head and neck pathologie

1081L. Cheng and D.G. Bostwick (eds.), Essentials of Anatomic Pathology, DOI 10.1007/978-1-4419-6043-6_24, © Springer Science+Business Media, LLC 2002, 2006, 2011

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Head and NeckJohn D. Henley, md and Don-John Summerlin, md

CoNteNtS

I. oral Cavity .......................................24-4Infection ...........................................................24-4

Candidiasis .............................................24-4Herpes Simplex Virus ............................24-4Oral Hairy Leukoplakia .......................24-4Human Papillomavirus .........................24-5Disseminated Fungal Infection .............24-5

Immune-Mediated Disease .............................24-5Lichen Planus .........................................24-5Benign Mucous Membrane

(Cicatricial) Pemphigoid ..................24-6Pemphigus Vulgaris ...............................24-6

Inflammatory/Nonneoplastic Lesions ............24-6Peripheral Ossifying Fibroma ..............24-6Peripheral Giant Cell Granuloma .......24-7Verruciform Xanthoma .........................24-7Traumatic Ulcerative Granuloma

with Stromal Eosinophilia ...............24-7Mucous Extravasation Phenomena

(Mucocele/Ranula) ............................24-8Necrotizing Sialometaplasia .................24-8

Benign Neoplasms ...........................................24-8Granular Cell Tumor ............................24-8Congenital Gingival Granular

Cell Tumor (Congenital Epulis) ......24-8Premalignant/Malignant Neoplasms .............24-9

“Leukoplakia” .......................................24-9Squamous Dysplasia/Carcinoma

In Situ ................................................24-9Proliferative Verrucous

Leukoplakia .......................................24-9Squamous Cell Carcinoma .................24-10Verrucous Carcinoma .........................24-10

Sarcomatoid (Spindle Cell) Carcinoma .......................................24-11

Papillary Squamous Cell Carcinoma .......................................24-11

Malignant Melanoma ..........................24-11Miscellaneous Lesions ...................................24-12

Adenomatoid Hyperplasia ..................24-12Amalgam Tattoo ..................................24-12Aphthous Stomatitis ............................24-12Dermoid Cyst .......................................24-12Geographic Tongue

(Erythema Migrans) .......................24-12Lingual Thyroid ...................................24-12Lymphoepithelial Cyst ........................24-12Melanoacanthoma ...............................24-12Nicotine Stomatitis ..............................24-12Oral Focal Mucinosis ..........................24-12Palisaded, Encapsulated (Solitary,

Circumscribed) Neuroma ..............24-12Salivary Duct Cyst ...............................24-13Smokeless Tobacco-Induced

Keratosis ..........................................24-13

II. Jaws ................................................24-13Nonodontogenic Cysts/Pseudocysts .............24-13

Nasopalatine Cyst ................................24-13Traumatic Bone Cavity .......................24-13

Odontogenic Cysts .........................................24-13Dentigerous Cyst ..................................24-13Odontogenic Keratocyst

(Keratocystic Odontogenic Tumor) .............................................24-14

Apical Periodontal Cyst ......................24-14

Essentials of Anatomic Pathology, 3rd Ed.

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Calcifying Odontogenic Cyst (Gorlin Cyst) ...................................24-14

Dentinogenic Ghost Cell Tumor (Included Here Given Similarity to Gorlin Cyst) ................................24-15

Reactive/Nonneoplastic Disease ...................24-15Cementoosseous Dysplasia .................24-15Odontoma .............................................24-15

“Giant Cell” and Giant Cell-Rich Lesions .......................................................24-15

Central Giant Cell Granuloma ..........24-15Giant Cell Tumor .................................24-16Aneurysmal Bone Cyst ........................24-16Cherubism ............................................24-16

Benign Neoplasms .........................................24-16Ameloblastoma ....................................24-16Adenomatoid Odontogenic Tumor ....24-17Calcifying Epithelial Odontogenic

Tumor (Pindborg Tumor) ..............24-17Squamous Odontogenic Tumor ..........24-17Ameloblastic Fibroma .........................24-18Cementoblastoma ................................24-18Central Cementoossifying

Fibroma ...........................................24-18Odontogenic Fibroma .........................24-18

Malignant Neoplasms ....................................24-19Ameloblastic Carcinoma .....................24-19Squamous Cell Carcinoma .................24-19Clear Cell Odontogenic

Carcinoma .......................................24-19Osteosarcoma .......................................24-19Chondrosarcoma .................................24-20Mesenchymal Chondrosarcoma .........24-20Metastatic Disease ...............................24-20Melanotic Neuroectodermal Tumor

of Infancy .........................................24-20Miscellaneous Lesions ...................................24-20

Stafne Defect ........................................24-20Tori ........................................................24-20Gingival Cyst/Lateral Periodontal

Cyst ..................................................24-21Central Mucoepidermoid

Carcinoma .......................................24-21

III. oro/Hypopharynx ..........................24-21Malignant Neoplasms ....................................24-21

Squamous Cell Carcinoma .................24-21Lymphoepithelial Carcinoma .............24-21Basaloid Squamous Carcinoma .........24-21Papillary Squamous

Cell Carcinoma ...............................24-22

IV. Nasal Cavity, Paranasal Sinuses, and Nasopharynx ............................24-22

Infection .........................................................24-22

Rhinosinusitis .......................................24-22Allergic Fungal Sinusitis .....................24-23Invasive Fungal Sinusitis.....................24-23Other Forms of Infectious

Sinusitis ............................................24-23Inflammatory/Nonneoplastic Lesions ..........24-23

Mucocele ...............................................24-23Wegener Granulomatosis....................24-24Sarcoidosis ............................................24-24Myospherulosis ....................................24-24Polyps ....................................................24-24

Benign Neoplasms .........................................24-25Lobular Capillary Hemangioma

(Granuloma Pyogenicums) ............24-25Hyperkeratotic Squamous

Papilloma .........................................24-25Sinonasal Papilloma (Schneiderian

Papilloma) .......................................24-25Hemangiopericytoma-Like Tumor

of the Nasal Cavity ..........................24-26Juvenile Nasopharyngeal

Angiofibroma ..................................24-27Malignant Neoplasms ....................................24-27

Squamous Cell Carcinoma .................24-27Malignant Lymphoma .........................24-28Adenoid Cystic Carcinoma .................24-28Olfactory Neuroblastoma

(Esthesioneuroblastoma) ................24-29Sinonasal Undifferentiated

Carcinoma (SNUC) ........................24-29Malignant Melanoma

(Sinonasal Melanoma) ....................24-30Small Cell (Neuroendocrine)

Carcinoma (SCNC) ........................24-30Adenocarcinoma ..................................24-31Rhabdomyosarcoma ............................24-31Nasopharyngeal Carcinoma (NPC) ...24-32

Miscellaneous Lesions ...................................24-32Respiratory Epithelial Adenomatoid

Hamartoma .....................................24-32Necrotizing Sialometaplasia ...............24-32Cholesterol Granuloma .......................24-32Chondromesenchymal

Hamartoma .....................................24-32Extranodal Sinus Histiocytosis

(Sinus Histiocytosis with Massive Lymphadenopathy, Rosai–Dorfman Disease) ............................................24-32

Fibromatosis.........................................24-33Hemangioma of Nasofacial Bones ......24-33Meningioma .........................................24-33Mesenchymal Chondrosarcoma .........24-33Osteoma ................................................24-33Metastatic Tumors ...............................24-33Pituitary Adenoma ..............................24-33

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Salivary Gland Tumors .......................24-33Sarcoma ................................................24-33Solitary Fibrous Tumor ......................24-33Teratoid Carcinosarcoma

(Teratocarcinosarcoma) .................24-33

V. Larynx and trachea .........................24-34Infection .........................................................24-34

Disseminated Fungal Infection ...........24-34Inflammatory/Nonneoplastic Lesions ..........24-34

Laryngocele ..........................................24-34Oncocytic Cyst .....................................24-34Vocal Cord Polyp

(Laryngeal Polyp) ...........................24-34Contact Ulcer .......................................24-35

Benign Neoplasms .........................................24-35Laryngeal Papillomatosis

(Squamous Papillomas) ..................24-35Premalignant/Malignant Neoplasms ...........24-35

Squamous Cell Hyperplasia (Hyperkeratosis) .............................24-35

Squamous Dysplasia/Carcinoma In Situ ..............................................24-36

Squamous Cell Carcinoma .................24-36

Verrucous Carcinoma .........................24-36Basaloid Squamous Cell

Carcinoma .......................................24-36Sarcomatoid Carcinoma

(Spindle Cell Carcinoma) ...............24-36Papillary Squamous

Cell Carcinoma ...............................24-37Lymphoepithelioma-Like

Carcinoma .......................................24-37Small Cell (Neuroendocrine)

Carcinoma (SCNC) ........................24-37Large Cell Neuroendocrine

Carcinoma (LCNC) ........................24-37Adenoid Cystic Carcinoma .................24-38Chondrosarcoma .................................24-38Mesenchymal/Soft Tissue Tumors .....24-38

VI. tNM Classifications for the Lip and oral Cavity (2010 Revision) .....24-38

VII. tNM Classifications for the Larynx (2010 Revision) ...................24-39

VIII. Suggested Readings .........................24-40

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oRAL CAVItY

InfectionCandidiasisClinical

This represents the most common opportunistic infection in ♦the oral cavity. It may be caused by a variety of species, most commonly Candida albicans. This can occur at any age, including infancy; however, it is usually secondary to under-lying disease (immunosuppression, diabetes), immunosup-pressive therapy, or local factors (ill-fitting dentures). It may appear as a curd-like pseudomembrane (pseudomembranous candidiasis), tissue hyperplasia (hyperplastic candidiasis), or erythema (atrophic candidiasis)

MicroscopicIn most instances, perpendicularly oriented (relative to ♦mucosa) pseudohyphae and spores are located in the superfi-cial parakeratin accompanied by neutrophilic exocytosis. Visualization of the organisms and spores may be aided by GMS and PAS stains

Herpes Simplex VirusClinical

Most herpetic lesions of the oral cavity are caused by Herpes ♦simplex virus, type I or type II. Typically, herpetic infections present as localized vesicles or ulcers on keratinized mucosa or lip vermilion. Mucosal eruptions can be widespread in children not previously exposed (gingivostomatitis)

MicroscopicThe histopathologic features include vesicles with acantho- ♦lytic cells (Tzanck cells). Commonly, the lesions are biopsied once they have ulcerated. If so, cells on margin of the ulcer-ation often demonstrate viral cytopathic effect (multinucleate cells with “ground glass” chromatin, angular nuclear out-lines, and intranuclear eosinophilic inclusions) (Fig. 24.1)

Oral Hairy LeukoplakiaClinical

This condition represents a peculiar manifestation of ♦Epstein–Barr virus (EBV) infection, mostly in immunosup-pressed hosts. Usually, bilateral linear striations are seen on the lateral border of tongue. Oral hairy leukoplakia may be seen in AIDS, organ transplant patients, diabetics, and can-cer patients. On rare occasions, this infection can be seen in immunocompetent hosts

MicroscopicUpon microscopic examination, hyperkeratosis is seen beneath, ♦which is a linear band of cells with edematous cytoplasm and nuclei that demonstrate chromatin margination (Fig. 24.2A,B). In situ hybridization will illuminate EBV within these cells. Superimposed candidiasis is present in most cases

Fig. 24.1. Multinucleate cells with ground glass nuclear change characterize infection with Herpes simplex virus.

Fig. 24.2. The hyperkeratotic lesions of oral hairy leukoplakia usually present on the lateral border of the tongue in immuno-suppressed patients (A). Cellular changes characterized by edematous cytoplasm and nuclei that demonstrate chromatin margination are secondary to Epstein-Barr virus (B).

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Differential DiagnosisMorsicatio linguarum (tongue chewing) ♦

This condition demonstrates thickened parakeratin with a −ragged surface and adherent bacterial colonies but lacks candidal infection and EBV

Human Papillomavirus

ClinicalHuman papillomavirus infection will produce papillary ♦lesions of the oral cavity – papillomas, condylomas, and ver-rucae. Commonly, these are seen in young patients on tongue, gingiva, and soft palate complex. These possess a papillary growth pattern and are generally small, localized lesions

MicroscopicThe squamous papilloma demonstrates a papillary epithelial ♦proliferation arising from stalk or pedunculated base. Verrucae demonstrate coarse keratohyaline granules, hyper-keratosis, and axial inclination of rete ridges. Condylomas demonstrate koilocytes and broader papillations and branch-ing. The presence of condylomas in children may suggest child abuse. Although not thought to be a significant risk fac-tor for carcinomas of the oral cavity proper, HPV types 16 and 18 are highly associated with squamous cell carcinomas of tonsil/oropharynx

Disseminated Fungal Infection

ClinicalA variety of disseminated fungal infections may have oral ♦manifestations, including histoplasmosis, blastomycosis, cryptococcosis, and coccidioidomycosis. Most, but not all, patients demonstrate a definable immunodeficient state (i.e., HIV, diabetes, status postorgan transplantation, malignancy). These infections are accompanied by oral ulceration, weight loss, and fevers. In many instances, oral lesions are preceded by pulmonary infection

MicroscopicTypically granulomatous inflammation is seen, including his- ♦tiocytes, giant cells, and necrosis (Fig. 24.3). The presence of a neutophilic infiltration with giant cells is characteristic of blastomycosis. Blastomycosis is notorious for associated pseudoepitheliomatous hyperplasia, simulating squamous cell carcinoma. Discrete granulomas may be absent in histo-plasmosis (i.e., organism-laden, foamy histiocytes with necrosis and nonspecific inflammation). Fungal stains (GMS and PAS) may aid identification of microorganisms

Immune-Mediated DiseaseLichen PlanusClinical

This mucocutaneous disease is characterized by bilateral, ♦symmetrical white striations (striae of Wickham) superim-posed upon an erythematous background. Most commonly this is seen in perimenopausal females on the buccal mucosa, tongue, or gingiva. In the erosive form, it presents as an ery-thematous lesion with faint peripheral striations

MicroscopicA band-like infiltrate of lymphocytes obscuring epithelial/ ♦connective tissue junction represents the seminal microscopic feature (Fig. 24.4). Spike-shaped rete ridges and dissolution of basal epithelial layer are also apparent

ImmunofluorescenceShould direct immunoflurescent testing be undertaken, gran- ♦ular deposition of fibrinogen is observed at the basement membrane level

Differential DiagnosisLichenoid mucositis ♦

Histologically this is similar to lichen planus but typically −is not symmetrical. This may be due to a variety of stimuli – dental products, dental materials, systemic medication

Fig. 24.3. Oral manifestations of histoplasmosis reflect dissemi-nated disease. Inset: GMS stain highlights yeast.

Fig. 24.4. Band-like inflammatory infiltrates and spike-shaped rete ridges characterize lichen planus.

