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Chapter 6 Nasopharynx and Waldeyer’s Ring 6

S. Regauer

Contents

6.1 Embryological Development 6.2.6.2 Papillary Adenocarcinoma of the Nasopharynx and Waldeyer’s Ring ...... 172 of the Nasopharynx ...... 182 6.2.7 Malignant Non-Epithelial Tumours 6.2 Nasopharynx ...... 173 of the Nasopharynx ...... 183 6.2.1 and Histology ...... 173 6.2.7.1 Chordoma ...... 183 6.2.2 Congenital Developmental Anomalies ...... 173 6.2.7.2 Sarcoma ...... 183 6.2.2.1 Nasopharyngeal Branchial Cleft Cysts ...... 173 6.2.2.2 Tornwaldt’s Cyst ...... 173 6.3 Waldeyer’s Ring ...... 183 6.2.2.3 Rathke’s Cleft Cyst/Ectopic Pituitary Tissue . . . . 174 6.3.1 Anatomy and Histology of Waldeyer’s Ring . . . . . 183 6.2.2.4 Craniopharyngioma ...... 174 6.3.2 Congenital Anomalies of Waldeyer’s Ring ...... 184 6.2.2.5 Heterotopic Brain Tissue/Encephalocele ...... 174 6.3.3 ...... 184 6.2.3 Congenital Tumours ...... 174 6.3.3.1 Bacterial Tonsillitis ...... 184 6.2.3.1 Anlage Tumour ...... 175 6.3.3.2 Viral Tonsillitis ...... 185 6.2.3.2 Hairy Polyp ...... 175 6.3.4 Benign Tumours of Waldeyer’s Ring ...... 187 6.2.3.3 Congenital Nasopharyngeal Teratoma ...... 175 6.3.4.1 Squamous Papilloma ...... 187 6.2.4 Benign Tumours and Tumour-Like Lesions . . . . . 175 6.3.4.2 Lymphangiomatous Tonsillar Polyp ...... 187 6.2.4.1 Nasopharyngeal Angiofi broma ...... 175 6.3.5 Carcinomas of Waldeyer’s Ring ...... 187 6.2.4.2 Respiratory Epithelial 6.3.6 Malignant of Waldeyer’s Ring . . . . . 189 Adenomatoid Hamartoma ...... 178 6.3.6.1 Mantle Cell ...... 189 6.2.4.3 Nasopharyngeal Inverted Papilloma ...... 178 6.3.6.2 Extranodal B-Cell Lymphoma 6.2.4.4 Solitary Fibrous Tumour ...... 179 of Mucosa-Associated Lymphoid Tissue ...... 190 6.2.4.5 Paraganglioma ...... 179 6.3.6.3 Extranodal NK/T-Cell Lymphoma, 6.2.4.6 Meningioma ...... 179 Nasal Type ...... 190 6.2.4.7 Glandular Retention Cysts ...... 179 6.3.6.4 Hodgkin’s Lymphoma ...... 190 6.2.5 Nasopharyngeal Carcinoma ...... 180 6.3.6.5 Extramedullary Plasmacytoma ...... 190 6.2.5.1 Non-Keratinising Nasopharyngeal 6.3.7 Systemic Disease Aff ecting Waldeyer’s Ring . . . . 190 Carcinoma ...... 180 References ...... 191 6.2.5.2 Keratinising Nasopharyngeal Carcinoma ...... 182 6.2.6 Nasopharyngeal Adenocarcinoma ...... 182 6.2.6.1 Salivary Gland-Type Adenocarcinoma of the Nasopharynx ...... 182 172 S. Regauer

6.1 Embryological Development al bursa in adults is located at the posterior median wall of the Nasopharynx of the nasopharynx above the superior pharyngeal con- and Waldeyer’s Ring strictor muscles at the lower end of the pharyngeal ton- sil and is known as Tornwaldt’s cyst (see Sect. 6.2.2.2). The is divided into an upper portion, the na- Remnants of the notochord give rise to cranial chordo- sopharynx, and a lower portion consisting of the oro- mas (see Sect. 6.2.7.1). pharynx and hypopharynx. The nasopharynx is located The oropharynx, mouth and larynx develop from above the soft and communicates with the nasal the pharyngeal (or branchial) apparatus during the passages. The oropharynx extends from the soft pal- 4th and 5th weeks of gestation. The growth of the fore- ate and the velum palatinum to the epiglottis. The hy- brain and the development of the pharyngeal/bran- popharynx extends from the tip of the epiglottis to the chial apparatus produce a prominent elevation of the lower margin of the cricoid cartilage. The term Waldey- head with a quite distinct first and second pharynge- er’s ring refers to the ring of lymphoid tissues extending al arch around day 24. At the end of the 4th embryonic 6 throughout the naso- and oropharynx and includes the week, four well-defined and two rudimentary bilateral palatine, pharyngeal, lingual and tubal . pairs of pharyngeal arches are separated by the pharyn- The earliest embryological stage relevant for the de- geal grooves. Each arch consists of a core of embryon- velopment of the nasopharynx is around the 3rd week of ic mesenchyme with an , a cartilage rod, a gestation. The embryo has already developed all three and a muscular component, and is covered externally germ layers and consists of the notochord with a noto- by ectoderm and internally by endoderm. The ectoder- chordal lumen [134]. At the cranial end, the notochord mally derived pharyngeal arches and grooves support is still fused with the ecto- and endodermal germ layers, the lateral walls of the primitive pharynx. The inner which form the bilaminar oropharyngeal (or buccopha- lining consists of endoderm with balloon-like diver- ryngeal) membrane. The first process in the formation ticuli called pharyngeal pouches, which are also pres- of the pharynx is the development of a primitive mouth ent in four well-defined pairs. The second pharynge- (or stomodeum) and a primitive pharynx during the 4th al pouch is the major contributor to the formation of week via rupture of the oropharyngeal membrane. At the pharynx and is largely obliterated when the pala- that time, the primitive nasal cavities and the nasophar- tine tonsils develop around weeks 12–14 post-concep- ynx are still separated from the oral cavity by the pri- tion. A part of the cavity of the second pouch remains mary palate and the oronasal membrane. The oronasal as the intratonsillar cleft (or ) in the pal- membrane ruptures around week 6, bringing the nasal atine tonsils (see Sect. 6.3.1). The neural crest-derived and oral cavity into continuity and forming the primi- mesenchyme will form most of the skeletal (cartilage tive choanae. During the posterior extension of the pri- and bone) and connective tissue structure of the head mary palate and development of the secondary palate, and neck, but the original mesenchyme of the second the choanae become located posteriorly and connect the arch forms the blood vessels and skeletal musculature newly formed nasal cavities and nasopharynx. The de- of the pharynx. The nerve supply of the pharynx devel- velopment of the pituitary gland (or hypophysis) begins ops from the 3rd (IX glossopharyn- around the middle of the 4th week with an upward pro- geal nerve). The adult vascular pattern of the head and liferation of the ectodermal roof of the stomodeum, the neck depends on a complex transformation of the pha- Rathke’s pouch (or hypophyseal duct), and a downgrowth ryngeal apparatus with involution and obliteration of from the diencephalon called the neurohypophyseal bud. the early vessels. Incomplete involution, particularly The Rathke’s pouch passes through the chondrification of the first pharyngeal artery, has been postulated to centres of the developing sphenoid bones. By the 5th be responsible for the development of nasopharyngeal week, both portions of the pituitary gland have come in angiofibromas (see Sect. 6.2.4.1). The auditory (Eusta- contact and the Rathke’s pouch becomes constricted at chian) tube is derived from the first pharyngeal arch its attachment to the oronasal . The stalk de- and pouch. Incomplete regression may be responsible generates and the Rathke’s pouch involutes to a series of for the occurrence of hairy polyps (see Sect. 6.2.3.2). microcysts, which persist throughout adult life in the pi- The also begins to develop at the end of the 4th tuitary gland. Occasionally, they can be recognised mac- week. The oral part of the tongue is derived from the roscopically by a zone of colloid cysts. Symptomatic en- first pharyngeal arch; the posterior pharyngeal tongue largement leads to the formation of a Rathke’s cleft cyst develops by fusion of the ventromedial parts of the sec- (see Sect. 6.2.2.3). Around the same time, during the in- ond and the third pharyngeal arch. The tissues derived volution of the notochord, a pharyngeal bursa is formed from the second pharyngeal arch are gradually over- temporarily at the site of early communication between grown by the third pharyngeal arch. the notochord and the roof of the pharynx. This ecto- The lymphoid tissues of Waldeyer’s ring develop be- dermally derived pharyngeal bursa normally obliterates tween the 14th and 18th weeks of gestation. The devel- during the 6th gestational week. A persistent pharynge- opment of the pharyngeal begins from an anlage Nasopharynx and Waldeyer’s Ring Chapter 6 173 consisting of longitudinal folds on the dorsal wall of the der associated with sleep apnoea and other craniofacial nasopharynx around the 12–14th gestational week. The anomalies [108, 137]. Far more common are congenital development of the palatine tonsils begins with a prolif- cysts and tumours arising from remnants of embryonic eration of the endodermal epithelium of the second pha- tissue. ryngeal pouch down into the surrounding mesenchyme, forming the epithelium-lined crypts. In the connec- tive tissue, mesenchymal cells of the second pharynge- 6.2.2.1 Nasopharyngeal al pouch form so-called condensation centres. The first Branchial Cleft Cysts primary follicles can be localised around week 14. The parafollicular areas develop into T-cell areas and pre- Nasopharyngeal branchial cleft cysts and fistulas are cursors of interdigitating cells can be identified. Around located in the lateral nasopharyngeal wall and can ex- week 16, the epithelium shows the first signs of cornifi- tend to the base of the skull through the parapharyngeal cation, and the lymphocytic infiltration of the epitheli- space. They occur unilaterally or bilaterally and have a um occurs [59, 60]. postulated second pharyngeal arch origin. Most naso- pharyngeal branchial cleft cysts are clinically silent dur- ing childhood and discovery may be delayed into early 6.2 Nasopharynx adulthood, when chronic induces prolif- eration of the lymphoid tissues. This produces a mass resulting in respiratory difficulties and nasal obstruc- 6.2.1 Anatomy and Histology tion. The cysts are lined with . Chronic irritation and inflammation induces squamous The nasopharynx is bordered anteriorly by the nasal metaplasia. Surgical specimens of nasopharyngeal cysts choanae and nasal cavities. The roof and posterior wall removed for symptomatic disease may therefore show of the nasopharynx form an arch just below the base of exclusively squamous epithelium and lymphoid hyper- the skull with the sphenoid sinus and the floor of the plasia in a fibrosed cyst wall [143, 177, 185]. sella turcica. The postero-superior roof contains the (naso)pharyngeal tonsil. At its lower end in the poste- rior midline lies a blind recess known as the pharyngeal 6.2.2.2 Tornwaldt’s Cyst bursa. The lateral walls of the nasopharynx contain the pharyngeal ostia of the auditory tubes, which are sur- A Tornwaldt’s cyst (or pharyngeal bursitis; named after rounded by small aggregates of lymphoid tissue, the Gustav Ludwig Tornwaldt, 1843–1910) is a dilatation of a . The cartilage of the auditory tube protrudes persistent pharyngeal bursa in the posterior median wall above the ostium and is called the , be- of the nasopharynx above the superior pharyngeal con- hind which the Rosenmüller fossa is located. The floor of strictor muscles and at the lower end of the pharyngeal the nasopharynx is formed by the and uvula. tonsil caudally and posteriorly to where Rathke’s cleft The anterior and cranial portions of the nasopharynx cysts arise [128]. The cysts arise at the site of embryonic are lined by respiratory mucosa with ciliated colum- communication between the notochord and the roof of nar epithelium with goblet cells and foci of metaplastic the pharynx and can be detected in up to 7% of adults squamous epithelium. Squamous mucosa predominates at routine autopsies [86]. Tornwaldt’s cysts are typically in the lower nasopharynx adjacent to the oropharynx. less than 1 cm in size and asymptomatic [92]. Obstruc- Small seromucinous glands and aggregates of lymphoid tion of the bursal orifice results in a cystic dilatation. tissue are present in the submucosa throughout the na- The cysts may become infected and inflamed with sub- sopharynx as a normal finding without qualifying as sequent abscess formation. Symptomatic disease, termed “chronic inflammation”. Tornwaldt’s disease, may present with nasal obstruction and nasopharyngeal drainage, dull occipital headaches, pain in the ears and neck muscles and occasionally neck 6.2.2 Congenital muscle stiffness [130]. Tornwaldt’s cysts are lined with Developmental Anomalies tall, columnar, ciliated respiratory epithelium, but in- flammation and infection induces squamous metaplasia Congenital developmental anomalies of the nasophar- and fibrosis of the walls. Tornwaldt’s cyst may contain ynx are rare and include choanal atresias and pharyn- varying amounts of lymphoid tissue (Fig. 6.1). Most sur- geal stenosis. Bilateral occlusion has been reported in gical specimens of symptomatic Tornwaldt’s cysts are up to 40% of patients with choanal atresias. Bilateral either devoid of an epithelial lining or lined with squa- atresias are typically osseous, unilateral atresias are mous epithelium. membranous. Pharyngeal stenosis is a paediatric disor- 174 S. Regauer

