Head and Neck Pathologie

24 Head and Neck
John D. Henley, MD and Don-John Summerlin, MD
COnTEnTs I. Oral Cavity........................................24-4

Infection............................................................24-4 Candidiasis..............................................24-4 Herpes Simplex Virus. ............................24-4 Oral Hairy Leukoplakia........................24-4 Human Papillomavirus..........................24-5 Disseminated Fungal Infection. .............24-5 Immune-Mediated Disease..............................24-5 Lichen Planus. .........................................24-5 Benign Mucous Membrane (Cicatricial) Pemphigoid...................24-6 Pemphigus Vulgaris................................24-6 Inammatory/Nonneoplastic Lesions.............24-6 Peripheral Ossifying Fibroma...............24-6 Peripheral Giant Cell Granuloma........24-7 Verruciform Xanthoma. .........................24-7 Traumatic Ulcerative Granuloma with Stromal Eosinophilia................24-7 Mucous Extravasation Phenomena (Mucocele/Ranula). ............................24-8 Necrotizing Sialometaplasia..................24-8 Benign Neoplasms............................................24-8 Granular Cell Tumor.............................24-8 Congenital Gingival Granular Cell Tumor (Congenital Epulis).......24-8 Premalignant/Malignant Neoplasms..............24-9 Leukoplakia........................................24-9 Squamous Dysplasia/Carcinoma In Situ.................................................24-9 Proliferative Verrucous Leukoplakia. .......................................24-9 Squamous Cell Carcinoma..................24-10 Verrucous Carcinoma..........................24-10 Sarcomatoid (Spindle Cell) Carcinoma........................................24-11 Papillary Squamous Cell Carcinoma........................................24-11 Malignant Melanoma...........................24-11 Miscellaneous Lesions....................................24-12 Adenomatoid Hyperplasia...................24-12 Amalgam Tattoo...................................24-12 Aphthous Stomatitis.............................24-12 Dermoid Cyst........................................24-12 Geographic Tongue (Erythema Migrans)........................24-12 Lingual Thyroid. ...................................24-12 Lymphoepithelial Cyst.........................24-12 Melanoacanthoma................................24-12 Nicotine Stomatitis...............................24-12 Oral Focal Mucinosis...........................24-12 Palisaded, Encapsulated (Solitary, Circumscribed) Neuroma...............24-12 Salivary Duct Cyst................................24-13 Smokeless Tobacco-Induced Keratosis...........................................24-13
II. Jaws.................................................24-13
Nonodontogenic Cysts/Pseudocysts..............24-13 Nasopalatine Cyst.................................24-13 Traumatic Bone Cavity........................24-13 Odontogenic Cysts. .........................................24-13 Dentigerous Cyst. ..................................24-13 Odontogenic Keratocyst (Keratocystic Odontogenic Tumor)..............................................24-14 Apical Periodontal Cyst.......................24-14
L. 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
1081
24-2
Essentials of Anatomic Pathology, 3rd Ed.
Calcifying Odontogenic Cyst (Gorlin Cyst)....................................24-14 Dentinogenic Ghost Cell Tumor (Included Here Given Similarity to Gorlin Cyst).................................24-15 Reactive/Nonneoplastic Disease....................24-15 Cementoosseous Dysplasia..................24-15 Odontoma. .............................................24-15 Giant Cell and Giant Cell-Rich Lesions........................................................24-15 Central Giant Cell Granuloma...........24-15 Giant Cell Tumor. .................................24-16 Aneurysmal Bone Cyst. ........................24-16 Cherubism.............................................24-16 Benign Neoplasms..........................................24-16 Ameloblastoma.....................................24-16 Adenomatoid Odontogenic Tumor.....24-17 Calcifying Epithelial Odontogenic Tumor (Pindborg Tumor)...............24-17 Squamous Odontogenic Tumor. ..........24-17 Ameloblastic Fibroma..........................24-18 Cementoblastoma.................................24-18 Central Cementoossifying Fibroma............................................24-18 Odontogenic Fibroma..........................24-18 Malignant Neoplasms. ....................................24-19 Ameloblastic Carcinoma. .....................24-19 Squamous Cell Carcinoma..................24-19 Clear Cell Odontogenic Carcinoma........................................24-19 Osteosarcoma........................................24-19 Chondrosarcoma..................................24-20 Mesenchymal Chondrosarcoma..........24-20 Metastatic Disease................................24-20 Melanotic Neuroectodermal Tumor of Infancy. .........................................24-20 Miscellaneous Lesions....................................24-20 Stafne Defect.........................................24-20 Tori. ........................................................24-20 Gingival Cyst/Lateral Periodontal Cyst...................................................24-21 Central Mucoepidermoid Carcinoma........................................24-21
III. Oro/Hypopharynx...........................24-21
Malignant Neoplasms. ....................................24-21 Squamous Cell Carcinoma..................24-21 Lymphoepithelial Carcinoma..............24-21 Basaloid Squamous Carcinoma..........24-21 Papillary Squamous Cell Carcinoma................................24-22
IV. Nasal Cavity, Paranasal Sinuses, and Nasopharynx. ............................24-22

Infection..........................................................24-22
Rhinosinusitis. .......................................24-22 Allergic Fungal Sinusitis......................24-23 Invasive Fungal Sinusitis.....................24-23 Other Forms of Infectious Sinusitis. ............................................24-23 Inammatory/Nonneoplastic Lesions...........24-23 Mucocele. ...............................................24-23 Wegener Granulomatosis....................24-24 Sarcoidosis. ............................................24-24 Myospherulosis.....................................24-24 Polyps. ....................................................24-24 Benign Neoplasms..........................................24-25 Lobular Capillary Hemangioma (Granuloma Pyogenicums).............24-25 Hyperkeratotic Squamous Papilloma..........................................24-25 Sinonasal Papilloma (Schneiderian Papilloma)........................................24-25 Hemangiopericytoma-Like Tumor of the Nasal Cavity. ..........................24-26 Juvenile Nasopharyngeal Angiobroma...................................24-27 Malignant Neoplasms. ....................................24-27 Squamous Cell Carcinoma..................24-27 Malignant Lymphoma. .........................24-28 Adenoid Cystic Carcinoma..................24-28 Olfactory Neuroblastoma (Esthesioneuroblastoma). ................24-29 Sinonasal Undifferentiated Carcinoma (SNUC).........................24-29 Malignant Melanoma (Sinonasal Melanoma). ....................24-30 Small Cell (Neuroendocrine) Carcinoma (SCNC).........................24-30 Adenocarcinoma...................................24-31 Rhabdomyosarcoma.............................24-31 Nasopharyngeal Carcinoma (NPC)....24-32 Miscellaneous Lesions....................................24-32 Respiratory Epithelial Adenomatoid Hamartoma......................................24-32 Necrotizing Sialometaplasia................24-32 Cholesterol Granuloma. .......................24-32 Chondromesenchymal Hamartoma......................................24-32 Extranodal Sinus Histiocytosis (Sinus Histiocytosis with Massive Lymphadenopathy, RosaiDorfman Disease).............................................24-32 Fibromatosis.........................................24-33 Hemangioma of Nasofacial Bones. ......24-33 Meningioma..........................................24-33 Mesenchymal Chondrosarcoma..........24-33 Osteoma.................................................24-33 Metastatic Tumors. ...............................24-33 Pituitary Adenoma...............................24-33
1082
Head and Neck
24-3
Salivary Gland Tumors........................24-33 Sarcoma.................................................24-33 Solitary Fibrous Tumor.......................24-33 Teratoid Carcinosarcoma (Teratocarcinosarcoma)..................24-33
V. Larynx and Trachea..........................24-34

Infection..........................................................24-34 Disseminated Fungal Infection. ...........24-34 Inammatory/Nonneoplastic Lesions...........24-34 Laryngocele...........................................24-34 Oncocytic Cyst......................................24-34 Vocal Cord Polyp (Laryngeal Polyp)............................24-34 Contact Ulcer........................................24-35 Benign Neoplasms..........................................24-35 Laryngeal Papillomatosis (Squamous Papillomas)...................24-35 Premalignant/Malignant Neoplasms............24-35 Squamous Cell Hyperplasia (Hyperkeratosis)..............................24-35 Squamous Dysplasia/Carcinoma In Situ...............................................24-36 Squamous Cell Carcinoma..................24-36
Verrucous Carcinoma..........................24-36 Basaloid Squamous Cell Carcinoma........................................24-36 Sarcomatoid Carcinoma (Spindle Cell Carcinoma). ...............24-36 Papillary Squamous Cell Carcinoma................................24-37 Lymphoepithelioma-Like Carcinoma........................................24-37 Small Cell (Neuroendocrine) Carcinoma (SCNC).........................24-37 Large Cell Neuroendocrine Carcinoma (LCNC).........................24-37 Adenoid Cystic Carcinoma..................24-38 Chondrosarcoma..................................24-38 Mesenchymal/Soft Tissue Tumors......24-38
VI. TNM Classications for the Lip and Oral Cavity (2010 Revision)......24-38 VII. TNM Classications for the Larynx (2010 Revision)....................24-39 VIII. Suggested Readings. .........................24-40
1083
24-4
ORAL CAVITY Infection Candidiasis Clinical

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 underlying disease (immunosuppression, diabetes), immunosuppressive therapy, or local factors (ill-tting dentures). It may appear as a curd-like pseudomembrane (pseudomembranous candidiasis), tissue hyperplasia (hyperplastic candidiasis), or erythema (atrophic candidiasis)
Oral Hairy Leukoplakia Clinical

This condition represents a peculiar manifestation of EpsteinBarr virus (EBV) infection, mostly in immunosuppressed 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 cancer patients. On rare occasions, this infection can be seen in immunocompetent hosts
Microscopic
Upon 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
Microscopic
In most instances, perpendicularly oriented (relative to mucosa) pseudohyphae and spores are located in the supercial parakeratin accompanied by neutrophilic exocytosis. Visualization of the organisms and spores may be aided by GMS and PAS stains
Herpes Simplex Virus Clinical

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)
Microscopic
The histopathologic features include vesicles with acantholytic cells (Tzanck cells). Commonly, the lesions are biopsied once they have ulcerated. If so, cells on margin of the ulceration often demonstrate viral cytopathic effect (multinucleate cells with ground glass chromatin, angular nuclear outlines, and intranuclear eosinophilic inclusions) (Fig.24.1)
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 immunosuppressed patients (A). Cellular changes characterized by edematous cytoplasm and nuclei that demonstrate chromatin margination are secondary to Epstein-Barr virus (B).
1084
Head and Neck
24-5
Differential Diagnosis
Morsicatio linguarum (tongue chewing) This condition demonstrates thickened parakeratin with a ragged surface and adherent bacterial colonies but lacks candidal infection and EBV
Human Papillomavirus Clinical

