INTRODUCTION — The head and neck region includes the upper aerodigestive tract (oral cavity, paranasal sinuses, pharynx, larynx, cervical esophagus (figure 1)), thyroid, associated lymph nodes, soft tissues, and bone. The diverse tissues in this anatomic region give rise to a broad spectrum of neoplasms with differing morphologies, molecular alterations, risk factors, and treatment options.
The most common malignancy of the head and neck is squamous cell carcinoma (SCC) and its variants. Other important primary neoplasms in the head and neck region include tumors of the major and minor salivary glands and mesenchymal lesions of the soft tissues and paranasal sinuses.
This section will deal primarily with SCC, including its precursors and variants. Selected benign epithelial proliferations are also clinically relevant and are considered here because of their clinical presentation as tumors. The most common forms of salivary gland neoplasia as well as mesenchymal tumors of special clinical significance to this anatomic region are also included. Detailed pathologic discussions of these entities are available in standard references of head and neck pathology [1-4]. The pathology of thyroid cancer is covered separately. (See "Atlas of thyroid cytopathology".)
MANAGEMENT OF PATHOLOGIC SPECIMENS — The discussion in this section is focused on squamous cell carcinoma (SCC) since it is the most common malignant tumor affecting the upper aerodigestive tract. Tumors of salivary gland or mesenchymal origin may be similarly approached.
Diagnosis — The initial diagnostic workup may utilize biopsy material (either incisional or excisional) or a cytologic specimen (ie, fine needle aspiration [FNA] or cell block).
●Biopsy – The conventional procedure for tissue acquisition is biopsy, either incisional or excisional. An excisional biopsy for suspected dysplasia or a potentially resectable tumor is optimal, since the tissue can be properly oriented, and valuable information can be derived from the assessment of tumor infiltration of the underlying connective tissue, as well as the presence of key prognostic factors, such as vascular and perineural invasion. Fixation and tissue processing can then be optimized, both for conventional histology and possible immunohistochemical or molecular studies.
Frozen section is not recommended as a stand-alone procedure for diagnostic purposes, as its use will compromise the quality of the submitted tissue. Frozen section may be appropriate to assess the adequacy of a biopsy sample but only if the surgeon is prepared to remove more tumor, not to be frozen, for definitive diagnosis or therapy.
●Cytology – The primary cytologic modality involved in the evaluation of head and neck lesions is FNA. A thin needle is inserted into the lesion under either palpation or ultrasound guidance. Small tissue fragments as well as individual cells are drawn into the needle by either suction or capillary action. This material is then typically expressed onto glass slides or into liquid medium. Slides may be air-dried for Giemsa or Diff-Quik staining, or quickly immersed in an alcohol-based fixative for Papanicolaou staining. Material may also be expressed into formalin, saline, or other fixatives for a variety of ancillary studies.
In the head and neck, FNA is primarily utilized for the evaluation of enlarged cervical lymph nodes, thyroid nodules, and salivary gland masses. Diff-Quik stained slides are often prepared intraprocedurally, allowing for real-time diagnosis and specimen adequacy assessment. However, biopsy is preferred over FNA when more specialized studies are necessary such as combined positive score or human papillomavirus (HPV) status.
Tumor excision and surgical margins — Complete excision of the tumor is the goal in most cases of invasive SCC that are managed operatively, and it requires that the surgical margins are free of invasive tumor. Assessment of tumor involvement at the surgical resection margins is an important component of the pathologic examination.
Given the compact and complex anatomy of the head and neck and the potential distortion of anatomic landmarks that may occur in a resected specimen, communication between the surgeon and the pathologist is essential during and after tumor excision . The real-time geographic relationship of the surgeon and the pathologist varies among institutions. To avoid miscommunication, it may be necessary for the surgeon to accompany the specimen to the gross pathology laboratory to speak directly with the pathologist. Proper orientation, accurate margin designation (usually by inking), and other points of clinical interest are discussed at that time. If indicated, immediate and additional assessments by intraoperative frozen section can then be initiated [6-9].
Surgical margin goals — The National Comprehensive Cancer Network (NCCN) has formulated a set of guidelines related to margins of resection, and these are used in the recommendations of the College of American Pathologists (CAP) . These recommendations can be summarized as follows:
●Complete resection of the tumor means the inked specimen margins are negative for in situ and invasive tumor
●Margin adequacy criteria varies by tumor site
●Clear margins are defined as at least 5 mm of clearance from invasive tumor
●Close margins are defined as less than 5 mm of clearance from invasive tumor
While many studies use 5 mm of clearance as an indicator of an adequate margin, this figure has not been standardized, and various publications have used distances ranging from 2 to 10 mm as indicators of margin adequacy [10,11]. In addition, the distance between invasive tumor and the excised edge is subject to a long list of poorly controlled potential artifacts, such as specimen shrinkage, method of margin assessment, and plane of tumor sectioning . Generally speaking, most studies have demonstrated a significant improvement in progression-free survival and locoregional recurrence following resection with negative as opposed to positive or "close" margins.
Approach to margin assessment — Two approaches to margin assessment are commonly employed [8,13]:
●"Specimen" margins – Surgical margins may be identified and designated in the main resection specimen for evaluation via frozen and/or permanent section.
●"Tumor bed" margins – Surgical margins may be removed from the surgical defect by the surgeon and sent separately for frozen or permanent section evaluation.
Following gross assessment, the specimen should be inked and cut perpendicular to the long axis of the tumor. An intraoperative frozen section may be performed on margins that are of interest to the surgeon or that are deemed close on gross inspection by the pathologist. Perpendicular "specimen" margins that include the invasive tumor front as well as the nearest resected edge of the specimen are preferable to en face margins as they allow an accurate measurement of distance between the tumor and margin.
The use of "tumor bed" margins separately removed from the surgical defect by the surgeon is associated with significantly lower rates of locoregional recurrence-free survival than "specimen" margins in cases where the margins are deemed negative. Furthermore, in cases where the "tumor bed" margin is negative, the distance between the tumor and true margin may be impossible to accurately assess. Despite the advantages to workflow and the preference of some surgeons, the use of "specimen" margins obtained from the main resection specimen should be the preferred manner of margin assessment for both intraoperative assessment as well as permanent section [14,15].
SQUAMOUS CELL CARCINOMA PRECURSORS — Histologic precursors to squamous cell carcinoma (SCC) include leukoplakia, erythroplakia, and leukoerythroplakia; squamous hyperplasia; squamous dysplasia; and proliferative verrucous leukoplakia. Patients with such mucosal changes potentially suspicious for such precursors should undergo evaluation and diagnostic biopsy.
