O, Kruger M, Koutsimpelas D, Emrich K, Ressing M, Zeissig SR, Simon C, Singer S: Changes in Incidence and Mortality Trends of Head and Neck Cancer in Rhineland-Palatinate, 2000-2009. Laryngorhinootologie 94: 451, 2015. 13 Cleveland JL, Junger ML, Saraiya M, Markowitz LE, Dunne EF, Epstein JB. The connection between human papillomavirus and oropharyngeal squamous cell carcinomas in the United States: implications for dentistry. J Am Dent Assoc. 142(8):915-24, 2011. 14 Gillison ML1, Broutian T, Pickard RK, Tong ZY, Xiao W, Kahle L, Graubard BI, Chaturvedi AK. Prevalence of oral HPV infection in the United States, 2009-2010. JAMA. 15;307(7):693-703. 2012. 15 See reference 2. 16 Poulopoulos A, Belazi M, Epivatianos A, Velegraki A, Antoniades D. The role of Candida in inflammatory papillary hyperplasia of the palate. J Oral Rehabil. 34(9):685-92, 2007.
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Lin HP, Wang YP, Chiang CP. Expression of p53, MDM2, p21, heat shock protein 70, and HPV 16/18 E6 proteins in oral verrucous carcinoma and oral verrucous hyperplasia. Head Neck. 33(3):334-40, 2011. 18 Gandolfo S, Castellani R, Pentenero M. Proliferative verrucous leukoplakia: a potentially malignant disorder involving periodontal sites. J Periodontol. 80(2):274-81, 2009. 19 Sonalika WG, Anand T. Oral verrucous carcinoma: A retrospective analysis for clinicopathologic features. J Cancer Res Ther. 12(1):142-5. 2016 20 th Goldman-Cecil Medicine, 25 Edition, Saunders-Elsevier. 2016. 190, 1297-1303. 21 Russell JO, Hoschar AP, Scharpf J. Papillary squamous cell carcinoma of the head and neck: a clinicopathologic series. American Journal of Otolaryngology. 32(6), 557-563, 2011. 22 Sun Y, Kuyama K, Burkhardt A, Yamamoto H.J Clinicopathological evaluation of carcinoma cuniculatum: a variant of oral squamous cell carcinoma. Oral Pathol Med. 41(4):303-8. 2012 23 Cumberland L, Dana A, Resh B, Fitzpatrick J, Goldenberg G. Verruciform xanthoma in the setting of cutaneous trauma and chronic inflammation: report of a patient and a brief review of the literature. J Cutan Pathol. 37(8):895-900. 2010. 24 See footnote 2 25 Kondori I, Mottin RW, Laskin DM. Accuracy of dentists in the clinical diagnosis of oral lesions. Quintessence Int. 42(7):575-7. 2011
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Legend Figure 1: Shows that the majority of lesions proved to be HPV related. Followed by hyperplasia, hyperplastic candidiasis, and dysplasia. Figure 2: Shows that the majority of HPV lesions were found on the tongue. Figure 3: Shows that most hyperplastic lesion were found on the tongue, followed by the gingiva and soft palate. Figure 4: Shows that hyperplastic candidiasis was most commonly found on the buccal mucosa, followed by the tongue and soft palate. Figure 5: Showed that a majority of dysplastic lesions were found in the vestibule. Figure 6: Shows that most malignant lesions were found on the gingiva. Figure 7: Shows that malignant and dysplastic lesions were seen in older patients and HPV related lesions were seen in significantly younger patients. Figure 8: A1- Papillary lesion on the palate A2- Histology showed a papilloma B1- Verruciform Xanthoma (Courtesy of Dr Noam Yarom, Sheba Medical Centre)
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B2-Low magnification showing papillary configuration B3-The mucosal papillae are infiltrated by large histiocytes with foamy cytoplasm B4- Immunohistochemical stain for CD68 which emphasizes the histiocytes in the connective tissue
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Figure 9: A1- Verrucous lesion of left mandibular canine area A2- The histology showed a verrucous carcinoma B1- Papillary lesion/proliferative verrucous leukoplakia on an edentulous palate B2-The histology showed papillary hyperplasia with dysplasia C1- Verrucous lesion on the palate C2- Histology showed a verruca vulgaris