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Epithelial dysplasia with lichenoid inflammation ♦

Epithelial alterations consistent with irreversible, precan- −cerous change, probably accounts for most cases of “malignant transformation” of lichen planus

Benign Mucous Membrane (Cicatricial) Pemphigoid

ClinicalThis immunologically mediated disease demonstrates general- ♦ized sloughing of epithelium leaving a bleeding erythematous base. The typical population is peri/postmenopausal females. Often sloughing can be elicited with gauze or a gloved finger. Ocular and genital mucosal involvement may also be seen

MicroscopicSubbasilar separation of the epithelium is characteristic of ♦this condition (Fig. 24.5). A diffuse chronic inflammatory infiltrate of lymphocytes is seen with a smattering of neutrophils

ImmunofluorescenceLinear deposition of C3 and IgG along the basement ♦membrane zone is seen in almost all cases in which direct immunofluorescence is performed

Differential DiagnosisLichen planus ♦

Can demonstrate separation but basal layer is lost. The −lymphocytic infiltrate is typically more band like

Pemphigus vulgaris ♦

Separation occurs above the basal layer, and Tzanck cells −may be present

Pemphigus Vulgaris

ClinicalWidespread sloughing and ulceration of mucosa is the typi- ♦cal manifestation. Young adult males and females are the

commonly afflicted individuals. This can manifest primarily as gingival desquamation without cutaneous lesions

MicroscopicSuprabasilar separation of the epithelium is seen, possibly ♦with evidence of Tzanck cells. The inflammatory infiltrate is composed mostly of lymphocytes

ImmunofluorescenceIntraepithelial (desmosomal) deposition of C3 and IgG in a ♦spider web pattern is characteristic of pemphigus when viewed with immunofluorescence (Fig. 24.6)

Differential DiagnosisLichen planus, see above ♦

Cicatricial pemphigoid, see above ♦

Drug-induced pemphigus ♦

Can be seen in particular with penicillamine −

Paraneoplastic pemphigus ♦

Supra and subbasilar splits are seen in patients with lym- −phoma and leukemia

Inflammatory/Nonneoplastic Lesions

Peripheral Ossifying Fibroma

ClinicalThis represents a reactive mesenchymal proliferation of peri- ♦odontal ligament origin that retains the capacity to form bone or cementum-like product. Most commonly seen in the sec-ond to third decade, the peripheral ossifying fibroma demon-strates a female predilection. Occurring exclusively on the gingiva, it presents as a broad-based nodule that is typically ulcerated and asymptomatic

Fig. 24.5. Subbasilar separation of the epithelium with chronic inflammation.

Fig. 24.6. Direct immunofluorescence revealing IgG positivity in the desmosomal areas.

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MicroscopicThe microscopic features include a cellular mesenchymal ♦tissue with intermixed calcifications that can resemble bone or cementum (Fig. 24.7). It often extends to the base because of its origin in the periodontal ligament, resulting in recurrence

Peripheral Giant Cell Granuloma

ClinicalConsidered a reactive proliferation of vascular mesenchy- ♦mal tissue with intermixed osteoclasts, the peripheral giant cell granuloma has a propensity to occur in older adults in the fourth to sixth decades. It appears as a lobular, blue to purple mass on the gingiva/alveolar ridge. It may erode bone superficially, resulting in an alveolar radiolucency

MicroscopicThe peripheral giant cell granuloma consists of an exuberant ♦mass of spindle-shaped cells with numerous extravasated erythrocytes, hemosiderin pigment (especially at the periph-ery), and multinucleated giant cells. Because of its location, it can recur with frequency

Verruciform Xanthoma

ClinicalThis interesting entity represents a peculiar reactive prolif- ♦eration of lipid-laden macrophages with a papillary surface configuration. Typically occurring on the gingiva or palatal mucosa in adults, it can appear red to yellow in coloration with a granular surface that may look like a volcano crater

MicroscopicThe histologic appearance is that of papillary proliferations ♦of epithelium with brightly eosinophilic keratin beneath, which the connective tissue papillae are filled with lipid-laden macrophages (Fig. 24.8). These cells will be confined to papillary lamina propria

Traumatic Ulcerative Granuloma with Stromal Eosinophilia

ClinicalThis peculiar exuberant reactive process can mimic squamous ♦cell carcinoma in its clinical presentation. Typically present on the dorsolateral tongue in adults, it manifests as an exophytic ulcerative mass usually of several weeks duration. This may be painful and persist even after multiple surgeries

MicroscopicSurface ulceration is seen overlying a proliferation of ♦inflamed granulation tissue with prominent, reactive endothelial cells (Fig. 24.9). Eosinophils and macrophages are prominent in the deeper aspects approximating and involving muscle

Fig. 24.7. Peripheral ossifying fibroma is a gingival-based nodule exhibiting matrix (i.e., bone or cementum) production.

Fig. 24.8. The connective tissue papillae are filled with lipid-laden macrophages in verruciform xanthoma.

Fig. 24.9. The ulcer bed in traumatic ulcerative granuloma with stromal eosinophilia can be extremely cellular and mistaken for a neoplastic process.

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Differential DiagnosisSquamous cell carcinoma, but only from a clinical ♦perspective

Lymphoma ♦

Atypical lymphoid cells, clonal −

Aside from NK/T-cell lymphomas, which may be poly- −morphous, most lymphomas are monomorphic infiltrates, contrasted to mixed infiltrate of traumatic ulcerative granuloma. Lymphoma will generally lack prominent eosinophils

Mucous Extravasation Phenomena (Mucocele/Ranula)Clinical

This is a reactive lesion representing spillage of mucin into ♦tissue due to duct damage. Typically young patients, first to second decade, represent the common population. Mucoceles occur most commonly in the lower lip, ranulae in the floor of mouth. The clinical appearance is that of a dome-shaped, fluid-filled lesion that may wax and wane with rupture. A “plunging ranula” presents as neck mass and may simulate thyroglossal duct cyst

MicroscopicPseudocystic accumulations of mucin surrounded by mac- ♦rophages, a wall of compressed granulation tissue and inflam-mation represent the salient diagnostic features (Fig. 24.10)

Necrotizing SialometaplasiaClinical

An ulcerative lesion involving salivary gland, necrotizing ♦sialometaplasia can mimic malignancy. Although its etiol-ogy is unclear, it is possibly due to underlying ischemic event. Younger adults are most commonly affected, with the

palate representing the most common site. Swelling with pain, followed by a sharply demarcated ulceration over a 2-week period represents the typical clinical progression

MicroscopicNecrotizing sialometaplasia is characterized by coagulative ♦necrosis of acinar units with surface ulceration and squamous metaplasia of salivary ducts. However, there is maintenance of lobular architecture of salivary gland. Because of the squamous metaplasia, it can mimic squamous cell carcinoma or mucoepidermoid carcinoma

Differential DiagnosisSquamous cell carcinoma ♦

Infiltrative growth, cytologic atypia, nonlobular growth −pattern, surface epithelial features

Mucoepidermoid carcinoma ♦

Infiltrative growth, prominent appearance to goblet cells, −no necrosis of acinar units

Benign NeoplasmsGranular Cell TumorClinical

This is a benign, nonneoplastic proliferation of probable ♦perineural sheath cells. Seventy percent occur on the tongue, primarily dorsum, as a deep mass with mainte-nance of surface architecture. These often represent long-standing processes

MicroscopicIll-defined collections of cells with granular cytoplasm, ♦eccentric nuclei, and indistinct cytoplasmic boundaries constitute the primary histologic feature (Fig. 24.11). Many cases have superimposed pseudoepitheliomatous hyperplasia, mimicking squamous cell carcinoma. Granular cell tumors tend not to recur, even with incomplete removal

ImmunohistochemistryS-100 protein+ ♦


Lacks the subepithelial granular cells that accompany −pseudoepitheliomatous hyperplasia. Rare on the dorsum of the tongue where granular cell tumor is common

Congenital Gingival Granular Cell Tumor (Congenital Epulis)

ClinicalThe congenital gingival granular cell tumor is a benign ♦proliferation of granular cells on the alveolar ridge in newborns. This manifests as an exophytic mass, often large (greater than 5 cm), on the maxillary alveolar ridge most commonly. As the name implies, it is typically pres-ent at birth

Fig. 24.10. Disruption of salivary gland ducts results in mucin extravasation into connective tissue.

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MicroscopicThis appears as a mass of cells with granular cytoplasm, ♦often demonstrating distinct cell boundaries. The overlying epithelium is typically atrophic

ImmunohistochemistryS-100− ♦

Premalignant/Malignant Neoplasms“Leukoplakia”

This represents strictly a clinical term and should never be ♦used as a microscopic diagnosis. All it confers is a white patch and, as such, carries no histologic implications. The clinical location, symptoms, and risk factors are far more important in assessing the risk of preneoplasia/carcinoma. The microscopic diagnosis ranges from hyperkeratosis to squamous cell carcinoma. It is recommended that the use of the term be discouraged

Squamous Dysplasia/Carcinoma In Situ

ClinicalAs with other sites, the oral epithelium tends to demonstrate ♦precursor lesions prior to frank invasion. Most classifications grade squamous dysplasia to carcinoma in situ dependent

upon the degree and thickness of epithelial involvement. This may present as a white patch, red patch (erythroplasia), or ulcer. Typically squamous dysplasia/carcinoma in situ is seen in patients over 40 who are also smokers and drinkers. Females now represent approximately 50% of cases. Ventrolateral tongue, floor of mouth, and soft palate complex represent high risk sites for these squamous cell carcinoma precursors

MicroscopicThe histologic features include nuclear enlargement, hyper- ♦chromatism, pleomorphism, loss of polarity, and architectural changes (i.e., formation of bulbous rete ridges) (Fig. 24.12)

♦ WHO Classification of oral dysplasia

− Mild – lower one-third abnormalities

− Moderate – lower one-half abnormalities

− Severe – lower two-thirds abnormalities

− Carcinoma in situ – full-thickness abnormalities

The grade of dysplasia does correlate with risk of squamous ♦cell carcinoma (i.e., the higher the grade, the greater the risk). Reproducibility of grading oral dysplasia (both intra- and interobserver) is generally poor

Proliferative Verrucous Leukoplakia

ClinicalProliferative verrucous leukoplakia represents a relatively ♦recently described progressive condition involving multiple sites in the oral cavity. It occurs in the fifth decade or later and has a female predilection. No strong tobacco association is apparent. Multiple white patches are seen that tend to enlarge, become verrucous and coalesce over time. It usually progresses to squamous cell carcinoma in less than a decade. It has yet to be successfully managed with consistency by any means

Fig. 24.11. Granular cell tumors are notorious for inducing pseudoepitheliomatous hyperplasia of the overlying epithelium.

Fig. 24.12. The most apparent atypical changes of severely dysplastic epithelium in the oral cavity may be limited to lower aspect of the epithelium.

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MicroscopicWithin a given patient, it can vary from site to site in the oral ♦cavity from verrucous hyperkeratosis to epithelial dysplasia to verrucous carcinoma to squamous cell carcinoma

Squamous Cell Carcinoma

ClinicalThis represents the most common malignancy in the oral ♦cavity. Ventrolateral tongue, floor of mouth, and gingiva are the common sites of origin. Mostly seen in smokers and/or drinkers over age of 40, some studies suggest an increasing element of cases in younger patients without known risk fac-tors. Although often suspected, HPV has yet to be shown to play a major role in oral cavity proper carcinomas. Once pre-dominantly a male disease, females are increasing in inci-dence to 50% of cases. It manifests as white patch, red patch, ulcer, or exophytic mass

MicroscopicCharacteristically, invasive and proliferative squamous epi- ♦thelium is seen demonstrating the cytologic and morphologic alterations seen in epithelial dysplasia, with the addition of

keratin pearls. The level of differentiation is graded as well, moderately, or poorly differentiated. Histologic grade does correlate with disease aggressiveness, although not as directly as clinical stage. Depth of invasion (>4 mm) and perineural invasion represent negative predictors. Currently, ~50% of patients survive 5 years, relatively unchanged over the last half century

Differential DiagnosisSee Table ♦ 24.1

Verrucous CarcinomaClinical

This represents a low grade, well-differentiated variant of ♦squamous cell carcinoma. Usually seen over the age of 60, it is more commonly seen in smokeless tobacco users than smokers. Characterized by a large (>4 cm) papillary mass with a broad base, verrucous carcinoma is often snow white due to hyperkeratosis. Generally, it is seen on tongue, alveo-lar mucosa, buccal mucosa and is often of long-standing duration. As it is usually nonmetastazing, neck dissection is not indicated

Table 24.1. Differential Diagnosis of the Poorly/Undifferentiated Sinonasal Neoplasm

Squamous cell carcinomaSquamous differentiation: keratin, intercellular bridges

and/or dyskeratotic cells

Lymphoma

NK/T lymphoma: midlineB-cell lymphoma: paranasal sinuses

Lymphoid markers+ (CD45RO, CD56, CD3, CD20)Cytokeratin−

Sinonasal undifferentiated carcinoma (SNUC) Cytokeratin +, neuroendocrine markers – prominent nucleoliScant cytoplasmProminent mitotic figures

Malignant melanoma S-100 protein+, cytokeratin−Melanoma markers+ (HMB 45, MelanA)

Olfactory neuroblastoma Synaptophysin+, chromogranin + S-100 protein + sustentacular cellsCytokeratin−

Basaloid squamous cell carcinoma Undifferentiated basaloid cellsSquamous differentiation, “mosaic pattern” of keratinization

Lymphoepithelioma-like carcinoma Cytokeratin+Lymphoma and melanoma markers−Histologically indistinguishable from nasopharyngeal carcinoma

Adenoid cystic carcinoma, solid pattern or so-called “dedifferentiated”

Evidence of glandular differentiation as tubular and/or cribriform structuresMyoepithelial differentiation (S-100, actin+)

Pituitary adenoma Synaptophysin+Cytokeratin +/−No (rare) mitotic figures

Rhabdomyosarcoma MyoD1+, myogenin+, desmin+, muscle-specific actin+CD99−Children

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MicroscopicVerrucous carcinoma varies from standard squamous cell ♦carcinoma by exhibiting broad papillations of squamous epithelium exhibiting minimal atypia with deeply invaginated folds of parakeratin (“parakeratin plugging”) (Fig. 24.13). If cytologic atypia is present, the diagnosis of “verrucous” type carcinoma should be doubted as it probably represents a papillary keratinizing well-differentiated squamous cell carcinoma. This malignancy has an excellent prognosis with a 95% 5-year survival rate

Differential DiagnosisPapillomas ♦

Typically smaller, well-confined lesions with a peduncu- −lated base

Sarcomatoid (Spindle Cell) Carcinoma

ClinicalThis represents a poorly differentiated variant of squamous ♦cell carcinoma. Usually, sarcomatoid carcinoma manifests after age of 40 and can occur in a history of radiation or burns, particularly electrical. Usually, it occurs as a polypoid, ulcerated mass on posterior tongue or in oropharynx

MicroscopicThe microscopic appearance is that of an exuberant prolif- ♦eration of anaplastic spindle-shaped cells that appear to ‘drop off’ from atypical surface epithelium (Fig. 24.14)

ImmunohistochemistryCytokeratin 5/6+, vimentin+, p63+ ♦

Differential DiagnosisSpindle cell sarcomas ♦

Cytokeratin− −

Most superficial spindle cell malignancies in the oral −cavity are carcinomas

Papillary Squamous Cell CarcinomaClinical

A relatively recent addition to the literature, this represents ♦an exophytic variant of squamous cell carcinoma that is highly associated with HPV types 16 and 18. There is a predilection for tonsil–oropharynx and hypopharynx. The prognosis is generally more favorable and probably relates to depth of stromal invasion more than size of exophytic component

MicroscopicA branching papillary architecture is seen with little ten- ♦dency to keratinize (Fig. 24.15). Brisk mitotic activity and notable cytologic atypia are commonly present

Differential DiagnosisSquamous papilloma ♦

Lacks the cytologic atypia and architectural complexity −of papillary squamous cell carcinomas

Malignant Melanoma

ClinicalThis is a rare malignancy arising from mucosal melanocytes. ♦Typically, it is seen in adults throughout the mucosa although more commonly in the nasal cavity and paranasal sinuses. It may present as a lesion of long- standing duration with wide-spread discoloration. In addition, it also can occur as an exo-phytic pigmented mass

MicroscopicThe cells are typically large with prominent red nucleoli and ♦abundant cytoplasm. Although often amelanotic, some dusky pigment can be seen with diligent searching. It is imperative to determine whether the lesion primary or metastatic. It is useful to identify atypical cells within the mucosal epithe-lium. Mucosal melanosis has a poor prognosis due to its aggressive nature and delay in diagnosis

Fig. 24.13. Verrucous carcinoma is a broad-based, hyperkeratotic tumor that infiltrates in a “pushing” fashion.