Leukoplakia, erythroplakia, and leukoerythroplakia — The clinical terms leukoplakia, erythroplakia, and leukoerythroplakia are oral squamous proliferations manifested as white, red, or speckled mucosal plaques, respectively, and do not denote specific pathologic entities. However, it is helpful to the pathologist to know whether a lesion demonstrates erythroplakic features, since these are more frequently associated with dysplasia or overt malignancy. The diagnosis of dysplasia or invasive carcinoma requires biopsy and microscopic examination.
Patients with known carcinogenic exposures and such potentially suspicious mucosal changes should undergo a diagnostic biopsy of the suspicious lesion(s). While dentists, oral surgeons, and otolaryngologists are aware of such potentially suspicious mucosal changes, utilizing scrape samples for cytologic study is of unproven efficacy for diagnostic purposes, and no screening procedure obviates the need for diagnostic biopsy . (See "Chemoprevention and screening in oral dysplasia and squamous cell head and neck cancer", section on 'Screening'.)
Squamous hyperplasia — The normal oral and pharyngeal mucosa is a nonkeratinized surface that originates from a single layer of relatively small basal cells. As these cells mature and ascend toward the mucosal surface, they become larger due to the acquisition of cytoplasm that contains keratin. Squamous hyperplasia is a reactive phenomenon consisting of a thickened squamous epithelium, and it includes both acanthosis (increased thickness of the spinous layers) and expansion of the basal cell layer (increase in basal/parabasal cells).
Localized hyperkeratosis, often in the form of a visible plaque, is seen clinically as leukoplakia. Squamous hyperplasia can be due to a variety of causes, ranging from ill-fitting dentures to toxic substances, and frequently results in some accompanying inflammation or granulation tissue. Suprabasilar mitotic figures and individual cell keratinization (dyskeratosis) may be present and make hyperplasia difficult to distinguish from true mild dysplasia.
Squamous dysplasia — Squamous dysplasia is a premalignant proliferation of squamous epithelium, and it can affect the mucosal surfaces of the upper aerodigestive tract. Squamous dysplasia is accepted as the precursor of SCC in most cancers not related to human papillomavirus (HPV). Squamous dysplasia may be related to a number of etiologic factors including tobacco use, alcohol consumption, and chewing of areca nuts or betel quid. Risk factors for and molecular alterations seen in oral dysplasia and head and neck SCC are discussed separately. (See "Epidemiology and risk factors for head and neck cancer", section on 'Risk factors' and "Chemoprevention and screening in oral dysplasia and squamous cell head and neck cancer", section on 'Field carcinogenesis and chemoprevention' and "Head and neck squamous cell carcinogenesis: Molecular and genetic alterations".)
The diagnosis and grading of dysplasia is based on the assessment of a constellation of features related to both nuclear atypia as well as architecture and maturation. Findings commonly used to support a diagnosis of oral squamous dysplasia include nuclear enlargement, irregular nuclear contours, abnormal keratinization (dyskeratosis), irregular cell stratification, and increased mitotic activity.
The pathologic evaluation of oral epithelial dysplasia remains inexact and is not consistently reproducible. The World Health Organization (WHO) Classification of Head and Neck Tumours endorses a three-tier system for the grading of oral dysplasia :
●Mild dysplasia – Abnormal architectural and cytologic features largely confined to the lower third of the epithelium.
●Moderate dysplasia – The dysplastic process extends into the middle third of the epithelium.
●Severe dysplasia/carcinoma in situ – Extension of the process into the upper third of the epithelium.
Similar to the cervical paradigm of HPV driven squamous dysplasia, oral squamous dysplasia is commonly graded based on thickness. However, in contrast to the cervical paradigm, some cases may receive a diagnosis of moderate or severe dysplasia based on a high degree of nuclear atypia, despite only involving the lower third of the epithelium. (See "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis".)
The WHO architectural and cytologic criteria are meant to improve interobserver agreement in classifying oral epithelial dysplasia [4,18]. Despite this, significant interobserver variability exists in the diagnosis and grading of oral squamous dysplasia. A switch to a two-tiered grading system has been proposed by some authors in order to improve reproducibility .
In contrast to the oral cavity, the WHO Classification of Head and Neck Tumours specifies a two-tier system of nomenclature for squamous dysplasia of the hypopharynx, larynx, and trachea . In this paradigm, dysplastic lesions are regarded as either low-grade dysplasia/squamous intraepithelial lesions or high-grade dysplasia/squamous intraepithelial lesions based on the degree of cytologic and architectural aberration. In this system, cases with the morphologic features of moderate dysplasia are included under the rubric of high-grade dysplasia/intraepithelial lesions based on their relatively high risk of malignant transformation . An optional third category of carcinoma in situ may be employed in cases of high-grade dysplasia/squamous intraepithelial lesions that demonstrate severe full thickness atypia.
Close clinical follow-up of squamous dysplasia is warranted, since histopathology is limited in its ability to predict malignant transformation. Although dysplasia is regarded as a precancerous condition, precursor lesions in the oral, laryngeal, and pharyngeal mucosa do not necessarily follow a linear progression. Dysplasia can regress, while invasive cancer can occur in the absence of surface dysplasia. Furthermore, dysplasia on a biopsy or resection is not necessarily predictive of subsequent malignancy [21,22]. As an example, one study that compared biopsy specimens with subsequent resection specimens found that the degree of dysplasia was underestimated in one-third of cases and carcinoma was missed in 7 percent of cases .
Proliferative verrucous leukoplakia — Proliferative verrucous leukoplakia (PVL) is increasingly recognized as an important precursor of SCC in the oral cavity. PVL is best characterized as a clinicopathologic syndrome of field cancerization. Lesions in PVL are multifocal and include a histologic spectrum ranging from simple squamous and verrucous hyperplasia to verrucous carcinoma and well differentiated SCC. The patients are most typically older adult females, and the lesions preferentially involve the tongue and buccal mucosa.
The disease course in PVL is progressive, with lesions often increasing in number and size. Histologically, lesions may advance from hyperplasia to verrucous carcinoma to conventional invasive SCC. As the pathologic features of PVL are nonspecific, diagnosis relies on correlation between the histologic and clinical findings [23,24].
SQUAMOUS CELL CARCINOMA — This section discusses pathologic aspects of conventional squamous cell carcinoma (SCC; ie, "not otherwise specified" [NOS]) as well as some variants with special features that may reflect differences in behavior or prognosis. These include verrucous, basaloid, and spindle cell variants of SCC.
