Head and Neck Tumors

Abstract

The head and neck region is a complex part of the human body. The diagnosis of soft tissue lesions of the head and neck comprises a wide variety of pathologic entities. These lesions may originate from developmental problems or from benign or malignant neoplastic transformation of normal tissue. Developmental problems arise from disturbances of organogenesis, histogenesis, or functional maturation of the involved structures. Therefore, these lesions can appear at any time during life, usually caused by the interaction of factors such as the environment and genetics.

This chapter highlights and discusses the most significant features for the diagnosis of epithelial and mesenchymal soft tissue tumors of the head and neck region, in addition to tumors of the temporomandibular joint. Tumors are divided into developmental tumors/tumorlike lesions, benign tumors, and malignant tumors and may have non-odontogenic, reactive, or neoplastic etiology.

Introduction

Tumors and tumorlike lesions of the head and neck are commonly encountered in contemporary oral medicine practice. Presentation of a mass in the head or neck should be evaluated with care and examined in detail. These masses may present as lumps with no associated symptoms noted incidentally by the patient, or may present as painful lesion attracting the patient’s attention. On presentation to the clinician, a comprehensive head and neck cancer examination should be undertaken in addition to a detailed risk assessment. Detailed information from the patient about their history, risk factors, habits, mass location, mass characteristics, mass growth pattern, and signs and symptoms are all useful pieces of information for establishing an accurate diagnosis. In addition to visual examination and palpation of the lesion, imaging studies and diagnostic studies are often undertaken to better ascertain the exact nature of a tumor in the head and neck region. Indeed many tumors of the laryngopharyngeal sites are not easily assessed clinically, and diagnostic imaging is often the first modality used to better understand the extent of the mass in question. A detailed understanding of the complex anatomy of the head and neck region is required for any clinician attempting to manage such conditions. The intricate and complicated structures of the head and neck region also require care and finesse when diagnostic investigations are undertaken, such as fine needle aspiration, core biopsy, image-guided biopsy, and incisional or excisional biopsy.

The varying tissues and structures of this complex region of the human body also predispose to a varying array of pathologies ranging from developmental lesions to neoplastic ones. Tissues include mucosal epithelium, lymphoid tissues, salivary glands, thyroid tissue, and sinonasal structures. These varying pathologies also call for differing treatment approaches which include surgery, radiation therapy, and chemotherapy. More recently, this has included immunotherapy particularly for head and neck squamous cell carcinomas. As our understanding of the molecular basis of these diseases increases, so will the success in managing these devastating cancers.

In this chapter, developmental tumors, benign and malignant epithelial tumors, soft tissue tumors, and tumors of the thyroid gland and temporomandibular joint are explored in detail expected of a contemporary oral medicine practitioner, particularly as this relates to their involvement in multidisciplinary head and neck teams and tumor boards. The content of this chapter is not exhaustive, and certain tumors are covered in other dedicated chapters such as “Oral Mucosal Malignancies,” “Salivary Gland Disorders and Diseases,” “Odontogenic Pathology,” and “Non-odontogenic Bone Pathology.” In this chapter, we focus on those parts of the anatomy not typically directly dealt with by the oral medicine specialist but for which they must have a comprehensive knowledge base. In addition, tumors not covered elsewhere in this book are also included here for completeness, with some minor overlap. It is expected that the oral medicine clinician will avail themselves of more comprehensive texts on the topics covered here for a more detailed appreciation of the complexity and scope of head and neck tumors (WHO Classification of Head and Neck Tumours 2017).

Developmental Lesions of the Head and Neck

The most significant transformation of the human body takes place during intrauterine life. The head and neck region has a significant role in all stages of in utero development, which makes it a key point for the diagnosis of developmental diseases. After birth, the developmental transformations are grouped in infancy, adulthood, and old age, each one related to its particular common diseases. This section will focus only on cysts and tumors that may rise in the head and neck region, but consideration should be given to the fact that some lesions are part of systemic developmental disorders, such as syndromes, sequences, and syntropy.

In order to fully understand the etiology of these lesions, a review of the basic nosology of these disorders is necessary. Problems during organogenesis lead to anomalies and malformations. These groups of lesions comprise incomplete formation diseases: such as agenesis, aplasia, hypoplasia, persistency, atresia, and stenosis. Also there are redundant lesions, called supernumerary, and the aberrant ones, known as ectopias, choristomas, and teratomas. Problems in histogenesis may lead to hamartomas or heteroplasias. Finally, problems in functional maturation are known as deformities. Table 1 outlines developmental terms and their definitions and common examples.

Table 1 Correlation of terminology applied to developmental disturbances with their definition and some clinical examples

Benign developmental tumors/tumorlike lesions of the head and neck comprise choristomas, teratomas, and hamartomas. Although developmental cysts have different explanations relating to their etiology, they are usually related to persistent, ectopic, or heteroplastic epithelium proliferation.

Although developmental lesions may appear at any time during life, 2–3% of these are diagnosed before birth, and this number rises to 4–6% until the fifth year of life. There is no gender predilection, and some lesions may be influenced by or influence hormonal activity, so other key periods of manifestation are puberty and old age.

These lesions usually have a multifactorial origin, but trauma, infections, carcinogenic agents, and spontaneous genetic mutations comprise the major causes of such lesions. These agents are also called dysontogenetic factors or teratogenic agents. Table 2 highlights different dysontogenetic factors and diseases directly related to them.

Table 2 Potential dysontogenetic factors and associated diseases

In order to improve the understanding of these different kinds of lesions, this chapter has grouped the developmental cysts and tumorlike lesions.

Dermoid Cyst

Epidemiology, Etiology, and Pathology

Dermoid cysts originate from cystic formation resulting from sudden proliferation of ectopic epithelium associated with adnexal structures such as hair follicles and sebaceous and sudoriferous glands. The most accepted theory of the origin of these epithelial remnants is that they probably are derived from the fusion of developmental processes. This presumption is based on the usual clinical location of such lesions, in the midline of the floor of the mouth and the soft palatal pillars. Other theories suggest that these lesions could represent a cystic manifestation of a teratoma. These cysts are not restricted to the head and neck region and are commonly found in the ovary and uterus. In these regions, it is usual to find the muscle and even neural tissue in the surrounding tissues of the cystic cavity. The presence of components of all embryonic tissues in these cases is compatible with the characteristics of a teratoma. Cysts found in the head and neck do not show such complexity.

Considered a rare lesion, it has no gender predilection and is usually diagnosed in intraoral sites. Affected patients are generally young and there are even congenital lesions described. The differential diagnosis of a dermoid cyst includes the epidermoid cyst. Lesions that occur close to the skin are more likely to contain adnexal structures nearby, so there is doubt if the latter form part of the lesion in biopsied specimens or just represent characteristics of the anatomic position, being usually diagnosed as epidermoid cysts. Dermoid and epidermoid cysts represent together about 7% of cysts found in the head and neck region, and only 1.6% are located within the oral cavity.

Clinical Presentation

Intraoral lesions present as a yellowish or normally colored fluctuating nodule, with soft resilient consistency on palpation (Fig. 1). Early clinical identification of these lesions can mimic a ranula or mucocele, mostly due to the coloration which is similar to the adjacent mucosa. Lesions vary in size, most of which measure 2–5 cm, but very large cysts (over 10 cm) have been described.

Fig. 1

Dermoid cyst involving the floor of mouth (a) and MRI sagittal view (b) shows a well-defined large cyst-like lesion positioned medially within the floor of the mouth extending inferolaterally above the hyoid bone

Investigations

Investigations include ultrasound, computerized tomography (CT), and magnetic resonance imaging (MRI) exams (Fig. 1), in addition to fine needle aspiration cytology (FNAC). Ultrasound examination is low cost and has the advantage that it can be used in real time with other clinical procedures such as FNAC. High-frequency probes (10–15 MHz) and mid-range frequency probes (5–10 MHz) provide better resolution but have less penetration. High-frequency probes are preferred for ultrasound images of superficial lesions (2–4 cm) deep such as dermoid cysts of the head and neck region. The echogenicity of the dermoid cyst is predominantly a hypoechoic circumscribed mass, indistinguishable from other mass lesions such as lipomas. Low-contrast CT imaging usually shows a circumscribed mass with low density, sometimes presenting scattered hyperdense structures, when calcified keratin material is present within the cystic content. High-contrast CT imaging provides a better view of the lesion but is less frequently used due to higher technical complexity. MRI has the best soft tissue quality of imaging, showing soft tissue structures and providing different sonographic appearances with different frequencies, providing a good view of the cystic content and its surrounding structures (Fig. 1) (Rumboldt 2015).

FNAC is useful for surgical planning. Keratin is normally found within the cystic cavity. The quick result from cytopathology also helps differentiate the lesion from a ranula for lesions located close to the midline of the floor of the mouth. This simple procedure may prevent unnecessary dissection of salivary glands which could give rise to a postsurgical mucocele.

Cytopathological examination reveals desquamative epithelial cells, mostly from the keratin layer. Some of these cells also present a clear cytoplasm with hydropic degeneration or signs of karyolysis giving a ghost cell-like appearance.

Gross specimen evaluation of the dermoid cyst usually shows a white-to-brown pasty to granular material. The characteristic keratin odor is usually not affected by tissue fixation. In empty specimens, the cystic internal lining presents as a smooth brilliant surface. Microscopic examination shows a stratified squamous cell orthokeratinized epithelium, without projections to the connective tissue capsule, with five to ten cells thick. The difference with epidermoid, trichilemmal , and pillar cysts is the marked hypergranulation layer and abrupt transition to the keratin layer. The differential diagnosis with epidermoid cyst is based on the presence of epithelial appendices like glands or hair follicles.

Treatment

Cyst enucleation is the treatment of choice for dermoid cyst. During dissection of the lesion, it can rupture. If this occurs, it is important to perform meticulous cleaning of the surgical site with saline solution to minimize the inflammatory potential of keratin, providing better immediate postsurgical recovery. Recurrence of such lesions is low. If chronic trauma or previous infection has occurred, adherence of the cystic capsule could increase the chance of surgical rupture of the cyst and elevate the chances of recurrence, when part of the lesion is left behind at the surgical site.

Epidermoid Cyst

Epidemiology, Etiology, and Pathology

The epidermoid cyst is considered an infundibular cyst. The infundibular region of the hair follicle represents a major interface zone of mammalian skin epithelium with the environment. A common manifestation, lesions in the head and neck region are usually related to trauma. This cause-effect relationship supports other conditions such as inclusion cysts and pillar cysts. Epidermoid cyst has a male gender predilection, mostly on areas related to razoring of the beard. These lesions are usually mislabeled sebaceous cysts, since its cystic content is mostly filled with keratin. The microscopic characteristics of epidermoid and dermoid cysts are similar, although epidermoid cysts are usually more superficial and more often related to the skin than oral mucosa. The most essential difference of the epidermoid cyst to the dermoid cyst is the hypergranular layer that is usually absent in dermoid cysts and the absence of adnexal structures in the cystic capsule.

Clinical Presentation

Epidermoid cysts manifest as well-circumscribed fluctuating nodules, resilient on palpation (Fig. 2). Due to its superficial position, secondary infection is common, also related to patients’ attempt to squeeze the lesion. In these cases, pain, hyperemia, and edema will be noted. Lesions that suffer repetitive drainage attempts also show peripheral fibrosis and inflammatory reactions to keratin and require the removal of at least part of the skin related to the lesion. Similar to the dermoid cyst, it has a particular odor related to keratin.

Fig. 2

Epidermoid cyst presenting as a soft tissue fluctuant mass in the anterior floor of mouth with no symptoms (a). MRI T1 coronal (b) and post-gadolinium coronal (c) and sagittal (d) views show a well-defined ovoid lesion within the floor of the mouth splaying the geniohyoid and genioglossus muscles and which measures 27 mm craniocaudal × 22 mm transverse × 28 mm AP (b). This is T1 hypointense, T2 mildly hyperintense, does not enhance with the administration of contrast (c + d) and does demonstrate diffusion restriction. It suppresses on fat suppression techniques

Investigations

The clinical manifestations of the epidermoid cyst are quite typical, making the presumptive diagnosis highly convergent with histopathological exam. Most cases are located subcutaneously, which makes direct access through the skin very practical. Only unusual site manifestations demand more meticulous investigations. Although less common, it is possible to reach lesions from an intraoral surgical access site. This may be required for esthetic reasons or after deep skin inclusions due to trauma. In this more complex clinical manifestation, the same methods used in dermoid cyst investigation can be applied here.

Ultrasound imaging of epidermoid cysts is similar to dermoid cysts, presenting with a well-circumscribed hypoechoic appearance. Secondary inflammation can contribute to liquid accumulation in the cystic cavity. These cases are reported to show hypoechoic mixed with round anechoic regions giving the cyst a “sack-of-marbles” appearance. Dystrophic calcifications in the keratin close to the epithelium can generate hyperechoic areas. For more complex cases, MRI and CT scans can provide more detail for surgical planning (Fig. 2).

Treatment

Cyst enucleation is the treatment of choice for epidermoid cysts (Fig. 3). During dissection of the lesion, it may rupture. If this occurs, it is important to perform a meticulous cleaning of the surgical site with saline solution to reduce the inflammatory potential of keratin, providing better immediate postsurgical recovery. Recurrence of such lesions is low. If chronic trauma, previous infection, or other changes have occurred, adherence of the cystic capsule could increase the chance of surgical rupture of the cyst and elevate the chances for recurrence.

Fig. 3

Epidermoid cyst. Clinical aspect of a fluctuating nodule on the cheek. FNAC was performed at the first visit. During the procedure, a characteristic odor was noticed (a). Microscopic findings of the FNAC revealing cornified epithelial cells without evident nuclei forming agglomerates of orthokeratin. The cytopathological diagnosis was suggestive of dermoid/epidermoid cyst (b). Surgical excision in the lip commissure was undertaken for esthetic reasons, and access to the cyst (c). During enucleation of the cyst, the cystic capsule ruptured revealing its yellow granular content (d). Sutures were placed after cleaning the surgical site with abundant irrigation with saline solution (e). Cystic cavity filled with keratin with thin epithelial lining of five to eight layers of stratified squamous epithelium with hypergranulosis and absence of epithelial projections and sudoriparous or sebaceous glands in the capsule confirming the diagnosis of epidermoid cyst (f). Differential diagnosis of the pillar inclusion cyst, revealing melanosis at the parabasal layers, areas of epithelial thickening with a marked granular layer. In this cyst, it is possible to see adnexal glands due to the proximity to the skin (g, h) (Hematoxylin and eosin stain)

Thyroglossal Duct Cyst

Epidemiology, Etiology, and Pathology

The tongue, the hyoid bone, and the thyroid and the parathyroid glands have their embryologic origin in the fusion of third, fourth, and fifth branchial arches. During the first 10–12 weeks of pregnancy, organogenesis of the thyroid and parathyroid glands begins inside the oral cavity, along with the posterior third of the developing tongue. During histodifferentiation, these glands descend through the thyroglossal duct and end their maturation over the newly formed hyoid bone. The duct has a tortuous path similar to major salivary ducts and blood vessels and is situated mostly in the para-medial region, starting on the tongue surface and ending up in the hyoid bone.

Usually, the cells of the thyroglossal duct enter apoptosis and the duct begins an involution phase. The usual anatomic vestige of its presence is the foramen cecum on the tongue. The thyroglossal cyst origins from remnant epithelial ductal cells that persist after its involution. These developmental problems can also affect the thyroid gland. In some cases, the duct involutes before completion of the gland descent, leading to ectopic positioning. The most extreme cases show the so-called lingual thyroid, when the gland, or part of it, fully develops on the tongue surface or in some part of the ductal pathway through the neck.

The lesions have a broad spectrum of age incidence, varying from congenital lesions to lesions in older patients. There is a small predilection of male-to-female incidence, according to most studies. These lesions are the most common middle neck mass (Adelchi et al. 2014). Although unusual, malignant transformation of the lesion to a thyroglossal duct carcinoma and the combination of thyroglossal duct cyst with thyroid carcinoma have been reported.

Clinical Presentation

Since the pathway of the duct is long, the lesions can appear at any part of its trajectory (Fig. 4). Most lesions present as a painless nodule located in the midline that are most visible during deglutition, with variable anteroposterior location from the base of the tongue to the hyoid bone. Intraoral lesions develop inside the muscle in the base of the tongue. In these cases, it is normal for the patient to expect symptoms such as dysphagia and dyslalia. Sometimes more than one cyst is present not necessarily close to each other. The usual presentation is a non-tender, mobile neck mass, which is painful on swallowing. Secondary infection is also possible, enhancing the painful sensation and interfering with surrounding tissues, sometimes giving the impression of a non-fluctuating mass on palpation.

Fig. 4

Thyroglossal duct cyst. Axial (a) and coronal (b) CT shows a 19 mm ovoid lesion in the position of an infrahyoid thyroglossal duct cyst (dashed orange oval)

Investigations

Most primary investigations comprise imaging procedures. Clinical access of the lesion is one of the major problems. FNAC is an option for preoperative diagnosis of thyroglossal duct cyst. Ultrasound guidance for this type of procedure prevents unsatisfactory sampling and transfixation damage of important anatomical structures, such as nerves and major blood vessels. The lesion usually has an anechoic echogenicity.

The cytomorphologic features of thyroglossal duct cyst include colloid (thick and fragmented, thin and watery, or mucinous), macrophages, lymphocytes, and predominantly neutrophils. The epithelium is ciliated columnar, metaplastic squamous, or of mature squamous type. Thyroid epithelium is rarely present. Identification of possible ectopic thyroid tissue can be also verified through scintillography.

Microscopic examination confirms cytomorphologic investigations. Cysts located adjacent to the tongue base are lined with stratified squamous epithelium, while those adjacent to the thyroid gland are lined with cells resembling the thyroidal acinar epithelium. More than half of all thyroglossal duct cyst walls contain ectopic rests of thyroid tissue. Hormonal alterations should also be investigated. Patients with ectopic thyroid tissue may have no other functional glands or present with hypofunctional problems.

Treatment

Enucleation with the Sistrunk technique is the treatment of choice for most cases. This technique dissects the region of the possible remnant of the duct and removes it along with the cyst, including part of the hyoid bone. Although this procedure reduces the chance of recurrence, due to the inconstant, irregular, and thin macroscopic appearance of the ductal remnants, recurrence is still possible.

Branchial Cleft Cyst/Lymphoepithelial Cyst

Epidemiology, Etiology, and Pathology

The branchial cleft cyst and the lymphoepithelial cyst share the same probable etiology despite different clinical locations (Figs. 5, 6, and 7). The most accepted hypothesis for their etiology is based on epithelial rests from the clefts of the branchial arches, entrapped and persistent after fusion of the branchial arches. These cysts are usually lined by pavemented squamous cell epithelium and found on the surrounding capsular connective tissue, with lymphoid structures, not always well arranged but sometimes exhibiting germinative centers and maturation zones. Another etiological hypothesis for the lymphoepithelial cyst suggests the reactive proliferation of the epithelium from the tonsillar crypts, which may enclose a cystic cavity (Fitzpatrick and Gordon 2013).

Fig. 5

Post-contrast CT showing a second branchial cleft cyst presenting as a fluid-filled lobular mass on the lateral aspect of the left neck, posterolateral to the submandibular salivary gland, lateral to the carotid space, and anterior to the sternocleidomastoid muscle (red arrows). (Images courtesy of Dr Chady Sader, Western ENT, Perth WA, Australia)

Fig. 6

Lymphoepithelial cyst at the posterior border of the tongue, presenting as a painless firm yellow nodule (a). Microscopic view of the cyst (b) revealing a deep lingual crypt that entrapped the mucosal epithelium forming a parakeratin and serofibrinous exudate-filled cavity. The epithelial lining is hyperplastic stratified pavementous squamous epithelium. The most characteristic feature of lymphoepithelial and branchial cysts is the presence of organized and disorganized foci of lymphocytic infiltrate, sometimes assuming a follicular pattern, localized close to the cystic epithelium (Hematoxylin and eosin stain)

Fig. 7

Lymphoepithelial cysts involving the floor of the mouth (a) and palatal mucosa (b)

These lesions have no gender predilection reported in most epidemiological studies. The most common of the two is the branchial cleft cyst, but both lesions are considered rare manifestations in the head and neck. Lesions are usually diagnosed in young patients, but there is a broad spectrum of age incidence, varying from congenital lesions to lesions in older patients. The branchial cleft cyst is usually diagnosed in the para-medial region of the neck and even within major salivary glands such as the parotid. Lymphoepithelial cysts are found close to intraoral areas of lymphoid tissue from the Waldeyer’s ring, which also comprise branchial cleft-derived regions. Therefore, the posterior border of the tongue and the soft palate pillars are the main intraoral sites of occurrence. These lesions can also develop inside major salivary glands such as the parotid, given it also has an ectomesenchymal origin (Luna and Pineda-Daboin 2006).

Clinical Presentation

Branchial cleft cysts are usually painless, fluctuating, flexible nodules on palpation, located in the para-medial line of the neck (Fitzpatrick and Gordon 2013) (Fig. 5). Movements of deglutition can help their detection on physical examination. The median size of these lesions varies from 1 to 3 cm. Larger lesions may give the impression of a double chin, suggesting other cysts such as the thyroglossal duct cyst or dermoid cysts. Sometimes these lesions can be associated with further defects of branchial arch fusion, such as the anatomic continuity of the cyst with a fistula or a sinus tract. In such cases, secondary infection could alter normal clinical presentation, adding pain and swelling and decreasing the lesion’s fluctuation on palpation.

Lymphoepithelial cysts are usually smaller submucosal yellowish, resilient nodules, ranging from 0.5 to 2 cm, located on the posterior border of the tongue and in the soft palate pillars (Figs. 6 and 7). Clinical differential diagnosis comprises salivary duct cysts, mucous extravasation cysts, lipomas, and dermoid cysts. Accessory lingual tonsils also have been related to lymphoepithelial cysts at the posterior border of the tongue. Usually superficial, these lesions can be easily emptied of their contents during puncture.

Investigations

Fine needle aspiration cytology is a good starting point for diagnosing branchial cleft cysts. This procedure has better results when it is performed along with ultrasound guidance. Cytopathologic smears usually comprise squamous epithelial cells, lymphocytes, and histiocytes along with keratinous eosinophilic content. The most common differential diagnoses of branchial cleft cysts are dermoid cysts and thyroglossal duct cysts. The most important differential diagnosis is cystic metastasis of a squamous cell carcinoma, which often originates from the oropharynx and is positive for HPV 16/18 and p16. Immunohistochemistry for cytokeratins may be useful to demonstrate islands of invasive squamous cell carcinoma in the wall of the cystic lesion, as well as staining for p16 and in situ hybridization for HPV 16/18, which is positive in cystic metastasis but not in branchial cyst (Zidar 2016). On ultrasound examination, the branchial cleft cyst presents as a subcutaneous hypoechoic fluctuating mass. Hypercontrast computerized tomographic images reveal a hyperdense nodule. On MRI T2, they present with an intense signal.

Oral lymphoepithelial cysts are usually easier to access and do not demand further imaging (Figs. 6 and 7). Lesions developing inside major salivary gland tissue may require ultrasound, CT, or MRI imaging.

Treatment

Both branchial cleft cysts and lymphoepithelial cysts have low recurrence rates once enucleated or excised. Treatment of branchial cleft cysts can be more complex if the cyst is in continuity with a fistula or a sinus tract.

Vascular Malformations

Epidemiology, Etiology, and Pathology

Vascular malformations comprise a set of different types of lesions all related to vascular nonneoplastic development. There are some controversial perspectives to their classification, as it is difficult to determine if the process is neoplastic or not on clinical examination alone. In fact, this group of lesions is poorly understood. The diagnosis of these lesions demands periodical follow-up prior to any intervention in order to observe progression and decide on whether the lesion is self-limiting or nonneoplastic.

Vascular malformations are appropriately named by their predominant vessel type. The International Society for the Study of Vascular Anomalies (ISSVA) convenes the official system for classification of congenital disorders of vascular development. Table 3 represents the latest ISSVA classification of vascular malformations approved at the 20th ISSVA Workshop in 2014 and subsequently revised (ISSVA Classification of Vascular Anomalies 2018).

Table 3 ISSVA classification of vascular malformations approved at the 2014 ISSVA workshop (ISSVA Classification of Vascular Anomalies 2018)

Vascular malfunctions have variable etiological factors such as genetic mutations or molecular changes related to syndromes, trauma, blood flow, and vascular wall resistance and may form part of other systemic diseases. These lesions can develop in any part of the body, and the most common intraoral sites are the tongue and lips. With a wide range of age manifestations, congenital lesions are usually labeled “birthmarks.” Intraosseous lesions are not as readily detected, usually incidentally found during other imaging procedures and routine examinations, but can cause asymmetry and even bone expansion.

This group of lesions comprises aneurysms, vascular stenosis, and tumorlike vascular lesions, such as hamartomatous proliferations. It is postulated that vascular malformations do not contain hyperplastic cells but consist of progressively enlarging aberrant and ectatic vessels composed of a particular vascular architecture such as veins, lymphatic vessels, venules, capillaries, arteries, or mixed vessel types (Buckmiller et al. 2010). These lesions can also be classified according to blood flow as either slow flow or high flow . Table 4 shows the most common vascular malformations of the head and neck region according to their blood flow pattern. Congenital vascular malformations are often visible vascular lesions known to affect 4–10% of newborn children (Friedman et al. 2013).

Table 4 Most common vascular malformations of the head and neck region according to blood flow pattern

Clinical Presentation

Clinically vascular malformations vary according to the extension of the lesion and location and neighboring tissue displacement. The so-called port-wine stain is one of the most common vascular malformations, found on the skin, in the oral mucosa, and even in the sclera (Fig. 8). They can be isolated or multiple and can be part of other systemic diseases. Sturge-Weber syndrome (SWS, encephalofacial angiomatosis, craniofacial angiomatosis, OMIM 185300) is characterized by intracranial vascular abnormality and leptomeningeal angiomatosis, usually involving the occipital and posterior parietal lobes, associated with facial cutaneous vascular malformations (port-wine stains), seizures, and glaucoma (Friedman et al. 2013) (Fig. 8).

Fig. 8

Sturge-Weber syndrome. Clinical presentation of port-wine stain affecting the head and neck, respecting the midline (a). The right sclera (b) and oral mucosa (c) also present with port-wine stain angiomatosis (white arrows)

Slow-flow vascular malformations are usually detected at birth. Venous malformations vary in color depending on depth, from normal coloration to deep purple (Fig. 9). The major differential diagnosis for these lesions is the hemangioma but differs from it due to the continuous growth to significant proportions during puberty, under hormonal influence.

Fig. 9

Vascular malformation at the apex of the tongue presenting clinically as a red patch (a). Diascopy (blanching procedure) reveals whitish appearance after compression (b). Low power magnification of venous-capillary malformation showing multiple blood vessels of variable width (c + d) (Hematoxylin and eosin stain)

High-flow vascular malformations usually appear before the third decade of life, appearing during childhood as a bluish coloration, sometimes resembling port-wine stains. Arteriovenous malformations (AVM) also commonly present at birth but commence with significant clinical changes during puberty (Figs. 10 and 11). Swelling, pain, and bleeding are the most reported events. The lesion is not fluctuant on palpation; sometimes the affected area becomes thickened and even pulsatile. Combined lesions with capillary, venous, and lymphatic vessels behave as high flow due to arterial supply. Lesions should be distinguished from those of conditions such as hereditary hemorrhagic telangiectasia (Fig. 12).

Fig. 10

Arteriovenous malformation involving right dorsal and lateral tongue in an elderly female

Fig. 11

High-flow arteriovenous malformation. The patient presents with a pinkish non-fluctuating nodule extending from the midline of the lower lip to the left labial commissure (a + b). The mucosal aspect of the lesion (c) and clinical compression exam (d) reveals the pulsating behavior of the lesion indicating its flow pattern. MRA exam reveals the arterial origin from the facial artery and the appearance of an arteriovenous fistula forming a plexiform arrangement with dilated vessels and the effluent mental vein (e–g). Microscopic aspect of the arteriovenous malformation (h), revealing the close relationship of arteries with thick walls and narrow lumen, and veins with dilated blood-filled lumen and thin vascular walls. The lesion infiltrates the surrounding tissue. In this specimen, adipose tissue is seen with striated skeletal muscle as well as neural fibers in the original connective tissue from the affected area (Hematoxylin and eosin stain)

Fig. 12

Patient with hereditary hemorrhagic telangiectasia presenting with multiple red colored lesions on the oral mucosa (a) and skin (b). (Images courtesy of Dr Sue-Ching Yeoh, Sydney Oral Medicine, Sydney NSW, Australia)

Investigations

The correct diagnosis of vascular malformations has an important role in appropriate treatment planning. The choice of a surgical removal, vascular sclerosis, embolization, or immunotherapy is linked to the classification of the lesion, if they can present with similar clinical features. Investigations commence with imaging, but microscopic evaluation provides the best impression of the vascular alterations present in the lesion. Sometimes biopsy procedures represent a high risk for the patient, so whenever microscopic evaluation is possible, correct characterization of the lesion is essential.

Hypercontrast CT examination along with MRI is the best imaging tool for the diagnosis and treatment planning of vascular malformations. Venous malformations have a propensity to occur in muscle groups but can also involve skin and mucosa. Areas frequently involved in the head and neck are masseter, temporalis, tongue musculature, and oral and airway mucosa. MRI remains the diagnostic modality of choice to assess the extent and plan treatment for these lesions. Regarding high-flow lesions such as AVM, MRI with T2-weighted processing will typically reveal a hyperintense, irregular lesion with numerous flow voids. A magnetic resonance arteriogram (MRA) and a computed tomography arteriogram (CTA) can give excellent images of the AVM (Ziyeh et al. 2005) (Figs. 11 and 13).

Fig. 13

Orthopantomogram showing deformity of the anterior right mandible demonstrating asymmetry and expansion of the inferior border (a). Maximum intensity projection (b) and 3D CT angiography (c) of same patient show feeding vessels to the right mandible and demonstrate arteriovenous malformation

Microscopic features such as the presence of arteries or arterioles as an integral part of the lesion are determined not only by morphology of the blood vessel but also by identification of specific structures with the aid of specific stains such as elastic tissue stains (Figs. 9 and 11). Further differences can be evaluated through immunohistochemical examination such as S-100, to study the various tissue components present in these lesions. The first important differential diagnosis is to determine whether the lesion is a hemangioma or vascular malformation. Nerve bundles are consistently present in vascular malformations and absent in hemangiomas, serving as a diagnostic clue to differentiate between the lesions and also confirming the hamartomatous nature of these lesions (Adegboyega and Qiu 2005).