Fig. 24.14. Spindle cell carcinoma, surrounding a focus of malignant basaloid cells, simulates sarcoma.

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Miscellaneous LesionsAdenomatoid Hyperplasia

This represents enlarged mucous glands in a tumor-like ♦pattern seen in the palate. It may actually represent normal glands overlying a neoplasm and thus should be investigated thoroughly

Amalgam TattooThe amalgam tattoo is a localized discolored area demon- ♦strating granular, black foreign material aligned along collagen fibers and staining basement membrane. It is typically seen in area of dental restorations

Aphthous StomatitisThese are ulcerations seen primarily in the lining mucosa in ♦a variety of patterns. Minor aphthae are less than 1 cm ulcers with a fibrinous membrane and halo of erythema. Herpetiform aphthae consist of multiple punctate erythematous ulcerations. Major aphthae are large, greater than 2 cm, ulcerations with significant pain. No distinctive histopathology is seen with these lesions, rather they are clinical diagnoses

Dermoid CystThis developmental anomaly is seen in the midline floor of ♦the mouth and exhibits a keratinized lining with adnexal structures. True teratomas are rarely seen

Geographic Tongue (Erythema Migrans)An inflammatory condition of the tongue primarily charac- ♦terized by superficial microabscesses, this may represent a form of psoriasis (Fig. 24.16)

Lingual ThyroidThis represents residual thyroid remaining on posterior dor- ♦sum or within the substance of the tongue, left from the embryologic descent of the thyroid enlarge

Lymphoepithelial CystThis developmental anomaly is lined by squamous epithe- ♦lium and surrounded by lymphoid follicles and is commonly seen in floor of the mouth, posterior/lateral tongue, and ton-sillar region

MelanoacanthomaA suddenly progressing and regressing pigmented lesion of ♦the buccal mucosa in African Americans, melanoacanthoma histologically demonstrates the presence of dendritic melanocytes within the spinous layer of epithelium

Nicotine StomatitisCharacterized by punctate erythematous areas surrounded by ♦white zones on the palate of primarily pipe smokers, nicotine stomatitis demonstrates a surface proliferation of squamous epithelium around a central salivary duct with associated inflammation

Oral Focal MucinosisThis represents a localized mass seen at any site in the ♦mucosa characterized by the presence of abundant ground substance and flattening of the rete ridges of the epithelium

Palisaded, Encapsulated (Solitary, Circumscribed) Neuroma

A discrete nodule usually less than 1 cm seen most frequently ♦on lip vermilion and hard palate, the palisaded, encapsulated neuroma is characterized by well-demarcated proliferation of Schwann cells with faint palisaded arrangements and has axons present (Fig. 24.17)

Fig. 24.16. Subcorneal abscess formation is prominent in geo-graphic tongue.

Fig. 24.15. Papillary squamous cell carcinoma has a predilection for the oropharynx, including the tonsil, and is associated with human papillomavirus.

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Salivary Duct CystThe salivary duct cyst is a focal, small cystic lesion lined by ♦salivary ductal epithelium seen most commonly in upper lip, buccal mucosa, and palate

Smokeless Tobacco-Induced KeratosisThis represents a somewhat unique lesion occurring as a ♦corrugated white patch seen in the location of placement of tobacco that demonstrates superficial epithelial necrosis and an amorphous hyalinized material histologically (Fig. 24.18)

JAWS

Nonodontogenic Cysts/PseudocystsNasopalatine CystClinical

Because it represents cystic degeneration of epithelial remnants ♦of the nasopalatine duct, this cyst is seen in the anterior maxilla, midline between the maxillary central incisors. It occurs in adults and may produce a swelling in the anterior hard palate

RadiographThe radiographic features are that of a pear or heart-shaped ♦well-demarcated radiolucency between the roots of the max-illary central incisors

MicroscopicThe lining consists of simple cuboidal, respiratory, or strati- ♦fied squamous epithelium with prominent neurovascular bundles in the wall

Traumatic Bone CavityClinical

The traumatic bone cavity is exactly that, a cavity in bone pos- ♦sibly due to trauma with subsequent lysis of clot. It is most com-monly seen in the posterior mandibular body with possible expansion and is often filled with serosanguineous fluid. Young adults are the typical population with a male predilection

RadiographThis represents a demarcated lucency with scalloping ♦between tooth roots

MicroscopicThe microscopic features demonstrate a thin fibrous connec- ♦tive tissue wall with or without inflammation

Odontogenic CystsDentigerous CystClinical

This represents a developmental odontogenic cyst occurring ♦around the crown of impacted tooth. It occurs most com-monly in mandibular third molar region. The lining of this cyst can give rise to ameloblastoma, squamous cell carci-noma, or intraosseous mucoepidermoid carcinoma

RadiographThe radiographic presentation is that of a unilocular radiolu- ♦cency around the crown of an impacted tooth

MicroscopicHistologically, a bilayer of cuboidal cells or stratified squamous ♦lining with myxomatous connective tissue containing small islands of odontogenic epithelium is seen (Fig. 24.19)

Fig. 24.17. Palisaded encapsulated neuroma is a circumscribed neural lesion and, thus, may be mistaken for schwannoma. Inset: Axonal proliferation distinguishes neuroma from nerve sheath tumor.

Fig. 24.18. Smokeless tobacco-induced keratosis is notable for acellular, subepithelial hyalinization.

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Odontogenic Keratocyst (Keratocystic Odontogenic Tumor)

ClinicalThis entity represents a peculiar keratinized odontogenic ♦cyst arising from prefunctional dental lamina. The WHO currently classifies this as an odontogenic tumor rather than a cyst due to mutational features. It is most common in the second to third decades and the posterior mandible. It can occur as multiple lesions, perhaps forming “daughter” cysts, making complete removal more difficult. This may be the feature that contributes to a 30% recurrence rate

It is associated with the ♦ nevoid basal cell carcinoma syn-drome (Gorlin–Goltz syndrome) that possesses the following characteristics

Autosomal dominant, defect in − ptch gene (chromosome 9)

Multiple basal cell carcinomas on non- or minimally sun- −exposed skin

Palmar and plantar pits −

Skeletal anomalies – bifid ribs, brachymetacarpalism, −kyphoscoliosis, calcified falx cerebri

Other tumors including medulloblastoma −

RadiographThe common radiographic pattern is that of a multilocular ♦radiolucency with possible expansion although it may be unilocular. The odontogenic keratocyst tends to demonstrate linear growth pattern within the jaw

MicroscopicThe odontogenic keratocyst demonstrates squamous epithe- ♦lium with a luminal layer of corrugated parakeratin (Fig. 24.20). A uniform thickness of 6–8 cell layers is appar-ent with a prominent basal layer with palisading nuclei

Differential DiagnosisKeratinizing odontogenic cyst ♦

This cyst demonstrates a luminal layer orthokeratin, an −indistinct basal layer and no association with the nevoid basal cell carcinoma syndrome

Apical Periodontal Cyst

ClinicalThis is an inflammatory cyst due to a pulpally infected tooth, ♦seen at the apex of a nonvital tooth

RadiographThe apical periodontal cyst appears as a unilocular lucency at ♦the apex of tooth

MicroscopicHistologically, proliferative squamous epithelial lining is ♦seen with a wall of inflamed granulation tissue

Calcifying Odontogenic Cyst (Gorlin Cyst)Clinical

This developmental odontogenic cyst may demonstrate ques- ♦tionable neoplastic potential. It is seen in the second to third decade and the anterior aspects of the jaws. It may also occur in an extraosseous fashion on the gingiva. It has a low recurrence rate of 10% and may be associated with ameloblastomas

RadiographThe Gorlin cyst appears as a unilocular or multilocular ♦expansile radiolucency with intermixed calcifications and may be associated with an odontoma

MicroscopicA lining of odontogenic epithelium is seen with a basal layer ♦of columnar cells with palisading nuclei. Prominent in this epithelium is the presence of “ghost” cells, squamous cells with abundant cytoplasm and central voids lacking nuclei (Fig. 24.21). Variable amounts of odontogenic product, “dentinoid,” may also be present

Fig. 24.19. A bland lining of squamous cells with a loose connective tissue wall constitute the diagnostic features of a dentigerous cyst.

Fig. 24.20. Odontogenic keratocysts are cytologically bland, locally aggressive cystic lesions.

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Dentinogenic Ghost Cell Tumor (Included Here Given Similarity to Gorlin Cyst)

This represents a noncystic neoplasm with microscopic ♦characteristics similar to the Gorlin cyst. These represent more aggressive lesions and rare malignant counterparts have been reported

Reactive/Nonneoplastic DiseaseCementoosseous DysplasiaClinical

This peculiar condition is a nonneoplastic proliferation of ♦periodontal ligament origin. Typically asymptomatic, it is found on routine radiographic survey. It demonstrates a predilection for African American females in the third to fifth decade. It occurs in a variety of clinical settings including periapical, which is seen around apices of mandibular anterior teeth; focal which is a single lesion seen in the posterior mandible; and florid which are multiple lesions seen in at least two quadrants. It does not

require removal, only identification. However, patients are at risk for osteomyelitis as the lesions calcify and become avascular

RadiographThese lesions appear as relatively well-demarcated, mixed ♦radiolucent/radiopaque lesions

MicroscopicCementoosseous dysplasia appears as curetted fragments ♦with high cellularity of spindle-shaped mesenchymal cells. These cells are mixed with calcified product, often small sphericals of cementum and/or bone

Differential DiagnosisCentral cementoossifying fibroma ♦

Field for field this is a histologically identical lesion −although it represents a benign neoplasm. It can be distin-guished by radiographic (well-demarcated, expansile lucency) and surgical findings (avascular, delineated solid mass)

Odontoma

ClinicalThe odontoma is a hamartomatous process of the odontogenic ♦apparatus that is seen primarily in the first two decades of life. It presents as two types: compound, which forms tooth-like structures most commonly in the anterior maxilla, and complex, which forms a mass of calcified product in the pos-terior jaws

RadiographThe compound odontoma demonstrates multiple tooth-like ♦structures with radiolucent rim. The complex odontoma exhibits a central mass of opaque material surrounded by radiolucent rim

MicroscopicOdontomas contain a mixture of enamel, enamel matrix, ♦dentin, pulp, and follicular tissue, either in appropriate con-text or haphazardly arranged

“Giant Cell” and Giant Cell-Rich LesionsCentral Giant Cell GranulomaClinical

This represents a central lesion seen most commonly in ♦females in the early second decade. It demonstrates a pro-pensity to occur in the anterior mandible crossing the mid-line. Its etiology is unknown and it exhibits a recurrence rate of 15%. Peripheral variant is seen most commonly on the mandibular gingiva or alveolar mucosa as a purplish, exo-phytic mass

RadiographTypically, this occurs as a multilocular radiolucency although ♦it can be unilocular. Expansion, tooth movement, and resorp-tion are all possible sequelae

Fig. 24.21. “Ghost” cells, prematurely keratinizing epithelial cells without nuclei, are the hallmark of the calcifying odonto-genic cyst.

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MicroscopicMicroscopically, the giant cell granuloma is characterized by ♦a cellular spindle-cell framework with clusters of multinu-cleated giant cells (osteoclasts), extravasated erythrocytes, and hemosiderin

Differential DiagnosisGiant cell lesions of the jaws constitute an area of confusion ♦

Much has been written as to whether giant cell granulo- −mas, giant cell tumors, and aneurysmal bone cysts repre-sent the same lesion, entities on a continuum or separate and distinct conditions

The brown tumor of hyperparathyroidism is indistinguish- ♦able from the central giant cell granuloma and, accordingly, this systemic disease must be excluded (Fig. 24.22)

Giant Cell TumorThis is a true neoplasm that rarely occurs in the oral cavity and ♦is discussed in detail in Chapter 21

Aneurysmal Bone CystClinical

The aneurysmal bone cyst is seen most commonly before the ♦age of 20 and does not exhibit a gender predilection. The mandible is more commonly afflicted by this rapidly expansile lesion. Often substantial recurrence is due to incomplete removal. This may occur in concert with other pathologic entities including fibroosseous lesions and osseous neoplasms. Its etiology is unknown although trauma is suspected

RadiographA symmetrically expansile, unilocular radiolucency with a ♦thin rim of residual bone is the typical manifestation although it can be multilocular

MicroscopicLarge pools of extravasated erythrocytes surrounded by cel- ♦lular mesenchymal tissue with giant cells bordering the cavi-ties are the salient histologic features. The cavities are not lined by endothelial cells

CherubismClinical

Cherubism represents an inherited disorder, transferred as ♦an autosomal dominant condition due to a defect on chro-mosome 4p16. It exhibits complete penetrance in males and incomplete penetrance in females. The usual age at diagnosis is 5 years. Bilateral expansion of the maxilla and mandible is seen clinically, producing chubby cheeks, hence the name. Cherubism typically regress at puberty without surgery, although it may require surgical inter-vention if grossly deforming

RadiographBilateral, expansile multilocular radiolucencies in the poste- ♦rior mandible and maxilla are the hallmarks of this disease

MicroscopicCellular, myxomatous mesenchymal tissue with intermixed ♦giant cells comprises the majority of the lesion, whereas perivascular cuffing of hyaline material represents a useful clue to the diagnosis

Benign NeoplasmsAmeloblastomaClinical

This is the most common epithelial odontogenic neoplasm, ♦recapitulating the enamel organ. Ameloblastoma occurs most commonly in the third to fifth decade of life and presents as painless expansion usually in the posterior mandible. Typically aggressive, the ameloblastoma demonstrates up to a 90% recurrence rate with curettage and a 15–20% recur-rence rate with resection. Rare examples of metastasis have been reported (malignant ameloblastoma). Peripheral vari-ant represents an ameloblastoma occurring in an extraosseous location (Fig. 24.23)

RadiographEither an expansile unilocular or multilocular (soap bubble) ♦radiolucency is the classic radiographic presentation. Perforation of the cortical plate is often seen

MicroscopicTwo histologic variants are typically seen. The unicystic ♦ameloblastoma demonstrates cystic areas with luminal proliferation of the plexiform pattern of ameloblastoma. The conventional ameloblastoma may exhibit a variety of patterns including follicular, plexiform, acanthomatous, granular cell, basal cell, and desmoplastic (Fig. 24.24). Both are typically characterized by a peripheral layer of columnar cells with reverse polarization and nuclear palisading. Central zones of stellate cells with exaggerated intercellular spacing are seen in more solid areas although the conventional ameloblastoma can be predominantly cystic

Fig. 24.22. Osteitis fibrosa cystica (“brown tumor”) results from hyperparathyroidism and is histologically indistinguishable from giant cell reparative granuloma. Inset: Reactive osteoid may be prominent.