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Date: 10th August 2017 To the Editor
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Journal of Oral and Maxillofacial Surgery
I have made a few changes as advised by the editorial reviewers: Reviewer Comments in bold followed by my response:
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1) Reviewer #1: I enjoyed your paper and the premise of inaccuracy in clinical diagnosis mandating soft tissue biopsy for definitive diagnosis of the verruca-papillary lesions. A similar rate of misdiagnosis (~43%) was determined in a study looking at oral lesion submission in 2011: Kondori, Ida, Roberta W. Mottin, and Daniel M. Laskin. "Accuracy of dentists in the clinical diagnosis of oral lesions." Quintessence International 42.7 (2011). Architecturally, rounded projections versus spire like projections are dependent upon different viral subtypes but are also determined by things like hyperplasia with broad pushing fronts extending for a blood supply or ."spires" pulling fibrovascular cores up with them It is necessary to stress soft tissue biopsy and submission of tissue in cases where the clinical diagnosis is questionable. I have inserted a highlighted reference, referring to said paper.
2) The alpha-numeric designation of Figures 8 and 9 was not listed on the pages with those images, and I felt the images could be better focused I have added the alpha-numeric designation to the description of the figures.
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3) Please remove all images from the manuscript document and add them as individual figure files
Sincerely,
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Figures removed and attached separately.
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Dr Sara Whitefield
Department of Oral Pathology and Medicine Goldschleger School of Dental Medicine, Tel-Aviv University Tel-Aviv, Israel
Email: [email protected]
S0278-2391(17)31153-9
DOI:
10.1016/j.joms.2017.08.030
Reference:
YJOMS 57965
To appear in:
Journal of Oral and Maxillofacial Surgery
Received Date: 0278-2391 0278-2391 Revised Date:
0278-2391 0278-2391
Accepted Date: 0278-2391 0278-2391
Please cite this article as: Sara W, Vadim R, Amir S, Shlomi K, Benjamin S, Ilana K, The Spectrum Of Oral Lesions Presenting Clinically With Papillary- Verrucous Features, Journal of Oral and Maxillofacial Surgery (2017), doi: 10.1016/j.joms.2017.08.030. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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THE SPECTRUM OF ORAL LESIONS PRESENTING CLINICALLY WITH PAPILLARYVERRUCOUS FEATURES
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WHITEFIELD SARA1, RAISER VADIM2, SHUSTER AMIR 1,2, KLEINMAN SHLOMI2, SHLOMI BENJAMIN1,2, KAPLAN ILANA1,2,3
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GOLDSCHLEGER SCHOOL OF DENTAL MEDICINE, TEL-AVIV UNIVERSITY, ISRAEL TEL-AVIV SOURASKY MEDICAL CENTER, TEL-AVIV, ISRAEL 3 SACKLER SCHOOL OF MEDICINE, TEL-AVIV UNIVERSITY, ISRAEL 2
Corresponding author;
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Key words Oral, verrucous, papillary, HPV, malignant
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Dr Sara Whitefield BDS – Resident in Oral Medicine and Private practitioner Dr Vadim Raiser DMD – Head of Maxillofacial Unit Dr Amir Shuster DMD PhD – Attending Surgeon Dr Shlomi Kleinman- Senior Surgeon Dr Benjamin Shlomi- DMD Former Head of Maxillofacial Unit (Retired) Professor Ilana Kaplan- Oral Pathologist
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Dr Sara Whitefield Department of oral Pathology and Medicine Goldschleger School of Dental Medicine, Tel Aviv University Tel Aviv, Israel Tel: 00 97254 6399810 Email address: [email protected]