Investigation of a series of genetic mutations is essential to diagnose syndromic conditions and other systemic diseases. Simple and combined vascular malformations may have altered genetic expression. Table 5 shows the known causal gene mutations correlated with various vascular malfunctions according to 2014 ISSVA classification.

Table 5 Known causal gene mutations correlated with the different conditions according to 2014 ISSVA classification (ISSVA Classification of Vascular Anomalies 2018)

Intraosseous vascular malformations can present variable imaging patterns. Lesions can present with poorly defined borders or a well-circumscribed halo, ranging from unilocular to multilocular and from unicystic bubble-shaped formations to a honeycomb appearance (Fig. 13). Bone expansion can also produce subperiosteal ossification assuming patterns resembling malignancies or reactive lesions. Differential diagnosis includes odontogenic cysts or tumors. It is difficult to establish immediate correlation of the lesion with the major vessels of the affected region. If the patient does not show asymmetry, pain, or bone expansion, it is extremely uncommon for the clinician to consider vascular malformations as a differential diagnosis.

Treatment

Multiple treatment options exist for vascular malformations, including conservative measures such as head-of-bed elevation and compression for venous malformations, laser therapy, sclerotherapy, embolization, and surgery. Decisions regarding which treatment course to follow vary widely with various specialties and institutions. Because of the wide variety of management options and patient presentations, it is strongly recommended that patients with vascular malformations undergo treatment at a multidisciplinary center for treating vascular anomalies (Buckmiller et al. 2010). Treatment effectiveness of vascular malformations and its prognosis is linked with the correct diagnosis of the lesion.

Conservative measures are only effective for venous malformations. These vascular malformations have a tendency to expand instead of proliferate; the resistance of the vascular wall and blood pressure in the area are the main causes of this undesirable development. Therefore, head-of-bed elevation is an important measure to prevent increase of local blood pressure while the patient is in bed. Compression is a good adjunctive conservative measure, effective in body extremities such as limbs, with aids of compressive sleeves, socks, and gloves, but not readily amenable in the head and neck region.

Systemic diseases such as syndromes will present with specific alterations that call for professional management. In cases of Sturge-Weber syndrome, for instance, gingival overgrowth, periodontal disease, and dental extractions will require patient hospitalization prior to performing these procedures. Blood loss control during these procedures is better achieved with aids of a 1.064 nm 10 W Nd:YAG laser, which allows deeper coagulation compared to 10,600 nm wavelength CO₂ laser (Bradley 1997). Electrocautery, presurgical embolization, and splinting of the region are also widely applied in these situations, but reported complications such as postoperative bleeding, infection, and scar formation are more frequent.

Laser therapy is the treatment modality most widely applied for vascular malformations, promoting thermocoagulation. Capillary malformations present good esthetic results with lasers, while superficial venous malformations have better results than deep and infiltrative lesions. Pulsed dye lasers ranging from 580 to 575 nm CO₂ lasers and Nd:YAG laser tunable to 1064 nm applying 30–70 W/cm² per session combined with simultaneous cooling offer good treatment outcomes (Zheng et al. 2010). Arteriovenous malformations are the exception for this treatment modality as these cases demand embolotherapy combined with surgical excision.

A recent systematic review of the literature has identified the most common sclerozing agents used for treating vascular malfunctions and evaluated their performance (Horbach et al. 2016). Table 6 summarizes the most common sclerozing agents along with their complication rates and effectiveness rates. The complications related to the use of these substances can be systemic or at the site of application including hemoglobinuria, infection, nausea, swelling, pain, ulceration, necrosis, and cellulitis.

Table 6 Most common sclerozing agents along with complication and effectiveness rates based on Horbach et al. (2016)

Surgical excision offers the best chance for cure of vascular malformations. Excision of extensive lesions remains a challenge, as these lesions are rarely well defined and intraoperative bleeding can make identification and preservation of important structures difficult. Preoperative sclerotherapy can be beneficial not only to decrease bleeding, which improves visibility and eases dissection, but also to decrease blood loss and operative time (Buckmiller et al. 2010). High-flow lesions demand MRA or CTA prior to the procedure, as well as adjunctive embolization. Regardless of approach, attention must be made to eradicate the nidus. If the nidus is left untreated, recruitment and collateralization of new vessels, along with early recurrence, are common (Friedman et al. 2013).

Embolization is usually achieved with cyanoacrylate, onyx, or absolute alcohol injection. Just like in sclerotherapy, alcohol is more often associated with complications such as nerve paralysis, significant swelling, necrosis, ulceration, scaring, and even cardiovascular collapse. Onyx is also very expensive and requires increased fluoroscopy time. Arteriovenous malformations usually recur, and treatment of very extensive lesions is always life-threatening. In bony lesions, the result of embolization is confirmed with new bone formation inside radiolucent spaces during imaging follow-up.

Lymphangioma Including Cystic Hygroma

Epidemiology, Etiology, and Pathology

Lymphangiomas are uncommon, benign, hamartomatous proliferation of lymphatic vessels. Given the benign nature of these anomalies and their wide-ranging manifestations, the preferred all-encompassing term is lymphatic malformations (LM), also applied by the ISSVA. Traditionally, vascular malformations involving the lymphatic vessels were known by a variety of terms including cystic hygroma, lymphangioma, and hemolymphangioma (Fig. 14) (Wall et al. 2016). They can potentially develop in any part of the body, and most of the lesions are identified during childhood.

Fig. 14

Facial asymmetry caused by lymphangiomas (a + b). Note the difference of a microcytic lymphangioma in (a) with more diffuse asymmetry and a macrocystic/cystic hygroma with more localized appearance (b)

Usually lesions consist of collections of ectatic lymph vessels that form endothelial lined cystic spaces, classified as macrocystic (single or multiple cysts >2 cm³), microcystic (single or multiple cysts >2 cm³), or mixed (Friedman et al. 2013). They can also be classified as simple, cavernous, or cystic, according to the diameter and number of lymphatic vessels in the lesion.

The etiology of these lesions is still an area of constant investigation. Lymphangiogenic growth factors (such as VEGF-C and transcription factor Prox-1) have been reported to be involved in the process through upregulation of VEGFR-3 (Itakura et al. 2009; Pavlov et al. 2009).

Clinical Presentation

Small individual intraoral lymphangiomas are difficult to differentiate from mucoceles and ranulas (de Carvalho et al. 2015). Oral lymphangiomas are usually superficial lesions formed by a cluster of transparent vesicles resembling the appearance of tapioca pudding or frog eggs (Fig. 15). These lesions show slow growth, normal to red-purple coloration, and size varying from 1 to 5 cm in diameter. Differential diagnoses include hemangiomas, dermoid cysts, thyroglossal duct cysts, angiogranulomas, and granular cell tumors . Diagnosis is usually made in childhood, and if not obvious from birth, it may become apparent with infections such as upper respiratory infection or otitis media, which can cause swelling of the malformation caused by increased lymph flow. Lesions typically grow slowly but may rapidly swell with infections or with hormonal changes such as puberty (Buckmiller et al. 2010).

Fig. 15

Intraoral view of a microcystic lymphangioma showing multiple vesicles

On palpation, lesions usually feel fluid filled and are non-compressible, which can help in distinguishing them from venous malformations. Mucosal and skin surfaces can be affected with vesicle formation, which represents small external fluid-filled cysts. Vesicle formation causes problems with bleeding, weeping of lymph fluid, and pain. Microcystic lymphatic malformations present as soft non-compressible masses with an overlying ill-defined area of clear, yellow, or red (secondary to intracystic bleeding) vesicles. The external component of these lesions continues to involve an increased amount of area with age.

Large lymphatic malformations involving the head and neck identified in utero have the potential to create airway obstruction upon delivery. The morbidity of such cases is usually related to the size and location of the lesions; therefore it is important to assess the extent of the lesion. In patients with more diffuse lesions, the airway must be examined. Macrocystic lymphatic malformations present as a lump beneath normal or slightly bluish skin. These are soft but not compressible (Fig. 14). The mass can undergo sudden enlargement secondary to intracystic bleeding or infection. When affecting the tongue, large lesions may cause airway obstruction and impair feeding and speech. Over time, cystic lymphatic lesions can develop bleeding, infection, and cutaneous vesicles. Recurrent infections and chronic wounds are common with superficial lesions.

Secondary bony overgrowth can cause craniofacial disfigurement. These can be asymptomatic or lead to pathologic fractures. When lymphatic malformations involve the cervicofacial skeleton or the surrounding soft tissues, they can lead to osseous hypertrophy resulting in maxillary or mandibular deformities, malocclusion, or open bite (Friedman et al. 2013).

Investigations

Lymphatic malformations are frequently diagnosed on prenatal ultrasound and may require special preparations for delivery if perinatal airway compromise is suspected. The best imaging modalities for lymphatic malformations are ultrasonography, MRI, and contrast lymphography. Ultrasound is valuable in differentiating lymphatic malformations from other vascular lesions that contain blood flow (e.g., hemangioma). Ultrasound is further able to characterize the size and extent of superficially localized lesions.

MRI remains the visualization method of choice for delineating the extent of the malformation, planning intervention, predicting outcome (macrocystic vs microcystic), and verifying diagnosis. MRI offers an additional advantage of axial imaging that can further identify the extent of large diffuse lesions and highlight the precise relationship between malformations and adjacent anatomical structures (Wall et al. 2016). For the fetus whose airway may be in jeopardy, it is important to try to differentiate, by prenatal MRI, between the soft and usually non-compressive lymphatic malformation from the firm and often airway compressing teratoma (Steigman et al. 2009).

If these lesions are biopsied, they show numerous vascular spaces with thin endothelial walls sometimes filled with plasma/lymph amorphous eosinophilic material (Fig. 16).

Fig. 16

Cavernous microcystic lymphangioma of the oral submucosa. Numerous vascular spaces with thin endothelial walls (a), sometimes filled with plasma/lymph amorphous eosinophilic material (b) (Hematoxylin and eosin stain)

Treatment

There are sporadic reports of spontaneous resolution of a small percentage of lymphatic malformations, although this is quite rare (Buckmiller et al. 2010). It has been proposed that the lesions that are most likely to resolve are small, macrocystic, and within the posterior triangle of the neck. Infected and inflamed lesions can show some regression after antibiotics and anti-inflammatory therapy with corticosteroids (Friedman et al. 2013).

Indications for definitive treatment of lymphatic malformations include esthetic considerations and functional compromise. Treatments include surgery, sclerotherapy, and laser therapy. Often, a combination of therapies is utilized. The timing of treatment depends on several variables including extent of functional deficit and cosmetic deformity as well as the possible negative impact of progression of the lesion. Life-threatening lymphatic malformations require early intervention (Friedman et al. 2013).

The preferred approach to sclerotherapy utilizes ultrasound guidance with cyst aspiration followed by injection of a sclerozing agent. Ethanol and sotradecol have traditionally been used to treat lymphatic malformations with good results preferentially in macrocystic lesions. Multiple treatment sessions may be required, and there are sometimes weight-limited dose concerns with these toxic agents in small children. Complications can include skin breakdown, prolonged swelling, pain, and airway compromise. Lymphatic malformations tend to recur and can do so several years after reporting a cure with sclerotherapy, so the literature must be analyzed carefully. Other sclerosants have been reported in an attempt to find an effective treatment while maximizing safety. These include doxycycline, OK-432, and bleomycin. Concerns still remain regarding complications with each treatment. Doxycycline can cause neural damage, OK-432 can be associated with sepsis, shock, myalgia, and bleomycin still carries a warning of pulmonary fibrosis, although this is related to total lifetime dose and doses received for treatment of lymphatic malformation usually do not approach that level. All of these sclerozants can still cause severe swelling with airway compromise, skin breakdown, and other toxic side effects. It must be emphasized that treatment outcomes are based on multiple treatments, sometimes in excess of five to ten treatments, and long-term follow-up data is lacking (Buckmiller et al. 2010).

Surgery is important not only for removing and hopefully eliminating the malformation but also for correcting the secondary deformities caused by the malformation. Surgical resection is typically required for the treatment of microcystic lesions. These lesions can encase major structures, and great care must be taken to avoid significant vascular and nerve damage. It is often stated that large microcystic lesions in the neck can be the most challenging benign lesions to safely resect. Some lesions can be well vascularized and transfusion may be required. Recurrence is reported from 15% to 50% after surgical resection. Recurrence is associated with incomplete resection, which is often due to the need to preserve critical structures that the cyst is adherent to, such as nerve tissue. Resection and particularly recurrences are associated with fat hypertrophy possibly due to excess lymph fluid and leaking that exits post resection (Wall et al. 2016).

Benign Tumors of the Head and Neck

Benign neoplastic proliferations of soft tissues of the head and neck are slow-growing masses, usually painless, that promote asymmetry. Although most benign soft tissue tumors are asymptomatic and present in the form of a painless nodule or mass, schwannomas and neurofibromas may be tender and painful. Some of these lesions can also form characteristic parts of syndromes. With few exceptions, benign soft tissue tumors are diseases of young and middle-aged adults. Most of these lesions are considered uncommon findings in clinical practice but represent one of the most common benign neoplasms diagnosed in oral and maxillofacial pathology services.

The average size of benign soft tissue tumors at a superficial location is seldom more than 2 cm. Deep tumors, however, may grow to several inches before being detected. Most small and superficial benign soft tissue tumors are diagnosed after surgical excision. Complete excision of such tumors should be considered diagnostic as well as therapeutic. These lesions can be well circumscribed by a fibrous capsule or present an infiltrative pattern demanding careful dissection from the surrounding structures in order to prevent unnecessary surgical sequelae.

Fibroma/Traumatic Fibroma

Epidemiology, Etiology, and Pathology

Fibroma is the most frequent soft tissue tumor of the oral cavity (Castellanos and Diaz-Guzman 2008). These lesions are characterized by collagen rich, hypovascularized connective tissue, lined by the oral mucosa. The true neoplastic nature of these lesions has always been questioned, since it can also be a reactive excess of collagen deposition by an inflammatory process, caused by chronic trauma or irritation (traumatic fibroma/fibroepithelial polyp). Low mitotic activity of the fibroblasts is also a characteristic of these lesions. The presence of inflammation is minimal except in scattered submucosal areas. It has a 2:1 male-to-female gender predilection and can appear at any part of the oral mucosa, although most lesions are found in the vestibular mucosa or areas related to masticatory function. Although fibromas can occur at any time of life, patients usually notice these tissue growths during the fourth to sixth decades.

The main difference of a fibroma from a traumatic fibroma and fibroepithelial polyp is the cause-effect clinical correlation and the intensity of the inflammatory process. While traumatic fibromas and fibroepithelial polyps exhibit areas of intense chronic inflammation, even ulcerated mucosa and epithelial hyperplasia, fibromas appear more mature and almost free from inflammation. In addition, a mature angiogranuloma is microscopically indistinguishable from a fibroma.

Clinical Presentation

These present as sessile or pedunculated, normal colored, soft-to-tender nodules, with slow progression (Fig. 17). Lesions can present with hyperkeratinization appearing white if local irritation is present. Fibromas are small lesions, with an average size of 7–8 mm, but can be larger (1–2 cm). Traumatic fibromas and fibroepithelial polyps can progress to more extensive lesions, mostly when related to old, ill-fitting complete prosthesis (Figs. 18 and 19) (van der Waal 2016).

Fig. 17

Fibroma/traumatic fibroma presenting as a pedunculated, normal colored, soft nodule, with slow progression. In this case, there is hyperkeratinization appearing as white patches at the inferior aspect of the nodule due to local irritation (a). Cause-effect relationship of a traumatic fibroma, with the patient reporting frequent incidental biting since beginning orthodontic treatment (b)

Fig. 18

Large traumatic fibromas caused by overworn upper complete denture in the vestibular sulcus

Fig. 19

Leaflike traumatic fibroma related to overworn, uncleaned, complete upper denture

Investigations

Microscopic investigations of this lesion show large areas of atrophic squamous cell epithelium almost without any projections into the underlying connective tissue. The connective tissue is collagenized with fibroblasts that can be fusiform, elongated, round or oval, and sometimes stellate shaped (Fig. 20) (Villa et al. 2016). Chronically inflamed areas are more likely to show epithelial hyperplasia, with typical features of acanthosis, hydropic degeneration, and pseudoepitheliomatous hyperplasia (Fig. 21).

Fig. 20

Collagen rich, hypovascularized connective tissue, lined by thin oral mucosa, without epithelial projections and without a significant inflammatory process (Hematoxylin and eosin stain)

Fig. 21

Chronically inflamed areas of traumatic fibroma (a) and fibroepithelial polyp (b) show epithelial hyperplasia, with typical features of acanthosis, hydropic degeneration, and pseudoepitheliomatous hyperplasia. The connective tissue presents with an intense diffusely spread lymphocytic exudate (Hematoxylin and eosin stain)

Treatment

Conservative surgical excision is the treatment of choice for these lesions. Recurrence is low if no further irritation or trauma persists in the affected region. Lesions related to prostheses require new, perfectly fitting replacements. Prosthetic hygiene is also necessary, so the clinician should educate and train the patient on how to take good care of prostheses.

Myofibroma

Epidemiology, Etiology, and Pathology

Myofibroma is a rare benign mesenchymal tumor mostly found in the head and neck region and characterized by the proliferation of fibroblasts, myofibroblasts, or both. Sometimes it manifests as a multifocal lesion called myofibromatosis. Myofibromatosis affects infants and young adults almost exclusively and is known as infantile myofibroma. There are various types of fibroblastic/myofibroblastic lesions, with different behaviors presenting as benign, intermediate with malignant potential, or malignant lesions. Myofibroma is part of the spectrum of these lesions that may also include nasopharyngeal angiofibroma, fibrosarcoma, nodular fasciitis, fibromyxoma, and fibrous hamartoma.

Clinical Presentation

Clinically, myofibromas present as single or multiple, hard, reddish-purple nodules in the skin, muscles, bones, viscera, or central nervous system (Fig. 22). Localized fibromatosis is the most common presentation, seen mainly in the soft tissues of the head and neck. Infantile fibromatosis should be included in the differential diagnosis of multiple bony, soft tissue, and central nervous system lesions in a child, along with Langerhans cell histiocytosis, multiple metastases from neuroblastoma, or sarcomas. Definitive diagnosis is established by means of biopsy (Hourani et al. 2015). Ulceration is a tumor characteristic that may be suggestive of a more aggressive biologic potential and should increase the clinician’s suspicion for malignancy. Microscopic evaluation of the lesion with appropriate use of immunohistochemical stains can provide the correct diagnosis.

Fig. 22

Myofibroma. Rapid growing solitary lesion involving the left mandible (a). Lytic expansile pattern of growth in the posterior mandible noted on CT reconstruction (b + c). Proliferation of fusiform cells arranged in interlaced bundles (d) and fascicles (e) (Hematoxylin and eosin stain)

Investigations

The most appropriate imaging exam to identify myofibromas is MRI, which reveals an ill-defined soft tissue mass best viewed with post-contrast enhancement on T1 scans with fat suppression. Computerized tomographic scanning of lesions involving bone structures reveals an expansive lytic behavior sometimes resembling malignancy but also mimicking odontogenic tumors such as myxoma and ameloblastoma (Fig. 22) (Nabavizadeh et al. 2017). On ultrasound, myofibroma presents as a hyperechoic mass with an anechoic or hypoechoic center traversed by thick septa and surrounded by a thick hypoechoic rim with rare flow on power Doppler (Koujok et al. 2005).

The histopathological examination of myofibroma usually reveals biphasic plexiform paucicellular regions and spindle cell and vascular regions (Fig. 22). Immunohistochemical panels show positive marking for muscle markers such as SMA, muscle-specific actin , HHF35, and vimentin and negativity to neural markers such as CD56, GFAP, and S100.

Treatment

Solitary lesions are amenable to conservative surgical resection. In the generalized form, lesions often regress spontaneously over 6–18 months. In multicentric life-threatening forms, chemotherapy with vinblastine and methotrexate promotes tumor regression (Hourani et al. 2015).

Lipoma

Epidemiology, Etiology, and Pathology

Lipomas are characterized by well-circumscribed benign neoplastic proliferations of adipose tissue and are usually found as long-standing soft nodular asymptomatic swellings covered by normal mucosa or skin. The size of the lesions does not follow the adipose tissue variation, increasing even when patients go through weight loss. Lipomas are more common in men and are one of the most frequent benign mesenchymal tumors, with 15–20% of them seen in the head and neck (Harnsberger and Osborn 2006; Harnsberger et al. 2006). There is a bimodal peak of presentation in children and during the fifth/sixth decades of life, often seen in overweight individuals. Intraoral lesions on the other hand are less frequent than lesions of the head and neck, representing only 1–4% of these tumors. These represent 0.1–5% of all benign tumors of the oral cavity (Fregnani et al. 2003). Lesions can be solitary manifestations or multiple. Patients with multiple lesions in the body should be investigated for syndromes and rare obesity disorders. A retrospective study of 46 cases of lipomas of the oral cavity found the mean age of patients was 52 years, ranging from 8 to 80 years, with 57.8% of female prevalence. The most common site was the buccal mucosa (45.7%), followed by the tongue and lips (13% each) and floor of the mouth (10.9%) (Fregnani et al. 2003). The size of lesions varied from 0.3 to 5 cm, with an average of 2 cm.

Clinical Presentation

Head and neck lipomas are usually found in the posterior neck subcutaneous tissue and in the scalp (Fig. 23). Lesions have soft-to-tender consistency on palpation and present mostly as a loose mobile fluctuating nodule with normal skin coloration.

Fig. 23

Axial T1 MRI showing 23 mm lipoma superficial to the right zygomatic arch and the adjacent superior portion of the masseter muscle, immediately deep to the superficial muscular aponeurotic system (SMAS) and temporalis fascia and closely related to the superficial parotid tissue and the zygomaticus major muscle

Oral cavity lipomas are slowly enlarging, with a soft, smooth surface mass of submucosal tissues. When superficial, there is a yellow surface coloration. Lesions may be pedunculated or sessile, and occasional cases show surface bosselation (Figs. 24, 25, and 26). Puncture of these lesions for FNAC reveals a wet, shiny, transparent or hyaline, gelatinous material. When fixation solution is sprayed over the surface of the slide, it forms a small goticular pattern (Fig. 27).

Fig. 24

Lipoma. Patient presenting with extraoral asymmetry involving the left lower lip (a). On palpation, a soft well-circumscribed fluctuating nodule was noticed (b). FNAC was performed at the first visit (c), which showed material with a wet appearance with formation of lobules after fixation spay was applied. The surgical presentation of the dissected lesion, with a thin fibrous capsule and yellow coloration (d)

Fig. 25

Lipoma. A small lesion on the posterior border of the tongue that resembles a lymphoepithelial cyst. These lesions float when placed in formalin solution

Fig. 26

Lipoma in the floor of the mouth (a) appearing as a yellow colored mass under the mucosal surface. Lump was completely excised (b)

Fig. 27

Microscopic features of FNAC cytologic smear from a lipoma. Hematoxylin and eosin stain (a), Papanicolaou stain (b), and Sudan red stain (c). A globular pattern of the adipocytes is noted, not all of which show preservation of the cytoplasmic membrane. The fat lobules are best visualized with Sudan red stain

Although lipomas are well circumscribed, intramuscular lesions require careful dissection and reconstitution of the muscular plane after surgical removal. Grossly, lipomas are of variable size. They tend to appear as smooth or lobulated, often well demarcated or encapsulated, with a yellow color. One distinctive behavior of lipomas is that they float when immersed in formalin solution.

The main differential diagnosis of lipoma includes fibroma, which is composed of fibrous tissue and is much more firm than lipoma. Other differential diagnoses include tumors such as granular cell tumor, liposarcoma, neurofibroma, tumor pleomorphic adenoma, traumatic fibroma, mucocele, and other salivary gland tumors (Fig. 28). Histopathological examination is therefore essential for diagnostic conclusion in cases of lipoma.

Fig. 28

Lump in the buccal sulcus suggestive of a lipoma but proven histopathologically to be a salivary plasmacytoid myoepithelioma

Investigations

Lipomas demonstrate characteristic low attenuation on CT and signal intensity similar to that of fat on all MRI sequences with minimal internal architecture and mass effect with displacement of the surrounding structures (Fig. 23). The margins may not be easily distinguishable from normal fat. There is no contrast enhancement on CT examinations (Nagornaya and Bhatia 2013).

Three different microscopic variations of lipomas are noted including typical lipomas, fibrolipomas, and spindle cell lipomas. Typical lipomas are by far the most common feature, exhibiting a delicate connective tissue capsule circumscribing lobules of hexagonal cells with transparent cytoplasm, with peripherally placed nucleus, resembling normal adipose tissue (Fig. 29). Larger lesions show connective tissue vascularized septa. Fibrolipomas are similar to lipomas by gross examination but microscopically present proportional amounts of connective tissue mixed with agglomerates of adipocytes, mature adipose tissue interspersed by broad bands, or fascicles of dense connective tissue; the capsule is less evident than typical lipomas or even absent. The histologic features of spindle cell lipoma comprise spindle cells, mature adipose tissue, collagen bundles, and myxoid interstitial matrix. Histochemical and immunohistochemical study of the lesion highlights numerous mast cells and immunohistochemical expression of CD34 and vimentin in the spindle cells (Fregnani et al. 2003).

Fig. 29

Microscopic characteristics of lipoma. In (a) the lesion was dissected and a thin fibrous capsule circumscribes the well-organized adipose tissue, with loose connective tissue forming bands through the lesion. If the amount of adipose tissue and connective tissue is similar, the lesion is termed a fibrolipoma. In (b), the lipoma was submucosal and was excised along with the surrounding tissue. There is still a thin fibrous capsule circumscribing the adipose tissue from the mucosal epithelium (Hematoxylin and eosin stain)

Other microscopic features described in the literature include angiolipomas where there is a well-vascularized lesion, pleomorphic lipomas when the lesion presents pleomorphic lipoblasts and adipocytes, intramuscular/infiltrating lipomas, and salivary gland lipomas according to the site of lipomatous proliferation.

Fine needle aspiration cytopathologic smears are good investigative tools for treatment planning, and when the clinical suspicion of lipoma is present, enough smears should be obtained to perform hematoxylin and eosin or Papanicolau and Sudan red stains (Fig. 27).

Several syndromes include lipomas or lipomatosis as their most significant features including Bannayan-Riley-Ruvalcaba syndrome, multiple symmetric lipomatosis, encephalocraniocutaneous lipomatosis, Proteus syndrome, Cowden syndrome, phosphatase and tensin homolog, and familial partial lipodystrophy type 2 (Fregnani et al. 2003).

Treatment

Surgical excision is the main treatment for lipoma, and recurrence is not likely to occur. For large and difficult-to-access lesions, it is of paramount importance to perform adequate imaging, diagnostic biopsy, and careful assessment before surgery is planned.

Neuroma Including Multiple Endocrine Neoplasia Type 2B (MEN2B)

Epidemiology, Etiology, and Pathology

Neuroma is an abnormal proliferation of hyperplastic axons well delimited by fibrous perineurium. Different pathologic entities use the term neuroma, such as traumatic/amputation neuroma, encapsulated palisaded (solitary circumscribed) neuroma, and mucosal neuroma in multiple endocrine neoplasia type 2B (MEN 2B).

A traumatic neuroma (Fig. 30) is a hyperplastic lesion caused by trauma or surgery that involves the peripheral nerves and is not considered to be a true neoplasm. Traumatic neuromas, also called amputation neuromas, are reactive proliferations of neural tissue that occur after transection or damage to a nerve bundle. These lesions can start after any surgical treatment, such as procedures that need tissue dissection such as biopsy, after tooth extraction, due to local chronic masticatory trauma caused by a total prosthesis to the mental nerve of patients with advanced stage alveolar ridge resorption. The most common sites for a traumatic neuroma in the head and neck are the inferior alveolar nerve, lingual nerve, and great auricular nerve.

Fig. 30

Traumatic neuroma. Clinical features of a traumatic neuroma after laceration of the right upper lip which healed without professional intervention, causing asymmetry and esthetic concern for the patient (a). Microscopically there is mild chronic inflammation (b), accentuated fibrosis, and disorganized axons with fibrous perineurium (c) (Hematoxylin and eosin stain)

Neuroma was first described by Reed et al. in 1972 as a palisaded, encapsulated, solitary, benign cutaneous tumor. It was classified as a primary hyperplasia of nerve fibers (axons and their sheath cells) with equal frequency in both sexes and limited anatomic distribution to areas bordering mucocutaneous junctions, predominantly on the face, with rare exceptions (Reed et al. 1972). The alternate designation solitary circumscribed neuroma was proposed based on the fact that most lesions were not fully encapsulated and showed only focal palisading (Fletcher 1989). A review of 55 cases of palisaded encapsulated neuromas found that tumors were located on the palate (31), maxillary or palatal gingiva (8) (including one example on an edentulous maxillary alveolar ridge), tongue (4), mandibular gingiva (3), upper lip vermillion border (3), mucosal part of the lower lip (3), lower lip vermillion border (2), and buccal mucosa (1). Patient age ranged from 20 to 73 years, with 70.3% being men and 29.7% women (Koutlas and Scheithauer 2010).

Multiple endocrine neoplasia type 2 is a syndrome of inherited susceptibility to tumors of endocrine cell types including the thyroid “C” cells, the adrenal medulla, and the parathyroid glands. In some disease subtypes, developmental abnormalities may also be present. MEN2 is caused by inherited mutations of the gene that encodes the RET receptor tyrosine kinase which leads to its unregulated activation and is transmitted in an autosomal dominant fashion. Subtypes of MEN2 are MEN2A, MEN2B, and FMTC (familial medullary thyroid carcinoma) (Castinetti et al. 2018). Because of its low point prevalence (0.9–1.65 per million) and incidence (1.4–2.6 per million live births per year), MEN2B (OMIM #162300) remains poorly described in the literature.

Clinical Presentation

Traumatic neuromas present clinically as nodules or masses, less than 2 cm in diameter that can be related to altered sensation on palpation, such as local pain, numbness, or shock (Fig. 30). The mucosa will present normal coloration. Sometimes patients do not remember the cause of trauma, for instance, lesions on the anterior border of the tongue are very common due to masticatory accidental biting. Long-lasting lesions do not show any sign of inflammation. Sometimes reactive fibrous hyperplasia or vascular malformations can be associated with the lesion. Lesions are not well circumscribed or encapsulated, so if the damaged nerve bundle is not visible during the biopsy procedure, it can be difficult to determine the exact extension of the lesion. Differential diagnosis comprises traumatic fibromas, granular cell tumor, schwannoma, and neurofibroma.

