INTRODUCTION — Head and neck cancers can arise in the oral cavity, pharynx, larynx, nasal cavity, paranasal sinuses, thyroid, and salivary glands and include a variety of histopathologic tumors.
An overview of the epidemiology, clinical presentation, diagnosis, and staging for head and neck cancer is presented here. More detailed discussions for specific primary tumor site are presented in the relevant site-specific topics. A general overview of treatment is also presented separately. (See "Overview of treatment for head and neck cancer".)
EPIDEMIOLOGY AND RISK FACTORS — There are large geographic differences in the incidence and primary site of head and neck cancers. These likely reflect the prevalence of risk factors, such as tobacco and alcohol consumption, as well as ethnic and genetic differences among populations.
Although the highest rates of head and neck cancer are in older males, the incidence has been increasing in young nonsmokers, as human papillomavirus (HPV) plays an increasingly prominent role as an etiologic factor in the development of oropharyngeal head and neck cancer. Globally, head and neck cancer constituted 5.7 percent of cancer-related mortality . Low- and middle-income countries are disproportionately burdened, as 67 percent of cases and 82 percent of deaths occurred in these countries.
Tobacco (smoked and smokeless) is the most important known risk factor for the development of head and neck cancer. There is some evidence for a genetic predisposition to the carcinogenic effects of tobacco. In addition, tobacco and alcohol consumption appear to have a synergistic effect. The repeated exposure of the mucosa of the upper aerodigestive tract to the carcinogenic effects of tobacco, alcohol, or both appears to cause multiple primary and secondary tumors in this "condemned mucosa," a phenomenon described as "field cancerization."
HPV infection is a causative agent for head and neck cancer. HPV associated head and neck cancers occur primarily in the oropharynx (tonsils and base of tongue), account for the younger age of patients with oropharyngeal squamous cell carcinoma, and define a subset of patients with improved treatment outcome. The use of HPV status in clinical decision-making remains investigational at this time, although there are multiple active deintensification trials currently in progress. The goal of these trials is to decrease the short- and long-term toxicity of treatment. Nonetheless treatment outside of a clinical trial remains the same as for patients without an HPV associated tumor. (See "Epidemiology, staging, and clinical presentation of human papillomavirus associated head and neck cancer".)
Other head and neck cancer risk factors include betel nut chewing, radiation exposure, vitamin deficiencies, periodontal disease, immunosuppression, and other environmental and occupational exposures. (See "Epidemiology and risk factors for head and neck cancer" and "Second primary malignancies in patients with head and neck cancers".)
ANATOMIC SUBSITES — Head and neck cancer encompasses a variety of malignancies, mostly squamous cell carcinoma, arising from a variety of sites. The head and neck region consists of several anatomic areas (figure 1A):
●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.
•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, which 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 – The nasal cavity and the paranasal sinuses (maxillary, ethmoid, sphenoid, and frontal).
●Salivary glands – The major (parotid, submandibular, and sublingual) and minor salivary glands. 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 exposure to various risk factors.
●Otalgia – Otalgia as a presenting symptom is significant. Cranial nerves 5, 7, 9, and 10 contribute afferents to the external and middle ear. Referred otalgia is considered a "red flag" in the evaluation of a patient with a possible head and neck malignancy.
●Nasopharyngeal carcinoma – The most frequent presenting complaint is a neck mass due to regional lymph node metastasis, which occurs in nearly 90 percent of patients. Symptoms due to the primary tumor may include hearing loss (associated with serous otitis media), tinnitus, nasal obstruction and pain, and its associated growth into adjacent anatomical structures, which can lead to muscle involvement and impaired function of cranial nerves II to VI. Adults with a unilateral effusion should have an examination of the nasopharynx.
●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. Up to 66 percent of patients with primary tongue lesions have cervical lymph node involvement, depending on T stage and depth of invasion, while the incidence is substantially lower in patients with hard palate cancers.
•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.
•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.
●Oropharyngeal tumors – Presenting complaints can include dysphagia, pain (odynophagia, otalgia), obstructive sleep apnea or snoring, bleeding, or a neck mass (picture 1).
