Human papillomavirus (HPV) is a member of the Papillomaviridae family of viruses, and it is an epitheliotropic, circular, double-strained virus that infects the basal layer of the epithelium.1 The virus causes infections in various regions such as the skin, oral cavity, upper airways, conjunctiva and anogenital tract. Clinical lesions induced by HPV in the oral cavity can be benign: oral squamous cell papilloma (termed by some authors as oral verrucal-papillary lesions), focal epithelial hyperplasia (known as Heck disease), verruca vulgaris papilloma, condyloma acuminatum, common wart or malignant: oral squamous cell carcinoma and salivary gland adenocarcinoma.2–6
The life cycle of HPV in the oral cavity starts with the infection of basal squamous epithelial cells through a trauma or erosion, which allows the entrance of the DNA virus into the host.7 To be active, the virus must infect an epithelial stem cell and at skin level, a stem cell from a hair follicle, which is rich in these cells.8 DNA multiplication takes place in the layers above the basal cells, and the virus replicates only in the nucleus of infected cells.9 The viral genome has 8 open reading frames to encode early proteins E1–E7 and late proteins L1–L2.10 Proteins E6 and E7 inhibit apoptosis and favor cell proliferation. They function by blocking the assembly of major histocompatibility complex peptides, the immune response, or by altering the function of T cells, CD4+ cells.11,12
Latent HPV infections involve 2 possible actions: one is a low-titer virus infection that does not allow virus multiplication and the other is a low-level viral gene expression after the regression of a lesion that was apparently cleared by the immune system and is reactivated when the child’s immunity is depressed.13
A 9-year-old patient presented to the Department of Oral Health and Rehabilitation for a villous lesion of the free and attached gingival margin of the upper left central incisor (2.1.), with both vestibular and palatal location. The growth of the lesion had been slow but continuous. The child’s parents had first noticed this exophytic vegetation 6–7 months before. Their concern was related to the etiology of the continuously growing tumor and to the resulting physiognomic disorders. Intraoral examination showed that the lesion surrounded incisor 2.1., had a vegetative appearance, extending in a cervical-coronal direction 4–5 mm on the vestibular side and 7–8 mm on the palatal side. On the vestibular side, the exophytic lesion had a villous, papillary appearance, with foreign body retention and was of a soft consistency. On the palatal side, the lesion had a verruciform appearance, was harder on palpation and was in contact with the incisal margin of the lower incisors because of deep bite. The lesion was nonpainful, nonbleeding, having the color of the adjacent attached gingiva, slightly whitish at the distal extremities of the villi, noninfiltrative and without ulcerations or locoregional adenopathy. Radiologic examination showed no changes of the local or adjacent underlying bone (Fig. 1).
The child had a history of bad habits such as interposition of various objects (pencils, erasers) or the lower lip between the dental arches, onychophagia and consuming milk only from a feeding bottle with a nipple.
Given that the child’s parents refused surgery under general anesthesia, surgical excision (with the scalpel) was decided under local infiltration anesthesia (4% articaine, 1/200,000 adrenaline), after topical anesthesia with 10% lidocaine. Cooperation of the child was satisfactory, but deep excision of the exophytic lesion could not be adequately performed. Histopathologic examination evidenced a squamous papilloma, with cytopathic HPV infection changes (Fig. 2).
In the excised fragments, viral DNA was determined by polymerase chain reaction. Determination was performed using the multiplex polymerase chain reaction system method, with a HPV4A ACE Screening kit (Seeplex, Seegene Inc., Seoul, Korea). The result was positive for HPV-6/11 (low-risk group) and negative for HPV-16, HPV-18 and HPV of the high-risk group (26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, 82).
Given that the squamous papilloma excision was performed in the superficial layers, recurrence in the vestibular region was obvious 1 week postoperation and 6 weeks postoperation in the palatal region. The need for further surgery was decided (under the conditions mentioned earlier) 1 month after the first surgery for the recurrence in the distal-vestibular region and 3 months after the first surgery for the recurrence in the palatal region (Fig. 3).
Collaboration with the orthodontist was decided to elevate occlusion, because the child had a deep bite, with the incisal margins of the lower incisors in contact with the palatal mucosa, with a risk for microlesions, reactivation of viral infection and recurrence. Orthodontic examination showed a class II malocclusion with a deep bite, crowding and asymmetry. Also, the patient had agenesis of all 4 second bicuspids and all 4 wisdom teeth, with late tooth eruption and reinclusion of the first upper deciduous molars creating lateral open bites in the area. From a skeletal point of view, the patient presented a class II skeletal pattern, with a reduced posterior facial height and a slight posterior rotation of the mandible.
