Prevention Methods

Understanding Head and Neck Cancer: Epidemiology

Jos I Almodvar, MDPresidente Sociedad de Otorrinolaringologa de Puerto Rico

Head & Neck CancerDiagnosis Treatment and RehabilitationSheraton Puerto Rico Convention CenterSeptember 25, 2010History

Evidence of head and neck carcinomas has been found in ancient skulls. The oldest known tumor is contained in a fossil found in east Africa by Leakey that dates back more than 500,000 years. Some historians speculate that a high incidence of nasopharyngeal cancer may have been present in some ancient populations because of the inhalation of wood smoke in poorly ventilated huts. In approximately 400 BC, Hippocrates described a common chronic ulcer at the edge of the tongue that he attributed to the presence of sharp teeth rubbing against the tongue.History

The ancient Indian physician Sushruta described the removal of tumors and developed great skill in plastic surgery, partly from defects created by frequent amputations of the nose and ears for punishment. Modern Western medicine received its foundation from early Roman medical writings. Little medical advancement was made for head and neck cancers until the advent of anesthesia and surgical excision in the 11th century.History

In 1893, President Grover Cleveland was found to have a squamous cell carcinoma of the hard palate that required surgical excision. The operation was performed secretly on a yacht so that he could manage the "financial panic of 1893." Cleveland was known for his heavy cigar smoking and social drinking.

EpidemiologySquamous cell carcinoma represents more than 90% of all head and neck cancers. A malignant tumor of epithelial origin, squamous cell carcinoma has a regional distribution involved in the biological activity of the neoplasm. Behavior of squamous cell cancer depends on its site of origin. Each anatomic site has its own particular spread pattern and prognosis.

EpidemiologyThe most common type of oral cancer is squamous cell carcinoma, which begins in the thin, flat cells that line the oral cavity. Squamous cell carcinoma usually develops from lesions on the mucous membranes, including leukoplakia (white patches) and erythroplakia (red patches). Other types of oral cancer include lymphoma, sarcoma, melanoma, and salivary gland tumors. Oral cancer occurs more often in men. The number of women with tongue cancer, however, has increased in recent years.

EpidemiologyThe number of new cases of head and neck cancers in the United States was 40,490 in 2006, accounting for about 3% of adult malignancies. 11,170 patients died of their disease in 2006.The worldwide incidence exceeds half a million cases annually. In North America and Europe, the tumors usually arise from the oral cavity, oropharynx, or larynx. In Southeast China and Taiwan, head and neck cancer, specifically nasopharyngeal cancer is the most common cause of death in young men.In 2008, there were 22,900 cases of oral cavity cancer, 12,250 cases of laryngeal cancer, and 12,410 cases of pharyngeal cancer in the United States.EpidemiologyMore than 70% of throat cancers are at an advanced stage when discovered.Men are 89% more likely than women to be diagnosed with, and are almost twice as likely to die of, these cancers.[37]African Americans are disproportionately affected by head and neck cancer, with younger ages of incidence, increased mortality, and more advanced disease at presentation.Laryngeal cancer incidence is higher in African Americans relative to white, Asian and Hispanic populations. Head and neck cancer increases with age, especially after 50 years. Most patients are between 50 and 70 years old.

EpidemiologyIn the United States, squamous cell carcinoma of the head and neck comprises about 4% of all malignancies. This corresponds to an estimated 17 per 100,000 persons with newly diagnosed squamous cell carcinoma of the head and neck per year. Male-to-female incidence rates are greater than 3:1. The discrepancy in the male-to-female ratio is even more pronounced in laryngeal tumors, in which carcinoma is 4-5 times more common in men.

EpidemiologyLaryngeal cancer generally is a disease of the elderly, with a peak incidence in the 50s and 60s. In certain parts of India and Southeast Asia, the practice of mixing cured tobacco with betel nuts has been associated with head and neck cancers. More than 200 million persons are thought to engage in this practice worldwide. A resultant 2.8 times higher relative risk of cancer exists for these individuals, and this increases to more than 10 times when smoking is also practiced. Inthese areas, the incidence of oral cancer alone is greater than 25 cases per 100,000 persons.

Etiology Squamous cell carcinoma of the head and neck is most commonly associated with the use of alcohol and tobacco. The risk for oral cancer is additive and is up to 40 times greater than in those who neither smoke nor drink. In squamous cell carcinoma, mutations in the p53 gene correlate with drinking and smoking habits. Some 15% of patients have a viral etiology. Epstein-Barr virus (EBV) has been implicated in the development of nasopharyngeal carcinoma.