6.2.2.4 Craniopharyngioma

ICD-O:9350/1 All reported extracranial craniopharyngiomas (or Rathke’s pouch tumour, craniopharyngeal duct tumour) were located in the nasopharynx, sella turcica and sphe- noid sinus, and presented during the first two decades of life with headaches, nasal obstruction and epistaxis (for reviews see [18, 67]). Intracranial craniopharyngiomas occur classically in an adamantinomatous and papillary subtype. The majority of the extracranial nasopharyn- geal craniopharyngiomas are of the adamantinomatous subtype with cords of basaloid squamous cells and foci 6 of squamous differentiation and horn pearls embedded in fibrous stroma. Other typical secondary changes are Fig. 6.1. Tornwaldt’s cyst. Tornwaldt’s cysts are thin-walled cysts of varying sizes located in the nasopharyngeal submucosa. Th e cysts filled with brown fluid, areas of necrosis, calcifica- nasopharyngeal surface is covered either by squamous epitheli- tions and cholesterol crystals. Treatment is surgical and um or respiratory epithelium. Th e cysts are lined by respiratory supplemented with radiotherapy in the case of incom- type epithelium with varying extent of squamous metaplasia. Th e cyst wall contains varying amounts of infl ammatory cells and may pletely resected tumours and recurrences. be fi brosed

6.2.2.5 Heterotopic Brain Tissue/ Encephalocele 6.2.2.3 Rathke’s Cleft Cyst/ Ectopic Pituitary Tissue Encephaloceles are herniations of brain through a con- genital opening of the skull. Glial heterotopias with and Rathke’s cleft cysts (or Rathke’s cyst; named after Mar- without encephaloceles cause neonatal airway obstruc- tin Heinrich Rathke, 1793–1860) arise from the Rathke’s tion and rhinorrhoea. Heterotopic brain in a nasopha- pouch (or hypophyseal duct), an ectodermal remnant of ryngeal location is rare [168]. From a pathologist’s per- the stomodeum that gives rise to the anterior lobe of the spective, encephaloceles and brain heterotopias can be pituitary gland. The Rathke’s pouch is normally obliter- distinguished only after correlation with the patient’s ated to become microscopic clefts, but remnants of the clinical and radiological findings. Histologically, ma- Rathke’s pouch are incidental findings in up to 33% of un- ture neuroglial tissues are embedded in fibrovascular selected autopsies. Rathke’s cleft cysts can have diameters stroma. Encephaloceles/glial heterotopias involving the ranging from 0.3 to 4 cm [90, 192]. The thin-walled cysts nasopharynx differ from the more common nasal glio- are lined with respiratory epithelium with interspersed mas in that they contain ependyma, choroid plexus, reti- goblet cells and are filled with a clear, colloid, mucinous, nal components and occasionally neoplastic tissue, such viscous, turbid or haemorrhagic fluid. In cases of inflam- as an oligodendroglioma [14]. mation, metaplastic non-keratinising squamous epitheli- um and a mural lymphocytic infiltrate dominate [72, 90]. Rupture induces a granulomatous and xanthomatous in- 6.2.3 Congenital Tumours flammation with fibrosis, cholesterol needles and foreign body cell reaction, and even amyloid deposition. Rathke’s Among the tumourous developmental abnormalities are cleft cysts are virtually never removed intact and surgi- hamartomas, choristomas and teratomas. A hamartoma cal specimens typically consist of inflamed fibrous tissue. is a benign tumour-like nodule composed of mature The epithelium is often elusive. Rare examples of Rathke’s cells and tissues that normally occur in the affected part, cleft cysts contain mural nodules of anterior pituitary tis- but often with one element predominating. Choristomas sue or concomitant pituitary adenoma. Most nasopha- represent a mass of histologically normal mature tissues ryngeal pituitary adenomas represent nasopharyngeal located at a site where these tissues do not normally oc- extension of intracranial pituitary adenomas. Primary cur. These tumours are also called aberrant rests or het- nasopharyngeal pituitary adenomas are extremely rare erotopic tissue. Teratomas are true neoplastic prolifera- and mostly non-functioning [110, 123]. Symptoms de- tions made up of mature or immature tissues in random pend on the type of secreted hormone and the location of organisation derived from all three germ layers. the adenoma. Histologically, ectopic pituitary gland tis- sue can display the entire spectrum with chromophobe, acidophilic and basophilic cells [29]. Nasopharynx and Waldeyer’s Ring Chapter 6 175