Clinically palisaded encapsulated neuromas (Fig. 31) are usually small, rarely ulcerated nodules, the size of which never exceeds 1.0 cm in greatest dimension. Lesion duration can vary from months up to 20 years, but asymptomatic lesion may be reported by the patient as unknown duration. Symptoms are unusual findings, but some patients report pain upon “drinking hot beverages” or “after irritation” (Koutlas and Scheithauer 2010).

Fig. 31

Palisaded encapsulated neuroma. Firm pedunculated nodule on the anterior border of the tongue (a). Nodular arrangement of well-circumscribed neural tissue of the palisaded encapsulated neuroma (b). Interlaced fascicles of fusiform Schwann cells with elongated prominent nuclei, in an oriented formation (c). Higher magnification showing wavy fusiform nuclei (d) (Hematoxylin and eosin stain)

MEN2B has a characteristic phenotype with medullary thyroid carcinoma (MTC) and pheochromocytoma. The face may have a wide-eyed expression with thickening and eversion of the upper eyelid margins and visible tarsal plates. Neuromas may be present on the eyelids and conjunctiva, and prominent thickened corneal nerves that extend to the pupillary area may be seen on slit lamp examination. The eyebrows are large and prominent. The face is elongated with prominent “blubbery” lips, and submucosal nodules present on the vermilion border, often laterally. Oral manifestations, which are often the first clue to the syndrome in infancy or early childhood, include mucosal neuromas on the anterior dorsal surface of the tongue. Mucosal neuromas of the tongue are almost pathognomonic in the presence of medullary thyroid carcinoma. Other oral features include palatal and pharyngeal neuromas, a high-arched palate, and a prominent jaw (Morrison and Nevin 1996). MEN2A accounts for about 75% of all MEN2 cases and expresses MTC, pheochromocytoma, and parathyroid gland hyperplasia. FMTC is another variant which accounts for about 20% of MEN2 cases and has a particularly benign course of MTC and a low incidence of other clinical manifestations. MEN2B accounts for only 5% of MEN2 cases; however, its clinical course is the most aggressive. The American Thyroid Association has recommended preventive thyroidectomy before the age of 1 in cases of MEN2B. Patients with MEN2B usually present with very early-onset MTC, a 50% lifetime risk of pheochromocytoma, and universal extra-endocrine features, mainly bowel problems due to diffuse intestinal ganglioneuromatosis (constipation, feeding difficulties in infancy, megacolon) and alacrima, both of which can be the earliest presenting features, in addition to mucosal neuromas and a marfanoid body habitus, both of which may not become clinically apparent until several years of age (Castinetti et al. 2018).

Investigations

Microscopic differential diagnosis of the different types of neuromas includes other benign neurogenic tumors such as schwannoma and neurofibroma. Key points of morphologic observations include perineural encapsulation, presence of mast cells, pattern of Schwann cell proliferation, presence of Verocay bodies, axons, and stromal arrangement (Figs. 30, 31, and 32). Inflammation has been mentioned as an important morphologic feature for diagnosis of traumatic neuromas, but long-lasting traumatic neuromas can present with almost an absence of inflammatory cells. Palisaded encapsulated neuromas, mucosal MEN2B neuromas, as well as other benign neurogenic tumors can also present with secondary inflammation caused by secondary trauma or infection (Woodruff 1993; Koutlas and Scheithauer 2010; Lee et al. 2017). Table 7 compares the most important features in the differential diagnosis of neuromas.

Fig. 32

MEN 2B neuroma showing abnormal hyperplastic axons well delimited by fibrous perineurium, without inflammation or cause-effect correlation (a). Higher magnification showing multiple well-delimited anaxonic bundles with perineural cells in the surrounding fibrous stroma (b) (Hematoxylin and eosin stain)

Table 7 Important features in differential diagnosis of neuromas

MEN2B is caused by a germline missense mutation in the RET proto-oncogene. The RET gene which is located on chromosome 10q11.2 encodes a receptor tyrosine kinase. It is expressed in neuroendocrine cells including thyroid C cells, urogenital system cells, adrenal glands, and parasympathetic and sympathetic ganglia. More than 90% of MEN2B cases are caused by a single point mutation of M918T at 918 codon on exon 16 of the RET gene.

Treatment

The treatment of traumatic neuromas and circumscribed/encapsulated palisaded neuromas is surgical excision with low recurrence rates (Woodruff 1993). Mucosal neuromas of MEN2B have insignificant repercussion on the quality of life of these patients. In such cases, all attention must be focused on prevention or treatment of MTC and pheochromocytoma which are life-threatening.

Neurilemoma/Schwannoma

Epidemiology, Etiology, and Pathology

Schwannomas are the most common benign neurogenic neoplasms and have propensity to affect sensory nerves more than motor nerves. They are a neoplastic proliferation comprised exclusively of cells that have ultrastructural characteristics closely resembling Schwann cells and have the antigenic phenotype of Schwann cells (WHO Classification of Head and Neck Tumours 2017). Some 25–45% of schwannomas are located in the head, and these often present as diagnostic and management challenges, mainly arising on the tongue, followed by the palate, mouth floor, buccal mucosa, gingiva, lips, and vestibule. It shows no gender predisposition, being more likely to affect middle-aged adults (Das Gupta et al. 1969; Colreavy et al. 2000).

Clinical Presentation

The majority of head and neck schwannomas are non-vestibular and extracranial. Clinically, schwannomas are benign, usually solitary, encapsulated masses of long duration at the time of presentation and rarely show a rapid growth course (Fig. 33). Usually schwannomas are painless and not ulcerated but, depending on location and whether a major nerve is involved, could initially manifest with facial hypoesthesia, paresthesia, or pain (Fig. 34). Obstructive symptoms may occur if the tumor gains enough size to compress the upper aerodigestive tract (Liu et al. 2011).

Fig. 33

Neurilemoma/schwannoma. Large firm nodule involving the right tongue. The patient complained about difficulty with speech but no pain or paresthesia (a). Surgical access to the lesion choosing the border of the tongue as election point because it is less vascularized (b). Gross specimen, a 5-cm-wide nodule (c). Surgical site after excision (d). Internal suture (e) aims to eliminate pathologic spaces and external continuous sutures (f) close the wound. Postsurgical follow-up at 3 weeks, the patient was referred to a speech pathologist and recovered from the dyslalia (g). Antoni A pattern of schwannoma showing Verocay bodies, eosinophilic hyalinized matrix delimited by fusiform palisading Schwann cells (h). In contrast, Antoni B pattern of schwannoma is characterized by storiform arrangement of fusiform cells with pleomorphic nuclei. This pattern varies between areas of more cellularized and vacuolated cells with myxoid areas (i) (Hematoxylin and eosin stain)

Fig. 34

Palatal oral schwannoma (a) with plexiform cutaneous schwannomas (b) in the same patient

Bilateral schwannomas are usually related to neurofibromatosis type 2 syndrome (NF2). The etiology of NF2 centers on unregulated growth of neural crest-derived tissues, including Schwann cells. This manifests as lesions involving cutaneous structures and the central and peripheral nervous system. The hallmark of NF2 is hearing loss secondary to bilateral vestibular schwannomas. Neurofibromatosis 2 (NF2) is associated with a rare, potentially treatable type of deafness. Hearing loss usually begins in the third decade and is most often an adult disease. NF2 is the result of inactivation of a classical tumor suppressor gene, NF2, on chromosome 22. Mutations in NF2 are causative, and molecular genetic testing of at-risk family members facilitates early diagnosis and treatment (Gallo et al. 1977; Kluwe et al. 2003).

Investigations

Ultrasound images of schwannoma are characterized by a round or elliptical cross section with a clear border with the internal echo reflective of histology. Patterns may be homogeneous to heterogeneous and cystic change may be seen. Ultrasound has greater diagnostic utility when the diameter of the nerve of origin is large and is connected to a well-delineated nerve.

Computed tomography usually shows well-defined homologous lesions. When a heterogeneous lesion is observed on CT, malignant change may be suspected (Cohen et al. 1986). MRI with contrast is the primary diagnostic test used for schwannomas. These lesions are hypointense on T1-weighted images with post-contrast enhancement with gadolinium. Schwannomas are iso- to hypointense on T2-weighted imaging. MRI is superior to CT at depicting schwannomas, as it is not degraded by dental artifact that plagues CT in the intraoral region. MRI also allows mass size to be accurately measured and mass localization in relation to other structures. Characteristically, these tumors usually appear to be smooth and well demarcated and do not invade surrounding structures.

Fine needle aspiration cytology (FNAC) can be performed for tumors located in the superficial part of the neck, although the histological diagnosis and its clearance should be confirmed on paraffin-embedded sections. Smears are expected to contain blood, degenerate cells, and spindle cells. The diagnostic accuracy of FNAC depends strongly on specimen quality and the experience of the cytopathologist.

Histologically, all schwannomas are encapsulated, and beneath the capsules, there are two main patterns observed, called Antoni A and Antoni B types (Fig. 33). The Antoni type A is highly cellular and is composed of elongated Schwann cells, exhibiting areas of organized spindle-shaped cells in a palisading arrangement around acellular, eosinophilic areas, forming Verocay bodies. The Antoni type B is also composed of elongated Schwann cells, but cells are arranged in a less dense myxoid manner and are more disorganized compared to Antoni type A (Fig. 33) (Table 7). Cystic change becomes more prominent as the tumor enlarges and is associated with mucinous degeneration, hemorrhage, necrosis, and microcyst formation.

Treatment

Complete resection is curative in cases of schwannomas and is not likely to recur. Malignant transformation has not been reported. Depending on the location of the lesion, and possible risk to a major nerve or other vital structures, it is possible to opt for close follow-up observation (Lee et al. 2017). For tumors arising from major cranial nerves, excision of the tumor with the division of the nerve of origin renders lifelong morbidity to the patients. On the other hand, other nerve-preserving excision methods, e.g., intracapsular enucleation, do not guarantee intact nerve function after surgery. Because of the substantial chance of nerve palsy after surgery, obtaining an accurate preoperative diagnosis, and preferably with the identification of the nerve of origin, is crucial to the management of the disease.

Neurofibroma Including Neurofibromatosis

Epidemiology, Etiology, and Pathology

Neurofibroma is a benign peripheral nerve sheath tumor composed of a variable mixture of Schwann, perineural-like, and fibroblastic cells, as well as ones with features intermediate between these various cells, contained in a collagenous or myxoid matrix. Neurofibromas may present either as solitary lesions or as part of the generalized syndrome of neurofibromatosis. Approximately, 25% of all neurofibromas are found in the head and neck region, and 6.5% occur in the oral cavity as solitary or multiple lesions associated with neurofibromatosis type 1 (Marocchio et al. 2007).

Neurofibromatosis type 1 (NF1) was described in 1882 by von Recklinghausen who gave the disease its first full description, including recognition that the tumors arose from the fibrous tissue surrounding small nerves, leading to his designation of these tumors as “neurofibromas.” The disease also known as von Recklinghausen disease is one of the most common dominantly inherited genetic disorders affecting about 1 in 3000 newborns. NF1 is an autosomal dominant condition caused by mutations of a gene cloned on chromosome 17q11.2. The gene acts as a tumor suppressor gene, and its mutation leads to the development of benign and malignant tumors. More than 500 different mutations of the NF1 gene have been identified which result in disease phenotype.

Clinical Presentation

Solitary neurofibromas are normal colored sessile or pedunculated lesions, a smooth, firm swelling on palpation, usually painless with an unpredictable growth pattern leading to local asymmetry (Fig. 35). Other possible clinical signs less commonly found comprise paresthesia and pain, mostly attributed to nerve compression produced by the lesion. These lesions range from small 1 to 2 cm to disfiguring proportions. Intraosseous lesions are considered to be extremely rare and are described as well-circumscribed non-encapsulated usually on the periphery of a nerve. In the maxilla, there are reports of lesions affecting the nasal sinus, and in the mandible, lesions are usually related to the mandibular nerve. Gross specimen evaluation of the mass shows a whitish to light brown color with a soft, friable consistency. Clinical differential diagnosis comprises other nerve sheath benign neurogenic tumors such as neuromas and schwannomas.

Fig. 35

Neurofibromatosis type I. Soft nodular subcutaneous lesions of neurofibromatosis (a + b). Café au lait spot on the arm (c). Enlarged fungiform papillae (d). Lisch nodules are seen in the iris of both eyes (e + f). Nodular neurofibroma revealing interlaced bundles of fusiform cells with pleomorphic nuclei varying from fusiform to round, ovoid, or stellate (g) (Hematoxylin and eosin stain). Toluidine blue stain reveals numerous mast cells within the tumor (h)

NF1 is typically characterized by multiple café au lait spots, multiple cutaneous neurofibromas, axillary and inguinal freckling, and Lisch nodules (Fig. 35). The underlying predisposition to tumor formation can manifest in a number of other serious conditions including malignant peripheral nerve sheath tumor, plexiform neurofibromas, and central nervous system gliomas (Hirsch and Moskowitz 2013).

Cutaneous neurofibromas develop in 99% of NF1 patients but do not undergo malignant change. They are soft and fleshy, ranging in color from blue to tan. They can be sessile or pedunculated and range in size from less than 1 mm to large and disfiguring masses. Subcutaneous neurofibromas frequently cause pain and neurological symptoms and are occasionally visible just beneath the skin. These are palpable firm and tender nodules. Plexiform neurofibromas are found in 50–60% of patients and can cause significant neurological deficits and disfigurement. Most plexiform neurofibromas are internal and not suspected clinically. They represent discrete tumors that arise in nerves within organs or tissues beneath the dermis, frequently clustering around proximal nerve roots. They vary in size and can extend along significant lengths of nerves (Chen 2012).

The average life expectancy of individuals with NF1 is reduced by approximately 15 years (Rasmussen et al. 2001). The appearance of malignant peripheral nerve sheath tumors (MPNSTs) and vasculopathy is the important cause of early death in patients with NF1, but the most common cause of death in patients with NF1 is malignancy. MPNSTs usually arise from pre-existing subcutaneous neurofibromas or plexiform neurofibromas but can develop de novo (Tucker et al. 2005). These are the most frequent malignant neoplasms associated with NF1. These tumors are very aggressive and are often fatal. MPNSTs are difficult to diagnose because they develop in patients who are generally habituated to develop other lumps and skin changes. Warning signs associated with the development of MPNST in a patient with pre-existing neurofibroma include persistent or nocturnal pain, rapid increase in size, asymmetric growth, new neurological deficit, or change to a more firm texture and consistency. The lifetime risk of developing an MPNST in a patient with NF1 is 5–13%. MPNSTs that develop in children and adolescents are rare but tend to be low grade. In contrast, MPNSTs that develop in patients in their 20s and 30s tend to be high-grade tumors.

Clinical diagnosis of NF1 is based on the criteria set forth by a National Institutes of Health Consensus Conference in 1987 and is still accepted for routine clinical use. The diagnostic criteria are met in a patient with the presence of at least two major disease features out of the following:

• A first-degree relative with NF1, six or more cafe´ au lait patches >5 mm in greatest diameter in prepubertal individuals, and >15 mm in greatest diameter in postpubertal individuals (Fig. 35)

• Axillary or groin freckling, two or more neurofibromas, or one plexiform neurofibroma

• Two or more Lisch nodules in the iris (Fig. 35)

• Optic pathway glioma

• A distinctive osseous lesion, including bony dysplasia of the sphenoid wing, or pseudoarthrosis of the long bones (Fig. 36)

  Fig. 36

  

  Neurofibromatosis 1 in a 25-year-old female. The left condylar head is significantly hypoplastic, and there is elongation of the left condylar neck and flattening of the right condylar head with osteophyte formation. There is deformity of the left sigmoid notch. There is thinning of the mandibular rami. There appears to be discontinuity of the infraorbital rim and hypoplasia of the paranasal sinuses. There is enlargement of the mandibular foramina. These changes are consistent with features of neurofibromatosis type 1. Other findings not described

Investigations

Neurofibromas may appear as soft tissue opacities on standard radiographs. On ultrasonography, these lesions appear as well-demarcated fusiform, hypoechogenic structures, in close relation to the native nerve. On CT, the lesions have low density. MRI is the imaging technique of choice for detection and characterization of tumors of peripheral nerves. On MRI, neurogenic tumors are of low to intermediate signal intensity on T1-weighted images and of variably increased signal intensity on T2-weighted MR images (Baert 2008).

Neurofibromas have a variable morphological pattern on histopathological examination. They are composed of fusiform cells in a mucoid/myxoid matrix. The tumor is composed of an irregular pattern of proliferative fibers and mucoid masses, with a variable mixture of Schwann, perineural-like, and fibroblastic cells (Fig. 35). Two major variants are described, a well-circumscribed nodular variant and the plexiform variant which produces poorly circumscribed tumors. The later carries risk of malignant transformation. Neurofibromas form tortuous cords along the segments and branches of a nerve with a tendency to develop centripetally along a nerve course. Inflammation is found in 44% of specimens (Marocchio et al. 2007), which is important when differentiating these from other neurogenic tumors such as traumatic neuromas. Other comparative morphologic characteristics of the tumor are displayed on Table 7.

Treatment

The gold standard treatment for neurofibromas is surgical excision. Easy-to-access lesions such as on the skin do not demand further precautions, but some head and neck lesions can show some complications related to anatomy, sacrifice of cranial nerves that can result in functional problems such as permanent anesthesia or loss of motor function, and even significant deformity. The clinical behavior of neurofibromas is characterized by a benign course with a low frequency of recurrence after surgical excision.

Other therapies such as photodynamic therapy have been proposed for large and difficult-to-access lesions, with promising results, but still lack long-term research of its effectiveness (Hamdoon et al. 2012).

Neurofibromatosis type 1 raises the need for periodic clinical follow-up of patients in order to prevent malignant neoplasms. The survival rate of most patients with NF1 exceeds 50 years. Once diagnosed with NF1, it is important to provide genetic counseling to the patient and their relatives.

Granular Cell Tumor

Epidemiology, Etiology, and Pathology

Granular cell tumor (GCT) was described in 1926 by Abrikossoff, and the etiology of this disease is controversial and much discussed in the literature. Schwann cells, fibroblasts, histiocytes, myoblasts, and undifferentiated mesenchymal cells have been identified in the histogenesis of GCT. It is a rare benign neoplasm of soft tissues, characterized by poorly demarcated proliferation of round or spindle plump cells with granular cytoplasm. The granular appearance is a result of increased accumulation of lysosomes in the cytosol of the cells.

Considered a rare lesion, the most common sites for this lesion are in the head and neck region accounting for 50% of cases, although it can appear in any area of the body. In the oral cavity, the most affected site is the tongue, but other sites such as the hard palate, buccal mucosa, lips, uvula, parotid gland, and gingiva have been reported. The peak age of incidence of GCT is 40–60 years, but it can affect all ages. Most reports describe a female-to-male ratio of 2:1, and higher incidence in black populations has been noticed.

Clinical Features

GCT presents as a firm, polypoid, or sessile tumor that forms a “lump” on the surface of the affected site (Fig. 37). It is superficial, poorly circumscribed, and slow-growing involving the subcutaneous or submucosal tissues. Most lesions are small, do not exceed 3 cm in diameter, and are covered by mucosa that can be normal colored, yellow colored, or with pale to leukoplakic appearance. On palpation, the tumor often appears demarcated but not encapsulated.

Fig. 37

Granular cell tumor. Sessile nodule forming a lump of pale coloration on the dorsum of the tongue (a), and raised hard lump with yellow coloration on dorsal tongue in a separate patient (b). Microscopic features of granular cell tumor of the tongue show epithelial hyperplasia of the mucosa (c) and a poorly circumscribed lesion consisting of large polygonal or elongated cells with clear, granular cytoplasm and an oval or round nucleus with loose chromatin (d) (Hematoxylin and eosin stain)

The differential diagnosis for these lesions comprises other benign soft tissue neoplasms such as fibromas, lipomas, neurofibromas, neuromas, and schwannomas. Reactive lesions such as traumatic fibroma can also resemble GCT, but the inflammatory process usually adds symptoms such as pain and discomfort as well as cause-effect correlation.

Investigations

Microscopic analysis shows a lesion mainly consisting of large polygonal or elongated cells with clear, granular cytoplasm and an oval or round nucleus with loose chromatin (Fig. 37). Periodic acid-Schiff (PAS)-stain-positive granule s are detected in the cytoplasm. The tumor cells are strongly positive for S-100, vimentin, and CD68 and are negative for GFAP and NFP. Intraoral lesions present frequently with pseudoepitheliomatous epithelial hyperplasia in the overlying mucosa; therefore, care should be taken to avoid an erroneous diagnosis of squamous cell carcinoma (Ferreira et al. 2017).

Multiple GCT may be familial and associated with syndromes such as LEOPARD, NF1, or Noonan, all related to the Ras/MAP kinase pathway probably caused by mutation in PTPN11 . Rare examples of malignant GCT characterized by pleomorphism, mitotic activity, and necrosis have also been described (van der Wal 2016).

Treatment

Surgical excision with a safe margin of tissue is the treatment of choice for GCT, although this is not always possible because the tumor lacks a capsule, as histologically demonstrated by an undefined cellular margin. Recurrence is low, although it has been reported in incompletely removed lesions and in patients with multiple GCT.

Rhabdomyoma

Epidemiology, Etiology, and Pathology

Rhabdomyoma is a rare benign proliferation of mesenchymal cells with skeletal striated muscle differentiation (Fig. 38). It is estimated that rhabdomyomas represent less than 2% of soft tissue tumors and are considerably less common than its malignant counterpart the rhabdomyosarcoma. Rhabdomyoma is classified into cardiac and extracardiac , based on anatomic location. It can manifest as a local or multifocal lesion. Among the different types of rhabdomyomas, the cardiac rhabdomyoma occurs almost exclusively in the heart of infants and young children, is the most prevalent, and is related to tuberous sclerosis. Extracardiac rhabdomyomas are subdivided into fetal, adult, and genital. Extracardiac rhabdomyomas are true neoplasms, with a reciprocal translocation between chromosomes 15 and 17 (Gibas and Miettinen 1992). Because rhabdomyomas are more commonly found in the neck and preauricular region, it is speculated that the etiology of these neoplastic cells is based on branchial musculature of the third and fourth branchial arches. The median age is 60 years with 3:1 male-female predominance.

Fig. 38

Rhabdomyoma. Large normal colored mass in the floor of the mouth (a). Intermediate magnification showing a uniform tumor formed by polyhedral granular cells with focal vacuolization (b) (Hematoxylin and eosin stain)

Clinical Features

In the head and neck region, only the fetal and adult forms are likely to occur; the genital form is exclusive to the female gender affecting the vagina and vulva of middle-aged women. Although usually solitary, adult-type rhabdomyoma can occasionally be multinodular and rarely multifocal. Multifocal adult-type rhabdomyoma usually presents as slow-growing lumps in the parapharyngeal region. Large or multilobulated lesions may be first identified due to complaints of progressive dysphagia, hoarseness, and snoring.

Investigations

Contrast-enhanced CT and MRI are the best imaging examinations to identify rhabdomyomas. Usually the tumors develop close to other skeletal muscles, as a well-circumscribed mass with homogenously similar intensity. Aspiration of these tumors contains diluted blood without agglutination; therefore schwannoma is included as the primary differential diagnosis (Lu et al. 2017). Radiologically rhabdomyoma presents as a well-circumscribed mass without invasion of surrounding soft tissues. In addition, the characteristically increased 18 F-fluoro-2-deoxy-D-glucose (18 F-FDG) uptake on positron-emission tomographic CT is vitally useful for the detection of multifocal adult rhabdomyoma, especially in the case of very small lesions, which are easily missed with traditional examination (de Trey et al. 2013).

Adult-type rhabdomyoma is the most common subtype of extracardiac rhabdomyoma, characterized by mature skeletal muscle differentiation forming homogeneous masses of polygonal cells sometimes with more than one nucleus, with eosinophilic granular cytoplasm resulting in a “spider web” appearance (Fig. 38). In contrast, fetal-type rhabdomyoma exhibits immature muscle differentiation, characterized by bland spindle cells associated with fetal myotubules haphazardly arranged in abundant myxoid stroma (Fig. 38). Microscopic differential diagnosis of rhabdomyoma comprises granular cell tumor, hibernoma, oncocytoma, paraganglioma, or crystal-storing histiocytosis. The lesion is PAS positive, and immunohistochemical panels show positivity for desmin, MSA, SMA, and myoglobin and negativity for S100, EMA, and cytokeratin.

Treatment

Surgical resection of the tumor performed through a transcervical approach and transoral incision under general anesthesia applies to most lesions due to its regular site manifestation. Rhabdomyomas are removed easily with blunt dissection. These tumors appear as a soft, tissue-encapsulated mass with a smooth shiny surface. Cut sections present with a pink and smooth texture that is similar to muscle tissue. Rhabdomyomas are not likely to recur if removed completely; however, when small lesions are located in vital structures, the risk-to-benefit ratio of complete excision should be carefully weighed.

Hemangioma

Epidemiology, Etiology, and Pathology

Hemangiomas are true neoplasms of blood vessels formed by endothelial proliferation assuming variable width. The lesion is usually present at birth and can regress spontaneously. They are distinct from vascular malformations due to a higher mitotic activity. Reactive lesions such as angiogranuloma, which are ulcerated and have a clear cause-effect relationship, have similar mitotic activity and microscopic appearance and frequently cause discussions as to whether it represents a true hemangioma, also named lobular capillary hemangioma.

The origin of hemangiomas, although still under debate, has been narrowed to embryonic placental angioblasts or intrinsic endothelial progenitor cells with the ability to clonally duplicate in a precise environment of cytokines and estrogen concentration (Yu et al. 2004). It is even possible that both theories regarding the origin of hemangiomas coexist. Hemangiomas likely arise from progenitor cells with directional preponderance to become placental-like tissue in specific organs such as skin and liver (Barnes et al. 2007).

The role of molecular signaling involved in vascularization is better understood in hemangioma development. Increased levels of common molecular contributions to endothelial cell migration and new vessel development have been discovered during the proliferative phase of hemangioma growth such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (b-FGF), insulin-like growth factor (IGF), and matrix metalloprotease-9 (MMP-9). Similarly, and as would be expected, the levels of angiogenic markers also wane during the involution phase of hemangiomas (Buckmiller et al. 2010).

Hemangiomas proliferate during the first 9–12 months of life and subsequently involute at a variable course over many years. The tumor has a female predominance, occurring commonly in the head and neck region but rarely in the oral cavity. These lesions are subdivided into two categories based on their clinical behavior and histology. The more common infantile hemangioma (IH) develops shortly after birth and follows the expected course of proliferation with prolonged involution. Infantile hemangiomas are vascular tumors comprised of rapidly dividing endothelial cells affecting up to 10% of the population with a greater incidence in Caucasians and premature and low-birth-weight infants. Approximately 60% occur in the head and neck region. Congenital hemangioma is rare, is present at birth, and does not follow the natural growth phase of its infantile counterpart.

Clinical Features

These lesions present a smooth reddish purple, sessile, polypoid, or pedunculated masses, often with increasing size and occasional bleeding (Fig. 39). Most infantile hemangiomas are not apparent at birth or may appear to be a small “scratch” or “bruise.” Infantile hemangiomas become evident shortly after birth as well-demarcated, red, vertically expansive lesions. They can be overlooked during the first month of life as they are difficult to differentiate from other common skin blushes seen in the newborn. During this period, they are flat, pink, and sometimes more pale or bluish than their surrounding tissue. Slower but continuous growth occurs up to 9 months in most patients. Rapid expansion can lead to adjacent skin and soft tissue ischemia, necrosis, and ulceration. The bright red discoloration is persistent until the onset of involution when resurfacing is observed as variable graying of the overlying skin. No two hemangiomas are the same, and the rate of growth is variable in the proliferative phase. Involution may occur as early as 6 months of age in isolated lesions or much later when deep or segmentally distributed hemangiomas are present.

Fig. 39

Infantile hemangioma in a 4-year-old female, presenting as a growing blue sessile mass, first noticed during her first year of life (a). Patient received sclerotherapy with four periodical local infiltrations of monoethanolamine oleate, with complete remission of the lesion after 8 months from initial diagnosis (b)

Infantile hemangiomas are usually superficial lesions, but their depth can vary, altering its clinical presentation. Depth can be expressed as superficial, deep, or mixed/compound which indicates the amount of tissue involvement. Superficial IH will typically have a deep red appearance on the skin or mucosa. Deep IH often will be visualized to have a bluish hue under the normal-appearing skin. Compound IH possess attributes of both (Friedman et al. 2013).

Investigations

Since most hemangiomas are superficial lesions and respond to objective tests such as diascopy, there is limited use for imaging exams, only applied for differential diagnosis or in deep or difficult-to-access lesions. For that matter, ultrasound and MRI are helpful tools. These can be used to distinguish between IH and vascular malformations if the diagnosis is in question. Color Doppler ultrasound will demonstrate either fast-flow or slow-flow lesions. The best diagnostic radiologic clue for IH is the presence of a high-flow soft tissue mass. On ultrasound, hyperechoic and/or hypoechoic lesions can be seen with variable presence of vessels. MRI for IH typically shows a well-defined, non-infiltrating lesion. Intermediate signal intensity is seen on T1-weighted images and increased signal intensity of T2-weighted sequences. After gadolinium injection, strong enhancement is observed.

MRI is especially important in the evaluation of patients with large facial hemangiomas to rule out neurocutaneous PHACES syndrome [OMIM #606519]. This syndrome is characterized by posterior cranial fossa anomalies (P), facial hemangiomas (H), and one or more major cervical and arterial cerebral vascular (A), cardiovascular (C), eye (E), and sternal or supra-umbilical (S) anomalies/defects (Heyer et al. 2008).

Microscopically hemangiomas are classified according to the lumina of the capillary vessels that are predominant in the lesion. Capillary hemangiomas consist of multilobular arrangements of proliferating endothelial cells and capillaries of various shapes and sizes surrounded by pericytes (Fig. 40). The capillary type appears more cellularly rich, but mitotic activity is similar to the cavernous type. The lumina may be subtle or dilated, especially in IH. Cavernous hemangiomas are named due to the similarity to the capillaries found in the penial cavernous body and show larger dilated vascular spaces lined by endothelial cells (Fig. 40).

Fig. 40

Low magnification of infantile hemangioma presenting as a cellular well-circumscribed lesion with endothelial cells in a lobular arrangement (a). Mature lesion of hemangioma with flattened endothelial cells and more evident vascular spaces in a more fibrous stroma (b) (Hematoxylin and eosin stain)

The most difficult microscopic differential diagnosis of hemangiomas is the angiogranuloma. Good clinical information is essential to avoid confusion between these lesions without molecular investigation; loss of integrity of skin/mucosal lining also favors the diagnosis of angiogranuloma. Other important differential diagnoses of vascular tumors include congenital hemangiomas, tufted angiomas, and a variety of hemangioendotheliomas. Final diagnosis of this lesion can demand the use of an immunohistochemical panel.

