ORAL SQUAMOUS PAPILLOMA
(Oral Warts)5
A circumscribed, benign epithelial tumor projecting from the surrounding surface more precisely, a benign epithelial neoplasm consisting of villous or arborescent outgrowths of fibrovascular stroma covered by neoplastic cells.6
The Oral Squamous Papilloma (OSP) occurs in one of every 250 adults & makes up approx. 3% of all oral lesions. According to WHO6, papillomas are common, with a prevalence of approximately 0.1%-0.5%.
Definition-
These form a range of localised hyperplastic exophytic and polypoid lesions of hyperplastic epithelium with a verrucous or cauliflower-like morphology.6
Etiology-
Human papilloma virus (HPV) is putative eiologic agent of papillomas of upper aerodigestive tract. HPV types 6 & 11 are commonly associated with squamous papilloma. HPV 2 & 4 are associated with cutaneous warts, HPV 3 & 10 are associated with flat warts of skin, HPV 16 & 18 are associated with neoplastic changes and to oropharyngeal squamous cell carcinoma. The primary means of HPV transmission to children is the ingestion of viral particles of infected cells from the birth canal, whereas in adults HPV is mainly transmitted through sexual contact. Harries et al (1995) speculated that this condition might actually be a reaction of the tissue to injury rather than a true neoplasia.
According to Yamaguchi et al (1998) , the majority of the lesions may be developed as a result of reactive growths due to constant traumatic injuries in the oral mucosa. Whether all intraoral squamous papillomas are related etiologically to classic cutaneous verruca vulgaris (warts) is unknown.
Paparotto Lopes and Meeks (2001) and Reszec et al (2002) stated that OSP is a true benign neoplasm probably associated with human papilloma virus infection.
Marx and Diane (2003) suggested that presence of HPV may be merely an incidental finding unrelated to the development of a squamous papilloma.
The incidence of the lesion increases in AIDS patients, It has been associated with the use of anti retroviral therapeutics, particularly highly active antiretroviral therapy (HAART) .
Pathogenesis-
Squamous papilloma is noteworthy for its uncertain pathogenesis though many pathologists accept its pathogenesis as being from HPV. The exact mode of transmission is unknown.7 HPV specifically infects basal epithelial cells and establishes productive infection only in stratified squamous epithelium of skin and mucosa. Replication of HPV occurs within the nuclei of epithelial cells with viral genome in both early and late stages. A latency or incubation period of 3 to 12 months has been suggested. Even though all HPV lesions are infective, squamous papilloma has shown extremely low virulence rate & infectivity.7 In HPV associated benign epithelial proliferations, the virus is episomal, while in HPV associated cancers, the virus is integrated into the host cell DNA.14
Zeuss et al (1991) & Regezi et al (2003)14, explained that HPV is a member of the papovavirus group. It is a DNA virus containing a single molecule of double-stranded DNA. The viruses themselves are nonenveloped icosahedral particles ranging from 45 nm to 55 nm in diameter with 72 capsomeres in a skewed arrangement. Various species are antigenically distinct, sharing some common antigenic determinants. Replication of HPV occurs within the nuclei of epithelial cells as a result of stimulation of host DNA synthesis. The viral genome is expressed in both early and late stages, with the host histone proteins being incorporated into the virions. If progeny production is blocked, persistent infection may result. However, if intact viruses are produced, new infective particles can be released with or without cell death.
Clinical Features-
Age & Sex-
It is diagnosed most often in persons 30 to 50 yrs of age. Some authors have asserted it develops predominantly in children. It occurs with equal frequency among males and females.7
Site-
Sites of predilection include tongue, lips and soft palate including uvula and also vermillion border of the lip, but any oral surface may be affected.7
Abbey et al (1980) stated that Papillomas may be found on the vermilion portion of the lips and any intraoral mucosal site, with a predilection for the hard and soft palate and the uvula. The latter three sites account for approximately one third of all lesions.