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Adenomatoid Odontogenic Tumor

ClinicalThis benign neoplasm of the odontogenic apparatus forms ♦gland-like spaces surrounded by odontogenic epithelium. Most commonly, it is seen in the anterior maxilla associated with an impacted canine tooth and demonstrates a 2:1 female predilection. Enucleation tends to be a curative surgical procedure

RadiographThe radiographic presentation is that of a pericoronal lucency ♦with or without calcification

MicroscopicMicroscopically, this neoplasm is characterized by a cystic ♦lesion with proliferation of epithelial cells demonstrating whorls and focal gland-like spaces lined by columnar cells. Dentinoid and amyloid may also be present

Calcifying Epithelial Odontogenic Tumor (Pindborg Tumor)Clinical

This benign epithelial odontogenic neoplasm can mimic ♦malignancy due to its cellular pleomorphism. It is seen mostly as a slowly progressing expansile mass in the poste-rior mandible in the fourth to sixth decades. It demonstrates a 15% recurrence rate after removal

RadiographThe Pindborg tumor appears as a well-demarcated ♦ multilocular radiolucency with calcifications (“driven snow” appearance)

MicroscopicThe microscopic appearance is that of sheets of polygonal ♦epithelial cells with prominent intercellular bridging. Marked pleomorphism is often seen but without mitotic activity. Spherical laminated calcifications (Liesegang rings) and amyloid are also present


Mitoses, invasive growth, and an ill-defined radiographic −appearance differentiate the two entities

Squamous Odontogenic TumorClinical

This, too, is a benign epithelial odontogenic neoplasm that can ♦mimic squamous cell carcinoma at the histologic level. Present in the third to fourth decades, it occurs in the posterior jaws as an expansile mass. Treated appropriately, it rarely recurs

RadiographThe characteristic appearance is that of a semilunar radiolu- ♦cency arising in alveolar bone

MicroscopicIslands of squamous epithelial cells without a prominent ♦basal layer are the histologic signature. Although worrisome, no atypia, mitotic figures, or central keratinization is seen (Fig. 24.25). The islands may demonstrate central cystic degeneration


Should demonstrate pleomorphism, mitoses, keratinization, −all of which are lacking in squamous odontogenic tumor

Ameloblastoma, acanthomatous type ♦

Prominent palisading arrangement of basal cell layer is −the distinguishing characteristic

Fig. 24.23. Peripheral ameloblastoma resembles its intraosseous counterpart. Note overlying mucosa.

Fig. 24.24. Ameloblastoma may show prominent cystic change. Peripheral cells exhibit nuclear palisading with reverse polar-ization; the latter is not conspicuous in this example.

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Ameloblastic FibromaClinical

This represents a mixed odontogenic tumor with coexistent ♦epithelial and mesenchymal components. It occurs in the first and second decades, with the majority in the posterior mandible impeding the eruption of the permanent first molar. Even with appropriate surgery, a 10–20% recurrence rate is seen

Radiograph

Radiographically, a unilocular or multilocular radiolucency ♦associated with an impacted tooth is the typical presentation

MicroscopicA bilayer of odontogenic epithelium embedded within cel- ♦lular myxomatous mesenchymal tissue constitutes the diag-nostic features (Fig. 24.26)

CementoblastomaClinical

This represents the benign odontogenic counterpart to the ♦osteoblastoma. Most common in the first two decades, it occurs in the mandibular first molar area and is characterized by pain and swelling. It can recur if incompletely removed

Radiograph

An opaque symmetrical mass merging imperceptibly with ♦the root of the tooth and possessing a radiolucent peripheral rim are the reproducible radiographic features

MicroscopicPeripheral radiation of cemental product punctuated by prom- ♦inent cementoblasts, cementoclasts, and vascularity are the salient characteristics. Because of these features, it is thought to represent the odontogenic analog of osteoblastoma

Central Cementoossifying FibromaClinical

The central cementoossifying fibroma is a benign product- ♦forming neoplasm of periodontal ligament origin. It occurs in the second to fourth decades with a female predilection. The posterior mandibular is most common and it manifests as a slowly progressing swelling. It rarely recurs when surgi-cally removed

RadiographTypically, this is a well-demarcated unilocular radiolucency ♦with characteristic bowing of the inferior border of the man-dible. Although product-forming histologically, it usually demonstrates only small flecks of calcification at the radio-graphic level

MicroscopicThis is an avascular, well-delineated mass of cellular ♦mesenchymal tissue demonstrating spindle-shaped cells arranged in whorls and fascicles. Usually, only limited punctate calcifications are interspersed within the cellular tissue

Odontogenic FibromaClinical

This benign neoplasm is comprised primarily of odonto- ♦genic mesenchymal tissue with variable epithelium and calcification. It can be central or peripheral and occurs at an average age of 40. A prominent female propensity is seen and the posterior maxilla is most commonly afflicted. On rare occasions, it may be associated with a peculiar cleft defect in the maxilla. Only rare recurrences have been reported

Fig. 24.25. Squamous odontogenic tumors demonstrate islands of squamous epithelium without atypical features or mitoses.

Fig. 24.26. Bilayers of ameloblastic cells embedded in a myx-omatous mesenchymal framework characterize ameloblastic fibroma.

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RadiographThe radiographic appearance is that of a unilocular or ♦multilocular radiolucency, often with expansion

MicroscopicThe simple type appears as a collagenous mesenchymal ♦proliferation with evenly dispersed bland spindle cells. The WHO type demonstrates cellular mesenchymal tissue with strands of odontogenic epithelium and variable calci-fied product

Malignant NeoplasmsAmeloblastic CarcinomaClinical

This is an odontogenic epithelial malignancy with amelo- ♦blastic differentiation. It occurs most commonly in the fourth decade with a mandibular predilection. It metastasizes prefer-entially to the lungs and demonstrates a <50% 5-year sur-vival rate

RadiographIt manifests as an ill-defined, lytic lesion with a variable ♦growth rate

MicroscopicThe microscopic appearance is that of an epithelial prolifera- ♦tion with peripheral cells demonstrating columnar morphol-ogy with reverse polarization (Fig. 24.27). Prominent pleomorphism and mitotic activity are usually seen

Squamous Cell CarcinomaClinical

This is a central odontogenic carcinoma demonstrating ♦squamous differentiation. Seen in adults, it demonstrates a

mandibular predilection. Its overall behavior is dependent on grade and stage. However, most of them represent local disease and are amenable to surgery

RadiographThis may occur as a poorly defined lytic lesion or arise from ♦a preexisting, long-standing odontogenic cyst

MicroscopicThis entity demonstrates the typical features of squamous ♦cell carcinoma; accordingly, one must rule out metastasis or an antral primary if occurring in the maxilla

Clear Cell Odontogenic CarcinomaClinical

This odontogenic malignancy is composed of odontogenic ♦epithelium with prominent cytoplasmic clearing. Occurring in the sixth decade or later, it is most common in the mandi-ble. Although metastasis is known to occur, it is not com-mon. However, multiple recurrences with locally aggressive behavior is the typical pattern

RadiographThe clear cell odontogenic carcinoma manifests as an ♦ill-defined lucency with bone destruction

MicroscopicStrands and sheets of cells with odontogenic differentiation ♦and cytoplasmic clearing are seen. These clear cells may or may not demonstrate glycogen with PAS stains. The stroma is often cellular with hyalinization around the epithelium

Differential DiagnosisMetastatic renal cell carcinoma ♦

Prominent vascular stroma without the stromal cellularity −should help delineate the two

OsteosarcomaClinical

Osteosarcoma of the jaws demonstrates a different character ♦relative to osteosarcoma of the long bones in the following ways

Tends to occur at a later age, average ~33 years −

Tends to be lower grade −

Tends to be chondroblastic −

The survival rate has remained relatively unchanged even ♦with the newer modalities of treatment. Osteosarcomas of the mandible demonstrate a 40% 5-year survival, and the maxilla demonstrates a 25% 5-year survival

RadiographOsteosarcomas tend to be ill-defined mixed radiolucent/ ♦opaque lesions, perhaps with a radiating calcified product (sunburst effect). Localized widening of the periodontal liga-ment space may be an early manifestation

Fig. 24.27. Cellular pleomorphism, as seen here, distinguishes ameloblastic carcinoma from ameloblastoma.

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MicroscopicAs in the long bones, osteosarcoma is characterized by tumor ♦bone punctuated by a frankly sarcomatous mesenchymal proliferation. Cartilage is often seen in osteosarcoma of the jaws and should always be treated with suspicion

ChondrosarcomaClinical

Some have speculated otherwise, but these do occur in the jaws. ♦The average age at diagnosis is ~30 years. Chondrosarcomas of the jaws tend to be slow-growing lesions and tend to be low grade

RadiographChondrosarcomas demonstrate many of the same radio- ♦graphic features of osteosarcoma although the product tends to be less linear and more rounded

MicroscopicGenerally, mature type cartilage is seen with minimally atyp- ♦ical chondrocytes and chondroblasts. Because of this, chon-drosarcomas of the jaws are often underdiagnosed as benign conditions

Mesenchymal ChondrosarcomaClinical

A rare tumor, the mesenchymal chondrosarcoma is seen in ♦the jaws as one of its more preferential locations. It may also arise in soft tissue and is seen most commonly in the second and third decades

MicroscopicUndifferentiated stromal cells with islands of mature carti- ♦lage are the histologic hallmarks. The stromal component may resemble “small blue cell tumors” and/or hemangio-pericytoma (“staghorn” vascular pattern). Mitotic figures may be scarce to frequent and the cartilaginous foci vary from prominent to scarce

Differential DiagnosisDistinction from Ewing sarcoma, hemangiopericytoma, and ♦others relies upon recognition of cartilaginous foci

Metastatic DiseaseClinical

Carcinomas of breast, lung, prostate, renal origin represent ♦the most common metastases to the jaws. Fully one-third of patients are unaware of primary tumor at time of diagnosis. These often present with pain and/or paresthesia

RadiographicPresenting most commonly as lytic, ill-defined lesions, ♦exceptions include prostatic and breast metastases that can be dramatically osteoblastic

Melanotic Neuroectodermal Tumor of InfancyClinical

This neoplastic process of neuroectodermal origin usually ♦manifests in the first year of life as an expansile lesion in the anterior maxilla. Often, elevated levels of urinary vanillyl-mandelic acid can be demonstrated. A 15% recurrence rate is seen, with 6% demonstrating malignant behavior

RadiographThe melanotic neuroectodermal tumor of infancy presents as ♦a demarcated radiolucency of the anterior maxilla with a pri-mary tooth “floating in space”

MicroscopicThis tumor is an epithelial lesion with two cell types: a small ♦cell with hyperchromatic nucleus and scant cytoplasm and a large cell with vesicular nucleus, abundant cytoplasm, and melanin pigment (Fig. 24.28). These are typically arranged in small islands and cords with the melanin occurring centrally

Miscellaneous LesionsStafne Defect

This is a bony defect present at the posterior inferior margin ♦of the mandible occupied by the submandibular gland – it should be recognized radiographically with no surgery necessary

ToriThese represent bony outcroppings seen in the midline of the ♦hard palate and bilaterally on the medial mandible – they represent variations of anatomic normal

Fig. 24.28. Larger pigmented cells surround small blue cells in the melanotic neuroectodermal tumor of infancy.

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Gingival Cyst/Lateral Periodontal CystThese cystic lesions of odontogenic apparatus are lined ♦by a bilayer of cuboidal to flattened epithelium with focal plaque-like thickenings and a single cavity. The gingival cyst is seen in mucosa, the lateral periodontal cyst in bone. The botryoid odontogenic cyst represents a multiple compartmented cyst in bone with similar histology but more aggressive clinical course. The glandular odonto-genic cyst demonstrates a luminal layer of cuboidal cells and duct-like structures with behavior much like amelo-blastoma with a high recurrence rate and significant expansion

Central Mucoepidermoid CarcinomaThis is a mucoepidermoid carcinoma arising within the ♦mandible primarily, probably from pluripotential odontogenic epithelium (Fig. 24.29). It is usually low grade with a good prognosis

oRo/HYPoPHARYNX

Malignant NeoplasmsSquamous Cell CarcinomaClinical

This is most commonly seen in the base of tongue and tonsil ♦and is typically large (T3–T4) by time of diagnosis. Dysphagia, exophytic mass, and otalgia are presenting complaints. Stage III and IV diseases have 5-year survival rates below 30%

MicroscopicTypically, these squamous cell carcinomas are less ♦differentiated with limited to no keratin production. HPV may be present in up to 50% of oropharyngeal squamous cell carcinomas

Lymphoepithelial CarcinomaClinical

A malignant epithelial neoplasm that is essentially ♦undifferentiated with prominent lymphoid component (evidence of squamous differentiation seen via electron microscopy). Related to EBV although evidence may be somewhat equivocal. Seen in adults, it rarely occurs in the tonsil and base of tongue. A fairly aggressive neoplasm, it demonstrates a less than 50% 5-year survival

MicroscopicSheets of undifferentiated epithelial cells are seen embedded ♦within lymphoid stroma. The nuclei tend to be vesicular and

large with prominent nucleoli. Cytokeratins generally will illuminate the epithelium

Basaloid Squamous CarcinomaClinical

This represents a peculiar high grade variant of squamous ♦cell carcinoma demonstrating both basaloid and squamous components. Occurring in the sixth to eighth decades, it exhibits a male predilection. It is seen primarily in the base of tongue when occurring in the oropharynx. The overall survival rate is poor with less than a 30% 5-year survival, although this may be due to overall stage, rather than more aggressive behavior

See section “Larynx and Trachea” ♦

MicroscopicA biphasic tumor (“mosaic pattern” of cells), basaloid ♦squamous carcinoma exhibits lobules and cords of cells with hyperchromatic nuclei and scanty cytoplasm, often sur-rounded by prominent hyalinization (Fig. 24.30). Peripheral palisading and central necrosis are common, and it often merges with typical squamous cell carcinoma. Surface epi-thelial alterations may be evident

Differential Diagnosis (See Table 24.1)Adenoid cystic carcinoma ♦

Lacks squamous differentiation and surface epithelial −involvement

Fig. 24.29. Central mucoepidermoid carcinoma arises within the mandible and resembles a salivary gland primary.