Immunohistochemical panels for the diagnosis of hemangiomas show CD34, CD31, and ERG positive. Infantile hemangiomas have a specific marker (GLUT1) which is negative for angiogranuloma and congenital hemangioma (2017).

Treatment

The treatment of hemangiomas comprises a variety of modalities that are best suited for each case. Infantile hemangiomas include observational follow-up, since up to 50% of lesions completely resolve by 5 years of age, 70% by 7 years, and 90% by 9 years. Bleeding, ulceration, functional risk, and esthetic concerns usually require professional intervention. Historically corticosteroid therapy was used in IHs. This therapy can be systemic or local infiltration. Systemic administration has important side effects in children, mostly related to long-term use. Steroids are effective in retarding the growth phase of IH, but if discontinued, the lesion returns to its normal growth.

Flash lamp dye laser therapy has also produced good results, promoting regression in the size of the lesions. This treatment modality offers the best results in superficial lesions. Such lesions require future excision of residual scar. Adjunctive antibiotic ointment before and after flash lamp dye laser therapy improves healing and prevents infection of ulcerated lesions.

In the past decade, propranolol has become first-line treatment for IH (Leaute-Labreze et al. 2008). Since the serendipitous discovery of the favorable results of beta-blockers in these lesions, many studies have shown good outcomes, initially with small case series, but lately larger sample size studies have reinforced its safe use with 96.9% effectiveness and low complications (3.8%). Complications include sleep disturbance, diarrhea, and bronchospasm. In one study, only 22.6% of cases had incomplete involution of IH and needed further assistance with other adjunctive therapies including timolol maleate or pulsed dye laser (Zhang et al. 2017). The mechanism of action of propranolol on reducing or curing hemangiomas remains unclear although the most likely mechanism is the pharmacologic stimulation of programmed endothelial cell death (apoptosis). A dose of 1–2 mg/kg/day for the treatment of infantile hemangiomas is currently being applied. The treatment may last for up to 6 months, demands close monitoring, and is terminated when the infant reaches 1 year of age.

Sinonasal Papilloma

Epidemiology, Etiology, and Pathology

Sinonasal papillomas are surface mucosal lesions of the sinonasal tract related to HPV infection, as well as exposure to solvents, smoking, and alcohol consumption. They manifest in three different forms: inverted type, oncocytic type, and exophytic type. This differentiation is based on the pattern of proliferation that these lesions can produce. The inverted papilloma is the most frequent type with estimated prevalence of 0.74–2.3 new cases per 100,000 population, affecting patients ranging from 6 to 84 years, 2.5–3 times as common in males as in females. The oncocytic papilloma has no gender predilection, and most patients are over 50 years of age. This type lacks correlation with HPV infection, which is distinct from the other two types. Sinonasal exophytic papilloma is most related to HPV infection with up to 63.5% of cases, affecting two to ten times more males than females, typically in patients aged 20–50 years. Malignant transformation and/or other malignant lesions arising from sinonasal papillomas are exceptions worth careful attention (Maitra et al. 2001).

Clinical Presentation

Patients with sinonasal papillomas first present with non-specific symptoms such as nasal obstruction, polyps, epistaxis, rhinorrhea, hyposmia, and headache. Unilateral nasal obstruction and the presence of an asymptomatic mass can also represent sinus papilloma progression. Exophytic sinonasal papillomas usually arise on the lower anterior nasal septum and present warty appearance.

Investigations

Because of its non-specific symptoms, delay in diagnosis is sometimes reported, as unsuccessful treatments of “recurrent sinusitis” or “chronic rhinitis.” Diagnostic imaging is important for diagnosis with CT and MRI offering the best information about the site of origin of the tumor. Endoscopy is also a valuable complementary exam for lesions affecting the nasal cavity.

Inverted growth is the hallmark of the inverted sinonasal papilloma, forming islands or nests of stratified squamous epithelium and/or columnar respiratory cells. The basement membrane is intact, with eventual mitotic figures only in the basal layer. Dysplastic features may cause concern about malignant transformation. The American Joint Committee on Cancer (AJCC) staging system is commonly used for staging these lesions. The oncocytic type presents both exophytic and endophytic growth patterns, and the oncocytic appearance of the epithelium is due to the hyperchromatic nuclei and the abundant granular eosinophilic cytoplasm. Cilia in various stages of regression are occasionally found in the superficial layers. Finally, the exophytic type resembles the endophytic epithelial lining changing only the direction of growth. Keratinization of the epithelial surface is possible, mostly in lesions exposed to trauma or drying effects of the air, and malignant transformation is less likely to occur. The main differential diagnosis of this lesion is the cutaneous squamous cell papilloma, which is more keratinized and does not present signs of respiratory epithelium and submucous glands in the specimen.

HPV is detected more frequently in exophytic papillomas than in endophytic ones, with a weighted prevalence of 65.3% (Lawson et al. 2008). Types 6/11 are found in most cases. HPV has been detected with variable frequency in inverted sinonasal papilloma, with a mean rate of 16% (Lawson et al. 2008). A preponderance of HPV 6/11 has been reported as compared to HPV 16/18, with a ratio of low-risk to high-risk HPV types of 2.8:1 (Lawson et al. 2008). The frequency of HPV detection increases in inverted papillomas with dysplasia and in lesions with malignant progression to carcinoma, with a shift toward a higher frequency of high-risk subtypes (Lawson et al. 2008).

Inverted papillomas present monoclonal proliferations, as shown by X chromosome analysis. However, the chromosomal loss of heterozygosities (LOHs) at arms 3p, 9p21, 11q13, 13q11, and 17p13 have not been detected (Califano et al. 2000). The main differential diagnosis of the inverted type is with sinonasal cylindrical cell carcinoma and squamous cell carcinoma, which can be distinguished by the presence of significant nuclear pleomorphism, atypical mitoses, and stromal invasion. Respiratory epithelial adenomatoid hamartoma can be separated from inverted sinonasal papilloma because it contains numerous gland-like structures lined by respiratory epithelium, surrounded by thick hyalinized basement membrane, which is not present in sinonasal papilloma.

The epithelial cells of oncocytic papillomas stain for the mitochondrial enzyme cytochrome C oxidase (Levine et al. 1987) and for cytokeratins (Maitra et al. 2001). Oncocytic papilloma may be confused with low-grade sinonasal adenocarcinoma , which often shows a papillary growth pattern but presents an epithelial growth characterized by a single-layered, non-oncocytic epithelium with some degree of atypia, occasional mitotic figures, and invasive growth. Due to the presence of several microcysts within the epithelial layer, oncocytic papilloma may also be confused with rhinosporidiosis. In this infectious disease, however, organisms are found both in the epithelium and the stroma, and the epithelium does not show oncocytic changes (Franchi 2016).

Treatment

Complete surgical excision is the treatment of choice, and these lesions are not likely to recur, but surgical access to the lesions can be difficult and incomplete removal may lead to recurrence. If high-risk HPV infection and/or dysplasia is detected, clean surgical margins should be pursued during surgical excision (Levine et al. 1987; Karligkiotis et al. 2014).

Malignant Epithelial Tumors of the Head and Neck

Laryngopharyngeal cancers constitute about 40% of all head and neck cancers. The pharynx is divided into three subsites: the nasopharynx which extends from the posterior choana to the level of free border of the soft palate, the oropharynx which consists of the soft palate, tonsils, lateral pharyngeal wall, and the base of the tongue. It extends from the level of the soft palate to the level along the superior surface of the hyoid bone. The hypopharynx is the region of the pharynx from the plane along the superior level of the hyoid bone to the plane along the inferior border of the cricoid bone. This region consists of the pyriform sinuses, the postcricoid region, and the posterior pharyngeal wall.

The larynx is subdivided into the supraglottis, glottis, and subglottis . The supraglottis extends from the superior level of the hyoid bone to the laryngeal ventricles and consists of the epiglottis, aryepiglottic folds, arytenoids, and false cord. The glottis includes the vocal cords and extends from the ventricles inferiorly by 1 cm. The subglottis extends from the level of the glottis to the inferior level of the cricoid cartilage (Fig. 41).

Fig. 41

Anatomy of the pharynx including the laryngopharyngeal subsites

In contrast to cancers of the oral cavity which mostly draw early attention due to a visible lesion, tumors originating in the oropharynx and hypopharynx usually present late due to their location in apparently hidden areas and non-specific symptoms masquerading as many benign conditions.

Apart from the routine blood investigations, which include complete blood count, renal function, and coagulation profile, tissue diagnosis and imaging are required for treatment planning. Diagnostic evaluation for HPV status is mandatory (Table 8).

Table 8 Principles, merits, and demerits of validated laboratory methods of HPV detection

A biopsy from the primary lesion is needed to establish the primary diagnosis. A deep biopsy (to include the basement membrane) from the most “representative” part of the lesion should be taken. Large ulcers tend to have a necrotic center, and biopsy from the necrotic area should be avoided. In cases of infiltrative disease which spreads submucosally, a wedge biopsy is required to target the most indurated area. Such lesions are common in the base of tongue (BOT) region (Fig. 42).

Fig. 42

Contrast-enhanced T1 MRI image showing an infiltrative tumor over the left base of tongue (arrow)

Imaging is complementary to clinical examination in treatment planning. While endoscopic evaluation maps the mucosal extent of the disease, involvement of the soft tissues, bone, and cartilage can be determined by imaging. Pretreatment staging is done based on both clinical and radiological findings. Contrast-enhanced CT of both the head and neck and chest are the most commonly employed imaging modalities. MRI with contrast is an alternate approach. If an organ preservation strategy using chemotherapy and radiotherapy is planned, PET/CT may be considered for response evaluation (Fig. 43). The advantages of each are depicted in Table 9 and are outlined in more detail in the chapter on “Diagnostic Imaging Principles and Applications in Head and Neck Pathology.” The imaging modality of choice varies with the subsite and the disease extent.

Fig. 43

PET/CT fusion axial image showing an enhancing lesion involving the right base of tongue suggestive of neoplastic etiology

Table 9 Commonly used imaging modalities

The same modality used to image the primary lesion is used to image the neck. Metastatic neck nodes on imaging appear enlarged and rounded and show necrosis, extracapsular spread, and invasion of adjacent structures. Necrosis is the most reliable criteria for metastasis. The sensitivity and specificity of CT for assessing neck nodal metastasis vary from 55% to 95% and 39–96%, respectively, while those for MRI are 64–92% and 40–81%, respectively (de Bondt et al. 2007).

Distant metastasis (DM) from head and neck squamous cell carcinomas most commonly spread to the lungs followed by the liver and bone (Mamelle et al. 1994). Factors associated with distant metastatic disease include histologic tumor type, T stage, N stage, extranodal tumor spread, and number and level of neck nodes. FDG-PET in head and neck SCC alters TNM stage in 43% and management in 13.7% of cases (Lonneux et al. 2010). The National Comprehensive Cancer Network (NCCN) guidelines recommend FDG-PET/CT for the initial work-up of patients with stage III and IV head and neck cancers. Taking into consideration the lack of availability and cost of FDG-PET/CT, a multi-slice CT (MSCT) of the chest is an equally good alternative in advanced cancers as the most common sites for DM are the lungs and mediastinal nodes (Fig. 44).

Fig. 44

Contrast-enhanced CT thorax axial sections showing multiple metastatic lung nodules (some shown by red arrows)

Treatment protocols are determined primarily by the oncologic outcome followed by the functional and cosmetic outcome. Cost-effectiveness, patient preferences, and quality of life (QoL) should also be taken into account. Early-stage cancers (stages I and II) are usually treated with single modality (surgery or radiation), while advanced stages (stages III and IV) are treated with multimodality treatment which includes surgery, radiation, and/or chemotherapy.

Posttreatment surveillance (Table 10) is an elaborate part of patient management. Identifying early recurrence improves the oncologic outcome. Functional and cosmetic issues can also be addressed through surveillance which improves the QoL for cancer survivors. There is no fixed protocol for frequency and duration of follow-up, but several guidelines exist such as the NCCN guidelines. Patient compliance, place of stay, nature of work, and commitment of caregivers decide how frequently the patient is followed up. Generally, patients are followed three monthly for the first 2 years, six monthly for the next 5 years, and yearly thereafter. All patients undergo a routine head and neck clinical examination to detect early recurrences or second primary cancers. Patients of oropharyngeal, hypopharyngeal, and laryngeal cancers should also undergo a flexible endoscopy with air insufflation (for pyriform sinus and postcricoid cancers ) or rigid endoscopic examination. First posttreatment imaging (MSCT or contrast-enhanced MRI) should be done within 6 months of treatment completion. For patients undergoing nonsurgical treatment, contrast-enhanced FDG-PET/CT is recommended for response assessment. PET/CT should not be carried out before 8 weeks and preferably after 12 weeks posttreatment completion to allow for the inflammatory response to subside. If residual disease, recurrence, or a synchronous second primary is suspected within 8 weeks, a MSCT or MRI is recommended. Yearly imaging of the chest is recommended especially in patients with a history of smoking. All patients undergoing radiation to the head and neck need to undergo a thyroid function test six monthly. As radiation adversely affects the constrictors, swallowing functions should be evaluated during follow-up. Voice evaluation is required in patients undergoing total laryngectomy. On each follow-up, patients need to undergo detailed nutritional assessment as they are prone to nutritional deprivation as a result of impaired swallowing. Shoulder function should be assessed in patients undergoing neck dissection and encouraged for active shoulder exercises. Tobacco cessation and alcohol counseling should be carried out with patients continuing these habits. Patients suffering from depression and psychosocial and end-of-life issues require proper psychiatric consultation and social support.

Table 10 Posttreatment surveillance

Oropharyngeal Cancer

Epidemiology, Etiology, and Pathology

Squamous cell carcinoma (SCC) constitutes more than 90% of malignant tumors of the oropharynx. Oropharyngeal tumors are now distinctly divided into two subtypes, namely, HPV-positive SCC and HPV-negative SCC. HPV-negative tumors tend to behave like their counterparts in the oral cavity and appear to be associated with increased risk of exposure to tobacco and alcohol.

Human papillomavirus (HPV) infection is now clearly associated with a subset of head and neck cancers. Among all subsites of head and neck SCC (HNSCC), HPV prevalence is the highest in oropharyngeal cancers where 40–80% are positive for the virus, and the number continues to increase (D’Souza et al. 2007; Adelstein et al. 2009; Dayyani et al. 2010; Chaturvedi et al. 2011). HPV is an epitheliotropic small double-stranded DNA virus with more than 200 identified subtypes (Oguejiofor et al. 2013). Of these, about 15 types are thought to have high-risk oncogenic potential. HPV strains 16, 18, 31, 33, and 35 are associated with oropharyngeal SCC (OPSCC) with strain HPV-16 being responsible for more than 90% of HPV-induced cancers (Marur et al. 2010).

HPV has a predilection for the basal cells of the epithelium. Initially the viral genome remains as an episome expressing early replicative protein E2. Subsequently integration into the host genome occurs following which E2 protein is suppressed and E6 and E7 proteins become activated. The main aim of E6 is to abrogate p53 function to facilitate its own replication and results in allowing genetic mutations in the absence of p53 function. E6 inhibits p53 directly as well as via E6-associated protein (ubiquitin ligase). The function of E7 is degradation of the Rb gene complex resulting in activation of E2F protein and subsequent progression of the cell cycle beyond the G1S checkpoint. Apart from the oncogenic proteins E6 and E7, E5 plays a significant role in oncogenesis by enhancing the transforming activity of E6 and E7, upregulating epidermal growth factor receptor (EGFR), and inhibiting major histocompatibility complex (MHC). More detailed discussion about HPV-associated tumors and molecular understanding of head and neck squamous cell carcinoma can be found in a later section of this chapter.

The oropharynx is also rich in minor salivary glands and lymphoid tissue and is the site for salivary gland neoplasms and hematolymphoid malignancies. Oropharyngeal salivary gland tumors constitute about 1.1–3.3% of all minor salivary gland tumors (Spiro et al. 1973; Eveson and Cawson 1985; Ellis et al. 1991). Nearly half of these salivary neoplasms are malignant adenoid cystic carcinoma (ACC) and mucoepidermoid carcinoma (MEC) (Eveson and Cawson 1985).

Adenoid cystic carcinomas are relatively common, and 42.5% of these occur in the minor salivary glands (Gnepp 2001). About 20% of these minor salivary gland ACCs occur in the oral cavity and oropharynx (Gnepp 2001). They usually present as a slow-growing submucosal mass with ulceration in advanced cases. The most common histologic subtype is the cribriform variant although tubular and solid patterns can also be seen (Waldron et al. 1988). The cribriform variant carries a favorable prognosis as compared to other variants. Perineural invasion is common and symptoms like pain raise the suspicion of such spread. These tumors commonly spread through the hematogenous route with the lungs being the most common site for metastatic disease. Neck nodal metastasis occurs in 10–15% of patients. Surgery remains the main treatment for ACCs with neck dissection being reserved for clinically metastatic neck disease. As these tumors are relatively radiosensitive, adjuvant radiation is warranted in most cases. Imaging of the chest is mandatory in the initial work-up and on a yearly basis in the follow-up period. As metastatic lesions usually have an indolent behavior, treatment of the primary lesion is undertaken even in the presence of metastatic disease.

Mucoepidermoid carcinomas are most common minor salivary gland malignancies and account for 9–23% of all salivary gland tumors (Eveson and Cawson 1985; Waldron et al. 1988; Ellis et al. 1991). In the oropharynx, they have a propensity to involve the palate. Treatment is essentially surgical resection with neck dissection being indicated in high-grade, high-stage tumors and those with evidence of neck nodal metastasis. Adjuvant radiation is indicated in high-grade, high-stage tumors, positive/close resection margins, perineural invasion, and lymphovascular spread.

Hematolymphoid malignancies, most commonly non-Hodgkin’s lymphoma, present with an exophytic mass, submucosal bulge, or an ulcerated lesion commonly involving the palatine tonsils or the base of tongue. Rarely, mucosal melanomas can present in the oropharynx as a blackish, gray, or reddish pigmented (rarely amelanotic) lesion. These are very aggressive tumors, and the mainstay of treatment is surgery with multimodality adjuvant therapy.

An increasing number of oropharyngeal cancers are associated with HPV. HPV has emerged as a mutagen for head and neck cancers with the oropharynx being the most common site and being associated with about 60–70% of oropharyngeal cancers (D’Souza et al. 2007). The prevalence of HPV-associated oropharyngeal cancers is low in the Asia-Pacific region in comparison to Western developed countries.

Presence of HPV is now considered a distinct clinical, pathological, and prognostic entity in the etiology of head and neck cancers, especially those of the oropharynx. Epidemiological studies have shown that the incidence of HPV-induced oropharyngeal cancers is increasing worldwide over the last decades, while the overall incidence of head-neck SCC has declined in the developed countries (Benson et al. 2014). Although HPV-positive OPSCC presents at a relatively advanced stage as compared to HPV-negative OPSCC, they have a significantly better prognosis with 60–80% reduced risk of death as compared to the HPV-negative counterpart (Gildener-Leapman et al. 2014). Multiple multiinstitutional trials have shown better prognosis of HPV-positive OPSCCs (Table 11). Compared to matched staged HPV-negative tumors, patients with HPV-positive tumors have better overall survival (Ang et al. 2010), and while this is not completely understood, these could be attributed to several factors including the fact that HPV-positive tumors respond better to chemotherapy and radiotherapy (perhaps due to the presence of non-mutated tumor suppressor genes, TP53 and RB), have higher immunogenic response to viral-specific tumor antigens, have lower risk of developing secondary tumors (perhaps due to less field cancerization), are less likely to express biomarkers of poor prognosis such as the epidermal growth factor receptor (EGFR), and are found in younger patients with fewer comorbidities and good performance status (Westra et al. 2008; Adelstein et al. 2009; Hong et al. 2010). Based on the evidence of better prognosis of HPV-positive OPSCC, the American Joint Committee on Cancer (AJCC) has staged HPV-positive OPSCC as an entity separate from HPV-negative OPSCC in the most recent AJCC 8th Edition Cancer Staging System (Lydiatt et al. 2017).

Table 11 Treatment outcome of HPV-positive and HPV-negative tumors in multiinstitutional trials

Clinical Presentation

Clinically, HPV-positive OPSCC is seen in younger subjects with less exposure to tobacco and alcohol. White men with higher socioeconomic status are more commonly affected (2017). Increased lifetime number of oral and genital sexual partners, younger age at the time of first sexual intercourse, infrequent use of condoms, and history of previous sexually transmitted infection has found to be associated with HPV-induced OPSCC (Heck et al. 2010). Patients with HPV-positive OPSCC commonly present with small primary tumors with large cystic lymph nodes (Fakhry et al. 2008). Tonsils, followed by the base of tongue, are the most common sites for primary OPSCC tumors (2017). Patients presenting with HPV-negative OPSCC typically present with sore throat or difficulty swallowing (2017).

Symptoms vary as per the subsite of origin (Table 12). The base of tongue, tonsillar fossa, and pyriform sinus are rich in lymphatics, and cancers of these subsites commonly present with metastatic neck nodes as the initial sign. Any patient presenting with neck nodal metastatic squamous cell carcinoma (SCC) without any obviously visible primary lesion should be meticulously evaluated for a hidden lesion in these subsites. Cancers arising from the base of tongue (BOT) usually present late. Early symptoms of a sore throat, feeling of a lump in the throat, and slight discomfort on swallowing are non-specific and often ignored by the patient as well as by the primary care physician. In most cases, metastatic neck nodes draw attention to the primary lesion. Late symptoms include dysphagia, referred otalgia, change in quality of speech (hot potato voice), and hemoptysis. Early tonsillar cancers remain hidden within the tonsil or the tonsillar bed and are rarely diagnosed at this stage, and metastatic level II neck nodes are the earliest presenting symptoms. Advanced tumors present with bleeding, pain, voice change, and trismus (due to masticatory muscle involvement).

Table 12 Common symptoms of oropharyngeal, hypopharyngeal, and laryngeal cancers

Investigations

Carcinomas of the oropharynx, hypopharynx, and nasopharynx are notorious for their presentation with metastatic neck nodes without any obviously discernible primary lesion. In these circumstances, a fine needle aspiration biopsy (FNAB) from the clinically suspicious neck nodes helps in establishing the tissue diagnosis as well as identifying the putative site of the primary tumor. It is an effective, minimally invasive, and cost-effective diagnostic tool with negligible risk of complications such as tumor seeding along the needle tract, bleeding, infection, and fistula formation. FNAB usually yields representative cellular samples both for routine histological staining and immunohistochemistry (IHC). With an experienced histopathologist, FNAB achieves a diagnostic sensitivity of 83–97% and a specificity of 91–100% for metastatic lesions (Gourin and Johnson 2000; Layfield 2007). However, for large cystic nodes (commonly seen in HPV-positive cancers), the sensitivity of FNAB drops to 33–50% (Pisharodi 1997) due to high false-negative results. Ultrasound-guided FNAB is useful in this scenario to guide the needle to the wall of the node for obtaining cellular material. A p16 IHC, HPV DNA ISH, and Epstein-Barr-encoded RNA on ISH can help to localize the site of primary tumor.

The presence of HPV can be detected by HPV in situ hybridization which detects the presence of HPV genetic material in tissue sections of the tumor and could simultaneously detect several high-risk HPV genotypes including HPV-16 and HPV-18. In addition, the expression of p16 which increases in HPV-positive tumors is a surrogate marker and can be detected by immunohistochemistry which can be performed routinely in most pathology laboratories. HPV detection in tumor cells can also be undertaken by polymerase chain reaction (PCR) for detection of HPV DNA (or reverse transcription PCR for detection of HPV mRNA). HPV classification is made when the sample is positive for HPV ISH and p16 immunohistochemistry (Westra 2009; Robinson et al. 2010). The principles, merits, and demerits of each are outlined in Table 8.

Imaging for early oropharynx cancers is a diagnostic challenge as abundant lymphoid tissue fills the oropharynx which enhances on contrast administration. An additional challenge with CT is distortion of image quality due to dental artifact (Figs. 45 and 46). Tongue and swallowing movements can hamper the quality of MRI images; however, for better delineation of tumor from adjacent soft tissues, MRI remains the investigation of choice for oropharyngeal cancers (Figs. 47 and 48). Staging of oropharyngeal tumors is outlined in Table 13. Lymph node compartments are separated into levels and sublevels as shown in Fig. 49.

Fig. 45

T1N2b squamous cell carcinoma of the palatine tonsil. CT (a) shows a heterogeneously enhancing centrally necrotic mass within the superior aspect of the left palatine tonsil, measuring up to 17 mm consistent with a left tonsillar SCC. Multiple centrally necrotic/cystic left cervical lymph nodes were present including a predominantly cystic 32 mm left level II node. On PET/CT (b) there is intense asymmetric activity at the left palatine tonsil corresponding to the lesion seen on CT

Fig. 46

Squamous cell carcinoma of the palatine tonsil. CT (a) shows an expansile enhancing mass lesion centered in the left palatine tonsil. The lesion has an unusual morphology, and it involves the entire left palatine tonsil and extends superiorly to the junction of the upper oropharynx with the lower nasopharynx. Anteriorly at the upper pole region, it crosses the midline and involves the posterior aspect of the soft palate and the uvula, and further inferiorly it involves the anterior tonsillar pillar and fills the glossotonsillar sulcus. It approximately measures 44 mm craniocaudal × 35 mm transverse oblique × 26 mm AP oblique. PET/CT (b) shows intense uptake centered on the left palatine tonsil with quite extensive involvement of the soft palate extending across the midline to the right side and superiorly to the junction of the oropharynx with the nasopharynx

Fig. 47

Base of tongue squamous cell carcinoma. MRI (a) shows a well-defined, left-sided tongue base mass measuring 26 mm in its superoinferior dimension with a mediolateral width of 21 mm and a depth of 13 mm. The lesion fills the left vallecula and has a peripheral enhancing margin merging with the normal oropharyngeal and tongue base mucosa. There is no overt invasion of the remainder of the tongue base, the oral tongue, or the oropharynx. The tumor extends to the midline including the median glossoepiglottic fold. The tumor is of identical signal to lymphoid tissue. PET/CT before surgery (b). Patient received TORS (c), neck dissection, and postoperative radiation, with excellent functional outcomes and disease-free at 54 months posttreatment (d) (Images courtesy of Dr Chady Sader, Western ENT, Perth WA, Australia)

Fig. 48

Contrast-enhanced T1 MRI image showing thickening of the tonsillar fossa (arrow) suggestive of an early tumor

Table 13 Staging of pharyngeal tumors. TNM clinical classification and staging of pharyngeal malignant tumors (Adapted from Brierley et al. 2017)

Fig. 49

Lymph node compartments separated into levels and sublevels. The level I node compartment includes the submental and submandibular nodes, above the hyoid bone and anterior to the posterior edge of the submandibular gland. The level II, III, and IV nodes are arrayed along the jugular veins on each side, bordered anteromedially by level VI and laterally by the posterior border of the sternocleidomastoid muscle. The level III nodes are bounded superiorly by the level of the hyoid bone and inferiorly by the cricoid cartilage; levels II and IV are above and below level III, respectively. Levels I, II, and V can be further subdivided as noted IA, IB, IIA, IIB, VA, and VB. The level V nodes are in the posterior triangle, lateral to the lateral edge of the sternocleidomastoid muscle. Level VI contains the thyroid gland, and the adjacent nodes bordered superiorly by the hyoid bone, inferiorly by the innominate (brachiocephalic) artery, and laterally on each side by the carotid sheaths. The inferior extent of level VI is defined as the suprasternal notch. Many authors also include the pretracheal and paratracheal superior mediastinal lymph nodes above the level of the innominate artery (sometimes referred to as level VII) in central neck dissection

Treatment

The current preferred therapy for oropharyngeal cancer is radiation or concurrent chemoradiation (depending on the stage of disease), and while these could result in good patient outcomes, they nevertheless are often linked with worrying side effects, such as damage to the larynx and throat which could affect speech and swallowing, respectively.

Early Oropharyngeal Cancers

For early-stage oropharyngeal cancers (Fig. 50), the fundamental principle is to maximize the likelihood of cure with a single modality treatment – either surgery or radiation therapy (RT). The preferred treatment modality is RT in most patients as it comprehensively addresses both the primary site and the neck nodes and has excellent functional outcome. A major advantage of RT is that it addresses the retropharyngeal nodes which carry a high chance of metastasis in oropharyngeal cancers and are not usually addressed in routine neck dissection. With improved radiation techniques such as intensity-modulated radiation therapy (IMRT), there has been significant improvement of function compared with conventional radiation treatment (Garden et al. 2007; Nutting et al. 2011). The major drawback of surgery is the associated morbidity and the high rate of occult neck metastasis which results in addition of adjuvant RT and its toxicities. However, proponents of surgery argue that the overall dose of radiation to the pharynx is less in the adjuvant setting compared to the definitive setting, thus reducing toxicities (Figs. 51 and 52). Minimally invasive surgery in the form of transoral laser surgery (TOLS) or transoral robotic surgery (TORS) is the treatment of choice in patients where it can be carried out with minimal functional morbidity and in appropriately selected salvage cases (Figs. 53 and 54).

