ASSOCIATION OF HUMAN WITH ORAL SQUAMOUS CARCINOMA – A BRIEF REVIEW

Rakesh S 1 Mahija Janardhanan 1 Vinodkumar R B 2 Vidya M 3

1 Reader 2 Professor & Head, Department of Oral and Microbiology,

Amrita School of Dentistry, Kochi, Kerala, India.

3 Former Professor & Head, Department of Oral Pathology and Microbiology,

Yenepoya Dental College, Mangalore, Karnataka, India.

ABSTRACT

Oral (OSCC) constitutes one of the most common with a wide geographic distribution. Its incidence in India is rated as one among the highest in the world. Though the use of tobacco in various forms is widely accepted to be the major etiologic factor in OSCC, Human Papilloma (HPVs) are now being increasingly associated with the cause of OSCC. Incidence of tongue carcinomas in patients below forty years, without any history of tobacco habits is also being attributed to HPV. Histological detection of HPV altered epithelial cells – – is considered pathognomonic of

HPV . Here a brief review is done to highlight the association of HPV with OSCC and the methods for timely detection of HPV in such cases.

Key Words: Papilloma virus, HPV, Oral , Squamous cell carcinoma, Koilocytes.

Oral & Maxillofacial Pathology Journal [ OMPJ ] Vol 1 No 2 Jul- Dec 2010 ISSN 0976-1225

Introduction the studies point out that HPV16 is the

Oral Squamous Cell Carcinoma (OSSC) most predominant type in represents 12 % of all cancers in men and OSCCs (5, 6).

8% of all cancers in the female The presence of HPV altered epithelial population. Its incidence in the Indian cells viz. Koilocytes, in histologic sections subcontinent is among the highest in the is thought to be a microscopic indicator of world. It has been estimated that 83000 HPV , and may serve as a new OSCC cases and 46000 deaths occur marker for further molecular studies annually in India (1). The widespread use involving the HPV (7). Among the of tobacco in various forms in India is OSCCs from different oral sites, lesions thought to play a major role in the from the tongue have the highest reported etiology of OSCC. Studies have also rates of HPV association. It is therefore pointed to a role for the Human mandatory to understand the possible role

Papilloma Virus (HPV) in the etiology of of HPV in OSCC and various diagnostic

OSCC, especially for those without criteria for their early detection in OSCC. established risk factors. Since the first History evidence of HPV in the etiology of OSCC In 1951, a Canadaian cytologist Ernest was shown in 1977, numerous studies Ayre described and demonstrated have been conducted in this regard squamous epithelial cells with a supporting the role of HPV as a causative ‘perinuclear halo’ in smears from the agent for OSCC (2). Though the true uterine cervix. These ‘halo cells’ were prevalence of HPV in OSCC is still under described as mononucleated or research, studies have estimated up to binucleated squamous cells with

60% positivity in OSCC (3, 4). Majority of hyperchromatic nuclei and peri-nuclear Oral & Maxillofacial Pathology Journal [ OMPJ ] Vol 1 No 2 Jul- Dec 2010 ISSN 0976-1225

‘clearing’. Ayre proposed that these The year 1977 was momentous, for, it was squamous cells with ‘halo’ were ‘pre- shown for the first time that these ‘ cancer cells and some long standing viruses’ were Human Papilloma Viruses infection or – viral or some (HPV) and they play a role in the etiology other type – was responsible for the of Squamous Cell Carcinoma and its appearance of these cells (8). This drew precursors (12). Soon many studies the attention of many other workers to followed and it was established that these cells and Koss and Durfee, in 1956, koilocytes are actually virus-infected named these squamous cells with peri- squamous epithelial cells and the virus nuclear clearing surrounded by a thin rim found in the nuclei of koilocytes is of cytoplasm, as “koilocytes”, from the consistent with HPV. (7,13).

Greek word ‘koilos’ meaning ‘hollow cell’ Carcinogenic Potential of HPV

(9). Following this, many scientists began The genetic material of HPV DNA is studying the koilocytes in detail, but known to contain 3 regions – a long unfortunately the exact nature and origin control region, an early region and a late of these cells remained a mystery for the region. Following the HPV infection of next ten years. It was in 1968 that this veil the host tissue, The HPV genome is of obscurity began to be lifted, by the integrated into the host genome and two ultrastructural finding of koilocytes and products are formed – ‘E6 protein’ that viral particles within them in genital forms a complex leading to the condylomas (10). Within the next decade, degradation of p53 gene thereby inhibiting containing condylomas of the , and ‘E7 protein’ that disturbs uterine cervix were established and proved the retinoblastoma to be an infection with ‘wart virus’ (11). thereby causing increased DNA synthesis Oral & Maxillofacial Pathology Journal [ OMPJ ] Vol 1 No 2 Jul- Dec 2010 ISSN 0976-1225

and proliferation. Most often, the basal has also pointed out the close association keratinocytes are the target cells for HPV of HPV with OSCC (22). where new virions are produced and It has been proposed that an important released, when the superficial cells flake pre-requisite for malignant transformation off (14,15). of these atypical squamous cells