Human papillomavirus infection will produce papillary lesions of the oral cavity papillomas, condylomas, and verrucae. 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
Microscopic
The squamous papilloma demonstrates a papillary epithelial proliferation arising from stalk or pedunculated base. Verrucae demonstrate coarse keratohyaline granules, hyperkeratosis, and axial inclination of rete ridges. Condylomas demonstrate koilocytes and broader papillations and branching. The presence of condylomas in children may suggest child abuse. Although not thought to be a signicant risk factor for carcinomas of the oral cavity proper, HPV types 16 and 18 are highly associated with squamous cell carcinomas of tonsil/oropharynx Fig.24.3. Oral manifestations of histoplasmosis reect disseminated disease. Inset: GMS stain highlights yeast.
Disseminated Fungal Infection Clinical

A variety of disseminated fungal infections may have oral manifestations, including histoplasmosis, blastomycosis, cryptococcosis, and coccidioidomycosis. Most, but not all, patients demonstrate a denable immunodecient 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
Microscopic
Typically granulomatous inammation is seen, including histiocytes, giant cells, and necrosis (Fig.24.3). The presence of a neutophilic inltration with giant cells is characteristic of blastomycosis. Blastomycosis is notorious for associated pseudoepitheliomatous hyperplasia, simulating squamous cell carcinoma. Discrete granulomas may be absent in histoplasmosis (i.e., organism-laden, foamy histiocytes with necrosis and nonspecic inammation). Fungal stains (GMS and PAS) may aid identication of microorganisms Fig.24.4. Band-like inammatory inltrates and spike-shaped rete ridges characterize lichen planus.
Microscopic
A band-like inltrate 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
Immune-Mediated Disease Lichen Planus Clinical

This mucocutaneous disease is characterized by bilateral, symmetrical white striations (striae of Wickham) superimposed 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 erythematous lesion with faint peripheral striations
Immunouorescence
Should direct immunourescent testing be undertaken, granular deposition of brinogen is observed at the basement membrane level
Lichenoid 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
1085
24-6
Epithelial dysplasia with lichenoid inammation Epithelial alterations consistent with irreversible, precancerous change, probably accounts for most cases of malignant transformation of lichen planus
commonly aficted individuals. This can manifest primarily as gingival desquamation without cutaneous lesions
Microscopic
Suprabasilar separation of the epithelium is seen, possibly with evidence of Tzanck cells. The inammatory inltrate is composed mostly of lymphocytes
Benign Mucous Membrane (Cicatricial) Pemphigoid Clinical

This immunologically mediated disease demonstrates generalized 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 nger. Ocular and genital mucosal involvement may also be seen
Immunouorescence
Intraepithelial (desmosomal) deposition of C3 and IgG in a spider web pattern is characteristic of pemphigus when viewed with immunouorescence (Fig.24.6)
Lichen 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 lymphoma and leukemia
Microscopic
Subbasilar separation of the epithelium is characteristic of this condition (Fig. 24.5). A diffuse chronic inammatory inltrate of lymphocytes is seen with a smattering of neutrophils
Immunouorescence
Linear deposition of C3 and IgG along the basement membrane zone is seen in almost all cases in which direct immunouorescence is performed
Inammatory/Nonneoplastic Lesions Peripheral Ossifying Fibroma Clinical

This represents a reactive mesenchymal proliferation of periodontal ligament origin that retains the capacity to form bone or cementum-like product. Most commonly seen in the second to third decade, the peripheral ossifying broma demonstrates a female predilection. Occurring exclusively on the gingiva, it presents as a broad-based nodule that is typically ulcerated and asymptomatic
Lichen planus Can demonstrate separation but basal layer is lost. The lymphocytic inltrate is typically more band like Pemphigus vulgaris Separation occurs above the basal layer, and Tzanck cells may be present
Pemphigus Vulgaris Clinical

Widespread sloughing and ulceration of mucosa is the typical manifestation. Young adult males and females are the
Fig.24.5. Subbasilar separation of the epithelium with chronic inammation.
Fig.24.6. Direct immunouorescence revealing IgG positivity in the desmosomal areas.
1086
Head and Neck
24-7
Fig.24.7. Peripheral ossifying broma is a gingival-based nodule exhibiting matrix (i.e., bone or cementum) production.
Fig.24.8. The connective tissue papillae are lled with lipid-laden macrophages in verruciform xanthoma.
Microscopic
The microscopic features include a cellular mesenchymal tissue with intermixed calcications 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 Clinical

Considered a reactive proliferation of vascular mesenchymal 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 supercially, resulting in an alveolar radiolucency
Microscopic
The peripheral giant cell granuloma consists of an exuberant mass of spindle-shaped cells with numerous extravasated erythrocytes, hemosiderin pigment (especially at the periphery), and multinucleated giant cells. Because of its location, it can recur with frequency
Fig.24.9. The ulcer bed in traumatic ulcerative granuloma with stromal eosinophilia can be extremely cellular and mistaken for a neoplastic process.
Verruciform Xanthoma Clinical

This interesting entity represents a peculiar reactive proliferation of lipid-laden macrophages with a papillary surface conguration. 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
Traumatic Ulcerative Granuloma with Stromal Eosinophilia Clinical

This 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
Microscopic
The histologic appearance is that of papillary proliferations of epithelium with brightly eosinophilic keratin beneath, which the connective tissue papillae are lled with lipidladen macrophages (Fig.24.8). These cells will be conned to papillary lamina propria
Microscopic
Surface ulceration is seen overlying a proliferation of inamed granulation tissue with prominent, reactive endothelial cells (Fig. 24.9). Eosinophils and macrophages are prominent in the deeper aspects approximating and involving muscle
1087
24-8
Squamous cell carcinoma, but only from a clinical perspective Lymphoma Atypical lymphoid cells, clonal Aside from NK/T-cell lymphomas, which may be polymorphous, most lymphomas are monomorphic inltrates, contrasted to mixed inltrate of traumatic ulcerative granuloma. Lymphoma will generally lack prominent eosinophils
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
Microscopic
Necrotizing 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
Mucous Extravasation Phenomena (Mucocele/Ranula) Clinical

This is a reactive lesion representing spillage of mucin into tissue due to duct damage. Typically young patients, rst to second decade, represent the common population. Mucoceles occur most commonly in the lower lip, ranulae in the oor of mouth. The clinical appearance is that of a dome-shaped, uid-lled lesion that may wax and wane with rupture. A plunging ranula presents as neck mass and may simulate thyroglossal duct cyst
Squamous cell carcinoma Inltrative growth, cytologic atypia, nonlobular growth pattern, surface epithelial features Mucoepidermoid carcinoma Inltrative growth, prominent appearance to goblet cells, no necrosis of acinar units
Microscopic
Pseudocystic accumulations of mucin surrounded by macrophages, a wall of compressed granulation tissue and inammation represent the salient diagnostic features (Fig.24.10)
Benign Neoplasms Granular Cell Tumor Clinical

This is a benign, nonneoplastic proliferation of probable perineural sheath cells. Seventy percent occur on the tongue, primarily dorsum, as a deep mass with maintenance of surface architecture. These often represent longstanding processes
Necrotizing Sialometaplasia Clinical

An ulcerative lesion involving salivary gland, necrotizing sialometaplasia can mimic malignancy. Although its etiology is unclear, it is possibly due to underlying ischemic event. Younger adults are most commonly affected, with the
Microscopic
Ill-dened 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
Immunohistochemistry
S-100 protein+
Squamous cell carcinoma 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) Clinical

The 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 5cm), on the maxillary alveolar ridge most commonly. As the name implies, it is typically present at birth
Fig.24.10. Disruption of salivary gland ducts results in mucin extravasation into connective tissue.
1088
Head and Neck
24-9
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. 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, oor of mouth, and soft palate complex represent high risk sites for these squamous cell carcinoma precursors
Fig. 24.11. Granular cell tumors are notorious for inducing pseudoepitheliomatous hyperplasia of the overlying epithelium.
Microscopic
This appears as a mass of cells with granular cytoplasm, often demonstrating distinct cell boundaries. The overlying epithelium is typically atrophic
Microscopic
The histologic features include nuclear enlargement, hyperchromatism, pleomorphism, loss of polarity, and architectural changes (i.e., formation of bulbous rete ridges) (Fig.24.12) WHO Classication 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
S-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
Proliferative Verrucous Leukoplakia Clinical

Proliferative verrucous leukoplakia represents a relatively recently described progressive condition involving multiple sites in the oral cavity. It occurs in the fth 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
Squamous Dysplasia/Carcinoma In Situ Clinical

As with other sites, the oral epithelium tends to demonstrate precursor lesions prior to frank invasion. Most classications grade squamous dysplasia to carcinoma in situ dependent
1089
24-10
Microscopic
Within 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 Clinical

This represents the most common malignancy in the oral cavity. Ventrolateral tongue, oor 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 factors. Although often suspected, HPV has yet to be shown to play a major role in oral cavity proper carcinomas. Once predominantly a male disease, females are increasing in incidence to 50% of cases. It manifests as white patch, red patch, ulcer, or exophytic mass
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
See Table24.1
Verrucous Carcinoma Clinical

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, alveolar mucosa, buccal mucosa and is often of long-standing duration. As it is usually nonmetastazing, neck dissection is not indicated
Microscopic
Characteristically, invasive and proliferative squamous epithelium is seen demonstrating the cytologic and morphologic alterations seen in epithelial dysplasia, with the addition of
Table24.1. Differential Diagnosis of the Poorly/Undifferentiated Sinonasal Neoplasm

Squamous cell carcinoma
Lymphoma NK/T lymphoma: midline B-cell lymphoma: paranasal sinuses Sinonasal undifferentiated carcinoma (SNUC) Lymphoid markers+ (CD45RO, CD56, CD3, CD20) Cytokeratin Cytokeratin +, neuroendocrine markers prominent nucleoli Scant cytoplasm Prominent mitotic gures S-100 protein+, cytokeratinMelanoma markers+ (HMB 45, MelanA) Synaptophysin+, chromogranin+S-100 protein+sustentacular cells Cytokeratin Undifferentiated basaloid cells Squamous differentiation, mosaic pattern of keratinization Cytokeratin+ Lymphoma and melanoma markers Histologically indistinguishable from nasopharyngeal carcinoma Evidence of glandular differentiation as tubular and/or cribriform structures Myoepithelial differentiation (S-100, actin+) Synaptophysin+ Cytokeratin +/ No (rare) mitotic gures MyoD1+, myogenin+, desmin+, muscle-specic actin+ CD99 Children
Squamous differentiation: keratin, intercellular bridges and/or dyskeratotic cells
Malignant melanoma Olfactory neuroblastoma Basaloid squamous cell carcinoma Lymphoepithelioma-like carcinoma
Adenoid cystic carcinoma, solid pattern or so-called dedifferentiated Pituitary adenoma
Rhabdomyosarcoma
1090
Head and Neck
24-11
Fig.24.13. Verrucous carcinoma is a broad-based, hyperkeratotic tumor that inltrates in a pushing fashion.
Fig. 24.14. Spindle cell carcinoma, surrounding a focus of malignant basaloid cells, simulates sarcoma.
Microscopic
Verrucous 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
Papillary Squamous Cell Carcinoma Clinical