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This represents an exophytic HPV-associated variant of ♦squamous cell carcinoma. It preferentially involves the ton-sil/oropharynx, larynx, and sinonasal tract. The prognosis likely relates to extent of invasion

MicroscopicPapillary condylomatous-like architecture is seen with ♦cytologic atypia that exceeds what is seen in papillomas/condylomas (Fig. 24.15). Keratinization is generally scant

Differential DiagnosisSquamous papillomas with or without dysplasia ♦

Exhibit less cytologic atypia and koilocytes are readily −present

NASAL CAVItY, PARANASAL SINUSeS, AND NASoPHARYNX

InfectionRhinosinusitisClinical

Classified into acute, subacute, and chronic based on the ♦duration of sign and symptoms. Chronic rhinosinusitis, one of the most commonly reported chronic diseases in the USA, is defined as the presence of nasal cavity and paranasal sinus inflammation for greater than 12 weeks. The pathophysiol-ogy comprises a spectrum of inflammatory and infectious diseases. Limited coronal computed tomography is the most definitive technique for the diagnosis

Allergy, fungus, and bacteria are potential causes, with the ♦latter giving rise to purulent sinusitis. Haemophilus influen-zae, Streptococcus pneumoniae, and Moraxella catarrhalis are more common offending agents. Ongoing inflammation, decreased in ostial size, retention of secretions, and decrease in mucociliary action contribute to the pathogenesis

MicroscopicEdema, hyperplastic seromucinous glands, thickened base- ♦ment membrane, and inflammatory cells (neutrophils, lym-phocytes, plasma cells, and eosinophils) are typical findings. Retention cysts (Fig. 24.31) are common, and obstruction may lead to mucocele (frontal and ethmoid sinuses most commonly affected) formation

Differential DiagnosisThe infiltrates of sinusitis are distinguished from lymphoma ♦by their mature appearance. They are rich with plasma cells and Russell bodies are common. High grade angiotropic

NK/T-cell lymphoma has larger cells with atypical nuclei and often exhibits angiotropic growth accompanied by thrombosis and necrosis

Allergic fungal sinusitis contains fungal hyphae (highlighted ♦via GMS stain) within dense, eosinophilic-rich exudates. Fungal elements are absent in nonspecific chronic sinusitis

The presence of necrosis, granulomatous inflammation, and/ ♦or vasculitis raises the specter ozf Wegener granulomatosis (WG). The histopathology of WG is typically incompletely developed, requiring serologic support (c-ANCA) for diagnosis

Fig. 24.30. Basaloid squamous carcinoma is an aggressive malig-nancy with a predilection for the base of tongue and larynx.

Fig. 24.31. Retention cysts are a common finding in the mucosa of individuals with chronic sinusitis.

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Allergic Fungal Sinusitis

ClinicalAllergic fungal sinusitis is a noninvasive mycosis and the ♦most common form of fungal rhinosinusitis. Patients are immunocompetent and often young and asthmatic. Bony erosion, rupture of the sinus walls, and/or orbital extension are not uncommon. The offending organisms are ubiqui-tous; dematiaceous fungi are common (i.e., Curvularia and Bipolaris species). Eradication is difficult and recurrence is common

MicroscopicThe hallmark is thick eosinophil-rich “allergic mucin” which ♦contains with fungal hyphae (highlighted via GMS stain). Charcot–Leyden crystals are common. There is no tissue invasion by organisms and the mucosal exhibits nonspecific changes of sinusitis with or without polyps

Differential DiagnosisInvasive fungal sinusitis shows angiotropic growth of ♦ fungus with thrombosis and necrosis. Fungus is found in viable and/or necrotic tissue and not confined to a mucinous or inflammatory exudate. Patients are generally diabetic or immunodeficientSinus mycetoma or “fungus ball” is a rare, noninvasive colo- ♦nization of a sinus cavity by fungus. These lesions lack the eosinophilic-rich infiltrate of allergic fungal sinusitis

Invasive Fungal SinusitisClinical

Rhinocerebral disease due to Zygomycetes ( ♦ Rhizopus–Mucor–Absidia) presents with headache, pain, and fever. Patients with diabetic ketoacidosis experience rapidly pro-gressive disease with extension into the CNS. The turbinates appear necroticNasoorbital disease due to ♦ Aspergillus species is typically seen in immunocompromised patients with AIDS, neutrope-nia, and/or hematologic malignancies

MicroscopicAngioinvasive growth of fungus (highlighted on GMS stain) ♦with thrombosis, hemorrhage, and infarction is characteristic. Zygomycetes exhibit irregular ribbon-like hyphae (generally 10–20 mm in width) devoid of septa, whereas Aspergillus has smaller hyphae (3–6 mm in width) with 45° branching and distinct cross-septa

Other Forms of Infectious SinusitisScleroma (Rhinoscleroma)

Microscopically, histiocytic foam cells (Mikulicz cell) con- ♦tain coccobacilli (Klebsiella rhinoscleromatis). Bacteria are highlighted on Warthin–Starry and Giemsa stains. The dif-ferential diagnosis includes Rosai–Dorfman disease, leprosy, and metabolic storage disease

RhinosporidiosisPolypoid mucosal lesions containing large sporangia (100– ♦400 mm) resemble “coccidioides immitis though bigger”

(Fig. 24.32). The etiology fungus is Rhinosporidium seeberi, which is endemic to India. These lesions can simulate angiomatous nasal polyp

Mycobacterial InfectionEtiologic bacteria include ♦ Mycobacterium tuberculosis and rarely atypical mycobacteria; the latter is typically encoun-tered in HIV patients. The histologic findings include caseat-ing and/or noncaseating granulomas, ulceration, histiocytic inflammation, and destruction of septal cartilage

LeprosyInvolvement of paranasal sinuses is common and of epidemi- ♦ological significance in lepromatous-type leprosy. Ulceration is accompanied by perivascular histiocytes, which contain the acid fact bacillus Mycobacterium leprae

SyphilisPrimary, secondary, and tertiary syphilis can all cause intra- ♦nasal pathology. Warthin–Starry staining may fail to reveal the pathogenic spirochetes, Treponema pallidum. Microscopic findings include plasma cell endarteritis, ulceration, and sep-tal perforation

Inflammatory/Nonneoplastic LesionsMucoceleClinical

With progressive expansion these lesions can simulate a ♦neoplasm and. They have a predilection for the mastoid, frontal, and ethmoid sinuses. A potential complication of sinusitis, they result from ostial obstruction and impaired lymphatic drainage

MicroscopicAn epithelial lining may or may not be apparent and goblet ♦cells may be hyperplastic. Degenerating debris, mucous, and muciphages are present

Fig. 24.32. Sporangia are numerous in the mucosal lesions of Rhinosporidiosis. Inset: Sporangium containing spores.

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Wegener GranulomatosisClinical

The sinonasal tract is involved in 60–95% of patients with ♦Wegener granulomatosis (WG). Features include ulceration of the nasal septum, sinus mucosa, oral mucosa or destruction of the vocal cord. Histologically, the diagnosis of WG is largely one of exclusion as other causes of granulomas and necrosis must be ruled out. Multiple biopsies of diseased mucosa are not uncommonly required to establish the diag-nosis. Corroborating the histologic findings with serologic studies is extremely important since most patients (70–90%) are c-ANCA positive (c-ANCA negative cases occur)

MicroscopicA histologic spectrum may be seen from neutrophilic ♦microabscesses to the signature triad of necrosis, granuloma-tous inflammation, and vasculitis (Fig. 24.33). Typically, the triad is incomplete and the histologic specificity for WG decreases as fewer elements of the triad are represented

Differential DiagnosisMalignant lymphoma and infection commonly warrant consid- ♦eration in cases of WG. Failure to identify atypical, neoplastic cells and microorganisms aids to exclude these possibilities

SarcoidosisClinical

Approximately 5% of patients with sarcoidosis have sinona- ♦sal involvement. Clinical features are nonspecific and include nasal obstruction and chronic sinusitis. Grossly, lesions man-ifest as mucosal crusting, studding, plaque-like changes, or polyps in the nose

MicroscopicNoncaseating granulomas (small foci of central caseous nec- ♦rosis can be seen) are present. The presence of microorganisms

should be ruled out via appropriate methodologies (i.e., special stains and culture)

Differential DiagnosisInfectious and noninfectious causes of granulomatous ♦inflammation warrant histologic and clinical consideration. Granulomatous vasculitis should be ruled out

MyospherulosisClinical

This lesion of iatrogenic origin consists of a foreign body/ ♦granulomatous reaction to petrolatum-based material used for nasal packing

MicroscopicLarge spherules simulating fungi contain altered erythrocytes ♦

Differential DiagnosisIf the diagnosis is in doubt, negative GMS staining can aid ♦ distinction from fungal infection

Polyps

ClinicalSinonasal polyps are common, affecting from up to 4% of ♦the population. They are typically multiple and bilateral. Their pathogenesis is poorly understood. Associations include sinusitis, allergy, immune deficiency, cystic fibrosis, ciliary dyskinesia, and aspirin hypersensitivity

Grossly, they are soft, edematous, and semitranslucent −

MicroscopicLarge quantities of extracellular fluid-edema separate bland ♦stromal cells (Fig. 24.34). Eosinophils are prominent in most cases. Seromucinous glands may be hyperplastic or inappar-ent and retention cysts common. A minority develop exten-sive vascular proliferation and ectasia with deposition of pseudoamyloid, see angiomatous variant below

Fig. 24.33. Consider the possibility of Wegener granulomatosis, lymphoma, and fungal infection in sinonasal specimens with prominent necrosis.

Fig. 24.34. Extracellular fluid and inflammation, particularly eosinophils, are features of nasal polyps.

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Variants ♦ A choanal polyp is a clinically defined variant originating in

a paranasal sinus that is histologically indistinguishable from typical polyps. They solitary, more prevalent in children and may undergo torsion/infarction

Repeated vascular compromise/insult and repair of an other- ♦wise typical sinonasal polyp can result in prominent angiom-atous changes (i.e., so-called angiomatous polyp). Choanal polyps at particularly predisposed to such change and may undergo complete infarction

♦ Polyp with stromal atypia has atypical stromal cells analo-gous to atypical polyps that can occur in the vagina, esopha-gus, and mouth

Differential DiagnosisLobular capillary hemangioma has densely packed capillary- ♦sized vessels with a lobular or “organized” configuration, which polyps lack. Sinonasal papillomas are defined by their characteristic proliferative epithelium, again lacking in polyps. Juvenile angiofibroma, specific to young males and the nasopharynx, has a stroma that is densely collagenous; polyps are typically edematous and inflamed

Benign NeoplasmsLobular Capillary Hemangioma (Granuloma Pyogenicums)Clinical

This benign capillary proliferation can grow rapidly and is ♦associated with microtrauma and pregnancy. Epistaxis can be problematic necessitating emergent care

MicroscopicA lobular proliferation of small capillaries defines these ♦tumors (Fig. 24.35A,B). The mucosa is commonly ulcerated

Differential DiagnosisA lobular architecture of the vasculature and the less collag- ♦enous stroma aid to distinguish hemangioma from juvenile nasopharyngeal angiofibroma, although occasional heman-giomas may have a more fibrotic stroma

Angiomatous polyp has vessels, which are congested, often ♦large and ectatic that lack the uniformity and organization of hemangioma

Hyperkeratotic Squamous PapillomaClinical

These lesions arise from nasal vestibule in contrast to sinona- ♦sal papilloma, which arises from the respiratory mucosa or Schneiderian membrane. They are analogous to their coun-terpart occurring elsewhere on the skin

MicroscopicThis papillary squamous proliferation typically exhibits ♦ hyperkeratosis and lacks significant cytologic atypia. Coexistent dysplasia is rare

Sinonasal Papilloma (Schneiderian Papilloma)Clinical

These locally aggressive, progressive tumors arise from the ♦Schneiderian membrane and require surgical removal. The WHO separates into three types: exophytic, inverted and oncocytic. There is a significant risk of recurrence, espe-cially for incompletely resected lesions. Coexistent carci-noma or progression to carcinoma with recurrence may occur and mandates careful histologic examination. Barnes found 11% of cases complicated by carcinoma in a large collective review

Patients may present with nasal obstruction, epistaxis, and ♦headaches. Proptosis and diplopia may reflect invasion of the orbit

Tumors arising on the nasal septum tend to be exophytic ♦(i.e., exophytic or fungiform papilloma) in appearance, while

Fig. 24.35. A lobular distribution of cells is extremely useful in recognizing lobular capillary hemangioma of the nasal cavity (A). Lobular capillary hemangioma is uncapsulated, abuts the mucosa, and often ulcerates (B).

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tumors occurring laterally and in the paranasal sinuses commonly exhibit an inverted pattern of growth (i.e., inverted papilloma). Microscopically, a mixed pattern of growth is not uncommon

Human papilloma virus DNA has been detected in up to ♦38% and 57% of fungiform and inverted papillomas, respectively

MicroscopicThese lesions are composed of basement membrane-bound ♦proliferations of cytologically bland squamous, transitional, and/or columnar cells, which grow in an exophytic papillary or “inverted” manner. Architecturally, both inverted and fungiform growth patterns are often present in a given lesion (Fig. 24.36A). Inverted growth occurs as the proliferative epithelium colonizes and expands the underlying seromuci-nous glands of the sinus mucosa

Mucous cells, microcytic change, and infiltration of the pro- ♦liferative epithelium by neutrophils is common and charac-teristic (Fig. 24.36B)

Surface parakeratin and koilocytic-like changes may be ♦observed. Dysplasia is not particularly common but occurs and evaluation for its presence, particularly severe dysplasia or carcinoma in situ should be made. Coexistent invasive car-cinoma must be ruled out

Differential DiagnosisPolyps with squamous metaplasia can simulate inverted pap- ♦illoma. Metaplastic changes are surface based, limited, and accompanied by injury and repair, including ulceration and inflammation

Inverted papilloma must be distinguished from carcinoma. ♦Papilloma lacks the atypia of carcinoma and the inverted growth is smooth bordered and basement membrane con-fined. Carcinoma shows irregular or jagged, invasive growth and incites desmoplasia. Abundant keratin production and/or well-developed squamous differentiation should raise the index of suspicion for carcinoma

Hemangiopericytoma-Like Tumor of the Nasal CavityClinical

These interesting tumors occur in adults (mean age: ~60 ♦years) who present with obstruction and/or epistaxis. Surgical excision is generally curative as the vast majority behave benignly

MicroscopicThese submucosal tumors are unencapsulated (Fig. ♦ 24.37A) and composed of plump spindle cells. The latter exhibits fas-cicular and solid to focally whorled patterns of growth. Cell borders are indistinct. Nuclei are round, oval, and/or spindle shaped with vesicular or mildly hyperchromatic chromatin. Nuclear pleomorphism is minimal. A delicate vasculature commonly exhibits a staghorn pattern

ImmunohistochemistryOnly vimentin is consistently positive. CD34 is negative ♦which aids distinction from solitary fibrous tumor

Differential DiagnosisSolitary fibrous tumor (SFT) has a wiry collagenous back- ♦ground and a tendency for variable cellularity from field to field; however, this latter feature is often subtle and not con-stant. Moreover, SFT is CD34 positive

Hemangioma exhibits richer vascularity, typically arranged ♦in lobular or segmented architecture and tends to be less cellular. Nonetheless, distinction may be difficult

Fig. 24.36. Inverted papilloma derives its name from its “inverted” pattern of growth; however, both inverted and exo-phytic growth patterns are often present in a given lesion (A). Intraepithelial cysts with clusters of neutrophils are common in inverted papilloma (B).