Fig. 50

Treatment algorithm of early oropharyngeal cancers

Fig. 51

Extensive osteoradionecrosis in a 71-year-old female post chemoradiation for oropharyngeal squamous cell carcinoma (a and b). Significant symptoms of pain, trismus, and an orocutaneous fistula were present. The patient underwent oromandibular resection and reconstruction with a free fibula flap (c + d). The patient had significant functional and quality of life improvement (e) (Images courtesy of Dr Chady Sader, Western ENT, Perth WA, Australia)

Fig. 52

Clinical (a) and CT radiological (b) appearance of osteoradionecrosis with a pathological mandibular fracture and orocutaneous fistula in a 50-year-old male who had previously undergone neck dissection and radiation for a left tonsillar squamous cell carcinoma. The 3D computer-generated model of the mandible (c) aided the free tissue reconstruction of the jaw (d). The skin paddle of the pedicle was used to reconstruct the cutaneous defect of the neck (e) (Images courtesy of Dr Chady Sader, Western ENT, Perth WA, Australia)

Fig. 53

Oropharyngeal cancer removed with transoral robotic surgery (TORS) (Image courtesy of Dr Chady Sader, Western ENT, Perth WA, Australia)

Fig. 54

TORS setup showing the surgical assistant at the bedside (a) ensuring patient safety, facilitating any adjustments to the robotic arms, communicating with the surgeon, and ensuring smoke evacuation and suction of blood/secretions. The surgeon is seated in the surgeon’s console (b) and operating the robot (Images courtesy of Dr Chady Sader, Western ENT, Perth WA, Australia)

Advanced Oropharyngeal Cancers

Concurrent chemoradiation is the preferred treatment modality for stage III and IV oropharyngeal cancers (Fig. 55). RT alone can be considered for low bulk stage III disease (T1, 2 N1). Primary surgery can also be considered for selected low-volume stage III cancers (T3 N0) (Hurtuk et al. 2012). If the margins of resection are negative with no pathological metastatic nodes or other adverse risk factors like perineural invasion (PNI) or lymphovascular spread (LVS), surgery alone may be adequate thus reducing the cost and treatment morbidity. On the contrary for other stage III diseases, patients require adjuvant radiation or even chemoradiation (if positive margins or extracapsular spread) resulting in significant morbidity. For stage IV cancers, concurrent chemoradiation is the treatment modality of choice. In general, it involves concomitant cisplatin chemotherapy with full-dose RT (70 Gy, 35#) to the primary site and the neck. Chemotherapy can be given either in three weekly or weekly doses.

Fig. 55

Treatment algorithm of advanced oropharyngeal cancers

HPV-Associated Oropharyngeal Cancers

HPV-associated oropharyngeal cancers have a relatively better prognosis as compared to HPV-negative counterparts. Selected HPV-positive patients (T1-3, N0-2a) treated by RT alone have low locoregional failure and distant metastasis (O’Sullivan et al. 2013). Based on these results, the concept of de-intensification of treatment in HPV-positive oropharyngeal cancers to reduce the treatment-related morbidities has been proposed (O’Sullivan et al. 2013). While this may be ideal, implementation has not been straightforward as clinical observation suggests that even within HPV-positive patients, there is a significant minority who still respond poorly to treatment and have a poor prognosis (Ang et al. 2010).

Currently there are no clinically relevant markers to distinguish these individuals, making the possibility of selecting patients who may benefit from treatment de-escalation rather challenging. Notwithstanding, based on features of these patients which include heavy smoking (>10 pack-years smoking) and advanced nodal disease (N2b and above), patients who match these criteria have been excluded from treatment de-escalation trials (Ang et al. 2010; Granata et al. 2012). Patients whose tumors have evident tumor-infiltrating lymphocytes have superior survival suggesting that the immune infiltrate could identify the subset of HPV-positive patients who have poor prognosis (Ward et al. 2014). While such biomarkers could impact on patient selection and have the potential to change clinical practice, the evaluation of tumor-infiltrating lymphocytes is still at an early stage and not yet in mainstream clinical use. Trials for de-escalation of treatment in HPV-positive OPSCC are underway (ADEPT, ECOG 3311, PATHOS).

The role of HPV vaccines in preventing oropharyngeal cancers is an area of active discussion. As the majority of oropharyngeal cancers are caused primarily by HPV-16, a particularly dangerous strain of the virus, it is conceivable that the two vaccines that protect against HPV-16 that are currently approved to prevent cervical cancer could also do the same for oropharyngeal cancer. The quadrivalent HPV vaccine types 6, 11, 16, and 18 (Gardasil/Gardisil/Silgard) are effective in preventing anal, cervical, vaginal, and vulvar precancers and cancers, while the bivalent HPV vaccine types 16 and 18 (Cervarix) have been demonstrated to be effective in cervical precancers and cancers (Garland and Smith 2010; Lu et al. 2011). More recently 9-valent HPV vaccine types 6, 11, 16, 18, 31, 33, 45, 52, and 58 (Gardasil 9) have been approved by the US FDA for routine vaccination of adolescents (girls and boys) at age 11 or 12 years and can be started as early as 9 years of age. While it is theoretically possible, studies to determine if HPV vaccine will prevent oropharyngeal cancers are hampered by the need for invasive sampling deep in the tonsillar area where the cancer arises, and therefore, the vaccine is currently not indicated for the prevention of head and neck cancers, but it is likely that population-based observation studies in vaccinated cohorts will reveal a positive benefit in the future (Scudellari 2013).

Hypopharyngeal Cancer

Epidemiology, Etiology, and Pathology

Although 95% of hypopharyngeal cancers are SCCs, rarely lymphomas, sarcomas, and adenocarcinomas can arise from the hypopharynx. While tobacco smoking is the primary etiologic factor of laryngeal cancers, hypopharyngeal cancers are associated with alcohol abuse (Spitz 1994). Ethyl alcohol during metabolism is first converted into acetaldehyde (a carcinogenic by-product) which is further metabolized into acetate (excretory end product) by an enzyme acetaldehyde dehydrogenase. Inability to convert acetaldehyde to acetate due to mutations in acetaldehyde dehydrogenase gene results in accumulation of carcinogenic metabolic intermediate acetaldehyde. The carcinogenic effect of acetaldehyde is exerted by generation of free radicals, direct DNA damage, and upregulation of enzymes of the cytochrome P450 system which results in activation of certain procarcinogens to carcinogens. Additionally, alcohol acts as a solvent for tobacco increasing the cellular permeability of tobacco carcinogens through the mucosa of the upper aerodigestive tract. Alcohol also impairs immunity and causes nutritional deficiencies thus lowering the resistance to cancer. Alcohol is believed to act synergistically to tobacco in the etiology of head and neck cancers.

Dietary risk factors have also been implicated as a risk factor for hypopharyngeal cancers. Plummer-Vinson syndrome is characterized by iron deficiency anemia, hypopharyngeal webs, koilonychias, weight loss, and dysphagia. This syndrome is accompanied by an increased risk of postcricoid SCC. Treatment of iron deficiency anemia has been found to decrease the risk of malignancy.

Clinical Presentation

Pyriform fossa and postcricoid tumors of the hypopharynx initially present with non-specific throat symptoms and metastatic cervical nodes. However, advanced tumors present with dysphagia, hoarseness of voice (due to laryngeal involvement), symptoms of aspiration, pain, earache (referred otalgia), and dyspnea.

Endoscopic evaluation of the upper aerodigestive tract is undertaken to map the extent of the disease as well as to take a biopsy from the primary lesion. Disease mapping includes assessment of the adequacy of the airway, evaluation of the mucosal extent of disease, and mobility of the vocal cords and arytenoids and signs of aspiration. All cases of hypopharyngeal cancers should undergo a rigid esophagoscopy to delineate the lower extent of tumor and for evaluation of a potential second primary lesion in the esophagus.

Investigations

Cross-sectional imaging with CT and MRI plays an indispensable complementary role to endoscopy in the pre-therapeutic work-up of hypopharyngeal cancer and is very valuable for the detection of tumor recurrence after surgery or radiation treatment as well. CT is the preferred imaging method for staging of hypopharyngeal cancer. The primary tumor typically appears as a solid soft tissue nodule or region of superficial thickening with increased enhancement. When it extends beyond the confines of the pharynx, the surrounding fat planes are obliterated. Careful assessment of cervical lymph nodes is essential as up to 75% of patients with hypopharyngeal SCCs have nodal metastases at the time of diagnosis (Fig. 56). MRI has the ability to be superior to CT in local staging and assessing perineural spread; however, relatively long acquisition times and degradation by motion artifact are sometimes challenging. Both CT and MRI are routinely used for detection of subtle cartilage invasion (Fig. 57), but there is still controversy about which modality can most accurately detect cartilage invasion, and both modalities have shortcomings (2003). As is the case with other metabolically active tumors, FDG PET/CT has an increasing role in the diagnosis, staging, and follow-up of hypopharyngeal tumors (Fig. 58). Staging of hypopharyngeal tumors is outlined in Table 13.

Fig. 56

Hypopharyngeal carcinoma. Post-contrast CT sagittal (a), axial (b), and coronal (c) views show an extremely large heterogeneous and partially necrotic left-sided mass lesion (arrows). This measures approximately 10 cm craniocaudal × 6.8 cm transverse × 4.5 cm AP. Cranially, the lesion is centered in the hypopharynx and aryepiglottic fold on the left extending anterior to involve the pre-epiglottic space but spreads into the left paralaryngeal space markedly narrowing and displacing the supraglottic airway to the right. It crosses posteriorly into the right side of the hypopharynx and involves both left and right false cords. It spreads laterally to erode the posterior aspect of the left thyroid cartilage and extends into the extra-laryngeal space where it infiltrates the undersurface of the strap muscles and extends inferiorly to infiltrate the superior aspect of the left lobe of the thyroid. There is associated extensive left-sided necrotic and obviously metastatic lymphadenopathy within the left IIA, IIIA, and IVA levels (d + e). PET/CT(F-18 FDG) fusion sagittal (f), coronal (g), and axial (h) views. There is a large invasive left neck mass centered on the hypopharynx which is intensely FDG-avid and appears to cross the midline to the right hypopharynx. There are enlarged left level IIa and III lymph nodes with central photopenia and peripheral intense FDG uptake, consistent with necrotic nodes

Fig. 57

Contrast-enhanced CT neck (bone window) showing a pyriform fossa tumor showing erosion of the inner lamina of the thyroid cartilage without exolaryngeal spread (arrow)

Fig. 58

PET/CT fusion axial image showing an enhancing lesion involving hypopharynx with gross exolaryngeal extension

Treatment

Early Hypopharyngeal Cancer

Radiotherapy is the preferred treatment modality for early hypopharyngeal cancers as surgery in this region results in high odds of aspiration (Fig. 59). Moreover, due to the high propensity of occult nodal metastasis, surgery frequently upstages the neck resulting in administration of multimodality treatment. Surgical procedures, if planned, are either TOLS or open partial laryngopharyngectomy. The morbidity of TOLS is significantly less than open surgery including the avoidance of a temporary tracheostomy and a shorter hospital stay. However, the neck must be addressed in all patients. If TOLS is the primary treatment modality, neck dissection can be carried out either simultaneously or after an interval of 7–10 days. The advantages of interval neck dissection include a second look into the operated cavity under general anesthesia and for margin revision if required based on the final histopathology, avoid acute edema of the larynx which can occur if bilateral neck dissection is undertaken simultaneously with the primary resection, and address transit lymphatics (not a universally accepted concept). The major drawback of interval neck dissection is the need for a second surgery under general anesthesia.

Fig. 59

Treatment algorithm for early hypopharyngeal cancer

Advanced Hypopharyngeal Cancers

In advanced lesions which require total laryngectomy with pharyngectomy, induction chemotherapy can be utilized to facilitate organ preservation (Fig. 60). An EORTC phase III RCT has shown that in the group randomized to the nonsurgical arm (induction chemotherapy with cisplatin and fluorouracil followed by radiation in responders), more than half of patients who survived preserved their larynx (Lefebvre et al. 1996, 2012). There was no difference in 5- and 10-year overall or progression-free survival between the surgical (surgery followed by adjuvant treatment) and nonsurgical arms (Lefebvre et al. 1996, 2012). To further facilitate organ preservation with induction chemotherapy, docetaxel has been used in combination with cisplatin and fluorouracil (5FU) in a triple therapy regimen commonly known as TPF (Taxotere, Platinol, Fluorouracil). Although overall survival was the same in the TPF and PF (cisplatin/5FU) arms, a higher tumor response rate (80% vs 59%) and laryngeal preservation rate (70% vs 57%) was seen in the TPF arm compared to PF arm (Pointreau et al. 2009).

Fig. 60

Treatment algorithm for advanced hypopharyngeal cancers

Concurrent chemoradiation remains a treatment option for advanced hypopharyngeal cancers, although there is no conclusive evidence for its role in exclusive hypopharyngeal cancer patients. Data is extrapolated from studies on laryngeal and general head and neck cancers. A meta-analysis of 17,346 patients of head and neck cancers demonstrated an absolute benefit of 6.5% and 2.4% in overall survival with concurrent chemoradiotherapy and induction chemotherapy with radiotherapy, respectively. The benefit of concurrent chemotherapy was predominantly seen in younger patients with no benefit seen in patients >70 years of age (Pignon et al. 2009).

In patients who are not candidates for concurrent chemotherapy (poor performance status, renal insufficiency, or sensorineural hearing loss), hyper-fractioned radiation can be considered. Similar to concurrent chemotherapy, no benefit of hyper-fractioned radiation has been demonstrated in patients >70 years old (Baujat et al. 2010). Alternatively, biological targeting agents can be used in patients not fit for concurrent chemotherapy. In a phase III RCT of advanced head and neck cancer patients comparing radiation alone with radiation plus weekly cetuximab, a 10% overall survival benefit was found in patients treated with concurrent cetuximab (Bonner et al. 2006). Cisplatin potentiates radiation-induced toxicities and causes its own toxicities limiting its doses and thus efficacy, whereas cetuximab on the other hand does not enhance radiation-induced toxicities and thus is better tolerated than concurrent cisplatin.

Advanced hypopharyngeal cancers with nonfunctional larynx or extra-laryngeal spread are candidates for total laryngectomy with partial or circumferential pharyngectomy with appropriate reconstruction followed by adjuvant treatment depending on final histopathology. Patients with positive resection margins or extracapsular nodal spread receive adjuvant chemoradiation, while others receive adjuvant radiation alone.

Laryngeal Cancer

Epidemiology, Etiology, and Pathology

Laryngeal cancers are primarily squamous cell carcinomas with minor salivary gland cancers, sarcomas, neuroendocrine tumors, and hematolymphoid tumors forming a minority of the cases.

Tobacco and alcohol are the two major risk factors of laryngopharyngeal cancers, with tobacco smoking representing the primary etiologic factor for laryngeal cancers. Tobacco is consumed in the smoked and the smokeless form. Tobacco smoke contains about 60 carcinogens of which polycyclic aromatic hydrocarbons constitute the main carcinogen followed by aromatic amines. Smokeless tobacco contains about 16 carcinogens, nitrosamines being the major constituent. Metabolism of tobacco products results in the formation of electrophilic intermediates which bind to normal DNA resulting in the formation of DNA adducts. These adducts are either repaired or undergo apoptosis. Persistence of miscoding leads to mutation of crucial genes regulating the cell cycle (e.g., RAS, MYC, p53, p16, RB) resulting in carcinogenesis.

Clinical Presentation

Laryngeal cancers as opposed to pharyngeal cancers present relatively early due to symptoms related to airway obstruction and voice change. Supraglottic cancers present initially with neck nodes and dyspnea. Hoarseness of voice appears relatively late. Glottis cancers on the other hand present at early stage with hoarseness of voice. Due to the paucity of lymphatics in the glottic region, neck nodes appear late when the tumor has spread to the adjacent subsites of supraglottis or the pyriform sinus.

Investigations

The pre-epiglottic space is best evaluated in axial and sagittal images (Figs. 61, 62, and 63). The sensitivities of CT and MRI are 100%, with specificity for CT being 93% and MRI being 84–90% (Becker 1998). Radiological invasion of the paraglottic space is best seen in axial and coronal sections (Figs. 64 and 65). The sensitivities for CT and MRI are 93% and 97%, respectively, while the specificity varies between 50% and 76%. Reduced specificity is due to disease overestimation because of peritumoral inflammation (Becker 1998). Overall, contrast-enhanced CT is the investigation of choice for laryngeal cancers (Fig. 66) with MRI reserved for cases with doubtful erosion on CT and in patients with allergy to iodinated contrast or compromised renal function. Videostroboscopy helps determine the location and size of a tumor, as well as how the tumor has affected the function of the larynx and hypopharynx. Histopathology shows squamous differentiation and invasion on biopsy. Cartilage invasion and extra-laryngeal spread are major determinants in upstaging the disease and management of laryngeal and hypopharyngeal cancers. Radiologically, cartilage invasion can be divided into three stages (Becker et al. 1997): (1) sclerosis, (2) erosion/lysis, and (3) extra-laryngeal tumor spread.

Fig. 61

Contrast-enhanced CT neck axial image showing tumor involvement of the pre-epiglottic space (yellow arrow) and necrotic level II lymph node (red arrow)

Fig. 62

Contrast-enhanced CT neck sagittal image showing a base of tongue tumor infiltrating into the pre-epiglottic space (yellow arrow)

Fig. 63

Contrast-enhanced CT neck sagittal image showing a supraglottic tumor almost completely filling the pre-epiglottic space (yellow arrow)

Fig. 64

Contrast-enhanced CT neck (soft tissue window) showing a pyriform fossa tumor with paraglottic extension (red arrow), erosion of the inner lamina of the thyroid cartilage without exolaryngeal spread (yellow arrow)

Fig. 65

Contrast-enhanced CT showing a glottic tumor involving the paraglottic space (yellow line)

Fig. 66

Contrast-enhanced CT neck showing a laryngeal tumor with sclerosis of the thyroid cartilage indicating early cartilage invasion

Sclerosis histologically corresponds to early perichondral involvement or microscopic intracartilaginous spread . CT is sensitive in detecting sclerosis but specificity varies between cartilages being lowest for thyroid cartilage (40%) and higher for cricoid (76%) and arytenoid cartilages (79%). Erosion or lysis corresponds to osteolysis without through and through cartilage disruption, with/without new bone formation. Contrast-enhanced CT has a high specificity for erosion detection (93%), but the sensitivity is poor (Fig. 67) (Becker et al. 1997). Extension of the tumor outside the laryngeal framework is termed as extra-laryngeal spread. Similarly, for extra-laryngeal spread multi-slice CT (MSCT) has high specificity (95%) with a poor sensitivity (Becker et al. 1997). MRI has higher sensitivity (89–95%) but lower specificity (74–84%) as compared to CT in detecting cartilage invasion. The negative predictive value of MRI is very high (94–96%) (Mukherji and Bradford 2006). Tumor infiltration of the marrow is best identified in T1 contrast images with fat suppression. Staging of laryngeal tumors is outlined in Table 14.

Fig. 67

Contrast-enhanced CT neck showing a supraglottic tumor with cartilage erosion and exolaryngeal spread (yellow arrow)

Table 14 Staging of laryngeal tumors. TNM clinical classification and staging of laryngeal malignant tumors (Adapted from Brierley et al. 2017)

Treatment

T1 Glottic Cancers

The primary goal of treatment is to maximize cure and minimize treatment-related morbidity. T1a glottic cancers can be treated either by definitive RT or transoral laser surgery (TOLS) (Table 15) (Fig. 68). Both treatment modalities have similar locoregional control and disease-specific survival (Khan et al. 2012; Canis et al. 2015). Although the oncologic outcomes are comparable, larynx preservation is higher in patients treated with TOLS (100%) compared to those treated with definitive RT (93%) (Remmelts et al. 2013).

Fig. 68

Treatment algorithm for T1 glottic cancers

Table 15 Benefits of different treatment modalities for early glottis cancers

No prospective study has been performed comparing the oncologic and voice outcomes of TOLS versus definitive RT for T1a glottic cancers. Available data from multiple retrospective series have not found any significant difference in oncologic or voice outcomes between the two treatment modalities although larynx preservation has been found to be better in TOLS patients. In a meta-analysis based on over 7600 patients, there was no difference in local control or laryngectomy-free survival between TOLS and RT (Higgins et al. 2009). Although there was a trend toward improved overall survival in patients treated with TOLS, and improved voice outcome in definitive RT patients, the difference did not reach statistical significance (Higgins et al. 2009). Another meta-analysis of 1729 patients comparing the oncologic and functional outcomes of TOLS and RT found no difference in local control, overall survival, disease-specific survival, or posttreatment voice quality between the two groups; however, larynx preservation was significantly higher in the TOLS group compared to the RT group (Abdurehim et al. 2012). Due to the lack of prospective data, the treatment modality for T1 glottic cancers should be individualized. Young patients with mid-cord lesions and a good endoscopic exposure are preferably treated with TOLS. Patients with lesions involving anterior commissure or involving both cords and patients who are voice professionals are preferably treated with definitive RT. Pros and cons of each treatment option should be discussed with the patient before choosing a treatment modality.

T2 Glottic Cancers

Similar to T1 glottic cancers, the treatment of T2 glottic cancers with mobile cords is TOLS or definitive RT (Fig. 69). The treatment should be individualized depending on institutional expertise and patient preference. Tumors with restricted cord mobility indicate infiltrative disease which responds poorly to RT alone. These patients are preferably treated with chemoradiation. TOLS has a limited role in these lesions as resection is extensive (a type III or IV cordectomy) rendering the patient with poor voice quality and significant chances of aspiration.

Fig. 69

Treatment algorithm for T2 glottic cancers

Early Supraglottic Cancers

Early supraglottic cancers can be treated either with definitive RT or surgery (Fig. 70). In view of the high propensity of occult neck nodal metastasis, surgery when used as the primary treatment modality frequently upstages the neck resulting in administration of adjuvant RT, converting a single modality into a multimodality treatment. Thus, definitive RT remains the treatment of choice for early supraglottic cancers. In patients with bulky tumors, concurrent chemoradiation may be considered as lesions >6 cm³ do not respond well to RT alone (Mancuso et al. 1999). Surgery, mostly TOLS or open partial laryngectomy, is usually considered in the salvage setting. Five-year local control with surgery (TOLS or open surgery) and radiation are comparable in T1 cancers (90–100% for surgery and 77–100% for radiation), while surgery has slightly better local control for T2 lesions (80–97% for surgery and 62–83% for RT) (Ambrosch 2007).

Fig. 70

Treatment algorithm for early supraglottic cancers

Advanced Laryngeal Cancers

Patients with advanced laryngeal cancers with a functional larynx and no extra-laryngeal spread are preferably treated on an organ preservation protocol (Fig. 71). Concurrent chemoradiotherapy is the treatment of choice, although recent evidence suggests a higher morbidity and mortality as compared to neoadjuvant chemotherapy followed by radiation. The VA trial published in 1991 was the first RCT comparing neoadjuvant chemotherapy followed by RT with the standard practice of total laryngectomy followed by adjuvant treatment in advanced laryngeal cancers (Department of Veterans Affairs Laryngeal Cancer Study et al. 1991). The estimated 2-year survival was 68% in both groups. In the nonsurgical arm, the larynx could be preserved in 64% of patients. The pattern of recurrence differed significantly with more local recurrences and few distant failures in the nonsurgical arm. Patients with stage IV tumors as compared to stage III tumors, and T4 disease as compared to smaller primaries, had significantly increased rates of salvage laryngectomies.

Fig. 71

Treatment algorithm for advanced laryngeal cancer

Concurrent chemoradiotherapy (CT RT) and neoadjuvant chemotherapy (NACT) followed by RT and RT alone have been used as treatment modalities in advanced laryngeal cancers (large-volume T4 lesions excluded) (Forastiere et al. 2003). Follow-up of patients with advanced laryngeal cancers treated with one of these modalities showed that larynx preservation was significantly higher in the CT RT group compared to the two other groups at 3.8 years posttreatment. Ten-year follow-up data revealed no difference in overall survival and laryngectomy-free survival between NACT followed by RT and concurrent chemoradiotherapy CT RT (Forastiere et al. 2013). Although local control and larynx preservation continued to be significantly better in the CT RT arm, there were significantly more noncancer-related deaths in the CT RT arm compared to NACT arm (Forastiere et al. 2013). Least number of salvage surgeries were required in the CT RT patients; however, fistula formation following salvage surgery was most commonly seen in these patients.

Patients with nonfunctional larynx (tracheostomy tube or Ryles tube in situ) and extra-laryngeal disease respond poorly to organ preservation and are treated with surgery (total/near-total laryngectomy with neck dissection) followed by appropriate adjuvant treatment (Fig. 72).

Fig. 72

Macroscopic appearance of the larynx sectioned transversely from superior to inferior (left to right) showing a left glottic squamous cell carcinoma which invades left paraglottic soft tissue and extends into subglottis. The tumor abuts the thyroid cartilage and crosses the midline anteriorly. The tumor does not involve overlying strap muscles or left hemithyroid (Image courtesy of Dr Chris Van Vliet, Pathwest, Perth WA, Australia)

Nasopharyngeal Cancer

Epidemiology, Etiology, and Pathology

The nasopharynx forms the superior most part of the pharynx and is a cuboidal cavity located beyond the choanae or the posterior nares. It comprises two lateral walls and a roof which slopes down till the level of the uvula thereby making the soft plate as its floor. Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma arising from the surface epithelium of this region (Wenig 1999).

NPC is endemic to Southeast Asia (Southern China) and also includes the first-generation emigrated Chinese population in the West. Alaskan Eskimos and Mediterraneans also report incidence of NPC. In the Indian subcontinent, it is more prevalent in the northeastern states which have a substantial mongoloid population. There are rare incidences of NPC in the rest of the world. In terms of age standardized ratio, the highest incidence is in Southern China ranging from 15 to 50 per 100,000. There is a high male preponderance with a male-to-female ratio of 3:1 and an usual age of presentation between 20 and 60 years of age (Marks et al. 1998; Harrison 2014).

NPC has a multifactorial etiology which is markedly different from other sites in the head and neck like tobacco and alcohol. Viral, genetic, and environmental factors contribute to NPC etiology. Salted fish with high content of nitrosamine, poor hygiene, improper ventilation, smoking, and the use of nasal balms have been attributed as environmental factors. There has been an increased genetic susceptibility associated with HLA-A2, B-17, B246, and BW58 genotypes, and reduced risk is associated with A11, B13, and B22 loci. There has been a drop in the incidence of NPC in the last 40 years which suggests the role of environmental factors². The viral etiology is mainly attributed to Epstein-Barr virus (EBV) for the endemic WHO type II/III. EBV is a B-lymphotropic herpes virus. It has a consistent role in the etiopathogenesis which can be seen from the early stages of the disease. EBV is absent in normal nasopharyngeal mucosa. Clonal viral genomes and latent membrane proteins (LMP-1) of EBV have been detected in NPC. Human papilloma virus (HPV) is associated with some NPC arising from oropharyngeal subsites (Marur et al. 2010).

The World Health Organization (WHO) classifies NPC into either keratinizing squamous cell carcinoma (WHO type I), non-keratinizing squamous cell carcinoma (WHO type II), or basaloid squamous cell carcinoma (Chan et al. 2005).

Clinical Presentation

Initially NPC involves the fossa of Rosenmuller in the majority of cases, and as it advances, it involves the nasal cavity, sphenoid sinus, posterior ethmoids, orbit, parapharyngeal space sphenopalatine fossa, foramen lacerum, and middle cranial fossa. Symptoms of NPC include breathing difficulty and nasal blockage, painless neck mass, hearing loss, ear discharge, epistaxis, cranial nerve deficits, proptosis, and trismus. Nine out of ten patients usually present with at least unilateral metastatic neck nodes either in parapharyngeal or the jugular digastric nodal stations (Marks et al. 1998; Chan et al. 2005).

Investigations

The nasopharynx can be clinically examined with a flexible fiber-optic endoscope or a rigid rod endoscope 0-degree or 70°. Neck examination by palpation is imperative. Imaging can be done by means of contrast-enhanced CT (CECT) which provides excellent information regarding the primary site, nodal burden, and bone invasion, whereas an MRI can be complementary for better soft tissue extent of the tumor, to differentiate between mucus and tumor and perineural spread of the tumor (Sakata et al. 1999) (Figs. 73, 74, and 75). More than 20% of NPC can present with distant metastasis to the bone, lung, and liver in increasing frequency. Hence a PET/CT is recommended in stage III/IV cases (Vikram et al. 1985). Biopsy can be either taken from the primary site using a punch forceps with the help of an endoscope under topical local anesthesia. FNAC from the nodes can also demonstrate NPC cells and can be used for tissue diagnosis. Serological markers like IgA antibody against viral capsid antigen of EBV can be used for screening which has a sensitivity upward of 80%. Plasma EBV DNA using PCR also is used as a serological marker with a sensitivity up to 96% and can be used in early detection (Leung et al. 2006).

Fig. 73

Shows an axial image of T2 MRI showing a right-side nasopharyngeal carcinoma

Fig. 74

T1N2M0 nasopharyngeal carcinoma. On MRI there is a polypoid carcinoma in the right central aspect of the nasopharyngeal mucosal space. The tumor demonstrates T1 isointensity (a) and T2 hyperintensity (b) with mild to moderate enhancement. The lesion measures 26 mm transverse × 9 × 22 mm AP and 8 mm craniocaudal. There is preservation of the normal marrow signal of the clivus with no evidence of central skull base invasion. The lesion is confined within the nasopharyngeal mucosal space with no convincing evidence of submucosal extension. There are no pathological retropharyngeal enlarged lymph nodes and no evidence of perineural tumor spread along the trigeminal nerve. PET/CT (c) shows intense abnormal FDG activity related to a soft tissue mass of the posterosuperior right nasopharynx. Activity appears well localized with no bone erosion

Fig. 75

T4N0M0 nasopharyngeal carcinoma. MRI shows an aggressive strongly enhancing lobular mass within the central skull base, occupying most of the basisphenoid and the anterosuperior aspects of the basiocciput, protruding minimally into the pre-pontine cistern, where it abuts the basilar artery, involving the posteromedial aspects of both sphenoid sinuses and extending in continuity with abnormal soft tissue in the central superior and nasopharynx. The extent of the lesion is up to 36 mm superoinferior × 29 mm transverse × 21 mm anteroposterior (a). The lesion is markedly T2 hypointense (b) and shows significant diffusion restriction, both features implying a densely cellular tumor consistent with a nasopharyngeal carcinoma

Treatment

NPC are distinct in regard to other cancers of the head and neck as they are extremely radiosensitive; therefore, they can be effectively treated with radiotherapy (Harrison 2014). Radiotherapy can cover all the areas of the nasopharynx and the potential sites of its spread without extensive morbidity or toxicity. Single modality treatment is advised in the early stages. In advanced stages, multiple trials have shown the advantage of using concurrent chemoradiation, with or without altered fractionation. An overview of the management is shown in Fig. 76. In cases of residual disease or recurrent cases, various modalities have been attempted in the salvage setting. These include salvage re-irradiation, nasopharyngectomy, salvage neck dissection, stereotactic radiosurgery, and intracavitary brachytherapy .

Fig. 76

Overview of management of nasopharyngeal carcinoma

Traditionally 2D techniques were used and they are still used at present in certain centers around the world. Two-dimensional techniques can be effectively used for early lesions. Shielding of the brainstem areas and the spinal cord is done to prevent toxicities. Three-dimensional conformal therapy (3DCRT) and IMRT are currently used and have improved dose homogeneity and permit dose escalation to high-risk areas with less toxicities to normal adjacent structures. Brachytherapy and stereotactic radiosurgery boost escalating doses to the primary site alone in early stages of NPC (Harrison 2014).