Patients with human papillomavirus (HPV) positive oropharyngeal cancers often present with neck masses (table 1). Many of these patients do not have other clinical complaints, including the classic symptoms of odynophagia and otalgia. Neck mass, which is often cystic, may be the only clinical complaint. 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 . For adult patients presenting with cystic neck mass, metastatic cystic squamous cell carcinoma associated with HPV needs to be strongly considered and excluded. (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.
●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.
Histology — 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. Less common histologies include verrucous carcinoma (a variant of squamous cell carcinoma), adenocarcinoma, adenoid cystic carcinoma, and mucoepidermoid carcinomas. (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. (See "Pathology of head and neck neoplasms", section on 'Squamous cell carcinoma precursors'.)
Clinical signs include leukoplakia and erythroplakia:
●Leukoplakia is characterized by hyperparakeratosis and is usually associated with underlying epithelial hyperplasia. In the absence of underlying dysplastic changes, the probability of malignant change is less than 5 percent .
●Erythroplakia is characterized by red superficial patches adjacent to normal mucosa. It is commonly associated with epithelial dysplasia and is associated with carcinoma in situ or invasive tumor in up to 40 percent of cases .
Histopathologic findings include dysplasia:
●Dysplasia is defined histopathologically by the presence of mitoses and prominent nucleoli. Involvement of the entire mucosal thickness is usually referred to as carcinoma in situ. Dysplasia is associated with progression to invasive cancer in 15 to 30 percent of cases.
HPV testing — Human papillomavirus (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 (CAP) and endorsed by the American Society of Clinical Oncology (ASCO) [4,5]. 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 [4,5]. 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".)
TNM STAGING SYSTEM — The eighth edition of the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) Tumor, Node, Metastasis (TNM) staging system is used to classify cancers of the head and neck . 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:
●Nasal cavity and paranasal sinuses (table 8) (see "Cancer of the nasal vestibule", section on 'Staging' and "Paranasal sinus cancer", section on 'Diagnosis and staging' and "Tumors of the nasal cavity")
DIAGNOSIS AND STAGING EVALUATION
Initial evaluation — The initial assessment of the primary tumor is based upon a thorough history and combination of inspection, palpation, indirect mirror examination, or direct flexible laryngoscopy. Physical examination should include careful assessment 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 (best seen on mirror examination or flexible laryngoscopy), palate, buccal and gingival mucosa, and posterior pharyngeal wall.
External auditory canal examination and anterior rhinoscopy should be undertaken.
For patients with non-laryngeal lesions but a strong alcohol or smoking history, flexible laryngoscopy is commonly undertaken to visualize potential other lesions and to document vocal cord mobility.
A metastatic work-up with appropriate imaging is recommended for all newly-diagnosed head and neck cancer patients, with particular attention to regional lymph node spread. For those with locoregionally advanced tumors, distant metastatic imaging, with attention to the lungs, is often performed. Patients with severe dysplasia or carcinoma in situ who have a strong smoking, alcohol, or family history of cancer may also benefit from a more extensive work-up for metastases or a second primary including a screening chest computed tomography (CT). Use of clinical judgement is important. (See "Screening for lung cancer".)
Visualization of lesions outside the mouth is best accomplished by mirror examination and/or the use of a flexible fiberoptic endoscope with the goal of examining all of the mucosa in the nasopharynx oropharynx, hypopharynx, and larynx. 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. The appropriate nodal drainage areas are examined by careful palpation of the neck. Examination of the neck for pathologic adenopathy or other masses is best done according to neck levels. The parotid glands are also palpated for abnormalities (figure 2).
Due to improved radiologic and in-office biopsy techniques, an examination under anesthesia (EUA) is most often performed only to obtain a tissue diagnosis, for surgical (eg, robotic) planning, and to search for carcinoma of unknown primary [7,8]. This examination is particularly useful for patients with laryngeal and hypopharyngeal malignancies. (See "Treatment of early (stage I and II) head and neck cancer: The larynx" and "Treatment of early (stage I and II) head and neck cancer: The hypopharynx" and "Treatment of locoregionally advanced (stage III and IV) head and neck cancer: The larynx and hypopharynx".)
