ISSN: 2456-8090 (online)
SANA KHALED1, SANTOSH R. BHARADWAJ2, BUSHRA ANJUM3, D. SATYANARAYANA*4
Cite this article as: Khaled S, Bharadwaj SR, Anjum B, Satyanarayana D. Verrucopapillary Lesions of the Oral Cavity: A Review. Int Healthc Res J. 2020;4(7):RV1-RV7. https://doi.org/10.26440/IHRJ/0407.10365
Contact Corresponding Author at: satya.gullu[at]gmail[dot]com
Verrucopapillary lesions are a spectrum of benign, potentially malignant and malignant lesions of the oral mucosa which usually are misdiagnosed. They pose a great diagnostic challenge mainly due to confusing terminology and also due to similar clinical and histopathological features which often makes these lesions indistinguishable from one another. The human papilloma virus (HPV) plays a important role in the pathogenesis of majority of these lesions. This review aims to summarize and highlight the key clinical and histopathological features of these lesions, and also provides a diagnostic approach to these entities.
KEYWORDS: Human Papilloma Virus (HPV), Oral mucosa, Malignancy
Most of the biopsied lesions of the oral mucosa have shown a unique proliferation of the stratified squamous epithelium, with or without inductive changes of the underlying stroma. These proliferations fall into three types: papillary exophytic masses, broad verruciform excesses of surface keratin and flat hyperplasias of spinous cell layer. The exophytic lesions represent as any pathologic growth that projects above the normal contours of the oral surface. The papillary lesions represent swelling with finger like projections imparting a cauliflower like appearance, these micro projections are rounded and blunt like fungiform papillae of the tongue. The verrucous lesions are similar to papillary lesions yet possess a more irregular surface. These papillary or verrucous type lesions are quite common in the oral and paraoral regions, representing 3% of biopsied oral lesions. Clinical information and an adequate biopsy are essential for making an accurate diagnosis of these lesions, but the primary objective must be to evaluate the epithelium for dysplastic features and signs of invasion. Hence, differentiation between verrucous and papillary lesion is based more on microscopic features rather than the clinical appearance. Biopsy is usually indicated to secure a definitive diagnosis and to follow a proper treatment plan.
Majority of verrucous lesions are thought to be induced by viral infection of the epithelium especially Human Papilloma Virus (HPV). Human papilloma viruses are a group of genetically related organisms that infect stratified squamous epithelium. There are more than 120 genetically different, yet closely related HPVs that are referred to as genotypes. Most of the oral and labial papillary lesions are HPV-associated and few are self-limited benign growths that do not progress to cancer, like keratoacanthoma.1
HPV EFFECTS ON ORAL EPITHELIA
The HPVs induce proliferative changes in oral epithelial cells that result in both benign and malignant tumors and can only infect parabasal or basal cells of the epithelium. Infection may be initiated by micro abrasions on the surface, which allows better access for this virus into the basal cells. When the virus initially enters host basal cells, it cannot replicate until the cell matures into a keratinocyte, as the host cell undergoes the normal differentiation, the virus also starts its replication. The virus starts its replication once the host cell mitosis occurs. Then virus expresses its the early proteins--E1, E2, E5, E6, and E7--in the lower spinous layers which occurs in the early phases of the infection. As the epithelial cells mature, the cell cycle is halted as part of forming a protective barrier; however, terminal differentiation is hindered by E7 and E6. This has most likely evolved to allow the host cell to continue to reproduce viruses.
As the host cell life progresses to the upper spinous layer, gene expression of HPV changes. The late proteins--L1 and L2--and E4 are upregulated and at this point, virus assembly occurs and exfoliating cells of the epithelium now releases complete virions. These cells are resilient in dry environments and virions shed from cornified squames have a higher chance of survival. Cornified squames are the epithelial cells that have more keratin which is a protective agent that hardens the cell. HPV then adheres to a specific receptor protein on the keratinocytes membrane in order to be assimilated into the cell by a process known as endocytosis. Once the virus enters into the cell, it divests itself of its protein coat and the viral DNA and then utilizes host cell DNA building blocks to replicate.