The NCCN guidelines have recommended repeat of the baseline imaging or PET/CECT after at least 8–12 weeks and 12 weeks, respectively, for response assessment. Routine follow-up should occur 1–3 months in the first year, 2–6 months in second year, and 4–8 months from 3 to 5 years with imaging every 6 months. Routine thyroid function test and speech and swallowing evaluation every 6 months have been recommended. Plasma EBV DNA in endemic patients can be used for surveillance and has been recommended by the NCCN guidelines (Adelstein et al. 2017).

Tumors of the Nasal Cavity and Paranasal Sinuses (Skull Base Tumors)

Etiology, Epidemiology, and Pathology

Tumors of the nasal cavity and paranasal sinuses generally referred to as skull base tumors constitute a heterogeneous group of tumors with varied characteristics. Management of these tumors is relatively challenging owing to the intricate anatomy and the presence of vital structures in the vicinity.

Tumors of the nose and paranasal sinuses (PNS) encompass a wide spectrum of clinicopathologically distinct tumors (Table 16). Benign sinonasal tumors are relatively common as compared to their malignant counterparts. Benign tumors can be classified into soft tissue tumors and fibro-osseous lesions. Sinonasal papillomas (also called Schneiderian papillomas ) are benign epithelial neoplasms of the nose and PNS. They are divided into three pathological subtypes – inverted, fungiform, and oncocytic papillomas. Inverted papillomas are the most common. These tumors are more commonly seen in males usually in the fifth and sixth decades of life and mostly originate from the lateral nasal wall. They are mostly unilateral (bilateral in 2–4% cases) and present as a pink nontranslucent polypoidal mass with a convoluted surface protruding from the nasal cavity. Microscopically, they are characterized by an endophytic growth pattern into the underlying stroma but with an intact basement membrane. Common differentials include nasal polyps and mucoceles.

Table 16 Common tumors of the nasal cavity and paranasal sinus

Juvenile angiofibromas (Fig. 77) are highly vascular tumors occurring in young males usually in the second decade of life (Neel et al. 1973; Bremer et al. 1986). They originate in the region of the sphenopalatine foramen and usually present with profuse epistaxis. As the name suggests, these tumors are composed of a fibrous and vascular component and are essentially benign. The vascular component ranges from capillaries to compressed slit-like spaces to ecstatic capillaries. Biopsy is not usually indicated as the clinical and radiological profile is adequate for diagnosis.

Fig. 77

Holman-Miller sign – anterior bowing of the posterior maxillary sinus wall (red arrow) (pathognomonic of juvenile angiofibroma)

Fibrous dysplasias are slow-growing fibro-osseous lesions. They result from a defect in osteoblastic differentiation and maturation that leads to replacement of the bone by fibrous tissue of variable cellularity and immature woven bone. They usually present at a young age. Clinically, fibro-osseous dysplasias are monostotic (80%) or polyostotic (20%). Monostotic lesions affect both genders equally, but polyostotic lesions have a female preponderance. Polyostotic fibrous dysplasia can be associated with McCune-Albright syndrome; the additional clinical features being cafe-au-lait spots , endocrine anomalies, and precocious puberty.

Malignant neoplasms of the nasal cavity and paranasal sinuses are relatively rare and constitute about 2–3% of upper aerodigestive tract cancers (Ali et al. 1986; Osguthorpe 1994). Squamous cell carcinoma is the most common subtype with a male preponderance and a peak incidence in the fifth and sixth decades of life although other age groups can be affected (Robin et al. 1979; Roush 1979; Grau et al. 2001; Myers et al. 2002; Bhattacharyya 2003). Increased incidence of SCC has been reported in nickel-refining workers with the risk directly proportional to the duration of exposure and inversely proportional to the age of exposure. Although smoking has traditionally not been associated as a major risk factor for sinonasal SCC (Fig. 78), there is substantial evidence that heavy smoking and snuff use are associated with nasal and PNS SCC. Furthermore, smoking has been found to be a multiplicative risk factor for SCC in nickel-refining workers (Andersen et al. 1996). Squamous cell cancers can occur after radiation exposure to the PNS after a long latent period. Thorotrast (thorium dioxide) is a radiopaque contrast agent injected into the maxillary sinus and was used in the past for imaging of the maxillary sinus. The dye gets retained in the maxillary sinus lifelong and decays into mesothorium which emits radioactivity which reaches its peak in 15 years. Squamous cell carcinoma is found to occur in patients who have undergone thorotrast injection after a period of 10–21 years (Wingo et al. 1998). Similarly SCC has been found in patients in radium dial painting industry after a long latent period of 30–40 years (Holmstrom and Lund 1991; Wingo et al. 1998). It is assumed that radium gets absorbed from the oral mucosa in workers who used to lick the paintbrushes during painting of the watch dials. Inverted papillomas have a 5–26% chance of being associated with a SCC – either synchronous or metachronous (Szabo 1954; Zak and Lawson 1974; Cove 1979; Hofbauer et al. 2002; Mannone et al. 2004; Bradley 2006).

Fig. 78

T2N2M0 sinonasal carcinoma. On CT there is a lobular irregular enhancing mass occupying most of the dorsa of the external nose with sparing of the nasal tip (a) and extending into and partially destroying the anterior aspect of the nasal septum (b). The mass measures up to 47 mm superoinferior × 38 mm anteroposterior × 22 mm transverse. Anteriorly it extends into the skin over the nasal dorsum and nasal bridge. Inferiorly it extends virtually to the philtrum, and there is erosion of the anterior nasal spine. Superiorly, it causes subtle erosion of both nasal bones. The tumor is slightly bulkier on the right. There is no evidence of extension to the anterior skull base. The posterosuperior margin of the tumor involves the septum about 4 mm below the anterior cribriform plate

Adenocarcinomas and adenoid cystic carcinomas are other epithelial malignancies arising in the nasal cavity and PNS. They tend to account for 10–15% of the PNS malignancies in the United States and as high as 40% in Europe. This disparity is primarily because of widespread of hardwood in Europe exposure to which has been found to be an etiology for adenocarcinoma (Klintenberg et al. 1984; Hanna 2009). The latency period from the exposure to the tumor development is long (about 40 years). The most common site for adenocarcinoma in the PNS is the ethmoids (Fig. 79). These tumors are pathologically divided into intestinal and subtypes. The intestinal type resemble adenocarcinomas arising in the intestinal tract; the non-intestinal type has a predominant seromucinous appearance.

Fig. 79

Contrast-enhanced CT of paranasal sinuses axial image showing a heterogeneously enhancing lesion (oval) involving the ethmoids with erosion of the nasal septum and medial wall of right orbit

Adenoid cystic carcinomas constitute about 10–15% of the PNS malignancies. The most common subsites are the maxillary sinus and the ethmoids. Three histologic subtypes have been described – tubular, cribriform, and solid. The peak incidence is in the fifth and sixth decades of life. No known etiologic factors are associated with ACCs.

Esthesioneuroblastomas are malignant neuroendocrine neoplasms arising from the olfactory mucosa. No definite etiologic factor is identified in its causation. It has a slight male preponderance with bimodal peak at the second to third and the sixth to seventh decades of life. They occur most commonly in the cribriform area and can spread early into the anterior cranial fossa through the olfactory fibers. Macroscopically, they present as a reddish gray polypoidal mass that bleeds easily. Microscopically they present as “small round cell tumors” with immunohistochemistry positive for general neuroendocrine tumors (NSE, SNP, S100).

Skull base sarcomas are anatomically and histologically distinct neoplasms arising from the mesenchymal tissue and constitute only 10% of sarcomas and 1% of head and neck tumors (Weber et al. 1986; Kraus et al. 1994; Landis et al. 1999; Jemal et al. 2002). Although most of them share a common embryonal origin, notable exceptions are malignant peripheral nerve sheath tumors and Ewing sarcoma which arise from the neuroendocrine tissue. The skull base and the neck are the commonest sites for head-neck sarcomas. Unlike extremity sarcomas where distant metastasis is a major cause of death, skull base sarcomas are prone to local recurrence involving vital structures (brain, internal carotid artery, cavernous sinus, orbital apex) which is the leading cause of death in these patients.

Sinonasal mucosal melanomas are extremely rare and account for 1% of all melanomas and 0.6–4% of all tumors of the nasal cavity and the PNS. They tend to occur in elderly individuals (60–70 years) with a slight male preponderance. In the head and neck, the nasal cavity is the most common site (55–79%) followed by the oral cavity. The lateral nasal wall and the inferior turbinate are most common sites for origin of melanomas. Macroscopically, these tumors are brown to black polypoidal lesions that tend to ulcerate. Microscopically, they display morphological diversity with undifferentiated small round cell being most common. Melanin pigment is found in two-thirds of cases. These tumors are positive for vimentin, HMB 45, and S100.

Clinical Presentation

Presenting symptoms depend on the biologic behavior and the anatomical location of the tumor. Common symptoms of skull base tumors are outlined in Table 17. Most patients initially present with unilateral nasal obstruction. Recurrent profuse epistaxis especially in young adult may be due to a juvenile angiofibroma, although malignant tumors like esthesioneuroblastoma and sarcomas cannot be ruled out. Anosmia as a presenting symptom can be due to a pathology located at the region of the cribriform plate; a common etiology being esthesioneuroblastoma. Tumors compressing or invading the orbit, the optic nerve, or the cavernous sinus can result in diplopia, proptosis, or loss of vision. Tumors located in the anteromedial aspect of the maxilla can infiltrate or obstruct the lacrimal duct causing epiphora. Tumors of the maxilla with erosion of the bone can result in facial swelling and asymmetry. Involvement of the branches of the trigeminal nerve can result in facial numbness or pain. Nasopharyngeal tumors or those involving the nasopharynx can cause blockage of the Eustachian tube resulting in conductive hearing loss. Malignant tumors can present with metastatic neck nodes, although not very common in nasal and PNS cancers.

Table 17 Common symptoms and signs of skull base tumors

Investigations

The goals of preoperative imaging are to study the anatomical relationship of the lesion with the normal structures and thus to map the extent of the disease. Furthermore, imaging can provide an insight to the differential diagnosis. Contrast-enhanced CT scan and MRI are complementary in imaging of the skull base. CT scan is the modality of choice for evaluating bony structures, skull base foramina, calcifications, and bony reactions to the tumor. High-resolution images with thin sections (<3 mm) with 1 mm overlap scans are ideal for imaging of the skull base. MRI on the other hand is the preferred modality for soft tissue delineation. Unenhanced axial T1-W images are used for anatomical relationships and to detect highly cellular lesions (e.g., malignant tumors). Water-rich tissues enhance on T2-W images, and these images are very important to differentiate tumors from retained secretions (Figs. 80, 81, and 82) and post-therapy fibrosis. Gadolinium enhancement with fat suppression (short tau inversion recovery, STIR) images is ideal for evaluation of malignant lesions, as the lesions become clearer with contrast and the margins better delineated due to fat suppression. MR angiography has replaced conventional angiography as it is noninvasive and nonionizing. MRI is contraindicated in patients with cardiac pacemakers and ferromagnetic intracranial aneurysm clips. Table 18 depicts the salient radiological findings of common skull base tumors.

Fig. 80

Axial T2 MRI image of paranasal sinuses showing tumor originating in the nasopharynx with extension into the nasal cavity with retained secretions in the left maxillary sinus (yellow arrow)

Fig. 81

Coronal T2 MRI image of paranasal sinuses showing tumor in the right nasal cavity with retained secretions in the right maxillary sinus (yellow arrow)

Fig. 82

Sagittal T2 MRI image of paranasal sinuses showing tumor occupying the entire nasal cavity and ethmoid sinuses with gross bone destruction and intracranial extension with retained secretions in the sphenoid sinus

Table 18 Salient radiological findings of common skull base tumors

Treatment

Benign tumors of the skull base are essentially treated by surgery. The treatment of most malignant tumors is a multimodality treatment approach which includes surgery, radiotherapy, and chemotherapy. Excepting for hematolymphoid malignancies, surgery plays a key role in the management of skull base malignancies. The basic principles of surgery are gross total resection and maximum preservation of function. Surgical approaches to the skull base are either open or endoscopic (Fig. 83).

Fig. 83

Treatment algorithm for nasal and paranasal cancers

The choice of the surgical approach depends on multiple factors: the site of origin, the extent and pathology of the tumor, and the surgical expertise available. The major advantages of endoscopic approaches include direct access to the tumor, no brain retraction and edema, lesser morbidity, and reduced hospital stay. However, the concept of “en bloc” tumor resection is violated by the endoscopic approaches, and it requires a steep learning curve. The indications and contraindications of endoscopic approaches are depicted in Table 19.

Table 19 Indications and contraindications for endoscopic approach to skull base tumors

Although no randomized controlled trial has been conducted comparing endoscopic and open surgical approaches to the skull base, data from different studies reveal similar oncologic results with reduced morbidity in patients undergoing endoscopic resection (Howard et al. 2006; Ganly et al. 2011; Abergel et al. 2012; Meccariello et al. 2016). However, proper patient selection and surgical expertise is a key to endoscopic approaches.

Endoscopic resection has several advantages over open surgery which include better cosmesis, better quality of life, less CSF leakage, less cranial morbidity, and better illumination. Radiotherapy is usually used as an adjuvant to surgery. Definitive radiation is usually not used for resectable skull base cancers for two reasons: poor oncologic outcome as compared to surgery with adjuvant radiation and toxicities (Choussy et al. 2008). Serious visual complications occur in 16–66% of patients with conventional radiation. Unilateral blindness occurs in 20–35% of patients and bilateral blindness in 6–10% of patients. Complications of skull base radiation include blindness, diplopia, painful red eye, brain necrosis, meningitis, hearing loss, memory loss, hypopituitarism, skin fistula, trismus, bone/cartilage necrosis, and saddle nose deformity. The most common cause of ipsilateral blindness is retinopathy and contralateral blindness is optic neuropathy. However, in unresectable tumors, radiotherapy alone has been found to have a modest local control (Jansen et al. 2000).

The objectives of systemic therapy in skull base cancers are to improve tumor control as well as organ preservation. The role of chemotherapy is well established in “small round cell tumors” which include Ewing sarcoma, rhabdomyosarcoma, and hematolymphoid malignancies. Sinonasal undifferentiated carcinoma and neuroendocrine carcinoma are aggressive tumors requiring multimodality therapy, and chemotherapy has a role in their management, although the optimal strategy is not yet determined. Tumor and patient characteristics need to be evaluated before planning the optimal regimen of systemic therapy.

Thyroid Cancer

Epidemiology, Etiology, and Pathology

More than 95% of thyroid tumors are benign. Thyroid carcinoma has an excellent prognosis when detected early and treated appropriately (Howlader et al. 2016). Thyroid cancer represents 1% of all cancers and is the most common endocrine malignancy (Reiners et al. 2004). It is the fifth most common cancer among women in the United States. There has been a significant and steady increase in the incidence of thyroid cancers in the last decade which is partly due to detection bias in developed countries, particularly South Korea. Thyroid malignancies encompass a wide spectrum of diseases ranging from well-differentiated thyroid cancers with excellent prognosis at one extreme to anaplastic thyroid cancers carrying an equally dismal prognosis at the other (Cabanillas et al. 2016) (Table 20).

Table 20 Classification of thyroid malignancies

Ionizing radiation has long been noted as an etiological factor for thyroid cancer. Its association was first described in the 1950s. Subclinical doses of radiotherapy have shown a dose-response relationship particularly when exposed during young age. Historical treatments of pediatric diseases like acne, impetigo, sinusitis, adenoid enlargements, keloids, and lymphomas with radiotherapy were associated with increased incidence of thyroid cancers in adulthood. The risk ratio (RR) in such individuals ranges from 4.6 to 14.6 times and has a dose-dependent increase in risk till 20 Gy (Favus et al. 1976). Risk of environmental exposure of radiation after the Chernobyl nuclear disaster of 1986 resulted in a significant increase in incidence of thyroid malignancy among individuals who were either fetuses or children till the age of 15 at the time of the radiation exposure. Geographic areas with high background radiation hold increased risk of thyroid carcinoma (Baverstock et al. 1992). Thyroid cancer is more common among females, and hence multiple studies have been carried out to investigate the association of female reproductive history and thyroid cancer; however, no conclusive trends have been found (Negri et al. 1999). The relationship between oral contraceptive use and thyroid cancer has also yielded variable results. Pooled analysis suggests oral contraceptives to be a promoter of thyroid cancer; however, the risk is eliminated once its use is ceased (La Vecchia et al. 1999). Genetic causes for thyroid cancers are well known for medullary thyroid carcinoma (MTC) with 25% of them being associated with MEN2 syndromes (Fig. 84 and Table 21). Five to ten percent of papillary thyroid cancers also have a known genetic predilection and are also associated with syndromes like familial adenomatous polyposis (FAP), Gardner’s syndrome, Cowden syndrome, and Carney complex (Richards 2010).

Fig. 84

MEN syndromes and medullary thyroid cancers

Table 21 Multiple endocrine neoplasia syndrome

Clinical Presentation

The thyroid gland is an endocrine gland located in the anterior aspect of the neck. It consists of two lobes connected by a thin isthmus which lies over the second to fourth tracheal rings (Harrison 2014). In about 50–75% of patients, an additional pyramidal lobe is present usually on the left side which is a remnant of the thyroglossal duct. The term “goiter” is used to describe any enlargement of the thyroid gland (Figs. 85 and 86). The enlargement can present either in the form of a solitary nodule (50%), multiple nodules, or smooth or diffuse enlargement (Reiners et al. 2004). Endemic goiter is the most common form and is defined when it is prevalent in 10% of the population in a particular geographic area or community.

Fig. 85

Benign thyroid nodule of the neck in a female patient (black dashed oval) histopathologically confirmed as colloid nodular goiter (Image courtesy of Dr Chady Sader, Western ENT, Perth WA, Australia)

Fig. 86

Large thyroid nodule in male patient (a), exposed during surgery (b), and final macroscopic specimen (c) confirmed histopathologically as benign nodular goiter (Images courtesy of Dr Chady Sader, Western ENT, Perth WA, Australia)

Investigations

Thyroid function tests (TFT) are the initial investigation for evaluation of a thyroid nodule. Most thyroid cancers are euthyroid at presentation. An elevated or normal thyroid-stimulating hormone (TSH) harbors increased risk of malignancy, and further investigations are directed toward the diagnosis of malignancy. Conversely, chances of malignancy are low if TSH is subnormal, and further investigations are directed toward diagnosis of a toxic nodule (Fig. 87). Ultrasound is complementary to TFT in the diagnosis of thyroid malignancies.

Fig 87

Initial work-up of a thyroid nodule

High-resolution ultrasound of the thyroid and the neck (7.5–12 MHz) is the next step in the work-up of a thyroid nodule. Ultrasound features suggestive of malignancy are depicted in Table 22 (Figs. 88 and 89). Although ultrasound is a simple, cost-effective, widely available, nonionizing, and recommended diagnostic tool for evaluation of thyroid nodule, a contrast-enhanced CT scan of the neck and thorax is indicated in certain situations. These include:

• (a) Suspected retrosternal extension of the thyroid nodule (clinically lower limit of the nodule is not felt above the thoracic inlet) (Fig. 90)

• (b) Suspected infiltration into adjacent structures like the trachea and esophagus (history of hoarseness of voice, aspiration, dyspnea and dysphagia, clinical finding of vocal cord paralysis) (Figs. 91 and 92)

• (c) Metastatic nodes at lower neck (level VI, IV, or V) which harbors high chance of mediastinal adenopathy (Fig. 93)

Table 22 Ultrasound features suggestive of malignancy in a thyroid nodule

Fig. 88

Ultrasound of thyroid nodule demonstrating intrinsic vascularity suspicious for thyroid carcinoma (Image courtesy of Dr Chady Sader, Western ENT, Perth WA, Australia)

Fig. 89

Papillary thyroid carcinoma. Left thyroid nodule with microcalcifications (a) and FNA of a partially cystic left neck node with metastatic lymphadenopathy (b) (Images courtesy of Dr Chady Sader, Western ENT, Perth WA, Australia)

Fig. 90

Contrast-enhanced CT axial section showing retrosternal extension of thyroid tumor

Fig 91

Axial contrast-enhanced CT image of a thyroid tumor of the left lobe with extrathyroidal extension and loss of fat plane with the strap muscles, trachea, and carotid artery

Fig. 92

Papillary carcinoma in a thyroglossal duct cyst. Ultrasound of mass in the superior midline of the anterior neck showing cystic lesion with solid nodule containing microcalcifications (red arrow) (a). CT sagittal reconstruction shows midline anterior neck cyst elevating strap muscles with mural solid nodule containing microcalcifications (yellow arrows) (b). (Images courtesy of Dr Chady Sader, Western ENT, Perth WA, Australia)

Fig. 93

Papillary thyroid carcinoma in a 21-year-old female. CT shows a large left thyroid mass biopsied and shown to be papillary carcinoma (a). This is associated with extensive left level II, III, and IV adenopathy on the left (b). Total thyroidectomy and central neck dissection specimen (c), and surgical bed demonstrating the trachea, both laryngeal nerves and right common carotid (d). (Images courtesy of Dr Chady Sader, Western ENT, Perth WA, Australia)

There has been a concern that contrast would interfere with postsurgery radioactive iodine (RAI) therapy making it less effective; however, RAI therapy is usually performed at least 4–6 weeks after surgery, and the contrast agent used for preoperative scanning is eliminated from the body by that time. PET/CT is usually not used in the preoperative work-up of thyroid cancers (Harrison 2014).

Fine needle aspiration cytology (FNAC) is used to investigate thyroid nodules. Ultrasound-guided FNAC improves the diagnostic yield and accuracy but may not be routinely performed due to logistic purposes. Ultrasound guidance is recommended to target the solid portion in a solid-cystic nodule, when nodules are located in the posterior aspect of the thyroid, in case of multinodular goiter to target the most suspicious nodule(s), for repeating nondiagnostic cytology on blind FNAC, and when non-palpable nodules are picked up on other imaging. The indications of FNAC in a thyroid nodule based on sonographic features have been outlined in the American Thyroid Association (ATA) 2015 guidelines (Table 23) (Haugen et al. 2016). In order to maintain uniformity in the reporting of thyroid FNAC, the Bethesda system is used (Table 24) (Crippa et al. 2010).

Table 23 Indications of fine needle aspiration cytology in a thyroid nodule (ATA guidelines 2015) (Haugen et al. 2016)

Table 24 Bethesda system of reporting of thyroid fine needle aspiration cytology (Crippa et al. 2010)

Work-up of a thyroid nodule with FNAC reported as medullary thyroid carcinoma includes serum calcitonin, urinary or plasma metanephrines, serum calcium, RET mutation analysis, locoregional and distant imaging, and assessment of vocal cord mobility. Staging of thyroid cancer is outlined in Table 25.

Table 25 Staging of thyroid cancer. TNM clinical classification and staging of thyroid malignant tumors (Adapted from Brierley et al. 2017)

Treatment

The management of patients with thyroid nodules is guided by thyroid function test, imaging, and FNAC. The goals of treatment are to:

• (a) Improve overall and disease-specific survival.

• (b) Reduce the risk of persistent/recurrent/metastatic disease.

• (c) Minimize the risk of treatment-related morbidity.

Surgery plays the major role in the management of thyroid malignancies. Adjuvant radioiodine treatment and radiotherapy are indicated in high-risk patients.

The Bethesda reporting system provides a uniform baseline for treatment of thyroid nodules.

Bethesda I

An US-guided FNAC is preferred and, if available, on-site cytologic evaluation is done. Repeatedly nondiagnostic nodules without a high-suspicion sonographic pattern require close observation or surgical excision for histopathologic diagnosis. Diagnostic surgery should be considered if there is high suspicion on US features, growth of the nodule (>20% in two dimensions) is detected during US surveillance, or clinical risk factors for malignancy are present.

Bethesda II

No further diagnostic or therapeutic intervention is required. Dietary iodine supplementation can be given in patients from iodine-deficient areas. There is no role of TSH suppression therapy in these patients.

Bethesda III

Repeat FNA or molecular testing may be used to supplement malignancy risk assessment. If repeat FNA cytology, molecular testing, or both are not performed or inconclusive, either surveillance or diagnostic surgical excision (hemithyroidectomy) may be performed based on clinical risk assessment, sonographic features, and patient preference.

Bethesda IV

Follicular neoplasm encompasses three types of histology: follicular adenoma, follicular carcinoma, and follicular variant of papillary carcinoma. Diagnostic surgical excision is the long-established standard of care for the management of follicular neoplasm. However, after consideration of clinical and sonographic features, molecular testing may be used to supplement malignancy risk assessment data, although there is no robust evidence for molecular testing as an alternative to diagnostic hemithyroidectomy in Bethesda IV lesions. The protocol for management of Bethesda IV tumors is depicted in Fig. 94.

Fig. 94

Management protocol for follicular neoplasm

Bethesda V and VI

Treatment of Differentiated Thyroid Cancer

The mainstay of treatment of thyroid cancers is surgery (Haugen et al. 2016). The extent of surgery (hemi- or total thyroidectomy) has been a matter of considerable discussion and evolution over the years. The indications of total and hemithyroidectomy for differentiated thyroid cancers are depicted in Fig. 95. Tumors >4 cm, those with extrathyroid extension, and metastatic (nodal or distant) disease at presentation are absolute indications for total thyroidectomy (Fig. 96). Intrathyroid unifocal <1 cm tumors without any nodal or distant metastasis and no family history of thyroid cancer or history of radiation exposure are indications for hemithyroidectomy. Tumors between these two extremes can be managed either with total or hemithyroidectomy; the decision of which needs to be taken unanimously by the physician and the patient. Based on retrospective studies, total thyroidectomy improves survival and decreases recurrence rates as compared to hemithyroidectomy. It also allows routine use of RAI remnant ablation and facilitates detection of remnant or persistent disease during follow-up. The major drawback of total thyroidectomy is the need for lifelong exogenous thyroid hormone therapy. The clinical outcome of hemithyroidectomy is very similar to total thyroidectomy in properly selected patients. Furthermore, follow-up regimen has moved away from diagnostic RAI scanning to serial ultrasound and detection of changing Tg levels. Most physicians are adopting a conservative approach to the relatively indolent cancer, and there is a shifting paradigm from total to hemithyroidectomy. However, careful patient selection is the key factor in the decision-making.

Fig. 95

Extent of surgery in differentiated thyroid cancers

Fig. 96

Papillary thyroid carcinoma surgery in a 19-year-old female. Intraoperative photo (a) shows the appearance after thyroidectomy illustrating the trachea (peanut swab), the left recurrent laryngeal nerve (green arrow), and the superior left parathyroid gland (yellow arrow). Intraoperative view at completion of neck dissection (b) shows the sternomastoid (white arrow) and omohyoid (black arrow) muscles as well as the internal jugular vein (red arrow). Appearance of postoperative wound (c) (Images courtesy of Dr Chady Sader, Western ENT, Perth WA, Australia)

The central compartment of the neck (levels VI and VII) is the first echelon nodal station from thyroid cancers. Therapeutic central compartment clearance is indicated in clinical or radiological evidence of metastatic nodes in central compartment. Prophylactic central compartment clearance is indicated in T3 or T4 primary tumors with N0 neck or in presence of metastatic lateral compartment nodes. Care should be taken to prevent injury to the parathyroids and their blood supply and the recurrent laryngeal nerves during central compartment clearance. If there is devascularization injury to the parathyroids, autotransplantation should be considered. Lateral compartment nodal dissection (levels II–V) is indicated in cases of metastatic lateral compartment nodes, in metastatic central compartment nodes, or in tumors located in the region of the upper pole of the thyroid gland.

Postsurgery patients of differentiated thyroid cancer are stratified into low, intermediate, and high risk based on clinical and histopathological criteria (Table 26). Based on these criteria, the need and extent of adjuvant treatment are planned. The details of adjuvant RAI treatment are depicted in Figs. 97, 98, 99, and 100.

Table 26 ATA risk stratification system with proposed modifications according to ATA guidelines 2015 (Haugen et al. 2016)

Fig. 97

Postsurgery management of low-risk patients treated with total thyroidectomy

Fig. 98

Postsurgery management of low-risk patients treated with hemithyroidectomy

Fig. 99

Postsurgery management of intermediate-risk patients

Fig. 100

Postsurgery management of high-risk patients

Treatment of Medullary Thyroid Cancer

Treatment of choice of medullary thyroid cancer (MTC) is surgery. There is no role for RAI in the management of MTC. Tumors ≥1 cm in size or with bilateral thyroid disease are treated with total thyroidectomy with bilateral central compartment clearance. Tumors <1 cm can be treated with total thyroidectomy, but central compartment clearance should preferably be considered. The role of adjuvant radiation is not clear (Harrison 2014) although it is recommended for tumors with extrathyroid extension (T4 tumors), gross residual disease where attempts of surgical re-excision have been ruled out, and in metastatic nodes with extracapsular spread (Adelstein et al. 2017). Prophylactic thyroidectomy is carried out in patients with MEN syndrome as depicted in Figs. 101 and 102.

Fig. 101

Prophylactic thyroidectomy in MEN 2A/FMTC patients

Fig. 102

Prophylactic thyroidectomy in MEN 2B patients

Differentiated thyroid carcinomas have a good overall survival upward of 90% (Society 2015). The 5-year survival and 10-year survival for both papillary and follicular carcinomas are approximately equal at almost 90% for age group <45 years. Above 45 years of age with increasing age, there is a significant decrease in the overall survival seen up to 50% in the group of 60–69 years at 10 years. Follow-up is usually done every 6 months with serum thyroglobulin, US, RAI scan, and thyroid function test with TSH suppression in cases of high risk (Durante et al. 2013; Haugen et al. 2016). Patients are re-risk stratified as low, intermediate, and high based on the criteria depicted in patients, and further treatment is planned as required. The follow-up protocol for MTC relies on calcitonin levels carried out 2–3 months postsurgery. MTC patients are started on thyroxine supplementation immediately after surgery.

Malignant Soft Tissue Tumors of the Head and Neck

Malignant neoplasms of the soft tissues display a diverse array of lesions and a wide spectrum of clinical activity ranging from relatively slow-growing lesions to aggressive local and regionally destructive lesions with the potential for systemic metastasis (Pellitteri et al. 2003). Sarcomas of the head and neck most commonly present as painless submucosal or subcutaneous masses of uncertain duration.

The success of treating these lesions has a strong correlation between how early and how quickly the diagnosis is made. The resemblance between some of these lesions is not restricted to their clinical behavior, most of which have microscopic features that make immunohistochemical investigation essential for conclusive diagnosis. Before molecular investigations, these lesions were collectively known as sarcomas, not otherwise specified.

