Overview of the diagnosis and staging of head and neck cancer

INTRODUCTION — 

Head and neck cancers can arise in the oral cavity, pharynx, larynx, nasal cavity, paranasal sinuses, and salivary glands. The most common histology is squamous cell carcinoma. Other common types include nasopharyngeal carcinoma and mucosal melanoma. This topic will review the initial evaluation, diagnosis, and staging of head and neck cancer.

Epidemiology, risk factors, pathology, and treatment of head and neck cancer are discussed separately:

●(See "Epidemiology and risk factors for head and neck cancer".)

●(See "Pathology of head and neck neoplasms".)

●(See "Overview of treatment for head and neck cancer".)

Specific details regarding the diagnosis of a selection of specific subtypes of head and neck cancers are discussed separately:

●(See "Epidemiology, staging, and clinical presentation of human papillomavirus associated head and neck cancer".)

●(See "Locoregional mucosal melanoma: Epidemiology, clinical diagnosis, and treatment".)

●(See "Epidemiology, etiology, and diagnosis of nasopharyngeal carcinoma".)

●(See "Head and neck sarcomas".)

The diagnosis, staging and treatment of thyroid cancer is also discussed separately:

●(See "Diagnostic approach to and treatment of thyroid nodules in adults".)

●(See "Differentiated thyroid cancer: Clinicopathologic staging".)

●(See "Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging".)

●(See "Papillary thyroid cancer: Clinical features and prognosis".)

ANATOMY — 

Head and neck cancers can arise from several anatomic areas. These include:

●Oral cavity – The oral cavity includes the mucosa of the lips (not the external, dry lip), the buccal mucosa, the anterior tongue, the floor of the mouth, the hard palate, and the upper and lower gingiva.

The anterior border of the oral cavity is defined by the portion of the lip that contacts the opposed lip (wet mucosa). The posterior border is defined by the circumvallate papillae of the tongue, the anterior tonsillar pillars (palatoglossus muscles), and the posterior margin of the hard palate. The hard palate defines the superior boundary of the oral cavity. Inferiorly, the oral cavity is defined by the mylohyoid muscles. The lateral boundary of the oral cavity is defined by the buccomasseteric region (buccal mucosa of the cheeks) and the retromolar trigone (which is located behind the mandibular third molar).

●Pharynx – The pharynx is divided into the nasopharynx, oropharynx, and hypopharynx (figure 1A).

•Nasopharynx – The nasopharynx forms the continuation of the nasal cavity. The boundary between the nasal cavity and nasopharynx is defined by the posterior choanae of the nasal cavity. The nasopharynx is defined superiorly by the basisphenoid and basiocciput (clivus) and inferiorly by the hard and soft palate. The prevertebral muscle and anterior margin of the cervical spine at C1 and C2 levels form the posterior margin of the nasopharynx.

The posterolateral boundary of the nasopharynx includes several important structures. The lateral wall of the nasopharynx is elevated by the torus tubarius, a cartilaginous structure that constitutes the opening of the Eustachian tube. The Eustachian tube allows communication between the middle ear and the nasopharynx through a defect (sinus of Morgagni) of the pharyngobasilar fascia, which lines the nasopharynx. The sinus of Morgagni may allow nasopharyngeal cancer to gain access into the skull base. The fossa of Rosenmüller (lateral nasopharyngeal recess), a common site of nasopharyngeal cancer, is located posterior to the torus tubarius. The nasopharynx also includes the adenoids (nasopharyngeal tonsils), located in the midline roof of the nasopharynx.

•Oropharynx – The soft palate defines the boundary between the nasopharynx and oropharynx. The oropharynx is separated anteriorly from the oral cavity by the circumvallate papillae and the anterior tonsillar pillars. The palatine tonsils, posterior tonsillar pillars, tongue base (posterior one-third of the tongue), valleculae, soft palate and the posterior pharyngeal wall are structures of the oropharynx. Inferiorly, the oropharynx is defined by the hyoid and the pharyngoepiglottic folds.

•Hypopharynx – The hypopharynx includes the pyriform sinuses, the posterior surface of the larynx (postcricoid area), and the inferior, posterior, and lateral pharyngeal walls.

●Larynx – The larynx is divided into three anatomic regions: the supraglottic region, the glottic larynx (true vocal cords and mucosa of the anterior and posterior commissures), and the subglottic larynx, which extends to the inferior border of the cricoid cartilage.

●Nasal cavity and paranasal sinuses – These include the nasal cavity and the paranasal sinuses (maxillary, ethmoid, sphenoid, and frontal).