Symptom-directed panendoscopy (laryngoscopy, bronchoscopy, and esophagoscopy) reveals a 2.4 to 4.5 percent incidence of second primary tumors of the upper aerodigestive tract but not of the lower airways [9-11]. Other authors have found that screening panendoscopy revealed second primary cancers only in patients with a current or past smoking history . There is evidence that positron emission tomography (PET) may complement or replace panendoscopy in detecting synchronous primary cancers , although some studies have shown there is still a risk of false negatives (9 in 589 patients in one study). In general, patients with a history of heavy alcohol or tobacco use should undergo a work-up for second primary tumors with PET or panendoscopy as part of their operative staging for characterization of the primary tumor or to look for distant disease in early stage disease. Operative staging and/or panendoscopy may find synchronous primaries that are too small to be identified with PET, while PET may identify lower aerodigestive tract tumors not seen with panendoscopy. In a retrospective study of 190 patients with unknown primary sites, it was found that panendoscopy with directed biopsies and tonsillectomy complemented PET scan studies. The authors maintain that panendoscopy and biopsies has a significant role in evaluation in patients with unknown primary sites, especially in patients with negative PET scans . Although the incidence of second or synchronous primary tumor is low, the impact on treatment for the individual patient is significant. Those with human papillomavirus (HPV) positive tumors without other known risk factors are not as likely to benefit from panendoscopy.
Imaging studies may augment the physical exam and evaluation of squamous cell carcinoma of the head and neck, particularly for assessing the degree of local invasion, involvement of regional lymph nodes, and presence of distant metastases or second primary malignancies. The most common metastatic sites 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. Ideally, imaging should take place prior to biopsy, which may distort anatomy and create a false-positive finding on PET scanning. (See 'Imaging studies' below and 'Evaluation for distant metastases' below.)
Fine needle aspiration biopsy — Fine needle aspiration (FNA) biopsy is frequently 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 technique has high sensitivity and specificity and a diagnostic accuracy that ranges from 89 to 98 percent [15-17]. 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".)
FNA biopsy of a suspected involved lymph node in the setting of an established primary tumor may provide relevant information when clinical and imaging evaluation of neck lymph nodes is equivocal and a positive or negative finding would change the clinical treatment approach (eg, radiation therapy field or dose, or the use of concurrent chemoradiotherapy versus radiation therapy alone). Several studies have compared ultrasound plus ultrasound-guided FNA biopsy with neck CT; the procedures were comparable in terms of overall accuracy (88 and 85 percent in one series compared with 69 percent by palpation) [18,19], while others noted better results with FNA [20,21]. 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 . Conversely, several enlarged nodes on CT scan were negative by cytology (ie, they potentially represented a false-positive finding). PET may also have a role in the evaluation of cervical lymph nodes, although PET scan will not identify occult/microscopic disease. (See 'PET and integrated PET/CT' below.)
Sentinel lymph node biopsy — Sentinel lymph node biopsy (SLNB) is another promising strategy for increasing the accuracy of overall staging of head and neck cancer [23-26]. 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 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 (NCCN) treatment guidelines [27,28].
Imaging studies — Imaging studies (CT, magnetic resonance imaging [MRI], PET, and integrated PET/CT) are important for assessing the degree of local infiltration, involvement of regional lymph nodes, and presence of distant metastases or second primary tumors.
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 . The risk estimation of CT radiation to individual patients is a difficult subject, as evolving CT technology continues to help reduce radiation dose  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 .
CT scan — 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 . 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. CT technology that reduces metallic artifact is also being incorporated into routine clinical practice .
Modern multidetector CT technology allows scanning to be performed with slice thickness less than 1 mm. 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. Dental amalgam can create severe beam hardening image artifacts that obscure image details in the scan plane. This problem can be remedied by rescanning the obscured area with angulated gantry.
●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 . 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. 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.
Distinction of cartilage invasion from non-ossified cartilage can be a difficult task for conventional CT. The new technology of dual energy and multispectral CT has demonstrated improved accuracy for assessing cartilage invasion compared with conventional CT . Preliminary results have demonstrated an increase of specificity for evaluation of thyroid cartilage invasion from 70 to 96 percent, with no compromise of sensitivity (86 versus 86 percent) [35,36]. In general, the advantage of improved tissue characterization offered by dual-energy and spectral CT may enhance the accuracy of CT for evaluation of tumor extent and staging .
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 . This was most likely to occur with hypopharyngeal tumors and least likely with glottic laryngeal tumors (90 and 16 percent, respectively).
