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Table of Contents   
GUEST EDITORIAL  
Year : 2011  |  Volume : 22  |  Issue : 3  |  Page : 365-366
Inherited proliferative oral disorder: A reductionist approach to proliferative verrucous leukoplakia


Department of Oral Pathology, Manipal College of Dental Sciences, Manipal University, Manipal, India

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Date of Web Publication3-Nov-2011
 

How to cite this article:
Radhakrishnan R. Inherited proliferative oral disorder: A reductionist approach to proliferative verrucous leukoplakia. Indian J Dent Res 2011;22:365-6

How to cite this URL:
Radhakrishnan R. Inherited proliferative oral disorder: A reductionist approach to proliferative verrucous leukoplakia. Indian J Dent Res [serial online] 2011 [cited 2019 Jul 18];22:365-6. Available from: http://www.ijdr.in/text.asp?2011/22/3/365/87053
Since the time the term "proliferative verrucous leukoplakia (PVL)" [1] has been introduced into the oral pathology lexicon, a number of papers have been written and letters communicated for greater clarity on this seemingly confusing jargon that has occupied a diffuse chunk of oral pathology literature, just the way the lesion presents and progresses. However, as the body of work on this entity increases by the day, the only conclusion that could be drawn upon from this persistent, aggressive, recurring yet seemingly harmless debate is that PVL is a potentially malignant oral disorder (OPMD) that pathologists agree in principle but agree to disagree in practice because of the absence of specific histological features leading to undiagnosed or underdiagnosed sign out.

The fact that PVL is persistent in nature, aggressive in behavior, and refractory to treatment makes this an insidious entity right from its onset. However, without paying much attention to its nosology and caring less about its nomenclature, the issue that is central and which needs to be unraveled is its clandestine pathogenesis, as nearly 60-70% of the affected patients develop either a verrucous carcinoma or squamous cell carcinoma in contrast to conventional oral leukoplakia where the malignant transformation rate is much lesser. [2] What is equally bewildering of this eventuality is how a lesion could digress into one of the two common oral epithelial malignancies if it was one specific phenomenon?

To answer this fundamental question, we need to understand that oral carcinogenesis is a multistep process at both the phenotypic and genotypic levels, resulting from the independent accumulation of multiple mutations in different cells, generating subclones with varying abilities to grow. Even though malignancies associated with PVL may be monoclonal in origin at its onset, they become extremely heterogeneous by the time they become clinically evident, thus resulting in diverse malignant phenotypes.

The mean age of diagnosis of carcinoma associated with PVL, being slightly over 60 years, [3],[4],[5] may be explained by the accumulation of somatic mutation associated with emergence of malignancies. Since the clinical presentation of PVL is highly variable, its diagnosis is one of exclusion and microscopic description of epithelial dysplasia may be inappropriate as it does not depict any one pathologic entity.

The preference of gingiva and palate being the more commonly affected sites in PVL-related squamous cell carcinoma where 80% of cases occur has prompted investigators to coin another subset called the proliferative verrucous leukoplakia of the gingiva (PVLG). [4],[6] As the tumor tends to occur at specific sites, it is only natural to conjecture that PVL associated carcinoma may characterize an inherited cancer syndrome, as these groups of tumors are often associated with specific marker phenotype and occurrence of multiple lesions in the affected tissue. The inherited mutation is usually a single-point mutation that greatly increases the risk of developing a tumor. Another feature of inherited precancerous condition that may be fitting to PVL pathogenesis is that it may be caused by defects in DNA repair gene, resulting in DNA instability. The confirmation of this sequence of events associated with carcinoma-associated PVL may qualify this lesion to be termed an "inherited proliferative oral disorder (IPOD)."

Without a shred of doubt, PVL portends a more aggressive behavior than the more innocuous white oral lesions termed leukoplakia, that it can resemble clinically. [7] Although the verrucous nature is classically observed in the later stages of PVL, this can be rarely present at the time of initial diagnosis. [5] Thus, the proposed staging of OPVL into four clinicopathological phases is arbitrary and impractical as the interpretation can vary and repeated sampling for confirmatory diagnosis is injudicious.

Histologically, the early lesions are deceptively bland, exhibiting only hyperkeratosis, but over time they become progressively verrucous and often show varying degrees of epithelial dysplasia and an abrupt transition from hyperparakeratosis to hyperorthokeratosis, associated with a corrugated or verruciform surface. [4],[5],[7] It is of interest that the early phase of these lesions usually exhibits a lymphocytic infiltrate at the interface that may have a pronounced lichenoid pattern characterized by basal vacuolar degeneration containing apoptotic cells and eosinophilic bodies, similar to types of oral lichenoid stomatitis such as lichen planus. [3] From the histological perspective, it is thus suggested that a stage of PVL must be considered in a lesion with features of lichenoid inflammation with basilar hyperplasia.

The inflammatory component, although nonspecific from the histologic standpoint, has a telling effect on cancer development. [8] This association has been demonstrated in the setting of unresolved chronic inflammation of viral hepatitis, owing to maladaptive immune response thereby promoting tumorigenesis. It has also been suggested that chronic inflammation may increase the pool of tissue stem cells which may become subjected to the effect of mutagens. Additionally, the activated immune cells produce reactive oxygen species that are directly genotoxic. It is perhaps because of this association that an overexpression of enzyme cyclooxygenase-2 (COX-2) is seen to increase manifold in oral premalignancy. [9] Despite this, the utility of COX-2 inhibitors in the management of PVL is unclear.