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THE SPECTRUM OF ORAL LESIONS PRESENTING CLINICALLY WITH PAPILLARYVERRUCOUS FEATURES
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WHITEFIELD SARA1, RAISER VADIM2, SHUSTER AMIR 1,2, KLEINMAN SHLOMI2, SHLOMI BENJAMIN1,2, KAPLAN ILANA1,2,3
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GOLDSCHLEGER SCHOOL OF DENTAL MEDICINE, TEL-AVIV UNIVERSITY, ISRAEL TEL-AVIV SOURASKY MEDICAL CENTER, TEL-AVIV, ISRAEL 3 SACKLER SCHOOL OF MEDICINE, TEL-AVIV UNIVERSITY, ISRAEL
Key words Oral, verrucous, papillary, HPV, malignant
Corresponding author;
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Dr Sara Whitefield Department of oral Pathology and Medicine Goldschleger School of Dental Medicine, Tel Aviv University Tel Aviv, Israel Tel: 00 97254 6399810 Email address: [email protected]
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Abstract
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Purpose: To study the spectrum of oral pathologies presenting clinically with papillary-verrucous features. Materials and Methods: 10-year retrospective study (2007 to 2016) of oral papillary lesions was undertaken. All biopsies which included a clinical description of papillary or verrucous architecture were retrieved. The data collected included clinical features, size, color, location, histopathological diagnosis age and gender. Results: The study included 137 patients, with a total of 151 lesions. The ages ranged from 10 weeks to 84 years (mean 49). Histopathologically, 60% of cases were HPV related, 19% showed hyperplasia, 11% hyperplastic candidiasis, 7% dysplastic or malignant and 3% benign of unknown etiology. Of the 7% diagnosed with dysplasia or malignancy, only 60% were suspected for malignancy at the time of biopsy. HPV-related lesions and hyperplasia were most frequently found on the tongue (38% and 41%) and soft palate (21 and 14%), respectively. Hyperplastic candidiasis was most frequent on the buccal mucosa and tongue (35 and 24%, respectively). 1.3% of total lesions were found to be squamous cell carcinoma (SCC) and 1.3% verrucous carcinoma. 50% of the verrucous/papillary malignant lesions were found on the gingiva. Most malignant lesions occurred in the 40-60 age group. Conclusion: The results of this study suggest, that due to the wide spectrum of entities presenting clinically as papillary-verrucous architecture, biopsy is necessary for diagnosis. The clinical presentations allowed for overall accurate diagnosis in only 47% of cases and 60% accuracy in dysplastic or malignant cases. It is of significant importance to correctly identify those lesions which are HPV-related, but at the same time to rule-out those lesions which are unrelated to HPV, to help alleviate a patient’s anxiety. Most importantly, biopsy is mandatory for recognition of the malignant lesions with a papillary verrucous architecture, which may mimic other benign entities in the group of papillary verrucous lesions.
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Introduction
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Exophytic, papillary-verrucous lesions are relatively common in the oral cavity. A clinical description of verrucous or papillary architecture includes a wide spectrum of histopathological diagnoses1. Their etiology varies from reactive, local irritation, viral, fungal, premalignant to malignant. The similarity in architecture and variety in histopathological diagnoses can prove to be challenging to the clinician at initial examination .A search of the English language literature for oral papillary lesions yielded only limited information regarding the epidemiological spectrum of such lesions.