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 tonsiloropharynx and hypopharynx. The prognosis is generally more favorable and probably relates to depth of stromal invasion more than size of exophytic component
Papillomas Typically smaller, well-conned lesions with a pedunculated base
Microscopic
A branching papillary architecture is seen with little tendency to keratinize (Fig.24.15). Brisk mitotic activity and notable cytologic atypia are commonly present
Sarcomatoid (Spindle Cell) Carcinoma Clinical

This 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
Squamous papilloma Lacks the cytologic atypia and architectural complexity of papillary squamous cell carcinomas
Malignant Melanoma Clinical

This 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 widespread discoloration. In addition, it also can occur as an exophytic pigmented mass
Microscopic
The microscopic appearance is that of an exuberant proliferation of anaplastic spindle-shaped cells that appear to drop off from atypical surface epithelium (Fig.24.14)
Cytokeratin 5/6+, vimentin+, p63+
Microscopic
The 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 epithelium. Mucosal melanosis has a poor prognosis due to its aggressive nature and delay in diagnosis
Spindle cell sarcomas Cytokeratin Most supercial spindle cell malignancies in the oral cavity are carcinomas
1091
24-12
Fig.24.16. Subcorneal abscess formation is prominent in geographic tongue. Fig.24.15. Papillary squamous cell carcinoma has a predilection for the oropharynx, including the tonsil, and is associated with human papillomavirus.
Lingual Thyroid
This represents residual thyroid remaining on posterior dorsum or within the substance of the tongue, left from the embryologic descent of the thyroid enlarge
Miscellaneous Lesions Adenomatoid 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
Lymphoepithelial Cyst
This developmental anomaly is lined by squamous epithelium and surrounded by lymphoid follicles and is commonly seen in oor of the mouth, posterior/lateral tongue, and tonsillar region
Amalgam Tattoo
The amalgam tattoo is a localized discolored area demonstrating granular, black foreign material aligned along collagen bers and staining basement membrane. It is typically seen in area of dental restorations
Melanoacanthoma
A 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
Aphthous Stomatitis
These are ulcerations seen primarily in the lining mucosa in a variety of patterns. Minor aphthae are less than 1cm ulcers with a brinous membrane and halo of erythema. Herpetiform aphthae consist of multiple punctate erythematous ulcerations. Major aphthae are large, greater than 2cm, ulcerations with signicant pain. No distinctive histopathology is seen with these lesions, rather they are clinical diagnoses
Nicotine Stomatitis
Characterized 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 inammation
Oral Focal Mucinosis

This represents a localized mass seen at any site in the mucosa characterized by the presence of abundant ground substance and attening of the rete ridges of the epithelium
Dermoid Cyst
This developmental anomaly is seen in the midline oor of the mouth and exhibits a keratinized lining with adnexal structures. True teratomas are rarely seen
Palisaded, Encapsulated (Solitary, Circumscribed) Neuroma

A discrete nodule usually less than 1cm 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)
Geographic Tongue (Erythema Migrans)

An inammatory condition of the tongue primarily characterized by supercial microabscesses, this may represent a form of psoriasis (Fig.24.16)
1092
Head and Neck
24-13
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.
Smokeless Tobacco-Induced Keratosis

This represents a somewhat unique lesion occurring as a corrugated white patch seen in the location of placement of tobacco that demonstrates supercial epithelial necrosis and an amorphous hyalinized material histologically (Fig.24.18)
Salivary Duct Cyst

The salivary duct cyst is a focal, small cystic lesion lined by salivary ductal epithelium seen most commonly in upper lip, buccal mucosa, and palate
JAWS Nonodontogenic Cysts/Pseudocysts Nasopalatine Cyst Clinical

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
Radiograph
This represents a demarcated lucency with scalloping between tooth roots
Microscopic
The microscopic features demonstrate a thin brous connective tissue wall with or without inammation
Radiograph
The radiographic features are that of a pear or heart-shaped well-demarcated radiolucency between the roots of the maxillary central incisors
Odontogenic Cysts Dentigerous Cyst Clinical

This represents a developmental odontogenic cyst occurring around the crown of impacted tooth. It occurs most commonly in mandibular third molar region. The lining of this cyst can give rise to ameloblastoma, squamous cell carcinoma, or intraosseous mucoepidermoid carcinoma
Microscopic
The lining consists of simple cuboidal, respiratory, or stratied squamous epithelium with prominent neurovascular bundles in the wall
Traumatic Bone Cavity Clinical

The traumatic bone cavity is exactly that, a cavity in bone possibly due to trauma with subsequent lysis of clot. It is most commonly seen in the posterior mandibular body with possible expansion and is often lled with serosanguineous uid. Young adults are the typical population with a male predilection
Radiograph
The radiographic presentation is that of a unilocular radiolucency around the crown of an impacted tooth
Microscopic
Histologically, a bilayer of cuboidal cells or stratied squamous lining with myxomatous connective tissue containing small islands of odontogenic epithelium is seen (Fig.24.19)
1093
24-14
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. This cyst demonstrates a luminal layer orthokeratin, an indistinct basal layer and no association with the nevoid basal cell carcinoma syndrome
Odontogenic Keratocyst (Keratocystic Odontogenic Tumor) Clinical

This entity represents a peculiar keratinized odontogenic cyst arising from prefunctional dental lamina. The WHO currently classies 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 difcult. This may be the feature that contributes to a 30% recurrence rate It is associated with the nevoid basal cell carcinoma syndrome (GorlinGoltz syndrome) that possesses the following characteristics Autosomal dominant, defect in ptch gene (chromosome 9) Multiple basal cell carcinomas on non- or minimally sunexposed skin Palmar and plantar pits Skeletal anomalies bid ribs, brachymetacarpalism, kyphoscoliosis, calcied falx cerebri Other tumors including medulloblastoma
Apical Periodontal Cyst Clinical

This is an inammatory cyst due to a pulpally infected tooth, seen at the apex of a nonvital tooth
Radiograph
The apical periodontal cyst appears as a unilocular lucency at the apex of tooth
Microscopic
Histologically, proliferative squamous epithelial lining is seen with a wall of inamed granulation tissue
Calcifying Odontogenic Cyst (Gorlin Cyst) Clinical

This developmental odontogenic cyst may demonstrate questionable 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
Radiograph
The 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
Radiograph
The Gorlin cyst appears as a unilocular or multilocular expansile radiolucency with intermixed calcications and may be associated with an odontoma
Microscopic
The odontogenic keratocyst demonstrates squamous epithelium with a luminal layer of corrugated parakeratin (Fig.24.20). A uniform thickness of 68 cell layers is apparent with a prominent basal layer with palisading nuclei
Microscopic
A 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
Keratinizing odontogenic cyst
1094
Head and Neck
24-15
require removal, only identication. However, patients are at risk for osteomyelitis as the lesions calcify and become avascular
Radiograph
These lesions appear as relatively well-demarcated, mixed radiolucent/radiopaque lesions
Microscopic
Cementoosseous dysplasia appears as curetted fragments with high cellularity of spindle-shaped mesenchymal cells. These cells are mixed with calcied product, often small sphericals of cementum and/or bone
Central cementoossifying broma Field for eld this is a histologically identical lesion although it represents a benign neoplasm. It can be distinguished by radiographic (well-demarcated, expansile lucency) and surgical ndings (avascular, delineated solid mass)
Odontoma Clinical
The odontoma is a hamartomatous process of the odontogenic apparatus that is seen primarily in the rst two decades of life. It presents as two types: compound, which forms toothlike structures most commonly in the anterior maxilla, and complex, which forms a mass of calcied product in the posterior jaws Fig. 24.21. Ghost cells, prematurely keratinizing epithelial cells without nuclei, are the hallmark of the calcifying odontogenic cyst.
Radiograph
The compound odontoma demonstrates multiple tooth-like structures with radiolucent rim. The complex odontoma exhibits a central mass of opaque material surrounded by radiolucent rim
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
Microscopic
Odontomas contain a mixture of enamel, enamel matrix, dentin, pulp, and follicular tissue, either in appropriate context or haphazardly arranged
Reactive/Nonneoplastic Disease Cementoosseous Dysplasia Clinical

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 fth 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 orid which are multiple lesions seen in at least two quadrants. It does not
Giant Cell and Giant Cell-Rich Lesions Central Giant Cell Granuloma Clinical
This represents a central lesion seen most commonly in females in the early second decade. It demonstrates a propensity to occur in the anterior mandible crossing the midline. 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, exophytic mass
Radiograph
Typically, this occurs as a multilocular radiolucency although it can be unilocular. Expansion, tooth movement, and resorption are all possible sequelae
1095
24-16
Microscopic
Large pools of extravasated erythrocytes surrounded by cellular mesenchymal tissue with giant cells bordering the cavities are the salient histologic features. The cavities are not lined by endothelial cells
Cherubism Clinical
Cherubism represents an inherited disorder, transferred as an autosomal dominant condition due to a defect on chromosome 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 intervention if grossly deforming
Fig. 24.22. Osteitis brosa cystica (brown tumor) results from hyperparathyroidism and is histologically indistinguishable from giant cell reparative granuloma. Inset: Reactive osteoid may be prominent.
Radiograph
Bilateral, expansile multilocular radiolucencies in the posterior mandible and maxilla are the hallmarks of this disease
Microscopic Microscopic
Microscopically, the giant cell granuloma is characterized by a cellular spindle-cell framework with clusters of multinucleated giant cells (osteoclasts), extravasated erythrocytes, and hemosiderin Cellular, myxomatous mesenchymal tissue with intermixed giant cells comprises the majority of the lesion, whereas perivascular cufng of hyaline material represents a useful clue to the diagnosis
Giant cell lesions of the jaws constitute an area of confusion Much has been written as to whether giant cell granulomas, giant cell tumors, and aneurysmal bone cysts represent the same lesion, entities on a continuum or separate and distinct conditions The brown tumor of hyperparathyroidism is indistinguishable from the central giant cell granuloma and, accordingly, this systemic disease must be excluded (Fig.24.22)
Benign Neoplasms Ameloblastoma Clinical

