Oral Squamous Cell Carcinoma (OSCC) constitutes one of the most common cancers ... of Squamous Cell Carcinoma and its .... carcinoma of the palatine tonsil.
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 ]
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
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
Oral & Maxillofacial Pathology Journal [ OMPJ ]
Vol 1
No 2
predominant
described
and
epithelial
as
type
demonstrated cells
with
mononucleated
squamous
Jul- Dec 2010
in
cells
a
or with
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 ‘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
Oral & Maxillofacial Pathology Journal [ OMPJ ]
Vol 1
No 2
a
are
actually
complex
Jul- Dec 2010
virus-infected
leading
to
the
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
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 ]
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
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 ]
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
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
Oral & Maxillofacial Pathology Journal [ OMPJ ]
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.
Oral & Maxillofacial Pathology Journal [ OMPJ ]
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
Oral & Maxillofacial Pathology Journal [ OMPJ ]
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
Oral & Maxillofacial Pathology Journal [ OMPJ ]
Vol 1
No 2
Jul- Dec 2010
ISSN 0976-1225