Dr. Farzad Yazdani MD.,AP.,CP. Tehran University of Medical Sciences HEAD & NECK Dr. Farzad Yazdani MD.,AP.,CP. Tehran University of Medical Sciences

ORAL CAVITY Diseases of the oral cavity can be broadly divided into two groups: those affecting the soft tissues (including the salivary glands) and those that involve the teeth. Excluded are extra-oral diseases that sometimes involve the mouth and pharynx, such as diphtheria, lichen planus, and leukemia, as well as dental disorders

ULCERATIVE AND INFLAMMATORY LESIONS It is important to remember that mechanical trauma and cancer may produce ulcerations in the oral cavity and must be considered in the differential diagnosis.

FIBROUS PROLIFERATIVE LESIONS The most common fibrous proliferative lesions of the oral cavity are fibroma (61%), peripheral ossifying fibroma (22%), pyogenic granuloma (12%), and peripheral giant cell granuloma (5%). The most common inflammatory/reactive ulcerations of the oral cavity are traumatic and aphthous ulcers.

FIBROUS PROLIFERATIVE LESIONS The so-called irritation fibroma primarily occurs in the buccal mucosa along the bite line or at the gingivodental margin. It consists of a nodular mass of fibrous tissue, with few inflammatory cells, covered by squamous mucosa. Treatment is complete surgical excision.

Figure 16-2 Fibroma. Smooth, pink, exophytic nodule on the buccal mucosa. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 16 February 2009 07:18 PM) © 2007 Elsevier 7

FIBROUS PROLIFERATIVE LESIONS The pyogenic granuloma is a highly vascular peduncular lesion, usually occurring in the gingiva of children, young adults, and, commonly, pregnant women (pregnancy tumor). The surface of the lesion is typically ulcerated and can be red to purple in color. In some cases, growth is alarmingly rapid, raising the fear of a malignant neoplasm.

FIBROUS PROLIFERATIVE LESIONS Histologically, these lesions demonstrate a highly vascular proliferation that is similar to granulation tissue. Because of this histologic picture, pyogenic granulomas can also be considered a form of capillary hemangioma . They either regress, particularly after pregnancy, or undergo fibrous maturation, and they may develop into a peripheral ossifying fibroma. Treatment is complete surgical excision

Figure 16-3 Pyogenic granuloma Figure 16-3 Pyogenic granuloma. Erythematous, hemorrhagic, and exophytic mass arising from the gingival mucosa. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 16 February 2009 07:18 PM) © 2007 Elsevier 10

FIBROUS PROLIFERATIVE LESIONS The peripheral ossifying fibroma is a relatively common growth of the gingiva that is considered to be reactive in nature rather than neoplastic. With a peak incidence in young and teenage females, peripheral ossifying fibromas appear as red, ulcerated, and nodular lesions of the gingiva. They are often mistaken clinically for pyogenic granulomas. Complete surgical excision down to the periosteum is the treatment of choice, as these lesions have a recurrence rate of 15% to 20%.

FIBROUS PROLIFERATIVE LESIONS The peripheral giant cell granuloma (giant cell epulis), a relatively common lesion of the oral cavity, characteristically protrudes from the gingiva at some site of chronic inflammation. The clinical appearance of peripheral giant cell granuloma can be similar to that of pyogenic granuloma Histologically, is made up of a striking aggregation of multinucleate, foreign body-like giant cells separated by a fibroangiomatous stroma. They should be differentiated from central giant cell granulomas found within the maxilla or the mandible and from the histologically similar but frequently multiple reparative giant cell "brown tumors" seen in hyperparathyroidism

Aphthous Ulcers (Canker Sores) These lesions are extremely common, small (usually <5 mm in diameter), painful, shallow ulcers. Characteristically, they take the form of rounded, superficial erosions, often covered with a gray-white exudate and having an erythematous rim. The lesions appear singly or in groups on the nonkeratinized oral mucosa, particularly the soft palate, buccolabial mucosa, floor of the mouth, and lateral borders of the tongue.

Figure 16-4 Aphthous ulcer Figure 16-4 Aphthous ulcer. Single ulceration with an erythematous halo surrounding a yellowish fibrinopurulent membrane. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 16 February 2009 07:18 PM) © 2007 Elsevier 14

Aphthous Ulcers (Canker Sores) They are more common in the first 2 decades of life and are often triggered by stress, fever, ingestion of certain foods, and activation of inflammatory bowel disease. In patients who are not immunosuppressed or do not have known viral infection such as with herpesvirus, an autoimmune basis is suspected. The canker sores are self-limited and usually resolve within a few weeks, but they may recur in the same or a different location in the oral cavity.