Most of these lesions are independent new neoplasms, but 10–20% have a history of malignant transformation from a benign counterpart. Since they can possibly initiate at any part of the body, it is also important to investigate if lesions of the head and neck region are in fact primary tumors or metastatic ones. Occurrence in the head and neck is rare, accounting for less than 1% of all malignant tumors in this site. These lesions may attain a great size before symptoms occur and are often noted on routine dental, head, neck, or pharyngeal examination.

Sarcoma growth and local advancement employ a compressive mechanism, whereby tissue adjacent to the tumor together with a local inflammatory response contributes to the formation of a pseudocapsule composed of normal tissue and both inflammatory and malignant neoplastic cells. Despite the advances in oncology, the treatment of these lesions consists of en bloc resection with normal tissue removal a considerable distance away from the identifiable tumor. This is due to the extension of the tumor along anatomic planes formed by the fascia, muscle, and bone.

Surgical treatment of these lesions is therefore frequently devastating, making the treatment itself just as harmful as the neoplasm itself. Size as related to the involvement of critical neurovascular structures, thus limiting en bloc resection, has obvious implications for unfavorably impacting both local control and survival. The rapidity of growth is variable depending on the biologic behavior and grade of the tumor. Symptoms attributable to growth vary according to location; those involving the aerodigestive tract generally become symptomatic earlier in the course of disease as compared with tumors involving the neck.

Tumor grade significantly impacts the biologic and clinical behavior of sarcomas and has implications with respect to treatment, control, and long-term survival. Metastatic potential is higher in higher-grade sarcomas. Lymph node metastasis occurs rarely and almost exclusively in high-grade tumors. Distant metastases occur early with high-grade sarcomas, but unfortunately even low-grade tumors can metastasize.

Fibrosarcoma

Epidemiology, Etiology, and Pathology

Fibrosarcoma is a malignant neoplasm of mesenchymal origin, with possible occurrence in the head and neck region (Fig. 103). Before the era of immunohistochemistry, fibrosarcoma was a very frequent diagnosis and represented one of the most common types of soft tissue sarcoma. With the development of immunohistochemical and molecular techniques, it is now rare for a sarcoma to be termed fibrosarcoma, which by its name implies fibroblasts as the cell of origin.

Fig. 103

Fibrosarcoma. CT of large soft tissue mass extending from the floor of the mouth, affecting the right side of the tongue, altering the air spaces, and invading the right mandibular bone (a) causing irregular osteolytic destruction affecting dental support (b). Intermediate (c) and high magnification (d) of the lesion characterized by fusiform cells with nuclear atypia, numerous atypical mitotic figures forming whorls, in a storiform pattern (Hematoxylin and eosin stain)

Fibrosarcoma can arise in soft tissues or within the bone. Intraosseous fibrosarcomas may develop endosteally or possibly periosteally, the latter affecting the bone by spread from adjacent soft tissue. The mean age for occurrence of fibrosarcoma is between the second and sixth decades with equal gender distribution.

Clinical Features

Clinically, the lesion can cause pain, swelling, paresthesia, and occasionally loss of teeth and ulceration of the overlying mucosa. The clinical behavior of fibrosarcoma is characterized by a high local recurrence rate and a low incidence of locoregional lymph node and/or distant hematogenous metastases. However, hematogenous metastasis may involve the lungs, mediastinum, abdominal cavity, and bone.

Fibrosarcoma of the oral cavity most often manifests as a clinically innocuous, lobulated, sessile, painless, and nonhemorrhagic submucosal mass of normal coloration. On the other hand, aggressive fibrosarcomas tend to be a rapidly enlarging (Fig. 103), hemorrhagic mass similar in clinical appearance to an ulcerated angiogranuloma, peripheral giant cell granuloma, or peripheral ossifying fibroma.

Investigations

Before therapy, the local extent of the neoplasm and the presence or absence of local and distant metastases must be determined. Evaluation continues with directed imaging to determine the extent of tumor and involvement of critical adjacent structures which may influence biopsy technique. Metastatic surveys should include chest radiography, scintigraphic bone scanning, and abdominal ultrasound and/or computed tomography.

Either CT or MRI represent forms of imaging which may be used individually or in combination. Contrast-enhanced head and neck CT has proven to be a valuable tool for delineating the size of the tumor and infiltration of neighboring tissue. MRI, especially with gadolinium contrast, may be used as a supplement or alternative to CT scanning. It has a distinct soft tissue advantage and is superior in delineating vascular involvement, especially with magnetic resonance angiography (MRA). CT offers an improved evaluation for bony structure involvement of the paranasal sinuses, orbit, and cranial base. Formal cranial angiography may be necessary to eliminate the possibility of carotid or vertebral artery involvement and for the assessment of the feasibility of performing angioinvasive techniques such as embolization and selective intra-arterial chemotherapy. Positron-emission tomography (PET) is of value in the staging of malignancy to determine distant disease.

The histological appearance of high-grade fibrosarcoma may be similar to other tumors, such as malignant fibrous histiocytoma, liposarcoma, or synovial sarcoma (Fig. 103). Fibrosarcoma can be graded as low- or high-grade malignancy. Low-grade fibrosarcoma shows spindle cells arranged in fascicles with low to moderate cellularity with a herringbone appearance. There is a mild degree of nuclear pleomorphism and rare mitosis, with a collagenous stroma. High-grade lesions show intense nuclear pleomorphism, greater cellularity, and atypical mitosis. The nuclei can be spindle shaped, oval, or round. Positive immunostaining for vimentin, together with negativity for muscular immune markers, helps to diagnose fibrosarcoma (Soares et al. 2006).

Treatment

Wide local excision remains the treatment of choice, with at least 1 cm of margin confirmed by histopathologic clearance. Unfortunately, it is often difficult to achieve complete resection of the tumor, and high recurrence rates have been observed with surgery alone.

Radiotherapy is mandatory when adequate safety margins cannot be obtained and salvage surgery is not possible. On the other hand, there is a significant number of radiotherapy-induced sarcomas of the head and neck region.

Adjuvant chemotherapy for sarcomas has been applied in tumors of the trunk and extremities, as well as in the head and neck. Although some reports have raised the possibility of some benefit in certain types of sarcomas, the benefit of adjuvant chemotherapy with regard to prolonged survival remains controversial. Chemotherapy is most commonly employed in the setting of attempted control of metastatic disease. Its role in adjuvant therapy aimed at cure is not established (Eeles et al. 1993).

Liposarcoma

Epidemiology, Etiology, and Pathology

Liposarcomas are malignant neoplastic proliferations of mesenchymal cells with adipocyte phenotype (2017). According to its grading and differentiation, the neoplastic cells show variable capability of lipid storage, generally assuming a multivacuolated form. Factors considered to be important in the etiology of liposarcoma include genetics, trauma, and irradiation.

Three biologic categories of liposarcomas are distinguished: well-differentiated/dedifferentiated, myxoid, and pleomorphic. The most common type is the well-differentiated/dedifferentiated type, and the most affected sites in the head and neck region are the pharynx, mouth (usually related to the tongue), larynx, and neck.

Liposarcoma of the head and neck region represents approximately 1% of head and neck sarcomas. Although considered a rare tumor of the head and neck region, liposarcomas usually affect older males, ranging from 40 to 60 years of age (Golledge et al. 1995).

Clinical Features

Despite its malignant nature, the tumor has a slow growth pattern, as a painless submucosal fatty-fibrous texture that can sometimes ulcerate. Depending on the location of the tumor, other symptoms can also be noted such as airway obstruction or dysphagia.

Investigations

The microscopic appearance of the most common type of liposarcoma is characterized by adipocytes of variable size, with hyperchromatic and enlarged nuclei. The surrounding fibrous tissue also presents atypical features. Non-lipogenic areas of dedifferentiation present with pleomorphic cells such as spindle cells, round cells, and giant cells or even fibroblast-like appearance in a myxoid matrix. Immunohistochemical panels include MDM2 and CDK4 positivity in 90% of tumors.

Treatment

Surgical excision is the treatment of choice for liposarcomas. The lesion has a high recurrence rate, up to 50%. There is a direct relationship with tumor site and grading with the prognosis of treatment. Oral liposarcoma is associated with a poor outcome despite the high proportion of low-grade tumors.

Malignant Peripheral Nerve Sheath Tumor

Epidemiology, Etiology, and Pathology

The malignant peripheral nerve sheath tumor (MPNST) also known as malignant schwannoma, neurofibrosarcoma, and malignant neurilemmoma is characterized by malignant proliferation of the soft tissues by peripheral nerves or benign nerve sheath tumors, with variable differentiation toward one of the cellular components of the nerve sheath, such as Schwann cells, fibroblasts, or perineural cells (Fig. 104) (Anghileri et al. 2006).

Fig. 104

Malignant peripheral nerve sheath tumor. CT scan of an irregular osteolytic lesion of the left maxilla (a). T2-weighted MRI revealing the extension of the lesion in the maxilla (b). Bone scintillography imaging showing increased radiotracer accumulation in the affected area (c). Fascicles of atypical fusiform cells with irregular nuclei forming variable patterns with highly cellularized areas of vacuolated cells with a myxoid matrix (d), alternating with whorls of storiform formations and palisaded cells (e) (Hematoxylin and eosin stain)

About 20% of all MPNSTs develop in the head and neck, representing 5% of all soft tissue sarcomas. As mentioned above, MPNST has a strong correlation with NF type 1 syndrome, affecting up to 25–30% of the patients with this particular syndrome. The peak occurrence of this lesion is during adulthood, during the third and fourth decades of life.

Clinical Features

MPNST can arise de novo or from a pre-existing neurofibroma. The most affected nerves of the head and neck region are the vagal and vestibular nerves. Malignant transformation of a pre-existing schwannoma is possible but considered to be rare. Symptoms include pain associated with a rapid growing mass, which may also compromise motor or sensory neural function (Eeles et al. 1993).

Tumors may present as a white, solid, firm consistency within or attached to a nerve trunk or neurofibroma. Sometimes the development of tumors in intraosseous neural branches can produce local enlargement of the nerve canal with or without bone destruction of the surrounding bone. Pseudocystic spaces originating from hemorrhage or focal necrosis may be observed during surgical incision of the tumor.

Investigations

Microscopic investigation of MPNST reveals an unencapsulated lesion, with highly infiltrative cells with different morphotypes such as epithelioid, pleomorphic, small round cells and spindle-shaped cells. The lesion is composed of interlacing fascicular arrangements, forming variable patterns, with highly cellularized areas of vacuolated cells with a myxoid matrix, alternating to whorls of storiform formations, with palisaded cells, sometimes assuming a rosette formation. The nuclei are large and hyperchromatic, sometimes small, and other times fusiform with eventual atypical mitosis or binucleated cells. The tumors are graded low grade and high grade according to their mitotic index, number of atypical mitosis, pleomorphism, and necrosis (Fig. 104).

Immunohistochemical investigation of the lesion is frequently necessary, as other sarcomas can present similar morphological features. This is essential for small incisional biopsies. The immunohistochemical panel should include S-100, SOX10, and nestin strong positivity, and cytokeratins, EMA, and CD34 may be positive, but their expression has not been described in the epithelioid variant. Genetic investigation of NF1 is also recommended if the patient has no other evident signs. There is loss of NF1 on 17q11 and TP53 on 17q13 (2017).

Treatment

MPNSTs are treated with radical surgical excision. The aggressive behavior of the lesion is frequently associated with large lesions. It is the main cause of death of NF1 patients representing up to 25% of deaths of NF1-affected patients. Therefore, to discover these tumors as early as possible, patients with NF1 syndrome should be followed carefully, because of the likelihood that they may develop MPNSTs. Presentation with either primary or recurrent disease, tumor size, and tumor location have major importance with regard to prognosis. Complete tumor resection with negative margins should be the objective of surgery (Minovi et al. 2007).

The recurrence rate is as high as 40%, and adjunctive radiotherapy and chemotherapy are often required, but the lesion usually metastasizes to the lungs and bone. Adjuvant radiation therapy should be delivered to improve local control and may also be beneficial for survival. High-grade and large MPNSTs have particularly aggressive behavior, and thus patients with these tumors should be considered for new adjuvant medical treatments.

Kaposi Sarcoma

Epidemiology, Etiology, and Pathology

Kaposi sarcoma (KS) is an angioproliferative malignant neoplasia of endothelial cells forming an infiltrative capillary-rich lesion that eventually disseminates to multiple cutaneous sites, viscera, and lymph nodes. Kaposi sarcoma was first described by Moritz Kaposi in 1872 as “idiopathic multiple pigmented sarcomas of the skin.” Until the HIV pandemic in the 1970s and 1980s, KS was considered a rare and usually nonaggressive lesion. After the pandemic infection with HIV virus, lesion incidence arose as one of the diseases related to acquired immunodeficiency syndrome (AIDS) with aggressive behavior becoming one of the major causes of death among AIDS patients.

Today KS is known to be caused by HHV8 infection of endothelial cells. HHV8 is found in immunocompetent people and is active in immunosuppression. In fact in the beginning of the twenty-first century, it was discovered that Tat protein produced by lymphoid cells infected with HIV promoted the infection of HHV8, contributing to the highly aggressive nature of AIDS-KS by inducing inflammatory cytokines and angiogenesis (Moore and Chang 1995; Gallo 1998; Aoki and Tosato 2004).

Until the AIDS epidemic, this tumor was identified in three different settings: classic KS (a slowly growing tumor particularly prevalent among elderly men of Mediterranean or Jewish ancestry), African-endemic KS, and immunosuppressive drug-related KS. All these forms of KS share a similar histopathology that has been divided into different progressive stages correlating with both clinical appearance and progression of lesions. AIDS-associated KS is the most frequent tumor of human immunodeficiency virus type I (HIV-l) infection and the most aggressive and rapidly growing form of KS in AIDS, with early dissemination in the skin and viscera. In spite of the clear clinical differences, the histopathology of the various KS forms is essentially the same, with characteristic changes related to stage in the development of the KS tumor. Only the AIDS-related type is associated with oral manifestations. As many as 20% of individuals with HIV-1 infection develop oral KS, usually in the fourth to fifth decades of life.

The incidence of KS has dramatically decreased in both the United States and Europe in the era of highly active antiretroviral therapy (HAART). However, KS remains the second most frequent tumor in HIV-infected patients worldwide and has become the most common cancer in sub-Saharan Africa. Since the beginning of the AIDS pandemic, AIDS-related KS has been more prevalent in homosexual and bisexual men.

Clinical Features

The most affected oral location of KS is the hard palate, followed by the gingiva and tongue (Figs. 105-108). Up to 70% of patients with cutaneous AIDS-related KS also have oral lesions. Multiple patches and papules with bluish to purple color are the most common skin and mucosal presentations (Fig. 105). With the progression of the disease, the patched lesions develop to a nodular stage (Fig. 108). Intraoral advanced lesions may present with hemorrhage, pain, ulceration, and secondary infections. Highly aggressive lesions are infiltrative, involving soft tissue and bone (Chen et al. 2014). These lesions may disseminate compromising visceral organs and lymphatic nodes.

Fig. 105

Multifocal macular AIDS-related Kaposi sarcoma and aggressive periodontal disease in 29 years old Zambian male. (Image courtesy of Dr Tim Hodgson, Eastman Dental Institute, University College London, UK)

Fig. 106

Gingival AIDS-related Kaposi sarcoma in 9 year old Malawian female. (Image courtesy of Dr Tim Hodgson, Eastman Dental Institute, University College London, UK)

Fig. 107

Extensive diffuse AIDS-related Kaposi sarcoma and tooth wear in a 45 year old Malawian male. (Image courtesy of Dr Tim Hodgson, Eastman Dental Institute, University College London, UK)

Fig. 108

Nodular palatal AIDS-related Kaposi sarcoma in 28 years old Zambian female. (Image courtesy of Dr Tim Hodgson, Eastman Dental Institute, University College London, UK)

Investigations

Early “patch-stage” KS lesions are histologically characterized by the proliferation of small and jagged endothelial-lined spaces surrounding normal dermal vessels and irregularly shaped, slit-like vascular spaces dissecting collagen bundles, often parallel to the epithelium, with extravasated erythrocytes and lymphocytes. The more advanced stages of KS consist of the accumulation of spindle-shaped cells, which are considered to be the tumor cells of KS, showing intra- and extracellular hyaline globules and increased mitotic activity.

The histologic differential diagnoses of Kaposi sarcoma include angiosarcoma, fibrosarcoma, arteriovenous malformations, and spindle cell hemangioendothelioma. Clinicopathological features, mainly immunohistochemical studies, help to exclude these differential diagnoses. Immunohistochemical investigation of KS targets HHV8 primarily, but podoplanin (D2-40), LYVE1, VEGFR3, PROX1, CD34, CD31, and ERG are also positive.

Treatment

The behavior and thus the treatment of KS depend on a number of factors such as the form of the disease, the symptoms, the location and extent of the lesion, the immunocompetence of the patient, and the general medical condition of the patient. Local excision, radiation therapy, chemotherapy, and the adjustment of immunosuppressive medications can all be considered (La Ferla et al. 2013).

Local recurrence is common in AIDS-KS patients, but survival is more related to the immunological status of these patients; the mortality rate can reach 20–25%. In patients with iatrogenic KS associated with immunosuppressants for rheumatic disease, tumor regression occurs in response to treatment in about two-thirds of cases. Primary mucosal KS appears to have a similar prognosis to that of the typical cutaneous form presenting on the extremities. Localized nodular KS has the best prognosis, with few deaths directly attributable to KS.

Clinical classification of KS may be the best prognosticator, comparing localized nodular disease, locally aggressive disease, and generalized KS. The association between the aggressive clinical course of classic KS and immunosuppression has previously been suggested. The immunological dysfunction underlying classic KS is unknown and may result from advanced age or chronic infection. Its induction by immunosuppressive therapy and its subsequent regression on removal of immunosuppression provided early clinical recognition of the reversibility of classic KS (Gallo 1998).

Angiosarcoma

Epidemiology, Etiology, and Pathology

Angiosarcoma , also referred to as hemangiosarcoma and lymphangiosarcoma, is a rare malignant tumor of vascular endothelial cells, representing 2% of all sarcomas. They appear during middle age, and their prognosis depends on location, size, and degree of tissue invasion. Angiosarcoma occurs predominantly in the elderly and is confined to the face and the scalp region in more than 50% of cases but has been described in the spleen, bone, liver, and breast. Most angiosarcomas of the head and neck arise in the dermis of the scalp and upper half of the face. Oral and salivary gland angiosarcomas are rare tumors in adults that generally behave more favorably than do angiosarcomas in other locations, regardless of grade.

There are three main types of angiosarcoma of the head and neck: idiopathic angiosarcoma of the head and neck in elderly patients, lymphoedema-associated angiosarcoma (Stewart-Treves syndrome ), and postirradiation angiosarcoma. Besides an association with persistent chronic lymphoedema, previous irradiation, and pre-existing vascular malformation, little is known regarding the causative factors of this disease. With respect to pathogenesis, among others, upregulation of the glycopeptide VEGF-D, a vascular endothelial growth factor, seems to be responsible for endothelial cell proliferation.

Clinical Features

Clinically the appearance of an angiosarcoma of the head and neck region can be variable. Early lesions most commonly present as single or multifocal ill-defined, bruise-like erythematous-purplish areas with indurated borders. Sometimes it may resemble hematoma-like lesions, being misinterpreted as benign inflammatory or allergic hyperemias. More advanced lesions can present as dark bluish, sometimes keratotic papules or nodules with ulceration and bleeding, mimicking other malignancies like squamous cell carcinoma, basal cell carcinoma, malignant melanoma, lymphoma, and metastases. Tumors usually extend transdermally for far wider distances than their clinical appearance suggests (Ettl et al. 2008; Trevino-Gonzalez et al. 2009).

Investigations

Microscopically a cutaneous angiosarcoma is typically characterized by numerous, irregular, and anastomosing vascular channels. These are lined by pleomorphic, hyperchromatic endothelial cells with variable mitotic activity (Fig. 109). Immunohistochemical positivity for the endothelial markers CD31 and factor VIII-related antigen as well as for the transcription factor Fli-1 may help to establish diagnosis. The differential diagnosis includes hemangioma, especially tufted, cavernous, and epithelioid hemangioma on the one hand and acantholytic carcinoma on the other hand. Especially in immunocompromised patients, Kaposi sarcoma might be a further differential diagnosis. Lack of cytoplasmic hyaline globules, spindled cells with distinctive cytoplasmic borders, and scattered plasma cells distinguish angiosarcoma from Kaposi sarcoma.

Fig. 109

Angiosarcoma. Vascular spaces delimited by pleomorphic hyperchromatic endothelial cells in a cellular stroma with fusiform and vacuolated cells (Hematoxylin and eosin stain)

Morphologically, oral and salivary gland angiosarcoma differs from that of angiosarcoma elsewhere (Fanburg-Smith et al. 2003). Although the most common angiosarcoma morphology in the oral and salivary gland location is spindled vasoformative and solid, one-third of oral and salivary gland angiosarcomas in the literature are the unusual epithelioid angiosarcoma variant. The epithelioid subtype is composed of plump atypical round cells with prominent nucleoli and definite intracytoplasmic lumina containing red blood cells (i.e., epithelioid endothelial cells).

Treatment

Radical surgery with ample margins is the treatment of choice in patients with head and neck angiosarcoma. Generally, the treatment of angiosarcoma is based on radical surgery and postoperative radiation therapy. Surgery is postulated to attain a wide excision of the tumor with histologically negative margins. Unfortunately achieving negative margins is difficult, as multifocal and extensive microscopic spread is common in this disease. Intraoperative frozen sections are often performed to assist in determining section margins (Morrison et al. 1995).

Radiation-induced angiosarcomas of the oral cavity, like non-oral primary angiosarcomas, are reported to behave poorly, with early onset of metastases and death within 2 years after treatment.

Angiosarcoma of the skin or soft tissue of the head and neck is associated with a 50% mortality rate within the first 25 months and a 12% survival rate at 5 years, compared to nasal cavity or paranasal sinus angiosarcoma, which have a 22% survival rate at 5 years according to grade of differentiation and early diagnosis. Because of this pattern of diffuse, clinically undetectable spread, the disease is very difficult to treat surgically, and long-term results using surgery alone have been very poor.

Leiomyosarcoma

Epidemiology, Etiology, and Pathology

Leiomyosarcoma is a malignant smooth muscle tumor, considered a rare lesion of the head and neck, with mostly case reports published in the literature. In the head and neck, smooth muscle is sparse and found mainly in the walls of blood vessels and in the erector pili musculature of the skin. It is presumed that these are the cells of origin of such tumors. These tumors are more likely to be found in adults ranging from third to seventh decades, with little predominance in men. Pediatric cases are described to represent the most aggressive forms.

Clinical Features

The lesion is poorly circumscribed, with firm consistency on palpation, usually measuring more than 2.5 cm, and can sometimes present with hemorrhage and necrosis. The lesions may affect the skin, scalp, neck, nose, tongue, gingiva, maxillary sinus, and hard and soft palate. Due to the rarity of the lesion, a preferred site in the head and neck region is inconclusive (Mindell et al. 1975; Montgomery et al. 2002).

Investigations

Microscopically, typical features of leiomyosarcoma consist of perpendicularly arranged fascicles of spindle cells with eosinophilic delicately fibrillary cytoplasm, hyperchromatic blunt-ended nuclei, and scattered paranuclear vacuoles growing in interlacing cords of cells with tapered nuclei and delicate tiny nucleoli. Nuclear palisading and myofibrils could also be noticed in well-differentiated lesions, but high-grade tumors exhibit more anaplastic features such as large, bizarre, pyknotic nuclei and a large number of mitotic figures. The lesions are mostly well circumscribed, although infiltrative areas may be noted at the periphery. Leiomyosarcomas in the head and neck tend to be more inflamed than leiomyosarcomas elsewhere.

Immunohistochemistry panels for leiomyosarcoma include smooth muscle actin (+), muscle-specific actin (+), desmin (+), cytokeratin (−), S100 protein (focally), myogenin (eventually +), CD34 (−), and Ki67 (5–50% nuclear staining). The differential diagnosis of adult spindle cell tumors in this site includes primarily spindled carcinoma and melanoma, other sarcoma types, and various benign fibrous tumors and pseudotumors. Spindle cell carcinomas in the head and neck are frequently polypoid mucosal-based tumors. Adequate sampling can sometimes detect an in situ or obviously epithelial infiltrating component, if one is present, and focal cytokeratin expression. However, the surface component can be lost by ulceration, and many spindle cell carcinomas are cytokeratin-negative yet can occasionally express immunoreactivity for actin. Sarcomas that should be distinguished from leiomyosarcoma in this area include myofibrosarcoma, fibrosarcoma, malignant nerve sheath tumor, malignant fibrous histiocytoma, and rhabdomyosarcoma. The latter is of the most clinical importance. Distinction among the others is less important than assigning a histological grade.

Treatment

Radical surgical excision with clear margins is always the preferred treatment for leiomyosarcomas. These tumors are likely to recur if incompletely excised, and morbidity relates to adequacy of surgical excision. However, the majority of leiomyosarcomas in the head and neck are aggressive intermediate- or high-grade tumors with little response to adjuvant therapy.

Rhabdomyosarcoma

Epidemiology, Etiology, and Pathology

Rhabdomyosarcomas (RMS) are malignant neoplasms of skeletal striated muscle cells. The head and neck are the most common anatomic sites for rhabdomyosarcoma, with an incidence currently placed at 0.104 cases per 100,000. Rhabdomyosarcomas are the most common soft tissue sarcomas in children and adolescents, accounting for 5–8% of all childhood malignancies. In contrast, it is rare in adults, occurs more frequently in the extremities, and is not as well characterized clinically and pathologically in the head and neck region.

The WHO classification divides rhabdomyosarcomas into four clinicopathologic variants: embryonal (ERMS), alveolar (ARMS), spindle cell-sclerosing (SRMS-ScRMS) RMS, and pleomorphic RMS. ERMS is the most common variant and occurs in younger patients. ARMS is the second most common variant and has a predilection for older children and young adults. Pleomorphic RMS is a rare variant, usually diagnosed in patients over the age of 45.

Although most RMS have a sporadic presentation, in a small subset of patients, RMS is part of a genetic syndrome, such as Beckwith-Wiedemann, Von Recklinghausen disease, Costello, Noonan, Gorlin, Rubinstein-Taybi, and Li-Fraumeni syndromes.

Clinical Features

The clinical presentation of head and neck RMS is divided into three subsites based on its anatomic location and local relapse: parameningeal (PM), including the paranasal sinuses, nasopharynx, nasal cavity, middle ear, mastoid, parapharyngeal region, pterygopalatine, and infratemporal fossa; orbital; and non-PM/non-orbital site, encompassing the neck, face, oral cavity, cheek, external ear, scalp, and larynx. PM subsite is the most common presentation and is associated with the least favorable outcome compared to other locations (Chen et al. 2017).

Investigations

Head and neck rhabdomyosarcoma in adults can manifest both classic and unique histologic features for each subtype. ERMS shows a morphologic resemblance to fetal skeletal muscle. ARMS, having a histological appearance of undifferentiated small blue round cells, is arranged in a variable alveolar or solid pattern. Spindle cell RMS (SRMS) is composed of monomorphic spindle cells arranged in intersecting fascicles, lacking overt rhabdomyoblastic differentiation (Fig. 110). A subset of SRMS display areas of hyaline sclerosis suggesting a morphologic overlap with the even less common sclerosing RMS (ScRMS). ScRMS may show an undifferentiated round cell component arranged in a pseudovascular or pseudoalveolar pattern in a prominent hyalinized stroma. SRMS-ScRMS represent a rare and recently recognized stand-alone pathologic entity, separated from the broad spectrum of ERMS. Pleomorphic RMS has a morphologic appearance of large pleomorphic cells.

Fig. 110

Rhabdomyosarcoma. Monomorphic spindle cells are arranged in intersecting fascicles, lacking overt rhabdomyoblastic differentiation (Hematoxylin and eosin stain)

Although no genetic abnormality prevails, small subsets of ERMS harbor loss of heterozygosity (LOH) at 11p15, as well as FGFR4, P53, BCOR, ARID1A, and RAS mutations, as shown in recent large genomic studies. The genetic hallmark of ARMS is either the more common t(2;13)(q35;q14) translocation or the t(1;13)(q36;q14) resulting in the PAX3-FOXO1 or PAX7-FOXO1 fusion, respectively (Owosho et al. 2016). SRMS-ScRMS share genetic alterations, although these vary depending on the clinical presentation: recurrent NCOA2 and VGLL2 related fusions in congenital/infantile setting, which are associated with a favorable outcome, or MYOD1-mutations in older children and adults which are associated with a poor prognosis (Kohsaka et al. 2014; Szuhai et al. 2014; Rekhi et al. 2016).

Treatment

The management of head and neck RMS remains challenging due to an increased failure of local control as well as a high rate of early metastases and high stage and recurrence rates, with often limited benefit from surgical management due to its proximity to vital structures. In the last three decades, RMS outcomes have improved significantly due to evolving multidisciplinary therapy paradigms, such as improved surgical techniques, aggressive chemotherapy regimens, and more effective conformal intensity-modulated radiotherapy. In adults, RMS presents an aggressive clinical behavior regardless of subtype. The prognostic factors in head and neck RMS have been multifactorial, such as age, tumor site, overall stage, distant metastases, histologic variant, nodal status, and status of primary surgical site (Agaram et al. 2014).

In children, RMS occurring in the head and neck tends to have favorable outcomes except for tumors arising in parameningeal sites such as the nasal cavity, paranasal sinuses, infratemporal fossa, and mastoid. Poorer outcomes for tumors in these sites are due in part to difficulty in achieving complete resection from these areas. Embryonal RMS is associated with the most favorable outcome compared to other variants. Alveolar RMS is associated with a poor prognosis. The 5-year overall survival rate of childhood RMS has risen to 62%, and the 5-year relative survival rate is estimated at 63%.

Tumors of the Temporomandibular Joints

Tumors of the temporomandibular joint (TMJ) are rare but comprise a broad spectrum of lesions. Given the potential for malignancies to mimic TMJ pathology or remain asymptomatic, the oral medicine clinician should be familiar with changes affecting the TMJ. Lesions discussed in this section constitute a representative sample of tumors involving the TMJ but are far from complete. Various conditions affecting the TMJ are covered in specific chapters such as “Non-odontogenic Bone Pathology,” “Arthritic Conditions Affecting the Temporomandibular Joint,” and “Internal Derangements of the Temporomandibular Joint.” In this section, we only highlight the more common tumors and pseudotumors affecting the TMJ.

