HEAD AND NECK CANCER

HEAD AND NECK CANCER

The principal cancers of the head and neck include squamous cell cancers arising from the mucosal surfaces of the upper aerodigestive tract and a diverse group of salivary gland neoplasms. Unique cancers of the region include Epstein-Barr virus (EBV)–associated nasopharyngeal carcinoma, human papillomavirus (HPV)–associated oropharynx cancer (HPVOPC), thyroid malignant neoplasms, esthesioneuroblastoma, and sinonasal undifferentiated carcinoma. A variety of other cancers arise from structures and tissues in the head and neck, including the more common skin cancers, lymphomas, and sarcomas.

Squamous cell carcinomas account for 95% of all malignant neoplasms of the head and neck, whereas salivary gland cancers represent nearly all of the remaining 5%. They represent 4% of all malignant neoplasms in the United States. Squamous cell cancers of the head and neck can be divided into two distinct groups based on pathogenesis, biology, and prognosis. Environmentally related cancers, caused principally by tobacco and alcohol, have been declining in incidence; however, they remain common. There has been an increasing incidence of HPV-related oropharynx cancer. HPVOPC now represents about 75% of oropharynx cancers seen in the United States and Europe. HPVOPC affects a younger population (50 to 60 years) than environmental cancers do (55 to 65 years). HPVOPC patients are also generally healthier and are not prone to comorbid illnesses and second cancers seen in environmentally related squamous cancers.

The mucosal surfaces of the head and neck are divided into six anatomic regions: the oral cavity, oropharynx, hypopharynx, larynx, nasopharynx, and paranasal sinuses. The site of anatomic origin for a squamous cell carcinoma of the head and neck has important albeit imperfectly defined implications for diagnosis, pathogenesis, spread, prognosis, and treatment. This is because of intrinsic differences in the biology of the mucosal cells and subsequent cancers at the sites of origin, carcinogenic viral tropisms, and differences in lymphatic drainage patterns and proximity to other structures in this compact region.

Oral Cavity

The oral cavity includes the floor of the mouth, anterior or oral aspect of the tongue, lips, buccal surfaces, hard palate, retromolar trigone, and gums. This region is easily appreciable by physical examination, and thus tumours in this area can frequently be detected early in their course. Tumors of the oral cavity, which are strongly related to the use of smokeless tobacco and other oral tobacco products and, in southern Asia, to betel nut and pan chewing, appear on the mid oral tongue and buccal and gingival surfaces in the sites where these products are held in contact with the mucosa for long periods. Anterior tongue cancers are more common in smokers. Lip cancers are particularly prevalent in transplant recipients and can be caused by DNA damage from solar ultraviolet light.

Oropharynx

The oropharynx consists of the tongue from the circumvallate papillae posteriorly to the epiglottis, the tonsils, the associated pharyngeal walls, and the soft palate. The oropharynx has become the most common location for head and neck tumours in the United States and is a common site of origin in Europe. This is due to a high rate of HPVOPC, which continues to increase in incidence. HPVOPC is caused almost exclusively by HPV-16, a high-risk HPV type associated with cervical, anal, and vulvar cancers. Other high-risk HPV types account for 10 to 15% of new diagnoses. High-risk HPV types are transmitted in body fluids and infect squamous mucosal surfaces of the anogenital tract and the oropharynx. Whereas smoking does not increase the risk of HPVOPC, 50% of smokers with oropharynx cancer have HPV as a cause. Compared with environmental cancers, HPVOPC often presents with lower primary T stage (T1 and T2) and higher nodal stage (N2 and N3), and it is frequently a cause of cancer of unknown primary origin because of small and difficult-to-identify primary tumours.

Hypopharynx

The hypopharynx comprises the piriform sinuses, the lateral and posterior pharyngeal walls, and the posterior surfaces of the larynx. These structures surround the larynx posteriorly and laterally. Tumors in this region can be difficult to detect because of the recesses and spaces surrounding the larynx. As a result, primary hypopharyngeal tumours may be asymptomatic and, like oropharyngeal tumours, may initially be recognized in an advanced state or diagnosed as an unknown primary. These tumours are associated with tobacco and alcohol use.

Larynx

The larynx includes the vocal cords, the subglottis, and the supraglottic larynx as well as the thyroid, cricoid, and arytenoid cartilages. Tumors arising in the true vocal cords are frequently symptomatic early and rarely spread beyond the confines of the larynx, whereas subglottic and supraglottic cancers can be relatively asymptomatic and have a much higher and earlier risk of spread to the lymphatics and regional sites. Laryngeal cancers are strongly associated with smoking.