Clinical Presentation-
The Squamous papilloma lesions appear as pink to white exophytic granular or cauliflower like surface alterations. It is an innocuous lesion that is neither transmissible nor threatening4. The lesions are generally asymptomatic.8 It is a soft, painless usually pedunculated, exophytic nodule with numerous finger like surface projections that impart a cauliflower like or wartlike appearance. The projections may be pointed or blunted and the lesion may be white, slightly red or normal in colour, depending on amount of surface keratinization. It is nearly always well circumscribed pedunculated lesion, occasionally sesssile. The lesions generally measure less than 1 cm in size. The lesion is usually solitary and enlarges rapidly to a maximum size of about 0.5 cm with a little or no change thereafter. However, lesions as large as 3 cm in greatest diameter have been reported.7 The lesions also tend to be multiple and recurrent.14 (Color Atlas Fig. 1)
Squamous papillomas are traditionally divided into two types: isolated-solitary and multiple-recurring. The former is usually found in an adult's oral cavity, while the latter is mostly found in a child’s laryngotracheobronchial complex. The isolated-solitary lesions are exophytic, pedunculated growths that resemble a cauliflower in appearance. They are usually white, but can occasionally be pink. Patients who are HIV-positive often have multiple oral lesions. Malignant transformation of a papilloma is more common in the multiple-recurring type.
Histopathologic Features-
Squamous papilloma is characteized by proliferation of keratinized stratified squamous epithelium in finger like projections with fibrovasular connective tissue cores9 extending above the surface of mucosa.7 The keratin layer is thickened with a whiter clinical appearance and the epitheium shows normal maturation pattern.5
Some papillomas exhibit hyperkeratosis.The essential feature is proliferation of spinous cells in papillary pattern. Occasional lesions demonstrate basillar hypeplasia and mild mitotic activity which should not be mistaken for mild epithelial dysplasia.7 The prickle cells may have a clear glycogen filled cytoplasm, paticularly in the lesions of soft palate. The upper eithelial cells demonstrate nucleii that are pyknotic (condensed) and crenated, often surrounded by edematous or optically clear zone forming the so called koilocytic cells.14 The lamina propria frequently contains a chronic inflammatory infiltrate.7 (Color Atlas Fig. 2)
Immunohistochemical Analysis-
Copete et al (1997) observed 93% positivity for p53 in the epithelial cells of the basal and parabasal layers of 28 papillomas. According to these authors, this high prevalence of positivity for protein p53 in oral papillomas is in consonance with the concept that the accumulation of mutant or wild-type protein p53 in the nucleus could allow augmented cell proliferation.
Van der Velden et al (1999) reported an overexpression of CK10 in hyperkeratinized benign lesions.
Barzal-Nowosielska et al (2004) stated infection by HPV and/or alterations in protein p53 can co-exist in papillomas of the oral cavity. They demonstrated over expression of p53 in 55% (n = 36) of the cases of papillomas evaluated. However, the authors also found over expression of p53 in 12 of 23 HPV-negative papillomas (52%), besides over expression of protein in 8 of 13 HPV-positive papillomas (61.5%).
Oliveira et al (2005) investigated the expression pattern of CK 10, 13, 14 and 16 in oral verrucous carcinoma (OVC) and oral squamous papilloma (OSP). They found increased CK 10 immunostaining in OSP compared with the normal epithelium. Furthermore, greater CK 10 immunoexpression was found in OVC than in OSP. They also found an intense immunoexpression in suprabasal to superï¬cial layers in OSP. They also identiï¬ed a higher CK 13 immunostaining in OSP compared with OVC. They found immunostaining for CK 14 only in basal cells in papilloma while, all epithelial layers in OVC exhibited strong immunostaining for CK 14. They found a higher CK 16 immunostaining in OSP than in normal epithelium.
Carneiro et al (2009) demonstrated immunohistochemical assays utilizing BP53-12 and Pab240 antibodies for p53 protein showed negative or weakly positive immunostaining (91.6%) for both immunomarkers in all the epithelial layers examined. suggesting a benign character for the lesions and a small risk of becoming malignant.