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Juvenile Nasopharyngeal AngiofibromaClinical

Juvenile nasopharyngeal angiofibroma (JNA) is a rare, ♦benign tumor that occurs exclusively in males in the second and third decades (mean age 16 years, range 10–26 years) of life. They arise in the pterygopalatine fossa and have a sig-nificant recurrence rate with incomplete surgical excision and potential for intracranial extension. Notorious for pro-fuse intraoperative bleeding preoperative embolization is desirable

JNA occurs up to 25 times more frequently in patients with ♦familial adenomatous polyposis

MicroscopicThin-walled blood vessels, a densely collagenous stroma and ♦spindled to stellate, mesenchymal cells comprise this tumor

(Fig. 24.37B). Mitotic figures are scarce and generally not seen. The vascular component may be inconspicuous on biopsy material and, in such cases, the diagnosis is aided by clinicopathologic correlation

ImmunohistochemistryTumor cells stain positively for vimentin and androgen ♦receptor, the latter in up to 75% of cases. CD34 is negative

Molecular BiologyBeta-catenin mutations have been reported in a significant ♦percentage of JNAs

Differential DiagnosisHemangioma is less fibrous and more cellular with densely ♦packed vascular channels. Angiomatous nasal polyp is typi-cally edematous, less fibrous and may be hemorrhagic and/or infarcted. The specific clinicopathologic features (i.e., char-acteristic age, sex, and location) of angiofibroma is very use-ful in their distinction for other entities

Malignant NeoplasmsSquamous Cell CarcinomaClinical

Squamous cell carcinoma is the most common malignancy ♦of nasal cavity and paranasal sinuses. This tumor principally arises in adults and the elderly. Associations include smok-ing, human papilloma virus infection, and exposure to nickel and chromium-refining processes

MicroscopicGenerally, aside from a few special variants, squamous cell ♦ carcinomas exhibit cytologic atypia and invasive growth within desmoplastic stroma. Squamous differentiation is defined by the presence of keratin production, intracellular bridges, and/or dyskeratotic cells. Endophytic, exophytic, and mixed patterns of growth may be encountered. Tumors are graded as well, moderately or poorly differentiated. Several variants occur (see below)

VariantsVerrucous carcinoma, as encountered more commonly in ♦the oral cavity, rarely occurs in the nasal cavity and parana-sal sinuses. These nonmetastasizing, progressive tumors exhibit a “pushing” margin of invasion with minimal cyto-logic atypia

Basaloid squamous cell carcinoma, as more commonly ♦encountered in the oropharynx and larynx, can arise in the nasal cavity and paranasal sinuses. Immunostains are dif-fusely and strongly positive for p63

Papillary squamous cell carcinoma is an HPV-associated ♦variant of squamous cell carcinoma. Sinonasal tract tumors have poorest prognosis relative to papillary squamous cell carcinoma arising elsewhere

Rarely, a spindle cell or sarcomatoid morphology may be ♦encountered

Fig. 24.37. (A) Hemangiopericytoma-like tumor is biologically indolent and composed of isomorphic cells with no consistent pattern of immunohistochemical staining, aside from vimentin positivity. (B) The typical appearance of juvenile nasopharyn-geal angiofibroma is present, including thin-walled blood vessels, a densely collagenous stroma and spindled to stellate, mesenchymal cells.

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Malignant LymphomaThe majority sinonasal lymphomas are represented by NK/ ♦T-cell, B-cell type, and peripheral T-cell type lymphomas. Hodgkin disease is very rare in sinonasal region. See the chapter on lymphoma

NK/T-cell lymphoma preferentially involves the midline of ♦the nasal cavity and is highly associated with EBV. A histo-logic spectrum may be seen from small to large lymphoid cells with irregular nuclei, often with clear/pale cytoplasm (Fig. 24.38). Angiocentric growth is accompanied by throm-bosis and necrosis. Tumor cells marked positively for CD45RO, CD2, and CD56

In contrast to NK/T-cell lymphoma, B-cell lymphoma is more ♦common in paranasal sinuses. Sheets of large atypical B-cells show positivity for CD45RO and CD20 (Fig. 24.39)

Adenoid Cystic CarcinomaClinical

Adenoid cystic carcinoma (AdCC) is the second most ♦common malignancy of the paranasal sinuses. These tumors are aggressive with a high incidence of local recurrence and distant metastasis. CNS extension is common and most cases are ultimately fatal. Solid variant tumors progress more quickly

MicroscopicAdCC may exhibit a cribriform, tubular, and/or solid pattern ♦of growth (Fig. 24.40A,B). Tumor cells are small and baso-philic with scant cytoplasm and inconspicuous nucleoli. Myoepithelial cells are detectable (via light microscopy or immunohistochemistry) peripherally within cribriform nests and tubular profiles

Ducts profiles in the tubular pattern can show a particularly ♦prominent bilayer of peripheral myoepithelial cells and luminal

Fig. 24.38. NK/T-cell lymphomas exhibit angiotropic growth, thrombosis, and necrosis. These tumors are typically polymor-phous; malignant cells may have clear cytoplasm.

Fig. 24.39. Diffuse large cell lymphoma shows sheets of atypical lymphoid cells with conspicuous mitotic figures.

Fig. 24.40. Adenoid cystic carcinoma is the most common malignant gland forming tumor of the nasal cavity and parana-sal sinuses. The cribriform pattern of adenoid cystic carcinoma is well recognized (A). Predominant tubular patterns of adenoid cystic carcinoma can be challenging diagnostically (B).

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cuboidal cells. Perineural invasion/spread is characteristic. Mitotic figures, nucleoli, and necrosis common in the solid and dedifferentiated variants

ImmunohistochemistryTumor cells are positive for cytokeratin and c-kit. Peripheral ♦myoepithelial cells stain for actin, p63, calponin, and S-100

Differential Diagnosis (See Table 24.1)The presence of myoepithelial differentiation aids to distin- ♦guish tubular AdCC from adenocarcinoma-NOS, which lacks such differentiation (actin-, ca lponin-). Polymorphous low grade adenocarcinoma is a potential consideration, but its occurrence in the nasonasal region is exceeding rare

Olfactory Neuroblastoma (Esthesioneuroblastoma)Clinical

These rare neuroectodermal tumors account for ~1–5% of ♦the malignant nasal cavity neoplasms. Tumors likely arise from the olfactory membrane or placode. Thus, involving or near the cribriform plate they carry a risk for intracranial extension. Patients (mean age: ~50 years) may present with obstructive symptoms, bleeding, pain, an optic disorder, and impaired sense of smell

Paraneoplastic syndromes (i.e., Cushing syndrome, SIADH, ♦etc.) can accompany these tumors

MicroscopicA histologic spectrum may be encountered: from uniform, ♦“small blue” cells embedded in fibrillary matrix to nests of epithelioid polygonal cells having a paraganglioma or carci-noid-like appearance (Fig. 24.41A). Tumor cell nests contain peripherally located S-100 positive sustentacular cells (Fig. 24.41B). The mitotic rate is variable; however, mitotic figures are often inconspicuous and few Prominent vascular proliferation typically accompanies nests ♦of tumor cells. Homer Wright pseudorosettes, when present, reflect neuroblastic differentiation. Melanin can occasionally be present. Immunohistochemical corroboration of the diag-nosis is very useful

ImmunohistochemistryTumor cells are positive for synaptophysin and chromogranin. ♦Cytokeratin should be negative; however, unusual keratin positivity is rarely encountered. S-100 positive sustentacular cells are present peripherally in tumor cell nests

Molecular FindingsThese tumors lack the characteristic t(11;22)(q24;q12) trans- ♦location of Ewing sarcoma/PNET. Comparative genomic hybridization results have shown complex, manifold gains, and losses; high stage tumors have shown frequent gains at 13q14.2–q14.3, 13q31.1, and 20q11.21–q11.23, and loss of Xp21.1

Differential Diagnosis (See Table 24.1)Other sinonasal “small blue cell tumors” must be considered. ♦High grade carcinomas, such as sinonasal undifferentiated and neuroendocrine carcinoma, are cytokeratin positive.

Rhabdomyosarcoma shows immunohistochemical evidence of myogenic differentiation. The possibility of sinonasal involvement by pituitary adenoma should not be forgotten

Sinonasal Undifferentiated Carcinoma (SNUC)Clinical

Patients affected by these aggressive tumors may present ♦with pain, obstruction, and epistaxis. Diplopia and proptosis are features of advanced stage disease

MicroscopicNests, trabeculae, and sheets of medium-sized cells with ♦hyperchromatic nuclei and variably prominent nuclei have small to moderate amounts of eosinophilic cytoplasm. (Fig. 24.42) The mitotic rate is high, necrosis is typical, and vascular invasion can be prominent

Fig. 24.41. A nested pattern of growth, isomorphic cells, and a prominent vasculature are features of olfactory neuroblastoma (A). S-100 protein positive sustentacular cells are a signature feature of olfactory neuroblastoma (B).

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ImmunohistochemistryCytokeratin is positive while neuroendocrine markers are ♦generally negative

Differential DiagnosisImmunohistochemistry is useful is distinguishing from other ♦considerations, such as olfactory neuroblastoma (S-100+ sustentacular cells, synaptophysin+, chromogranin+), neuroendocrine carcinoma (cytokeratin+, synaptophysin+, chromogranin+), rhabdomyosarcoma (desmin+, muscle-specific actin+, myogenin+, MyoD1+) malignant lymphoma (lymphoid markers+), and malignant melanoma (S-100+, cytokeratin−)

The presence of readily discernable nucleoli in SNUC aids ♦distinction from small cell neuroendocrine carcinoma

Malignant Melanoma (Sinonasal Melanoma)Clinical

Primary melanoma of the sinonasal cavity affects older indi- ♦viduals (mean age ~70 years). Patients present with epistaxis, obstruction, and mass. The prognosis is poor with a 5-year survival less than 50%

MicroscopicTumor cells can be either epithelioid and/or spindled ♦(Fig. 24.43). Small and pleomorphic cell types are less com-mon. Prominent eosinophilic nucleoli are common and neo-plastic cells are frequently arranged in a peritheliomatous distribution. Sinonasal melanoma is commonly amelanotic

ImmunohistochemistryThese tumors stain similar to their cutaneous counterparts. ♦Positive stains include S-100 protein, HMB 45, Melan A, tyro-sinase, microphthalmia transcription factor, and vimentin

Cytokeratin is negative and useful in distinguishing mela- ♦noma from carcinoma

Differential DiagnosisImmunohistochemistry is extremely useful is establishing ♦the diagnosis and excluding other considerations such as car-cinoma (cytokeratin+, vimentin−), olfactory neuroblastoma (synaptophysin+, chromogranin+/−, S-100+ sustentacular cells), and lymphoma (lymphoid cell markers+, S-100 protein−)

Small Cell (Neuroendocrine) Carcinoma (SCNC)Clinical

The mean age is ~50 years. Recurrences and metastasis occur ♦in 70% and may be seen later than the third year beyond diagnosis

MicroscopicTumors resemble small cell carcinoma of the lung. Cellular ♦nests, cords, and trabeculae are comprised of hyperchromatic cells with scanty cytoplasm. Nuclei are oval or round and nucleoli inconspicuous. Necrosis and hemorrhage are com-mon, as is nuclear molding and crush artifact. Ultrastructurally, dense core granules are present

ImmunohistochemistryImmunohistochemistry is extremely useful in establishing ♦the diagnosis. Tumor cells should express cytokeratin (AE1/AE3 and CAM 5.2) and neuroendocrine markers (i.e., synap-tophysin and/or chromogranin). 34betaE12 is generally neg-ative, and if positive only weakly so

Fig. 24.42. This sinonasal undifferentiated carcinoma was meta-static to the skin of the neck and negative for neuroendocrine markers. Fig. 24.43. Malignant melanoma. Cytokeratin and S-100 immuno-

histochemistry is crucial in the workup of any undifferentiated sinonasal tumor in which melanoma is a diagnostic consideration.

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Differential DiagnosisOther undifferentiated and “blue cell” tumors should be ♦considered. Olfactory neuroblastoma is cytokeratin negative, neuroendocrine marker positive, S-100 positive in susten-tacular cells are present in most cases. Malignant melanoma is cytokeratin negative and melanoma marker positive. Sinonasal undifferentiated carcinoma is cytokeratin positive and neuroendocrine marker negative

AdenocarcinomaClinical

These are relatively rare tumors. Variants include low grade ♦tubulopapillary and intestinal-type adenocarcinoma (ITAC)

Intestinal-type adenocarcinoma occur both sporadically and ♦as a result of occupation exposure to wood dust. Woodworkers with nasal exposure to wood dust have 70–500 times the risk for these tumors relative to the general population

MicroscopicThe low grade tubulopapillary variant is the most common ♦pattern. These tumors exhibit unencapsulated papillary or tubular proliferations of cytologically bland cuboidal to columnar cells with uniform round nuclei. Tubular prolifera-tions consist of back-to-back glandular profiles with little to no intervening stroma. Mitotic figures are typically few. Necrosis is generally not present and goblet cells are not common

Intestinal-type adenocarcinoma can be divided into four sub- ♦types: papillary tubular cylinder cell, alveolar goblet cell, signet-ring cell, and transitional or mixed pattern. Most belong to the first subtype. Tumors are histologically diverse and resemble the iterations of adenocarcinoma encountered throughout the gastrointestinal tract. Tumor cells can have a nondescript columnar, goblet cell, or signet-ring appearance. Necrosis and karyorrhexic debris are common. Mitotic activ-ity is variable

ImmunohistochemistryThe majority of ITACs are positive for CK7, CD20, and ♦CDX2; a minority is MUC2 positive. Low grade adenocarci-nomas are CK7 positive and negative for CD20, CDX2, and MUC2

Differential DiagnosisLow grade adenocarcinoma can be sufficiently bland to sim- ♦ulate an adenoma of salivary gland type; however, aside from pleomorphic adenoma such tumors are virtually nonexis tent in this location

Metastatic prostate carcinoma to the nasal sinus can simulate ♦primary low grade adenocarcinoma. Enteric-type carcino-mas must be distinguished from metastatic carcinoma of colonic origin

Cytokeratin 7 may be useful in aiding distinction between ♦intestinal-type adenocarcinoma of the sinus, which often shows some CK7 positivity, and adenocarcinoma of the colon (CK7−)

Molecular FindingsH-ras mutation has been found in a minority of ITACs and ♦appears to be associated with poor prognosis. K-ras-2 muta-tion, common in colorectal adenocarcinoma, is absent in ITAC

RhabdomyosarcomaClinical

Generally, this is a tumor of childhood with a mean age of 4 ♦years. The nasopharynx is the second most common site in head and neck after the orbit. They may occur in nasal cavity and paranasal sinuses. The embryonal variant is the most common subtype (85% of cases)

MicroscopicThese “small blue cell” tumors are highly cellular and com- ♦posed of small cells, variably spindled, with scant cytoplasm and hyperchromatic nuclei. Mitotic figures are numerous (Fig. 24.44). Larger cells with opaque eosinophilic cyto-plasm with cross- striations may be present. The stroma is commonly myxoid

Ultrastructurally, Z-bands and myofilaments are ♦demonstrated

ImmunohistochemistryImmunohistochemistry is fundamental in establishing the ♦diagnosis. Tumor cells are positive for MyoD1, myogenin, desmin, and muscle-specific actin. CD99 is negative

Differential DiagnosisOther small round blue cell tumors of childhood, see the ♦chapter on soft tissue

Molecular FindingsSee the chapter on soft tissue ♦

Fig. 24.44. Immunohistochemistry is fundamental in the diag-nosis of small blue cell tumors. This rhabdomyosarcoma of the head and neck was metastatic to lymph node.