At approximately 1 year after the first surgery, new lesions developed in the upper interincisive papilla, the distal-vestibular gingival margin and the palate. This time, laser surgical excision was chosen. A laser device was used: LightWalker DT standard (Fotona, Ljubljana, Slovenia) with dentistry’s 2 most effective laser wavelengths: Er:YAG (2940 nm) and Nd:YAG (1064 nm). Under local (topical) anesthesia with 10% lidocaine, the hyperplastic gingival tissue was excised layer by layer, with the Er:YAG laser. After activating the laser [long pulse (LP)], this was softly passed over the tissue, each movement across the tissue removing a single thin layer. We completed the treatment in variable LP mode. Laser parameters for the vaporization of gingival tissue were as follows: source, Er:YAG; hand piece R14; mode, LP; energy, 150 mJ; frequency, 10 Hz; and mode, variable LP; energy, 250 mJ; frequency, 20 Hz. At the end of the intervention, we used laser Nd:YAG for hemostasis and gingival tissue excision. Laser parameters were as follows: source, Nd:YAG; hand piece with fiber of 300 μm; mode, short pulse; power, 4 W; frequency, 50 Hz. After surgery, recommendations were to avoid trauma of the operated area, liquid and soft nutrition, good oral hygiene and mouthwash rinses (Fig. 4).
The prevalence of oral HPV infection in children is low, with varied values reported by the literature, because of the different evaluation methods used. In a study performed by Polish researchers on 4150 children between 10 and 18 years of age, the prevalence of oral HPV infection was 1.08%, and the most common type was HPV 11.14
The transmission of HPV infection in children can be both vertical and horizontal. Vertical transmission in utero is supported by the isolation of the HPV virus in the amniotic fluid, placental cells and umbilical cord trophoblast cells. Vertical transmission is also possible during conception or birth. Horizontal transmission can occur within the family from parents or other persons, through saliva, kissing, hand contact or sharing eating utensils. About a quarter of children with HPV infection have at least 1 viral subtype in common with the parental HPV subtype.15
Transmission can also take place by autoinoculation with the persistence of HPV infection. Sexual abuse should be considered. The presence of anogenital warts or oral condyloma acuminata can raise a suspicion, in association with behavioral disorders. However, some studies show that anogenital HPV infections in adults who practice oral sex do not predispose them to oral HPV infection.16–18
The infection of the child in the case report was probably by horizontal transmission within the family. The child’s father had warts on the forearm and inguinal regions. The child traumatized his anterior palatal region by interposing various objects, some of which were rigid and hard, between the dental arches. The child had no warts on his hands, only periungual excoriations. There was also a possibility for the intrauterine or perinatal vertical transmission of HPV infection. However, given that no serological or vaginal secretion/seminal fluid measurements had been performed for the confirmation of HPV 6/11 infection, this means of infection could not be established.
Based on the child’s habit of drinking milk from a bottle with a nipple until the age of 9 years, an attachment disorder could be suspected. Another question raised was whether the HPV infection was transmitted after sexual abuse, but there were no signs of suspicion for sexual abuse. The parents refused psychological examination.
Local causes such as mechanical irritations or inflammation can induce a reactivation of latent HPV infection.13 In our case, initial excision was not sufficiently deep (limited cooperation of the child under local anesthesia). The favoring factors were palatal occlusal trauma and bad habits. Immunodepression might also be considered.
The prognosis of dysmorphosis and malocclusion is good if the patient accepts orthodontic treatment. Because of the patient’s age and the favorable growth pattern of the mandible, all prerequisites are met for an improvement of malocclusion with orthodontic treatment. However, in the absence of orthodontic treatment, there is no favorable prognosis for spontaneous correction because of the severe anterior deep bite, multiple agenesis in the posterior areas and the already present posterior rotation of the mandible.
HPV infection can be asymptomatic, and up to 47% of clinically healthy children can be HPV carriers.15 It is possible for children diagnosed positive for HPV infection type 16 to become negative in up to 40% of cases.19
Most of the time, the infection is diagnosed after it becomes clinically manifest. The recommendation for HPV lesions is surgical excision at the base to the depth of the submucosa. Usually there are no recurrences. Minor surgery such as cryotherapy or laser therapy is another option. Medication such as retinoids, salicylic acid or immunotherapy could be helpful.20 Retinoids (vitamin A) can limit the extension of the lesions in immunosuppressed patients. Topical agents, including cidofovir (an antiviral drug), are used as 1% cream, gel or intralesional injection in refractory condyloma acuminata and recurrent genital herpes, as well as in oral lesions.21,22
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