6.2.3.1 Salivary Gland Anlage Tumour casional smooth muscle and striated muscle fibres. The stalk may contain foci or plates of hyaline cartilage [27]. Salivary gland anlage tumours are rare tumours of neo- Hairy polyps fulfil the definition of a choristoma, al- nates that arise from minor salivary glands of the naso- though the literature refers to hairy polyps mistakenly pharynx and are also known as congenital pleomorphic often as “teratoma”. adenoma [13, 38, 73]. The firm, polypoid, pedunculated midline masses can reach up to 3 cm in size and cause respiratory distress and feeding problems. Salivary 6.2.3.3 Congenital gland anlage tumours are multinodular and usually Nasopharyngeal Teratoma solid tumours. Histologically, they are characterised by an epithelial proliferation imitating embryonic salivary ICD-O:9080/1 glands (Fig. 6.2). The epithelial proliferation can be ex- Congenital teratomas are most common in the saccro- tensive with solid squamous areas with focal keratini- coccygeal region; less than one-third of all teratomas sation, keratinised nests, cyst and pearls. Calcification arise in the head and neck region. The nasopharynx is within the cysts occurs. Salivary gland anlage tumours an exceptionally rare location [84, 167, 187]. Teratomas may contain branching ductal and glandular structures, are ill-formed, lobular solid and cystic tumour masses occasionally with complex intraluminal papillations. typically diagnosed in the neonatal period with airway The surrounding stroma may be loose and myxoid with obstruction. Mature teratomas are completely benign numerous inflammatory cells, but may also show some and consist of mature tissues of ecto-, meso- and en- fibrosis. Other salivary gland anlage tumours consist dodermal derivation in a more or less organised fash- predominantly of densely packed sheet and nodules ion. Optimal treatment is complete excision. Immature of small fusiform spindle cells with occasional regular teratomas contain tissues of varying degrees of differen- mitoses. Rare keratinised duct and cystic structures are tiation and maturation. Immature teratomas in infants seen in these areas. Haemorrhage and focal necrosis can have an excellent prognosis, quite in contrast to adult be seen [125]. Immunohistochemically, all cells stain patients with immature teratomas. positive for salivary gland amylase. The spindle cells are immunoreactive with to vimentin, cytokera- tins, EMA and smooth muscle actin, but are negative for 6.2.4 Benign Tumours S-100 and GFAP. The epithelial structures stain for cy- and Tumour-Like Lesions tokeratin and EMA. The exact classification of the sali- vary gland anlage tumour as a hamartoma or true (be- nign) neoplasm has not yet been resolved. Dehner and 6.2.4.1 Nasopharyngeal Angiofibroma colleagues favour a hamartomatous origin, although the present name indicates a tumourous growth [38]. ICD-O:9160/0 Nasopharyngeal angiofibromas (or juvenile nasopha- ryngeal angiofibromas) are rare benign tumours with an 6.2.3.2 Hairy Polyp incidence of 0.5% of all head and neck tumours. They occur exclusively in adolescent males and become clini- Hairy polyps (or dermoids) are found in the naso- and cally evident between 10 and 25 years of age with nose oropharynx of neonates or young infants. About 60% of bleeds, respiratory distress, headaches or sometimes the roughly 140 reported cases arose as single, pedun- visual disturbances. Nasopharyngeal angiofibromas culated or sessile, 0.5 to 6 cm polyps in the lateral vault arise from the posterior lateral wall of the nasal cavity of the nasopharynx near the orifice near the pterygo-palatine fossa at the superior margin and very rarely within the Eustachian tube and middle of the foramen sphenopalatinum and extend into adja- ear [17, 78, 109]. The remaining cases occurred in the cent structures such as maxillary, sphenoid or ethmoid tonsillar region (for tonsillar and bilateral location see sinuses and the nasal cavity. The most advanced cases Sect. 6.3.2). Hairy polyps cause respiratory distress or show intracranial extension [153, 203]. The blood supply feeding problems. Simultaneous congenital abnormali- of nasopharyngeal angiofibromas comes from the exter- ties such as cleft palate are more common than ipsilat- nal carotid artery with the internal as eral branchial sinus, congenital atresia of the carotid feeding branch. In a minority of cases, the feeding ves- artery, osteopetrosis and malformations of the auricle sels are the sphenopalatine artery and the ascending [36, 68]. Treatment is simple surgical resection. A hairy pharyngeal artery [75, 153]. Diagnosis of a nasopha- polyp is covered by keratinised or glycogenated squa- ryngeal angiofibroma is based on clinical examination mous epithelium containing hair with sebaceous glands and computer tomography, which shows two consistent and sweat glands. The mesenchymal core consists of features: 1) localisation in the posterior nasal cavity mature fibroadipose tissue and blood vessels with oc- and pterygopalatine fossa, and 2) bone erosions of the 176 S. Regauer

6

a

b c

d e

fg Nasopharynx and Waldeyer’s Ring Chapter 6 177

ab

c d

e f

Fig. 6.3. Nasopharyngeal angiofi broma. a–b Nasopharyngeal an- ma. Th e muscular vessels exhibit irregular muscle walls with vary- giofi bromas are large, white, fi rm, bulging tumours covered by re- ing thickness and arbitrary arrangement of the individual smooth spiratory mucosa. c–d Abnormal large muscular and smaller sinu- muscle cells. e–f Th e stroma is either fi brous or myxoid with stel- soidal vessels are embedded in a fi brous and partly sclerotic stro- late or spindled cells

Fig. 6.2. Salivary gland anlage tumour. a–c Salivary gland anla- id squamous areas with keratin-fi lled cysts and calcifi cations. f–g ge tumours have an intact surface epithelium, which may be part- Other areas are dominated by proliferations of spindle cells in sol- ly keratinized. Th e branching epithelial proliferations show ducts id, fascicular and nested arrangement with occasional ductal and fi lled with proteinaceous casts. eTh stroma is myxoid and con- cystic elements. Haemorrhage is common tains numerous plasma cells and . d–e Th ere are sol- 178 S. Regauer

sphenopalatine foramen with extension to the upper mas originate. This theory explains the abnormal vas- medial pterygoid plate [118]. Nasopharyngeal angio- cular structures and the complex anatomical extensions fibromas are unencapsulated, lobulated, firm, grey to of nasopharyngeal angiofibromas. The growth stimula- tan tumours. Abnormal blood vessels of different sizes tion during puberty and the restriction to males remain and irregular architecture in arbitrary arrangement are unexplained by this theory, however. Treatment of na- embedded in a myofibroblastic stroma. The proportions sopharyngeal angiofibromas is surgical after embolisa- of both components can vary considerably (Fig. 6.3). tion, although radiation therapy and hormonal therapy The vascular component can be divided into small si- have been used extensively in the past [15, 37]. Nasopha- nusoidal vessels and large muscular vessels with irregu- ryngeal angiofibromas have no malignant potential, ex- lar and incomplete smooth muscle layers with abrupt cept for radiation-related malignant transformation. transitions from a muscular coat to an endothelial cell lining only. Irrespective of their architecture, all vessels are lined with a continuous layer of single regular endo- 6.2.4.2 Respiratory Epithelial 6 thelial cells. The stromal component varies in amount Adenomatoid Hamartoma and cellularity. The majority of stromal fibroblasts are plump and stellate, others assume an elongated spindled Respiratory epithelial adenomatoid hamartoma (or pol- configuration. Mitoses are inconspicuous. The majority ypoid hamartomas) typically arises within the nasal cav- of stromal cells react with vimentin only, while a sub- ity and paranasal sinuses (see also Chap. 2), but has also population is characterised by co-expression of vimen- been reported in the nasopharynx [199]. Patients are tin and smooth muscle actin. adults with an age range of 24–81 years. The polypoid Despite the body of literature, there is still uncertain- exophytic hamartomas are rubbery, tan to brown and ty about the aetiology of nasopharyngeal angiofibromas. can reach up to 6 cm in size. They are lined with cili- They have been called haemangioma and vascular ham- ated respiratory epithelium with mucin-secreting goblet artoma arising from ectopic vascular tissue of the infe- cells. The widely spaced glandular proliferations arise rior turbinate. Other theories have included overgrowth from invagination of the surface epithelium. A thick of paraganglionic tissue, hyperplasia in response to al- eosinophilic basement membrane surrounds the glands lergic stimulus, fibromatosis, teratoma arising from the and surface epithelium. The ample stroma may be oe- occipital plate, but also an androgen-dependent neoplas- dematous and well-vascularised or fibrous with vary- tic process due to an imbalance of the pituitary–andro- ing amounts of lymphocytes and inflammatory cells genital system [9]. A concomitant presentation of naso- (Fig. 6.4). Glandular acinar proliferations may be scant pharyngeal angiofibromas and the familial adenoma- and large cysts may predominate when the fibrous stro- tous polyposis syndrome has been reported in 4 out of ma predominates [206]. Some nasopharyngeal hamar- 825 patients at the Johns Hopkins’ Registry for familial tomas include a chondro-osseous component and cysts colonic polyposis [47, 62]. A mutation in the APC gene, lined with squamous epithelium. Due to overgrowth of however, was not demonstrated in 9 patients with na- a single mesenchymal element, respiratory epithelial sopharyngeal angiofibroma, and a comparative genom- adenomatoid hamartomas may resemble fibromas, lipo- ic hybridisation study describes a normal chromosome mas or chondromas [199]. Treatment of choice is sur- 5 in 3 patients with nasopharyngeal angiofibroma [70, gery. The differential diagnoses of respiratory epithelial 170]. The same study reports gains on chromosome 8 adenomatoid hamartoma include inverted papilloma at the site of the genes for TGF-ß inducible early growth and adenocarcinoma. The presence of excess glands and response and LYN (v-yes-1 Yamaguchi sarcoma viral-re- the respiratory epithelium distinguish the hamartoma lated oncogene homologue), and on chromosome 6, on readily from an inverted papilloma. The lack of malig- which the gene for the vascular endothelial growth fac- nant cytological and histological features and invasion tor is located [170]. The additional complex gains on the distinguishes the respiratory epithelial adenomatoid X chromosome and losses on the Y chromosome may ex- hamartoma from an adenocarcinoma. plain the exclusive occurrence in male patients. The in- terpretation of nasopharyngeal angiofibromas as a vas- cular malformation has proved to be the most consistent 6.2.4.3 Nasopharyngeal theory over the past few decades. A recent publication Inverted Papilloma proposes that nasopharyngeal angiofibromas arise from an embryological vascular remnant of the first pharyn- ICD-O:8121/1 geal arch artery, which normally regresses to a vascular Inverted papillomas (or Schneiderian papillomas) aris- plexus, giving rise to the maxillary artery [75, 153, 171]. ing outside the sinonasal tract are extremely rare. One Incomplete involution leaves behind vascular remnants publication reported 15 pharyngeal inverted papillomas, in the lateral nasal wall in the area of the sphenopala- 11 of which arose in the nasopharynx [183]. The pink or tine foramen from where nasopharyngeal angiofibro- grey firm polyps had a convoluted surface, which cor- Nasopharynx and Waldeyer’s Ring Chapter 6 179

