Head and neck cancer

Head and neck cancer
Classification and external resources
Specialty Oncology
ICD-10 C07-C14
C32-C33
ICD-9-CM 140-149
Patient UK Head and neck cancer
MeSH D006258

Head and neck cancer is cancer that starts in the lip, oral cavity (mouth), nasal cavity (inside the nose), paranasal sinuses, pharynx, larynx or parotid glands.

Most head and neck cancers are biologically similar. 90% of head and neck cancers are squamous cell carcinomas, so they are called head and neck squamous cell carcinomas (HNSCC). These cancers commonly originate from the mucosal lining (epithelium) of these regions.[1] Head and neck cancers often spread to the lymph nodes of the neck, and this is often the first (and sometimes only) sign of the disease at the time of diagnosis.

Head and neck cancer is strongly associated with certain environmental and lifestyle risk factors, including tobacco smoking, alcohol consumption, UV light, particular chemicals used in certain workplaces, and certain strains of viruses, such as human papillomavirus.[2] These cancers are frequently aggressive in their biologic behavior; patients with these types of cancer are at a higher risk of developing another cancer in the head and neck area.[2] Head and neck cancer is highly curable if detected early, usually through surgery, but radiation therapy may also play an important role, while chemotherapy is often ineffective.[3]

HNSCC is the sixth leading cancer by incidence worldwide and eighth by death.[4] There are 0.5 million new cases a year worldwide. Two-thirds occur in industrialized nations. HNSCC usually develops in males in the 6th and 7th decade. The five-year survival rate of patients with HNSCC is about 40-50%.[5][6]

Signs and symptoms

Throat cancer usually begins with symptoms that seem harmless enough, like an enlarged lymph node on the outside of the neck, a sore throat or a hoarse sounding voice. However, in the case of throat cancer, these conditions may persist and become chronic. There may be a lump or a sore in the throat or neck that does not heal or go away. There may be difficult or painful swallowing. Speaking may become difficult. There may be a persistent earache. Other possible but less common symptoms include some numbness or paralysis of the face muscles.

Presenting symptoms include

Causes

Alcohol and tobacco

Alcohol and tobacco play a significant role.[7] Alcohol and tobacco are likely synergistic in causing cancer of the head and neck.[7] Smokeless tobacco is an etiologic agent for oral and pharyngeal cancers (oropharyngeal cancer).[8] Cigar smoking is an important risk factor for oral cancers as well.[9] Other potential environmental carcinogens include occupational exposures such as nickel refining, exposure to textile fibers, and woodworking. Use of marijuana, especially while younger, is linked to an increase in squamous-cell carcinoma cases[10] while other studies suggest use is not shown to be associated with oral squamous cell carcinoma, or associated with decreased squamous cell carcinoma.[11][12] However, cigarette smokers have a lifetime increased risk for head and neck cancers that is 5- to 25-fold increased over the general population.[13] The ex-smoker's risk for squamous cell cancer of the head and neck begins to approach the risk in the general population twenty years after smoking cessation. The high prevalence of tobacco and alcohol use worldwide and the high association of these cancers with these substances makes them ideal targets for enhanced cancer prevention.

Diet

Excessive consumption of processed meats and red meat were associated with increased rates of cancer of the head and neck in one study, while consumption of raw and cooked vegetables seemed to be protective.[14]

Vitamin E was not found to prevent the development of leukoplakia, the white plaques that are the precursor for carcinomas of the mucosal surfaces, in adult smokers.[15] Another study examined a combination of Vitamin E and beta carotene in smokers with early-stage cancer of the oropharynx, and found a worse prognosis in the vitamin users.[16]

Betel nut

Betel nut chewing is associated with an increased risk of squamous cell cancer of the head and neck.[17]

Infection

Human papillomavirus

Recent evidence is accumulating pointing to a viral origin for some head and neck cancers.[18]