Differential diagnosis-
The differential diagnosis of squamous papilloma when solitary, includes verruciform xanthoma, papillary hyperplasia and condyloma acuminatum.6
Verruciform xanthoma resembles squamous papilloma, though this lesion has a predilection for gingiva and alveolar ridge and contains xanthoma cells. (foamy cells).6
Condyloma acuminatum resembles squamous papilloma. It shows short blunt rounded fronds of hyperplastic epithelium of even length forming a smooth or nodular, flat or rounded surface. Keratin is usually absent or sparse. Unlike squamous papilloma, rete processes are bulbous and short, of even length and do not curve inwards.10 It may be larger than papilloma, have a broader base and appear pink to red.14
Papillary hyperplasia usually occurs on the hard palate below poorly fitting denture. Rete processes are usually rounded or sharply defined at the base of the lesion but there may be pseudoepitheliomatous hyperplasia with keratin pearls and a poorly defined deep margin.6
Treatment & Prognosis-
Removal of lesion by surgical excision including the base of mucosa into which the pedicel inserts is a treatment of choice. Surgical excision can be performed with electrocautery, cryosurgery, cold-steel excision and intralesional injections of interferon. Laser ablation is also effective. Surgical excision can be done with diode laser. The laser assisted surgery has several advantages such as excellent hemostasis, high precision in tissue destruction, devoid of sutures, wound sterilization and minimal post-operative pain and edema.23
Removal should never be done by incision in the pedicel.7 If properly exicised, recurrence is rare11, although it is common in HIV patients.14 The possibility of malignant degenertion is quite unlikely, although the lesions with fixation of base or induration of deeper tissues should be seen with suspicion.
INVERTED PAPILLOMA
(Ringertz tumor, trasitional cell papilloma, fungiform papilloma, cylindrical cell papilloma, schneiderian cell papilloma, epithelial papilloma, papillary sinusitis, soft papilloma and sinonasal type papillomas)
Inverted papilloma is a true epithelial neoplasm characterized by hyperplastic epithelium inverting into the underlying connective tissue. It is a benign epithelial growth extending into the underlying stroma of the nasal cavity and paranasal sinus. The tumor is well known for its invasiveness, tendency to recur and association with malignancy.24
History 24
In 1854, Ward first documented the occurrence of inverted papilloma in the sinonasal cavity.
In 1935, Reingertz histologically described the nature of the tumor and noted its classic inverted nature in underlying connective tissue stroma.
In 1971, Hymans reviewed several cases of this tumor and subdivided sinonasal papilloma into inverted, fungiform and cylindrical cell types.
Definition-
Lawson et al (1989) defined inverted papilloma as a group of benign neoplasm arising from the sinonasal (Schneiderian) mucosa and is composed of squamous or columnar epithelial proliferation with associated mucous cells.
Etiology-
The etiology of inverted papilloma is still unknown. Possible causes include 25
1. Allergy
2. Chronic sinusitis
3. Occupational exposure to dusts and aerosols
4. Tobacco
5. Viral infections –
a) HPV genomes have been demonstrated in inverted papillomas particularly HPV types 6 and 11 have been identified, sometimes HPV 16 and 18, and exceptionally HPV 57.
b) Epstein-Barr virus (EBV) DNA has been identified in 65% of inverted
papillomas.