papillomas have an increased potential for recurrence, which is higher in the nasopharynx than in the sinonasal location. This probably reflects the high rate of incom- plete initial removal due to the unexpected nature of the lesion and the difficult nasopharyngeal anatomy. As in a sinonasal location, inverted papillomas are at risk of malignant transformation. For a detailed description of inverted papillomas, see Chap. 2.

6.2.4.4 Solitary Fibrous Tumour

ICD-O:8815/0 a Solitary fibrous tumours are exceptionally rare in the upper respiratory tract. In the nasopharynx, only 4 cases have been described to date [96, 122, 201].

6.2.4.5 Paraganglioma

ICD-O:8680/1 Paraganglioma (or chemodectoma) arise in the head and neck region most commonly in the carotid body, glomus tympanicus and glomus jugulare. They are extremely rare in the nasopharynx with about 20 cases described (for review see [101]), but need to be considered when profuse haemorrhage and a pulsatile mass are encoun- tered in the nasopharynx. These slowly enlarging, pain- b less, firm, encapsulated tumours are characterised by nests (so-called Zellballen) of small to medium-sized pale monomorphous cells with prominent, rounded hyperchromatic nuclei and a prominent network of en- dothelial cell lined vascular channels (see also Chaps. 8 and 9).

6.2.4.6 Meningioma

ICD-O:9530/0 Among the rarest tumours of the nasopharynx are ex- tracranial meningiomas [162]. In a series of 30 extracra- nial meningiomas, 3 were located in the nasopharynx c [188]. There is only a single case report of a primary ton- sillar ectopic meningioma [107]. Extracranial meningio- Fig. 6.4. Respiratory epithelial adenomatoid hamartoma. a Th is mas show the same histological subtypes, differentiation fragmented surgical specimen of polypoid hamartoma displays numerous fl uid and mucin fi lled cysts. b Th e surface is lined by and prognosis as intracranial meningiomas, but the syn- tall columnar respiratory epithelium and there are widely spaced cytial (meningothelial) subtype predominates. For me- acinar proliferations embedded in a fi brous stroma. c Th e acinar ningiomas at other sites in the head and neck area, see proliferations are in continuity with invaginations of the surface respiratory epithelium and recapitulate either seromucous glands. Chaps. 2, 8 and 10. Th e basement membrane is typically thickened

6.2.4.7 Glandular Retention Cysts responded histologically to a multilayered, transitional- type epithelium with foci of respiratory and squamous Glandular retention cysts are rather common in the oro- epithelium growing endophytically into the underlying and nasopharynx and some may become large enough loose and myxoid stroma. Nasopharyngeal inverted to mimic nasopharyngeal tumours. They arise from di- 180 S. Regauer

lated and occluded excretory ducts of the seromucinous pharyngeal carcinomas show a strong male predilection. salivary glands of the nasopharynx. The cysts are filled While most patients with non-keratinising nasopharyn- with mucin and lined with a single layer of cuboidal geal carcinoma are older than 50 years in endemic areas, epithelium. Varying amounts of squamous metaplasia there is a bimodal age distribution with a peak presen- and oncocytic metaplasia can be observed, and when tation in the 2nd and 6th decades in intermediate- and extensive, the designation oncocytic cyst or nasopharyn- low-incidence areas [8, 43, 63, 77, 175]. The causative and geal oncocytoma may be most appropriate [3, 12, 136]. aetiological role of EBV is well established in invasive Retention cysts may rupture. The ensuing inflamma- and in situ nasopharyngeal carcinomas, irrespective of tion induced periductal fibrosis and an inflammatory the ethnic origin of the patient and the histological sub- infiltrate. The epithelium is destroyed and replaced by type [31, 158]. However, environmental factors seem to macrophages. These mucin-filled cysts are then called play a role, since the incidence of non-keratinising na- mucoceles. sopharyngeal carcinoma decreases among second and third generation Chinese living in non-endemic areas 6 [83]. Nasopharyngeal carcinomas arise in the lateral 6.2.5 Nasopharyngeal Carcinoma walls of the nasopharynx in the area of the Rosenmüller fossa and presenting symptoms may be nasal obstruc- Classification of nasopharyngeal carcinomas has under- tion, epistaxis, post-nasal drip, tinnitus and cranial gone several changes in the past editions of the WHO nerve palsy. Hearing loss and unilateral otitis media classification. The 1991 edition separates nasopharyn- are related to auditory tube involvement. In more than geal carcinoma into two subtypes, the keratinising and 50% of patients, however, metastases to cervical lymph the non-keratinising carcinoma [176]. The non-kerati- nodes are the presenting sign. Since most nasopharyn- nising carcinomas have been further subdivided into geal carcinomas are difficult to visualise on endoscopic undifferentiated and differentiated forms. This subdi- examination, “blind” biopsies of the nasopharynx, base vision, however, is nowadays considered optional since of tongue and palatine tonsils are necessary to establish their distinction is of no clinical or prognostic signifi- a histological diagnosis of undifferentiated nasopha- cance. Whether basaloid-squamous carcinoma merits ryngeal carcinoma. In patients presenting with lymph separate recognition or merely represents a morphologic node metastases and clinically occult primary carcino- variant of non-keratinising carcinoma has not yet been ma, demonstration of EBV in the metastatic carcinoma clarified [7, 138, 159, 194]. may be a helpful diagnostic tool to correctly identify the primary nasopharyngeal carcinoma [26, 40, 119, 191]. Nasopharyngeal carcinomas are highly responsive to 6.2.5.1 Non-Keratinising radiation therapy. The overall 5-year survival has been Nasopharyngeal Carcinoma reported to be between 25 and 50% in the past, but the results of treatment have improved due to refinements In the past, non-keratinising nasopharyngeal carcino- in staging and techniques of therapy [4, 115]. mas have been divided into the more common undif- Histologically, non-keratinising nasopharyngeal car- ferentiated nasopharyngeal carcinoma (ICD-O:8082/3), cinomas lack glandular differentiation. The undifferen- (synonymous lymphoepithelial carcinoma, lymphoepi- tiated subtype consists of bland uniform undifferentiat- thelioma of Regaud and Schmincke, undifferentiated car- ed cells in large cohesive nests and cords as well as small- cinoma with lymphoid stroma) and the less common dif- er nests and groups of epithelial cells with numerous mi- ferentiated nasopharyngeal carcinoma (ICD-O:8073/3) toses. They may be sharply outlined and separated from (or transitional-type carcinoma, intermediate cell car- the surrounding infiltrate or permeated by a dense in- cinoma). The distinction between undifferentiated and flammatory infiltrate consisting of numerous lympho- differentiated carcinoma is considered unimportant for cytes, plasma cells and eosinophilic granulocytes. This therapy and prognosis, as these two subtypes represent pattern often has a distinctly non-carcinomatous and a spectrum of the same tumour. Nasopharyngeal carci- lymphoma-like appearance. The infiltrating lympho- noma is by far the most common carcinoma in China cytes are a mixture of plasma cells, B-cells and T-cells, and Taiwan, accounting for 18% of all carcinomas there, with B-cells usually predominating. Portions of the T- with an incidence of 10–20/100,000 [83]. Nasopharyn- cells are cytotoxic cells. A variant of undifferentiated geal carcinomas also occur in endemic forms in Asia, carcinoma shows extensive acantholysis resulting in a Greenland, Alaska and Africa. In these high-incidence pseudoglandular and pseudovascular pattern. The dif- areas, 99% of nasopharyngeal carcinomas are of the ferentiated subtype shows cellular stratification often in non-keratinising subtype. In the western world – a low- a plexiform growth, reminiscent of transitional cell car- incidence area with 0.4–1/100,000 – the non-keratinising cinoma of the urinary bladder (Fig. 6.5). The stroma of nasopharyngeal carcinoma accounts for 75% compared non-keratinising nasopharyngeal carcinoma can be fi- with 25% for keratinising carcinoma [8, 43, 141]. Naso- brous, but is rarely desmoplastic. Coagulative necrosis Nasopharynx and Waldeyer’s Ring Chapter 6 181