●Salivary glands – These include the major (parotid, submandibular, and sublingual) and minor salivary glands (figure 1B). Minor salivary glands are found within the submucosa throughout the oral cavity, palate, paranasal sinuses, pharynx, larynx, trachea and bronchi, but are most concentrated in the buccal, labial, palatal, and lingual regions.

CLINICAL PRESENTATION — 

The clinical presentation of head and neck cancer varies widely depending upon the primary site and type of malignancy. There is overlap in some symptoms regardless of where the tumor originated from because similar anatomic structures will be involved based on the close proximity of structures in the head and neck region.

When to suspect — Head and neck cancer may be suspected in patients who present with one or more of the following symptoms if they are otherwise unexplained:

●Otalgia – Cranial nerves 5, 7, 9, and 10 contribute afferents to the external and middle ear. The presence of referred otalgia should prompt evaluation for a head and neck malignancy.

●Neck mass – A neck mass in an adult is abnormal and should prompt evaluation. Patients can present with a neck mass due to lymph node involvement. The lymph nodes are often firm and fixed or with reduced mobility. There may be ulceration of the overlying skin.

●Hoarseness or voice change.

●Nasal congestion or epistaxis.

●Odynophagia or dysphagia.

●Hemoptysis or blood in saliva.

●Mouth or skin ulcerations.

●Unilateral tonsil enlargement.

●Palpable lesions in the salivary glands, especially when they are asymptomatic.

●Solitary masses in the thyroid or a change in a pre-existing goiter. (See "Diagnostic approach to and treatment of thyroid nodules in adults".)

Clinical features by tumor site — Tumors presenting in specific anatomic locations (eg, oral cavity, pharynx, larynx, or sinuses) will have a distinct set of presenting symptoms. Examples of these include:

●Oral cavity tumors – Patients may present with mouth pain or nonhealing mouth ulcers, loosening of teeth, ill-fitting dentures, dysphagia, odynophagia, weight loss, bleeding, or referred otalgia.

•Tongue cancer may grow as an infiltrative and/or exophytic lesion. The presenting symptom is often pain, with or without dysarthria. Dysarthria implies deep muscle invasion of advanced tumor stage. There may be a history of longstanding leukoplakia or erythroplakia. Up to two-thirds of patients with primary tongue lesions have cervical lymph node involvement.

•Lip cancer usually presents as an exophytic or ulcerative lesion of the lower lip, occasionally associated with bleeding or pain. Some patients complain of numbness of the skin of the chin due to involvement of the mental nerve.

●Nasopharynx – Patients may present with hearing loss (associated with serous otitis media), tinnitus, nasal obstruction, and pain. The growth of the tumor into adjacent anatomical structures can lead to muscle involvement and impaired function of cranial nerves 2 to 6. Nasopharyngeal carcinoma begins in the nasopharynx. However, the most frequent presenting complaint for this malignancy is a neck mass due to regional lymph node metastasis, which occurs in nearly 90 percent of patients. (See "Epidemiology, etiology, and diagnosis of nasopharyngeal carcinoma", section on 'Clinical presentation'.)

●Oropharyngeal tumors – Presenting complaints can include dysphagia, pain (odynophagia, otalgia), obstructive sleep apnea or snoring, bleeding, or a neck mass (picture 1).

Unlike patients with human papillomavirus (HPV)-negative tumors who often present with odynophagia and otalgia, patients with HPV-positive oropharyngeal cancers often present with a neck mass (often cystic) as their only complaint (table 1). These cystic neck masses are often mistaken for branchial cleft cyst carcinomas. In reality, branchial cleft cyst carcinoma is exceptionally rare and its diagnosis should be one of exclusion rather than presumption [1]. (See "Epidemiology, staging, and clinical presentation of human papillomavirus associated head and neck cancer".)

●Hypopharyngeal tumors – Patients with these tumors often remain asymptomatic for a longer period and are therefore more likely to be seen in the later stages of the disease. Dysphagia, odynophagia, otalgia, weight loss, hemoptysis, dyspnea, and neck mass are common presenting symptoms.

●Laryngeal cancer – The symptoms associated with cancer of the larynx depend upon location. Persistent hoarseness may be the initial complaint in glottic cancers; later symptoms may include dysphagia, referred otalgia, chronic cough, hemoptysis, and stridor. Supraglottic cancers are often discovered later and may present with airway obstruction or palpable metastatic lymph nodes. Primary subglottic tumors are rare. Affected patients typically present with stridor or complaints of dyspnea on exertion.

●Nasal cavity – Patients with nasal cavity tumors often have symptoms of locally advanced disease at presentation including nasal obstruction and epistaxis. As the disease progresses the tumor can involve adjacent structures and cause facial swelling/pain, proptosis, cranial nerve dysfunction, seizure, and lymph node enlargement. (See "Tumors of the nasal cavity".)