Nasopharynx

The nasopharynx includes the mucosal surfaces and structures of the cavity behind the nasal passages. Nasopharyngeal cancers are common in the Pacific Rim, northern Africa, and the Middle East. In some areas of China and Southeast Asia, nasopharyngeal cancers occur with a frequency that rivals that of lung cancer. In North America, there are about 2000 cases each year, but numbers are increasing as high-risk ethnic populations settle in North America. Nasopharyngeal cancers are frequently associated with the presence of latent infection of the epithelial tumour cells by EBV, the etiologic agent of infectious mononucleosis. Nasopharyngeal cancers are also associated with both environmental and genetic factors in susceptible populations that have migrated to North America and remain at high risk for this disease. Unlike other squamous cell carcinomas of the head and neck, nasopharyngeal cancers can occur at an early age, with a distinct peak in adolescence and young adulthood. Nasopharyngeal cancers are categorized into three histologic subtypes by the World Health Organization (WHO): the undifferentiated (WHO III) and nonkeratinizing forms (WHO II) are latently infected with EBV in 95% of cases and represent the majority of cases in North America and worldwide; the well-differentiated (WHO I) form is rarer and represents about 5% worldwide but about 15 to 25% of all nasopharyngeal cancers in North America, and it is usually associated with traditional risk factors such as smoking. Nasopharyngeal cancers have a high risk of early regional lymph node involvement, a prolonged natural history, and a very high risk of spread to distant sites.

Paranasal Sinuses

The paranasal sinuses comprise the maxillary, ethmoid, sphenoid, and frontal sinuses as well as the nasal cavity. These are relatively rare locations for tumours of the head and neck in North America, but there is an unexplained higher rate of malignant sinus disease among the Japanese. Squamous maxillary sinus cancers are more common in smokers. Up to 50% of cancers of the sinuses may be of salivary gland origin. Adenocarcinomas have often been related to exposure to dust from woodworking, tanning, or leather working. On occasion, neuroendocrine tumours and the rare sinonasal undifferentiated carcinoma are found. Sinus cancers are frequently diagnosed late in their course at the time of symptomatic invasion of surrounding structures, including the orbit, nasal cavity, base of the skull, and cranial nerves.

Salivary Glands

Salivary glands occur in all the regions described as well as in the trachea and oesophagus. Tumors can develop in all of the major and minor salivary glands with an incidence that is roughly proportional to the quantity of glandular tissue. The most common single site is the parotid. Although tumours can develop at any age, including childhood, the peak incidence is between 55 and 65 years of age. Salivary gland cancers have diverse histologic findings and manifest different behaviour on the basis of their histologic classification. A substantial fraction of parotid salivary tumours can be benign. Risk factors for salivary gland cancers are poorly understood, but previous radiation therapy in adjacent areas increases the risk.

Tobacco products and alcohol are major etiologic and risk factors for squamous cell carcinoma of the head and neck. Both show a clear dose response. Any irritating smoked product increases the risk for local cancer, but nicotine in tobacco as well as in other tobacco leaf components directly affects the oral mucosa and increases the risk for squamous cancer. Alcohol is also a carcinogen, and alcohol consumption as well as its direct application in mouthwashes is associated with an increased risk. Moreover, alcohol affects local and systemic detoxification enzymes and may increase the carcinogenic potential of other environmental carcinogens. Other environmental risk factors include radiation exposure and solar radiation; welding, metal refining, diesel and wood stove exhaust, and asbestos exposure; chronic irritants; vitamin A deficiency; and immunosuppression.

Carcinogenic viruses are responsible for the increasing incidence of head and neck cancer in the United States and Europe. Pathogenic HPV subtypes, most frequently HPV-16, independently account for approximately 75% of oropharyngeal cancer cases. HPV is transmitted by epithelial contact and body fluids. There is increased risk of HPVOPC associated with increasing numbers of individual sexual partners, although the majority of HPVOPC patients do not have sexual activity above the average. HPV DNA can be found in the tumour cells, and the oncogenic viral proteins E6 and E7 are frequently expressed and are responsible and necessary for the growth and survival of the cancer cells by affecting critical signalling pathways. Men have a three-fold greater incidence of HPVOPC than women do, although the cause for this imbalance in incidence is not known. Of great importance, HPVOPC patients have a three-fold better prognosis than that of patients with environmentally related cancers. This is due to three factors: fewer comorbid illnesses in patients with HPVOPC; few second cancers caused by tobacco and alcohol; and increased sensitivity of HPVOPC tumours to treatments. The majority of nasopharyngeal cancer is caused by another more complex virus that infects keratinocytes, EBV. The classic nasopharyngeal cancer, which is also called lymphoepithelioma , is associated with a brisk lymphoid infiltrate that can be confused with a lymphoma. Careful examination reveals the malignant epithelial cells, with EBV detectable in the tumour cells. EBV is also rarely associated with epithelial tumours of the oropharynx, tonsil, and salivary gland.

Several inherited diseases and genetic abnormalities are associated with the development of head and neck cancer. Fanconi anaemia, a rare disorder of a family of related gene products, has been linked to the development of tongue cancer, as has Cowden syndrome, which is associated with mutation of the PTEN gene. NOTCH1 may function as a tumour suppressor gene rather than as an oncogene in head and neck squamous cell carcinoma. Finally, common inherited allelic variants of the alcohol dehydrogenase and P-450 genes may be associated with increased susceptibility to alcohol and other environmental carcinogens.