Herpesvirus Infection Herpetic stomatitis is an extremely common infection caused by herpes simplex virus (HSV) type 1. The pathogen is transmitted from person to person, most often by kissing; by middle life over three-fourths of the population have been infected. In most adults the primary infection is asymptomatic, but the virus persists in a dormant state within ganglia about the mouth (e.g., trigeminal ganglia).

Herpesvirus Infection With reactivation of the virus (which may be caused by fever, sun or cold exposure, respiratory tract infection, trauma), solitary or multiple small (<5 mm in diameter) vesicles containing clear fluid appear. They occur most often on the lips or about the nasal orifices and are well known as cold sores or fever blisters. They soon rupture, leaving shallow, painful ulcers that heal within a few weeks, but recurrences are common

Morphology The vesicles begin as an intraepithelial focus of intercellular and intracellular edema. The infected cells become ballooned and develop intranuclear acidophilic viral inclusions. Sometimes adjacent cells fuse to form giant cells known as multinucleated polykaryons.

Morphology Necrosis of the infected cells and the focal collections of edema fluid account for the intraepithelial vesicles detected clinically . Identification of the inclusion-bearing cells or polykaryons in smears of blister fluid constitutes the diagnostic Tzanck test for HSV infection.

Figure 15-1 Herpesvirus pharyngitis. A, Herpesvirus blister in mucosa Figure 15-1 Herpesvirus pharyngitis. A, Herpesvirus blister in mucosa. B, High-power view of cells from blister in A, showing glassy intranuclear herpes simplex inclusion bodies. Downloaded from: StudentConsult (on 13 February 2009 05:34 PM) © 2005 Elsevier

Morphology Antiviral agents may accelerate healing of the lesions. In 10% to 20% of those with this condition-particularly in the immunocompromised-a more virulent disseminated eruption develops, producing multiple vesicles throughout the oral cavity, including the gingiva and pharynx (herpetic gingivostomatitis), and lymphadenopathy. In particularly severe cases, viremia may seed the brain (causing encephalitis) or produce disseminated visceral lesions.

Morphology HSV type 1 may localize in many other sites, including the conjunctivae (keratoconjunctivitis) and the esophagus when a nasogastric tube is introduced through an infected oral cavity. As a result of changes in sexual practices, genital herpes produced by HSV type 2 (the agent of herpes genitalis) is increasingly seen in the oral cavity. The infection produces vesicles in the mouth, which have the same histologic characteristics as those that develop on the genital mucous membranes and external genitalia.

Oral Candidiasis Candida albicans is a normal inhabitant of the oral cavity found in 30% to 40% of the population it causes disease only when there is some impairment of the usual protective mechanisms. Pseudomembranous candidiasis (thrush, moniliasis) is the most common fungal infection of the oral cavity and is particularly common among persons rendered vulnerable by diabetes mellitus, anemia, antibiotic or glucocorticoid therapy, immunodeficiency, or debilitating illnesses such as disseminated cancer. Persons with the acquired immunodeficiency syndrome (AIDS) are at particular risk.

Morphology Typically, oral candidiasis takes the form of an adherent white, curdlike, circumscribed plaque anywhere within the oral cavity . The pseudomembrane can be scraped off to reveal an underlying granular erythematous inflammatory base. Histologically, the pseudomembrane is composed of a myriad of fungal organisms superficially attached to the underlying mucosa.

Morphology In milder infections there is minimal ulceration, but in severe cases the entire mucosa may be denuded. The fungi can be identified within these pseudomembranes as boxcar-like chains of tubular cells producing pseudohyphae from which bud ovoid yeast forms, typically 2 to 4 μm in greatest diameter.