Etiology Human papillomavirus infection is another factor implicated in the carcinogenesis of upper aerodigestive tract tumors. In particular, human papillomavirus-16 (HPV-16) can be isolated in up to 72% of oropharyngeal cancers. The recent increase in cancer of the tongue and tonsils in developed countries, particularly in patientsyoungerthan45, has been linked to HPV infection.3

Etiology Environmental exposures to paint fumes, plastic byproducts, wood dust, asbestos, and gasoline fumes have been implicated as risk factors.There is a strong association between gastroesophageal reflux disease (GERD) and adenocarcinoma of the esophagus. Gastroesophageal reflux disease is now thought to be a significant risk factor for cancer of the larynx and especially the anterior two thirds of the vocal cords. Irritation from poorly fitting dentures also has been implicated. Dietary deficiencies are also important risk factors. Vitamin A deficiency and iron deficiency associated with Plummer-Vinson syndrome have been linked to oral and pharyngeal cancers.Pathophysiology

Squamous cell carcinoma is thought to arise from keratinizing or malpighian epithelial cells. The hallmark of squamous cell carcinoma is the presence of keratin or "keratin pearls" on histologic evaluation. These are well-formed desmosome attachments and intracytoplasmic bundles of keratin tonofilaments. The term epidermoid can be substituted for squamous.Morphologically, squamous cell carcinoma is variable and may appear as plaques, nodules, or verrucae. These, in turn, may be scaly or ulcerated and white, red, or brown. Verrucous carcinoma has a more favorable prognosis because of infrequent nodal and distant metastasis.

Clinical presentation

Squamous cell carcinomas usually begin as surface lesions with erythema and slight elevation. These lesions are termed erythroplasia and deserve biopsy. These early red lesions are asymptomatic and may be either carcinoma in situ or invasive carcinoma. One third of lesions are pure white; they are known as leukoplakia but only 10% of them are carcinoma in situ or invasive carcinoma. The most common sites for squamous cell carcinoma are the floor of the mouth, the tongue, the soft palate, the anterior tonsillar pillar, and the retromolar trigone.

Clinical presentation

Tender, painful lesions usually are suggestive of perineural invasions. When lesions become palpable masses, symptoms such as a vague persistent sore throat or ear infection occur.In more advanced cases, dissemination to ipsilateral submandibular and jugulodigastric nodes is common, and the patient may present with a mass in the neck. When lymph node or remote bone and organ metastases are associated with an early oral primary lesion, often a second, more advanced primary upper aerodigestive or lung cancer is responsible for the metastases. Synchronous primaries, may have an incidence of 20%.

TNM ClassificationT - Primary tumor Tis - Preinvasive cancer (carcinoma in situ)T0 - No evidence of primary tumorT1 - Tumor 2 cm or less in greatest dimensionT2 - Tumor larger than 2 cm but not larger than 4 cmT3 - Tumor larger than 4 cmT4 - Tumor with extension to bone, muscle, skin, antrum, neckTx - Minimum requirements to assess primary tumor cannot be metN - Regional lymph nodes N0 - No evidence of regional lymph node involvementN1 - Evidence of involvement of a movable homolateral regional lymph node smaller than 3 cmN2a - Evidence of involvement of a movable homolateral regional lymph node3-6 cmN2b - Evidence of involvement ofmultiplehomolateral regional lymph nodes smaller than 6 cmN2c - Evidence of involvement of contralateral or bilateral regional lymph nodessmaller than 6 cmN3 - Any lymph node larger than 6 cmNx - Minimum requirements to assess the regional nodes cannot be metM - Distant metastases M0 - No evidence of distant metastasesM1 - Evidence of distant metastasesMx - Minimum requirements to assess the presence of distant metastases cannot be met

Staging

Stage 1 - T1/N0/M0Stage 2 - T2/N0/M0Stage 3 - T3/N0/M0, T3/N1/M0Stage 4 Any T/N1/M0, any T/N0/M0, any T/N2/M0, any T/N3/M0, any T/any N/M1Depth of infiltration is predictive of prognosis. With increasing depth of invasion of the primary tumor, the risk of nodal metastasis increases and survival decreases.Risk Factors: Alcochol, Tobacco and Gastroesophageal Reflux Disease

Who can get cancer?Doctors cannot always explain why one person gets cancer and another does not.

