association of human papilloma virus with oral squamous cell carcinoma

ASSOCIATION OF HUMAN PAPILLOMA VIRUS WITH ORAL SQUAMOUS CELL CARCINOMA – A BRIEF REVIEW Rakesh S 1 Mahija Janardhanan 1 Vinodkumar R B 2 1

Reader

2

Professor & Head,

Vidya M 3

Department of Oral Pathology 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 Squamous Cell Carcinoma (OSCC) constitutes one of the most common cancers 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 Viruses (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 – Koilocytes – is considered pathognomonic of HPV infection. 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 cancer, Squamous cell carcinoma, Koilocytes.

Oral & Maxillofacial Pathology Journal [ OMPJ ]

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Introduction

the studies point out that HPV16 is the

Oral Squamous Cell Carcinoma (OSSC)

most

represents 12 % of all cancers in men and

OSCCs (5, 6).

8%

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 infections, 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

have been conducted in this regard

squamous

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

research, studies have estimated up to

binucleated

60% positivity in OSCC (3, 4). Majority of

hyperchromatic nuclei and peri-nuclear

of

all

cancers

in

the


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predominant

described

and

epithelial

as

type

demonstrated cells

with

mononucleated

squamous

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in

cells

a

or with

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‘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 ‘wart

cancer cells and some long standing

viruses’ were Human Papilloma Viruses

infection or inflammation – 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

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

condylomas (10). Within the next decade,

degradation of p53 gene thereby inhibiting

koilocyte containing condylomas of the

apoptosis, and ‘E7 protein’ that disturbs

uterine cervix were established and proved

the retinoblastoma tumor suppressor gene

to be an infection with ‘wart virus’ (11).

thereby causing increased DNA synthesis


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a

are

actually

complex

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virus-infected

leading

to

the

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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

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

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

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

types

of

HPV

have

these

atypical

squamous

mutagenic

steps

in

cells

the

most common site for malignancy in the Oral & Maxillofacial Pathology Journal [ OMPJ ]

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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

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).

cytopathic

is

Allen et al in their detailed study of cases

considered to give a clue to the diagnosis

diagnosed as severe epithelial dysplasia of

of HPV infection. Presence of koilocytes

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).

effect

of

HPV,

and

evidence

mucosa,

of

concluded

HPV

that

by

‘Oral

and the specificity was 72% (27). This has Oral & Maxillofacial Pathology Journal [ OMPJ ]

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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

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.

squamous

cell

carcinoma:

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

References

Cancer 1996; 66: 464-9.

1.

2.

Ferlay J, Parkin DM, Pisani P.

6.

Smith

EM,

Summersgill

mortality and prevalence worldwide.

papilloma virus and risk of oral cancer.

Lyon: IARC press, 2004.

Laryngoscope 1998; 108: 1098-103. 7.

et

al.

HT,

Globcan 2002- Cancer incidence,

zur Hausen H. Human Papilloma

KS

Hoffman

Human

Syrjanen K, Syrjanen S, Lamberg M et

Viruses and their possible role in

al.

squamous cell carcinomas. Curr Top

immunohistochemical evidence suggesting

Microbiol Immunol 1977; 78:1-30.

human


Vol 1

No 2

Morphological

and

papillomavirus

Jul- Dec 2010

(HPV)

ISSN 0976-1225

involvement in oral squamous cell

8.

9.

13. Laverty CR, Russel P, Hills E et al.

carcinoma. Int J Oral Surg 1983;

The significance of non-condyloma wart

12(6): 418-24.

virus infection of the cervix

Ayre JE. Cancer cytology of the uterus.

transformation zone: A review with

Grune Stratton, New York, 1951.

discussion of two illustrative cases. Acta

Koss LG, Durfee GR. Unusual

Cytol 1978; 22: 195-201.

pattern of squamous epithelium of

14. Van Der Burg SL, Offringa R, Melief

uterine cervix, cytologic and pathologic

CJM. Cancer vaccines: cancer antigens;

study of koilocytic atypia. Ann NY

viral antigens. In: Rosenberg SA,

Acad Sci 1956; 63:1245-61

editor. Principles and practice of the

(Medline)

Biologic Therapy of Cancer.

10. Dunn AEG, Ogiluie NM.

Philadelphia, 2000; 518-22.