The most frequent lesions affecting the TMJ are benign (81.8%); however, the greater majority of these are pseudotumors (synovial chondromatosis (Figs. 111 and 112), pigmented villonodular synovitis (Fig. 113), eosinophilic granuloma, and osteochondroma (Fig. 114)) representing 71.6% of lesions and do not represent true benign tumors (Poveda-Roda et al. 2013). The majority of true tumors are indeed malignant, making up almost two-thirds of cases of true tumors. Of the pseudotumors, the majority present as synovial chondromatosis (61.8%), followed by osteochondroma (24%), pigmented villonodular synovitis (4.4%), and eosinophilic granuloma (4.4%). Of the true benign tumors, chondroblastoma (Fig. 115) represents the largest single entity (17.2%), followed by osteoid osteoma (Fig. 116) (13.8%) and then chondroma, osteoma (Fig. 117), and osteoblastoma (Fig. 118) (10.9% each). Malignant tumors are mostly sarcomas of various types (synovial sarcoma, chondrosarcoma, osteosarcoma) making up 53.8% of malignant disease, followed by metastatic disease (Fig. 119) (32.7%) (Poveda-Roda et al. 2013).

Fig. 111

Synovial chondromatosis with noncalcified bodies in the superior joint space of the right temporomandibular joint. CT sagittal (a), proton density sagittal (b), fat saturation T2 sagittal (c), and coronal proton density MRI (d). White arrows in (b + c) show erosion of the roof of the glenoid fossa. (Images courtesy of Clinical Associate Professor Andy Whyte, Perth Radiological Clinic, Perth WA, Australia)

Fig. 112

Synovial chondromatosis with calcified bodies in the superior joint space of the left temporomandibular joint. CT sagittal (a), post-gadolinium T1 fat saturation sagittal reconstruction (b), CT coronal (c), fat saturation T2 coronal (d). Synovial proliferation enhances with gadolinium and is hyperintense on T2. The “bodies” are low signal on all sequences whether they are calcified or not. MRI shows many more bodies than CT for this reason. Note remodeled condyle (white arrows in c + d) probably due to pressure from the distended medial and lateral recesses of the upper joint space. (Images courtesy of Clinical Associate Professor Andy Whyte, Perth Radiological Clinic, Perth WA, Australia)

Fig. 113

Pigmented villonodular synovitis. Orthopantomogram (a) showing circumscribed lucency overlying the right articular eminence (white dotted oval). No temporomandibular joint arthropathy or other osseous abnormalities are seen. On CT (b–d) there is an avidly enhancing 27 × 24 × 27 mm right preauricular mass lesion which appears to be centered within the posterior aspect of the masseter muscle (b) and extends anterosuperiorly to involve the posterior aspect of both the medial and lateral pterygoid muscles (b + c). This component scallops the greater wing of the sphenoid bone (d) and the anterior aspect of the articular eminence of the right temporomandibular joint. There is only a tiny component of the soft tissue that projects into the temporomandibular joint itself. On MRI (e–g), there is a large multilobulate mass with dimensions of 36 × 30 × 27 mm (e–g) arising within the markedly distended lateral aspect of the anterior recess of the superior compartment of the right temporomandibular joint. The smaller superior lobule represents the component eroding the articular eminence as seen on the CT. The larger inferolateral lobule indents the posterosuperior fibers of masseter and the anteromedial aspect of the superficial lobe of the right parotid gland (f + g). On its medial margin, this larger lobule extends to the coronoid notch. The meniscus is normally positioned with an upper compartment effusion and additional small, intra-articular foci, the largest of which is situated in the posterior recess and measures 6 mm in diameter. The roof of the glenoid fossa is focally eroded with adjacent synovial proliferation and opacification of overlying mastoid air cells. The enhancement of the lesion and the superior compartment synovitis, capsulitis, and pericapsular edema are consistent with pigmented villonodular synovitis. (Images courtesy of Clinical Associate Professor Andy Whyte, Dr Gavin Chapeikin, and Dr Rudolf Boeddinghaus, Perth Radiological Clinic, Perth WA, Australia)

Fig. 114

Osteochondroma of the right condyle. Axial soft tissue CT reconstruction (a), axial bone window of the right condyle (b), and lateral, bone window, sagittal reconstruction of the right condyle (c). An exostosis of cortical and medullary bone projects anteriorly and laterally from the right condyle (white arrows in b and c). Overlying the bony component, there is a non-ossified cartilage cap (curvilinear white dotted line in a). (Images courtesy of Clinical Associate Professor Andy Whyte, Perth Radiological Clinic, Perth WA, Australia)

Fig. 115

Chondroblastoma of the right articular eminence, glenoid fossa, and middle cranial fossa. Sagittal bone window CT reconstruction (a), sagittal post-contrast CT soft tissue reconstruction (b), coronal CT soft tissue reconstruction (c), and post-gadolinium, fat saturation, coronal T1-weighted MRI (d). There is a large enhancing mass (black arrows) destroying the articular eminence and glenoid fossa (black dotted oval in a) which extends superiorly into the middle cranial fossa with mass effect on the right temporal lobe (TL in b–d). Inferior extension of the tumor into the right lateral pterygoid muscle (LP in b) and lateral extension into the temporalis (orange arrows in c and d) is also present; the latter is more clearly shown on MRI (d). (Images courtesy of Clinical Associate Professor Andy Whyte, Perth Radiological Clinic, Perth WA, Australia)

Fig. 116

Osteoid osteoma of the left glenoid fossa and articular eminence; presentation with pain and trismus in a young adult patient. Sagittal bone window CT reconstruction (a), coronal bone window reconstruction (b), fat saturation T2 sagittal MRI of the left TMJ (c), and post-gadolinium, fat saturation T1 coronal MRI (d). There is a round sclerotic nidus representing an osteoid osteoma with a lucent margin measuring 10 mm in diameter in the roof of the glenoid fossa (orange arrows). There is diffuse sclerosis of the articular eminence, root of the zygoma, remainder of the glenoid fossa, and to a lesser extent the condyle (white dotted oval in a, white dotted square in b). Extensive, hyperintense marrow and soft tissue edema is present within the nidus of osteoid osteoma, adjacent sclerotic bone, condyle, joint, and lateral pterygoid muscle (orange dashed outline in c). Following gadolinium contrast, the nidus and its lucent margin, joint, surrounding soft tissues, and condylar marrow show diffuse enhancement (orange dotted oval in d). Faint enhancement is present in marrow surrounding the nidus in the glenoid fossa with subtle meningeal thickening in the overlying left middle cranial fossa (white arrows in d). (Images courtesy of Clinical Associate Professor Andy Whyte, Perth Radiological Clinic, Perth WA, Australia)

Fig. 117

Osteoma of the left condylar head and neck. CT shows a well-defined pedunculated, dense, sclerotic, ovoid lesion with a maximum length of 15 (AP) × 17 (transverse) × 9 (height) mm, projecting anteriorly from the junction of the left condylar head and neck (a). There is diffuse thickening of the anteromedial cortex of the junction of the condylar head and neck contiguous with the pedicle of the described lesion (b). This lesion had increased in size significantly as compared with a CT taken 11 years earlier (c). (Images courtesy of Clinical Associate Professor Andy Whyte, Perth Radiological Clinic, Perth WA, Australia)

Fig. 118

Osteoblastoma of the right glenoid fossa superimposed on internal derangement, remodeling, and early arthropathy of the right TMJ in a 17-year-old female. Initial fat saturation T2 sagittal of the right TMJ demonstrates an attenuated, anteriorly displaced disc (Disc) and marrow edema in the right condylar head and neck (white dotted oval in a) and retro-condylar soft tissue edema (white dotted arrows). There is a subtle band of edema in the roof of the glenoid fossa (orange dotted arrow in a). Fourteen months later, there is now a 16 mm, edematous round nidus in the expanded posterosuperior aspect of the glenoid fossa demarcated by more marked marginal edema (orange arrows in b) on a similar fat saturation T2 sequence. The condylar marrow edema has resolved; the soft tissue edema posterior to the condyle (white dotted arrows in b) is unchanged. The external auditory canal (EAC) is indicated. Sagittal (c) and coronal (d) CT bone window reconstructions demonstrate the large, sclerotic nidus (orange arrows), an irregular thin relatively lucent margin, and marked adjacent sclerosis and thickening of the temporal bone. There is joint space narrowing, articular surface flattening, and subarticular sclerosis in the TMJ (white arrows in c) due to remodeling and early degenerative arthropathy. (Images courtesy of Clinical Associate Professor Andy Whyte, Perth Radiological Clinic, Perth WA, Australia)

Fig. 119

Metastatic renal cell carcinoma. CT coronal (a), sagittal (b), and axial of the left condyle and ramus (c) demonstrate permeative radiolucency of cortical and medullary bone of the left ramus with buccal periosteal new bone formation (white arrows and white oval). Combined low-dose CT isotope bone scan coronal (d), sagittal (e), and axial (f) images show additional metastases (white dotted arrows) in the clivus and the left articular eminence as well as the lesion seen on CT in the left ramus. (Images courtesy of Clinical Associate Professor Andy Whyte, Perth Radiological Clinic, Perth WA, Australia)

Tumors of the temporomandibular joint are characteristically found in young adults, and because of the scant specificity of their symptoms, many are initially diagnosed and treated as temporomandibular joint dysfunction or derangement (Poveda-Roda et al. 2013). The mean age of presentation is 42 years and 1 month ±16 years and 2 months. Tumors are more common in females. The mean time from symptom onset to consultation is 30 months and 8 days ±41 months and 9 days, and almost 19.6% of cases are initially diagnosed and treated as TMJ dysfunction. The most frequent clinical manifestations are pain, swelling, and the limitation of joint movement. Both clicks and crepitus are more common among the pseudotumors than in true tumors. No significant differences are noted between malignant and benign tumors in terms of joint sounds. Other more specific alterations such as facial asymmetry or occlusal disorders are less common. Occlusion alterations, one of the signs most suggestive of TMJ tumors together with the presence of swelling, are reported in 20.5% of patients. The most common occlusal disorders are ipsilateral posterior open bite, contralateral cross-bite, and anterior cross-bite (Poveda-Roda et al. 2013).

Many tumors show no radiological alterations on routine panoramic imaging (Fig. 113). Radiolucencies, and especially a poorly defined tumor contour, are suggestive of malignancy (Fig. 119). The most common radiological findings in the case of benign and malignant lesions are radiopacities and radiolucencies, respectively. Radiolucencies are significantly more frequent in tumors (77.8%) than in pseudotumors (22.0%). In contrast, radiopacities are significantly more common in pseudotumors (61.0%) (Figs. 115, 116, 117, and 118) than among tumors (7.4%). No panoramic radiographic alterations are observed in 14.6% of benign tumors and in 7.7% of malignant lesions (Poveda-Roda et al. 2013).

Treatment usually involves surgery, and relapse is observed in 10% of the cases – particularly among malignant tumors. The most frequent treatment method is total or partial synovectomy, which is a commonly used approach for synovial chondromatosis which makes up a large proportion of cases requiring treatment. Arthroscopic treatment is used in 7.3% of cases, and practically all of these correspond to synovial chondromatosis. The most common surgical procedure in the case of malignant disease is tumor resection with margins, followed by simple tumor resection. Sequelae are noted in 18.2% of cases, with tumor relapse in 9.1%. The most common problems are mandibular deviation, limited range of movement, facial palsy, crepitus, and pain. The 4-year survival rate in the case of malignant tumors of TMJ is 72.2%, with a mean survival of 6 years, in comparison with metastatic disease which presents with a mean survival of 11.4 months. Benign lesions respond well to treatment, with minimal postsurgical complications (Poveda-Roda et al. 2013).

Molecular Aspects of Head and Neck Squamous Cell Carcinoma

Head and neck squamous cell carcinomas (HNSCC) arising from the mucosal epithelia of the head and neck region have diverse etiologies and are managed differently depending on anatomical site and disease extent. While they may appear to be morphologically similar, molecular studies have underscored the heterogeneity of HNSCC demonstrating that they are instead composed of distinct diseases at the molecular level. While much work remains to demonstrate how these molecular subtypes affect patient and treatment outcomes, the development of molecular targeted therapies may very well change the way we classify and treat patients with HNSCC.

Cancer is a disease that is driven by genetic alterations, and this can occur at multiple levels, either at DNA, RNA, or protein. With the advent of high-throughput technologies, initially microarrays, array comparative genomic hybridization, and then next-generation sequencing, there currently exists the capability to catalogue genetic alterations that occur in cancer cells to unprecedented detail. This section discusses recent molecular findings in HNSCC and where appropriate how these have impacted on the clinical understanding of the disease. While etiologies, management, and outcomes of HNSCC from different subsites are distinct, much of the literature in HNSCC unfortunately does not distinguish the subsites included in studies and typically include the major sites within the head and neck region such as the oral cavity, oropharynx, hypopharynx, larynx, and less commonly nasopharynx. Therefore, this section covers HNSCC in general, but data on specific subsites is provided where possible.

Genome-Wide Studies

To date, several large-scale genomic studies on the characterization of HNSCC have been completed (Agrawal et al. 2011; Stransky et al. 2011). The largest and most comprehensive yet is the Cancer Genome Atlas (TCGA) study where 279 head and neck cancer specimens were analyzed comprehensively (2015). This study included specimens from the oral cavity (n = 172), oropharynx (n = 33), larynx (n = 72), and hypopharynx (n = 2), and comprehensive analyses revealed chromosomal changes, mutational profiles, and gene expression signatures in HNSCC. This and previous studies unveiled the catalogue of genetic alterations in cancer and provide insights into the possible vulnerabilities within cancer cells that could be targeted for therapeutic purposes.

Copy Number Alterations

Global genetic alterations can be examined at different molecular levels; the most fundamental changes occur at the DNA level. Changes within the DNA have been reported at the chromosomal level where advancements in technology have enabled the examination of these alterations beyond the resolution of classical cytogenetics. Initially analyzed by array comparative genomic hybridization (aCGH) and more recently by single nucleotide polymorphism (SNP) arrays, chromosomal aberrations in terms of loss or gain of focal regions within chromosomes are found to be common in HNSCC. This is perhaps not surprising as a comprehensive analysis of more than 3000 tumors across 12 cancer types showed that HNSCC are broadly categorized as “C” class tumors, where these tumors are largely driven by chromosomal aberrations (Ciriello et al. 2013). Loss of chromosomal regions of 3p and 8p and gains of 3q, 5p, and 8q are found in the majority of HNSCC (Agrawal et al. 2011; Stransky et al. 2011; Seiwert et al. 2015), and these mimic observations in lung squamous cell carcinoma (Cancer Genome Atlas Research 2012). The copy number changes within these regions are consistent with changes in the genes that reside within these regions such as squamous lineage transcription factors TP63 and SOX2 and the oncogene PIK3CA (3q), the c-MYC oncogene (8q), and the fragile histidine triad gene (FHIT) (3p).

When comparing HPV-positive to HPV-negative tumors, differences in chromosomal aberrations are apparent. HPV-positive tumors were characterized by loss of the 11q region (containing the DNA repair gene ATM1), TNF receptor-associated factor 3 (TRAF3) implicated in innate and acquired antiviral responses (Oganesyan et al. 2006), and gain of the transcription factor E2F1. HPV-positive tumors are also less likely to have the deletion of the 9p region containing the CDKN2a gene and amplification of the 7p region which hosts the EGFR gene. By contrast, HPV-negative tumors are characterized by frequent loss of CDKN2a and co-amplification of 11q13 (CCND1, FADD, and CTTN) and 11q22 (BIRC2 and YAP1) regions. Recurrent focal amplifications in receptor tyrosine kinase (EGFR, ERBB2, and FGFR1) are also more likely to occur in HPV-negative cancers (2015).

Mutations

With the advent of Sanger sequencing in 1977 (Sanger et al. 1977), mutations at the single base level of DNA could be commonly detected. At the start of the twenty-first century, and with the advent of next-generation sequencing which enables massive parallel sequencing, it is now possible to characterize the genome of many organisms to unprecedented depth, allowing the cataloguing of mutations that are associated with diseases including cancer. In 2011, the first literature that comprehensively described the mutational landscape by whole exome sequencing of HNSCC was published, and subsequently other large studies provided further insights into the mutational profiles of HNSCC (Agrawal et al. 2011; Stransky et al. 2011; India Project Team of the International Cancer Genome 2013). These studies reported an average of 130 coding mutations per tumor which is comparable with other smoking-related cancers such as small-cell lung cancer and lung adenocarcinomas (Lee et al. 2010b; Pleasance et al. 2010). From the largest of the sequencing studies, mutations were found to be enriched in 11 significant genes ( CDKN2A , FAT1, TP53, CAPS8, AJUBA, PIK3CA, NOTCH1, KMT2D, NSD1, HLA-A, and TGFBR2). The majority of these genes regulate and control critical pathways such as the cell cycle (CDKN2A, TP53, AJUBA), squamous differentiation (NOTCH1), or immunosurveillance (KMT2D, HLA-A). PIK3CA is the only oncogene that achieved statistical significance in HNSCC; however, it is noteworthy that an additional 20% of tumors have PIK3CA amplified without any sign of mutations. Again, distinct differences in the mutational profiles of HPV-positive and HPV-negative tumors were obvious. CDKN2A, TP53 , AJUBA, and FAT1 mutations were more predominantly seen in HPV-negative tumors, and while 86% of HPV-negative tumors had TP53 mutations, only ~3% of HPV-positive tumors had these mutations (2015). Gain-of-function mutations in PIK3CA , E542K, E545K, and H1047R/L are predominantly observed in HPV-positive tumors (2015, Chung et al. 2015; Seiwert et al. 2015). Patients who are HPV-positive and those who are HPV-negative with TP53 wild-type tumors demonstrated favorable outcomes compared to TP53 mutants and those with 11q13/CCND1-amplified tumors (2015).

Gene Expression

There are four validated gene expression subtypes of HNSCC (Chung et al. 2004; Walter et al. 2013), namely, basal, mesenchymal, atypical, and classical. More recently these subtypes have been also reported within the TCGA dataset where the largest subtype was basal (31%), followed by mesenchymal (27%), atypical (24%), and classical (18%). By integrating the genomic features with these gene expression subtypes, it is evident that these subtypes are characterized by distinct features (2015). Mutations in TP53, CDKN2A, 3q amplification, alteration of oxidative stress genes, heavy smoking history, and larynx subsite characterize the classical subtype. The basal subtype is represented by activation of EGFR and is associated with NOTCH1 mutations, an intact oxidative stress signaling, and fewer alterations of chromosome 3q. Further, the majority of tumors with HRAS and CASP8 co-mutations and with co-amplification of 11q13/q22 were of this subtype. The atypical subtype is defined by lack of chromosome 7 amplifications and enrichment of HPV-positive tumors with activating mutations in PIK3CA. The mesenchymal subtype has distinct immunological features, where high levels of alterations in innate immunity genes including high expression of natural killer cell marker CD56 and a low frequency of HLA class 1 mutations are observed, suggesting that this group may respond particularly well to immunotherapy.

Targeting Key Signaling Pathways

To date, the only approved molecular targeted therapy for head and neck cancers is cetuximab, which inhibits EGFR signaling, and the drug is indicated for regionally advanced and metastatic cancers (Baselga et al. 2005; Vermorken et al. 2008). While the molecular subtypes described above do not currently dictate therapeutic regimes, the ability to integrate genomic and gene expression information has given some insights into the critical pathways that could be targeted for cancer control. Among these, receptor tyrosine kinases such as EGFR continue to be targeted and to improve in efficacy; cetuximab is now being tested in combination with other targeted therapies such as those targeting ERBB2 (NCT02538627). PIK3CA is the most commonly mutated oncogene in HNSCC, and actionable mutations within PIK3CA afford an opportunity to inhibit the PI3K pathway. Indeed, PI3K inhibitors are actively being evaluated either alone or in combination with other agents in HNSCC (NCT02540928, NCT02646748, NCT01602315). Further, targeting of mTOR, which is a downstream target in the PI3K pathway, is also being actively pursued (NCT01051791, NCT01009346, NCT01195922).

It is evident that many of the genes that govern the cell cycle are altered in HNSCC suggesting that this pathway could be exploited for tumor control. Cyclin-dependent kinase (CDK) inhibitors are of much interest especially among HNSCC with amplified cyclin D (CCND1) and loss of CDKN2A. Recently, a CDK4/6 inhibitor, palbociclib, was approved for the treatment of estrogen receptor (ER)-positive and HER2-negative breast cancers in combination with letrozole (Finn et al. 2015). More recently, a Phase I trial demonstrated that palbociclib administered with cetuximab was safe in HNSCC patients (Michel et al. 2016) making way for a Phase II trial to evaluate palbociclib in combination with cetuximab in recurrent/metastatic HNSCC (NCT02499120). Other drugs targeting the cell cycle including inhibitors of WEE-1, a kinase that phosphorylates components within the cell cycle, are also currently being evaluated (NCT02508246, NCT02585973).

Several challenges remain in targeting the HNSCC genome. Firstly, biomarkers of response that could help with the identification of patients who would likely respond to a particular therapy are needed. Secondly, it is very likely that single agents may not be able to completely inhibit the many perturbed pathways in cancer cells, and innovative predictive methods on which drug combinations would work without causing prohibitive toxicity would be important moving forward. Last but not least, novel ways to target tumors with loss-of-function mutations and identification of new targets are necessary to enable further development of novel ways to treat HNSCC. Projects such as the Genomics of Drug Sensitivity (GDSC) and Cancer Therapeutics Response Portal (CTRP) among other emerging studies are enabling the identification of plausible biomarkers of response (Barretina et al. 2012; Garnett et al. 2012; Basu et al. 2013; Seashore-Ludlow et al. 2015; Rees et al. 2016). Further, techniques such as the gene editing tool CRISPR/Cas9 (Koike-Yusa et al. 2014; Shalem et al. 2014; Wang et al. 2014) that can systematically knock down genes within the HNSCC genome may reveal genes that are critical for the survival of cancer and hence could be targeted for tumor control.

Immune Markers and Immunotherapy

Molecular characterization of tumors has enabled identification of cancers with high mutational burden, i.e., those that have a high number of mutations within the tumor. Cancers that are associated with high mutational burden are typically those that are associated with external and known carcinogens such as melanoma which is associated with UV exposure and lung cancer which is associated with tobacco use (Lawrence et al. 2013). HNSCC falls within this group of cancers of high mutational burden, and these cancers have been reported to have a high number of infiltrating lymphocytes within the tumor (called tumor-infiltrating lymphocytes, TIL). This is possibly attributed to the increase in mutated proteins that are unique and immunogenic (not been encountered by the immune system previously) that could induce the immune system to mount an immune response. In fact, HNSCC is among the top 10 cancers with the highest level of immune infiltrates (Senbabaoglu et al. 2015; Mandal et al. 2016), making this cancer a relevant model to study cancer immunotherapy.

The equilibrium between factors that promote or suppress anticancer immunity has been recently proposed and described as the concept of “cancer-immune set point” (Chen and Mellman 2017), and in order to induce a positive immune response, induction of an effect that surpasses this point is required to illicit a protective immune effect in cancer patients. For example, the presence of CD8⁺ cytotoxic T cells and high immune infiltration has been associated with good prognosis in cancer patients, while other features including the presence of regulatory T cells (Treg) and other molecules involved in immune blockade such as CTLA-4, PD-1, and PD-L1 are indicative of immunosuppression and poor prognosis (Teng et al. 2015).

A recent bioinformatic analysis of transcriptome data from TCGA revealed the global immune repertoire of HNSCC (Mandal et al. 2016). This information provides a snapshot of the immune status of HNSCC patients, which could provide ability to subcategorize HNSCC into clinically actionable groups with important therapeutic implications, particularly in the application of cancer immunotherapy. While this analysis revealed a wide range in the level of immune infiltrates across HNSCC, overall, HNSCC are marked with high levels of immune cell infiltration which is also accompanied by a striking observation that these cancers had notable signs of immunosuppression marked by high Treg infiltration and high Treg/CD8+ ratios. Another unique immune feature of HNSCC revealed by this study was the presence of natural killer (NK) cells within the tumor where among ten most common tumor types that were examined, HNSCC was the cancer with the highest level of NK cells. With these observations, HNSCC presents as one of the most exciting and promising areas of research in immunotherapy and could be a tumor type that is highly likely to respond to immunotherapeutic strategies.

Comparing among the subsites of HNSCC, tumors of the oropharynx have the highest levels of T cell infiltration and immune activation compared to the hypopharynx, larynx, and oral cavity; however, in parallel, tumors of the oropharynx also have higher levels of immunoregulatory influence with higher Treg infiltration and low CD8+/Treg ratios. The immune repertoire is also influenced by the gene expression patterns of the tumor. Comparing the immune cell subsets across the four gene expression subgroups of HNSCC (Chung et al. 2004; Walter et al. 2013; Cancer Genome Atlas 2015), the atypical and mesenchymal subtypes have a higher degree of immune infiltration and T cell activation, compared to the basal and classical subtypes. As explained above, the atypical subtype is highly associated with HPV positivity, while the classical subtype is associated with the use of tobacco. Consistently, mutational signatures associated with tobacco smoking (Alexandrov et al. 2013) are also inversely associated with levels of immune infiltrates. While the immunosuppressive mechanism of smoking is not well defined, a recent study suggests that smoking could have suppressive effects on specific subsets of immune cells including natural killer (NK) cells, CD8+ T cells, and dendritic cells (DC) (Stampfli and Anderson 2009).

HPV status has a significant influence on the survival of HNSCC patients, and HPV-positive patients experience higher cure rates and better overall survival (Ang et al. 2010). While this could be attributed to the differences in the genetic background of HPV-positive tumors, it is conceivable that the differences in immune infiltration may also mediate part of these survival differences as suggested in other cancers (Fridman et al. 2012). Indeed, looking at the TCGA study, patients with high immune infiltration had significantly improved survival regardless and independent of HPV status. Interestingly, Treg infiltration was associated with better prognosis, and higher levels of Treg were associated with superior overall survival – however, when examined further and taking into consideration the trafficking of other immune cells into the tumor, Treg levels did not remain an independent prognostic factor underscoring the complexity and the interaction between the cells within the immune system and those that infiltrate into the tumor. NK cells are also associated with prognosis. The presence of a subset of activated NK cells (CD56dim) within the tumor is associated with superior survival.

There are two basic requirements for the immune system to control tumor growth effectively; the immune cells must overcome interstitial pressures in order to infiltrate the tumor and recognize appropriate tumor antigens. In addition, to sustain an immune response, the immune system must be free from immune inhibitory influences from the tumor (Zitvogel et al. 2006). A critical immune checkpoint often found to be downregulated the patient’s immune response is programmed cell death 1 (PD-1), an inhibitory receptor expressed on many subsets of immune cells including T cells, dendritic cells, natural killer cells, macrophages, and B cells. PD-1 function is dependent on the binding of its ligand PD-L1 or PD-L2 which are upregulated in many solid tumors including HNSCC (Cho et al. 2011; Lyford-Pike et al. 2013; Zandberg and Strome 2014). Studies have suggested a role for PD-1 in mediating T cell exhaustion in advanced solid cancers including the head and neck (Topalian et al. 2012; Lipson et al. 2015). High levels of PD-1 on T cells coupled with the presence of PD-L1 in the tumor could cause a state of anergy and an impairment in the immune system that could facilitate tumor growth (Lyford-Pike et al. 2013). Recently, two immune checkpoint inhibitors pembrolizumab and nivolumab targeting PD-1 were approved for treatment of chemotherapy refractory HNSCC. Patients treated with pembrolizumab showed an overall response rate of 18%, and the 6-month progression-free survival and overall survival rates were 23% and 59%, respectively (Chow et al. 2016; Ranee Mehra et al. 2016). On the other hand, nivolumab demonstrated an overall response rate of 13% compared to 5.8% in the standard therapy group, where the overall survival of nivolumab-treated patients was 7.5 months compared to 5.1 months in the standard therapy group (Ferris et al. 2016). These trials have now led to the approval of both pembrolizumab and nivolumab for the treatment of advanced head and neck cancers, increasing the therapeutic options for HNSCC patients with advanced disease. Several clinical trials combining anti-PD1 with standard and new agents are underway. Further, the use of monoclonal antibodies targeting the ligand of PD-1 (anti-PD-L1) as monotherapy or in combination is also in progress (Pai et al. 2016) (NCT02501096, NCT02646748, NCT02454179, NCT02586987).

The emerging understanding of the unique aspects of the immune landscape of HNSCC provides a strong rationale to use immunotherapy on these cancers, and in addition to immune checkpoint inhibitors that have been recently approved, HNSCC could also benefit from immune agonists which could reactivate the immune system, some of which like vaccines are currently in clinical testing (Yoshitake et al. 2015). Furthermore, the presence of NK cells within HNSCC affords an opportunity to reactivate NK cells by monoclonal antibodies, and these strategies are currently in preclinical and clinical investigation (NCT02643550). Therapies such as inhibitors of indoleamine-2,3-dioxygenase (IDO) with the potential to target Treg could exhibit activity in HNSCC. These work by increasing bioavailable tryptophan within the tumor microenvironment and decreasing the proliferation and activation of Tregs (Munn 2011). Further, directly targeting molecules that are highly expressed in Tregs such as glucocorticoid-induced tumor necrosis factor-related receptor (GITR) or the inducible T cell co-stimulator (ICOS) have shown promising results (Schaer et al. 2013; Mandal and Chan 2016) but have yet to be used in HNSCC.

Conclusions and Future Directions

The head and neck region is a complex part of the human body which necessitates a thorough understanding of its anatomy and resultant pathologies. The diversity of lesions, masses, and tumors that arise in this complex structure can be challenging to any clinician and underscores the importance of a multidisciplinary team approach in diagnosis, management, and surveillance of patients with such lesions. Morbidity and mortality for many years have been poor, although in recent time, mortality and morbidity for HPV-positive oropharyngeal carcinomas have improved significantly, as too has our understanding of the molecular basis of head and neck squamous cell carcinoma. As HPV-positive tumors of the head and neck region dominate the attention of practitioners and researchers alike, an equal amount of effort is required to better understand other diseases with poor outcomes. Targeted immunotherapies, precision medicine approaches, and diagnostic and prognostic biomarkers are shaping the way patients are treated. Clinicians practicing in head and neck oncological teams must stay abreast of developments in the underlying sciences which underpin these advancements in diagnosis, stratification, and management. Primary prevention of HPV-associated tumors through HPV vaccination is an important global challenge and one that requires a concerted effort across the globe. Finally, evidence-based guidelines for follow-up, surveillance, and monitoring are urgently required to better inform our management approaches and to enhance secondary prevention measures in the long-term survivor.

Cross-References

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