●Regional nodes – Imaging by CT or MRI 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 as well as the appearance of lymph nodes to differentiate involved from uninvolved lymph nodes. The use of size criteria alone results in frequent false-positive and false-negative assessment of regional nodes. CT is also highly sensitive for detection of extracapsular spread of tumor.
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 [39-42]. The choice of how a lymph node is measured is often controversial and reflects a tradeoff between sensitivity and specificity. In general, size criteria based on measurement of minimal axial diameter are considered the most accurate and effective [43,44], and probably the most reproducible . Other features that suggest pathological lymph nodes include rounded shape, loss of normal fatty hilum, increased or heterogeneous contrast enhancement, lymph node clustering, and sentinel lymph node location . In one study, data from 47 consecutive patients with head and neck cancer (total of 53 neck dissections) were combined with findings from a 15-year MEDLINE review of the English-language literature to compare physical examination with CT scan . 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).
Although CT is superior to physical examination, the use of size criteria and the presence of central necrosis are limitations that prevent detection of borderline-sized nodes, nonnecrotic nodes, or extracapsular spread confined within the radiologically-defined margin of nodes. These cannot be differentiated by CT from reactive or normal nodes . This is an important issue since microscopic or occult nodal adenopathy is not unusual in head and neck cancer.
In one series of 957 lymph nodes from patients with head and neck cancer, 102 (11 percent) harbored malignant cells . The following findings were noted in terms of nodes that would not be called malignant by CT:
•Sixty-seven percent of tumor-containing nodes were 10 mm or smaller.
•Twenty percent of malignant nodes had extracapsular spread; almost one-third of these nodes were 10 mm or smaller and some were less than 5 mm.
•Central necrosis was found primarily in nodes larger than 20 mm, suggesting that it is a late event in metastatic adenopathy.
•Extracapsular spread of nodal metastasis is an important prognostic factor that should be assessed on imaging. Imaging findings that suggest extracapsular spread of nodal metastasis include irregular border of the lymph node, infiltration of adjacent fat planes, and loss of cleavage plane with adjacent anatomical structures.
Magnetic resonance imaging — MRI provides superior soft tissue definition compared with CT  and can often provide information that is complementary to CT. For example, MRI 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. On the other hand, CT scanning is better than MRI for detection of bone cortex invasion since MRI shows no bony detail. The availability of dual energy and multispectral CT, however, may decrease the advantage of MRI in cartilage evaluation [35,36,51].
MRI is superior to CT for evaluation of perineural spread, skull base invasion, and intracranial extension of head and neck cancer. 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 NCCN guidelines to evaluate skull base erosion for nasopharyngeal cancer .
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 (STIR) images. 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.
In most studies, CT scanning outperforms MRI for the detection of pathologic nodal metastases. The reported sensitivity of MRI is as low as 57 to 67 percent. However, neither test reliably detects clinically occult regional node involvement.
PET and integrated PET/CT — With PET, injected positron-emitting radionuclides, such as fluorine-18, are taken up by metabolically or functionally active tissues. PET images are created by detecting these emissions by an array of detectors and then using reconstruction techniques to create a three dimensional image. The most commonly used agent is fluorodeoxyglucose (FDG), which is taken up into cells in different concentrations depending on the relative metabolism of different tissues. It is fairly specific for tumors because metabolic rates are very high in many tumors.
PET has intrinsically lower spatial resolution than other imaging modalities. In addition, it may be difficult to localize the anatomic location of the FDG uptake. These issues are addressed with integrated PET/CT imaging, in which PET and CT are performed sequentially during the same imaging session on a hybrid PET/CT scanner. The images are then coregistered using fusion software, enabling the physiologic data obtained on PET to be localized according to the anatomic CT images.
Historically, CT images obtained from integrated PET/CT scanners had lower spatial resolution compared with dedicated CT scanners. This problem is now being overcome by new generation of PET/CT scanners that offer volumetric CT capability
PET appears to be at least as sensitive and specific as CT and MRI in detecting primary head and neck tumors [53,54]. In patients presenting with cervical nodal metastases of unknown origin, the sensitivity of PET for detection of primary tumors is approximately 97 percent . A false negative is most likely seen in small lesions and in primary tumors located at pharyngeal lymphoid tissues with high background physiologic activity.