Human papillomavirus (HPV), in particular HPV16, is a causal factor for some head and neck squamous cell carcinoma (HNSCC).[19][20] Approximately 15 to 25% of HNSCC contain genomic DNA from HPV,[21] and the association varies based on the site of the tumor, especially HPV-positive oropharyngeal cancer, with highest distribution in the tonsils, where HPV DNA is found in (45 to 67%) of the cases,[22] less often in the hypopharynx (13%–25%), and least often in the oral cavity (12%–18%) and larynx (3%–7%).[23]

Some experts estimate that while up to 50% of cancers of the tonsil may be infected with HPV, only 50% of these are likely to be caused by HPV (as opposed to the usual tobacco and alcohol causes). The role of HPV in the remaining 25-30% is not yet clear.[24] Oral sex is not risk free and can result in HPV-related cancer.[25]

Positive HPV16 status is associated with improved prognosis over HPV-negative OSCC.[26]

Induction of cancer can be associated for the expression of viral oncoproteins, the most important E6 and E7, or other mechanisms many of them run by the integration such as the generation of altered transcripts, disruption of tumor suppressors, high levels of DNA amplifications, interchromosomial rearrangements, or changes in DNA methylation patterns, the latter being able to find even when the virus is identified in episomes.[4] E6 active p53 degradation while pRb inhibits E7. p53 prevents cell growth when DNA is damaged by activating apoptosis and p21, a transcription factor that blocks the formation of cyclin D / Cdk4 avoiding pRb phosphorylation and thereby prevents release of E2F is a transcription factor required for activation of genes involved in cell proliferation. pRb remains bound to E2F while this action phosphorylated preventing activation of proliferation. Therefore, E6 and E7 act synergistically in triggering cell cycle and uncontrolled proliferation.[27]

Epstein–Barr virus

Epstein–Barr virus (EBV) infection is associated with nasopharyngeal cancer.[18] Nasopharyngeal cancer occurs endemically in some countries of the Mediterranean and Asia, where EBV antibody titers can be measured to screen high-risk populations.[18] Nasopharyngeal cancer has also been associated with consumption of salted fish, which may contain high levels of nitrites.

Gastroesophageal reflux disease

The presence of acid reflux disease (GERD – gastroesphogeal reflux disease) or larynx reflux disease can also be a major factor. Stomach acids that flow up through the esophagus can damage its lining and raise susceptibility to throat cancer.

Hematopoietic stem cell transplantation

Patients after hematopoietic stem cell transplantation (HSCT) are at a higher risk for oral squamous cell carcinoma. Post-HSCT oral cancer may have more aggressive behavior with poorer prognosis, when compared to oral cancer in non-HSCT patients.[28] This effect is supposed to be owing to the continuous lifelong immune suppression and chronic oral graft-versus-host disease.[28]

Other possible causes

There are a wide variety of factors which can put someone at a heightened risk for throat cancer. Such factors include smoking or chewing tobacco or other things, such as gutkha, or paan, heavy alcohol consumption, poor diet resulting in vitamin deficiencies (worse if this is caused by heavy alcohol intake), weakened immune system, asbestos exposure, prolonged exposure to wood dust or paint fumes, exposure to petroleum industry chemicals, and being over the age of 55 years. Another risk factor includes the appearance of white patches or spots in the mouth, known as leukoplakia;[2] in about ⅓ of the cases this develops into cancer. Other heightened risks: breathing or inhaling silica from cutting concrete, stone or cinder-blocks, especially in enclosed areas such as a warehouse, garage or basement.

Diagnosis

Left inferior internal jugular node metastases with extranodal invasion, two years after brachytherapy of tongue cancer. PET-CT scanning of a male patient in his 30's, 64 minutes after fludeoxyglucose (18F) was administered, shows some fluff around the tumor.

A patient usually presents to the physician complaining of one or more of the above symptoms. The patient will typically undergo a needle biopsy of this lesion, and a histopathologic information is available, a multidisciplinary discussion of the optimal treatment strategy will be undertaken between the radiation oncologist, surgical oncologist, and medical oncologist.