After all this, the etiology of PVL is unknown as tobacco does not appear to play a major role, nor does the coexistence of Candida species, and the role of human papillomavirus (HPV), subtype 16, as a cofactor in PVL is only questionable. [4] Studies investigating the role of HPV in PVL have not yielded indisputable link between HPV and PVL as a few studies have found no significant difference between PVL and oral leukoplakia for risk of HPV infection. [10] For the first time it has been shown that frequent alteration of cell cycle regulatory genes, p16INK4a and p14ARF, is common in oral verrucous leukoplakia. These changes thus illustrate that molecular alterations are associated with distinct histologic types of oral premalignancy, which may affect disease progression, treatment strategies, and ultimately patient prognosis. [11]

It is generally difficult to sort out the hereditary and acquired basis of a tumor because these factors often interact closely. Also, in the classic experimental progression model of chemical carcinogenesis, a clear distinction between initiation and promotion may explain the onset of tumorigenesis. Initiation causes permanent DNA damage and promoters induce tumors in an initiated cell but are not tumorigenic by themselves. An indirect carcinogen in the form of benzo(a)pyrene in tobacco smoke requires metabolic conversion before becoming active. Most of the known carcinogens are metabolized by cytochrome P450 dependent monoxygenases. The genes that encode these enzymes are quite polymorphic and the activity and inducibility of these enzymes have been shown to vary among different individuals. Thus, it may be possible to assess cancer risk in a given individual by genetic analysis of such enzyme polymorphisms. [12]

There are numerous questions to be answered as we dig deeper using the molecular reductionist approach, where the focus has switched from the big picture of the disease to the study of tumor-host interaction at the molecular level. Reductionism strongly reflects a certain perspective on causality. The development of virtual models described above will allow simulation and prediction of consequences and translation of these into suitable therapeutic protocols. The grand challenges encountered by the post-omic era are to integrate the powerful information obtained from in vitro studies into a comprehensive understanding of the disease in vivo. Within this fundamental framework, the PVL can be described as an epiphenomenon and not just an en masse diagnosis.

 
   References Top

1.Hansen LS, Olson JA, Silverman S Jr. Proliferative verrucous leukoplakia. Oral Surg Oral Med Oral Pathol 1985;60:285-98.  Back to cited text no. 1
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2.Silverman S Jr, Gorsky M. Proliferative verrucous leukoplakia: A follow-up study of 54 cases. Oral surg oral med oral pathol oral radiol endod 1997;84:154-7.  Back to cited text no. 2
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3.Morton TH, Cabay RJ, Epstein JB. Proliferative verrucous leukoplakia and its progression to oral carcinoma: Report of three cases. J Oral Pathol Med 2007;36:315-8.  Back to cited text no. 3
[PUBMED]  [FULLTEXT]  
4.Fettig A, Pogrel MA, Silverman S Jr, Bramanti TE, Da Costa M, Regezi JA. Proliferative verrucous leukoplakia of the gingiva. Oral surg oral med oral pathol oral radiol endod 2000;90:723-30.  Back to cited text no. 4
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5.van der Waal I, Reichart PA. Oral proliferative verrucous leukoplakia revisited. Oral Oncol 2008;44:719-21.  Back to cited text no. 5
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6.Bagan JV, Jimenez Y,Sanchis JM, Poveda R, Milian MA, Murillo J, et al. Proliferative verrucous leukoplakia: High incidence of gingival squamous cell carcinoma. J Oral Pathol Med 2003;32:379-82.   Back to cited text no. 6
[PUBMED]  [FULLTEXT]  
7.Bagan J, Scully C, Jimenez Y, Martorell M. Proliferative verrucous leukoplakia: A concise update. Oral Dis 2010;16:328-32.   Back to cited text no. 7
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8.Tlsty TD, Coussens LM. Tumor stroma and regulation of cancer development. Annu Rev Pathol 2006;1:119-50.  Back to cited text no. 8
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9.Mohan S, Epstein JB. Carcinogenesis and cyclooxygenase: The potential role of COX-2 inhibition in upper aerodigestive tract cancer. Oral Oncol 2003;39:537-46.  Back to cited text no. 9
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10.Bagan JV, Jimenez Y, Murillo J, Gavaldá C, Poveda R, Scully C, et al. Lack of association between proliferative verrucous leukoplakia and human papillomavirus infection. J Oral MaxillofacSurg 2007;65:46-9.  Back to cited text no. 10
    
11.Kresty LA, Mallery SR, Knobloch TJ, Li J, Lloyd M, Casto BC, et al. Frequent alterations of p16 INK4a and p14 ARF in oral proliferative verrucous leukoplakia. Cancer Epidemiol Biomarkers Prev 2008;17:3179-87.  Back to cited text no. 11
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12.Vineis P, Veglia F, Benhamou S, Butkiewicz D, Cascorbi I, Clapper ML, et al. CYP1A1 T3801 C polymorphism and lung cancer: A pooled analysis of 2451 cases and 3358 controls. Int J Cancer 2003;104:650-7.  Back to cited text no. 12
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   Authors Top



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Correspondence Address:
Raghu Radhakrishnan
Department of Oral Pathology, Manipal College of Dental Sciences, Manipal University, Manipal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0970-9290.87053

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