This is the most common epithelial odontogenic neoplasm, recapitulating the enamel organ. Ameloblastoma occurs most commonly in the third to fth 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 1520% recurrence rate with resection. Rare examples of metastasis have been reported (malignant ameloblastoma). Peripheral variant represents an ameloblastoma occurring in an extraosseous location (Fig.24.23)
Giant Cell Tumor

This is a true neoplasm that rarely occurs in the oral cavity and is discussed in detail in Chapter 21
Radiograph
Either an expansile unilocular or multilocular (soap bubble) radiolucency is the classic radiographic presentation. Perforation of the cortical plate is often seen
Aneurysmal Bone Cyst Clinical

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 aficted by this rapidly expansile lesion. Often substantial recurrence is due to incomplete removal. This may occur in concert with other pathologic entities including broosseous lesions and osseous neoplasms. Its etiology is unknown although trauma is suspected
Microscopic
Two 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
Radiograph
A symmetrically expansile, unilocular radiolucency with a thin rim of residual bone is the typical manifestation although it can be multilocular
1096
Head and Neck
24-17
Microscopic
Microscopically, 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 posterior mandible in the fourth to sixth decades. It demonstrates a 15% recurrence rate after removal Fig.24.23. Peripheral ameloblastoma resembles its intraosseous counterpart. Note overlying mucosa.
Radiograph
The Pindborg tumor appears as a well-demarcated multilocular radiolucency with calcications (driven snow appearance)
Microscopic
The 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 calcications (Liesegang rings) and amyloid are also present
Squamous cell carcinoma Mitoses, invasive growth, and an ill-dened radiographic appearance differentiate the two entities
Squamous Odontogenic Tumor Clinical

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
Fig.24.24. Ameloblastoma may show prominent cystic change. Peripheral cells exhibit nuclear palisading with reverse polarization; the latter is not conspicuous in this example.
Radiograph
The characteristic appearance is that of a semilunar radiolucency arising in alveolar bone
Microscopic Adenomatoid Odontogenic Tumor Clinical

This 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 Islands of squamous epithelial cells without a prominent basal layer are the histologic signature. Although worrisome, no atypia, mitotic gures, or central keratinization is seen (Fig. 24.25). The islands may demonstrate central cystic degeneration
Squamous cell carcinoma 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
Radiograph
The radiographic presentation is that of a pericoronal lucency with or without calcication
1097
24-18
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 myxomatous mesenchymal framework characterize ameloblastic broma.
Ameloblastic Fibroma Clinical

This represents a mixed odontogenic tumor with coexistent epithelial and mesenchymal components. It occurs in the rst and second decades, with the majority in the posterior mandible impeding the eruption of the permanent rst molar. Even with appropriate surgery, a 1020% recurrence rate is seen
Central Cementoossifying Fibroma Clinical

The central cementoossifying broma is a benign productforming 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 surgically removed
Radiograph
Radiographically, a unilocular or multilocular radiolucency associated with an impacted tooth is the typical presentation
Radiograph
Typically, this is a well-demarcated unilocular radiolucency with characteristic bowing of the inferior border of the mandible. Although product-forming histologically, it usually demonstrates only small ecks of calcication at the radiographic level
Microscopic
A bilayer of odontogenic epithelium embedded within cellular myxomatous mesenchymal tissue constitutes the diagnostic features (Fig.24.26)
Cementoblastoma Clinical
This represents the benign odontogenic counterpart to the osteoblastoma. Most common in the rst two decades, it occurs in the mandibular rst molar area and is characterized by pain and swelling. It can recur if incompletely removed
Microscopic
This 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
Radiograph
An opaque symmetrical mass merging imperceptibly with the root of the tooth and possessing a radiolucent peripheral rim are the reproducible radiographic features
Odontogenic Fibroma Clinical

This benign neoplasm is comprised primarily of odontogenic mesenchymal tissue with variable epithelium and calcication. 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 aficted. On rare occasions, it may be associated with a peculiar cleft defect in the maxilla. Only rare recurrences have been reported
Microscopic
Peripheral radiation of cemental product punctuated by prominent cementoblasts, cementoclasts, and vascularity are the salient characteristics. Because of these features, it is thought to represent the odontogenic analog of osteoblastoma
1098
Head and Neck
24-19
Radiograph
The radiographic appearance is that of a unilocular or multilocular radiolucency, often with expansion
mandibular predilection. Its overall behavior is dependent on grade and stage. However, most of them represent local disease and are amenable to surgery
Microscopic
The 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 calcied product
Radiograph
This may occur as a poorly dened lytic lesion or arise from a preexisting, long-standing odontogenic cyst
Microscopic
This entity demonstrates the typical features of squamous cell carcinoma; accordingly, one must rule out metastasis or an antral primary if occurring in the maxilla
Malignant Neoplasms Ameloblastic Carcinoma Clinical

This is an odontogenic epithelial malignancy with ameloblastic differentiation. It occurs most commonly in the fourth decade with a mandibular predilection. It metastasizes preferentially to the lungs and demonstrates a <50% 5-year survival rate
Clear Cell Odontogenic Carcinoma Clinical

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 mandible. Although metastasis is known to occur, it is not common. However, multiple recurrences with locally aggressive behavior is the typical pattern
Radiograph
It manifests as an ill-dened, lytic lesion with a variable growth rate
Radiograph
The clear cell odontogenic carcinoma manifests as an ill-dened lucency with bone destruction
Microscopic
The microscopic appearance is that of an epithelial proliferation with peripheral cells demonstrating columnar morphology with reverse polarization (Fig. 24.27). Prominent pleomorphism and mitotic activity are usually seen
Microscopic
Strands 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

This is a central odontogenic carcinoma demonstrating squamous differentiation. Seen in adults, it demonstrates a
Metastatic renal cell carcinoma Prominent vascular stroma without the stromal cellularity should help delineate the two
Osteosarcoma Clinical
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
Radiograph
Fig.24.27. Cellular pleomorphism, as seen here, distinguishes ameloblastic carcinoma from ameloblastoma. Osteosarcomas tend to be ill-dened mixed radiolucent/ opaque lesions, perhaps with a radiating calcied product (sunburst effect). Localized widening of the periodontal ligament space may be an early manifestation
1099
24-20
Microscopic
As 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
Chondrosarcoma Clinical
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
Radiograph
Chondrosarcomas demonstrate many of the same radiographic features of osteosarcoma although the product tends to be less linear and more rounded Fig.24.28. Larger pigmented cells surround small blue cells in the melanotic neuroectodermal tumor of infancy.
Microscopic
Generally, mature type cartilage is seen with minimally atypical chondrocytes and chondroblasts. Because of this, chondrosarcomas of the jaws are often underdiagnosed as benign conditions
Melanotic Neuroectodermal Tumor of Infancy Clinical

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

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
Radiograph
The melanotic neuroectodermal tumor of infancy presents as a demarcated radiolucency of the anterior maxilla with a primary tooth oating in space
Microscopic
Undifferentiated stromal cells with islands of mature cartilage are the histologic hallmarks. The stromal component may resemble small blue cell tumors and/or hemangiopericytoma (staghorn vascular pattern). Mitotic gures may be scarce to frequent and the cartilaginous foci vary from prominent to scarce
Microscopic
This 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
Distinction from Ewing sarcoma, hemangiopericytoma, and others relies upon recognition of cartilaginous foci
Metastatic Disease Clinical

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
Miscellaneous Lesions Stafne 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
Radiographic
Presenting most commonly as lytic, ill-dened lesions, exceptions include prostatic and breast metastases that can be dramatically osteoblastic
Tori
These represent bony outcroppings seen in the midline of the hard palate and bilaterally on the medial mandible they represent variations of anatomic normal
1100
Head and Neck
24-21
Gingival Cyst/Lateral Periodontal Cyst

These 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 odontogenic cyst demonstrates a luminal layer of cuboidal cells and duct-like structures with behavior much like ameloblastoma with a high recurrence rate and significant expansion
Central Mucoepidermoid Carcinoma

This 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 Fig. 24.29. Central mucoepidermoid carcinoma arises within the mandible and resembles a salivary gland primary.
ORO/HYPOPHARYNX Malignant Neoplasms Squamous Cell Carcinoma Clinical

This is most commonly seen in the base of tongue and tonsil and is typically large (T3T4) by time of diagnosis. Dysphagia, exophytic mass, and otalgia are presenting complaints. Stage III and IV diseases have 5-year survival rates below 30% large with prominent nucleoli. Cytokeratins generally will illuminate the epithelium
Basaloid Squamous Carcinoma Clinical

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
Microscopic
Typically, 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 Carcinoma Clinical

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
Microscopic
A biphasic tumor (mosaic pattern of cells), basaloid squamous carcinoma exhibits lobules and cords of cells with hyperchromatic nuclei and scanty cytoplasm, often surrounded by prominent hyalinization (Fig.24.30). Peripheral palisading and central necrosis are common, and it often merges with typical squamous cell carcinoma. Surface epithelial alterations may be evident
Differential Diagnosis (See Table24.1)

Adenoid cystic carcinoma Lacks squamous differentiation and surface epithelial involvement
Microscopic
Sheets of undifferentiated epithelial cells are seen embedded within lymphoid stroma. The nuclei tend to be vesicular and
1101
24-22

This represents an exophytic HPV-associated variant of squamous cell carcinoma. It preferentially involves the tonsil/oropharynx, larynx, and sinonasal tract. The prognosis likely relates to extent of invasion
Microscopic
Papillary condylomatous-like architecture is seen with cytologic atypia that exceeds what is seen in papillomas/ condylomas (Fig.24.15). Keratinization is generally scant
Squamous papillomas with or without dysplasia Exhibit less cytologic atypia and koilocytes are readily present
Fig.24.30. Basaloid squamous carcinoma is an aggressive malignancy with a predilection for the base of tongue and larynx.
NASAL CAVITY, PARANASAL SINUSES, AND NASOPHARYNX Infection Rhinosinusitis Clinical

Classied 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 dened as the presence of nasal cavity and paranasal sinus inammation for greater than 12 weeks. The pathophysiology comprises a spectrum of inammatory and infectious diseases. Limited coronal computed tomography is the most denitive technique for the diagnosis Allergy, fungus, and bacteria are potential causes, with the latter giving rise to purulent sinusitis. Haemophilus inuenzae, Streptococcus pneumoniae, and Moraxella catarrhalis are more common offending agents. Ongoing inammation, decreased in ostial size, retention of secretions, and decrease in mucociliary action contribute to the pathogenesis
Microscopic
Edema, hyperplastic seromucinous glands, thickened basement membrane, and inammatory cells (neutrophils, lymphocytes, plasma cells, and eosinophils) are typical ndings. Retention cysts (Fig. 24.31) are common, and obstruction may lead to mucocele (frontal and ethmoid sinuses most commonly affected) formation
Fig.24.31. Retention cysts are a common nding in the mucosa of individuals with chronic sinusitis. 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 nonspecic chronic sinusitis The presence of necrosis, granulomatous inammation, 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
The inltrates of sinusitis are distinguished from lymphoma by their mature appearance. They are rich with plasma cells and Russell bodies are common. High grade angiotropic
1102
Head and Neck
24-23
Allergic Fungal Sinusitis Clinical