Histopathology

Throat cancers are classified according to their histology or cell structure, and are commonly referred to by their location in the oral cavity and neck. This is because where the cancer appears in the throat affects the prognosis - some throat cancers are more aggressive than others depending upon their location. The stage at which the cancer is diagnosed is also a critical factor in the prognosis of throat cancer.

Squamous-cell carcinoma

Squamous-cell carcinoma is a cancer of the squamous cell – a kind of epithelial cell found in both the skin and mucous membranes. It accounts for over 90% of all head and neck cancers,[29] including more than 90% of throat cancer.[2] Squamous cell carcinoma is most likely to appear in males over 40 years of age with a history of heavy alcohol use coupled with smoking.

The tumor marker Cyfra 21-1 may be useful in diagnosing squamous cell carcinoma of the head/neck.[30]

Adenocarcinoma

Adenocarcinoma is a cancer of epithelial tissue that has glandular characteristics. Several head and neck cancers are adenocarcinomas (either of intestinal or non-intestinal cell-type).[29]

Prevention

Avoidance of recognised risk factors (as described above) is the single most effective form of prevention. Regular dental examinations may identify pre-cancerous lesions in the oral cavity.

When diagnosed early, oral, head and neck cancers can be treated more easily and the chances of survival increase tremendously.

It is expected that HPV vaccines may reduce the risk of HPV-induced head and neck cancer.[31]

Types

Oral cavity

Main article: Oral cancer

Squamous cell cancers are common in the oral cavity, including the inner lip, tongue, floor of mouth, gingivae, and hard palate. Cancers of the oral cavity are strongly associated with tobacco use, especially use of chewing tobacco or "dip", as well as heavy alcohol use. Cancers of this region, particularly the tongue, are more frequently treated with surgery than are other head and neck cancers.

Surgeries for oral cancers include

The defect is typically covered/improved by using another part of the body and/or skin grafts and/or wearing a prosthesis.

Nasopharynx

Main article: Nasopharynx cancer

Nasopharyngeal cancer arises in the nasopharynx, the region in which the nasal cavities and the Eustachian tubes connect with the upper part of the throat. While some nasopharyngeal cancers are biologically similar to the common HNSCC, "poorly differentiated" nasopharyngeal carcinoma is lymphoepithelioma, which is distinct in its epidemiology, biology, clinical behavior, and treatment, and is treated as a separate disease by many experts.

Oropharynx

Main article: Oropharyngeal cancer

Oropharyngeal squamous cell carcinomas (OSCC) begins in the oropharynx, the middle part of the throat that includes the soft palate, the base of the tongue, and the tonsils. Squamous cell cancers of the tonsils are more strongly associated with human papillomavirus infection than are cancers of other regions of the head and neck. HPV-positive oropharyngeal cancer has a significantly more positive prognosis than HPV-negative disease (see HPV-positive oropharyngeal cancer for citations). People with oropharyngeal carcinomas are at high risk of developing second primary head and neck cancer.[32]

Hypopharynx

The hypopharynx includes the pyriform sinuses, the posterior pharyngeal wall, and the postcricoid area. Tumors of the hypopharynx frequently have an advanced stage at diagnosis, and have the most adverse prognoses of pharyngeal tumors. They tend to metastasize early due to the extensive lymphatic network around the larynx.

Larynx

Main article: Laryngeal cancer

Laryngeal cancer begins in the larynx or "voice box." Cancer may occur on the vocal folds themselves ("glottic" cancer), or on tissues above and below the true cords ("supraglottic" and "subglottic" cancers respectively). Laryngeal cancer is strongly associated with tobacco smoking.

Surgery can include laser excision of small vocal cord lesions, partial laryngectomy (removal of part of the larynx) or total laryngectomy (removal of the whole larynx). If the whole larynx has been removed the person is left with a permanent tracheostomy. Voice rehabilitation in such patients can be achieved through 3 important ways - esophageal speech, tracheoesophageal puncture or electrolarynx. One would likely require the help of intensive teaching and speech therapy and/or an electronic device.

Trachea

Cancer of the trachea is a rare malignancy which can be biologically similar in many ways to head and neck cancer, and is sometimes classified as such.