●Sinus tumors – Common presenting symptoms of sinus tumors include epistaxis and unilateral nasal obstruction. Facial and/or head pain may be seen in later stages, due to pressure or tumor infiltration into nerves or periosteum. (See "Paranasal sinus cancer", section on 'Clinical presentation'.)

●Salivary gland tumors – Patients with salivary gland tumors will often have swelling or a mass form at the tumor location. Symptoms of more advanced disease depend on which gland is involved. (See "Salivary gland tumors: Epidemiology, diagnosis, evaluation, and staging", section on 'Clinical presentation'.)

Gradual facial weakness or twitching can be a sign of nerve involvement from a parotid gland malignancy. This must be distinguished from Bell's palsy, which is more sudden in onset. (See "Bell's palsy: Pathogenesis, clinical features, and diagnosis in adults".)

DIAGNOSTIC EVALUATION — 

The initial evaluation of a patient with a suspected head and neck cancer involves a physical exam, imaging studies, and tissue diagnosis (algorithm 1).

Overview of evaluation — Patients suspected of having head and neck cancer based on the initial history and physical examination should:

●Be referred to a specialist (eg, otolaryngologist or ear, nose, and throat specialist) for a targeted head and neck examination in the office or under anesthesia.

●Undergo a neck computed tomography (CT) or magnetic resonance imaging (MRI) evaluation with intravenous contrast. A full description of imaging studies for complete staging and alternatives such as positron emission tomography (PET)/CT are discussed separately. (See 'Imaging studies' below.)

●Undergo biopsy (typically a fine-needle aspiration, although some may require core or open biopsy).

Physical exam — The initial assessment of the primary tumor is based upon a thorough physical exam. We perform the following:

●Examination of the nasal cavity and oral cavity with visual examination and/or palpation of mucous membranes, the floor of the mouth, the anterior two-thirds of the tongue, tonsillar fossae and tongue base, palate, buccal and gingival mucosa, and posterior pharyngeal wall.

●A flexible laryngoscopy is used to examine the mucosa in the nasopharynx, oropharynx, hypopharynx, and larynx. Indirect mirror examination is an alternative but can only visualize the tongue base and laryngeal structures. Aside from mucosal irregularities, other abnormalities that should be specifically searched for are impairment of vocal cord mobility, pooling of secretions, anatomic asymmetries, and bleeding.

●Examination of nodal drainage areas and the parotid glands (figure 2).

●External auditory canal examination and anterior rhinoscopy.

Imaging studies

Choice of imaging study — Imaging is recommended for all patients with newly-suspected or diagnosed head and neck cancer to help determine the extent of both locoregional and metastatic disease. There is debate about the best imaging modality to use. We use the following approach:

●CT of the neck with contrast and CT of the chest with contrast are our preferred imaging modality for most patients.

●MRI of the neck with contrast is an acceptable alternative to CT of the neck, especially for patients with oral primaries or nasopharyngeal cancer.

●PET/CT is also an acceptable alternative and our preferred modality for patients with bulky disease or risk factors for a second primary (eg, history of heavy alcohol or tobacco use), and in patients with head and neck carcinoma of unknown primary [2,3]. However, insurance companies may not approve PET imaging without a cancer diagnosis. If the diagnosis of head and neck cancer is established, CT and/or MRI of the neck with contrast is often required for radiation or surgical planning as it has superior anatomic imaging.

The preferred imaging modality is evolving, and some institutions may order a PET/CT as the initial imaging for most patients with established new head and neck cancer. Ideally, imaging should take place prior to biopsy, which may distort anatomy and create a false-positive finding on PET/CT scanning.

Each imaging modality has advantages and disadvantages over other modalities. As examples:

●Compared with MRI, CT provides greater spatial resolution, can be performed with faster acquisition times (thereby virtually eliminating motion artifact), and is better at evaluating bone destruction.

●MRI provides superior soft tissue contrast. It can provide more accurate definition of tumors of the tongue and is more sensitive for superficial tumors. MRI is also better than CT for discriminating tumor from mucus and in detecting bone marrow invasion. For this reason, MRI can be useful for evaluation of cartilage invasion, particularly for non-ossified cartilage that can pose difficulty for CT.

●PET/CT is useful for finding occult distant metastases, unknown primary lesions, and synchronous second primary tumors.

Imaging studies assess the degree of local invasion, involvement of regional lymph nodes, and presence of distant metastases or second primary malignancies. Common sites of metastatic disease are the lungs, liver, and bone, while the most common sites of second primary malignancies are the head and neck, followed by the lungs and esophagus for squamous cell carcinoma. Distant metastases at initial diagnosis are usually asymptomatic. Screening tests such as chest radiograph, serum alkaline phosphatase, and liver function tests are insensitive to the presence of distant metastases [4-6]. The reported incidence of metastatic disease for squamous cell carcinoma is between 2 and 26 percent and varies based on locoregional control, nodal involvement (number and presence of extracapsular extension), primary site (particularly hypopharynx), histologic grade, and T stage [7-10].