Allergic 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 ubiquitous; dematiaceous fungi are common (i.e., Curvularia and Bipolaris species). Eradication is difcult and recurrence is common
Microscopic
The hallmark is thick eosinophil-rich allergic mucin which contains with fungal hyphae (highlighted via GMS stain). CharcotLeyden crystals are common. There is no tissue invasion by organisms and the mucosal exhibits nonspecic changes of sinusitis with or without polyps
Invasive fungal sinusitis shows angiotropic growth of fungus with thrombosis and necrosis. Fungus is found in viable and/or necrotic tissue and not conned to a mucinous or inammatory exudate. Patients are generally diabetic or immunodecient Sinus mycetoma or fungus ball is a rare, noninvasive colonization of a sinus cavity by fungus. These lesions lack the eosinophilic-rich inltrate of allergic fungal sinusitis
Fig.24.32. Sporangia are numerous in the mucosal lesions of Rhinosporidiosis. Inset: Sporangium containing spores.
(Fig.24.32). The etiology fungus is Rhinosporidium seeberi, which is endemic to India. These lesions can simulate angiomatous nasal polyp
Mycobacterial Infection
Etiologic bacteria include Mycobacterium tuberculosis and rarely atypical mycobacteria; the latter is typically encountered in HIV patients. The histologic ndings include caseating and/or noncaseating granulomas, ulceration, histiocytic inammation, and destruction of septal cartilage
Invasive Fungal Sinusitis Clinical

Rhinocerebral disease due to Zygomycetes (Rhizopus MucorAbsidia) presents with headache, pain, and fever. Patients with diabetic ketoacidosis experience rapidly progressive disease with extension into the CNS. The turbinates appear necrotic Nasoorbital disease due to Aspergillus species is typically seen in immunocompromised patients with AIDS, neutropenia, and/or hematologic malignancies
Leprosy
Involvement of paranasal sinuses is common and of epidemiological signicance in lepromatous-type leprosy. Ulceration is accompanied by perivascular histiocytes, which contain the acid fact bacillus Mycobacterium leprae
Syphilis
Primary, secondary, and tertiary syphilis can all cause intranasal pathology. WarthinStarry staining may fail to reveal the pathogenic spirochetes, Treponema pallidum. Microscopic ndings include plasma cell endarteritis, ulceration, and septal perforation
Microscopic
Angioinvasive growth of fungus (highlighted on GMS stain) with thrombosis, hemorrhage, and infarction is characteristic. Zygomycetes exhibit irregular ribbon-like hyphae (generally 1020mm in width) devoid of septa, whereas Aspergillus has smaller hyphae (36 mm in width) with 45 branching and distinct cross-septa
Other Forms of Infectious Sinusitis Scleroma (Rhinoscleroma)

Microscopically, histiocytic foam cells (Mikulicz cell) contain coccobacilli (Klebsiella rhinoscleromatis). Bacteria are highlighted on WarthinStarry and Giemsa stains. The differential diagnosis includes RosaiDorfman disease, leprosy, and metabolic storage disease
Inammatory/Nonneoplastic Lesions Mucocele Clinical

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
Rhinosporidiosis
Polypoid mucosal lesions containing large sporangia (100 400 mm) resemble coccidioides immitis though bigger
Microscopic
An epithelial lining may or may not be apparent and goblet cells may be hyperplastic. Degenerating debris, mucous, and muciphages are present
1103
24-24
Fig.24.33. Consider the possibility of Wegener granulomatosis, lymphoma, and fungal infection in sinonasal specimens with prominent necrosis.
Fig. 24.34. Extracellular uid and inammation, particularly eosinophils, are features of nasal polyps. should be ruled out via appropriate methodologies (i.e., special stains and culture)
Wegener Granulomatosis Clinical

The sinonasal tract is involved in 6095% 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 diagnosis. Corroborating the histologic ndings with serologic studies is extremely important since most patients (7090%) are c-ANCA positive (c-ANCA negative cases occur)
Infectious and noninfectious causes of granulomatous inammation warrant histologic and clinical consideration. Granulomatous vasculitis should be ruled out
Myospherulosis Clinical
This lesion of iatrogenic origin consists of a foreign body/ granulomatous reaction to petrolatum-based material used for nasal packing
Microscopic
A histologic spectrum may be seen from neutrophilic microabscesses to the signature triad of necrosis, granulomatous inammation, and vasculitis (Fig.24.33). Typically, the triad is incomplete and the histologic specicity for WG decreases as fewer elements of the triad are represented
Microscopic
Large spherules simulating fungi contain altered erythrocytes
If the diagnosis is in doubt, negative GMS staining can aid distinction from fungal infection
Malignant lymphoma and infection commonly warrant consideration in cases of WG. Failure to identify atypical, neoplastic cells and microorganisms aids to exclude these possibilities
Polyps Clinical
Sinonasal 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 deciency, cystic brosis, ciliary dyskinesia, and aspirin hypersensitivity Grossly, they are soft, edematous, and semitranslucent
Sarcoidosis Clinical
Approximately 5% of patients with sarcoidosis have sinonasal involvement. Clinical features are nonspecic and include nasal obstruction and chronic sinusitis. Grossly, lesions manifest as mucosal crusting, studding, plaque-like changes, or polyps in the nose
Microscopic
Large quantities of extracellular uid-edema separate bland stromal cells (Fig.24.34). Eosinophils are prominent in most cases. Seromucinous glands may be hyperplastic or inapparent and retention cysts common. A minority develop extensive vascular proliferation and ectasia with deposition of pseudoamyloid, see angiomatous variant below
Microscopic
Noncaseating granulomas (small foci of central caseous nec rosis can be seen) are present. The presence of microorganisms
1104
Head and Neck
24-25
Variants
A choanal polyp is a clinically dened 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 otherwise typical sinonasal polyp can result in prominent angiomatous 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 analogous to atypical polyps that can occur in the vagina, esophagus, and mouth
Lobular capillary hemangioma has densely packed capillarysized vessels with a lobular or organized conguration, which polyps lack. Sinonasal papillomas are dened by their characteristic proliferative epithelium, again lacking in polyps. Juvenile angiobroma, specic to young males and the nasopharynx, has a stroma that is densely collagenous; polyps are typically edematous and inamed
Benign Neoplasms Lobular 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
Microscopic
A lobular proliferation of small capillaries denes these tumors (Fig. 24.35A,B). The mucosa is commonly ulcerated 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).
A lobular architecture of the vasculature and the less collagenous stroma aid to distinguish hemangioma from juvenile nasopharyngeal angiobroma, although occasional hemangiomas may have a more brotic stroma Angiomatous polyp has vessels, which are congested, often large and ectatic that lack the uniformity and organization of hemangioma
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 signicant risk of recurrence, especially for incompletely resected lesions. Coexistent carcinoma 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 reect invasion of the orbit Tumors arising on the nasal septum tend to be exophytic (i.e., exophytic or fungiform papilloma) in appearance, while
Hyperkeratotic Squamous Papilloma Clinical

These lesions arise from nasal vestibule in contrast to sinonasal papilloma, which arises from the respiratory mucosa or Schneiderian membrane. They are analogous to their counterpart occurring elsewhere on the skin
Microscopic
This papillary squamous proliferation typically exhibits hyperkeratosis and lacks signicant cytologic atypia. Coexistent dysplasia is rare
1105
24-26
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
Microscopic
These 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 seromucinous glands of the sinus mucosa Mucous cells, microcytic change, and inltration of the proliferative epithelium by neutrophils is common and characteristic (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 carcinoma must be ruled out
Polyps with squamous metaplasia can simulate inverted papilloma. Metaplastic changes are surface based, limited, and accompanied by injury and repair, including ulceration and inammation Inverted papilloma must be distinguished from carcinoma. Papilloma lacks the atypia of carcinoma and the inverted growth is smooth bordered and basement membrane conned. 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 Cavity Clinical

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
Fig. 24.36. Inverted papilloma derives its name from its inverted pattern of growth; however, both inverted and exophytic growth patterns are often present in a given lesion (A). Intraepithelial cysts with clusters of neutrophils are common in inverted papilloma (B).
Only vimentin is consistently positive. CD34 is negative which aids distinction from solitary brous tumor
Microscopic
These submucosal tumors are unencapsulated (Fig.24.37A) and composed of plump spindle cells. The latter exhibits fascicular 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
Solitary brous tumor (SFT) has a wiry collagenous background and a tendency for variable cellularity from eld to eld; however, this latter feature is often subtle and not constant. 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 difcult
1106
Head and Neck
24-27
(Fig. 24.37B). Mitotic gures 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
Tumor cells stain positively for vimentin and androgen receptor, the latter in up to 75% of cases. CD34 is negative
Molecular Biology
Beta-catenin mutations have been reported in a signicant percentage of JNAs
Hemangioma is less brous and more cellular with densely packed vascular channels. Angiomatous nasal polyp is typically edematous, less brous and may be hemorrhagic and/or infarcted. The specic clinicopathologic features (i.e., characteristic age, sex, and location) of angiobroma is very useful in their distinction for other entities
Malignant Neoplasms Squamous Cell Carcinoma Clinical

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 smoking, human papilloma virus infection, and exposure to nickel and chromium-rening processes 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 nasopharyngeal angiobroma is present, including thin-walled blood vessels, a densely collagenous stroma and spindled to stellate, mesenchymal cells.
Microscopic
Generally, aside from a few special variants, squamous cell carcinomas exhibit cytologic atypia and invasive growth within desmoplastic stroma. Squamous differentiation is dened by the presence of keratin production, intracellular bridges, and/or dyskeratotic cells. Endophytic, exophytic, and mixed patterns ofgrowth may be encountered. Tumors are graded as well, moderately or poorly differentiated. Several variants occur (see below)
Juvenile Nasopharyngeal Angiofibroma Clinical