The development of environmentally related squamous cell carcinoma of the head and neck is a multistep process in which early genetic changes evolve into frank malignancy. In environmentally related cancers, an abnormal premalignant clone of mucosal cells may be localized to a single site within the head and neck, or clones may occur independently in many sites. The pathogenesis of HPVOPC is less well understood. Second cancers are rare with HPVOPC in the short term, and long-term risk is unknown. In contrast, about 20% of patients with environmentally caused cancers will develop a second primary cancer, most commonly in the head and neck, lung, and oesophagus; 5% of patients are initially seen with a synchronous second primary. In environmentally related cancers, the cell cycle is dysregulated by the early loss of p16, an inhibitor of cyclin D1, or by upregulation of cyclin D1; p53 is disabled through a number of mechanisms preventing programmed cell death; mitogenic signalling is enhanced by upregulation of epidermal growth factor (EGF) receptor function; cyclooxygenase 2 is overexpressed, thereby inhibiting apoptosis and promoting angiogenesis; and chromosomal instability with aneuploidy develops. Many of these early molecular and functional changes occur without obvious alteration in the physical appearance of the oral mucosa, although leukoplakia can occur. In HPVOPC, the RB and p53 pathways are inactivated by the HPV oncogenic proteins E6 and E7. As a result, the p16 protein is upregulated as a biomarker of HPV tumour origin. As a consequence of RB and p53 inactivation, these patients have dysregulation of cell growth and DNA damage control/programmed cell death, respectively. The differences between the genetic and molecular determinants of cancer in HPVOPC and environmentally related cancers can be differentially targeted for therapy.

In environmentally related cancers, high-risk early lesions can occasionally be identified as leukoplakia and erythroplakia. Leukoplakia is diagnosed clinically as a white patch of mucosal tissue in the oral mucosa or larynx. It can unpredictably progress to cancer during a period of several years in approximately 30% of patients. Erythroplakia, a red hyperkeratotic change in the mucosa, is a more advanced premalignant lesion with an approximately 60% rate of progression to oral cancer. Surgical resection of leukoplakia or erythroplakia has no effect on the subsequent development of invasive cancer. There is no proven chemopreventive therapy for persons with oral premalignant lesions. Because continued smoking or alcohol consumption increases the risk for recurrence and second primaries dramatically, patients with prior environmentally related cancers should stop alcohol and tobacco use.

The symptoms and clinical manifestations of tumours in the head and neck can vary broadly and are related to the structures at the site of the primary tumour as well as regional lymph node drainage. Small tumours of the oral cavity and larynx can be easily appreciated because of physical self-discovery or early compromise of the function of a critical structure. As a result of the propensity for squamous cell carcinoma of the head and neck to remain a local and regional disease, it is unusual for this cancer to be associated with abnormalities outside the head and neck. Salivary gland malignant neoplasms are less constrained and frequently spread distantly; however, because the primary tumours are also frequently accessible to direct physical examination and early discovery, it is still uncommon to identify these tumours as a result of metastatic spread outside the region.

Clinical manifestations of tumours in the oral cavity include a painless lump, a painful mass or ulcer, or simple thickening of the mucosa. Small lesions in the lateral aspect of the tongue and the floor of the mouth can cause pain referred to the mandible, gums, and ear because of the shared sensory nerves supplying these areas. Antibiotics can relieve symptoms and even reduce the size of a tumour or lymph nodes when superficial infection and inflammation are contributing to the pain; however, recurrent or continued pain in an adult should trigger early suspicion about more ominous disease. Speech may be affected late if the tumour causes restricted tongue motion or cranial nerve XII dysfunction. Gingival tumours can loosen teeth and invade the mandible along tooth sockets.

In true vocal cord cancer, hoarseness and other forms of voice change are common and expected early symptoms, but they may be later manifestations of supraglottic and subglottic laryngeal tumours , which become relatively large without affecting the voice. Tumors of the piriform sinus can affect the voice when they become large and impair the recurrent laryngeal nerve or are associated with deep local invasion; pain in the ear or pain on swallowing referred to the ear is also a common and important feature of these tumours. Adults with ear pain or persistent hoarseness should be referred to an otolaryngologist for evaluation. Because this posterior area is difficult to assess directly, primary tumours are frequently missed in routine office examinations. Tumours of the supraglottic region, subglottic cancers, and cancers of the piriform sinus can also be manifested as acute, emergency airway obstruction. Frequently, patients have a history of wheezing and mild upper airway distress in the period leading up to the emergency situation. On occasion, such findings are confused with adult-onset asthma.

A middle ear infection or effusion in an adult should also prompt an ear, nose, and throat evaluation. Nasopharyngeal cancer may be manifested as an ear infection in young adults. Haemoptysis or epistaxis may be the only clue to a nasopharyngeal cancer or a paranasal sinus tumour . Cranial nerve findings from deep invasion of the base of the skull are late events and include lateral gaze abnormalities, diplopia, facial pain, or facial nerve paralysis. Sinus tumours can also be associated with these later findings, although nasal stuffiness occurs frequently and can be confused with sinusitis. New and persistent symptoms of sinusitis or facial pain should raise suspicion of sinus cancer and prompt an evaluation.