However, scientists have studied general patterns of cancer in the population to learn what things around us and what things we do in our lives may increase our chance of developing cancer. Risk FactorsAnything that increases a person's chance of developing a disease is called a risk factor; anything that decreases a person's chance of developing a disease is called a protective factor. Some of the risk factors for cancer can be avoided, but many cannot. Prevention means avoiding the risk factors and increasing the protective factors that can be controlled so that the chance of developing cancer decreases. Although many risk factors can be avoided, it is important to keep in mind that avoiding risk factors does not guarantee that you will not get cancer. Also, most people with a particular risk factor for cancer do not actually get the disease.

High Risk GroupsHeavy exposure to tobacco and heavy use of alcohol are well documented as major risk factors for head and neck cancer. In addition, patients cured of HNSCC have an approximately ten percent risk of developing second primary cancers of the head and neck at five years after treatment.

High Risk GroupsIndividuals with a pre-malignant lesion in the mouth known as dysplastic oral leukoplakia have an almost 30 percent risk of oral cancer at ten years after treatment.

High Risk GroupsIndividuals with the following diseases and syndromes are at increased risk for head and neck cancer: Fanconi's anemia, a rare, inherited disease in which the bone marrow fails to function properly; Li Fraumeni syndrome, a rare, inherited disorder that greatly increases the risk of developing several types of cancer; and Plummer-Vinson syndrome, a disorder characterized by long-term iron deficiency anemia, which causes swallowing difficulty. EnvironmentalExposure to known carcinogens such as industrial toxins (for example, asbestos, benzenes). Causative agents are identified when individuals have a specific type of cancer and are found to have a history of high exposure to particular agents. It is repeated exposure to such agents (i.e. chemicals in tobacco and tobacco smoke) which can cause cellular alterations leading to cancer. Carcinogens are believed to play a part in damaging or destroying genes that control cell proliferation. Unrestrained proliferation of rapidly dividing cells results in a mass of abnormal cells known as a tumor. Carcinogens may selectively enhance the growth of tumor cells.

BehavioralSocioeconomic factors (particularly with regards to ethnicity) have a defined role in the acquisition of oral cancer. In cases where individuals have an underprivileged lifestyle, nutrition may be deficient. Individuals who use tobacco products such as cigarettes, cigars, pipes and chewing tobacco are at a greater risk of acquiring the disease. The combined use of both alcohol and tobacco increases this risk more than using either substance alone.

TobaccoTobacco smoke is the single most lethal carcinogen in the United States. Tobacco contains multiple chemicals; at least 60 are cancer-causing agents and are contributing factors in one-third of all annual cancer deaths. This includes the frequency, quantity of cigarettes smoked and duration of the habit. The risk is significantly greater for individuals who began smoking at a young age.

Secondhand smokeHealth risks posed by environmental tobacco smoke are not limited to smokers. Secondhand or passive smoking contributes annually to a few thousand cancer diagnoses; and, in some cases deaths from lung cancer can be attributed to secondhand smoke.Frequent inhalation of secondhand smoke has the same effect as breathing environmental pollutants. In the past decade, the Environmental Protection Agency has classified passive cigarette smoke as a Group "A" carcinogen, thereby categorizing it as a known human carcinogen.AlcoholFrequent and heavy use of alcohol has an impact on many health disorders and diseases. However, when it is combined with tobacco, the two substances are believed to have a synergistic effect whereby one substance significantly amplifies the hazardous effects of the other.

Genetics Genetics influence the development of some cancers, as it predisposes one to the possibility of acquiring the disease. Through genetics, it is possible to inherit gene mutations that promote growth of cancer cells. However, genetics are responsible for less than five percent of the development of fatal cancers. Genetic variables are higher within races than between.

MortalityThe cure rates for cancer of the oral cavity varies depending on the stage and site. Early stage cancers are thought to have a cure rate as high as 90 percent. Moderate or advanced cancers may be controlled by combined modality therapies such as surgery or radiation or both. In the case of the latter, the survival rate differs and is dependent upon the site and the extent of spread of the disease.