Juvenile nasopharyngeal angiobroma (JNA) is a rare, benign tumor that occurs exclusively in males in the second and third decades (mean age 16 years, range 1026 years) of life. They arise in the pterygopalatine fossa and have a signicant recurrence rate with incomplete surgical excision and potential for intracranial extension. Notorious for profuse intraoperative bleeding preoperative embolization is desirable JNA occurs up to 25 times more frequently in patients with familial adenomatous polyposis
Variants
Verrucous carcinoma, as encountered more commonly in the oral cavity, rarely occurs in the nasal cavity and paranasal sinuses. These nonmetastasizing, progressive tumors exhibit a pushing margin of invasion with minimal cytologic 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 diffusely 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
Microscopic
Thin-walled blood vessels, a densely collagenous stroma and spindled to stellate, mesenchymal cells comprise this tumor
1107
24-28
Malignant Lymphoma
The 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 histologic 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 thrombosis 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 Carcinoma Clinical

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
Microscopic
AdCC may exhibit a cribriform, tubular, and/or solid pattern of growth (Fig.24.40A,B). Tumor cells are small and basophilic with scant cytoplasm and inconspicuous nucleoli. Myoepithelial cells are detectable (via light microscopy or immunohistochemistry) peripherally within cribriform nests and tubular proles Ducts proles 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 polymorphous; malignant cells may have clear cytoplasm.
Fig.24.39. Diffuse large cell lymphoma shows sheets of atypical lymphoid cells with conspicuous mitotic gures.
Fig. 24.40. Adenoid cystic carcinoma is the most common malignant gland forming tumor of the nasal cavity and paranasal sinuses. The cribriform pattern of adenoid cystic carcinoma is well recognized (A). Predominant tubular patterns of adenoid cystic carcinoma can be challenging diagnostically (B).
1108
Head and Neck
24-29
cuboidal cells. Perineural invasion/spread is characteristic. Mitotic gures, nucleoli, and necrosis common in the solid and dedifferentiated variants
Tumor cells are positive for cytokeratin and c-kit. Peripheral myoepithelial cells stain for actin, p63, calponin, and S-100

The presence of myoepithelial differentiation aids to distinguish 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 ~15% 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
Microscopic
A histologic spectrum may be encountered: from uniform, small blue cells embedded in brillary matrix to nests of epithelioid polygonal cells having a paraganglioma or carcinoid-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 gures are often inconspicuous and few Prominent vascular proliferation typically accompanies nests of tumor cells. Homer Wright pseudorosettes, when present, reect neuroblastic differentiation. Melanin can occasionally be present. Immunohistochemical corroboration of the diagnosis is very useful
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). Rhabdomyosarcoma shows immunohistochemical evidence of myogenic differentiation. The possibility of sinonasal involvement by pituitary adenoma should not be forgotten
Tumor 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 Findings
These tumors lack the characteristic t(11;22)(q24;q12) translocation of Ewing sarcoma/PNET. Comparative genomic hybridization results have shown complex, manifold gains, and losses; high stage tumors have shown frequent gains at 13q14.2q14.3, 13q31.1, and 20q11.21q11.23, and loss of Xp21.1
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
Microscopic
Nests, 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

Other sinonasal small blue cell tumors must be considered. High grade carcinomas, such as sinonasal undifferentiated and neuroendocrine carcinoma, are cytokeratin positive.
1109
24-30
Fig.24.42. This sinonasal undifferentiated carcinoma was metastatic to the skin of the neck and negative for neuroendocrine markers.
Fig.24.43. Malignant melanoma. Cytokeratin and S-100 immunohistochemistry is crucial in the workup of any undifferentiated sinonasal tumor in which melanoma is a diagnostic consideration.
Cytokeratin is positive while neuroendocrine markers are generally negative Cytokeratin is negative and useful in distinguishing melanoma from carcinoma
Immunohistochemistry is useful is distinguishing from other considerations, such as olfactory neuroblastoma (S-100+ sustentacular cells, synaptophysin+, chromogranin+), neuroendocrine carcinoma (cytokeratin+, synaptophysin+, chromogranin+), rhabdomyosarcoma (desmin+, musclespecic 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
Immunohistochemistry is extremely useful is establishing the diagnosis and excluding other considerations such as carcinoma (cytokeratin+, vimentin), olfactory neuroblastoma (synaptophysin+, chromogranin+/, S-100+ sustentacular cells), and lymphoma (lymphoid cell markers+, S-100 protein)
Malignant Melanoma (Sinonasal Melanoma) Clinical

Primary melanoma of the sinonasal cavity affects older individuals (mean age ~70 years). Patients present with epistaxis, obstruction, and mass. The prognosis is poor with a 5-year survival less than 50%
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
Microscopic
Tumors 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 common, as is nuclear molding and crush artifact. Ultrastructurally, dense core granules are present
Microscopic
Tumor cells can be either epithelioid and/or spindled (Fig.24.43). Small and pleomorphic cell types are less common. Prominent eosinophilic nucleoli are common and neoplastic cells are frequently arranged in a peritheliomatous distribution. Sinonasal melanoma is commonly amelanotic
Immunohistochemistry is extremely useful in establishing the diagnosis. Tumor cells should express cytokeratin (AE1/ AE3 and CAM 5.2) and neuroendocrine markers (i.e., synaptophysin and/or chromogranin). 34betaE12 is generally negative, and if positive only weakly so
These tumors stain similar to their cutaneous counterparts. Positive stains include S-100 protein, HMB 45, Melan A, tyrosinase, microphthalmia transcription factor, and vimentin
1110
Head and Neck
24-31
Other undifferentiated and blue cell tumors should be considered. Olfactory neuroblastoma is cytokeratin negative, neuroendocrine marker positive, S-100 positive in sustentacular 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
Molecular Findings
H-ras mutation has been found in a minority of ITACs and appears to be associated with poor prognosis. K-ras-2 mutation, common in colorectal adenocarcinoma, is absent in ITAC
Rhabdomyosarcoma Clinical
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)
Adenocarcinoma Clinical
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 70500 times the risk for these tumors relative to the general population
Microscopic
These small blue cell tumors are highly cellular and composed of small cells, variably spindled, with scant cytoplasm and hyperchromatic nuclei. Mitotic gures are numerous (Fig. 24.44). Larger cells with opaque eosinophilic cytoplasm with cross- striations may be present. The stroma is commonly myxoid Ultrastructurally, Z-bands and myolaments are demonstrated
Microscopic
The 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 proliferations consist of back-to-back glandular proles with little to no intervening stroma. Mitotic gures are typically few. Necrosis is generally not present and goblet cells are not common Intestinal-type adenocarcinoma can be divided into four subtypes: papillary tubular cylinder cell, alveolar goblet cell, signet-ring cell, and transitional or mixed pattern. Most belong to the rst 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 activity is variable
Immunohistochemistry is fundamental in establishing the diagnosis. Tumor cells are positive for MyoD1, myogenin, desmin, and muscle-specic actin. CD99 is negative
Other small round blue cell tumors of childhood, see the chapter on soft tissue
Molecular Findings
See the chapter on soft tissue
The majority of ITACs are positive for CK7, CD20, and CDX2; a minority is MUC2 positive. Low grade adenocarcinomas are CK7 positive and negative for CD20, CDX2, and MUC2
Low grade adenocarcinoma can be sufciently bland to simulate 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 carcinomas 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)
Fig.24.44. Immunohistochemistry is fundamental in the diagnosis of small blue cell tumors. This rhabdomyosarcoma of the head and neck was metastatic to lymph node.
1111
24-32
Nasopharyngeal Carcinoma (NPC) Clinical

The WHO most recent classication 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 identied 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 rst presentation of disease (i.e., neck mass) in ~50% Undifferentiated and differentiated nonkeratinizing carcinomas 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 association with EBV, arise in older patients, and have a 5-year survival of less than 40%. They are generally larger tumors at presentation
Immunohistochemistry aids distinction from lymphoma (lymphoid marker+ and cytokeratin) and melanoma (S-100+, HMB 45+, and cytokeratin)
Molecular Findings
EBER (EBV-encoded RNA) positivity via in situ hybridization is present in greater than 90% of nonkeratinizing NPC and is a favorable prognostic indicator Cell proliferation may be upregulated via alterations of mitogen-activated protein kinases, and Akt and Wnt pathways. p16, cyclin D1, and cyclin E, among others, have been implicated in cell cycle abnormalities Polymorphism of a nitrosamine metabolizing gene, CYP2A6, may play a fundamental role in NPC susceptibility in certain populations
Miscellaneous Lesions Respiratory 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 Sialometaplasia
Infarction 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 Granuloma
Cholesterol granuloma may be encountered in the frontal and maxillary sinuses, less commonly in the paranasal sinuses. Cholesterol clefts, giant cells, foam cells, hemosiderin, and macrophages are present within brous granulation tissue. The changes are the result of resorbing hemorrhage
Microscopic
Keratinizing 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 inammation accompanies the tumor cells Undifferentiated nonkeratinizing carcinoma exhibits polygonal cells with indistinct cytoplasmic membranes imparting a syncytical appearance. Dense lymphoplasmacytic inammation 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
Chondromesenchymal Hamartoma
These intranasal/paranasal tumors occur in infants. Bland spindle cells, brous 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, RosaiDorfman Disease)
The nasal and paranasal cavities are, after the skin, the second most common site of extranodal involvement by Rosai Dorfman disease. The dening lesional cells are large foamy S-100 positive histiocytes that may contain intact intracytoplasmic lymphocytes (emperiopolesis)
These tumors are positive for cytokeratin
1112
Head and Neck
24-33
Fibromatosis
These tumors are rare and histologically similar to bromatosis occurring elsewhere. The differential diagnosis includes solitary brous tumor and low grade sarcomas
Hemangioma of Nasofacial Bones

Osseous hemangioma commonly produces bony irregularities. Cavernous thin-walled vessels ll and expand cancellous bone
Meningioma
Sinonasal 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 Chondrosarcoma
These primitive appearing spindle cell tumors often have a hemangiopericytoma-like appearance with foci of cartilaginous matrix. A paucity of cartilaginous matrix makes the diagnosis difcult
Fig. 24.45. Pituitary adenoma may rarely present as a sinus tumor as in this case.
Osteoma
Osteomas 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, bromatosis, and keratinous cysts
Metastatic Tumors
The most common metastatic tumor found in the nasal cavity-paranasal sinus region is renal cell carcinoma followed by lung, breast, thyroid, and prostate primaries
Pituitary Adenoma
Sinus involvement may occur via extension from an intrasellar lesion or as primary ectopic tumor (Fig.24.45) 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.
Salivary Gland Tumors

While adenoid cystic carcinoma is relatively common, other types of salivary gland tumors rarely involve the sinuses
Sarcoma
A wide array of sarcomas may involve the nasal cavity-sinus region including, brosarcoma, osteosarcoma, chondrosarcoma, and Ewing sarcoma/PNET
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 amplication is a recent study
Solitary Fibrous Tumor