Tumors in the tonsil or base of the tongue can cause local pain and referred ear pain; however, they are frequently asymptomatic and can attain a large size before becoming evident as a result of changes in speech (“hot potato voice”), a sense of globus, trismus, or restriction of tongue movement. Manifestation as a painless lump in the neck is increasingly common with the increased incidence of HPVOPC. Tumors of the tonsil or base of the tongue may also lose their mucosal component, not be seen or felt on direct inspection, and occur as a solid or cystic neck mass. Isolated neck masses can wax and wane with antibiotics. A mass, especially a cystic mass, in the neck in an adult is cancer and specifically HPVOPC until proved otherwise and should prompt an ear, nose, and throat evaluation and positron emission tomography (PET)/computed tomography (CT) imaging, fine-needle aspiration, and examination under anaesthesia before excisional biopsy.

The staging of squamous cell carcinoma of the head and neck is based on the TNM (tumour, node, metastasis) staging system, and prognosis is related primarily to the N and T stages. The risk of the cancer’s spreading to lymph nodes is directly related to the location of the primary and secondarily to the size of the primary. Tumors of the oropharynx have a high risk for nodal metastases, followed in risk by the supraglottic larynx and piriform sinus (hypopharynx), oral portion of the tongue, soft palate, oral cavity and floor of the mouth, and larynx. Nasopharyngeal cancer is often associated with extensive nodal spread, whereas paranasal sinus cancers rarely spread to the lymph nodes. The location of lymph node spread is determined in part by site. Nasopharyngeal cancer spreads to the posterior cervical lymph nodes as well as to the high cervical nodes. Oropharynx, larynx, and piriform sinus tumours spread to the high cervical nodes. Nodal metastases from these locations can be bilateral. Oral cavity tumours spread to the submental nodes and submandibular nodes. Spread tends to be orderly from the submandibular nodes to the midcervical nodes. Oral cavity cancers can have as high as a 20% risk of clinically unappreciated contralateral spread.

The relative accessibility of the head and neck to direct inspection makes physical examination critical for diagnosis and staging. Patients with localized symptoms or a sign such as an ulcer or a small mass should have a thorough head and neck office examination performed by their primary physician and by a specialist, including inspection of the visible structures and palpation of the base of the tongue and tonsil areas as well as the neck. Specialized office examination with fibreoptics should be included in the preliminary assessment. Regardless of whether cancer is suspected, excisional biopsies should be discouraged because margins are frequently violated and inadequate, thereby leading to larger re-excisions. A simple punch biopsy is sufficient for diagnosis, particularly in the oral portion of the tongue where tumours can spread readily through lymphatics.

When cancer is highly suspected and before definitive surgical intervention, PET/CT of the body and a high-resolution CT scan from the base of the skull to the clavicles, preferably with the spiral technique, are indicated. Magnetic resonance imaging (MRI) provides added information in evaluating soft tissue involvement, especially in the base of the tongue and the parapharyngeal spaces and for sinus tumours. MRI can distinguish between soft tissue masses and retained secretions, whereas PET/CT and high-resolution CT are more helpful in assessing nodal spread in the neck, and CT is effective in identifying extracapsular nodal extension and bone invasion, which are important prognostic and clinical findings. PET scanning provides an important adjunct to CT scanning and can identify occult disease. PET is particularly helpful when the patient has an “unknown primary tumour,” before biopsy, to guide the evaluation and to reduce the risk of inadequate diagnostic and premature therapeutic procedures.

When a biopsy indicates cancer or cancer is highly suspected, an examination under anaesthesia with endoscopy can be performed to stage the primary tumour before definitive therapy is undertaken. This procedure, which may be part of definitive therapy, provides information about the extent of disease, the appropriateness of the planned definitive procedure, and the presence of second primaries. It is an absolute requirement before definitive therapy can be completed. Endoscopy and palpation under anaesthesia can identify unexpected local spread or a synchronous second primary (found synchronously in about 5% of patients with environmentally related cancers), which can substantially alter the treatment plan.

Approach to the Patient with an Unknown Primary Site

Patients frequently seek care from their primary physician because of an enlarged lymph node, a cystic mass, or a collection of lymph nodes in the upper part of the neck. Such masses in an adult should be considered cancer until proved otherwise. Masses in the supraclavicular areas usually derive from primary tumours below the clavicles, and masses in the midneck and cervical regions are almost always from the head and neck. Identification of a primary site is critical to focus therapy, to reduce morbidity, and to determine prognosis.

