HPV-positive oropharyngeal cancer
Encyclopedia
Human papillomavirus
(HPV)-positive oropharyngeal cancer
(OPC) also known as HPV16+ oropharyngeal cancer or HPV+ OPC is a recognized subtype of Oropharyngeal squamous cell carcinomas
(OSCC), associated with the HPV type 16 virus.
Immunosuppression
seems to be an increased risk factor for HPV+ OPC. Individuals with TGF-β1
genetic variations, specially T869C, are more likely to have HPV16+ OPC. TGF-β1 plays an important role in controlling the immune system.
A 1999 study has found that patients with human papillomavirus (HPV)-associated anogenital cancers had a 4.3-fold increased risk of tonsillar squamous-cell carcinoma.
Although evidence suggests that HPV16 is the main cause of OPC between non-smokers and non-drinkers, the degree to which tobacco and/or alcohol use may contribute to increase the risk of HPV+ OPC is unclear.
Concomitant human herpesvirus-8
infection can potentiate the effects of HPV-16.
HPV associated cancers are caused by the expression of HPV's E6 and E7 proteins that bind to and inactivate tumor suppressor proteins p53
and retinoblastoma protein
(pRB), respectively, leading to malignant transformation of HPV infected cells.
The biology of HPV+ OPC is distinct of HPV- OPC with P53
degradation (inactivated by E6 instead of by genetic mutation), pRB pathway inactivation (by E7 instead of Cyclin D1
amplification), and P16
upregulation (over-expression instead of inactivation).
The tonsils epithelia (palatine and lingual
) share similar nonkeratinization
characteristic with the cervix, where HPV infection play the major role in cases of cervical cancer
.
than HPV- OPC.
Genetic signatures of HPV+ and HPV- OPC are different.
HPV OPC is associated with expression level of the E6/E7 mRNAs and of p16
. Nonkeratinizing squamous cell carcinoma strongly predicts HPV-association.
HPV OPC is not merely characterized by the presence of HPV-16. Only the expression of viral oncogenes within the tumor cells plus the serum presence of E6 or E7 antibodies is unambiguously conclusive.
There's not a standard HPV testing method in head and neck cancers, both in situ hybridization
and PCR
are commonly used. A 2010 study has concluded that both have comparable performance for HPV detection, however it's important to use appropriate sensitivity controls.
history of oral-genital sex, (125% >= 4 partners) history of anal–oral sex
, female partner had a history of either an abnormal Pap smear
or a cervical dysplasia, frequent marijuana use, chronic periodontitis, and, among men, decreasing age at first intercourse and history of genital warts.
A 2010 study concluded that current tobacco users with advanced HPV+ OSCC are at higher risk of disease recurrence compared with never-tobacco users.
HPV vaccine
s have a theoretical potential to prevent oral HPV infection.
A 2010 review study has found that HPV16 oral infection was rare (1.3%) among the 3,977 healthy subjects analyzed.
It's hypothesized that HPV+ OPC patients benefit better from radiotherapy and concurrent cetuximab
treatment than HPV- OPC patients receiving the same treatment.
High grade of p16 staining is thought to be better than HPV PCR analysis in predicting radiotherapy response.
The higher increase incidence of HPV associated OPC is also seen in other countries, like Sweden
, with a 2007 incidence of over 80% for cancer in the tonsils, Finland
and Czech Republic
.
In Australia incidence of HPV associated OPC is 1.56 cases per 100,000 males/year.
stated HPV was a cause for oral cancers.
Human papillomavirus
Human papillomavirus is a member of the papillomavirus family of viruses that is capable of infecting humans. Like all papillomaviruses, HPVs establish productive infections only in keratinocytes of the skin or mucous membranes...
(HPV)-positive oropharyngeal cancer
Oropharyngeal cancer
Oropharyngeal cancer is a disease which malignant cells form in the tissue of oropharynx. Oropharynx is a middle part of the throat which includes the base of the tongue, the tonsils, the soft palate, and the walls of the pharynx.-Studies:...
(OPC) also known as HPV16+ oropharyngeal cancer or HPV+ OPC is a recognized subtype of Oropharyngeal squamous cell carcinomas
Oropharyngeal squamous cell carcinomas
Oropharyngeal squamous cell carcinomas is a type of head and neck cancer that begins in the oropharynx, the middle part of the throat that includes the soft palate, the base of the tongue, the tonsils and the side and back wall of the throat...
(OSCC), associated with the HPV type 16 virus.