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Objectives
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To investigate the spectrum of lesions presenting clinically or histologically as verrucous or papillary and to characterize each subgroup. In addition, to analyze correlations between the histopathological diagnosis and the clinical diagnosis, with emphasis on cases with histopathological dysplasia or malignancy. Methods
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A retrospective analysis of biopsy results from the Institute of Pathology between the years 2007-2016 was undertaken. The study was conducted in accordance with ethical requirements (both Israeli and GCP-ICH standards) of clinical trials. The institute is a referral center for Oral and Maxillofacial Surgery and the biopsies were diagnosed by a certified oral pathologist (IK). All intra-oral biopsy reports with a clinical and/or histopathological description of papillary or verrucous architecture were retrieved. Data collected included demographic data and clinical features of the lesions as well as histopathological diagnosis. The histopathological diagnoses were divided into the following groups: candidal hyperplasia, papillary hyperplasia, HPV-related, epithelial hyperplasia with dysplasia, malignancy and others. Each parameter was compared between groups. Statistical analysis was performed comparing each variable between the groups. One way analysis of variants (ANOVA) was performed to assess differences in age at presentation between the groups. Pearson Chi squared analysis was used to identify differences in gender distribution between the groups. The Kruskal Wallis Test was used to evaluate the differences in lesion diameter between the groups. Results
A total of 151 lesions with verrucous or papillary architecture, were obtained from 137 patients, 67 males and 70 females, almost equal gender distribution. 12 (8.7 %) patients had more than 1 lesion, one of which had 4 lesions. The most frequent diagnoses were HPV- induced lesions, 89 (60%) and papillary hyperplasia 29 (19%). 17 (11%), were hyperplastic candidiasis, 10 (7%) dysplasia or malignancy and 5 (3%) were benign lesions of unknown etiology. (Fig 1) Of the 7% diagnosed with dysplasia or malignancy, only 60% were suspected for malignancy at the time of biopsy.
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Lesions with a histopathological diagnosis of papilloma, verruca or condyloma were grouped as HPVrelated. These were most frequently found on the tongue 34 (38%) and soft palate 19 (21%). Followed by lower lip, buccal mucosa and hard palate. (Fig 2). Hyperplastic lesions were most frequently on the tongue 12 (41%) followed by gingiva and soft palate 4 (14% each), lower lip and floor of mouth (Fig 3). Hyperplastic candidiasis was most frequent on the buccal mucosa and tongue 6 and 7 (35% and 24% respectively), followed by the commissure and soft palate (Fig 4). There were 6 lesions with dysplasia, 2 of which were in the vestibule (33%), and one in each of tongue, commissure, floor of mouth and retromolar region. (17% each) (Fig 5). 2.6% of the lesions were malignant, 1.3% Squamous cell carcinoma, 1.3% verrucous carcinoma. 50% of the verrucous/papillary malignant lesions were found on the gingiva (Fig 6). Most of these lesions were found in the 40- 60-year age group (Fig 7).
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The mean age of patients with HPV induced lesion was 48 years, malignant or dysplastic lesions - 67 years and hyperplastic lesions - 43 years. Lesions with dysplasia and malignancy were seen in an older age group than HPV induced lesions and hyperplastic lesions (found to be statistically significantANOVA, p<0.05). The average clinical size for each group of lesions was as follows: dysplasia 20mm, HPV induced lesions 5.7mm, hyperplastic lesions 5.4 mm, hyperplastic candidiasis 4.3 mm, malignancy 22 mm and others 5mm. The dysplastic and malignant lesions were larger than the remainder of the lesions (Kruskal Wallis Test). Analysis of the clinical diagnoses submitted with the biopsy showed that overall, 47% of cases included the correct diagnosis in the differential. 61% of HPV induced lesions and 31% of candida involved lesions were suspected as such in the differential diagnosis. 60% of malignancies were suspected at the time of biopsy.
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Discussion
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The purpose of this study was to investigate the spectrum of pathologies of lesions which present clinically with a papillary-verrucous architecture. A deeper understanding of the types of lesions in this group as well as their relative frequencies may aid the clinician to more effectively devise a differential diagnosis and a treatment plan. For analysis lesions were grouped into six subgroups. HPV-induced lesions were the most frequent diagnosis; however, they account for only 60% of cases in the present series, oral squamous papilloma (Fig8A) being the most common in that group. In a study2 of 464 lesions, squamous papilloma was defined as an “exophytic arrangement of multiple papillary projections of stratified squamous epithelium arranged around a central fibrovascular connective tissue core”. The squamous papilloma has since been clearly associated with Human Papilloma Virus (HPV), most frequently types 6 and 113. Verruca vulgaris (the common wart) (Fig9C) is an additional lesion induced by HPV, most frequently HPV type 2. It has been described in the literature as "pebbly". The clinicians in our group most frequently described these lesions as papillary and exophytic. Verruca vulgaris is a relatively common lesion in children4, but, in the present cohort, verruca have been observed in a wide age range- children and adults alike. Condyloma is also associated with HPV types 6 and 11, although additional HPV types, 16 and 18 have been described in condyloma. Condyloma is also characterized by a proliferation of squamous epithelium, with short blunt surface projections, which in contrast to papilloma, has a sessile base. In the present study, most papilloma presented as white lesions, and measured 5-6 mm in diameter. Condylomas were described as pink and larger in size and broad based. Condylomas are considered sexually transmitted diseases5, and are not uncommon in the
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oral cavity. For the majority of the cases in the present study there is no clinical information regarding genital lesions in the same patients. Verruca and papilloma are macroscopically very similar, making the differentiation between the two challenging. If properly sectioned during lab processing prior to embedding, papilloma will present a central stalk around which the papillary projections are arranged, whereas verruca will have a broad base with the epithelial extensions at the base of the lesion converging towards the center. However, distinction between the two may not be possible on a microscopic basis due to orientation of the tissue and final diagnosis relies on the clinical description of sessile or pedunculated lesions. In a majority of these lesions focal koilocytes can be observed.