The most common primary sites for painless lumps are the oropharynx (base of the tongue and tonsil) and piriform sinus. Oropharynx cancers are frequently due to HPV, and a positive HPV or EBV-encoded RNA (EBER) finding in the biopsy specimen or fine-needle aspirate is presumptive evidence of oropharynx or nasopharynx origin, respectively. Salivary gland cancers, lymphomas, melanomas, and skin cancers can also occur in this manner. Bilateral nodal disease or nodal disease with systemic symptoms may suggest lymphoma. By comparison, pain, warmth, and erythema may suggest an infectious aetiology. Intraparotid nodes most likely represent metastases from skin malignant neoplasms. Physical examination should include a careful investigation for primary skin cancers. CT, PET, and MRI should be part of the initial evaluation. Fine-needle aspiration with HPV and EBER testing for squamous tumours should be performed. CT-guided biopsy may be indicated if the mass is difficult to approach. If squamous cells are identified, the tumour is most likely a squamous cell carcinoma of the head and neck. Next, endoscopy under anaesthesia should be performed with bilateral tonsillectomy and directed biopsies of any abnormalities, areas of firmness, and the base of the tongue, nasopharynx, and ipsilateral piriform sinus, even if they appear normal. Core or excisional (single node <3 cm) biopsy of the lymph node should be performed if the pathologic findings are equivocal and a primary site is not confirmed. Neck dissection can be accomplished if a primary site is not identified and the patient has an N1 or small N2a/b manifestation. Some unknown primaries with squamous histology are never identified. Currently, HPV and EBV are the only molecular markers known to distinguish head and neck cancer from skin or salivary gland squamous cancer. EBV positivity indicates a nasopharyngeal cancer, and HPV an oropharyngeal primary. Although p16 immunohistochemistry is often used as a surrogate for HPV testing, it is not adequate for a final therapeutic decision to be made and may be positive in up to 20% of non-HPV cancers.

In contrast to squamous cell carcinoma of the head and neck, salivary gland cancers are heterogeneous in their natural history and treatment. The three most common histologic types are adenoid cystic carcinoma, mucoepidermoid cancer, and adenocarcinoma. Other histologic types include the aggressive salivary ductal cancer and squamous cell cancers, whereas less aggressive histologic varieties include adenocarcinoma ex pleomorphic adenoma and acinic cell carcinoma. Because adenoid cystic carcinoma travels along nerves and can spread haematogenously, careful assessment of the cranial nerves and the chest by CT is indicated before major surgery is undertaken. Patients should also be evaluated for bone and liver metastases. PET scan may not be positive in acinic cell carcinoma because of slow proliferation and metabolism in the malignant cells. Formal lymph node dissection is not indicated. Ethmoid and sphenoid sinus adenoid cystic carcinomas are locally and regionally aggressive and require specialized surgery and radiation therapy techniques for local and regional control. The behaviour of mucoepidermoid carcinoma is determined by histology. Low- and intermediate-grade lesions rarely metastasize. Isolated high-grade tumours spread to local lymph nodes and by hematogenous routes and carry a high risk for the development of lung metastases. Local therapy should be directed at local and regional control with lymph node dissection. Radiation therapy is indicated for close microscopic margins or lymph node involvement. Adenocarcinoma, salivary ductal cancers, and squamous cell carcinoma are poor prognosis lesions with aggressive local and distant behaviour. These tumours should be evaluated in the same fashion as aggressive mucoepidermoid carcinomas. Salivary ductal carcinomas may be positive for overexpression of EGFR2 or androgen receptor and should be tested for these markers to guide therapy with targeted agents. Acinic cell carcinoma and carcinoma ex pleomorphic adenoma are relatively rare. They have a propensity for local and regional recurrence if they are not removed in toto. Metastases are rare in acinic cell carcinoma and tend to be slow growing.

Other Tumors of the Head and Neck

Lymphomas in the head and neck frequently are manifested either as nodal disease in the neck or as tumour involving the lymphoid tissues of Waldeyer’s ring. A primary head and neck cancer may later develop in patients with lymphoma as a consequence of past exposure to tobacco, radiation therapy, or immunosuppression. The tonsil is a preferred site for mantle cell and undifferentiated lymphomas. Mucosa-associated lymphoid tissue lymphomas can affect the salivary glands.

In the context of an isolated neck mass, a systematic evaluation should be undertaken, even in young adults without a smoking history. The sinonasal T-cell and natural killer cell lymphomas, also known as lethal midline granulomas, represent a unique family of lymphomas of the head and neck. These lymphomas are associated with EBV infection. Solitary, extramedullary plasmacytoma can also occur in the nasopharynx or paranasal sinuses.

Sarcomas that arise in the head and neck include osteogenic sarcomas and nerve sheath tumours. Paragangliomas, which are rare malignant tumours of the chief cells of nerve paraganglia, can be extensive, multicentric, and vascular. Rhabdomyosarcomas, which have a predilection for the orbit and sinuses, occur in younger persons; the prognosis tends to be better for tumours of the head and neck than for other locations. Olfactory neuroblastomas or esthesioneuroblastomas invade the nasal cavity and base of the skull.

Many skin tumours, including melanoma and squamous cell cancer, can be accompanied by adenopathy of the neck or parotid area. An unusual skin appendage tumour, Merkel cell cancer, can be confused with other neuroendocrine epithelial tumours. Merkel cell tumours are associated with HIV infection and may, in up to 50% of cases, be caused by Merkel cell polyomavirus.