Invasive squamous cell carcinoma
Risk factors — While other mechanisms exist, invasive SCC in the head and neck evolves along three major pathways: tumors related to tobacco and alcohol, tumors associated with human papillomavirus (HPV), and tumors related to Epstein-Barr virus. (See "Epidemiology and risk factors for head and neck cancer" and "Head and neck squamous cell carcinogenesis: Molecular and genetic alterations".)
●Tobacco and alcohol use – Tobacco- and alcohol-related SCCs are associated with a mutated and overexpressed p53 gene, frequently in conjunction with chromosome 7 aneuploidy, and have an increased proliferative index as measured by Ki-67 immunohistochemistry (IHC) . These parameters are seldom, if ever, assessed on routine clinical material.
●Human papillomavirus – HPV infection (in particular high-risk serotype such as HPV 16) is responsible for the majority of SCCs arising in the oropharynx (chiefly represented by the lymphoid-rich areas of the base of tongue and tonsil) .
HPV has also been identified as the driver of a minority of SCCs arising at a number of other subsites including the larynx, oral cavity, parotid gland, and sinonasal tract. In general, HPV driven carcinomas tend to occur in younger patients and are associated with sexual activity (table 1). In the oropharynx, this subset of tumors is associated with early nodal metastases and markedly improved outcomes relative to tumor (T) and node (N) stage. At other subsites, the prognostic significance of HPV is less well established. (See "Epidemiology, staging, and clinical presentation of human papillomavirus associated head and neck cancer", section on 'Epidemiology'.)
Morphologically, HPV driven SCCs of the oropharynx classically show no to minimal keratinization, nested growth, a lack of overlying dysplasia, and absent desmoplasia (picture 1). HPV driven SCCs occurring at other head and neck subsites may have a similar or "warty" morphology in some cases; however, the morphologic spectrum in cases occurring outside of the oropharynx is less well established .
In clinical practice, the mechanism of HPV driven carcinogenesis can be exploited by the use of p16 IHC, which is typically expressed on cells infected with HPV. Diffuse expression of p16 suggests driver HPV in the context of an oropharyngeal tumor and favors the oropharynx as the site of origin in the context of a metastatic head and neck SCC of unknown primary site . As p16 IHC is not entirely specific, further investigation of p16 positive SCC tumors using HPV in situ hybridization (ISH), polymerase chain reaction, or RNA sequencing is currently indicated in cases with variant morphology or which occur outside of the oropharynx or upper jugular chain lymph nodes. Serotypes other than HPV 16 may have a different biology. Further details on the virology of HPV infection are discussed separately. (See "Epidemiology, staging, and clinical presentation of human papillomavirus associated head and neck cancer" and "Virology of human papillomavirus infections and the link to cancer".)
●Epstein-Barr virus – Epstein-Barr virus (EBV) is strongly associated with SCC arising in the nasopharynx and may also play a role in primary SCC arising in salivary gland tissue. While associated with almost all cases of nasopharyngeal carcinomas in endemic regions (eg, Southern China, North Africa, Southeast Asia), EBV is also found in the majority of cases of SCC in other regions where nasopharyngeal carcinoma is less common. Given the ubiquity of EBV infection, this suggests that other environmental factors may be important in the pathogenesis of EBV driven SCC. Diet in general and consumption of salted fish in particular have been proposed as playing an important role .
EBV driven SCC most commonly has an undifferentiated morphology with minimal keratinization and an abundant lymphoid stroma (ie, "lymphoepithelial carcinoma"). The tumor cells display a syncytial growth pattern with indistinct cell borders, large vesicular nuclei, and prominent nucleoli. Desmoplasia is typically not prominent (picture 2). Use of RNA in ISH for EBV early RNA (EBER) is the standard method for detection of EBV in paraffin embedded tissue.
The role of EBV in carcinogenesis is likely related to expression of the LMP1 and LMP2 proteins, which interact with a number of cell-signaling pathways and inhibit apoptosis. While data are limited, EBV driven tumors in the nasopharynx do not appear to have a significantly different prognosis than HPV driven tumors or non-virus-related tumors in the nasopharynx (picture 2) [28,29]. (See "Virology of Epstein-Barr virus".)
Invasion in SCC is defined as penetration by the neoplastic cells into the underlying connective tissue beneath the basement membrane. This sequence is logically visualized if there is coexistent high-grade surface dysplasia or carcinoma in situ. However, in contrast with other anatomic sites such as the uterine cervix, SCC in the head and neck region may occur without coexistent carcinoma in situ. The histologic appearance of the invasive tumor may be represented by a broad confluent band ("pushing") or by irregular tumor nests, cords, or single cells. Frequently a desmoplastic or fibrous host response accompanies the invasion.
Keratinization is often deemed the ultimate direction of squamous cytoplasmic differentiation. Keratinization is typically represented by whorls (pearls) of dense keratin within tumor nests and may be found either focally or more generally in head and neck SCC. By itself, keratinization is not a reliable grading feature, even though in the past grading was based upon resemblance of the tumor to the normal maturation sequence of squamous epithelium. Tenacious tight junctions between cells (visualized as "intercellular bridges") are another important and diagnostically useful feature of squamous differentiation.
In cases of poorly differentiated SCC where associated squamous dysplasia is not seen and intercellular bridges and frank keratinization are absent, IHC may be used to confirm squamous differentiation. In this context, the transcription factor p63 or its more specific isoform, p40, holds the greatest utility. In some cases, IHC for high molecular weight keratins (CK5/6, 34bE12) may also hold value, although they are less specific.
Stage — Prognostically, the most important factor is the stage, which is principally determined at most sites by tumor size and nodal metastasis. The Tumor, Node, Metastasis (TNM) staging system is widely used, and specific criteria have been developed, depending upon the primary tumor site as follows (see "Overview of the diagnosis and staging of head and neck cancer"):
●Oropharynx (table 4A-B and table 5A-B) – (See "Treatment of early (stage I and II) head and neck cancer: The oropharynx", section on 'Staging'.)
●Nasal cavity and paranasal sinuses (table 8) – (See "Tumors of the nasal cavity" and "Cancer of the nasal vestibule", section on 'Staging' and "Paranasal sinus cancer", section on 'Diagnosis and staging'.)
●Salivary glands (table 9A-B) – (See "Salivary gland tumors: Epidemiology, diagnosis, evaluation, and staging", section on 'Staging'.)
Is histologic grade prognostic for SCC? — Despite its ubiquity, histologic grading of invasive squamous cell carcinoma (SCC) of the head and neck is irreproducible and of limited value. The prognostic value of histologic grading is unclear in regard to its association with survival [30-33]. The criteria used in grading SCC are somewhat subjective and usually include mitotic activity, nuclear pleomorphism, and degree of resemblance to normal squamous cells (differentiation). Despite these limitations, histologic grading is mandated by the current College of American Pathologists (CAP) guidelines in resected specimens. The modifiers well (picture 3), moderately (picture 4), or poorly differentiated carcinoma (picture 5) are used.