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Pathologists recognize the presence of koilocytes in a lesion as proof that it is HPV induced6; with the increased access of PCR techniques it has been shown that the presence of koilocytes in lesions is 80% accurate in proving association with HPV7. Therefore, to achieve a higher level of accuracy in diagnosing HPV lesions, PCR may be carried out in addition to histopathological analysis. In the present study, histopathological analysis alone had been performed, so approximately 80% accuracy can be expected. In clinical practice, PCR analysis and genotyping of HPV has not been accepted yet as mandatory for every case of oral HPV-related lesion, and no treatment or follow-up protocol has yet been accepted which would put into use the results of molecular studies, although this may change in the future. Following excision, which is the accepted form of treatment, there is mixed data regarding recurrence of HPV induced lesions, ranging between 0-18%8. There is accumulated evidence of the association of oropharyngeal cancers and HPV9+10, including identifying HPV viral genomes within the tumor11. An increase in HPV positive oropharyngeal (base of tongue and pharynx) carcinomas in the last 3 decades has been observed12+13. Supporting this, Gillisons14 study of individuals aged 14 to 69 years in the US (2009-2010), found the prevalence of oral HPV to be increased to 6.9%. However, the majority of oral HPV related lesions are induced by low-risk species, and not related with malignancy. Therefore, it is important for specialists in oral surgery and oral medicine to have a wider understanding of the nature and behavior of HPV induced lesions, and then to accurately diagnose, as well as relate the correct information to the anxious patient. Furthermore, only 61% of HPV-related lesions were recognized as such prior to biopsy, emphasizing limitations of clinical diagnosis.
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The second relatively common group in the present study was papillary hyperplasia. Inflammatory papillary hyperplasia, is most often seen underneath ill-fitting dentures, however, it may also be present without a denture. Usually asymptomatic, the mucosa has a pebbly, papillary appearance. Histologically, there are multiple papillary projections of the surface of the mucosa, and there is an associated chronic inflammatory component15. Papillary hyperplasia has been frequently associated with candida infection16. The microscopic features which would help in differentiating papillary hyperplasia from HPVrelated lesions would be a predominant lack of the typical hyperkeratosis, (sometimes described as "church spire keratosis") which is seen in papilloma and verruca, as well as absence of koilocytosis, common in most HPV-related lesions. Some oral malignancies may also present with papillary-verrucous surface characteristics. Verrucous carcinoma (VC) (Fig9A) is a low-grade variant of the squamous cell carcinoma, which has been associated in several reports with HPV type 6, 11, 16 and 1817. Clinically seen as a mass with a verrucous or papillary surface, VC has been known to develop from proliferative verrucous leukoplakia (PVL) in some cases18, but may also be related to chewing tobacco 19, or develop spontaneously. The most frequent type of oral malignancy (95%) is squamous cell carcinoma20. The clinical appearance of oral SCC is wide and varied, including leukoplakic, ulcerated and exophytic masses. Papillary SCC is a relatively uncommon subtype, most cases have been found in the larynx and far fewer in the oral
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cavity21. It may present a papillary exophytic component clinically, and there is a possible association with HPV. In addition, carcinoma cuniculatum, a rare form of oral cancer may also present with an exophytic papillary-verrucous component22. These lesions usually have features other than papillaryverrucous surface which may raise suspicion for malignancy, (such as a larger size, induration, or foulsmelling secretion in the case of carcinoma cuniculatum). However, as has been demonstrated in the present group, close to half of the cases of dysplasia or malignancy had not been suspected as such at the time the biopsy had been submitted. Thus, in lesions with a clinical description of verrucous or papillary surface VC and SCC cannot be excluded from the differential diagnosis list with a high degree of confidence. However, considering the relative low frequency of VC or papillary SCC, they probably need not be high on the list of DD. Since papillary- verrucous lesions which are dysplastic or frankly malignant cannot always be separated clinically from the majority of benign lesions in this groups, biopsy is mandatory.