Selection of a treatment program for an individual patient is based on three factors: (1) the primary site and stage of the tumour; (2) the patient’s comorbid conditions, including performance status and preferences; (3) and the biology of the tumour. Early-stage lesions, T1N0 and T2N0, are defined by their size, and their prognosis is site specific. For example, early larynx cancer involving the true vocal cords has an excellent prognosis and can be treated by local excision. Voice-preserving larynx conservation surgery is effective for selected patients. Radiation therapy is equally effective for early cancer. When there is a risk of lymph node spread, radiation therapy must be given postoperatively, and the primary value of surgery is significantly diminished. Intensity-modulated radiation therapy allows radiation to be delivered in a more conformal manner to the tumour and areas at risk while sparing critical structures such as the spinal cord and noncritical but important structures such as the salivary glands and swallowing structures. Intensity-modulated radiation therapy is now a standard of care for almost all patients with head and neck cancer.

GENERAL APPROACH TO SQUAMOUS CELL HEAD AND NECK CANCER

STAGE TNM DISEASE-SPECIFIC SURVIVAL TREATMENT APPROACH SPECIAL CONDITIONS
I T1N0 85-95% Surgery or radiation therapy Consider organ function and long-term toxicity
II T2N0 75-90% Surgery, radiation therapy, or chemoradiotherapy Consider organ function
Combined modality treatment for high-volume tumour
Postoperative chemoradiotherapy for poor prognostic findings on pathologic staging
III T3N0 50-75% Combined modality treatment Primary chemoradiotherapy or TPF induction therapy or sequential therapy for organ function
T1-3N1 Postoperative chemoradiotherapy
More aggressive approach (sequential therapy) for high-volume disease or hypopharynx tumours
IV T1-3N2-3 20-60% Combined modality treatment Combined modality therapy
T4N0-3 Limited surgery
Any M1 Postoperative chemoradiotherapy
Palliative therapy for M1 (curative therapy for isolated lung metastases)

Oral tongue, piriform sinus, and environmentally related oropharynx tumours have a poor prognosis and are difficult to stage accurately because of submucosal spread or lymphatic involvement. Stage I and stage II cancers are cured with local and regional surgery or radiation therapy in 70 to 90% of cases. Surgery may be preferred for oral cavity and anterior lesions. In surgically treated patients, those with a positive margin, two or more positive lymph nodes, or extracapsular spread have a significantly poorer survival rate (<30%) at 5 years. Perineural invasion and lymphovascular invasion may also be associated with a poor prognosis. Postoperative cisplatin-based chemoradiotherapy improves local and regional control as well as has a trend to increased survival, and it should be given to patients with a poor prognosis if their condition permits. At present, aside from HPV status and p16 immunohistochemistry, no molecular or immunohistochemical finding definitively adds to the information gleaned from pathology, staging, and performance status.

When organ preservation and function are issues for stage III or stage IV cancers or when radiation therapy is required regardless of surgical outcome, primary chemoradiotherapy or sequential therapy should be considered. The curative treatment of intermediate (stage III, T1-3N1, T3N0) and locally advanced (stage IV, T1-3N2-3, T4) disease remains controversial. Long-term (3 years) survival rates in patients with stage III disease are generally between 50 and 75%, whereas only 15 to 50% of stage IV patients survive for 3 years. Intermediate-stage tumours are usually resectable, but organ preservation may be an important consideration. In many of these cases, a combined modality approach that includes chemotherapy and radiation therapy is the standard of care.

Patients with anterior lesions may do better with initial surgical treatment. The oral cavity is easy to access and is relatively forgiving for surgery and reconstruction; postoperative radiation therapy or chemoradiotherapy can be moderated in the absence of poor prognostic features. For intermediate and advanced tumours of the oral cavity, newer microvascular surgical techniques can substantially improve functional outcome and may help increase local-regional control. Radiation therapy or chemoradiotherapy remains a necessary adjunct to prevent recurrence. In contrast, tumours of oropharyngeal base of tongue or hypopharynx are almost always more extensive than is clinically appreciated, and functional outcome can be compromised by surgery followed by chemoradiotherapy. These may be more suited to a nonsurgical regional and systemic approach. In addition, patients with rapidly growing tumours are more suitable for a combined modality approach. Patients with extensive N2 or N3 nodal disease (stage IV) should be considered relatively unresectable because of a poor prognosis from regional recurrence and distant metastases. Certain locations, such as the nasopharynx and posterior pharynx, should also be considered for definitive radiation therapy, sequential therapy, or chemoradiotherapy.

Surgical therapy has changed radically in the last 5 years. Microvascular reconstructive techniques have improved outcomes in the oral cavity and have substantially reduced functional morbidity and permitted previously morbid resections to be accomplished with good functional outcomes. Transoral laser microdissection and transoral robotic surgery have created the opportunity to operate on previously “inoperable” tumours of the oropharynx and hypopharynx. Surgery with these technologies is performed without bystander tissue damage, which often leads to complications and required prolonged hospitalizations. These technologies are being integrated into combined modality approaches.

Radiation therapy has been proved by randomized trials to yield better local control and disease-free survival if it is given in twice-daily fractionated treatments rather than as daily therapy. However, the absolute benefit of hyperfractionated radiation therapy at 5 years is only 3 to 4%, and a twice-daily schedule is not advantageous with chemotherapy or better than chemotherapy and standard once-daily approaches. Studies strongly support the notion that altered fractionation radiation therapy with chemotherapy is substantially less efficacious or more toxic than standard fraction chemotherapy and that chemoradiotherapy with standard fractionation is more efficacious than altered fractionation alone. Proton beam radiation therapy has become available for tumours of the base of skull or those close to the eyes or the optic chiasm and is suitable in that context.