Alternative schema for histologic grading that focus on tumor nest size and budding at the invasive front have been proposed. These criteria have been demonstrated to correlate better with outcomes in a small number of series but have not been widely adopted [34,35].
Other prognostic factors — Additional prognostic factors can be derived from histopathologic examination and may influence treatment, as follows:
●Tumor depth of invasion – Tumor depth of invasion (DOI) is related to the risk of nodal metastases in oral SCC independent of tumor size and has been incorporated into the staging of tumors at this site in the eighth edition of the American Joint Committee on Cancer (AJCC) Staging Manual [36,37].
●Pattern of invasion – A prognostic model incorporating pattern of invasion at the invasive front has been shown to be associated with recurrence and overall survival in the oral cavity and potentially at other subsites. In these models, a worst pattern of invasion (WPOI) demonstrating discontinuous groups of small cells or individual cells is associated with poor outcomes [4,7,38].
●Perineural and lymphovascular invasion – Perineural invasion and invasion of the lymphatic vessels are associated with increased risk of local recurrence or metastasis, respectively .
●Surgical margin status – Local recurrence is associated with margin status as outlined. (See 'Tumor excision and surgical margins' above.)
●Extracapsular extension – Extracapsular extension of tumor from involved lymph nodes into the surrounding fibroconnective tissue is an important negative prognostic indicator, particularly in non-HPV associated tumors [39,40]. As such, this feature has been incorporated into the staging of non-HPV associated tumors in the eighth edition of the AJCC Staging Manual. To facilitate accurate assessment, grossly involved lymph nodes should be generously sampled for histologic examination and meticulously examined for evidence of extracapsular extension. At minimum, one histologic section per centimeter of tumor should be examined. Stellate tumor deposits within soft tissue without an identifiable lymph node should be regarded as lymph nodes with extensive extracapsular extension for prognostic purposes .
Despite its importance, the assessment of minimal amounts of extranodal extension suffers from a substantial degree of interobserver variability .
Histologic variants of squamous cell carcinoma
Verrucous carcinoma — Verrucous carcinoma accounts for less than 5 percent of cases of SCC; it is an indolent tumor that is most often seen in older adult patients with or without a history of smoking . Despite its name and distinctive morphology, this tumor subtype is unrelated to HPV . Histologically, there is a spectrum of verrucous lesions encountered in the oral cavity, oropharynx, and larynx that makes accurate and reproducible diagnoses difficult.
Verrucous lesions clinically present as a velvety or warty exophytic mass (picture 6). The spectrum of noninvasive mucosal lesions with a verrucoid appearance includes isolated verrucoid hyperplasia (picture 7) and lesions associated with proliferative verrucous leukoplakia (PVL). Verrucous lesions are histologically characterized by extensive keratinization, bland cytology, an exophytic growth pattern with thickened club-like projections and broad, bulbous rete pegs. Verrucous carcinoma is distinguished from verrucous hyperplasia based on extension of the lesion into the underlying stroma.
Verrucous carcinoma by definition does not exhibit conventional destructive invasion or dysplasia. Lesions displaying these features even focally should be characterized as conventional invasive squamous cell carcinomas. As such, the distinction of verrucous carcinoma from a verrucous hyperplasia is difficult and somewhat subjective, particularly in small biopsies. An unequivocal diagnosis of verrucous carcinoma requires the demonstration of extension of the lesion below the epithelial-stromal interface of the adjacent uninvolved mucosa. This critical feature is best assessed in an excisional specimen (picture 8).
When defined by strict criteria, verrucous carcinomas do not metastasize. Although they demonstrate progressive local growth, in some cases into the underlying bone, the prognosis is favorable . Differences in expression of matrix metalloproteinases have been invoked to partially explain the less aggressive behavior of verrucous carcinomas, as compared with conventional SCC .
Complete surgical excision is generally the primary therapy for verrucous carcinomas. Although radiation therapy was historically avoided in verrucous carcinomas (because of concerns that radiation may cause conversion of a relatively indolent tumor to a more aggressive poorly differentiated SCC), this concept is no longer considered valid .
Basaloid SCC — Basaloid squamous cell carcinomas (SCCs (picture 1)) are typically related to tobacco use and are most commonly localized to the larynx, although they may also occur at other anatomic sites in the head and neck region. Histologically, basaloid SCCs are poorly differentiated and comprised of cells with high nuclear:cytoplasmic ratios and often with brisk mitotic activity and karyorrhexis. Hyaline stroma and necrosis are frequently present, and a trabecular or nested growth pattern with peripheral palisading is typical. Areas of conventional SCC and squamous dysplasia are often admixed.
Our understanding of basaloid SCC is confounded by the fact that HPV associated SCCs, typically from the oropharynx, were previously included under this rubric owing to their histologic similarity until basaloid SCC was recognized as a distinct entity. When HPV associated cases are excluded, and this entity is more strictly defined as proscribed by the fourth edition of the WHO classification of head and neck tumors, basaloid SCCs are found to have a significantly higher mortality and stage at presentation than conventional SCC [48,49].
Spindle cell SCC — Spindle cell squamous cell carcinomas (SCCs) are rare, poorly differentiated forms of SCC that should not be confused with true sarcomas. Although spindle cell SCC may be found at any site within the head and neck, the most common sites are the larynx and oral cavity.
The gross appearance of these tumors varies and can include smooth polypoid nodules, fungating masses, or flat ulcers. Histologically, these tumors morphologically resemble sarcomas frequently with a spindle cell growth pattern and collagenous stroma. Areas of bone and cartilage formation may also be seen (picture 9). These areas of mesenchymal differentiation may encompass the entirety of the tumor or be admixed with conventional SCC. In addition to a true sarcoma, the other major element in the differential diagnosis is malignant melanoma. While IHC is useful to classify these tumors correctly, the recognition of foci of conventional SCC (in situ or invasive) is by far the most helpful feature. In difficult cases where morphologic evidence of squamous differentiation is not seen, immunoreactivity for pancytokeratin may support a diagnosis of spindle cell SCC.
Spindle cell carcinomas are characterized by high rates of locoregional recurrence . Prognosis has been associated with tumor location, tumor size and stage, DOI, and presence of keratin staining in the spindle cells [51,52]. Data from case series support the role of surgery as primary therapy; some, but not all, have found these tumors to be relatively radioresistant [51,52].