CT scan — Almost all patients presenting with a head and neck cancer will receive a CT during the evaluation period. CT can identify tumors of the head and neck based upon either anatomic distortion or specific tumor enhancement (image 1). In general, tumors enhance more than normal head and neck structures except for mucosa, extraocular muscles, and blood vessels [11].

Slice thickness of 3 mm is generally optimal, while slice thickness greater than 5 mm does not offer sufficient spatial resolution. Images should be reconstructed and viewed in both soft tissue and bone windows. CT technology that reduces metallic artifact is also being incorporated into routine clinical practice [12].

●Primary site – For cancers of the oral cavity, contrast-enhanced CT can help determine the extent of tumor infiltration into deep tongue musculature and whether or not the mandible is involved. The "puffed cheek" technique improves evaluation of lesions of the oral cavity. This technique requires patients to self-insufflate their oral cavity with air by puffing out their cheek [13].

For other head and neck cancers, CT is particularly useful in upstaging cancers that have deeper local invasion or infiltration into adjacent structures that is difficult to detect on physical examination. In one review of 81 patients with head and neck cancer, CT resulted in a change in assigned clinical stage in 54 percent of cases [14]. This was most likely to occur with hypopharyngeal tumors and least likely with glottic laryngeal tumors (90 and 16 percent, respectively).

CT can provide information on invasion of the pre-epiglottic space, laryngeal cartilage, paraglottic space and subglottic extension, and can evaluate retropharyngeal, parapharyngeal, upper mediastinal, and paratracheal nodes. In addition, bone and cartilage invasion, a criterion for stage T4 disease, can be more readily detected. Improved technologies such as dual energy and multispectral CT improves upon the accuracy in assessing cartilage invasion compared with conventional CT [15-17].

●Regional nodes – Imaging is complementary to the clinical examination for the staging of the neck lymph nodes. CT evaluation of regional lymph nodes primarily relies upon size criteria and lymph node appearance to differentiate involved from uninvolved lymph nodes. CT is also highly sensitive for detection of extracapsular spread of tumor. However, CT is unable to detect extracapsular spread confined within the radiologically defined margin of nodes; borderline-sized, non-necrotic nodes; and microscopic nodal metastasis.

Pathologic lymphadenopathy is usually defined radiologically as a node greater than 10 to 11 mm in minimal axial diameter or one that contains central necrosis [18-25]. In a meta-analysis of 647 neck dissections that used nodal size and/or evidence of necrosis to define lymph node involvement, CT was superior to physical examination in terms of sensitivity (83 versus 74 percent), specificity (83 versus 81 percent), accuracy (83 versus 77 percent), and detection of pathologic cervical adenopathy (91 versus 75 percent) [26]. Sensitivity is limited by its inability to detect microscopic nodal metastasis. One study of almost 1000 patients found 67 percent of lymph nodes containing tumor cells were under 10 mm in size and therefore below the size cutoff used to define radiologically detectable lymph node involvement [27].

●Metastatic sites – A chest CT scan identifies metastases in 4 to 19 percent of patients with newly diagnosed head and neck cancer [6,28-33]. Although chest CT detects distant metastases more frequently than chest radiograph, it fails to detect the 2 to 5 percent of patients who will have distant metastases outside the chest [28,34,35].

There is increased awareness of patient exposure to radiation dose during medical imaging. Although the overall risk of radiation-induced malignancy is small, it is non-negligible when population-based screening is considered. Previous literature estimates that approximately 1.5 to 2 percent of all cancers in the United States may be attributable to radiation from CT studies [36]. The risk estimation of CT radiation to individual patients is a difficult subject, as evolving CT technology continues to help reduce radiation dose [37] and the risk of induced cancer decreases with patient age. The potential risk versus the anticipated benefits of CT scans must be taken into account [38].

PET/CT — PET/CT is often obtained after other imaging modalities when there is an indeterminate finding or need for further evaluation. PET/CT is useful for finding occult distant metastases, unknown primary lesions, and synchronous second primary tumors. It may also alter radiation fields and doses for patients who are not undergoing neck dissection. False negatives of PET may be seen in lymph nodes less than 5 mm, necrotic or cystic lymph nodes, tumors of low metabolic activity, or tumors located at pharyngeal lymphoid tissues with high background physiologic activity. In addition, false positives are common and findings that would change treatment decisions should be confirmed with a biopsy.