Clinical Features-
Incidence & prevalene-
It is a rare benign tumor with incidence rate of 0.6 cases/100,000 people/year. It comprises 0.5–4% of all primary nasal tumors. It is noted with greater prevalence in Caucasians.25
Age & Sex-
The inverted papilloma seldom occurs in patients younger than 20 years of age; the median age is 55 years. It is prevalent in the fifth and sixth decades of life.25 It has a strong male predilection. (2: 1 male to female ratio)28
Site-
It usually arises from the lateral nasal wall in the region of the middle turbinate or ethmoid recesses or a paranasal sinus, usually the antrum. In the middle meatus, often extending to the ethmoid and maxillary sinuses. They may or may not involve nasal cavity. In advance cases, extension into all of the ipsilateral peripheral nervous system may occur whereas intracranial growth and dural penetration are rare.24
Clinical Presentation-
Inverted papillomas present as pink, tan brown or grey; nontranslucent; soft to moderately firm, polypoid or nodular growths with a convoluted or wrinkled surface.28 Multiple lesions may be present. Typically, the schneiderian papillomas are unilateral; bilateral papillomas may also occur.24
The symptoms include nasal obstruction, hyposmia, frontal headache, epistaxis, and rhinorrhea.19 Typically, the inverted papilloma results in unilateral nasal obstruction. Other manifestations include nasal drainage, anosmia, headaches (especially frontal), epiphora, proptosis, and diplopia. Pain, on the other hand, is an uncommon initial complaint, occurring in only about 10% of all cases. When present, it should always arouse suspicion of secondary infection or malignant change.24, 25 (Color Atlas Fig. 3)
Radiographic Features-
CT scan and magnetic resonance imaging (MRI) scan are most commonly used to evaluate inverted papilloma.24 Bony changes including bowing of the bones located near the mass are common CT findings. Tumors involving the maxillary sinus may lead to widening of infundibulum on CT scan, making the uncinate process difficult to discern.26 Bone remodeling may be a better term to describe the changes that occur secondary to the constant pressure and mass effect on surrounding bony structures from inverted papilloma. It is postulated that the bony skull base may have limited response to pressure caused by inverted papilloma, leading to more erosive changes rather than remodeling. In addition, contrast CT scan may demonstrate slight enhancement and calcification.24
Pressure erosion of the underlying bone is usually present and may be visible radiographically as an irregular radiolucency. Primary sinus lesions may be distinguishable only as a soft tissue radiodensity or mucosal thickening on radiographs; sinus involvement generally represents extension from the nasal cavity.28
Histopathologic Features-
The inverted papilloma is characterized by squamous epithelial proliferation into the submucosal stroma. The basement membrane remains intact, and the epithelium appears to be "pushing" into underlying connective tissue.28 The epithelium varies in cellularity and is composed of squamous, transitional and columnar cells (all 3 may be present in a given lesion) with admixed mucocytes (goblet cells) and intraepithelial mucin microcysts.24 Goblet (mucous) cells and mucin filled microcysts frequently are noted within the epithelium. Keratin production is uncommon, but thin surface keratinization may be seen.21 A mixed chronic inflammatory cell infiltrate is characteristically seen within all layers of the surface epithelium.
The cells are generally bland in appearance with uniform nuclei and no piling up; however, pleomorphism and cytoplasmic atypia may be present. The epithelial component may demonstrate extensive clear cell features indicative of abundant glycogen content. Papillary surface projections are present and deep clefts may be seen between projections.26 Mitotic figures may be seen in the basal and parabasal layers, but atypical mitotic figures are not seen, varying degrees of dysplasia may be seen. Intraepithelial mucocytes show intra cytoplasmic mucin positive material, which is Mucicarmine positive and diastase–resistant, PAS positive, varying degrees of dysplasia may be seen.28
The stromal components vary from myxoid to fibrous, with admixed chronic inflammatory cells and variable vascularity.28 (Color Atlas Fig. 4)
Differential diagnosis-
Differential diagnosis includes sinonasal inflammatory polyps, nonkeratinizing respiratory carcinoma and verrucous carcinoma.24
Sinonasal inflammatory polyps are clinically similar, but histopathologically epithelial alterations are seen in inverted papillomas and not in the inflammatory polyps.24
Nonkeratinizing respiratory carcinoma mimics inverted papillomas and they can be differentiated by the presence of dysplastic features in carcinoma.24,26
In verrucous carcinoma, characteristically, cleft like spaces lined by a thick layer of parakeratin extending from the surface deeply into the lesion which is the hallmark of verrucous carcinoma, is seen and is absent in inverted papilloma.24
Immunohistochemical Analysis-
Kato et al (2012) performed an immunohistochemical study in which the tumor cells were positive for cytokeratin and epithelial membrane antigen, while negative for calponin, S-100 protein, -SMA, vimentin, and desmin. This result indicated that the lesion arises from the excretory duct near the oral mucosal surface but not the myoepithelial cells.