OTHER MUCOSAL EPITHELIAL TUMORS
Schneiderian papillomas — Schneiderian papillomas arise from the mucosa of the nasal cavity and sinuses (Schneiderian epithelium). These lesions may exhibit multifocality. They are divided into three categories:
●Fungiform papillomas – Fungiform (everted) papillomas arise from the nasal septum and have an exophytic growth pattern (picture 10).
●Inverted papillomas – Inverted papillomas arise from the lateral nasal or sinus wall or paranasal sinuses and show an endophytic or mixed exophytic/endophytic growth pattern. The lining of an inverted papilloma consists of multilayered nonkeratinized squamous epithelium with scattered mucous cells and microcysts filled with neutrophils (picture 11). (See "Paranasal sinus cancer", section on 'Inverted papilloma'.)
●Oncocytic Schneiderian papillomas – Oncocytic Schneiderian papillomas (formerly known as cylindrical cell papillomas) arise from the lateral sinus wall or paranasal sinuses and have a stratified lining of bright pink granular columnar cells with microcysts (picture 12).
Both inverted and oncocytic Schneiderian papillomas carry an increased risk (5 to 10 percent) of subsequent or concurrent carcinoma ; thus, wide excision and long-term follow-up are required. Inverted papillomas almost invariably harbor mutually exclusive activating mutations of EGFR or infection by low-risk HPV (lrHPV) serotypes . lrHPV-related inverted papillomas are often associated with an exophytic component and condyloma-like appearance in contrast with EGFR driven lesions. While both groups of inverted papillomas may give rise to invasive squamous cell carcinoma (SCC), this phenomenon is more common in lrHPV driven lesions . By contrast, HPV associated sinonasal SCCs unassociated with Schneiderian papillomas are almost always related to high-risk viral serotypes. (See "Virology of human papillomavirus infections and the link to cancer".)
Most if not all cases of oncocytic Schneiderian papilloma have been found to be associated with KRAS mutations involving codons 12 and 61. These mutations are also present in associated cases of SCC .
Recurrent respiratory papillomatosis — Recurrent respiratory papillomatosis (RRP) is a disease associated with HPV infection seen in both adults and children. It is characterized by multiple benign squamous papillomas of the respiratory tract (picture 13) and principally involves the larynx. The tracheobronchial tree and the lungs are rarely involved (<1 percent of cases). RRP is also occasionally an incidental finding at autopsy . (See "Common causes of hoarseness in children", section on 'Papillomatosis'.)
RRP typically involves squamociliary junctions, such as tracheostomy stomas (where chronic inflammation induces squamous metaplasia) and iatrogenically induced squamociliary junctions. Morphologically, RRP is a benign condition. However, patients with RRP can experience multiple, multifocal recurrences that require excision. Lower respiratory tract involvement often leads to respiratory obstruction; in this situation, common causes of death include pneumonia, abscesses, parenchymal lung destruction, and respiratory failure [58-61].
In children and adolescents, RRP has been associated with vertical transmission of HPV during pregnancy or delivery . However, the rarity of RRP does not correlate with frequency of HPV infection and associated dysplasias in the female genital tract; therefore, HPV infection may be a co-factor, along with other environmental or host factors. In adults, RRP may be related to reactivation of a latent infection or a new mucosal exposure.
Histologically, RRP consists of benign proliferations of squamous epithelium with HPV associated pathologic changes comparable to those found in the female genital tract. Although the association between dysplasia and possible recurrence or malignant change is controversial, RRP commonly exhibits varying degrees of squamous dysplasia throughout the clinical disease course. HPV 6 and 11, regarded as low-risk genotypes, have been the most commonly documented in RRP. Other high-risk HPV genotypes (eg, 16, 18, 31, 33, 35) are rarely found. (See "Virology of human papillomavirus infections and the link to cancer" and "Virology of human papillomavirus infections and the link to cancer", section on 'HPV Genotypes and risk of cancer'.)
Malignant transformation of RRP is rare in either children or adults. SCC is the only malignancy directly associated with RRP, and can potentially affect either the upper or lower respiratory tracts. Potential risk factors for malignant transformation include multiple recurrences, smoking, alcohol consumption, irradiation, immunosuppression, and chemotherapy; these are also associated with the development of SCC. The definitive molecular mechanisms leading to malignancy in RRP are still poorly understood, especially the unexplained association of HPV 6 and 11 in this regard, since these two HPV genotypes are not linked to the development of SCC in other locations. Data suggest that the malignant transformation associated with HPV 11, at least in part, does not involve the disabled retinoblastoma (Rb) signaling pathway and aberrant p53 regulation .
Sinonasal undifferentiated carcinoma — Sinonasal undifferentiated carcinoma (SNUC) is a poorly differentiated and rapidly growing malignancy that arises from Schneiderian mucosa. The tumors are composed of sheets, nests, or trabeculae of malignant, pleomorphic cells with round to oval hyperchromatic nuclei, variably prominent nucleoli, and moderate eosinophilic cytoplasm (picture 14). Abundant mitotic activity and areas of necrosis are often seen. Minimal if any evidence of squamous, glandular, or neuroendocrine differentiation should be seen by morphology or immunohistochemistry [64,65]. (See "Olfactory neuroblastoma (esthesioneuroblastoma)", section on 'Differential diagnosis' and "Paranasal sinus cancer", section on 'Sinonasal undifferentiated carcinoma'.)
In addition to excluding poorly differentiated SCC, adenocarcinoma, and neuroendocrine carcinoma, a number of newer entities defined on the basis of genetic alterations should be excluded to establish a diagnosis of SNUC. These include loss of SMARCA4 or SMARCB1, rearrangements involving nuclear protein in testis (NUT), and infection with HPV [66-70]. (See "Pathogenesis, clinical features, and diagnosis of Merkel cell (neuroendocrine) carcinoma", section on 'Histopathology' and "Squamous cell carcinoma of unknown primary site", section on 'NUT midline carcinoma'.)
Point mutations involving the IDH1/2 genes have been identified in a large proportion of cases of SNUC. In addition to their occurrence in SNUC, similar IDH1/2 genetic alterations have also been identified in small subsets of other high-grade tumor types occurring in the sinonasal tract (high-grade neuroendocrine carcinoma, olfactory neuroblastoma, high-grade adenocarcinoma) .
Sinonasal adenocarcinoma — Primary head and neck adenocarcinomas can arise from the minor salivary glands or epithelium of the sinonasal tract. Sinonasal adenocarcinomas may resemble common salivary gland tumors, seromucinous tumors, tumors with enteric-type differentiation, or other rare variants . The seromucinous type adenocarcinomas range from low-grade tumors with fusion of glands composed of bland seromucinous cells to those with cystic or tubulopapillary growth patterns (picture 15). Intestinal-type adenocarcinomas histologically and immunohistochemically resemble carcinoma from the lower gastrointestinal tract (picture 16) [73-75].