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There are some additional lesions of unknown etiology which may present with a verrucous or papillary surface. Verruciform xanthoma (Fig8) is described as a hyperplastic proliferation of the epithelium with a sub epithelial accumulation of lipid-laden histiocytes, thought to be caused by trauma23. The accumulation of these large histiocytes underneath the surface pushes the surface into the typical pebbly architecture, which may take on a yellowish hue. These lesions are not related to HPV, a fact which may be reassuring for the patient, once the correct diagnosis has been obtained following biopsy.
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A small number of giant cell fibromas were seen in the present group. Giant cell fibromas are fibrous tumors, appearing clinically as a sessile or a pedunculated mass, which is usually asymptomatic and generally, no bigger than 1cm. Frequently, the surface of this lesion is described as papillary and so can be mistaken for a papilloma. Histologically, the giant cell fibroma is made up of a mass of dense fibrous connective tissue, with numerous, large stellate fibroblasts, sometime observed to have multiple nuclei24. Although, HPV is the etiological factor in a significant proportion of lesions, it is by no means the unique cause of verrucous-papillary lesions. In the present study 40% of lesions had another diagnosis, including candida induced, dysplastic and even malignancy.
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The age of the patient definitely plays a role in guiding the clinician towards a differential diagnosis, which in the over 60-year age group, should include malignancy or dysplasia. Although the biopsies were carried out by trained specialists or residents of the Oral-Maxillofacial and ENT departments, the ability to provide an accurate provisional diagnosis, based solely on clinical examination had limitations, with an overall accuracy below 50% of cases, and only 60% in malignant or dysplastic lesions. A similar level of accuracy was seen previously in a study by Kondori et.al. of excised oral lesions25. These results indicate that there is a need to excise and submit for histopathological diagnosis all oral papillary lesions, for accurate diagnosis and treatment planning. Due to recent media coverage on the papilloma virus and its association with both cancer and sexually transmitted disease, it is of growing importance to correctly identify those lesions which are HPV-related, but at the same time to rule-out those lesions which are unrelated to HPV, to help in alleviating patients, and their partners' anxieties. Although only a relatively small fraction of the papillary-verrucous lesions was dysplastic or malignant, they could not all be identified clinically as such, again emphasizing the need for biopsy and histopathological evaluation. Conclusion
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Lesions with a clinical papillary- verrucous architecture present a wide spectrum of entities, benign in the majority but not all cases, with various etiologies, which include HPV as well as candida, and some lesions of undetermined etiology. Although the size of the lesions and patients age may help in developing a more accurate differential diagnosis, the clinical presentations allowed for overall accurate diagnosis in only 47% of cases, 60% in dysplastic or malignant cases. This indicates there is a need to biopsy all papillary-verrucous lesions, since it is of significant importance to correctly identify those lesions which are HPV-related, but at the same time to rule-out those lesions which are unrelated to HPV, to help in alleviating a patient’s anxiety. Most importantly, biopsy is mandatory for recognition of the malignant lesions with a papillary verrucous architecture, which may mimic other benign entities in the group of papillary verrucous lesions.