Cancer in the Young!Cancers of the head and neck are usually caused by tobacco and alcohol, but recent studies show that about 25% of mouth and 35% of throat cancers are caused by HPV.HPV-associated head and neck cancer rates by race and ethnicity, United States, 19982003Among whites, about 1.3 women and 5.1 men per 100,000 were diagnosed with HPV-associated head and neck cancer.Among blacks, about 1.5 women and 6.8 men per 100,000 were diagnosed with HPV-associated head and neck cancer.Among Hispanics, about 0.7 women and 3.6 men per 100,000 were diagnosed with HPV-associated head and neck cancer.HPVPeople testing positive for HPV16 oral infection have a 14 times increased risk of developing Oropharyngeal Cancer.

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.A prospective study has found that increased HPV+ OPC risk was observed more than 15 years after HPV exposure. 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.

HPVThere'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.Risk factors are high number of sexual partners,(25% increase >= 6 partners) history of oral-genital sex, (12.5% >= 4 partners) history of analoral 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 vaccines have a theoretical potential to prevent oral HPV infection.HPVHPV+ 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. In Australia incidence of HPV associated OPC is 1.56 cases per 100,000 males/year.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 WHO stated HPV was a cause for oral cancers.Prevention MethodsHead and Neck Cancer Screening TestsCurrently, there are no screening methods that have been proven to increase survival rates for HNSCC. A screening physical examinationof the neck, oropharynx (the middle section of the throat that includes the soft palate, the base of the tongue, and the tonsils), and the mouth has been widely adopted as part of a routine dental examination. There are no HNSCC screening guidelines from the American Cancer Society, the National Comprehensive Cancer Network (NCCN), or the National Cancer Institute. And, at present, there are no known tests of blood or saliva proven to be effective for detection of HNSCC.

RecommendationsMost doctors advise that all individuals have a yearly physical examination of the head and neck and oropharynx (the middle section of the throat that includes the soft palate, the base of the tongue, and the tonsils) conducted by their primary care physician, as well as a yearly routine dental evaluation to include examination of the neck and inspection of the oropharynx and the mouth.

Follow Up for Cancer PatientsYear One: every 1 to 3 months Year Two: every 2 to 4 months Years Three to Five: every 4 to 6 months Year Five and Beyond: every 6 to 12 monthsChest x-ray annuallyIf an individual has received radiation treatment of the thyroid, then TSH thyroid function test annually

Outcome and Prognosis

For all sites and stages in the head and neck region, 5-year survival rates average 59%. Treatment of early lymphatic nodal spread and use of multiple modalities has resulted in improved survival in selected sites. Depth of lesion and percent survival9 mm - 65%Patients with early stage oral cancer have an 82% survival rate at 5 years but only 27% survival for advanced stages at 5 years. In addition, the incidence of multiple primaries is 40% in long-term survivors; therefore, early detection of head and neck cancers and cessation of alcohol and tobacco use is essential to improve prognosis.MortalityThe cure rates for cancer of the oral cavity varies depending on the stage and site. Early stage cancers are thought to have a cure rate as high as 90 percent. Moderate or advanced cancers may be controlled by combined modality therapies such as surgery or radiation or both. In the case of the latter, the survival rate differs and is dependent upon the site and the extent of spread of the disease.

Advances in Prevention for Head & Neck Cancer Prevention is possible in head and neck cancers. Leukoplakia, a precancerous condition in the mouth, can be prevented by the use of vitamin A, said Marshall Urist, MD, professor and director of General Surgery, University of Alabama. Treatment with vitamin A does not permanently stop leukoplakia. It will return when treatment stops. But it points to a method of preventing precancerous cells from turning into cancer in patients who are at high risk, he said.The use of 13-cis-retinoic acid (isotretinoin) at a dose of 1 mg/kg/day for 3 months, has been shown to prevent the development of squamous cell carcinoma of the upper aerodigestive tract. However, the vitamin A dose offered has many side effects and cannot be maintained indefinitely. When stopped, the leukoplakia returned, and TGF-alpha levels rose again. A new trial is using the same 3-month treatment with a follow-up maintenance dose of 0.25 mg/kg/day for 9 months. This is a first step toward reversing cellular changes that lead to cancer, he said.

Advances in Head & Neck Cancer

New surgical methods have improved treatment and overall survivalMultistage surgical reconstruction

Future and Controversies

Photosensitizers and interstitial laser therapy Immune therapyGene therapyTargeted therapy Molecular markers that have prognostic and treatment value are currently under investigation. Epidermal growth factor receptors (EGFR) and human papillomavirus (HPV) are already being used in this manner, and many new markers are currently under investigation.