a b

c d

ef

Fig. 6.5. Non-keratinizing nasopharyngeal carcinoma. a–b Na- tinizing nasopharyngeal carcinoma can be heavily infi ltrated by sopharyngeal carcinoma grows in solid sheets of large epithelial the lymphocytes. f Tumour cells are large, undiff erentiated, with cells which are clearly demarcated by a mixed infl ammatory in- abundant pale cytoplasms, inconspicuous cell membranes, and fi ltrate consisting of lymphocytes, plasma cells and histiocytes. large nuclei with prominent nucleoli c globular amyloid deposition is not uncommon. d–e Non-kera-

may be present. Small amyloid globules can be found tures are associated with a better prognosis of nasopha- within the tumour cells or scattered among the carci- ryngeal carcinoma: high density of dendritic cells, high nomatous stroma. Epithelioid granulomas, occasional- number of infiltrating lymphocytes, and low numbers ly with caseous necrosis, have been described in naso- of granzyme-B positive cytotoxic cells [58, 80, 151, 208]. pharyngeal carcinoma in up to 18% of cases. Some fea- The most reliable and sensitive method of detection of 182 S. Regauer

EBV in paraffin sections in routine diagnostic pathol- an insidiously growing tumour with a predisposition ogy is EBER in situ hybridisation [88, 93, 157, 196]. The for perineural spread, local recurrence and distant me- main differential diagnosis of nasopharyngeal carcino- tastasis. Regional metastases are rare. His- ma is a non-Hodgkin’s lymphoma, particularly the large tologically, cystic carcinomas are classified in cell lymphoma. The diagnosis of a nasopharyngeal car- tubular, cribriform and solid subtypes. The tubular and cinoma can be confirmed by positive staining with anti- cribriform subtypes are considered low-grade tumours; bodies to cytokeratins, especially high molecular weight the solid sub-type is a high-grade tumour with a rapid, keratin. fatal course and a higher incidence of distant metasta- sis with a poor prognosis [114]. When compared with conventional nasopharyngeal carcinoma, adenoid cystic 6.2.5.2 Keratinising carcinoma has a higher incidence of cranial nerve in- Nasopharyngeal Carcinoma volvement, but a lower incidence of cervical lymph node metastases. 6 ICD-O:8070/3 Polymorphous low-grade adenocarcinoma of mi- Keratinising nasopharyngeal carcinoma (squamous cell nor salivary glands (ICD-O:8525/3) (or terminal duct carcinoma, SCC) occurs typically after 40 years of age carcinoma, lobular carcinoma, low-grade papillary ad- and shows obvious squamous differentiation with vary- enocarcinoma) is a low-grade neoplasm typically oc- ing amounts of keratinisation. The stroma is desmoplas- curring in the oral cavity. It has been documented in tic and infiltrated by variable numbers of lymphocytes, the nasopharynx in rare cases [144, 198]. The poly- plasma cells, neutrophils and eosinophils. Poorly dif- morphous low-grade carcinoma has a wide diversity ferentiated SCC may only contain rare horn pearls or of histological patterns including solid areas, papillary focal areas of easily recognisable cornification. Immu- growth, ductal differentiation, cystic spaces and an in- nohistochemical analysis with to involucrin filtrative growth pattern with perineural invasion. The is helpful in identifying areas of abortive keratinisation main bulk of the carcinoma is found in the submuco- [98]. EBV is almost always positive in nasopharyngeal sa and the surface epithelium is often intact. In the na- SCC in endemic areas for nasopharyngeal carcinoma, sopharynx, surgery or radiotherapy is the treatment of but only a small number of cases in low incidence ar- choice. Polymorphous low-grade carcinomas of sali- eas are positive for EBV. SCC shows a greater propensity vary gland origin have a potentially aggressive biolog- for localised advanced tumour growth, but a lower rate ical course with metastases to cervical lymph nodes. of lymph node metastases [141, 164]. Radical surgery is For a detailed description of salivary gland tumours not performed since radiotherapy is extremely effective. see Chap. 5. Survival and prognosis of SCC depends on tumour stage and has been reported to be better than that for non-ke- ratinising nasopharyngeal carcinoma. 6.2.6.2 Papillary Adenocarcinoma of the Nasopharynx

6.2.6 Nasopharyngeal ICD-O:8260/3 Adenocarcinoma Papillary adenocarcinomas of the nasopharynx are ex- tremely uncommon, slow-growing, low-grade carcino- Adenocarcinomas of the nasopharynx are extremely mas without known risk factors [76, 114]. In a series of uncommon tumours and can be separated into carci- 9 patients, aged 11 to 64 years, the papillary adenocar- nomas arising from the surface epithelium or from the cinomas of the nasopharynx were confined to the roof mucoserous salivary glands. The salivary gland-type and postero-lateral walls of the nasopharynx [198]. Pap- carcinomas are more common than those arising from illary nasopharyngeal adenocarcinomas are unencapsu- the surface epithelium [114]. lated, exophytic, cauliflower-like tumours with an oc- casional gritty consistency due to numerous psammoma bodies. Complex papillations arise from the surface epi- 6.2.6.1 Salivary Gland-Type thelium. The papillae and crowded back-to-back glands Adenocarcinoma are lined with uniform, bland, tall, columnar cells with of the Nasopharynx intermixed mucin-containing, PAS-positive goblet cells. Some areas show overlapping vesicular nuclei with gran- Adenoid cystic carcinoma (ICD-O:8200/3), the most ular cytoplasm resembling thyroid carcinomas. Stromal common carcinoma of the salivary type in the oral cav- calcifications and psammoma bodies can be found. Vas- ity and , is rare in the nasopharynx [21, 114, cular, lymphatic or neural invasion is uncommon. Low- 181]. Adenoid cystic carcinomas of the nasopharynx are grade papillary adenocarcinomas of the nasopharynx more common in Japan than in the western world. It is should be distinguished from the polymorphous low- Nasopharynx and Waldeyer’s Ring Chapter 6 183 grade carcinoma of salivary gland origin because they palatopharyngeal muscles. In the lateral walls, at the do not metastasise. widest points of the pharynx, lies the triangular tonsil- lar fossa, which contains the . The tonsils of Waldeyer’s ring belong to the gut-associated lympho- 6.2.7 Malignant Non-Epithelial epithelial organs, which show a close morphological and Tumours of the Nasopharynx functional correlation between lymphatic tissue of mes- enchymal origin and the endodermal epithelium of the second pharyngeal pouch. The Waldeyer’s ring tonsils 6.2.7.1 Chordoma are composed of the paired palatine tonsils in the ton- sillar fossa, the unpaired (naso)pharyngeal tonsil in the ICD-O:9370/3 roof of the nasopharynx, the bilateral tubal tonsils in the Chordomas are tumours arising from remnants of the lateral walls of the nasopharynx at the entrance to the notochord in the axial skeleton near its cranial and cau- auditory tube and the lingual tonsil in the retrolingual dal ends. The cranially located chordomas comprise region. Lymphoid aggregations close to the epiglottis are about one-third of all chordomas, arise earlier than the also counted as part of Waldeyer’s ring. sacral chordomas, around the 3rd to the 5th decade and The palatine tonsils are the largest of the tonsils and in children. Most chordomas in nasopharyngeal loca- lie in the tonsillar fossa along the anterolateral border tion are extensions of cranial chordomas, but they rarely of the oropharynx between the palatoglossal and pala- arise de novo in the nasopharynx and paranasal sinuses topharyngeal muscle arches. The lateral surface of the [19, 34, 54]. For a more detailed description of chordo- palatine tonsil has a fibrous capsule, but skeletal muscle ma, see Chap. 4. fibres and islands of mostly elastic cartilage are normal findings there. The medial surface has 10–30 epitheli- um-lined, extensively branching and anastomosing ton- 6.2.7.2 Sarcoma sillar crypts that extend deeply into the lymphoid tissue. The surface of the palatine tonsils is lined by stratified The most common sarcoma in the head and neck area squamous epithelium, the crypts are covered by non- is the rhabdomyosarcoma, specifically the embryonal keratinising stratified (“transitional-type”) epithelium rhabdomyosarcoma (ICD-O:8910/3) in children less with a discontinuous basement membrane and numer- than 5 years of age [49]. Primary nasopharyngeal rhab- ous intraepithelial lymphoid cells. This so-called lym- domyosarcomas are rare [20, 39, 50] as are primary na- phoepithelium represents the specialised epithelium of sopharyngeal chondrosarcomas (ICD-O:9220/3) [54, the tonsils and contains M-cells (resembling the intesti- 56]. Case reports of primary nasopharyngeal sarcomas nal membranous [M] cells of the Peyer’s patches), T- and include an osteosarcoma in an 11-year-old girl after B-cells, and patchily distributed macrophages and den- multi-agent chemotherapy and radiation treatment of a dritic cells [140, 152]. The surface epithelium is even- retinoblastoma, a liposarcoma and a granulocytic sar- ly infiltrated by T-cells and B-cells; up to 30% of the in- coma in a 37-year-old Chinese man [5, 42, 139]. The fol- traepithelial T-cells are JGT-cells, which are involved in licular dendritic cell sarcoma, a tumour of -pre- antigen recognition independent of MHC restriction senting cells of B-follicles of lymphoid tissues, is com- and prior antigen processing [66, 149]. A clustering of monly found extranodally in the head and neck area, but CD4+ T-cells with B-cells is typical within the lympho- rarely in the nasopharynx [10, 22, 23]. It is characterised epithelium of the crypts and in the submucosa [66]. The by positivity for CD21, CD35 and CD23, as well as indo- submucosal lymphoid tissue contains numerous prima- lent clinical behaviour and a low risk of recurrence and ry and secondary lymph follicles with germinal centres, metastasis [87]. a and a network of follicular dendritic cells. T-cells, interdigitating dendritic cells, plasma cells, mac- rophages and high-endothelial venules are found in the 6.3 Waldeyer’s Ring extrafollicular regions [140]. The palatine tonsils have no afferent lymph vessels. The rich efferent lymphatic drainage is via the retropharyngeal lymph nodes to the 6.3.1 Anatomy and Histology upper deep cervical lymph nodes. of Waldeyer’s Ring The small unencapsulated (naso)pharyngeal tonsil with about 12–15 shallow crypts is lined with a colum- The term Waldeyer’s ring refers to the ring of lymphoid nar ciliated respiratory surface epithelium with numer- tissues occurring in the nasopharynx and oropharynx. ous goblet cells, which may also be seen in the lympho- The oropharynx is separated from the nasopharynx epithelial lining of the short and plump crypts [200]. The by the oropharyngeal isthmus, which is formed by the lymphoid tissue contains numerous lymph follicles with merging muscular pillars of the palatoglossal and the germinal centres. Minor salivary glands in the periph- 184 S. Regauer