Exposure to wood or leather dust is highly associated with intestinal-type adenocarcinomas arising in the ethmoid sinus, with such exposure reported in more than 90 percent of cases . The clinical behavior of these tumors is more closely related to tumor grade, although intestinal-type adenocarcinomas are reported to be more aggressive than seromucinous-type carcinomas [77,78]. (See "Paranasal sinus cancer".)
SALIVARY GLAND TUMORS — Salivary gland tumors include a heterogeneous group of lesions. The variable contribution of luminal and abluminal cells, in conjunction with matrix production by the latter, produces a wide range of histologic patterns, even within the same tumor subtype. Most salivary gland tumors are composed of more than one cell type. These can be divided into luminal (acinar and ductal) and abluminal (myoepithelial and basal) types with analogies to the composition of normal salivary glands. A complete classification of benign and malignant salivary gland tumors is available from the World Health Organization (WHO) blue book (table 10) .
The following section will discuss selected entities of clinicopathologic importance. The diagnosis and treatment of salivary gland tumors are discussed separately. (See "Salivary gland tumors: Epidemiology, diagnosis, evaluation, and staging" and "Salivary gland tumors: Treatment of locoregional disease" and "Malignant salivary gland tumors: Treatment of recurrent and metastatic disease".)
In most cases, fine needle aspiration (FNA) is the diagnostic modality of choice for initial diagnosis and triage of salivary gland tumors. While some common tumor types (eg, Warthin tumor, pleomorphic adenoma) lend themselves to diagnosis via FNA, many others (in particular adenoid cystic carcinoma [ACC] and oncocytic tumors) present a nonspecific morphologic pattern and require resection for accurate diagnosis. The Milan System for Reporting Salivary Gland Cytology is a proposed framework for reporting of salivary gland cytology results that accounts for the diagnostic areas of ambiguity inherent in these specimens . (See 'Diagnosis' above.)
Benign salivary gland tumors — The most common salivary gland tumors are pleomorphic adenoma and Warthin tumor. Both tumors typically have very distinct morphology and as such are readily diagnosed in fine needle aspirates. A cardinal feature of all benign salivary gland tumors is circumscribed growth and the absence of an infiltrative growth pattern.
Warthin tumor — Warthin tumor is strongly associated with smoking and occurs almost exclusively in the parotid gland. Warthin tumor is frequently cystic and may often be bilateral. A tripartite histology with areas of cyst formation, bilayered oncocytic epithelium, and lymphoid stroma are present in varying amounts (picture 17). In some cases, particularly following FNA, areas of squamous or mucinous metaplasia may be seen and raise the possibility of an oncocytic mucoepidermoid carcinoma (MEC).
Pleomorphic adenoma — Pleomorphic adenomas arise most frequently in the parotid gland, although these tumors can also be seen in other major and minor salivary glands (especially in the palate). Pleomorphic adenomas are particularly important because malignant tumors (carcinoma ex pleomorphic adenoma) may originate within these lesions. (See 'Carcinoma ex pleomorphic adenoma' below.)
Pleomorphic adenomas contain stromal material as well as groups of epithelial and myoepithelial cells in varying states of organization. Well-formed glands with a myoepithelial layer may coexist with lumenless groups of admixed stromal cells. The myoepithelial cells frequently separate from the epithelial nests and give rise to a chondromyxoid or hyalinized stroma. Thus, the demarcation between epithelial nests and stromal cells may be indistinct, as myoepithelial cells appear to drop off from the epithelial nests (picture 18). The different proportions of cell types (luminal and abluminal) and the variable amount and type of stroma give rise to a variety of morphologic appearances and affect the cytologic representation of material obtained on preoperative needle aspirations.
While by definition lacking infiltrative growth, pleomorphic adenomas may have broad blunt extensions (ie, "pseudopods") that project somewhat beyond the borders of the rest of the lesion. These projections may contribute to recurrence, particularly in cases treated with enucleation.
The majority of pleomorphic adenoma cases harbor rearrangements involving either HMGA2 or PLAG1 .
Malignant salivary gland tumors — The incidence and proportion of malignant tumors of a specific histologic type vary between major and minor salivary glands [81-84]. Furthermore, there are large differences in the relative incidence in different geographic regions.
Overall, MEC and ACC are the most common histologic types, accounting for 33 and 24 percent of cases, respectively . Key features in identifying malignant potential in any salivary gland tumor include invasion of adjacent tissue, perineural or lymphatic/vascular invasion, and necrosis. In contrast with other anatomic sites, highly aggressive malignant tumors, in particular ACC and myoepithelial carcinoma, may be extremely bland and cytologically monotonous and display minimal mitotic activity.
For purposes of management, low- and high-grade carcinomas must be accurately distinguished from each other. While MEC is routinely graded in order to drive management, most of the other forms of salivary gland carcinoma have an intrinsic grade .
The pathology of a subset of more common salivary gland malignancies are discussed below .
Mucoepidermoid carcinoma — MEC is the most common malignant salivary gland tumor in adults and children . It consists of a mixture of mucin-producing columnar cells, epidermoid (squamous) cells, and polygonal intermediate cells (picture 19). Overt keratinization is rare.
Histologic grade is important in driving the management of this tumor and particularly in determining the need for adjuvant radiation therapy. As a practical matter, low-grade lesions are typically cystic; higher-grade lesions become progressively more solid in growth and more difficult to classify correctly.
The major competing grading systems (Brandwein, Armed Forces Institute of Pathology [AFIP], and modified Healey) are tabulated and summarized in standard textbooks . The AFIP and Brandwein systems assign points to individual histologic features, which contribute to a final score. Grading of tumors within these schema has the usual problem of interobserver reproducibility. Furthermore, the utility of many of the less contemporary grading systems is questionable as many of the cases used to validate the grading criteria in the past would not be considered MEC by modern criteria.
A simpler alternative grading system has been proposed by the Memorial Sloan Kettering Cancer Center group, which predominantly evaluates lesions based on the presence of coagulative necrosis and greater than or equal to 4 mitotic figures per 10 high power fields. In this series of 52 confirmed cases of MEC, tumors containing either of these risk factors were classified as high-grade disease, and all patients with such high-grade tumors suffered disease recurrence or died. Recurrence in patients whose tumors lacked these features was limited to a single patient with a positive margin .
