Introduction
In the last decades, an increasing number of subjects infected by HPV, of both sexes, has been observed. HPV is a non-cultured DNA virus form the Papovaviridae family, presenting considerable tropism in epithelial and mucous tissues. This condition is most frequently observed in the anus-genital area, although it has been increasingly found in the mouth mucosa, as oral sex practices have intensified in last years.
More than 100 types of HPV have been identified so far. Out of these, 24 types were associated with oral lesions.5 In the oral mucosa, this virus has been considered an etiological agent for papilloma, condyloma, verruca vulgaris, leukoplasias, lichen planus, focal epithelial hyperplasia, and carcinoma6. Genetics and molecular biology improvements have crucially contributed to these viruses study. Out of all techniques for identification of HPV DNA, Polymerase Chain Reaction (PCR) has proved to be the most accurate one.7
For this study, a literature review on oral manifestations associated with human papillomavirus (HPV), its diagnosis, treatment and prophylaxis have been performed.
Review of the literature
HPV is an acronym for Human Papillomavirus, which causes condyloma acuminatum (in Greek kondilus, a circular tumor; latin acuminare, i.e., to become pointed), also known as "rooster crest" or "genital wart".1,2 They are small non-enveloped epitheliotropic viruses, with double circular DNA, pertaining to the Papovaviridae family. They may be responsible for sub-clinical disease and be associated with premalignant lesions as well as with certain intraepithelial neoplasias.2,3 They present approximately 55 nm in diameter and 8,000-pair base genome with molecular weight of 5.2 x 106 daltons; 72 capsomers capsideum of icosahedric structures.2,3 It presents considerable tropism on epithelial and mucous tissues.
This condition has been observed in the nasal and oral cavities, conjunctiva, paranasal sulcus, larynx, tracheobronchial mucosa, esophagus, urethra, anus-genital tract and skin.10,11
Currently, the genital infection by HPV is the most frequent viral sexually transmissible disease (STD) among the sexually active population worldwide. In 1996, the Center for Disease Control and Prevention (CDC) had estimated the rise of 500 thousand up to 1 million new cases of HPV infections per year. On that occasion, HPV rates were supplanted only by Chlamydia infection (4 million) and Tricomoniasis (3 million).1,4
In 1996, the World Health Organization considered HPV as the most important cause of cervical cancer in women, accounting for 99.7% of cases worldwide.
More than 100 types of HPV have already been identified, out of which 24 types were associated with oral lesions (HPV-1, 2, 3, 4, 6, 7, 10, 11, 13, 16, 18, 30, 32, 33, 35, 45, 52, 55, 57, 59, 69, 72 and 73).7
Based on the association of HPV as precursors of lesions and cancer, HPVs are distributed between low-risk type groups (6, 11, 42, 43 and 44) and high-risk type groups (16, 18, 31, 33, 34, 35, 39, 45, 46, 51, 52, 56, 58, 59, 66, 68 and 70).4,13
In the oral mucosa, HPV prevalence as well as its pathogenic role in dysplasias and cancer has not been fully clarified so far.14 Terai M. et al. (1999), in a study on HPV prevalence on normal oral cavity in adults, reported that human papillomavirus was found in the normal oral mucosa by PCR method and observed a predominance of HPV-18 in sub-clinical or latent infection, suggesting that the oral cavity is a reservoir of this virus and the infection, in combination with other substances - such as cigarette and alcohol - may lead to the development of neoplasias.11
Transmission of HPV to the oral mucosa occurs by self-inoculation and oral sex practices.2,15 Early beginning of sexual life associated with other factors, such as a great number of partners, smoking, parity and other sexually transmitted diseases, may enhance the chances of developing HPV infection.8 In the oral cavity, the tongue is the most affected area for HPV lesions, with 55% incidence, as reported by Premoli de Percoco & Christensen in 1992. Other areas in the mouth are the palate, oral mucosa, gingiva, lips, tonsils, uvula and floor of the mouth 16. The latter is where much saliva is concentrated and in which cancerous agents - such as alcohol and tobacco - are dissolved, allowing viral deleterious action to occur.4 Incubation period of condyloma acuminatum ranges from 2 to 8 weeks and is related to the individual's immunity level. Evolution from the incubation phase to active expression depends on 3 factors: cellular permissiveness, virus type and host immunity status.1