Causes
HPV oral infection precedes the development of HPV+ OPC. Slight injuries in the mucous membrane serve as an entry gate for HPV, which thus works into the basal layer of the epithelium. People testing positive for HPV16 oral infection have a 14 times increased risk of developing HPV+ OPC.Immunosuppression
Immunosuppression
Immunosuppression involves an act that reduces the activation or efficacy of the immune system. Some portions of the immune system itself have immuno-suppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reaction to treatment of other...
seems to be an increased risk factor for HPV+ OPC. Individuals with TGF-β1
TGF beta 1
Transforming growth factor beta 1 or TGF-β1 is a polypeptide member of the transforming growth factor beta superfamily of cytokines. It is a secreted protein that performs many cellular functions, including the control of cell growth, cell proliferation, cell differentiation and apoptosis...
genetic variations, specially T869C, are more likely to have HPV16+ OPC. TGF-β1 plays an important role in controlling the immune system.
A 1999 study has found that patients with human papillomavirus (HPV)-associated anogenital cancers had a 4.3-fold increased risk of tonsillar squamous-cell carcinoma.
Although evidence suggests that HPV16 is the main cause of OPC between non-smokers and non-drinkers, the degree to which tobacco and/or alcohol use may contribute to increase the risk of HPV+ OPC is unclear.
Concomitant human herpesvirus-8
Kaposi's sarcoma-associated herpesvirus
Kaposi's sarcoma-associated herpesvirus is one of seven currently known human cancer viruses, or oncoviruses. It is also the eighth human herpesvirus; its formal name according to the International Committee on Taxonomy of Viruses is HHV-8. Like other herpesviruses, its informal name is used...
infection can potentiate the effects of HPV-16.
Mechanism
A prospective study has found that increased HPV+ OPC risk was observed more than 15 years after HPV exposure, pointing to a slow development of the disease, like in cervical cancer.HPV associated cancers are caused by the expression of HPV's E6 and E7 proteins that bind to and inactivate tumor suppressor proteins p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
and retinoblastoma protein
Retinoblastoma protein
The retinoblastoma protein is a tumor suppressor protein that is dysfunctional in the majority types of cancer. One highly studied function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide...
(pRB), respectively, leading to malignant transformation of HPV infected cells.
The biology of HPV+ OPC is distinct of HPV- OPC with P53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
degradation (inactivated by E6 instead of by genetic mutation), pRB pathway inactivation (by E7 instead of Cyclin D1
Cyclin D1
G1/S-specific cyclin-D1 is a protein that in humans is encoded by the CCND1 gene.Immunohistochemical staining of cyclin D1 antibodies is used to diagnose mantle cell lymphoma.-Interactions:...
amplification), and P16
P16 (gene)
Cyclin-dependent kinase inhibitor 2A, also known as multiple tumor suppressor 1 , is a tumor suppressor protein, that in humans is encoded by the CDKN2A gene...
upregulation (over-expression instead of inactivation).
The tonsils epithelia (palatine and lingual
Lingual tonsils
The lingual tonsils are rounded masses of lymphatic tissue that cover the posterior region of the tongue.They are located on the dorsal surface at the base of the tongue. Their lymphatic tissue are dense and nodular, their surface is covered with stratified squamous epithelium which invaginates as...
) share similar nonkeratinization
Stratified squamous epithelium
A stratified squamous epithelium consists of squamous epithelial cells arranged in layers upon a basement membrane. Only one layer is in contact with the basement membrane; the other layers adhere to one another to maintain structural integrity...
characteristic with the cervix, where HPV infection play the major role in cases of cervical cancer
Cervical cancer
Cervical cancer is malignant neoplasm of the cervix uteri or cervical area. One of the most common symptoms is abnormal vaginal bleeding, but in some cases there may be no obvious symptoms until the cancer is in its advanced stages...
.
Diagnosis
HPV+ OPC is usually diagnosed at a more advanced stageCancer staging
The stage of a cancer is a description of the extent the cancer has spread. The stage often takes into account the size of a tumor, how deeply it has penetrated, whether it has invaded adjacent organs, how many lymph nodes it has metastasized to , and whether it has spread to distant organs...
than HPV- OPC.
Genetic signatures of HPV+ and HPV- OPC are different.
HPV OPC is associated with expression level of the E6/E7 mRNAs and of p16
CDKN2A
CDKN2A can refer to:* P16 * p14arf...
. Nonkeratinizing squamous cell carcinoma strongly predicts HPV-association.
HPV OPC is not merely characterized by the presence of HPV-16. Only the expression of viral oncogenes within the tumor cells plus the serum presence of E6 or E7 antibodies is unambiguously conclusive.