A translocation involving (11;19)(q21;p13), which produces a unique fusion product, MECT1-MAML2, occurs in approximately 50 percent of cases of MEC. Although the presence of this translocation was initially regarded as prognostically favorable [89,90], this may not be the case , as many cases previously diagnosed as high-grade MEC are now assigned to other histologies. Although testing for a MAML2 rearrangement is not indicated for routine diagnosis, it may be useful for detecting mucin poor or oncocytic MEC, particularly when the differential diagnosis includes a benign entity .
Adenoid cystic carcinoma — ACC was previously considered to be the most common form of malignant minor salivary gland tumor . Many of these cases subsequently have been reclassified as polymorphous adenocarcinoma. ACC arises in both major and minor salivary glands. The tumor is locally aggressive, with recurrences often arising after many years. As such, the five-year survival rate of ACC (77 percent) does not accurately reflect its long-term consequences (45 percent at 15 years) .
Three basic growth patterns are commonly seen: tubular, cribriform (picture 20), and solid. These patterns are often mixed, and extensive perineural invasion is seen in almost all resected cases. The biologic aggressiveness of ACC correlates with the presence of a solid component within the tumor . Despite the aggressive behavior of this tumor, the individual cells are monotonous with scant cytoplasm, bland nuclei, and minimal coagulative necrosis and mitotic activity. While ACC may be graded, usually on the basis of its growth pattern, all cases should be considered high grade for the purposes of prognostication and management.
Despite an often classic appearance, ACC may be difficult to distinguish from other bland monotonous tumors including basal cell adenoma, epithelial myoepithelial-carcinoma, and even cellular pleomorphic adenoma. Similar to these mimics, ACC is comprised of both an epithelial component as well as myoepithelial component, which may be highlighted by immunohistochemistry (IHC) for p63 or its isoform, p40. While IHC for CD117 is often utilized to aid in this distinction, this marker is neither sensitive nor specific for ACC.
MYB-NFIB and MYBL1-NFIB rearrangements can be identified via fluorescence in situ hybridization (FISH) in the majority of cases of ACC and can serve as a useful confirmatory test in difficult cases. While almost all cases of ACC harbor MYB or MYBL1 fusions, a large proportion of cases demonstrate fusion partners other than NFIB . MYB RNA in situ hybridization (ISH), while not widely available, can also be useful in this context and may be more sensitive than FISH .
Salivary gland ductal carcinoma — Salivary duct carcinoma is a high-grade salivary gland carcinoma, typically occurring in the parotid gland, which bears a biological and morphologic resemblance to triple-negative carcinoma of the breast . (See "Pathology of breast cancer", section on 'Secretory carcinoma' and "ER/PR negative, HER2-negative (triple-negative) breast cancer".)
The tumor shows a predominantly solid and nested growth pattern with high-grade cytology and prominent comedonecrosis within tumor nests. The individual cells display marked pleomorphism and have abundant granular eosinophilic cytoplasm, suggestive of apocrine differentiation.
IHC stains for mammaglobin, GATA3, and androgen receptor are positive in salivary gland ductal carcinoma consistent with its apocrine mammary phenotype. A significant proportion of cases (20 to 40 percent) will harbor overexpression of human epidermal growth factor receptor 2 (HER2). Identification of this subset is clinically relevant, as such patients with locally advanced or metastatic disease may be candidates for treatments targeting HER2. This topic is discussed separately. (See "Malignant salivary gland tumors: Treatment of recurrent and metastatic disease", section on 'HER2 overexpression' and "Malignant salivary gland tumors: Treatment of recurrent and metastatic disease", section on 'Androgen receptor positive'.)
Polymorphous adenocarcinoma — Polymorphous adenocarcinoma is an infiltrative tumor typically originating in minor salivary glands that is composed of bland, uniform cells with multiple growth patterns within the same tumor. Polymorphous adenocarcinoma most commonly occurs in the palate and is almost always low grade.
These tumors resemble and may be confused with adenoid cystic carcinoma since both are cytologically bland and tend to invade the perineural spaces (picture 21); polymorphous adenocarcinoma uncommonly invades bone. Polymorphous adenocarcinoma can be distinguished from its morphologic mimics, primarily ACC and pleomorphic adenoma based on the pattern of p63 and p40 staining. While ACC and pleomorphic adenoma will show scattered p63+/40+ myoepithelial cells throughout the tumor, polymorphous adenocarcinoma will demonstrate a diffuse albeit weaker pattern of p63 reactivity with no staining for p40 .
Cribriform adenocarcinoma of the tongue is regarded by many authors as a variant of polymorphous adenocarcinoma. It is distinguished from polymorphous adenocarcinoma based on the presence of vesicular ("papillary thyroid carcinoma-like") nuclei, a cribriform growth pattern, and predilection for the base of the tongue.
Genetic alterations involving protein kinase D (PRKD) are characteristic of both polymorphous adenocarcinoma (hotspot mutations) as well as cribriform adenocarcinoma (rearrangements) .
Carcinoma ex pleomorphic adenoma — Carcinoma ex pleomorphic adenoma is a malignant tumor that may arise from a pre-existing pleomorphic adenoma (picture 22). This entity may be present as a sudden growth of a previously stable mass in a salivary gland, usually the parotid gland [100,101]. (See 'Pleomorphic adenoma' above.)
Salivary gland ductal carcinoma and myoepithelial carcinoma are the most common histologies seen in carcinoma ex pleomorphic adenoma . Epithelial-myoepithelial carcinoma and SCC may also occur in this setting. In the case of myoepithelial carcinoma, cases arising in a background of pleomorphic adenoma have a more aggressive disease course than those arising de novo . (See 'Salivary gland ductal carcinoma' above.)
Cases of carcinoma ex pleomorphic adenoma with no or minimal extension into the tissue surrounding the pre-existing pleomorphic adenoma may have a lower incidence of metastatic spread than cases with extensive infiltration into the adjacent tissue. This is in contrast to the previous belief that noninvasive tumors had no metastatic capability. Other important negative prognostic indicators in these cases include myoepithelial carcinoma histology, high mitotic rate, and vascular invasion .
Cases of carcinoma ex pleomorphic adenoma commonly harbor the same recurrent cytogenetic abnormalities involving PLAG1 and HMGA2 as seen in the preceding pleomorphic adenoma .
Less common malignant tumors — Several other less common malignant tumors also arise in salivary glands:
●Acinic cell carcinoma – Acinic cell carcinoma is a low-grade primary salivary gland malignancy that occurs almost invariably in the parotid gland. These tumors are comprised of sheets and acini of tumor cells containing abundant coarsely granular cytoplasm. Similar to their normal counterparts, the tumor cells contain abundant zymogen granules. Acinic cell carcinoma exhibits low-grade behavior and is associated with a favorable long-term prognosis .