ery and within the submucosa of the pharyngeal ton- “(hyperplastic) ”. Tonsillar hypertrophy is as- sil are a normal finding. The tubal tonsils are poorly de- sociated with normal childhood development, mostly fined condensations of lymphoid tissue located around due to viral challenge or can be secondary to specific the auditory tube in the nasopharynx and around the bacterial or viral infections. Childhood hypertrophy of fossa of Rosenmüller. The term lingual tonsil refers to the the pharyngeal tonsil begins at approximately 2 years of abundant non-encapsulated lymphoid tissue in the adult age or during infancy and usually regresses by 8 years of posterior tongue. The crypts do not appear until birth, age. Palatine tonsils hypertrophy at the end of the first are shallow and much less branched than in the palatine decade, somewhat later than the pharyngeal tonsil. They tonsil. The surface is covered by non-keratinising squa- regress by puberty and are atrophied in adults. The lin- mous epithelium. Adipose tissue and skeletal muscle fi- gual tonsil enlarges at the time of puberty and regresses bres at the base of the lingual tonsil, and mucous sali- very little during adult life [41]. Tonsillar hypertrophy vary glands and lymph follicles within the lingual ton- is usually symmetrical and diffuse, but can be papillary sil are integral parts of the tongue. Efferent lymphatic and unilateral. 6 vessels of the posterior tongue drain into the deep cer- The normal flora of the naso- and oropharynx in- vical lymph nodes, after they pass through the pharyn- cludes anaerobic bacteria such as gram-positive Acti- geal wall in front of or behind the external carotid ar- nomyces and Proprionibacterium, and gram-negative tery [41]. bacteria such as Bacteroides, Fusobacterium and Vib- rio [202]. Actinomyces israelii is a common nosocomial saprophyte in the oro-/nasopharyngeal cavity. The true 6.3.2 Congenital Anomalies incidence of tonsillar manifestations of actinomyces is of Waldeyer’s Ring unknown, but has been reported to be as high as 40% [57, 120]. Occasionally, actinomyces form small sulphur Congenital anomalies include the extremely rare ab- granules that can be seen as small yellow dots on the sence of palatine tonsils and accessory tonsils within the tonsillar surface. Larger aggregates of actinomyces may oral cavity [68, 155]. Slightly more common is the “hairy produce a tumour-like mass [172]. The tangled mass- polyp”, a choristoma, which arises from remnants of the es of gram-positive branching mycelial-like bacteria lie ectodermal and mesodermal germ layers in the palatine within the crypts or are attached to the surface epitheli- tonsil and nasopharynx (see also Sect. 6.2.3.2). The uni- um of normal tonsils. for hypertrophied lateral pedunculated hairy polyps of up to 5 cm arise tonsils or adenoids are one of the most common surgi- mostly on the superior pole of the palatine tonsil and cal procedures, but the term “tonsillitis” is still poor- present with acute respiratory distress [129]. A rare bi- ly defined. Surgical resection specimens may demon- lateral presentation has been described [52]. These pol- strate only hyperplastic lymphoid tissue and lymph fol- yps show a mesenchymal fibrovascular core, often with licles with enlarged germinal centres or no pathology at adipose tissue and skeletal muscle fibres and are covered all [91]. in regular skin with hair appendages. In tonsillar hairy polyps, submucosal plates of elastic cartilage of uniform thickness resembling the external ear auricular tags and 6.3.3.1 Bacterial Tonsillitis auricular cartilage have been reported [78]. Hairy pol- yps of the tonsils have been postulated to arise from the Bacterial suppurative tonsillitis is among the most fre- second pharyngeal pouch [17], but due to the presence quent paediatric infections. Group A beta-haemolytic of the cartilage plates they have also been interpreted as streptococci are the most frequent cause. Other common accessory auricles with a postulated origin from the first isolates in bacterial tonsillitis are Hemophilus , pharyngeal arch [78]. Streptococcus pyogenes, Streptococcus milleri and Staphy- lococcus aureus [97, 202, 205]. Children with acute strep- tococcal tonsillitis are significantly older than children 6.3.3 Tonsillitis with viral tonsillitis. The treatment of choice is penicil- lin administration for 10 days. Prevention of acute rheu- The lymphoid tissues of Waldeyer’s ring play a key role matic is the principal goal of treatment. Surgical in initiating immune responses against inhaled and specimens of acute tonsillitis are rarely encountered. The ingested pathogens. The tonsils are responsible for the surface epithelium may be ulcerated, and the surface and recognition and processing of presented to the crypt epithelium is infiltrated by neutrophilic granulo- pharynx. The size of the tonsils is directly proportional cytes producing a cryptitis with crypt abscesses. Acute to the amount of lymphoid tissue, which increases dur- bacterial infections may advance to intraparenchymal ing antigen challenge. The reactive lymphoid hyperpla- and peritonsillar abscesses (quinsy) with a lateral exten- sia of the palatine tonsils is often simply referred to as sion into the parapharyngeal space, base of skull and the “tonsillitis” and in the case of the pharyngeal tonsil as sheath of the carotid artery [33, 64]. Rare other bacteria Nasopharynx and Waldeyer’s Ring Chapter 6 185 causing acute necrotising tonsillitis include Clostridium receptor gene rearrangements are lacking in infectious perfringens and Bartonella henselae with an unusual pre- mononucleosis. The differential diagnosis of ulcerat- sentation of cat scratch disease [61, 121]. ing tonsillitis includes infections with herpes virus hom- inis (usually Herpes simplex virus type 1). Herpes sim- plex virus can produce a vesiculo-bullous 6.3.3.2 Viral Tonsillitis and may involve the palatine tonsils [106, 195]. Rupture of the vesicles results in sharply circumscribed shallow The most common causes of upper respiratory tract ulcers infiltrated by neutrophilic granulocytes. Infect- infections and pharyngo-tonsillitis in the general pop- ed epithelial cells show the characteristic multinucleat- ulation, including infants and young children, are vi- ed giant cells with nuclear viral inclusion. The lymphoid ruses such as influenza virus, Coxsackie’s virus (group infiltrate and hyperplasia of a Herpes simplex virus in- A), adenovirus, and the ubiquitous herpes virus Ep- fection may mimic a NK/T-cell lymphoma [184]. Group stein-Barr virus [205]. EBV infects epithelial cells and A Coxsackie’s virus also produces punched-out vesicles B-lymphocytes of Waldeyer’s ring, which represent and is often associated with a concomitant Herpes sim- the reservoir for life-long viral persistence [104, 186]. plex virus infection. Rare systemic autoimmune diseas- Primary infections with EBV occur early in infancy es, like the anti-phospholipid antibody syndrome, may and childhood in developing countries and are gener- cause tonsillar ulcers [79]. ally asymptomatic. In contrast, in developed countries, Chronic and recurrent tonsillitis are typically associ- primary infection occurs in adolescents and young ated with respiratory syncytial virus, reactivation of la- adults. EBV infections may cause the mostly self-lim- tent Epstein-Barr virus, H. influenza and Staphylococcus iting acute disease , affecting aureus [44, 117, 204]. After episodes of recurrent tonsil- adolescents and young adults in the western world. In litis, the palatine tonsils show extensive fibrosis at the Japan, however, an endemic area for EBV, acute cases of site of the former capsule and scarring with entrapped, infectious mononucleosis are commonly diagnosed in “pulled up” skeletal muscle fibres at the base of the tonsil children less than 4 years of age [100]. The symptoms and atrophic lymphoid tissue with small lymphoid fol- include enlarged swollen palatine tonsils, occasionally licles with atrophic germinal centres. Granulomas may with peritonsillar abscesses, sore , fever, mal- be present. The crypts are distended and filled with ke- aise, cervical , lymphocytosis and ratinous debris, inflammatory cells and occasional ag- occasional hepato- [133]. The diagnosis gregates of actinomyces. Retention cysts can be formed in typical cases is made clinically and/or serologically within the deep crypts of chronically irritated palatine [69]. Histologically, the changes of a primary EBV in- tonsils after occlusion of the orifice. The crypt epithe- fection can be dramatic [30]. The surface epithelium lium becomes keratinised. Calcification of the desqua- of the palatine tonsils is often necrotic. Follicular hy- mated debris following deposition of inorganic salts perplasia with fused or bizarre-shaped follicles and may result in tonsillar calculi, so-called tonsilloliths. The numerous tangible body macrophages and distended presence of actinomyces is not associated causally with interfollicular areas with atypical immunoblasts, plas- recurrent tonsillitis [57, 120]. ma cells, plasmacytoid lymphocytes and histiocytes, Human immunodeficiency virus 1 (HIV-1) infects occasionally grouped around necrotic foci, are typical. lymphocytes of lymph nodes and extranodal lymphoid Mitoses are numerous. Rare Reed-Sternberg-like cells tissue. Hypertrophy of the nasopharyngeal and palatine with single or multiple nuclei without nucleoli may be tonsils is among the earliest clinical manifestations of present beneath the crypt epithelium. The often atypi- HIV-1 infections. Enlargement of the palatine tonsils is cal immunoblasts may simulate lymphoma, but in in- usually bilateral and large ulcers may lead to complete fectious mononucleosis, they often merge with cells in destruction of the tonsils [28]. The histological chang- the reactive follicles and paracortex (Fig. 6.6). The pro- es in HIV-induced tonsillar hypertrophy vary with stage liferating lymphoid cells are predominantly activated and progression of the infection. The earliest changes in- T lymphocytes with CD8-positive T-cells dominating clude florid reactive follicular hyperplasia with irregular- over CD4-positive T-cells. The immunoblasts can be of ly shaped germinal centres with an attenuated or absent B-cell or T-cell type, and are occasionally CD30-posi- mantle cell zone. Another early change suggesting HIV tive, but CD15-negative [1]. Infected cells are reactive infection is “follicle lysis”, with permeation and disrup- for EBV nuclear antigen (EBNA) [2] and latent mem- tion of germinal centres by “infiltrating” small lympho- brane protein (LMP) [182, 186]. cytes creating a “moth eaten” appearance. Follicle lysis/ The most important differential diagnosis of infec- follicular involution involves loss of tangible body mac- tious mononucleosis, especially in older patients, is the rophages as well as the mantle zone of lymph follicles. In- extranodal manifestation of Hodgkin’s lymphoma and terfollicular haemorrhage is another feature of follicular non-Hodgkin’s lymphoma (large cell and immunoblas- involution. Multinucleated giant cells are a typical and tic types). Immunoglobulin rearrangements and T-cell specific feature of HIV tonsillitis. The multinucleated gi- 186 S. Regauer