●Primary lesions – PET appears to be at least as sensitive and specific as CT and MRI in detecting primary head and neck tumors [39-42]. In one series of 30 patients with newly diagnosed head and neck cancer, PET/CT (98 percent) was better than CT (70 percent) and MRI alone (80 percent) in identifying primary tumor invasion of specific anatomical structures [43]. Findings on PET/CT imaging altered management in 7 of 30 patients (23 percent). In patients presenting with cervical nodal metastases of unknown origin, the sensitivity of PET for detection of primary tumors is approximately 97 percent [41].

●Synchronous, second primary lesions – Patients with a history of heavy alcohol or tobacco use are at increased risk of a synchronous, second primary malignancy, which would impact treatment decisions. We typically obtain a PET/CT in these patients to evaluate for a synchronous primary. Panendoscopy is an alternative, but is less commonly performed because PET/CT provides more detail and accuracy and is less invasive. This is discussed in more detail separately. (See "Second primary malignancies in patients with head and neck cancers".)

Both modalities have benefits in this high-risk patient population [44,45]. Panendoscopy may find synchronous primaries that are too small to be identified with PET/CT, while PET/CT may identify lower aerodigestive tract tumors not seen with panendoscopy. In a retrospective study of 190 patients with unknown primary sites, panendoscopy with directed biopsies and tonsillectomy complemented PET/CT studies especially in those with a negative PET/CT scan [46]. Other studies have found that PET/CT is superior to panendoscopy in finding synchronous tumors in patients with human papillomavirus (HPV)-positive oropharyngeal cancer [47]. Also, synchronous primaries found with panendoscopy correlated highly with PET avid lesions, which supports performing panendoscopy on an individual basis [48].

●Metastatic disease – In many institutions, PET and integrated PET/CT have greatly replaced other tests for detection of distant metastases [35,39,49-52]. PET/CT is superior to both CT and MRI for detecting regional nodal metastases, as well as distant metastases [53-59]. In a multicenter prospective study, the addition of PET/CT imaging to CT and/or MRI improved the Tumor, Node, Metastasis (TNM) staging of primary cancer and altered the management in 14 percent of patients [56].

●Clinically N0 neck – In patients with a clinically node-negative (N0) neck, the role of PET/CT is evolving in helping to determine the changes in the surgical plan. In one multicenter study of 212 patients with a clinically N0 neck that used neck pathology as the gold standard, the negative predictive value of PET/CT in patients with T2 to T4 cancers was 87 percent [60]. Moreover, the neck dissection surgical treatment plan was modified in 22 percent of patients based upon the PET/CT findings.

Despite high sensitivity with PET/CT, false-positive findings are common, underscoring the need to undertake histologic confirmation of any sites of abnormal uptake. In a series of 349 patients with head and neck tumors who underwent preoperative head/neck CT or MRI and whole body PET/CT, there were 14 second primary tumors (4 percent) and 26 patients with distant metastases (7.4 percent) detected during staging or within 15 months of surgery [50]. PET/CT correctly identified all but one (a patient with CT-demonstrable metastases in the lungs and gluteus muscle). However, there were 23 false-positive PET/CT results. Overall, the sensitivity and specificity were 98 and 93 percent, respectively.

MRI — MRI is often complementary to other imaging modalities. We obtain MRI in the following situations:

●Evaluation of perineural spread, skull base invasion, and intracranial extension, especially for nasopharyngeal cancers [61]

●Tumors of the tongue

●Evaluation of cartilage invasion, particularly for non-ossified cartilage that can pose difficulty for CT

●Evaluation of bone marrow involvement [62]

MRI may also provide additional benefits compared with CT in the evaluation of the base of tongue and parotid glands. MRI scan is the imaging modality recommended by the National Comprehensive Cancer Network guidelines to evaluate skull base erosion for nasopharyngeal cancer [63]. (See "Epidemiology, etiology, and diagnosis of nasopharyngeal carcinoma", section on 'Initial diagnostic evaluation'.)

The most important imaging sequences for head and neck imaging include noncontrast-enhanced T1-weighted images, contrast-enhanced T1-weighted images with fat suppression, and fat-suppressed fluid-sensitive sequences, such as T2-weighted images with fat suppression or short-tau inversion recovery images. Optional diffusion weighted imaging provides additional characterization of lesion cellularity and may improve visualization of some primary tumors and nodal metastasis. Images in axial and coronal plane are the most useful. For general purpose, slice thickness should be no more than 5 mm. Some applications, such as evaluation of skull base and perineural spread, may require thinner slice thickness, typically around 3 mm.

Establishing a diagnosis with biopsy — A diagnosis of head and neck cancer is commonly made by either a fine needle aspiration (FNA) of a suspected neck lymph node or a biopsy of the primary lesion [43,64-70].