Most tumors of the salivary glands differ from the common carcinomas of the head and neck in etiology, histopathology, clinical presentation, and therapy, Other uncommon tumors arising in the head and neck include teratomas, adenocarcinomas, adenoid cystic carcinomas, and mucoepidermoid carcinomas.[2] Rarer still are melanomas and lymphomas of the upper aerodigestive tract.

Management

General considerations

Improvements in diagnosis and local management, as well as targeted therapy, have led to improvements in quality of life and survival for head and neck cancer patients since 1992.[33]

After a histologic diagnosis has been established and tumor extent determined, the selection of appropriate treatment for a specific cancer depends on a complex array of variables, including tumor site, relative morbidity of various treatment options, patient performance and nutritional status, concomitant health problems, social and logistic factors, previous primary tumors, and patient preference. Treatment planning generally requires a multidisciplinary approach involving specialist surgeons and medical and radiation oncologists.

Several generalizations are useful in therapeutic decision making, but variations on these themes are numerous. Surgical resection and radiation therapy are the mainstays of treatment for most head and neck cancers and remain the standard of care in most cases. For small primary cancers without regional metastases (stage I or II), wide surgical excision alone or curative radiation therapy alone is used. More extensive primary tumors, or those with regional metastases (stage III or IV), planned combinations of pre- or postoperative radiation and complete surgical excision are generally used. More recently, as historical survival and control rates are recognized as less than satisfactory, there has been an emphasis on the use of various induction or concomitant chemotherapy regimens.

Many different treatments and therapies are used in the treatment of throat cancer. The type of treatment and therapies used are largely determined by the location of the cancer in the throat area and also the extent to which the cancer has spread at time of diagnosis. Patients’ also have the right to decide whether or not they wish to consent to a particular treatment. For example, some may decide to not undergo radiation therapy which has serious side effects if it means they will be extending their lives by only a few months or so. Others may feel that the extra time is worth it and wish to pursue the treatments.

Surgery

Surgery as a treatment is frequently used in most types of head and neck cancer. Usually the goal is to remove the cancerous cells entirely. This can be particularly tricky if the cancer is near the larynx and can result in the patient being unable to speak. Surgery is also commonly used to resect (remove) some or all of the cervical lymph nodes to prevent further spread of the disease.

CO2 laser surgery is also another form of treatment. Transoral laser microsurgery allows surgeons to remove tumors from the voice box with no external incisions. It also allows access to tumors that are not reachable with robotic surgery. During the surgery, surgeon and pathologist work together to assess the adequacy of excision (“margin status”), minimizing the amount of normal tissue removed or damaged.[34] This technique helps give the patient as much speech and swallowing function as possible after surgery.[35]

Radiation therapy

Radiation mask used in treatment of throat cancer

Radiation therapy is the most common form of treatment. There are different forms of radiation therapy, including 3D conformal radiation therapy, intensity-modulated radiation therapy, and brachytherapy, which are commonly used in the treatments of cancers of the head and neck. Most patients with head and neck cancer who are treated in the United States and Europe are treated with intensity-modulated radiation therapy using high energy photons.

Chemotherapy

Chemotherapy in throat cancer is not generally used to cure the cancer as such. Instead, it is used to provide an inhospitable environment for metastases so that they will not establish in other parts of the body. Typical chemotherapy agents are a combination of paclitaxel and carboplatin. Cetuximab is also used in the treatment of throat cancer.

Docetaxel-based chemotherapy has shown a very good response in locally advanced head and neck cancer. Taxotere is the only taxane approved by US FDA for Head and neck cancer, in combination with cisplatin and fluorouracil for the induction treatment of patients with inoperable, locally advanced squamous cell carcinoma of the head and neck.[36]

While not specifically a chemotherapy, amifostine is often administered intravenously by a chemotherapy clinic prior to a patient's IMRT radiotherapy sessions. Amifostine protects the patient's gums and salivary glands from the effects of radiation.