There's not a standard HPV testing method in head and neck cancers, both in situ hybridization
In situ hybridization
In situ hybridization is a type of hybridization that uses a labeled complementary DNA or RNA strand to localize a specific DNA or RNA sequence in a portion or section of tissue , or, if the tissue is small enough , in the entire tissue...
and PCR
Polymerase chain reaction
The polymerase chain reaction is a scientific technique in molecular biology to amplify a single or a few copies of a piece of DNA across several orders of magnitude, generating thousands to millions of copies of a particular DNA sequence....
are commonly used. A 2010 study has concluded that both have comparable performance for HPV detection, however it's important to use appropriate sensitivity controls.
Prevention
Risk factors are high number of sexual partners, (25% increase >= 6 partners)history of oral-genital sex, (125% >= 4 partners) history of anal–oral sex
Anal–oral sex
Anilingus Anilingus Anilingus (from anus + lingus (Latin Lingere: to lick), also spelled analingus, also referred to or described as anal–oral contact or anal–oral sex, is a form of oral sex involving contact between the anus or perineum of one person and the mouth (lips) or tongue of another....
, female partner had a history of either an abnormal Pap smear
Pap smear
The Papanicolaou test is a screening test used in to detect pre-cancerous and cancerous processes in the endocervical canal of the female reproductive system. Changes can be treated, thus preventing cervical cancer...
or a cervical dysplasia, frequent marijuana use, chronic periodontitis, and, among men, decreasing age at first intercourse and history of genital warts.
A 2010 study concluded that current tobacco users with advanced HPV+ OSCC are at higher risk of disease recurrence compared with never-tobacco users.
HPV vaccine
HPV vaccine
The human papilloma virus vaccine prevents infection with certain species of human papillomavirus associated with the development of cervical cancer, genital warts, and some less common cancers...
s have a theoretical potential to prevent oral HPV infection.
A 2010 review study has found that HPV16 oral infection was rare (1.3%) among the 3,977 healthy subjects analyzed.
Treatment
Currently HPV+ OPC are treated similarly to stage-matched and site-matched unrelated OPC. However less intensive use of radiotherapy or chemotherapy, as well as specific therapy, is under research.It's hypothesized that HPV+ OPC patients benefit better from radiotherapy and concurrent cetuximab
Cetuximab
Cetuximab is a chimeric monoclonal antibody, an epidermal growth factor receptor inhibitor, given by intravenous infusion for treatment of metastatic colorectal cancer and head and neck cancer.- Distribution :Cetuximab is manufactured and distributed in North America by ImClone and Bristol-Myers...
treatment than HPV- OPC patients receiving the same treatment.
Prognosis
Tumor HPV status is strongly associated with positive therapeutic response and survival compared with HPV-negative OPC. A possible explanation is "the lower probability of occurrence of 11q13 gene amplification, which is considered to be a factor underlying faster and more frequent recurrence of the disease" Presence of TP53 mutations, a marker for HPV- OPC, is associated with worse prognosis.High grade of p16 staining is thought to be better than HPV PCR analysis in predicting radiotherapy response.
Epidemiology
HPV+ OPC patients tend to be younger than HPV- patients. Currently in the US there is a growing incidence of HPV associated oropharyngeal cancers, perhaps as a result of changing sexual behaviors. Tonsil and oropharyngeal cancers increased in male predominance between 1975 and 2004, despite reductions in smoking. Recently, in the US, HPV associated OPC represent about 60% of OPC cases compared with 40% in the previous decade. By 2007, in the US, incidence of general OPC, including non-HPV associated, is 3.2 cases per 100,000 males/year and 1.9 per 100,000 all-sexes/year.The higher increase incidence of HPV associated OPC is also seen in other countries, like Sweden
Sweden
Sweden , officially the Kingdom of Sweden , is a Nordic country on the Scandinavian Peninsula in Northern Europe. Sweden borders with Norway and Finland and is connected to Denmark by a bridge-tunnel across the Öresund....
, with a 2007 incidence of over 80% for cancer in the tonsils, Finland
Finland
Finland , officially the Republic of Finland, is a Nordic country situated in the Fennoscandian region of Northern Europe. It is bordered by Sweden in the west, Norway in the north and Russia in the east, while Estonia lies to its south across the Gulf of Finland.Around 5.4 million people reside...
and Czech Republic
Czech Republic
The Czech Republic is a landlocked country in Central Europe. The country is bordered by Poland to the northeast, Slovakia to the east, Austria to the south, and Germany to the west and northwest....
.
In Australia incidence of HPV associated OPC is 1.56 cases per 100,000 males/year.
History
In 1983, it was first suggested that HPV might be the agent involved in the development of at least certain special types of oral cancers. In 2007 the World Health OrganizationWorld Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
stated HPV was a cause for oral cancers.
Further reading
- Ramqvist T, Dalianis T. (2010) Oropharyngeal cancer epidemic and human papillomavirus. Emerg Infect Dis.