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Nasopharyngeal Carcinoma (NPC)Clinical

The WHO most recent classification of NPC ♦

Keratinizing squamous cell carcinoma −

Nonkeratinizing carcinoma −

(a) Undifferentiated

(b) Differentiated

Basaloid squamous cell carcinoma −

All types of NPC are considered variants of squamous cell ♦carcinoma

High risk populations for NPC include southern Chinese, ♦Eskimos and other natives of the Arctic region. NPC is the most common head and neck malignancy in southeastern China and Taiwan. Ethnic background, EBV exposure, and ingestion of volatile nitrosamines are thought to determine risk for NPC

HLA-A2 and HLA-B-Sin 2 histocompatibility loci have ♦been identified as possible markers for genetic susceptibility. There is a bimodal age incidence with peaks occurring near 20 and 65 years of age in low risk populations. High risk populations lack an early peak

Patients commonly present with otitis media and hearing ♦loss. Metastatic disease is the first presentation of disease (i.e., neck mass) in ~50%

Undifferentiated and differentiated nonkeratinizing carcino- ♦mas have a strong association with EBV. EBV-associated tumors are highly sensitive to radiation therapy and have a 5-year survival of greater than 60%

Keratinizing squamous cell carcinoma has a weaker associa- ♦tion with EBV, arise in older patients, and have a 5-year sur-vival of less than 40%. They are generally larger tumors at presentation

MicroscopicKeratinizing squamous cell carcinoma has histology similar to ♦tumors occurring elsewhere in the upper aerodigestive tract

Differentiated nonkeratinizing carcinoma manifests nests and ♦sheets of epidermoid appearing cells lacking keratinization. Nuclei are large, oval, and vesicular with prominent nucleoli. Robust lymphoplasmacytic inflammation accompanies the tumor cells

Undifferentiated nonkeratinizing carcinoma exhibits polygo- ♦nal cells with indistinct cytoplasmic membranes imparting a syncytical appearance. Dense lymphoplasmacytic inflamma-tion dominants the histology and may obscure tumor cells. Vesicular nuclei exhibit little chromatin and distinct nuclei membranes. Nucleoli are prominent

Basaloid squamous cell carcinoma appears similar to tumors ♦occurring elsewhere

ImmunohistochemistryThese tumors are positive for cytokeratin ♦

Differential DiagnosisImmunohistochemistry aids distinction from lymphoma ♦(lymphoid marker+ and cytokeratin−) and melanoma (S-100+, HMB 45+, and cytokeratin−)

Molecular FindingsEBER (EBV-encoded RNA) positivity via in situ hybridiza- ♦tion is present in greater than 90% of nonkeratinizing NPC and is a favorable prognostic indicator

Cell proliferation may be upregulated via alterations of mito- ♦gen-activated protein kinases, and Akt and Wnt pathways. p16, cyclin D1, and cyclin E, among others, have been impli-cated in cell cycle abnormalities

Polymorphism of a nitrosamine metabolizing gene, CYP2A6, ♦may play a fundamental role in NPC susceptibility in certain populations

Miscellaneous LesionsRespiratory Epithelial Adenomatoid Hamartoma

These are benign polypoid, nonneoplastic proliferations of ♦ciliated respiratory epithelium. They most commonly arise on the posterior septum. Their cause is unknown. They may be mistaken for inverted papilloma

Necrotizing SialometaplasiaInfarction or necrosis of seromucinous glands at any site of ♦upper aerodigestive tract can lead to squamous metaplasia, often extensive with cytologic atypia, that mimics squamous cell carcinoma

Cholesterol GranulomaCholesterol granuloma may be encountered in the frontal ♦and maxillary sinuses, less commonly in the paranasal sinuses. Cholesterol clefts, giant cells, foam cells, hemosid-erin, and macrophages are present within fibrous granulation tissue. The changes are the result of resorbing hemorrhage

Chondromesenchymal HamartomaThese intranasal/paranasal tumors occur in infants. Bland ♦spindle cells, fibrous stroma, and foci of cartilage comprise these tumors. Aneurysmal bone cyst-like change with giant cells may be present

Extranodal Sinus Histiocytosis (Sinus Histiocytosis with Massive Lymphadenopathy, Rosai–Dorfman Disease)

The nasal and paranasal cavities are, after the skin, the sec- ♦ond most common site of extranodal involvement by Rosai–Dorfman disease. The defining lesional cells are large foamy S-100 positive histiocytes that may contain intact intracyto-plasmic lymphocytes (emperiopolesis)

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FibromatosisThese tumors are rare and histologically similar to fibroma- ♦tosis occurring elsewhere. The differential diagnosis includes solitary fibrous tumor and low grade sarcomas

Hemangioma of Nasofacial BonesOsseous hemangioma commonly produces bony irregulari- ♦ties. Cavernous thin-walled vessels fill and expand cancel-lous bone

MeningiomaSinonasal meningioma is rare. The histology is similar to ♦those of conventional intracranial lesions, including nuclear pseudoinclusions and psammoma bodies. Immunostains for EMA and vimentin are positive

Mesenchymal ChondrosarcomaThese primitive appearing spindle cell tumors often have a ♦hemangiopericytoma-like appearance with foci of cartilagi-nous matrix. A paucity of cartilaginous matrix makes the diagnosis difficult

OsteomaOsteomas are dense tumor-like lesions of lamellar bone and ♦are relatively common in the craniofacial skeleton. Patients with Gardner syndrome are at increased risk for craniofacial osteomas, gastrointestinal adenomas, fibromatosis, and kera-tinous cysts

Metastatic TumorsThe most common metastatic tumor found in the nasal cav- ♦ity-paranasal sinus region is renal cell carcinoma followed by lung, breast, thyroid, and prostate primaries

Pituitary AdenomaSinus involvement may occur via extension from an intra- ♦sellar lesion or as primary ectopic tumor (Fig. 24.45)

Salivary Gland TumorsWhile adenoid cystic carcinoma is relatively common, other ♦types of salivary gland tumors rarely involve the sinuses

SarcomaA wide array of sarcomas may involve the nasal cavity-sinus ♦region including, fibrosarcoma, osteosarcoma, chondrosar-coma, and Ewing sarcoma/PNET

Solitary Fibrous TumorThere are many recent reports of sinonasal solitary fibrous ♦tumor. Immunohistochemistry is useful in establishing the diagnosis as these tumors are positive for CD34 and vimen-tin. CD99 is positive in 60–70% of cases

Teratoid Carcinosarcoma (Teratocarcinosarcoma)

The histopathology of these highly malignant tumors is ♦complex with features of an immature teratoma mixed with carcinoma. Carcinomatous elements can be gland forming and/or squamoid. Primitive neuroectodermal elements (including rosette-like structures), rhabdomyoblasts, and cartilaginous areas are typical (Fig. 24.46). Three of three tested cases were negative for chromosome 12p amplifica-tion is a recent study

Fig. 24.46. Teratocarcinosarcoma is an unusual sinus tumor that is reminiscent of germ cell neoplasia. Primitive or blastema-like elements are common and may accompany malignant squamous and/or glandular components.

Fig. 24.45. Pituitary adenoma may rarely present as a sinus tumor as in this case.

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InfectionDisseminated Fungal InfectionClinical

A variety of disseminated fungal infections may have ♦laryngeal manifestations, including histoplasmosis, blasto-mycosis, cryptococcosis, and coccidioidomycosis. Infection of the larynx is typically preceded by pulmonary infection. The clinical impression is often laryngeal carcinoma or tuberculosis

MicroscopicA granulomatous inflammatory response, including histio- ♦cytes, giant cells, and necrosis, is generally present. Well-defined granulomas may or may not be present. Bug-laden, foamy histiocytes with necrosis and nonspecific inflamma-tion, with limited evidence of giant cells or granulomas, may be encounter with histoplasmosis

Blastomycosis is notoriously for inducing pseudoepithe- ♦liomatous hyperplasia and associated neutrophilic inflamma-tion with giant cells (Fig. 24.47)

Inflammatory/Nonneoplastic LesionsLaryngoceleClinical

This lesion is represented by either congenital or an acquired ♦air-filled (can accumulate fluid) dilatation of the laryngeal saccule

MicroscopicThey are lined by respiratory-type epithelium, which may ♦undergo oncocytic metaplasia. The presence of neutrophils indicates secondary infection (i.e., laryngopyocele)

Oncocytic CystClinical

Oncocytic cysts arise in elderly patients and most common ♦occur within the ventricle. Patients present with complaints of hoarseness

MicroscopicThese cysts are lined by large oncocytic cells and arise within ♦and involve the seromucinous glands of the larynx (Fig. 24.48). Variable papillary infoldings are encountered and maybe so prominent that a diagnosis of papillary cysta-denoma is entertained

Differential DiagnosisOther benign cysts occur in the larynx including small ductal ♦cysts lined by cuboidal cells of no special type and tonsillar retention cysts. The latter have the appearance of dilated, cystic tonsillar crypts, are squamous lined, and rich in lym-phoid follicles

Vocal Cord Polyp (Laryngeal Polyp)Clinical

These appear as sessile or pedunculated, raspberry-like ♦lesions involving the true vocal cords. Their occurrence is associated with chronic voice abuse and heavy smoking

MicroscopicThese polypoid lesions vary in appearance. Typical stromal ♦changes include vascular congestion, hemorrhage, myxoid change, perivascular hyalinization, thrombosis, and increased stromal cellularity (Fig. 24.49). A given lesion may have many or few of the above findings. The overlying squamous epithelium may show atypia, which may be related to isch-emia and should not be mistaken for dysplasia

LARYNX AND tRACHeA

Fig. 24.48. Oncocytic cysts laryngeal cysts are nonneoplastic lesions that occur with increasing frequency in the elderly.

Fig. 24.47. In blastomycosis, granulomatous inflammation is typically rich with neutrophils. Inset: GMS stain showing broad-based budding yeast.

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Contact UlcerClinical

These lesions involve the posterior commissure of the vocal ♦folds. They often recur and gastric reflux has been implicated in their pathogenesis

MicroscopicThe mucosa is typically ulcerated; however, squamous ♦hyperplasia maybe seen adjacent to the ulcer. The signature portion of this lesion is the exuberant granulation tissue com-prising the ulcer base, which can be extremely cellular and mimic neoplasia

Differential DiagnosisThe characteristic location and clinical features aid distinc- ♦tion from potential histologic mimics such as hemangioma, spindle cell carcinoma, and granulomatous inflammation

Benign NeoplasmsLaryngeal Papillomatosis (Squamous Papillomas)Clinical

Resulting from the vertical transmission of human papilloma ♦virus (HPV) types 6 and 11, the onset of juvenile laryngeal papillomatosis is, as the name suggests, generally in child-hood or adolescence. The lesions are centered upon true cords and extension to false cords, vestibule and subglottis is not uncommon. They rarely involve trachea and bronchi. Adult cases tend to be solitary, recur less often, and have the same HPV association

While multiple recurrences are typical, most cases eventu- ♦ally regress. Nonetheless, progressive disease occurs and can lead to death

MicroscopicDelicate fibrovascular cores are lined by relatively bland ♦squamous epithelium exhibiting basal cell hyperplasia. While parakeratosis is common, hyperkeratosis can be pres-ent. There is basal cell hyperplasia and mild nuclear enlargement

Koilocytic and koilocytic-like changes, including perinuclear ♦halos and hyperchromatic, raisinoid nuclei, are present. Atypia is common and manifests as loss of polarity, mild nuclear enlargement and pleomorphism, binucleation, apop-tosis, individual cell keratinization, and increased mitotic figures (Fig. 24.50)

These lesions grow exophytically although extension into ♦respiratory glands can be seen

ImmunohistochemistryImmunohistochemical positivity for HPV antigen and in situ ♦hybridization positivity for HPV 6/11 is common

Differential DiagnosisHistologically, invasive papillomatosis is identical to typical ♦papillomatosis. Recognition of the former is based upon an invasive growth beyond the larynx into adjacent soft tissues

Papillary squamous cell carcinoma exhibits greater cytologic ♦atypia than papilloma, affects older individuals, and lacks the koilocytic changes of papilloma

Premalignant/Malignant NeoplasmsSquamous Cell Hyperplasia (Hyperkeratosis)Clinical

While hyperkeratosis manifests clinically as whitish mucosa ♦plaques or thickenings, microscopically these lesions show hyperkeratosis accompanied by acanthosis or squamous hyperplasia. The true cords and interarytenoid area are the

Fig. 24.49. Laryngeal polyps are characterized by myxoid stroma and are often exhibit hemorrhage and thrombosis as seen in this case.

Fig. 24.50. Numerous HPV-induced squamous papillomas are encountered in laryngeal papillomatosis.

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most commonly affected areas. Such change is associated with hoarseness and encountered in smokers and voice abusers

MicroscopicThe mucosa shows hyperkeratosis and typically acanthosis. ♦Squamous cells are cytologically bland and maintain polarity

♦ Verrucous hyperkeratosis (verrucous hyperplasia) is a vari-ant exhibiting verrucoid or papillary architecture. These lesions lack the papillary branching of papilloma and the pushing invasion of verrucous carcinoma

Squamous Dysplasia/Carcinoma In SituKeratotic lesions show spectrum of dysplasia ranging from ♦mild squamous dysplasia to squamous cell carcinoma in situ. The WHO grades dysplasia into mild, moderate, severe, and carcinoma in situ

There is correlation between degree of dysplasia and pro- ♦gression to invasive carcinoma. Progression to invasion may take years. The reproducibility of dysplasia grading is poor

Cytologic atypia induced by previous radiation therapy may ♦simulate dysplasia/carcinoma in situ

Squamous Cell CarcinomaClinical

Squamous cell carcinoma is the most common neoplasm of ♦the larynx. Over 90% of carcinomas are squamous type. The mean age at diagnosis is 60 years. Smoking is the dominant risk factor for all types, including variants

Segregating tumors according to laryngeal subsite has rele- ♦vant prognostic import. Most tumors are glottic (65%), fol-lowed by supraglottic (35%) and subglottic (<5%). Glottic tumors have the best survival followed by supraglottic and then subglottic

MicroscopicRecapitulating squamous epithelium tumors manifest keratin ♦production, intracellular bridges, and/or dyskeratotic cells. Endophytic, exophytic, and mixed patterns of growth may be encountered. Stromal invasion is reflected by the presence of desmoplasia. Tumors are graded as well, moderately, or poorly differentiated. Several variants occur (see below)

Molecular FindingsImplicated genetic abnormalities in the development of head ♦and neck squamous cell carcinoma are complex and numer-ous, including alterations of p16ink4A, p53, cyclin D1, p14ARF, FHIT, RASSF1A, epidermal growth factor recep-tor (EGFR), and Rb

Verrucous Carcinoma

ClinicalThis low grade variant of squamous cell carcinoma occurs most ♦frequently in the oral cavity. The clinicopathologic features similar to those occurring elsewhere (i.e., nonmetastasizing)

Grossly, these are gray-white, warty, broadly implanted −mucosal growths. They represent no more than 2% of glottic carcinomas

Diagnosis can be difficult on biopsy (due to lack of atypia ♦and difficulty in establishing invasion) and requires coopera-tion between the pathologist and the clinician

MicroscopicSee above section “Oral Cavity.” A diagnosis of verrucous ♦carcinoma should not be made when there is notable or prominent cytologic atypia. Moreover, broad-based, ‘push-ing’ invasion beyond the limits of the nonneoplastic mucosa should be demonstrated

Differential DiagnosisVerrucous hyperkeratosis (verrucous squamous hyperplasia) ♦lacks “pushing” invasion. Any large and/or broadly implanted lesion raises suspicion for carcinoma and warrants clinical input prior to diagnosis

Basaloid Squamous Cell CarcinomaClinical

This biologically high grade, variant of squamous cell carci- ♦noma has a predilection for the supraglottic larynx, hypophar-ynx, and tongue base. There is a propensity for nodal as well as systemic metastases. The 5-year survival rate is ~18%

MicroscopicThese highly cellular neoplasms are composed of nests of ♦hyperchromatic, basaloid-appearing cells exhibiting periph-eral nuclear palisading. Squamous differentiation is encoun-tered more centrally. Lobular, solid, trabecular, and cribriform patterns are encountered. Nuclei are hyperchromatic and vari-ably pleomorphic with inconspicuous to prominent nucleoli

Cytoplasm, likewise, is variable and single dyskeratotic cells ♦are typical and have been noted to impart a “mosaic” pattern upon the tumor

Central necrosis within tumor nests is common. Intercellular ♦basement membrane-like material is often encountered in thin membranous structures or as droplets

ImmunohistochemicalImmunostains are positive for cytokeratin and p63. ♦Neuroendocrine markers and TTF-1 are negative

Differential DiagnosisThe solid variant of adenoid cystic carcinoma can mimic ♦basaloid squamous cell carcinoma (BSCC); however, the former lacks squamous differentiation and is less pleomor-phic than BSCC

Immunohistochemically, small cell neuroendocrine carci- ♦noma is positive for neuroendocrine markers and negative for p63

Sarcomatoid Carcinoma (Spindle Cell Carcinoma)Clinical

The larynx is the most common site for this variant of squamous ♦cell carcinoma, which is also encountered in the oral and nasal cavities, paranasal sinus, hypopharynx, and esophagus The average age at presentation is 66 years. Most tumors ♦are glottic with a mean tumor size of less than 2 cm.