There are many recent reports of sinonasal solitary brous tumor. Immunohistochemistry is useful in establishing the diagnosis as these tumors are positive for CD34 and vimen tin. CD99 is positive in 6070% of cases
1113
24-34
LARYNX AND TRACHEA Infection Disseminated Fungal Infection Clinical

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

Oncocytic cysts arise in elderly patients and most common occur within the ventricle. Patients present with complaints of hoarseness
Microscopic
These 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 cystadenoma is entertained
Microscopic
A granulomatous inammatory response, including histiocytes, giant cells, and necrosis, is generally present. Welldened granulomas may or may not be present. Bug-laden, foamy histiocytes with necrosis and nonspecic inammation, with limited evidence of giant cells or granulomas, may be encounter with histoplasmosis Blastomycosis is notoriously for inducing pseudoepitheliomatous hyperplasia and associated neutrophilic inammation with giant cells (Fig.24.47)
Other 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 lymphoid follicles
Inammatory/Nonneoplastic Lesions Laryngocele Clinical

This lesion is represented by either congenital or an acquired air-lled (can accumulate uid) dilatation of the laryngeal saccule
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
Microscopic
These 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 ndings. The overlying squamous epithelium may show atypia, which may be related to ischemia and should not be mistaken for dysplasia
Microscopic
They are lined by respiratory-type epithelium, which may undergo oncocytic metaplasia. The presence of neutrophils indicates secondary infection (i.e., laryngopyocele)
Fig. 24.47. In blastomycosis, granulomatous inammation is typically rich with neutrophils. Inset: GMS stain showing broadbased budding yeast.
Fig. 24.48. Oncocytic cysts laryngeal cysts are nonneoplastic lesions that occur with increasing frequency in the elderly.
1114
Head and Neck
24-35
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.
Contact Ulcer Clinical

These lesions involve the posterior commissure of the vocal folds. They often recur and gastric reux has been implicated in their pathogenesis
Microscopic
Delicate brovascular cores are lined by relatively bland squamous epithelium exhibiting basal cell hyperplasia. While parakeratosis is common, hyperkeratosis can be present. 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, apoptosis, individual cell keratinization, and increased mitotic gures (Fig.24.50) These lesions grow exophytically although extension into respiratory glands can be seen
Microscopic
The mucosa is typically ulcerated; however, squamous hyperplasia maybe seen adjacent to the ulcer. The signature portion ofthis lesion is the exuberant granulation tissue comprising theulcer base, which can be extremely cellular and mimic neoplasia
The characteristic location and clinical features aid distinction from potential histologic mimics such as hemangioma, spindle cell carcinoma, and granulomatous inammation
Immunohistochemical positivity for HPV antigen and in situ hybridization positivity for HPV 6/11 is common
Histologically, 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
Benign Neoplasms Laryngeal 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 childhood 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 eventually regress. Nonetheless, progressive disease occurs and can lead to death
Premalignant/Malignant Neoplasms Squamous 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
1115
24-36
most commonly affected areas. Such change is associated with hoarseness and encountered in smokers and voice abusers
Diagnosis can be difcult on biopsy (due to lack of atypia and difculty in establishing invasion) and requires cooperation between the pathologist and the clinician
Microscopic
The mucosa shows hyperkeratosis and typically acanthosis. Squamous cells are cytologically bland and maintain polarity Verrucous hyperkeratosis (verrucous hyperplasia) is a variant exhibiting verrucoid or papillary architecture. These lesions lack the papillary branching of papilloma and the pushing invasion of verrucous carcinoma
Microscopic
See above section Oral Cavity. A diagnosis of verrucous carcinoma should not be made when there is notable or prominent cytologic atypia. Moreover, broad-based, pushing invasion beyond the limits of the nonneoplastic mucosa should be demonstrated
Verrucous 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
Squamous Dysplasia/Carcinoma In Situ

Keratotic 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 progression 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
Basaloid Squamous Cell Carcinoma Clinical

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

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 relevant prognostic import. Most tumors are glottic (65%), followed by supraglottic (35%) and subglottic (<5%). Glottic tumors have the best survival followed by supraglottic and then subglottic
Microscopic
These highly cellular neoplasms are composed of nests of hyperchromatic, basaloid-appearing cells exhibiting peripheral nuclear palisading. Squamous differentiation is encountered more centrally. Lobular, solid, trabecular, and cribriform patterns are encountered. Nuclei are hyperchromatic and variably 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
Microscopic
Recapitulating 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 reected by the presence of desmoplasia. Tumors are graded as well, moderately, or poorly differentiated. Several variants occur (see below)
Immunohistochemical
Immunostains are positive for cytokeratin and p63. Neuroendocrine markers and TTF-1 are negative
The solid variant of adenoid cystic carcinoma can mimic basaloid squamous cell carcinoma (BSCC); however, the former lacks squamous differentiation and is less pleomorphic than BSCC Immunohistochemically, small cell neuroendocrine carcinoma is positive for neuroendocrine markers and negative for p63
Molecular Findings
Implicated genetic abnormalities in the development of head and neck squamous cell carcinoma are complex and numerous, including alterations of p16ink4A, p53, cyclin D1, p14ARF, FHIT, RASSF1A, epidermal growth factor receptor (EGFR), and Rb
Verrucous Carcinoma Clinical

This 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
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.
1116
Head and Neck
24-37
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
lymph node metastasis occurring in most patients. Visceral dissemination of disease occurs in up to 25% of patients
Microscopic
These 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 conrm the diagnosis. Such foci can be quite limited, and diligent search for squamous differentiation should be made. Foci of benign or malignant-appearing cartilage and/or bone may be present (so-called carcinosarcoma). The presence of adjacent carcinoma in situ may also be present and aids in the diagnosis
Microscopic
Large, poorly to undifferentiated, nonkeratinized tumor cells intermingled with small nonneoplastic lymphocytes and plasma cells
Immunohistochemical
If in doubt, cytokeratin positivity aids to distinguish from lymphoma and melanoma
Immunostains are extremely useful in establishing the diagnosis when in doubt. Malignant spindle cells are anticipated to be positive for cytokeratin and vimentin. EMA may also be positive
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
Spindle 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 eld 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 precursor lesion (i.e., carcinoma in situ)
Microscopic
Hyperchromatic, 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
Immunohistochemical
Immunohistochemistry is extremely useful in establishing the diagnosis as cells are expected to be positive for cytokeratin, neuroendocrine markers, and TTF-1 (i.e., synaptophysin and/or chromogranin positive)

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
The differential includes lymphoma (lymphoid markers+, cytokeratin), basaloid squamous cell carcinoma (p63+, neuroendocrine marker, and TTF-1), and variants of adenoid cyst carcinoma (see below)
Microscopic
Tumors exhibit nger-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 generally full-thickness and mitotic gures are readily apparent
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 systemic metastasis are typical
Squamous 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
Microscopic
Larger, polygonal tumor cells exhibit a nested and/or trabecular pattern of growth. Eosinophilic cytoplasm may appear granular. Nuclei are large, pleomorphic, and hyperchromatic with viable chromatin Mitotic gures are readily apparent and necrosis is common. Ultrastructurally, dense core neurosecretory granules are present
Molecular Findings
HPV 6 and 16 are the subtypes most commonly associated with papillary squamous cell carcinoma
Lymphoepithelioma-Like Carcinoma Clinical

This tumor exhibits histology similar to its nasopharygeal counterpart (see above) and behaves in a like manner with
Immunohistochemical
The diagnosis of LCNC is dependent upon immunohistochemical (or ultrastructural) evidence of neuroendocrine differentiation (i.e., synaptophysin and/or chromogranin positivity). Cytokeratin staining is positive as well
1117
24-38
Paraganglioma can bear a supercial resemblance to LCNC but lack mitotic activity and necrosis. Furthermore, paraganglioma is cytokeratin negative and contains S-100 positive sustentacular cells
are low grade (grade 1 or 2). Conservative resection is advocated for low grade tumors
Microscopic
Lobules of well-differentiated cartilage exhibit increased cellularity and chondrocyte atypia (including nucleoli, binucleation, and pleomorphism) as seen in low grade chondrosarcoma occurring at other sites (i.e., long bones)
Adenoid Cystic Carcinoma Clinical

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
The principal diagnostic consideration is chondroma. Distinction can be difcult as is the case for cartilaginous tumors occurring elsewhere. Some have advocated considering 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. Weurge corroborating the histologic ndings with the clinical and radiographic ndings in all cartilaginous lesions of thelarynx
Microscopic
They 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
Chondrosarcoma Clinical
Chondrosarcoma, the most common malignant adult mesenchymal tumor of the larynx, typically is centered upon the cricoid cartilage. With a mean size of 3.5cm, the majority
Mesenchymal/Soft Tissue Tumors

Isolated 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 Classication
The classication applies only to carcinomas. There should be histologic conrmation of the disease The following are the procedures for assessing T, N, and M categories
T categories N categories M categories Physical examination, laryngoscopy, and imaging Physical examination and imaging Physical examination and imaging
Denition of TNM Primary Tumor (T)

TX T0 Tis T1 T2 T3 T4a Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ Tumor 2cm of less in greatest dimension Tumor more than 2cm but not more than 4cm in greatest dimension Tumor more than 4cm in greatest dimension Moderately advanced local disease* (lip) Tumor invades through cortical bone, inferior alveolar nerve, oor 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) Very advanced local disease. Tumor invades masticator space, pterygoid plates, or skull base and/or encases internal carotid artery
T4b
*Note: Supercial erosion alone of bone/tooth socket by gingival primary is not sufcient to classify a tumor as T4
1118
Head and Neck
24-39
Regional Lymph Nodes (N)

NX N0 N1 N2 Regional lymph nodes cannot be assessed No regional lymph node metastasis Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension Metastasis in a single ipsilateral lymph node, more than 3cm but not more than 6 cm in greatest dimension; or in multiple ipsilateral lymph nodes, none more than 6cm in greatest dimension; or in bilateral or contralateral lymph nodes, none more than 6cm in greatest dimension: Metastasis in a single ipsilateral lymph node more than 3cm but not more than 6cm in greatest dimension Metastasis in multiple ipsilateral lymph nodes, none more than 6cm in greatest dimension Metastasis in bilateral or contralateral lymph nodes, none more than 6cm in greatest dimension Metastasis in a lymph node more than 6 cm in greatest dimension
Distant Metastasis (M)