PET is superior to both CT and MRI for detecting regional nodal metastases, as well as distant metastases and second primary tumors [55-58]. In a multicenter prospective study, PET imaging alone or in combination with CT improved the TNM staging of primary cancer and altered the management in 13.7 percent of patients .
When used for the initial staging of head and neck cancer, integrated PET/CT imaging appears superior to CT, MRI, or PET alone:
●In one series of 30 patients with newly diagnosed head and neck cancer, PET/CT (98 percent) was better than CT (70 percent) and MR alone (80 percent) in identifying primary tumor invasion of specific anatomical structures. Findings on PET/CT imaging altered management in 7 of 30 patients (23 percent) . Similar findings have been reported by others [59,60].
●The superiority of PET/CT in evaluating the cervical nodes was shown in a series in which integrated PET/CT was compared with CT alone in 63 patients with newly diagnosed head and neck cancer . While CT alone identified 14 of 17 diseased heminecks (82 percent sensitivity) and 9 of 9 negative heminecks (specificity 100 percent), PET/CT detected metastatic disease in all 17 diseased heminecks and in 26 of 27 nodal zones that were histologically positive at the time of dissection.
●In a second report of 68 patients (52 with a squamous cell cancer of the head or neck, 8 with a squamous cell cancer of unknown origin, and 8 with recurrent or metastatic thyroid cancer), six proven malignancies were missed by PET, but only one was missed with PET/CT . Of the 157 foci with abnormal FDG uptake, the fraction of equivocal lesions decreased by 53 percent with the integration of PET and CT (from 39 of 155 with PET to 18 of 157). Findings on PET/CT changed the treatment plan in 12 patients (18 percent).
●In a retrospective report of 123 patients with previously untreated head and neck cancer who underwent pretreatment PET/CT, the scan was true positive in 103 (83 percent), while 15 (12.2 percent) had a false-positive study at the primary or elsewhere . Synchronous lesions were found in 10 patients (8.3 percent) and distant metastases in 19 (15.4 percent). Of the 40 heminecks that underwent dissection, PET was positive in 19 of the 22 involved sides (sensitivity 86 percent) and it was negative in 16 of 17 uninvolved sides (specificity 96 percent). Overall, management was altered in 38 patients (31 percent) as a result of the PET scan. The originally planned surgery was canceled (19 patients, 15 percent) because of metastatic disease or finding a primary tumor residing outside of the head and neck region.
●False negatives of PET may be seen in lymph nodes less than 5 mm, necrotic or cystic lymph nodes, and tumors of low metabolic activity.
●The sensitivity of PET/CT may be lower for patients with a clinically negative (N0) neck, a reflection of its limitations in detecting occult nodal metastases less than 5 mm.
●One multicenter study of 212 participants sought to determine the negative predictive value of PET/CT for the clinically N0 neck based upon neck dissection pathology . In this study, the negative predictive value of PET/CT in patients with T2 to T4 cancers was 87 percent. Moreover, the neck dissection surgical treatment plan was modified in 22 percent of patients based upon the PET/CT findings.
Taken together, these data indicate that PET/CT is accurate for detecting occult cervical nodal metastases, although it does not have the sensitivity to replace neck dissection. Its main utility is in finding occult distant metastases, unknown primary lesions, and synchronous second primary tumors, as well as altering radiation fields and doses for patients who are not undergoing neck dissection. (See 'Evaluation for distant metastases' below.)
Contemporary studies suggest that PET/CT may be beneficial and cost effective for restaging of advanced head and neck cancer [65-67]. Negative PET/CT findings after chemoradiation may accurately determine early disease response, making further surgical intervention unnecessary . In a prospective randomized controlled trial including patients with initial N2 or N3 disease treated initially by chemoradiation, patients undergoing PET/CT surveillance were shown to have similar survival rates compared with those with postchemoradiation neck dissection .
Evaluation for distant metastases — A component of the initial staging evaluation for patients with new or recurrent head and neck cancer is the search for distant metastases. The reported incidence 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 [68-71].
Distant metastases at initial diagnosis are usually asymptomatic; the most common sites are the lungs followed by the liver and bone. Screening tests such as chest radiograph, serum alkaline phosphatase, and liver function tests are insensitive to the presence of distant metastases [72-74].