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Exophytic growth is a characteristic and may simulate a benign polyp. Recurrences may develop in up to ~50% of patients. Survival is related to the depth of invasion

MicroscopicThese malignant spindle cell tumors may be cytologically ♦bland or markedly atypical. Coexistent foci of obvious squamous differentiation may or may not be present and when present confirm the diagnosis. Such foci can be quite limited, and diligent search for squamous differentiation should be made. Foci of benign or malignant-appearing car-tilage and/or bone may be present (so-called “carcinosar-coma”). The presence of adjacent carcinoma in situ may also be present and aids in the diagnosis

ImmunohistochemistryImmunostains are extremely useful in establishing the diag- ♦nosis when in doubt. Malignant spindle cells are anticipated to be positive for cytokeratin and vimentin. EMA may also be positive

Differential DiagnosisSpindle cell carcinoma can be cytologically quite bland and ♦easily mistaken for a benign mesenchymal process. Cytokeratin positivity argues for a diagnosis of carcinoma. Recurrent masses in a field of prior radiation should be viewed with a very high index of suspicion despite bland cytology

Sarcomas lack immunohistochemical evidence of epithelial ♦differentiation (i.e., cytokeratin negative) and lack a precur-sor lesion (i.e., carcinoma in situ)


These exophytic tumors are HPV-associated variants of ♦squamous cell carcinoma (see section “Oropharynx”). Laryngeal primary tumors have the best prognosis relative to papillary squamous cell carcinoma arising elsewhere

MicroscopicTumors exhibit finger-like papillary architecture. Invasion ♦into the underlying stroma may or may not be present. The prognosis corresponds to the extent of invasion. The cytologic atypia exceeds that encountered in papillomas. Atypia is gen-erally full-thickness and mitotic figures are readily apparent

Differential DiagnosisSquamous papillomas, with or without dysplasia, exhibit ♦less cytologic atypia than papillary squamous cell carcinoma. Koilocytes, typical of papilloma, are not readily apparent in papillary squamous cell carcinoma

Molecular FindingsHPV 6 and 16 are the subtypes most commonly associated ♦with papillary squamous cell carcinoma

Lymphoepithelioma-Like CarcinomaClinical

This tumor exhibits histology similar to its nasopharygeal ♦counterpart (see above) and behaves in a like manner with

lymph node metastasis occurring in most patients. Visceral dissemination of disease occurs in up to 25% of patients

MicroscopicLarge, poorly to undifferentiated, nonkeratinized tumor cells ♦intermingled with small nonneoplastic lymphocytes and plasma cells

ImmunohistochemicalIf in doubt, cytokeratin positivity aids to distinguish from ♦ lymphoma and melanoma

Small Cell (Neuroendocrine) Carcinoma (SCNC)Clinical

Laryngeal SCNC is histologically identical to it pulmonary ♦counterpart. As with SCNC occurring at most sites there is early development of metastatic disease. There is a strong association with smoking and mean survival is 11 months

MicroscopicHyperchromatic, small cells with scant cytoplasm show ♦nuclear molding and crush artifact. Mitotic activity is high, and apoptotic nuclei debris is conspicuous. Nucleoli are not readily apparent and small if seen

ImmunohistochemicalImmunohistochemistry is extremely useful in establishing ♦the diagnosis as cells are expected to be positive for cytok-eratin, neuroendocrine markers, and TTF-1 (i.e., synapto-physin and/or chromogranin positive)

Differential DiagnosisThe differential includes lymphoma (lymphoid markers+, ♦cytokeratin−), basaloid squamous cell carcinoma (p63+, neuroendocrine marker−, and TTF-1−), and variants of ade-noid cyst carcinoma (see below)

Large Cell Neuroendocrine Carcinoma (LCNC)Clinical

Most cases of laryngeal LCNC arise in the supraglottis. ♦There is a strong association with smoking. Prognosis is poor with a mean survival of 36 months. Lymph node and sys-temic metastasis are typical

MicroscopicLarger, polygonal tumor cells exhibit a nested and/or trabe- ♦cular pattern of growth. Eosinophilic cytoplasm may appear granular. Nuclei are large, pleomorphic, and hyperchromatic with viable chromatin

Mitotic figures are readily apparent and necrosis is common. ♦Ultrastructurally, dense core neurosecretory granules are present

ImmunohistochemicalThe diagnosis of LCNC is dependent upon immunohis- ♦tochemical (or ultrastructural) evidence of neuroendocrine differentiation (i.e., synaptophysin and/or chromogranin positivity). Cytokeratin staining is positive as well

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Differential DiagnosisParaganglioma can bear a superficial resemblance to LCNC ♦but lack mitotic activity and necrosis. Furthermore, paragan-glioma is cytokeratin negative and contains S-100 positive sustentacular cells

Adenoid Cystic CarcinomaClinical

Adenoid cystic carcinoma is the second most common ♦malignant tumor of trachea after squamous cell carcinoma. These tumors have a slow but relentless course with poor prognosis

MicroscopicThey are histologically similar to those occurring elsewhere ♦(see Chapter 23, Salivary Gland Tumors). Solid pattern and dedifferentiated variants must be distinguished from the basaloid variant of squamous cell carcinoma and small cell carcinoma

ChondrosarcomaClinical

Chondrosarcoma, the most common malignant adult mesen- ♦chymal tumor of the larynx, typically is centered upon the cricoid cartilage. With a mean size of 3.5 cm, the majority

are low grade (grade 1 or 2). Conservative resection is advo-cated for low grade tumors

MicroscopicLobules of well-differentiated cartilage exhibit increased ♦cellularity and chondrocyte atypia (including nucleoli, binu-cleation, and pleomorphism) as seen in low grade chondro-sarcoma occurring at other sites (i.e., long bones)

Differential DiagnosisThe principal diagnostic consideration is chondroma. ♦Distinction can be difficult as is the case for cartilaginous tumors occurring elsewhere. Some have advocated consider-ing all symptomatic lesions as representing chondrosarcoma – nomenclature aside, surgeons must be informed that conserva tive resections is the treatment of choice for low grade tumors. Nonneoplastic anatomic cartilage should be rule out as biopsy of an occasional “mass” will retrieve such material. We urge corroborating the histologic findings with the clinical and radiographic findings in all cartilaginous lesions of the larynx

Mesenchymal/Soft Tissue TumorsIsolated case reports describe a wide spectrum of benign and ♦malignant mesenchymal neoplasms arising in the larynx (see the chapter on soft tissue)

The most frequent malignant laryngeal neoplasm in children ♦and adolescents is the embryonal variant of rhabdomyosarcoma

tNM CLASSIFICAtIoNS FoR tHe LIP AND oRAL CAVItY (2010 ReVISIoN)

Rules for ClassificationThe classification applies only to carcinomas. There should ♦be histologic confirmation of the disease

The following are the procedures for assessing T, N, and M ♦categories

T categories Physical examination, laryngoscopy, and imagingN categories Physical examination and imagingM categories Physical examination and imaging

Definition of TNM

Primary Tumor (T)

TX Primary tumor cannot be assessedT0 No evidence of primary tumorTis Carcinoma in situT1 Tumor 2 cm of less in greatest dimensionT2 Tumor more than 2 cm but not more than 4 cm in greatest

dimensionT3 Tumor more than 4 cm in greatest dimensionT4a Moderately advanced local disease*

(lip) Tumor invades through cortical bone, inferior alveolar nerve, floor of mouth, or skin of face, that is, chin or nose (oral cavity) Tumor invades adjacent structures only (e.g., through cortical bone [mandible or maxilla] into deep [extrinsic] muscle of tongue [genioglossus, hyoglossus, palatoglossus, and styloglossus], maxillary sinus, skin of face)

T4b Very advanced local disease. Tumor invades masticator space, pterygoid plates, or skull base and/or encases inter-nal carotid artery

*Note: Superficial erosion alone of bone/tooth socket by gingival primary is not sufficient to classify a tumor as T4

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Regional Lymph Nodes (N)

NX Regional lymph nodes cannot be assessedN0 No regional lymph node metastasisN1 Metastasis in a single ipsilateral lymph node, 3 cm or less in

greatest dimensionN2 Metastasis in a single ipsilateral lymph node, more than 3 cm

but not more than 6 cm in greatest dimension; or in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimen-sion; or in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension:

N2a Metastasis in a single ipsilateral lymph node more than 3 cm but not more than 6 cm in greatest dimension

N2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension

N2c Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension

N3 Metastasis in a lymph node more than 6 cm in greatest dimension

Distant Metastasis (M)

MX Distant metastasis cannot be assessedM0 No distant metastasisM1 Distant metastasis

Definition of TNMPrimary Tumor (T)

TX Primary tumor cannot be assessedT0 No evidence of primary tumorTis Carcinoma in situ

Supraglottis

T1 Tumor limited to one subsite of supraglottis with normal vocal cord mobility

T2 Tumor invades mucosa of more than one adjacent subsite of supraglottis or glottis or region outside the supraglottis (e.g., mucosa of base of tongue, vallecula, medial wall of pyriform sinus) without fixation of the larynx

T3 Tumor limited to larynx with vocal cord fixation and/or invades any of the following: postcricoid area, preepiglottic space, para-glottic space, and/or inner cortex of thyroid cartilage

T4a

T4b

Moderately advanced local diseaseTumor invades through the thyroid cartilage and/or invades tis-sues beyond the larynx (e.g., trachea, soft tissues of neck includ-ing deep extrinsic muscle of the tongue, strap muscles, thyroid, or esophagus)Very advanced local diseaseTumor invades prevertebral space, encases carotid artery, or invades mediastinal structures

Glottis

T1

T1aT1b

Tumor limited to the true vocal cords (may involve anterior or posterior commissure) with normal mobilityTumor limited to one true vocal cordTumor involves both true vocal cords

T2 Tumor extends to supraglottis and/or subglottis and/or with impaired true vocal cord mobility

T3 Tumor limited to the larynx with vocal cord fixation and/or invasion of paraglottic space, and/or inner cortex of the thyroid cartilage

T4a

T4b

Moderately advanced local diseaseTumor invades through the outer cortex of the thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft tis-sues of neck including deep extrinsic muscle of the tongue, strap muscle, thyroid, or esophagus)Very advanced local diseaseTumor invades prevertebral space, encases carotid artery, or invades mediastinal structures

Subglottis

T1 Tumor limited to the subglottisT2 Tumor extends to vocal cords with normal or impaired mobilityT3 Tumor limited to larynx with vocal cord fixationT4a

T4b

Moderately advanced local diseaseTumor invades cricoid or thyroid cartilage and/or invades tis-sues beyond the larynx (e.g., trachea, soft tissues of neck includ-ing deep extrinsic muscles of the tongue, strap muscles, thyroid, or esophagus)Very advanced local diseaseTumor invades prevertebral space, encases carotid artery, or invades mediastinal structures

tNM CLASSIFICAtIoNS FoR tHe LARYNX (2010 ReVISIoN)

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Nasal Cavity, Paranasal Sinuses, and NasopharynxBanks ER, Frierson HF Jr, Mills SE, Swanson PE, et al. Basaloid

squamous cell carcinoma of the head and neck. A clinicopathologic and immunohistochemical study of 40 cases. Am J Surg Pathol 1992; 16:939–946.

Barnes L. Schneiderian papillomas and nonsalivary glandular neoplasms of the head and neck. Mod Pathol 2002;15:279–297.

Bourne TD, Bellizzi AM, Stelow EB, et al. p63 Expression in olfactory neuroblastoma and other small cell tumors of the sinonasal tract. Am J Clin Pathol 2008;130:213–218.

Devaney K. Wenig BM. Abbondanzo SL. Olfactory neuroblastoma and other round cell lesions of the sinonasal region. Mod Pathol 1996;9: 658–663.

Devaney KO, Travis WD, Hoffman G, et al. Interpretation of head and neck biopsies in Wegener’s granulomatosis. A pathologic study of 126 biopsies in 70 patients. Am J Surg Pathol 1990;14:555–564.

Fletcher CD. Distinctive soft tissue tumors of the head and neck. Mod Pathol 2002;15:324–330.

Friedman GC, Hartwick RW, Ro JY, et al. Allergic fungal sinusitis. Report of three cases associated with dematiaceous fungi. Am J Clin Pathol 1991;96:368–372.

Frierson HF Jr, Mills SE, Fechner RE, et al. Sinonasal undifferentiated carcinoma. An aggressive neoplasm derived from schneiderian epithe-lium and distinct from olfactory neuroblastoma. Am J Surg Pathol 1986; 10:771–779.

Heffner DK, Hyams VJ. Teratocarcinosarcoma (malignant teratoma?) of the nasal cavity and paranasal sinuses a clinicopathologic study of 20 cases. Cancer 1984;53:2140–2154.

Iezzoni JC, Mills SE. “Undifferentiated” small round cell tumors of the sinonasal tract: differential diagnosis update. Am J Clin Pathol 2005;124 Suppl:S110–121.

Ohshima K, Suzumiya J, Shimazaki K, et al. Nasal T/NK cell lympho-mas commonly express perforin and Fas ligand: important mediators of tissue damage. Histopathology 1997;31:444–450.

Ridolfi RL, Lieberman PH, Erlandson RA, et al. Schneiderian papillomas: a clinicopathologic study of 30 cases. Am J Surg Pathol 1977;1:43–53.

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Derkay CS, Wiatrak B. Recurrent respiratory papillomatosis: a review. Laryngoscope 2008;118:1236–1247.

Regional Lymph Nodes (N)

NX Regional lymph nodes cannot be assessedN0 No regional lymph node metastasisN1 Metastasis in a single ipsilateral lymph node, 3 cm or less in

greatest dimensionN2

N2a

N2b

N2c

Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension, or in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension, or in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimensionMetastasis in a single ipsilateral lymph node more than 3 cm but not more than 6 cm in greatest dimensionMetastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimensionMetastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension

N3 Metastasis in a lymph node more than 6 cm in greatest dimension

Distant Metastasis (M)

MX Distant metastasis cannot be assessedM0 No distant metastasisM1 Distant metastasis

SUGGeSteD ReADINGS

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Ferlito A, Devaney KO, Rinaldo A. Neuroendocrine neoplasms of the larynx: advances in identification, understanding, and management. Oral Oncol 2006;42:770–778.

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