●Mammary analog secretory carcinoma – Many cases previously regarded as hypogranular acinic cell carcinoma have now been recognized to harbor recurrent gene fusions involving NTRK and have been designated mammary analog secretory carcinoma (MASC), or secretory carcinoma. These tumors are morphologically and biologically analogous to secretory carcinoma of the breast . (See "Malignant salivary gland tumors: Treatment of recurrent and metastatic disease", section on 'Secretory (NTRK gene fusion positive)' and "TRK fusion-positive cancers and TRK inhibitor therapy".)
●Squamous cell carcinoma – Primary SCC may also uncommonly occur in salivary gland tissue. The majority of SCCs that occur in major salivary glands represent metastatic lesions, usually from a cutaneous primary. Less commonly, carcinoma ex pleomorphic adenoma may take the form of SCC. A subset of primary salivary gland SCC may be related to infection with high-risk HPV genotypes . SCC occurring outside of these contexts is extremely rare. (See 'Squamous cell carcinoma' above and 'Carcinoma ex pleomorphic adenoma' above.)
RARE AND MISCELLANEOUS TUMORS
Head and neck sarcomas — Head and neck sarcomas are rare, accounting for approximately 2 percent of all head and neck malignancies. Head and neck sarcomas are discussed separately. (See "Head and neck sarcomas".)
Olfactory neuroblastoma — Olfactory neuroblastoma (ONB; esthesioneuroblastoma) is a rare tumor arising from the cribriform plate and paranasal sinuses. The pathology on olfactory neuroblastoma, along with its diagnosis, staging, and treatment, is discussed separately (picture 23). (See "Olfactory neuroblastoma (esthesioneuroblastoma)".)
Juvenile nasopharyngeal angiofibromas — Juvenile nasopharyngeal angiofibromas (JNA) are rare tumors exclusively seen in adolescent males, presenting with epistaxis . The lesion is locally invasive but morphologically deceptively bland, showing thin-walled vessels, devoid of smooth muscle, often exhibiting staghorn shapes, and set in a fibrous to myxoid stroma (picture 24). Local involvement of the nasal cavity and paranasal sinuses may be extensive, with occasional invasion of the skull base. Intraoperative bleeding may be marked and potentially life threatening. Preoperative measures to diminish blood loss (eg, tumor embolization) may be clinically useful.
Some cases appear to be manifestations of the familial adenomatous polyposis syndrome with abnormal nuclear localization of beta-catenin described in stromal cells of the tumor [107,108]. (See "Clinical manifestations and diagnosis of familial adenomatous polyposis", section on 'Other manifestations'.)
A number of growth factors and receptors have been identified in stromal cells of JNA, including vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR2), transforming growth factor beta 1 (TGFbeta1), and insulin-like growth factor 2 (IGF-2) [107,108]. These tumors were previously thought to express androgen receptors but not estrogen receptors (ER). One report has identified strong expression of the more recently described ER isoform, ER-beta . Such receptors may represent potential new treatment targets.
Ameloblastoma — Ameloblastomas are rare odontogenic tumors that arise in the jaw. They are typically large, disfiguring, and locally aggressive, although most do not metastasize. Ameloblastomas commonly recur if not adequately resected. These tumors have been associated with the V600E mutation of BRAF and may respond to therapy that targets this pathway [110-112]. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations".)
SUMMARY AND RECOMMENDATIONS
●Head and neck neoplasms – The head and neck region is an anatomically and histologically varied site that gives rise to a broad spectrum of neoplasms with differing morphologies, molecular alterations, risk factors, and treatment options (figure 1). (See 'Introduction' above.)
●Initial diagnostic work-up – For most head and neck neoplasms, the initial diagnostic work-up may utilize biopsy material (either incisional or excisional) or a cytologic specimen (ie, fine needle aspiration [FNA] or cell block). (See 'Management of pathologic specimens' above and 'Diagnosis' above.)
●Tumor excision and surgical margins – For tumors undergoing surgical excision, proper management of the surgical specimen is critical for histopathologic analysis and assessment of surgical margin status. Appropriate communication between the surgeon and pathologist is essential. (See 'Tumor excision and surgical margins' above.)
●Squamous cell carcinoma precursors – Histologic precursors to squamous cell carcinoma (SCC) include leukoplakia, erythroplakia, and leukoerythroplakia; squamous hyperplasia; squamous dysplasia; and proliferative verrucous leukoplakia. (See 'Squamous cell carcinoma precursors' above.)
•Patients with known carcinogenic exposures and mucosal changes potentially suspicious for such precursors should undergo evaluation and diagnostic biopsy.
•For patients with squamous dysplasia, close clinical follow-up is warranted since histopathology is limited in its ability to predict malignant transformation. (See 'Squamous dysplasia' above.)
●Squamous cell carcinoma – SCC of the various head and neck sites is associated with different clinicopathologic risk factors (eg, tobacco and alcohol use, human papillomavirus [HPV], Epstein-Barr virus [EBV]), morphologies, and management. (See 'Squamous cell carcinoma' above and 'Risk factors' above.)
•Prognostic factors – For patients with SCC, certain histologic risk factors are prognostic and influence treatment, such as staging; tumor depth of invasion (for oral SCC); pattern of invasion; perineural and lymphovascular invasion; surgical margin status; and extracapsular extension. The prognostic value of histologic grading in SCC is unclear. (See 'Prognostic factors' above.)
●Other mucosal epithelial tumors – Other mucosal epithelial tumors include Schneiderian papillomas, recurrent respiratory papillomatosis, and sinonasal undifferentiated carcinomas. Schneiderian papillomas, consisting of fungiform papillomas, inverted papillomas, and oncocytic Schneiderian papillomas, most often arise from the ectodermally derived mucosa of the nasal cavity and sinuses (Schneiderian epithelium). (See 'Other mucosal epithelial tumors' above.)
●Salivary gland tumors – Salivary gland tumors vary histologically and can be benign or malignant. (See 'Salivary gland tumors' above.)
•Benign tumors – Common benign tumor histologies include Warthin tumor and pleomorphic adenoma. (See 'Benign salivary gland tumors' above.)
•Malignant tumors – Common malignant histologies include mucoepidermoid carcinoma; adenoid cystic carcinoma; salivary gland ductal carcinoma; polymorphous adenocarcinoma; and mammary analog secretory carcinoma. (See 'Salivary gland tumors' above.)
●Rare tumors of the head and neck – Rare tumors of the head and neck region include head and neck sarcomas and olfactory neuroblastoma, among others. (See 'Rare and miscellaneous tumors' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges G Kenneth Haines III, MD, and Jerome Taxy, MD, who contributed to earlier versions of this topic review.
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