CT scan was the most sensitive method to screen for distant metastases in patients with head and neck cancer, identifying malignant findings in between 4 and 19 percent of newly diagnosed cases [74-80]. 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 [75,81,82].
PET and integrated PET/CT have greatly replaced other tests for detection of distant metastases and synchronous second primary tumors [59,81-86]. However, false-positive findings are common, underscoring the need to undertake histologic confirmation of any sites of abnormal uptake. PET/CT is sensitive and superior for evaluation of deep lesions, while panendoscopy is highly accurate for evaluation of smaller or more superficial second primary mucosal lesions. PET/CT and direct mucosal inspection therefore play important complimentary roles in the work-up of head and neck cancers. (See 'PET and integrated PET/CT' above.)
These issues can be illustrated by a series of 349 patients with head and neck tumors who underwent preoperative head/neck CT or MRI and whole body PET/CT . Further diagnostic imaging was guided by the results of the PET/CT scan. Overall 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. 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, specificity, positive predictive value and negative predictive value were 98, 93, 63, and 99.7 percent, respectively.
Incidence of second and multiple primaries — At-risk patients (ie, those with strong tobacco and alcohol use or family history) are prone to develop second primary cancers of the upper aerodigestive tract. Such tumors may be present at presentation or develop subsequently. (See "Second primary malignancies in patients with head and neck cancers".)
Future molecular staging 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. (See "Head and neck squamous cell carcinogenesis: Molecular and genetic alterations".)
●Molecular profiling and DNA genotyping has been shown to predict radiosensitivity and radiotoxicity in patients with head and neck cancer .
●COMT and MATE1 genotyping were found to predict cisplatin-induced ototoxicity in 206 head and neck cancer patients .
●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 [89-91]. (See "Treatment of human papillomavirus associated oropharyngeal cancer", section on 'Surveillance'.)
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 5th to 6th 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 10th to 12th 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 malignancies, 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 'Anatomic subsites' above and 'Pathology' above.)
●Clinical presentation – For patients with head and neck cancer, initial symptoms and subsequent staging depend upon the site of the primary tumor. (See 'Clinical presentation' above and 'TNM staging system' above.)
●Diagnostic evaluation – Proper staging of the primary tumor, regional lymph nodes, and distant metastases is required to develop an optimal treatment plan. (See 'Initial evaluation' above.)
•Physical exam – The initial assessment of the primary tumor includes a combination of inspection, palpation, indirect mirror examination, and direct endoscopy.
•Biopsy – For patients who present with a neck mass (metastatic cervical lymph node) without an obvious primary mucosal/upper aerodigestive tract site, a fine needle aspiration (FNA) biopsy is frequently used to make an initial tissue diagnosis of a head and neck cancer. (See 'Fine needle aspiration biopsy' above.)
•Indications for EUA – Due to improved biopsy techniques, an examination under anesthesia (EUA) is most often performed to obtain a tissue diagnosis, for surgical planning, and to search for carcinoma of unknown primary. EUA may be particularly useful for patients with laryngeal and hypopharyngeal malignancies.
•Imaging – Imaging studies (computed tomography [CT], magnetic resonance imaging [MRI], positron emission tomography [PET], and integrated PET/CT) are important to assess the degree of local infiltration, involvement of regional lymph nodes (figure 2), and presence of distant metastases or second primary tumors. The evaluation of regional lymph nodes has improved significantly with the development of imaging modalities such as integrated PET/CT, but these approaches still can miss more limited degrees of tumor involvement. (See 'Imaging studies' above.)
-CT or MRI of the head and neck – All patients should have a staging CT scan or MRI of the head and neck (although CT scan of the brain is not needed). (See 'CT scan' above and 'Magnetic resonance imaging' above.)
-Indications for PET/CT – The role of a routine PET scan in staging of all patients is less clear. PET/CT imaging is indicated for patients at high risk for metastatic disease, in those with equivocal findings on CT or MRI scan, or in those at increased risk of second malignancy (especially those with a smoking history) who are not having an operative panendoscopy (laryngoscopy, esophagoscopy, bronchoscopy). For restaging of head and neck cancer after initial therapy, PET/CT may provide additional benefits. (See 'PET and integrated PET/CT' above and 'Evaluation for distant metastases' above.)
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