Photodynamic therapy

Photodynamic therapy may have promise in treating mucosal dysplasia and small head and neck tumors.[2] Amphinex is giving good results in early clinical trials for treatment of advanced head and neck cancer.[37]

Targeted therapy

Targeted therapy, according to the National Cancer Institute, is "a type of treatment that uses drugs or other substances, such as monoclonal antibodies, to identify and attack specific cancer cells without harming normal cells." Some targeted therapy used in squamous cell cancers of the head and neck include cetuximab, bevacizumab and erlotinib.

The best quality data are available for cetuximab since the 2006 publication of a randomized clinical trial comparing radiation treatment plus cetuximab versus radiation treatment alone.[38] This study found that concurrent cetuximab and radiotherapy improves survival and locoregional disease control compared to radiotherapy alone, without a substantial increase in side effects, as would be expected with the concurrent chemoradiotherapy, which is the current gold standard treatment for advanced head and neck cancer. Whilst this study is of pivotal significance, interpretation is difficult since cetuximab-radiotherapy was not directly compared to chemoradiotherapy. The results of ongoing studies to clarify the role of cetuximab in this disease are awaited with interest.

Another study evaluated the impact of adding cetuximab to conventional chemotherapy (cisplatin) versus cisplatin alone. This study found no improvement in survival or disease-free survival with the addition of cetuximab to the conventional chemotherapy.[39]

However, another study which completed in March 2007 found that there was an improvement in survival.

A 2010 review concluded that the combination of cetuximab and platin/5-fluorouracil should be considered the current standard first-line regimen.[40]

Gendicine is a gene therapy that employs an adenovirus to deliver the tumor suppressor gene p53 to cells. It was approved in China in 2003 for the treatment of head and neck squamous cell carcinoma.[41]

Head and neck cancer clinical trials employing bevacizumab, an inhibitor of the angiogenesis receptor VEGF, were recruiting patients As of March 2007.

Erlotinib is an oral EGFR inhibitor, and was found in one Phase II clinical trial to retard disease progression.[42] Scientific evidence for the effectiveness of erlotinib is otherwise lacking to this point. A clinical trial evaluating the use of erlotinib in metastatic head and neck cancer is recruiting patients as of March, 2007.

The mutational profile of HPV+ and HPV- head and neck cancer has been reported, further demonstrating that they are fundamentally distinct diseases. [43]

Prognosis

Although early-stage head and neck cancers (especially laryngeal and oral cavity) have high cure rates, up to 50% of head and neck cancer patients present with advanced disease.[44] Cure rates decrease in locally advanced cases, whose probability of cure is inversely related to tumor size and even more so to the extent of regional node involvement. Consensus panels in America (AJCC) and Europe (UICC) have established staging systems for head and neck squamous cancers. These staging systems attempt to standardize clinical trial criteria for research studies, and attempt to define prognostic categories of disease. Squamous cell cancers of the head and neck are staged according to the TNM classification system, where T is the size and configuration of the tumor, N is the presence or absence of lymph node metastases, and M is the presence or absence of distant metastases. The T, N, and M characteristics are combined to produce a “stage” of the cancer, from I to IVB.[45]

Problem of second primaries

Survival advantages provided by new treatment modalities have been undermined by the significant percentage of patients cured of head and neck squamous cell carcinoma (HNSCC) who subsequently develop second primary tumors. The incidence of second primary tumors ranges in studies from 9%[46] to 23%[47] at 20 years. Second primary tumors are the major threat to long-term survival after successful therapy of early-stage HNSCC.[48] Their high incidence results from the same carcinogenic exposure responsible for the initial primary process, called field cancerization.

Digestive system

As it can impair a person’s ability to swallow and eat, throat cancer affects the digestive system. The difficulty in swallowing can lead to a person to choke on their food in the early stages of digestion and interfere with the food’s smooth travels down into the esophagus and beyond.