●Suspected metastatic disease – If a patient has a suspected site of metastatic disease (eg, lung metastases), this site should be biopsied to confirm the diagnosis and accurately stage the disease.

●No metastases, abnormal neck node present – If an abnormal neck node is present, an FNA can both establish the diagnosis and provide information about nodal staging. As such, it is often used to make an initial tissue diagnosis of a head and neck cancer.

•When a patient presents with a neck mass (metastatic cervical lymph node) without an obvious primary mucosal/upper aerodigestive tract site, this can confirm the diagnosis. Additional evaluation is needed to locate the primary tumor.

•When the primary is already known or suspected, tissue confirmation of regional spread of disease is important as this changes the management. There is no need to biopsy the primary site if there is already an adequate tissue diagnosis from either regional or metastatic disease.

An FNA has high sensitivity, specificity, and diagnostic accuracy that ranges from 89 to 98 percent [64-66]. Nondiagnostic aspirations occur in 5 to 16 percent of cases, most commonly in cystic neck masses, as is common in the presentation of patients with HPV-associated oropharyngeal cancers. If an initial FNA is negative from a suspicious neck node, repeat FNA may be considered before doing an excisional biopsy. (See "Head and neck squamous cell carcinoma of unknown primary".)

●No metastases or abnormal neck nodes present – For patients who do not have a suspicious lymph node to biopsy, tissue sampling of the primary site is indicated. For easily accessible lesions this can be done in the office setting.

●When to perform exam under anesthesia – Due to improved radiologic and in-office biopsy techniques, an examination under anesthesia is most often performed only to obtain a tissue diagnosis, for surgical (eg, robotic) planning, and to search for carcinoma of unknown primary [71,72]. This examination is particularly useful for patients with laryngeal and hypopharyngeal malignancies.

PATHOLOGY

Histology — Multiple different histologies can arise in the head and neck region. A diagnosis requires tissue confirmation and sometimes additional testing on the biopsy specimen to determine additional therapy options (eg, molecular testing for melanoma or human papillomavirus (HPV) testing for squamous cell carcinoma). Squamous cell carcinoma is the most common histology in the head and neck area. Less common histologies include melanoma, nasopharyngeal carcinoma, sarcoma, adenocarcinoma, adenoid cystic carcinoma, and mucoepidermoid carcinomas.

Examples of histologies in the head and neck region include:

●Squamous cell carcinoma – Squamous cell carcinomas account for 90 to 95 percent of the lesions in the oral cavity and larynx. They can be categorized as well differentiated (greater than 75 percent keratinization), moderately differentiated (25 to 75 percent keratinization), and poorly differentiated (less than 25 percent keratinization) tumors. Verrucous carcinoma is a less common variant of squamous cell carcinoma. (See "Pathology of head and neck neoplasms", section on 'Squamous cell carcinoma'.)

Squamous cell carcinoma of the head and neck often develops through a series of changes from premalignant entities due to carcinogen exposure. Leukoplakia, erythroplakia, and dysplasia can be precursor lesions. (See "Pathology of head and neck neoplasms", section on 'Squamous cell carcinoma precursors'.)

•HPV testing – HPV infection is a causative agent for oropharyngeal squamous cell carcinoma, and HPV tumor status is incorporated into the staging system of these tumors. We agree with the approach to HPV evaluation proposed by the College of American Pathologists and endorsed by the American Society of Clinical Oncology [73,74]. HPV tumor status should be determined for all cases of newly diagnosed oropharyngeal squamous cell carcinoma. HPV tumor status is not appropriate for the routine evaluation of nonsquamous carcinoma of the oropharynx or nonoropharyngeal squamous cell carcinoma of the head and neck. It may be useful in select cases of oropharyngeal cancer with uncertain histology.

The preferred method for determining HPV tumor status is surrogate marker p16 immunohistochemistry [73,74]. Overexpression of this surrogate marker is strongly associated with transcriptionally active high-risk HPV. The threshold for positivity is at least 70 percent nuclear and cytoplasmic expression with at least moderate to strong intensity. However, there can be false-positive and false-negative results; HPV in situ hybridization or polymerase chain reaction can be used to clarify HPV status when the clinical scenario and p16 results are discordant. Additional information about HPV-associated head and neck cancer is discussed separately. (See "Epidemiology, staging, and clinical presentation of human papillomavirus associated head and neck cancer".)

●Melanoma – Melanoma can originate in the mucosal surfaces. Once a diagnosis of melanoma is confirmed, additional testing should look for targetable mutations such as a KIT mutation. (See "Melanoma: Clinical features and diagnosis", section on 'Diagnosis confirmation'.)