Diagnosis of human papillomavirus in the oral mucosa is obtained by clinical exam, cytology, biopsy, immunohistochemistry, DNA hybridization, hybrid capture and PCR (Polymerase Chain Reaction).7,17,18 Cytological aspect of HPV infection is characterized by minor or major criteria. The major criteria are: coilocytes with perinuclear cytoplasmatic halos and nuclear dysplasia; minor criteria include: diskeratocytes, metaplasia, macrocytes and bi-nucleation.1 The biopsy provides histopathological study of the sample, with confirmation and graduation of the lesion, although it is not suitable to identify the type of HPV. To that end, there are molecular biology techniques (in situ hybridization, hybrid capture and PCR).8,17,19 PCR, a revolutionary technique in Virology due to its accuracy, may detect one virus genome among 100,000 cells. Under optimal experimental conditions, it is the most accurate method for virus detection.7,8
Recently, two methods broadly used and with similar accuracy are hybrid capture and PCR with general primers. This version of PCR is highly capable of detecting all types of mucous HPVs, and the consensus primers GP%=/GP6+ and degenerated primers MY09/11 are the most used ones.
According to some authors, among the oral alterations probably associated with HPV, the following should be emphasized: papilloma, condyloma acuminatum, verruca vulgaris, focal epithelial hyperplasia, lichen planus, leukoplasia, squamous cell carcinoma and verrucous carcinoma.4,6,10
Squamous Cell Papilloma
This is a benign tumor that may occur at any age. Generally, it affects the soft palate. Clinically, it appears to be a rosaceous or whitish exophytic lesion of wrinkled surface, and may be pediculated or sessile. HPVs 6 and 11 are the most frequently involved types.
Condyloma acuminatum
In the mouth, the condyloma is transmitted by oral sex or by self-inoculation. Clinically, it appears as small, multiple, rosaceous or whitish nodules, with papillary proliferation and may be pediculated or sessile. In the majority of cases, the surface is outlined with cauliflower-like aspect. Again, types 6 and 11 were the most frequently found.16,22,23
Verruca vulgaris
Oral warts are lesions of firm consistency, wrinkled surface and sessile base. Clinical and histopathologically, they are similar to papilloma and condyloma. They frequently occur on the tongue and lips. HPV types 2 and 4 were the causes of the majority of the cases.4,14
Focal Epithelial Hyperplasia (Heck's Disease)
Clinically, the lesion arises as multiple, raised, smooth and rounded asymptomatic nodules. The color varies from pale rose to normal mucosa color. The lesion disappears as the mucosa is stretched. This condition was observed in American and Brazilian Indians, as well as in Alaskan Eskimos. The viral etiology has been suggested in several studies. Lutznet and Syrjanen detected HPV antigens and many other studies reported the presence of HPV 13 and 32. 4,24,25
Lichen planus
This is a relatively common disease of unknown etiology that may affect the skin and oral mucosa. In the oral cavity, it shows lesions consisting of radiated whitish or gray velvet papules with linear filiform, annular or rectiform configuration in the oral mucosa. Syrjânen et al., 1987 detected the presence of HPV 6 and 11 from a lichen planus biopsy sample; however, the etiological viral role still remains unclear.10,21
Oral Leukoplasia
This is a whitish stain or plaque, which cannot be clinical or histopathologically characterized as any other disease. Histologically, leukoplasia may present a variety of epithelial alterations, varying from innocuous epithelial hyperplasia to different grades of dysplasia. In some cases of leukoplasia, types 6, 11 and 16 were found, although HPV role in the etiology of oral leukoplasia is not clear.4,10,21
Oral Carcinoma
The squamous cell carcinoma is the most frequent form of this condition, which can be a nodular tumor or even a chronic ulcer. In 1983, Syrjanen et al. suggested the involvement of HPV in mouth cancer, when they associated cell alterations found in some malignant and pre-malignant lesions in the mouth with the same lesions found in the uterine cervix. HPV 16 seems to be the most frequent HPV type associated with oral carcinomas.