6 ab

c d

e

Fig. 6.6. EBV tonsillitis. a Th e hypertrophic palatine tonsil con- cytes. c–d Th e atypical large immunoblasts with prominent nucle- tains reactive lymph follicles which are distended by a dense in- oli show numerous mitoses and merge with the germinal centres. terfollicular infi ltrate.b Th e surface epithelium is also heavily in- e Th e atypical immunoblasts may be binuclear atypical lympho- fi ltrated by numerous atypical lymphocytes, plasma cells, histio- blasts

ant cells are arranged preferentially in clusters beneath to S-100 and CD68. Other features of chronic HIV infec- the squamous surface and crypt epithelium, and are only tion are monocytoid B-cell hyperplasia, paracortical and occasionally seen in intrafollicular areas. They have a interfollicular expansion with immunoblasts and plasma foamy cytoplasm and the nuclei are arranged at the pe- cells, often with Russell bodies, and prominent interfol- riphery of the cells. The giant cells react with antibodies licular clusters of . The histolog- Nasopharynx and Waldeyer’s Ring Chapter 6 187 ical features in patients with advanced disease are efface- squamous epithelium (lymphocytic epitheliotropism) ment of nodal architecture, loss of the normal lymphoid or in the submucosa beneath the basement mem- cell population with replacement by benign plasma cells brane (Fig. 6.7). The stalk consists of dense fibrous and increased vascularity [53, 174, 197]. tissue, adipose tissues or myxoid and oedematous Acute non-bacterial tonsillitis and hypertrophy can stroma, which contains numerous small to medium- be the first sign of a post-transplant lymphoprolifera- sized, endothelial-lined, lymphatic/vascular chan- tive disorder [163]. In a study of 42 paediatric transplant nels filled with proteinaceous fluid and lymphocytes patients, 28% had involvement of Waldeyer’s ring [147]. [82]. Valves can be appreciated. Some endothelial In immunosuppressed children in particular with rapid cells stain with antibodies to factor VIII, CD31 and progressive enlargement of the tonsils lymphoma should CD34; others are non reactive. The pathogenesis of be suspected [180]. the lymphangiomatous polyps is uncertain. They may be a hamartomatous proliferation, but they may also be the result of a chronic inflammatory hyperplasia. 6.3.4 Benign Tumours Especially in children, lymphangiomatous polyps and of Waldeyer’s Ring papillary lymphoid polyps may be a manifestation of a chronic tonsillitis.

6.3.4.1 Squamous Papilloma 6.3.5 Carcinomas ICD-O:8121/0 of Waldeyer’s Ring Squamous papillomas represent the majority of benign tonsillar and oropharyngeal tumours [89]. They arise on ICD-O:8070/3 the soft palate and uvula, but also on the posterior wall Carcinomas of Waldeyer’s ring are typically squamous of the oropharynx. They have an exophytic appearance. cell carcinomas (SCC) arising in the palatine tonsil and The fibrovascular stalk is covered in a regular, strati- the base of the tongue. They are more common in men fied, non-keratinising or keratinising squamous mu- than in women and present during the 5th and 7th de- cosa, with occasional parakeratosis. The vast majority cades. Smoking, alcohol, poor hygiene, but also HPV show no viral cell changes. Some papillomas, however, infections, are risk factors [32, 51, 160]. Some SCC may show HPV-related cell changes with the typical koilo- be fungating and exophytic tumours, others present as cytes with small pyknotic nuclei and a perinuclear halo, deeply ulcerated infiltrative lesions. The majority of the so-called tonsillar condylomata [190]. Subtyping for SCC of the palatine tonsil and base of the tongue typi- HPV demonstrates typically low-risk HPV 6 and 11. For cally grow undetected for some time as they arise from a detailed description of squamous papilloma in the oro- the crypt epithelium. At the time of clinical detection, pharynx see Chap. 1. extensive infiltration of the surrounding tissues and regional cervical lymph node metastases are typical. The metastases to cervical lymph nodes are often the 6.3.4.2 Lymphangiomatous presenting symptom of tonsillar carcinomas (Fig. 6.8). Tonsillar Polyp Histologically, primary carcinomas of the palatine tonsil and base of the tongue can be divided into ke- Lymphangiomatous tonsillar polyps are benign tu- ratinising and non-keratinising subtypes. The solid mours of the palatine tonsil, accounting for about 2% non-keratinising carcinomas predominate. Tonsillar of all tonsillar neoplasms. They have been reported carcinomas may show a “transitional type” differentia- by a number of different names such as angiomas, tion resembling lymphoepithelial carcinoma and EBV angiofibromas, fibrolipoma, polypoid tumour contain- positivity [111, 132]. A basaloid-squamous carcinoma ing fibro-adipose tissue and hamartomatous tonsillar of Waldeyer’s ring has also been described [7, 159]. The polyp and lymphangiectatic fibrous polyp [105]. They lymph node metastases can be quite large and are often are pedunculated, mostly unilateral proliferations in cystic with multilocular complex lumina and papil- the upper pole of the palatine tonsils in adults and lary projections [165, 166, 189]. The majority of cystic children (age range of reported cases 3–63 years, with metastases are lined with a stratified epithelium with a median age of 26 years). Clinical symptoms are dys- cytological atypia and numerous mitoses. Foci of kera- phagia, sore throat and the sensation of “a mass in the tinisation can be appreciated. The cysts mostly contain throat”. Lymphangiomatous tonsillar polyps measure necrotic tumour cells and debris. A minority of the between 0.5 and 4 cm. They are covered by respira- cystic lymph node metastases is filled with clear fluid. tory epithelium or glycogenated or keratinised squa- Fluid-filled cystic metastases are more common in car- mous epithelium with foci of hyper- and parakera- cinomas of the base of the tongue than those arising tosis. Clusters of lymphocytes are found within the from the palatine tonsils. It has been postulated that 188 S. Regauer