●Nasopharyngeal carcinoma – Nasopharyngeal carcinoma has three separate histopathologic types. These are discussed elsewhere. (See "Epidemiology, etiology, and diagnosis of nasopharyngeal carcinoma", section on 'Histology'.)

●Head and neck sarcoma – Several types of sarcoma can occur in the head and neck including osteosarcoma, chondrosarcoma, rhabdomyosarcoma, and angiosarcoma. (See "Head and neck sarcomas", section on 'Histologic grade and tumor size'.)

●Salivary gland tumors – The most common types of salivary gland tumors include adenoid cystic carcinoma and mucoepidermoid carcinoma. These are discussed elsewhere. (See "Pathology of head and neck neoplasms", section on 'Malignant salivary gland tumors'.)

Future molecular methods — Analyzing differences in gene expression patterns across individual patients with a certain type of cancer may reveal molecular differences that permit refinements in their classification, prognostication, and treatment selection. However, this is still an evolving area and further research is needed before this becomes because incorporated into patient care. (See "Head and neck squamous cell carcinogenesis: Molecular and genetic alterations".)

As examples:

●Molecular profiling and deoxyribonucleic acid (DNA) genotyping has been shown to predict radiosensitivity and radiotoxicity in patients with head and neck cancer [75].

●COMT and MATE1 genotyping were found to predict cisplatin-induced ototoxicity in 206 head and neck cancer patients [76].

●Circulating tumor DNA (ctDNA) is being used to determine driver mutations, which could subsequently direct targeted molecular therapy. The role of ctDNA is also being investigated to detect disease recurrence as part of posttreatment surveillance, which are discussed separately [77-79]. (See "Treatment of human papillomavirus associated oropharyngeal cancer", section on 'Surveillance'.)

STAGING — 

The staging of head and neck cancer is based on a combination of physical exam, imaging, and pathologic findings. There are specific staging classification systems for tumors arising from different anatomic regions of the head and neck.

Evaluation of neck nodes — Evaluation of the neck nodes is an essential part of staging patients with head and neck cancer. Depending on clinical factors along with imaging findings some patients may have an elective neck dissection while others may have a sentinel lymph node biopsy (SLNB) to help increase the accuracy of staging.

●Imaging-directed FNA – Fine needle aspiration (FNA) is often helpful in diagnosing malignant lymph nodes in the neck. Several studies have compared ultrasound plus FNA biopsy versus neck CT. In some studies the procedures were comparable while others noted better results with FNA [43,67-69]. In one report of 86 patients with clinically node-negative (N0) necks, ultrasound with FNA detected malignancy in five who did not fulfill radiologic criteria for malignancy by CT scan [70]. Conversely, several enlarged nodes on CT scan were negative by cytology (ie, they potentially represented a false-positive finding).

●Role of SLNB – SLNB is a promising strategy for increasing the accuracy of overall staging of head and neck cancer [80-83]. Further details on the use of SLNB in patients with early-stage oral cavity tumors (including technique, approach, and subsequent management) are discussed separately. (See "Treatment of stage I and II (early) head and neck cancer: The oral cavity", section on 'Sentinel lymph node biopsy'.)

When performed at centers with clinical expertise in this approach, SLNB at or before surgery is a reliable and reproducible method for staging the clinically and radiologically N0 neck in patients with early-stage oral cavity cancer. SLNB can also be used to determine the best treatment for contralateral N0 neck in patients with midline malignancies and node-positive, ipsilateral disease. SLNB is technically feasible, reliable (high sensitivity if the three highest intensity nodes are sampled), oncologically safe, and associated with less morbidity than elective neck dissection. This technique is becoming more widely used in the United States and has been integrated into the National Comprehensive Cancer Network treatment guidelines [84,85].

●Elective neck dissection – Elective neck dissection provides pathologic staging and is often performed in patients with resectable oral cavity tumors. (See "Treatment of stage I and II (early) head and neck cancer: The oral cavity", section on 'Elective neck dissection'.)

TNM staging system — The eighth edition of the American Joint Committee on Cancer and the Union for International Cancer Control Tumor, Node, Metastasis (TNM) staging system is used to classify cancers of the head and neck [86]. The T classifications indicate the extent of the primary tumor and are site specific; there is considerable overlap in the cervical N classifications.