Intranuclear viral particles in human

15. Steinberg BM. Human papillomavirus

genital wart tissue. J Ultrastruc Res

and head and neck. In: Harrison LB,

1968; 22: 282-95 (Medline)

Sessions RB et al, editors. Head &

11. Meisels A, Fortin R. Condylomatous

Neck Cancer: A Multidisciplinary

lesions of the cervix and vagina:

Approach. Philadelphia, 2004; 975-

cytologic patterns. Acta Cytol 1976;

80.

20: 505-9 (Medline)

16. Munoz N, Bosch FX, de San Jose S et

12. Steven I Hajdu. The link between

al. Epidemiologic classification of

koilocytes and human papillomaviruses.

human papillomavirus types associated

Ann Clin & Lab Sci 2006; 36: 485-

with cervical cancer. NEJM 2003;

7.

348: 518-27.


Vol 1

No 2

Jul- Dec 2010

ISSN 0976-1225

17. Balram P, Nalinakumari KR,

21. Charfi L, Jouffroy T, de Cremoux P et

Abraham E et al. Human

al. Two types of squamous cell

papillomaviruses in 91 oral cancers

carcinoma of the palatine tonsil

from Indian betel quid chewers-high

characterized by distinct etiology,

prevalence and multiplicity of infections.

molecular features and outcome. Can

Int J Cancer 1995; 61(4): 450-4.

Lett 2008; 260 (1-2): 72-8.

18. Chang F, Syrjanen S, Nuutinen J et

22. Andrews E, Seaman WT, Webster-

al. Detection of human papillomavirus

Cyriaque J. Oropharyngeal carcinoma

(HPV) DNA in oral squamous cell

in non-smokers and non-drinkers: a

carcinomas by in situ hybridization and

role for HPV. Oral Oncol 2008;

polymerase chain reaction. Arch

45(6): 486-91.

Dermatol Res 1990; 282(8): 493-7.

23. Diaz EM, Kies MS, Sturgis EM et

19. Shroyer KR, Greer RO Jr. Detection of

al. Neoplasms of the head and neck. In:

human papillomavirus DNA by in

Kufe DW, Bast RC, Hait WN et al

situ hybridization and polymerase chain

editors. Holland-Frei Cancer Medicine.

reaction in premalignant and malignant

London, Canada: BC Decker 2006;

oral lesions. Oral Surg Oral Med Oral

1131-78.

Pathol 1991; 71(6): 708-13.

24. Jones JB, Lampe HB, Cheung HW.

20. Jon Mork, Kathrine Lie, Eystein

Carcinoma of the tongue in young

Glattre et al. Human papillomavirus

patients. J Otolaryngol 1989; 18(3):

infection as a risk factor for squamous

105-8. (Medline).

cell carcinoma of the head and neck. N

25. Sandra DX, Ivo B Filho, Carmem

Eng J Med 2001; 344: 1125-31.

LP et al. Prevalence of histological findings of human papilloma virus


Vol 1

No 2

Jul- Dec 2010

ISSN 0976-1225

(HPV) in oral and oropharyngeal

lesions. Histopathology 2007; 51(5):

squamous cell carcinoma biopsies:

713-6.

preliminary study. Rev Bras

28. Carl M Allen, Maria Fornatora, Ann

Otorinolaryngol 2005; 71(4): 510-4.

Cale Jones et al. Human

26. Khalid Al-Qahtani V, Diana B,

papillomavirus-associated oral epithelial

Paczesny et al. Koilocytosis in oral

dysplasia (Koilocytic dysplasia) An

squamous cell carcinoma: What does it

entity of unknown biologic potential.

mean? J Otolaryngol 2007; 36(1): 26-

Oral Surg Oral Med Oral Pathol

31.

1996; 82(1): 47-56.

27. Cabibi D, Giovanneli L, Martorana

29. M Fornatora, J Ghannoum, RF Reich

A et al. Predictive role of histological

et al. Oral koilocytic dysplasia

features and Ki67 pattern of high risk

associated with squamous cell carcinoma

HPV presence in atypical cervical

Oral Surg Oral Med Oral Pathol 2004; 98(2): 205

30. .

Sorce of Support: Nil Conflict of Interest: None declared


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