These viruses elaborate early gene proteins that are able to regulate the host cell cycle or mitotic capabilities. E6 and E7 proteins are the most important in this respect, as they bind to the host proteins that are regulators of the keratinocytes cell division cycle. E6 binds to a protein designated p53, a molecule that arrest cell division, however once bound, it is degraded and this causes inhibition of keratinocytes mitosis to be nullified. Likewise, E7 binds a protein termed Rb; and it leads to cell cycle regulation disruuption.2
E1 – Viral replication
E2 – Regulates viral transcription and replication
E4 – Interacts with cytoskeletal proteins
E5 – Downregulation of MHC Class 1 molecules
E6 – Oncoprotein, binds to tumor suppressor protein p53
E7 – Oncoprotein, binds to tumor suppressor protein retinoblastoma (Rb)
L1 – Major viral caspid protein
L2 – Minor viral caspid protein
ANATOMICAL LANDMARKS RESEMBLING VERRUCOUS-PAPILLARY LESIONS
Some of the normal anatomic structures in the oral cavity, presenting as a papillary pattern are accessory tonsillar tissue, filiform papillae, fungiform papillae, foliate papillae, circumvallate papillae, retrocuspid, retromolar papillae and stensens's papillae. Sometimes, these structures attain such a size that they are mistaken for pathoses. The anatomic locations of the structures, however, usually enable immediate recognition.3
CLASSIFICATIONS OF VERRUCOUS-PAPILLARY LESIONS
(A) According to Regezi JA et al, Verrucous lesions of the oral cavity are classified into:4
III. Idiopathic/Miscellaneous Lesions
(B) According to Gareth J Thomas, A William Barrette, Papillary and Verrucous lesions of the oral mucosa are classified into:5
(C) According to Eversole LR, Papillary, papular, and multiple polypoid lesions are classified into:6
DIAGNOSIS OF VERRUCOUS-PAPILLARY LESIONS
Usually clinical appearance and characteristic histopathologic features are useful for the diagnosis of verrucous papillary lesions. Occasionally, other diagnostic tools are also needed for the definitive diagnosis of few of these entities. Special stains are used for molluscum bodies in molluscum contagiosum are stained by Feulgen staining which demonstrates DNA-containing viral inclusions as Magenta, in Verruciform Xanthoma, acanthotic epithelial process, may assume an unusual orange color in H & E stained slides. In addition, large foamy cells with diastase- resistant, PAS positive granules fill the papillary corium and cytological smears may show presence of koilocytes, especially of PAP smears. Ultrastructural studies such as use of electron microscopy enables visualization of HPV particles in verrucous lesions associated by HPV. These HPV viral particles appear in scattered form within the nuceli of the affected epithelial cells. However, due to its low sensitivity, electron microscopy has merely historical diagnostic value.
Furthermore, even if HPV particles are detected, an identification of the specific HPV genotype present is not possible.9 Immunohistochemical (IHC) studies are also done as they are found to be most consistent and reproducible traditional method for HPV detection. IHC of papilloma virus structural proteins may confirm the presence particular HPV genotype. However, inconsistence in antigen detection may result from sampling error, and destruction of antigens during tissue processing or lengthy storage.9 However, there are recent molecular methods being considered at present as a key tool in the detection of HPV in verrucous-papillary lesions. The molecular methods which enable the detection of viral DNA in tissue morphology content such as In situ hybridization which detects HPV in tissue specimens and those in which tissue destruction is unavoidable for detection of HPV DNA such as Polymerase chain reaction (PCR) which is currently the most sensitive method for HPV detection. However, because of frequent contamination problem, it should be applied in diagnostic settings with great caution.9
SUMMARY AND CONCLUSION
The diagnosis of benign, reactive verrucous and papillary oral lesions usually little difficult, whereas the lesions with their dysplastic counterparts unless the lesion is at either end of the spectrum of verrucous hyperplasia and verrucous carcinoma cane be diagnosed with characteristic histopathlogical features. HPV is found to be associated with majority of these lesions. HPV effects the oral epithelium causing various proliferative and dysplastic changes in the epithelium. There are few lesions like papillary hyperplasia, verruciform xanthoma, cowden syndrome, nevus unius lateris, acanthosis nigricans which are without known viral association. Many of these lesions have overlapping features both clinically and microscopically, therefore proper examination of the lesion followed by biopsy and in some cases special diagnostic methods are to be done for accurate diagnosis.
ORAL MANIFESTATIONS AND HISTOPATHOLOGICAL FEATURES OF VERRUCOPAPILLARY LESIONS2,4,7,8
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