Figure 15-2 Oral candidiasis ("thrush") Figure 15-2 Oral candidiasis ("thrush"). A white plaquelike membrane coats the gingival mucosa of the left lower jaw. This pseudomembrane is composed of a layer of candidal pseudohyphae. (Courtesy of Dr. Harvey P. Kessler, Department of Oral Surgery, College of Dentistry, University of Florida, Gainesville, Florida.) Downloaded from: StudentConsult (on 13 February 2009 05:34 PM) © 2005 Elsevier

Morphology In the particularly vulnerable host, candidiasis may spread into the esophagus, especially when a nasogastric tube has been introduced, or it may produce widespread visceral lesions when the fungus gains entry into the bloodstream. Disseminated candidiasis is a life-threatening infection that must be treated aggressively. For poorly understood reasons, local candidal lesions may appear in the vagina, not only in predisposed females but also in apparently healthy young women, particularly during pregnancy, or in women who are using oral contraceptives or broad-spectrum antibiotics.

AIDS and Kaposi Sarcoma AIDS and less advanced forms of human immune deficiency virus (HIV) infection are often associated with lesions in the oral cavity. They may take the form of candidiasis, herpetic vesicles, or some other microbial infection (producing gingivitis or glossitis).

AIDS and Kaposi Sarcoma Hairy leukoplakia is an uncommon lesion seen virtually only in persons infected with HIV. It consists of white confluent patches, anywhere on the oral mucosa, that have a "hairy" or corrugated surface resulting from marked epithelial thickening. It is caused by Epstein-Barr virus infection of epithelial cells. Occasionally, the development of hairy leukoplakia calls attention to the existence of the underlying HIV infection. More than 50% of individuals with Kaposi sarcoma develop intraoral purpuric discolorations or violaceous, raised, nodular masses; sometimes this involvement constitutes the presenting manifestation.

LEUKOPLAKIA AND ERYTHROPLAKIA As generally used, the term leukoplakia refers to a whitish, well-defined mucosal patch or plaque caused by epidermal thickening or hyperkeratosis. As defined by the World Health Organization, leukoplakia is a white patch or plaque that can not be scraped off and cannot be characterized as any other disease. Thus, the term is not applied to other white lesions, such as those caused by candidiasis, lichen planus, or many other disorders.

LEUKOPLAKIA AND ERYTHROPLAKIA The plaques are more frequent among older men and are most often on the vermilion border of the lower lip, buccal mucosa, the hard and soft palates, and less frequently on the floor of the mouth and other intraoral sites. They appear as localized, sometimes multifocal or even diffuse, smooth or roughened, leathery, white, discrete areas of mucosal thickening.

LEUKOPLAKIA AND ERYTHROPLAKIA On microscopic evaluation they vary from banal hyperkeratosis without underlying epithelial dysplasia to mild to severe dysplasia bordering on carcinoma in situ . Only histologic evaluation distinguishes these lesions. The lesions are of unknown cause except that there is a strong association with the use of tobacco, particularly pipe smoking and smokeless tobacco (pouches, snuff, chewing). Less strongly implicated are chronic friction, as from ill-fitting dentures or jagged teeth; alcohol abuse; and irritant foods. More recently, human papillomavirus antigen has been identified in some tobacco-related lesions, raising the possibility that the virus and tobacco act in concert in the induction of these lesions.

Figure 15-3 A, Leukoplakia of the tongue in a smoker Figure 15-3 A, Leukoplakia of the tongue in a smoker. Microscopically, this lesion showed severe dysplasia with transformation to squamous cell carcinoma in the posterior elevated portion (arrow). B, Leukoplakia with marked epithelial thickening and hyperkeratosis. Downloaded from: StudentConsult (on 13 February 2009 05:34 PM) © 2005 Elsevier

Figure 16-6 Leukoplakia. Clinical appearance of leukoplakias is highly variable and can range from A, smooth and thin with well-demarcated borders. B, diffuse and thick. C, irregular with a granular surface. D, diffuse and corrugated. (Courtesy of Drs. Neville, Damm, Allen, Bouquot [eds], Oral & Maxillofacial Pathology, Philadelphia, WB Saunders, 2002.) Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 16 February 2009 07:18 PM) © 2007 Elsevier 34

Figure 16-6 Leukoplakia. Clinical appearance of leukoplakias is highly variable and can range from A, smooth and thin with well-demarcated borders. B, diffuse and thick. C, irregular with a granular surface. D, diffuse and corrugated. (Courtesy of Drs. Neville, Damm, Allen, Bouquot [eds], Oral & Maxillofacial Pathology, Philadelphia, WB Saunders, 2002.) Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 16 February 2009 07:18 PM) © 2007 Elsevier 35