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Kallarakkal. T.G, Ramanathan A, Rosnah Binti Zain. Verrucous Papillary Lesions: Dilemmas in Diagnosis and Terminology. Int j Dent. 2013. 2 Abbey LM, Page DG, Sawyer DR: The clinical and histopathologic features of a series of 464 oral squamous cell papillomas. Oral Surgery, Oral Med Oral Pathol 49: 419, 1980. 3 th Neville B, Damm DD, Allen CM, Bouquot J. Oral and Maxillofacial Pathology. 4 ed. St Louis: Saunders-Elsevier; 2016. 332. 4 Castro TP, Bussoloti Filho I: Prevalence of human papillomavirus (HPV) in oral cavity and oropharynx . Braz J Otorhinolaryngol 72: 272, 2006. 5 Anderson KM, Perez-Montiel D, Miles L, Allen CM, Nuovo GJ: The histologic differentiation of oral condyloma acuminatum from its mimics. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 96: 420, 2003. 6 Aggarwal S, Arora VK, Gupta S, Singh N, Bhatia A. Koilocytosis: correlations with high-risk HPV and its comparison on tissue sections and cytology, urothelial carcinoma. Diagn Cytopathol 37: 174-177, 2009. 7 Miyahara GI, Simonato LE, Mattar NJ, Camilo DJ, Biasoli ER: Correlation between koilocytes and human papillomavirus detection by PCR in oral and oropharynx squamous cell carcinoma biopsies. Mem Inst Oswaldo Cruz 106: 166, 2011. 8 Bouquot JE, Wrobleski GJ. Papillary (pebbled) masses of the oral mucosa: more than simple papillomas. Pract Periodontics Aesthet Dent. 8(6):533-43, 1996 9 Smith EM, Hoffman HT, Summersgill KS, Kirchner HL, Turek LP, Haugen TH. Human papillomavirus and risk of head and neck cancer. Laryngoscope; 108:1098-103, 1998 10 Franceschi S, Munoz N, Snijders PJ. How strong and wide is the link between HPV and oropharyngeal cancer? Lancet; 356:871-2, 2000 11 Smith EM, Ritchie JM, Summersgill KF, Klussman JP, Lee JH, Wang D, Haugen TH, Turek LP. Age, sexual behavior and human papillomavirus infection in oral cavity and oropharyngeal cancers. Int. J. Cancer: 108 766-772, 2004. 12 Bayer O, Kruger M, Koutsimpelas D, Emrich K, Ressing M, Zeissig SR, Simon C, Singer S: Changes in Incidence and Mortality Trends of Head and Neck Cancer in Rhineland-Palatinate, 2000-2009. Laryngorhinootologie 94: 451, 2015. 13 Cleveland JL, Junger ML, Saraiya M, Markowitz LE, Dunne EF, Epstein JB. The connection between human papillomavirus and oropharyngeal squamous cell carcinomas in the United States: implications for dentistry. J Am Dent Assoc. 142(8):915-24, 2011. 14 Gillison ML1, Broutian T, Pickard RK, Tong ZY, Xiao W, Kahle L, Graubard BI, Chaturvedi AK. Prevalence of oral HPV infection in the United States, 2009-2010. JAMA. 15;307(7):693-703. 2012. 15 See reference 2. 16 Poulopoulos A, Belazi M, Epivatianos A, Velegraki A, Antoniades D. The role of Candida in inflammatory papillary hyperplasia of the palate. J Oral Rehabil. 34(9):685-92, 2007.