6 ab

c d

e f

Fig. 6.7. Lymphangiomatous tonsillar polyp. a Lymphangioma- fl uid and lymphocytes. c–d Th e surface is covered by either squa- tous polyps vary in size between several millimetres to several mous epithelium with numerous intraepithelial lymphocytes or centimetres. Th e stalk may be composed of fi bro-vascular stroma by respiratory epithelium with a dense lymphocytic infi ltrate.e–f or adipose tissue. b Th e stroma may be fi brotic and contains nu- Markedly dilated lymphatic vessels accompanied by lymphocyt- merous thin-walled vascular channels fi lled with proteinaceous ic infi ltrate

carcinomas that produce cystic metastases originate A search for the primary carcinoma within the from the excretory ductal system of the submucosal pharynx in patients with clinically occult tumours minor salivary glands within the base of the tongue should include multiple blind biopsies of the base of and the palatine tonsil [165]. the tongue and oro- and nasopharynx and/or ton- Nasopharynx and Waldeyer’s Ring Chapter 6 189

lymph node or carcinoma arising in a branchiogenic cyst is probably a hypothetical entity. Reports of a sup- posed branchiogenic carcinoma included an extreme- ly well-differentiated SCC arising in the background of longstanding chronic inflammation and scarring, one carcinoma arising from pre-auricular ectodermal remnants of the first pharyngeal/branchial cleft and another report of a well-differentiated mucoepider- moid branchiogenic carcinoma [16, 154, 178]. Treat- ment of SCC of Waldeyer’s ring is surgical resection with a .

6.3.6 Malignant Lymphomas of Waldeyer’s ring

This section gives a brief overview of lymphomas of Waldeyer’s ring. For a more detailed description, in- a cluding genetic characteristics of these lymphomas see the WHO classification and the revised European- American classification of lymphoid neoplasms [74, 95]. Extranodal lymphomas of Waldeyer’s ring con- stitute about 5–10% of all lymphomas in the USA and Europe, about 15% in Hong Kong and about 10–20% in Japan. Of all lymphomas involving Waldeyer’s ring, 80% are primary to this site and the tonsillar fossa is the most common location, followed by the nasophar- ynx and the base of the tongue. Up to 20% of patients with tonsillar lymphoma have an associated gastroin- testinal involvement. Clinical presentation is that of a localised neoplasm, sore throat, dysphagias, and in cases of nasopharyngeal involvement cranial nerve, auditory and nasal symptoms. Between 85 and 90% of all non-Hodgkin’s lymphomas in Waldeyer’s ring are of the B-cell phenotype, the remainder are of the T-cell type, but regional differences have been reported [146, 150]. The vast majority of Waldeyer’s ring lymphomas b are high-grade lymphomas, with only less than 15% being of low grade [113]. The majority of AIDS-related Fig. 6.8. Tonsillar carcinoma. a Tonsillar squamous cell carcino- extranodal head and neck lymphomas are aggressive mas frequently arise from the crypt epithelium. Th e carcinoma in- fi ltrates deeply into the surrounding structures including skeletal B-cell lymphomas of the Burkitt type or immunoblas- muscles. b Cystic lymph node metastasis showing complex papil- tic diffuse large B-cell lymphomas [207]. lations which are lined by squamous epithelium; the cyst content is necrotic debris 6.3.6.1 Mantle Cell Lymphoma sillectomies. This practice has provided overwhelm- ICD-O:9673/3 ing evidence that isolated carcinomas in neck lymph Mantle cell lymphoma (or centrocytic (mantle cell) lym- nodes are metastases and not so-called primary phoma in the Kiel classification; diffuse, small cleaved “branchiogenic carcinomas” within a cervical lymph cell type in the Working Formulation) constitutes about node. The evolution of in situ or invasive SCC from 5% of all non-Hodgkin’s B-cell lymphomas. Common non-neoplastic squamous epithelium through dyspla- extranodal sites are the , , gastroin- sia is viewed as the most important criterion for the testinal tract and Waldeyer’s ring, particularly the pala- histopathological diagnosis of a primary branchiogen- tine tonsil. ic carcinoma. Primary cystic carcinoma arising in a 190 S. Regauer

6.3.6.2 Extranodal Marginal Zone 6.3.6.4 Hodgkin’s Lymphoma B-Cell Lymphoma of Mucosa-Associated ICD-O:9650/3 Lymphoid Tissue Although exceptionally rare in extranodal sites, prima- ry Hodgkin’s lymphoma does occur in Waldeyer’s ring ICD-O:9699/3 and nasopharynx. In a review of 659 upper respiratory Mucosa-associated lymphoid tissue (MALT lymphomas tract lymphomas, 6 cases of Hodgkin’s lymphoma in or immunocytoma in the REAL classification; small lym- Waldeyer’s ring were identified [35, 103]. The WHO di- phocytic, lymphoplasmacytoid, diffuse small cleaved cell vides Hodgkin’s lymphomas into the nodular lympho- lymphoma in the Working Formulation) are low-grade cyte predominant Hodgkin’s lymphoma and the classi- extranodal lymphomas that comprise about 8% of all B- cal Hodgkin’s lymphoma (subdivided into - cell lymphomas, typically in gastrointestinal locations. rich, nodular sclerosis, mixed cellularity and lympho- Up to 14% occur in the head and neck area, but MALT cyte-depleted Hodgkin’s lymphoma) [95]. Waldeyer’s 6 lymphomas arising in Waldeyer’s ring are exception- ring Hodgkin’s lymphomas belong predominantly to ally rare [112, 145]. In epithelial tissues, the MALT lym- the classical subtypes: seven primary cases of nodular phoma cells infiltrate the epithelium, forming lympho- lymphocyte-rich Hodgkin lymphoma were reported epithelial lesions. In Waldeyer’s ring, however, caution in two studies with a total of 27 patients [25, 179]. In is advised not to over-interpret the normally occurring another series with 16 patients with Waldeyer’s ring intraepithelial lymphocytes within the tonsillar and Hodgkin’s lymphoma, 50% were classified as mixed nasopharyngeal mucosa as lymphoma [94]. In general cellularity, 25% as nodular sclerosis, one case was a MALT lymphomas run an indolent course with a ten- nodular lymphocyte predominant subtype and three dency to remain localised. They are sensitive to radia- were unclassified [103]. Epstein-Barr virus has been tion therapy. Patients have prolonged disease-free inter- postulated to play a pathogenetic role in Hodgkin’s vals after treatment, but recurrences may involve other lymphoma since it has been demonstrated in the ma- extranodal sites. jority of Hodgkin’s lymphomas of Waldeyer’s ring at a higher incidence than in nodal Hodgkin’s lymphomas [81, 103]. In addition, patients often had a history of 6.3.6.3 Extranodal NK/ infectious mononucleosis. Therapy is local irradiation T-Cell Lymphoma, Nasal Type with or without chemotherapy.

ICD-O:9719/3 The extranodal NK/T-cell lymphoma, nasal type (or 6.3.6.5 Extramedullary angiocentric T-cell lymphoma in the REAL classifi- Plasmacytoma cation; other historical names: lethal midline granu- loma, malignant midline reticulosis, angiocentric im- ICD-O:9734/3 munoproliferative lesion) shows a predilection for the The upper aerodigestive tract is the most common site nasal cavity, nasopharynx and palate, but also occurs for extra-osseous plasmacytomas, with 80% arising in in skin, soft tissues, and testis. the head and neck area. In a series of 299 cases, 22% The denominator “nasal type” indicates that the na- arose in the nasopharynx and 7% in the tonsil [55, 102, sal cavity is the most common and prototypic site of 124]. Plasmacytomas of Waldeyer’s ring proceed less involvement (Chap. 2). Some cases can be accompa- often to multiple myeloma than those of other loca- nied by secondary lymph node involvement. Rapid tions. systemic dissemination is common, but bone marrow involvement is very rare. NK/T-cell lymphoma is more common in Asia, Mexico and South America than in 6.3.7 Systemic Disease Affecting Europe and North America, and shows a strong as- Waldeyer’s Ring sociation with Epstein-Barr virus [24, 65, 99, 135, 142, 148]. The prognosis of nasal NK/T-cell lymphoma is Tangier’s disease (familial hypo-alpha-lipoproteinemia) variable despite aggressive therapy. Some patients re- is an autosomal-recessive metabolic disease with a de- spond well and others die with disseminated disease. ficiency of high-density lipoproteins and extremely low The prognostic influence of the cytological differen- levels of plasma cholesterol [85]. 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