The treatments for throat cancer can also be harmful to the digestive system as well as other body systems. Radiation therapy can lead to nausea and vomiting, which can deprive a body of vital fluids (although these may be obtained through intravenous fluids if necessary). Frequent vomiting can lead to an electrolyte imbalance which has serious consequences for the proper functioning of the heart. Frequent vomiting can also upset the balance of stomach acids which has a negative impact on the digestive system, especially the lining of the stomach and esophagus.

Respiratory system

In the cases of some throat cancers, the air passages in the mouth and behind the nose may become blocked from lumps or the swelling from the open sores. If the throat cancer is near the bottom of the throat it has a high likelihood of spreading to the lungs and interfering with the person’s ability to breathe; this is even more likely if the patient is a smoker, because they are highly susceptible to lung cancer.

Others

Like any cancer, metastasization affects many areas of the body, as the cancer spreads from cell to cell and organ to organ. For example, if it spreads to the bone marrow, it will prevent the body from producing enough red blood cells and affects the proper functioning of the white blood cells and the body's immune system; spreading to the circulatory system will prevent oxygen from being transported to all the cells of the body; and throat cancer can throw the nervous system into chaos, making it unable to properly regulate and control the body.

Symptoms and side effects

Patients with head and neck cancer may experience the following symptoms and treatment side effects:[2]

Epidemiology

Age-standardized death from oro-pharyngeal per 100,000 inhabitants in 2004.[49]
  no data
  less than 2
  2-4
  4-6
  6-8
  8-10
  10-12
  12-14
  14-16
  16-18
  18-20
  20-25
  more than 25

The 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.[50] 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, whereas nasopharyngeal cancer is more common in the Mediterranean countries and in the Far East. In Southeast China and Taiwan, head and neck cancer, specifically nasopharyngeal cancer is the most common cause of death in young men.[51]

Epigenetic deficiency in DNA repair

A screen of 145 DNA repair genes for aberrant promoter methylation was performed on head and neck squamous cell carcinoma tissues from 20 patients and from head and neck mucosa samples from 5 non-cancer patients.[55] DNA repair gene NEIL1 had the most significantly increased frequency of methylation among the 145 genes tested. The hypermethylation corresponded to a decrease in NEIL1 mRNA expression. Further study of NEIL1 with an additional 135 tumor and 38 normal tissues showed that 71% of HNSCC tissue samples had elevated NEIL1 promoter methylation.[55] Promoter methylation of NEIL1 would cause its deficiency, and such an epigenetic deficiency in NEIL1 DNA repair would likely cause increased accumulation of DNA damages and increase the risk for carcinogenic mutations.

Other DNA repair enzymes that are frequently epigenetically reduced in head and neck cancers and the frequencies with which they are deficient include MGMT (54%) and MLH1 (31% - 33%) (see carcinogenesis).

Tobacco smoke

When DNA undergoes oxidative damage, two of the most common damages change guanine to 8-hydroxyguanine or to 2,6-diamino-4-hydroxy-5-formamidopyrimidine.

Tobacco smoke is one of the main risk factors for head and neck cancer and one of the most carcinogenic compounds in tobacco smoke is acrylonitrile.[56] (See Tobacco smoking). Acrylonitrile appears to cause DNA damage indirectly by increasing oxidative stress, leading to increased levels of 8-oxo-2'-deoxyguanosine (8-oxo-dG) and formamidopyrimidine in DNA[57] (see image). Both 8-oxo-dG and formamidopyrimidine are mutagenic.[58][59] DNA glycosylase NEIL1 prevents mutagenesis by 8-oxo-dG[60] and removes formamidopyrimidines from DNA.[61] Since deficiency of NEIL1 is common in head and neck cancer there may be a causal relationship between epigenetically decreased NEIL1 and the induction of head and neck cancer.

See also

References

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  27. ↑
  28. 1 2 Elad S, Zadik Y, Zeevi I, et al. (December 2010). "Oral cancer in patients after hematopoietic stem-cell transplantation: long-term follow-up suggests an increased risk for recurrence". Transplantation 90 (11): 1243–4. doi:10.1097/TP.0b013e3181f9caaa. PMID 21119507.
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