Induction chemotherapy is the delivery of chemotherapy before definitive local-regional treatment. Sequential therapy adds chemoradiotherapy to induction chemotherapy. Induction chemotherapy with docetaxel (75 mg/m ), cisplatin (75 to 100 mg/m by intravenous bolus), plus 5-fluorouracil (750 to 1000 mg/m /day for 4 to 5 days by intravenous infusion), repeated every 3 or 4 weeks (TPF), is an effective, standard regimen. For patients with advanced oropharynx, larynx, and hypopharynx tumours, sequential chemotherapy with chemoradiotherapy using concomitant carboplatin and once-daily radiation therapy improves survival and preserves function compared with radiation, surgery, or cisplatin and 5-fluorouracil chemotherapy (PF).

Chemoradiotherapy integrates chemotherapy and radiation therapy together and has led to significant improvements in overall survival in patients with advanced disease compared with radiation therapy alone. For example, patients with unresectable disease who received cisplatin (100 mg/m by intravenous bolus) every 3 weeks during radiation therapy have significantly better survival than do those treated with radiation therapy alone. In a trial of patients with oropharyngeal carcinoma, those treated with carboplatin and 5-fluorouracil plus simultaneous radiation therapy had significantly better survival than did those treated by radiation therapy alone. Cetuximab plus radiation therapy has also proved effective in improving survival in patients with locally advanced head and neck cancer compared with radiation therapy alone in a single trial. Compelling data for an improvement of cetuximab or equivalence with cisplatin-based chemoradiotherapy in either toxicity or survival has not been produced. Conventional chemoradiotherapy results in more favourable outcomes than chemotherapy with accelerated radiation therapy or very accelerated radiation therapy alone in patients with locally advanced head and neck carcinoma.

Patients with locally advanced or unresectable disease (or both) should receive chemotherapy and radiation therapy as part of a combined modality approach. Surgery may be integrated into this approach. Organ preservation should be offered to patients who can tolerate the treatment and participate in the post-treatment rehabilitation.

Treatment of tumours of the paranasal sinuses is a special case. They rarely metastasize, and treatment should focus on surgical resection with postoperative radiation therapy or chemoradiotherapy for resectable stage III and stage IV disease and on chemoradiotherapy for local and regional control of unresectable disease. Proton beam irradiation may be more suited for tumours in and around the base of the skull, optic chiasm, orbits, and brain.

Follow-up

Patients need lifelong follow-up. Surveillance examinations for second primaries and recurrences should be performed monthly to bimonthly in the first year and then less frequently over time. PET/CT scan can provide evidence of local-regional persistence approximately 12 to 16 weeks after completion of radiation therapy and can be used to guide early salvage surgery and neck management. Biannual PET/CT scan as postoperative surveillance can identify early metastases or recurrence and increase the rate and success of salvage surgery. Treatment failure after 5 years is uncommon, but second primaries and distant metastases may continue to be identified in environmentally related cancers and HPVOPC, respectively. It is important to counsel these patients to avoid tobacco products.

During radiation therapy and immediately after radiation therapy, patients benefit from pain medications, local anaesthetics, mucolytics, and saline mouthwash. Patients must avoid alcohol-containing preparations or irritants. Long-acting agents such as fentanyl or time-release narcotics should be added when needed. A percutaneous endoscopic gastrostomy feeding tube is often effective for maintaining weight, improving healing, and managing nutrition during radiation therapy. Because depression is a major problem, psychiatric support and antidepressants may be very helpful. Salivary function improves during more than 4 years after radiation therapy, but most improvement occurs in the first 2 years. Pilocarpine and cevimeline (Evoxac) are effective stimulants of salivary flow in about 20% of patients.

Long-term sequelae of radiation therapy include dependence on a feeding tube in patients treated with aggressive chemoradiotherapy or radiation therapy alone. Attention should be paid to preservation of swallowing function by means of training in speech and swallowing as well as by dilation in selected patients. Hypothyroidism occurs in up to 50% of patients and as early as 3 months after treatment. Patients should be monitored by determining serum thyroid-stimulating hormone levels at regular intervals and then treated as appropriate. Dental failure is a common problem. Patients must be counselled to see their dentists regularly for cleanings and to obtain fluoride therapy daily for dental preservation. Patients are at substantial lifelong risk for complications from dental manipulations after radiation therapy. Bone necrosis is painful, can be confused with recurrent tumour, and requires vigorous antibiotic therapy, débridement, and possibly hyperbaric oxygen to promote healing. Late vascular compromise of the carotid artery should lead to routine carotid ultrasound beginning about 10 years after radiation therapy.