HPV and OSCC (koilocytes), is a continuous, persistent

Many studies carried out since 1980 have infection with HPV. This has been proved the presence of HPV (koilocytes) supported by the studies of Balram et al, in OSCC cases. Though nearly 100 who suggested that the high prevalence of distinct types of HPV have been HPV in OSCC point to the continuous identified, only a few are seen to be viral infection being an etiologic factor associated with OSCC (16). Balram et al with the betel quid (tobacco) causing have reported high prevalence of HPV-16 additional mutagenic steps in the and HPV-18 (42% & 47% respectively) in carcinogenic process (17). their study on oral cancer from Indian Classically the mean age for diagnosis of betel quid chewers (17). Chang et al (18), OSCC has been approximately 60 years.

Shroyer & Greer (19), Mork et al (20) and Many recent studies have pointed to a

Charfi et al (21) have, in separate studies disturbing trend of increasing incidence of demonstrated the high association rate of OSCC of the tongue in patients below 40

HPV-16 in OSCC cases as between 62% years of age, in the absence of any known and 95%. The constant detection of the habit of using tobacco (23). It has been

HPV in OSCC patients who do not reported to have increased over the past habitually use tobacco or consume alcohol decade and is thought to be the second

most common site for malignancy in the Oral & Maxillofacial Pathology Journal [ OMPJ ] Vol 1 No 2 Jul- Dec 2010 ISSN 0976-1225

oral cavity (24). Microscopic evidence of led many scientists to believe that koilocytes and HPV DNA (by molecular presence of koilocytes in histopathologic methods) have been demonstrated in sections from OSCC cases makes it a around 75% of these tongue cancer simple and reliable criteria to detect the patients, suggesting a direct etiologic role presence of HPV in these lesions. Many for HPV in these cases, in the absence of studies have further confirmed this any other known factor. histologic evidence of HPV by

Koilocytes – Histologic markers for performing molecular biology techniques

HPV like in-situ hybridization and Polymerase

Presence of koilocytes in histologic Chain Reaction (PCR), to demonstrate sections is thought to represent a HPV DNA in those lesions (18,19). of HPV, and is Allen et al in their detailed study of cases considered to give a clue to the diagnosis diagnosed as severe epithelial of of HPV infection. Presence of koilocytes oral mucosa, concluded that ‘Oral has been documented in smears and tissue Koilocytic Dysplasia’ (OKD) represented sections of OSCC cases (25). High a unique pathological entity and the prevalence of koilocytes (koilocytosis) has presence of HPV could be predicted been reported in OSCC cases, and it has under light microscopy with 80% accuracy been found to be equally distributed (28). Studies by Fornatora et al have also among the different tumor grades (26). A reported OKD in association with OSCC, recent study by Cabibi et al shows that the which exhibits features of both HPV sensitivity of detection of HPV infection infection (koilocytes) and oral epithelial by identification of koilocytes was 74% dysplasia (29). and the specificity was 72% (27). This has Oral & Maxillofacial Pathology Journal [ OMPJ ] Vol 1 No 2 Jul- Dec 2010 ISSN 0976-1225

Conclusion 3. Gillison ML, Shah KV. Human

Due to the evidence of increasing Papilloma virus associated head and association of HPV with OSCC, timely neck squamous cell carcinoma: diagnosis of the presence of HPV in such mounting evidence for an etiologic role lesions is essential. Studies indicate that for Human Papilloma Virus in a the microscopic presence of koilocytes in subset of head and neck cancers. Curr the epithelium from such cases may be Opin Oncol 2001; 13:183-8. used as a significant marker for the 4. Mckaig RG, Baric RS, Olhan AF. detection of HPV in OSCC. This may be Human Papilloma virus and head and further confirmed by techniques like PCR neck cancer: epidemiology and molecular or in-situ hybridization. The growing biology. Head Neck1998; 20: 250-65. incidence of HPV in association with 5. Snijders PJ, Scholes AG, Hart CA et tongue carcinomas is also a matter of al. Prevalence of mucosotropic Human concern and requires further studies in Papilloma viruses in squamous cell this regard. carcinoma of head and neck. Int J

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30. .

Sorce of Support: Nil

Conflict of Interest: None declared

Oral & Maxillofacial Pathology Journal [ OMPJ ] Vol 1 No 2 Jul- Dec 2010 ISSN 0976-1225