MX M0 M1 Distant metastasis cannot be assessed No distant metastasis Distant metastasis
N2a N2b N2c N3
TNM CLASSIFICATIONS FOR THE LARYNX (2010 REVISION) Denition of TNM Primary Tumor (T)
TX T0 Tis Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ
Glottis
T1 T1a T1b T2 T3 Tumor limited to the true vocal cords (may involve anterior or posterior commissure) with normal mobility Tumor limited to one true vocal cord Tumor involves both true vocal cords Tumor extends to supraglottis and/or subglottis and/or with impaired true vocal cord mobility Tumor limited to the larynx with vocal cord xation and/or invasion of paraglottic space, and/or inner cortex of the thyroid cartilage Moderately advanced local disease Tumor invades through the outer cortex of the thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft tissues of neck including deep extrinsic muscle of the tongue, strap muscle, thyroid, or esophagus) Very advanced local disease Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures
Supraglottis
T1 T2 Tumor limited to one subsite of supraglottis with normal vocal cord mobility 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 xation of the larynx Tumor limited to larynx with vocal cord xation and/or invades any of the following: postcricoid area, preepiglottic space, paraglottic space, and/or inner cortex of thyroid cartilage Moderately advanced local disease Tumor invades through the thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft tissues of neck including deep extrinsic muscle of the tongue, strap muscles, thyroid, or esophagus) Very advanced local disease Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures
T4a
T3
T4b
T4a
Subglottis
T1 T2 T3 T4a Tumor limited to the subglottis Tumor extends to vocal cords with normal or impaired mobility Tumor limited to larynx with vocal cord xation Moderately advanced local disease Tumor invades cricoid or thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft tissues of neck including deep extrinsic muscles of the tongue, strap muscles, thyroid, or esophagus) Very advanced local disease Tumor invades prevertebral space, encases carotid artery, or invades mediastinal structures
T4b
T4b
1119
24-40
Regional Lymph Nodes (N)

NX N0 N1 N2 Regional lymph nodes cannot be assessed No regional lymph node metastasis Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension Metastasis in a single ipsilateral lymph node, more than 3cm but not more than 6cm 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 6cm in greatest dimension Metastasis in a single ipsilateral lymph node more than 3cm but not more than 6cm in greatest dimension Metastasis in multiple ipsilateral lymph nodes, none more than 6cm in greatest dimension Metastasis in bilateral or contralateral lymph nodes, none more than 6cm in greatest dimension Metastasis in a lymph node more than 6cm in greatest dimension
Distant Metastasis (M)

MX M0 M1 Distant metastasis cannot be assessed No distant metastasis Distant metastasis
N2a N2b N2c N3
SUGGESTED READINGS Nasal Cavity, Paranasal Sinuses, and Nasopharynx

Banks 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; 16:939946. Barnes L. Schneiderian papillomas and nonsalivary glandular neoplasms of the head and neck. Mod Pathol 2002;15:279297. Bourne TD, Bellizzi AM, Stelow EB, etal. p63 Expression in olfactory neuroblastoma and other small cell tumors of the sinonasal tract. Am J Clin Pathol 2008;130:213218. Devaney K. Wenig BM. Abbondanzo SL. Olfactory neuroblastoma and other round cell lesions of the sinonasal region. Mod Pathol 1996;9: 658663. Devaney KO, Travis WD, Hoffman G, etal. Interpretation of head and neck biopsies in Wegeners granulomatosis. A pathologic study of 126 biopsies in 70 patients. Am J Surg Pathol 1990;14:555564. Fletcher CD. Distinctive soft tissue tumors of the head and neck. Mod Pathol 2002;15:324330. Friedman GC, Hartwick RW, Ro JY, et al. Allergic fungal sinusitis. Report of three cases associated with dematiaceous fungi. Am J Clin Pathol 1991;96:368372. Frierson HF Jr, Mills SE, Fechner RE, etal. Sinonasal undifferentiated carcinoma. An aggressive neoplasm derived from schneiderian epithelium and distinct from olfactory neuroblastoma. Am J Surg Pathol 1986; 10:771779. Heffner DK, Hyams VJ. Teratocarcinosarcoma (malignant teratoma?) of the nasal cavity and paranasal sinuses a clinicopathologic study of 20 cases. Cancer 1984;53:21402154. Iezzoni JC, Mills SE. Undifferentiated small round cell tumors of the sinonasal tract: differential diagnosis update. Am J Clin Pathol 2005;124 Suppl:S110121. Ohshima K, Suzumiya J, Shimazaki K, etal. Nasal T/NK cell lymphomas commonly express perforin and Fas ligand: important mediators of tissue damage. Histopathology 1997;31:444450. Ridol RL, Lieberman PH, Erlandson RA, et al. Schneiderian papillomas: a clinicopathologic study of 30 cases. Am J Surg Pathol 1977;1:4353. Seethala RR, Hunt JL, Baloch ZW, LiVolsi VA, et al. Adenoid cystic carcinoma with high-grade transformation: a report of 11 cases and a review of the literature. Am J Surg Pathol 2007;31: 16831694. Thompson LD, Miettinen M, Wenig BM. Sinonasal-type hemangiopericytoma: a clinicopathologic and immunophenotypic analysis of 104 cases showing perivascular myoid differentiation. Am J Surg Pathol 2003;27: 737749. Thompson LD, Wieneke JA, Miettinen M. Sinonasal tract and nasopharyngeal melanomas: a clinicopathologic study of 115 cases with a proposed staging system. Am J Surg Pathol 2003;27: 594611.
Larynx and Trachea

Banks ER, Frierson HF Jr, Mills SE, etal. Basaloid squamous cell carcinoma of the head and neck. A clinicopathologic and immunohistochemical study of 40 cases. Am J Surg Pathol 1992;16:939946. Baumann JL, Cohen S, Evjen AN, etal. Human papillomavirus in early laryngeal carcinoma. Laryngoscope 2009;119:15311537. Cook JR, Hill DA, Humphrey PA, Pfeifer JD, et al. Squamous cell carcinoma arising in recurrent respiratory papillomatosis with pulmonary involvement: emerging common pattern of clinical features and human papillomavirus serotype association. Mod Pathol 2000;13: 914918. Derkay CS, Wiatrak B. Recurrent respiratory papillomatosis: a review. Laryngoscope 2008;118:12361247.
1120
Head and Neck
24-41
Ferlito A, Devaney KO, Rinaldo A. Neuroendocrine neoplasms of the larynx: advances in identication, understanding, and management. Oral Oncol 2006;42:770778. Mills SE. Neuroectodermal neoplasms of the head and neck with emphasis on neuroendocrine carcinomas. Mod Pathol 2002;15: 264278. Thompson LD, Gannon FH. Chondrosarcoma of the larynx: a clinicopathologic study of 111 cases with a review of the literature. Am J Surg Pathol 2002;26:836851.
Thompson LD, Wieneke JA, Miettinen M, etal. Spindle cell (sarcomatoid) carcinomas of the larynx: a clinicopathologic study of 187 cases. Am J Surg Pathol 2002;26:153170. Wenig BM. Necrotizing sialometaplasia of the larynx. A report of two cases and a review of the literature. Am J Clin Pathol 1995;103:609613. Wiernik G, Millard PR, Haybittle JL. The predictive value of histological classication into degrees of differentiation of squamous cell carcinoma of the larynx and hypopharynx compared with the survival of patients. Histopathology 1991;19:411417.
1121

Head and Neck Pathologie

Încărcat de

Informații document

Drepturi de autor

Formate disponibile

Partajați acest document

Partajați sau inserați document

Opțiuni de partajare

Vi se pare util acest document?

Este necorespunzător acest conținut?

Drepturi de autor:

Formate disponibile

Head and Neck Pathologie

Încărcat de

Drepturi de autor:

Formate disponibile

24 Head and Neck

John D. Henley, MD and Don-John Summerlin, MD

COnTEnTs I. Oral Cavity........................................24-4

Essentials of Anatomic Pathology, 3rd Ed.

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

Head and Neck

V. Larynx and Trachea..........................24-34

Essentials of Anatomic Pathology, 3rd Ed.

ORAL CAVITY Infection Candidiasis Clinical

Oral Hairy Leukoplakia Clinical

Herpes Simplex Virus Clinical

Head and Neck

Human Papillomavirus Clinical

Disseminated Fungal Infection Clinical

Immune-Mediated Disease Lichen Planus Clinical

Essentials of Anatomic Pathology, 3rd Ed.

Benign Mucous Membrane (Cicatricial) Pemphigoid Clinical

Inammatory/Nonneoplastic Lesions Peripheral Ossifying Fibroma Clinical

Pemphigus Vulgaris Clinical

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

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

Head and Neck

Peripheral Giant Cell Granuloma Clinical

Verruciform Xanthoma Clinical

Traumatic Ulcerative Granuloma with Stromal Eosinophilia Clinical

Essentials of Anatomic Pathology, 3rd Ed.

Mucous Extravasation Phenomena (Mucocele/Ranula) Clinical

Benign Neoplasms Granular Cell Tumor Clinical

Necrotizing Sialometaplasia Clinical

Congenital Gingival Granular Cell Tumor (Congenital Epulis) Clinical

Head and Neck

Premalignant/Malignant Neoplasms Leukoplakia

Proliferative Verrucous Leukoplakia Clinical

Squamous Dysplasia/Carcinoma In Situ Clinical

Essentials of Anatomic Pathology, 3rd Ed.

Squamous Cell Carcinoma Clinical

Verrucous Carcinoma Clinical

Table24.1. Differential Diagnosis of the Poorly/Undifferentiated Sinonasal Neoplasm

Squamous differentiation: keratin, intercellular bridges and/or dyskeratotic cells

Adenoid cystic carcinoma, solid pattern or so-called dedifferentiated Pituitary adenoma

Head and Neck

Papillary Squamous Cell Carcinoma Clinical

Sarcomatoid (Spindle Cell) Carcinoma Clinical

Malignant Melanoma Clinical

Essentials of Anatomic Pathology, 3rd Ed.

Miscellaneous Lesions Adenomatoid Hyperplasia

Oral Focal Mucinosis

Palisaded, Encapsulated (Solitary, Circumscribed) Neuroma

Geographic Tongue (Erythema Migrans)

Head and Neck

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

Smokeless Tobacco-Induced Keratosis

Salivary Duct Cyst

JAWS Nonodontogenic Cysts/Pseudocysts Nasopalatine Cyst Clinical

Odontogenic Cysts Dentigerous Cyst Clinical

Traumatic Bone Cavity Clinical

Essentials of Anatomic Pathology, 3rd Ed.

Odontogenic Keratocyst (Keratocystic Odontogenic Tumor) Clinical

Apical Periodontal Cyst Clinical

Calcifying Odontogenic Cyst (Gorlin Cyst) Clinical

Head and Neck

Reactive/Nonneoplastic Disease Cementoosseous Dysplasia Clinical

Essentials of Anatomic Pathology, 3rd Ed.

Benign Neoplasms Ameloblastoma Clinical