In the development of oral cancer, the most commonly associated factors are smoking, alcohol, syphilis, nutritional deficiencies, sun (specially in lip lesions), trauma, poor hygiene and irritation by sharp borders of teeth or dentures. Added to those, viruses have been widely investigated for their role as carcinogenic agents. Treatment of oral lesions by HPV, such as condyloma, papilloma or wart may be either clinical or surgical. In the latter, the main goal is to remove the visible lesion, once there is no effective treatment for definitive eradication of HPV. Recurrence may happen in previously treated areas or new areas in 20-30% of the cases.
For clinical treatment, caustic agents are used for tissue destruction; the most used substance is 50-90% solution of trichloroacetic acid (TCA) on the lesion once a week, for 4 weeks. Another agent is 25% podophylin in alcohol solution or 0.5% gel applied on the lesion 2-3 times a week. There are also antiblastic solutions such as 5-fluouracil cream with efficacy comparable to other agents; however, due to its high cost and skin intolerance (extreme local irritation), its use is restricted. Surgical treatment with laser or electric excision may be an alternative for lesions, with the benefit of preserving a sample of tissue for clinical pathology analysis. Electric cauterization or cryotherapy may be an alternative, although it may be painful in case of extensive lesions or highly innerved sites, such as vulva, vagina and perineum.1,26-28
Prophylaxis consists of clinical counseling, during which patient is told that treatment can eradicate the lesion, although the virus may remain in the oral mucosa and, therefore, oral hygiene, monogamy along with the use of condoms and periodical clinical checkups are imperative. Also smoking habits and alcohol ingestion should be avoided.26, 29
Vaccines face some obstacles, mainly due to the variety of virus types and unfeasibility of tissue culture.1,26 Prevention as a way to control HPV transmission and promote early diagnosis must involve constant and continued education of the general population. Therefore, educational activities should include information focused on associated risk factors, particularly on what sexual behaviors and preventive measures are concerned.30
Discussion
The human papillomavirus (HPV) is the most frequent sexually transmitted virus and has an important role in the cytopathology of uterine cervix cancer, while in the oral mucosa its role still remains undefined. Currently, oral sex practices and variation of partners enhance the risk of HPV transmission in the oral mucosa.
Many studies report that HPV diagnosis is obtained by clinical examination, biopsy and molecular biology techniques. However, clinical exam and biopsy provide information on the lesion characteristics that are suggestive of HPV, while exams such as PCR and hybrid capture identify the types of HPV, proving to be the most accurate and used methods today.
Among all oral lesions observed in this study, it was verified that the most frequent manifestations likely to be associated with HPV were condyloma, papilloma and wart in the oral cavity, which were mainly caused by types 6 and 11.
Some studies found papillomavirus in lesions of the oral mucosa, such as lichen planus, focal epithelial hyperplasia, leukoplasia and oral cancer. However, HPVs etiopathogenic role in these pathologies remains unproven. HPV type 16 demonstrated to be the most related to carcinoma of the oral mucosa.
Smoking and alcohol are the most frequent contributing factors, which, in combination with the virus in the oral cavity, may give rise to a neoplasia.
The treatment of HPV adopted by several authors is focused on clinical cure, since there is no definitive eradication of the virus, in which recurrence of disease depends on individual's immunity level.
Literature states that prophylaxis of HPV aims at controlling transmission of virus and early diagnosis of disease, which proves the need of educational programs on sexually transmitted diseases and preventive measures for the general population. Vaccination will be the solution for disease control in the future, although it is still under investigation.
Closing Remarks
It is expected that future research may provide more information on HPV and its infection on the oral mucosa, particularly in sub-clinical lesions and oral carcinoma, and that prophylaxis reduces the incidence of HPV, a condition that is rapidly increasing, especially among young people and teenagers. Vaccination will hopefully be a solution in the future for this condition that concerns us all.
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