Patients with recurrent disease, a second primary, or metastatic disease must be evaluated for potential curability. Symptomatically, persistent pain may be the most important indicator of a recurrence, and repeated biopsy should be considered when a suspicious lesion is observed. If patients have a recurrence or second primary, curative treatment options are defined by their current stage, their previous therapy, and the interval from their original therapy. Patients who have previously been treated with surgery but not radiation therapy can undergo surgery and chemoradiotherapy as part of a curative treatment plan. Patients with a surgically treatable recurrence in an irradiated field should undergo surgery as appropriate. Surgical salvage may cure as many as 30% of patients with recurrent oral cavity, larynx, or hypopharyngeal tumours. The surgery must encompass the entire recurrence. A repeated course of radiation therapy or chemoradiotherapy is also acceptable in selected patients.

Patients who are incurable can be managed effectively with palliative therapy to improve quality of life and survival (e.g., tracheostomy for airway control, laryngectomy for pain and aspiration, percutaneous endoscopic gastrostomy tube for feeding). These manoeuvres can improve comfort and care in appropriate patients.

Palliative chemotherapy can provide meaningful benefit to some patients. Response rates with single agents are generally poor, and combination therapy offers higher response rates (30 to 50%). The combination of a platinum (cisplatin or carboplatin) plus 5-fluorouracil with an anti-EGF receptor antibody, cetuximab, significantly improves survival, response rate, and progression-free survival compared with the same chemotherapy without cetuximab.

Salivary Gland Tumors

In contrast to squamous cell carcinoma of the head and neck, salivary gland cancers are heterogeneous in their natural history and treatment; however, the mainstays of therapy for these tumours are surgery and radiation therapy. Early symptoms of local-regional recurrence include cranial nerve dysfunction and progressive pain. A PET scan may be useful in distinguishing recurrence from the neuropathy that may result from radiation therapy.

There are no highly active agents or combinations for treatment of metastatic salivary gland tumours with the exception of anti-Her2 therapy for Her2-positive tumours. Local therapy can include surgical removal of isolated metastases, radio frequency ablation, and radiation therapy. Response rates are generally in the range of 20 to 35%, but prolonged responses are occasionally seen.

Future Directions

Antibodies that target newly identified molecular targets are being evaluated and may improve local and regional control as well as survival when they are delivered in combination with other therapies. Therapeutic vaccines may improve outcomes in EBV nasopharyngeal carcinoma and HPVOPC, and preventive vaccines in adolescents may prevent later malignant disease. New immune checkpoint blockade inhibitors appear to be showing promise in viral and environmentally caused head and neck cancers.

The prognosis for patients with squamous cell carcinoma of the head and neck is directly related to the presence of HPV, stage, and performance status. The risk for recurrence declines dramatically at 3 years after definitive treatment, and survival and possible cure can be defined after 5 years. HPV status and then N (nodal) stage are the most important prognostic indicators of potential recurrence, with T (tumour) stage and smoking history being next. Stage I patients (T1N0) have a 90% likelihood of tumour control, whereas stage II patients (T2N0) have greater than 70 to 85% tumour control. Tumour control in stage III patients (T1-2N1, T3N0-1) is site dependent, is HPV status and smoking history dependent, and varies from 35 to 95%. Patients with stage IVa and IVb environmentally related cancers (T1-3, N2-3, or T4NX) have a 20 to 50% tumour-specific 5-year survival rate compared with 60 to 90% 5-year survival for HPVOPC. Poor prognostic signs in advanced-stage (IVb) patients are related to N3 nodal disease, extracapsular extension, and invasion of basic structures (carotid artery encasement, base of the skull, pterygoid muscles). Patients with M1 disease are categorized as stage IVc. Patients with single lung metastases, whether as a second primary or as an isolated recurrence, can be cured. Cures with metastatic disease caused by HPVOPC may be seen after aggressive management. Patients with recurrent disease and no curative options have a median survival of 6 to 9 months.

Distant metastases occur in about 15 to 20% of patients, but this rate is increasing as better local and regional control prolongs survival in patients with locally advanced disease. Oropharyngeal, tonsil, and piriform sinus tumours have the highest risk for distant metastases. A single synchronous lung metastasis in a patient at initial evaluation or at follow-up can be cured in about 20% of cases.

Salivary gland cancers vary in behaviour, depending on their histology. Adenocarcinoma, salivary ductal cancer, salivary squamous cell cancer, and high-grade mucoepidermoid cancer not only spread to lymph nodes but also spread rapidly haematogenously. The presence of lymph node metastases signals a high risk for distant metastases. Adenoid cystic carcinoma infrequently involves lymph nodes but spreads along nerves. Regional recurrences along cranial nerves are frequent and associated with “skip” lesions. Adenoid cystic carcinoma is also associated with the late development of lung metastases, but these patients can have a prolonged lifespan lasting more than 20 years. Low-grade mucoepidermoid cancer and acinic cell carcinoma have little risk of distant spread and are more notable for local recurrence if they are not completely removed.

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Genomic Medicine UK is the home of comprehensive genomic testing in London. Our consultant medical doctors work tirelessly to provide the highest standards of medical laboratory testing for personalised medical treatments, genomic risk assessments for common diseases and genomic risk assessment for cancers at an affordable cost for everybody. We use state-of-the-art modern technologies of next-generation sequencing and DNA chip microarray to provide all of our patients and partner doctors with a reliable, evidence-based, thorough and valuable medical service.

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