TNM staging varies depending upon the primary tumor site:

●Oral cavity (table 2) (see "Treatment of stage I and II (early) head and neck cancer: The oral cavity", section on 'Staging')

●Nasopharynx (table 3) (see "Treatment of early and locoregionally advanced nasopharyngeal carcinoma", section on 'Staging')

●Oropharynx (see "Treatment of early (stage I and II) head and neck cancer: The oropharynx", section on 'Staging')

•HPV-negative tumors, clinical staging (table 4)

•HPV-negative tumors, pathologic staging (table 5)

•HPV-positive tumors, clinical staging (table 6)

•HPV-positive tumors, pathologic staging (table 7)

●Hypopharynx (see "Treatment of early (stage I and II) head and neck cancer: The hypopharynx", section on 'Anatomy and staging')

•Clinical staging (table 8)

•Pathologic staging (table 9)

●Larynx (table 10) (see "Treatment of early (stage I and II) head and neck cancer: The larynx", section on 'Staging and anatomy')

●Nasal cavity and paranasal sinuses (table 11) (see "Cancer of the nasal vestibule", section on 'Staging' and "Paranasal sinus cancer", section on 'Diagnosis and staging' and "Tumors of the nasal cavity")

●Salivary glands (see "Salivary gland tumors: Epidemiology, diagnosis, evaluation, and staging", section on 'Staging')

•Clinical staging (table 12)

•Pathologic staging (table 13)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Head and neck cancer".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Mouth sores (The Basics)" and "Patient education: Tongue cancer (The Basics)" and "Patient education: Laryngeal cancer (The Basics)" and "Patient education: Throat cancer (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Sites of disease – Head and neck cancer encompasses a variety of histologies, mostly squamous cell carcinomas, which can arise from a variety of sites, such as the oral cavity, pharynx, larynx, nasal cavity and paranasal sinuses, or salivary glands (figure 1A-B). (See 'Anatomy' above.)

●Clinical presentation – For patients with head and neck cancer, initial symptoms and subsequent staging depend upon the site of the primary tumor. Head and neck cancer may be suspected in patients who present with one or more of the following symptoms if they are otherwise unexplained: otalgia, neck mass, voice changes, nasal congestion or epistaxis, odynophagia or dysphagia, hemoptysis or blood in the saliva, mouth or skin ulcers, unilateral tonsil enlargement, palpable lesions of the salivary glands, solitary masses in the thyroid or a change in a pre-existing goiter. Tumors presenting in specific anatomic locations (eg, oral cavity, pharynx, larynx, or sinuses) will have a distinct set of presenting symptoms related to their location. (See 'Clinical presentation' above.)

●Diagnostic evaluation – Proper staging of the primary tumor, regional lymph nodes, and distant metastases is required to develop an optimal treatment plan (algorithm 1). (See 'Diagnostic evaluation' above.)

•Physical exam – The initial assessment of the primary tumor includes a combination of inspection, palpation, and flexible laryngoscopy. (See 'Physical exam' above.)

•Imaging – Imaging is recommended for all patients with newly suspected or diagnosed head and neck cancer to help determine the extent of both locoregional and metastatic disease. There is debate about the best imaging modality to use. We use the following approach (see 'Imaging studies' above):

-CT of the neck with contrast and CT of the chest with contrast are our preferred imaging modality for most patients.

-MRI of the neck with contrast is an acceptable alternative to CT of the neck, especially for patients with oral primaries or nasopharyngeal cancer.

-Positron emission tomography (PET)/CT is also an acceptable alternative and our preferred modality for patients with bulky disease or risk factors for a second primary (eg, patients with a history of heavy alcohol and tobacco use), and in patients with neck carcinoma of unknown primary. If the diagnosis of head and neck cancer is established, CT and/or MRI of the neck with contrast is often required for radiation or surgical planning.

•Biopsy – If a patient has a suspected site of metastatic disease (eg, lung metastases), this site should be biopsied to confirm the diagnosis and accurately stage the disease. For patients without suspected metastases who present with a neck mass (metastatic cervical lymph node) without an obvious primary mucosal/upper aerodigestive tract site, a fine needle aspiration biopsy is frequently used to make an initial tissue diagnosis of a head and neck cancer or to help with staging in patients with a known primary. If no enlarged nodes are present, the primary site should be biopsied. (See 'Establishing a diagnosis with biopsy' above.)

●Pathology – Multiple histologies can arise from the head and neck region. Squamous cell carcinomas account for 90 to 95 percent of the lesions in the oral cavity and larynx. (See 'Pathology' above.)

Human papillomavirus (HPV) tumor status should be determined for all cases of newly diagnosed oropharyngeal squamous cell carcinoma. HPV tumor status is not appropriate for the routine evaluation of nonsquamous carcinoma of the oropharynx, or nonoropharyngeal squamous cell carcinoma of the head and neck. It may be useful in select cases of oropharyngeal cancer with uncertain histology. (See 'Histology' above.)

●Staging – The eighth edition of the American Joint Committee on Cancer and the Union for International Cancer Control Tumor, Node, Metastasis (TNM) staging system is used to classify cancers of the head and neck. (See 'TNM staging system' above.)