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Lin HP, Wang YP, Chiang CP. Expression of p53, MDM2, p21, heat shock protein 70, and HPV 16/18 E6 proteins in oral verrucous carcinoma and oral verrucous hyperplasia. Head Neck. 33(3):334-40, 2011. 18 Gandolfo S, Castellani R, Pentenero M. Proliferative verrucous leukoplakia: a potentially malignant disorder involving periodontal sites. J Periodontol. 80(2):274-81, 2009. 19 Sonalika WG, Anand T. Oral verrucous carcinoma: A retrospective analysis for clinicopathologic features. J Cancer Res Ther. 12(1):142-5. 2016 20 th Goldman-Cecil Medicine, 25 Edition, Saunders-Elsevier. 2016. 190, 1297-1303. 21 Russell JO, Hoschar AP, Scharpf J. Papillary squamous cell carcinoma of the head and neck: a clinicopathologic series. American Journal of Otolaryngology. 32(6), 557-563, 2011. 22 Sun Y, Kuyama K, Burkhardt A, Yamamoto H.J Clinicopathological evaluation of carcinoma cuniculatum: a variant of oral squamous cell carcinoma. Oral Pathol Med. 41(4):303-8. 2012 23 Cumberland L, Dana A, Resh B, Fitzpatrick J, Goldenberg G. Verruciform xanthoma in the setting of cutaneous trauma and chronic inflammation: report of a patient and a brief review of the literature. J Cutan Pathol. 37(8):895-900. 2010. 24 See footnote 2 25 Kondori I, Mottin RW, Laskin DM. Accuracy of dentists in the clinical diagnosis of oral lesions. Quintessence Int. 42(7):575-7. 2011
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Legend Figure 1: Shows that the majority of lesions proved to be HPV related. Followed by hyperplasia, hyperplastic candidiasis, and dysplasia. Figure 2: Shows that the majority of HPV lesions were found on the tongue. Figure 3: Shows that most hyperplastic lesion were found on the tongue, followed by the gingiva and soft palate. Figure 4: Shows that hyperplastic candidiasis was most commonly found on the buccal mucosa, followed by the tongue and soft palate. Figure 5: Showed that a majority of dysplastic lesions were found in the vestibule. Figure 6: Shows that most malignant lesions were found on the gingiva. Figure 7: Shows that malignant and dysplastic lesions were seen in older patients and HPV related lesions were seen in significantly younger patients. Figure 8: A1- Papillary lesion on the palate A2- Histology showed a papilloma B1- Verruciform Xanthoma (Courtesy of Dr Noam Yarom, Sheba Medical Centre)
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B2-Low magnification showing papillary configuration B3-The mucosal papillae are infiltrated by large histiocytes with foamy cytoplasm B4- Immunohistochemical stain for CD68 which emphasizes the histiocytes in the connective tissue
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Figure 9: A1- Verrucous lesion of left mandibular canine area A2- The histology showed a verrucous carcinoma B1- Papillary lesion/proliferative verrucous leukoplakia on an edentulous palate B2-The histology showed papillary hyperplasia with dysplasia C1- Verrucous lesion on the palate C2- Histology showed a verruca vulgaris
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Date: 10th August 2017 To the Editor
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Journal of Oral and Maxillofacial Surgery
I have made a few changes as advised by the editorial reviewers: Reviewer Comments in bold followed by my response:
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1) Reviewer #1: I enjoyed your paper and the premise of inaccuracy in clinical diagnosis mandating soft tissue biopsy for definitive diagnosis of the verruca-papillary lesions. A similar rate of misdiagnosis (~43%) was determined in a study looking at oral lesion submission in 2011: Kondori, Ida, Roberta W. Mottin, and Daniel M. Laskin. "Accuracy of dentists in the clinical diagnosis of oral lesions." Quintessence International 42.7 (2011). Architecturally, rounded projections versus spire like projections are dependent upon different viral subtypes but are also determined by things like hyperplasia with broad pushing fronts extending for a blood supply or ."spires" pulling fibrovascular cores up with them It is necessary to stress soft tissue biopsy and submission of tissue in cases where the clinical diagnosis is questionable. I have inserted a highlighted reference, referring to said paper.
2) The alpha-numeric designation of Figures 8 and 9 was not listed on the pages with those images, and I felt the images could be better focused I have added the alpha-numeric designation to the description of the figures.
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3) Please remove all images from the manuscript document and add them as individual figure files
Sincerely,
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Figures removed and attached separately.
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Dr Sara Whitefield
Department of Oral Pathology and Medicine Goldschleger School of Dental Medicine, Tel-Aviv University Tel-Aviv, Israel
Email: [email protected]