Figure 16-6 Leukoplakia. Clinical appearance of leukoplakias is highly variable and can range from A, smooth and thin with well-demarcated borders. B, diffuse and thick. C, irregular with a granular surface. D, diffuse and corrugated. (Courtesy of Drs. Neville, Damm, Allen, Bouquot [eds], Oral & Maxillofacial Pathology, Philadelphia, WB Saunders, 2002.) Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 16 February 2009 07:18 PM) © 2007 Elsevier 36

Figure 16-6 Leukoplakia. Clinical appearance of leukoplakias is highly variable and can range from A, smooth and thin with well-demarcated borders. B, diffuse and thick. C, irregular with a granular surface. D, diffuse and corrugated. (Courtesy of Drs. Neville, Damm, Allen, Bouquot [eds], Oral & Maxillofacial Pathology, Philadelphia, WB Saunders, 2002.) Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 16 February 2009 07:18 PM) © 2007 Elsevier 37

LEUKOPLAKIA AND ERYTHROPLAKIA Oral leukoplakia is an important finding because 3% to 25% (depending somewhat on location) undergo transformation to squamous cell carcinoma . It is impossible to distinguish the innocent lesion from the ominous one on visual inspection. The transformation rate is greatest with lip and tongue lesions and lowest with those on the floor of the mouth. Those lesions that display significant dysplasia on microscopic examination have a greater probability of cancerous transformation.

LEUKOPLAKIA AND ERYTHROPLAKIA Three somewhat related lesions must be differentiated from the usual oral leukoplakia. Hairy leukoplakia, described earlier and seen virtually only in persons with AIDS, has a corrugated or "hairy" surface rather than the white, opaque thickening of oral leukoplakia and has not been related to the development of oral cancer.

LEUKOPLAKIA AND ERYTHROPLAKIA Verrucous leukoplakia shows a corrugated surface caused by excessive hyperkeratosis. This seemingly innocuous form of leukoplakia recurs and insidiously spreads over time, resulting in a diffuse warty-type of oral lesion that may yet harbor squamous cell carcinoma. Erythroplakia refers to red, velvety, often granular, circumscribed areas that may or may not be elevated, having poorly defined, irregular boundaries. Histologically, erythroplakia almost invariably reveals marked epithelial dysplasia (the malignant transformation rate is >50%), so recognition of this lesion becomes even more important than identification of oral leukoplakia

Figure 16-5 Erythroplakia. A, Lesion of the maxillary gingiva Figure 16-5 Erythroplakia. A, Lesion of the maxillary gingiva. B, Red lesion of the mandibular alveolar ridge. Biopsy of both lesions revealed carcinoma in situ. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 16 February 2009 07:18 PM) © 2007 Elsevier 41

Figure 16-5 Erythroplakia. A, Lesion of the maxillary gingiva Figure 16-5 Erythroplakia. A, Lesion of the maxillary gingiva. B, Red lesion of the mandibular alveolar ridge. Biopsy of both lesions revealed carcinoma in situ. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 16 February 2009 07:18 PM) © 2007 Elsevier 42

CANCERS OF THE ORAL CAVITY AND TONGUE The overwhelming preponderance of oral cavity cancers are squamous cell carcinomas. Although they represent only about 3% of all cancers in the United States, they are disproportionately important clinically. Almost all are readily accessible to biopsy and early identification, but about half result in death within 5 years and indeed may have already metastasized by the time the primary lesion is discovered. These cancers tend to occur late in life and rarely before the age of 40 years.

Risk Factors for Oral Cancer

Figure 16-7 Clinical, histologic, and molecular progression of oral cancer. A, The typical clinical progression of oral cancer. B, The histologic progression of squamous epithelium from normal, to hyperkeratosis, to mild/moderate dysplasia, to severe dysplasia, to cancer. C, The sites of the most common genetic alterations identified as important for cancer development. (Clinical photographs courtesy of Sol Silverman, M.D., from the text Silverman S: Oral Cancer. Hamilton, Ontario, BD Dekker, 2003.) Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 16 February 2009 07:18 PM) © 2007 Elsevier 45

Figure 15-4 Oral squamous cell carcinoma Figure 15-4 Oral squamous cell carcinoma. Invasive tumor islands show formation of keratin pearls. Downloaded from: StudentConsult (on 13 February 2009 05:34 PM) © 2005 Elsevier

Clinical Features These lesions may cause local pain or difficulty in chewing, but many are relatively asymptomatic and so the lesion (very familiar to the exploring tongue) is ignored. Significant number are not discovered until beyond cure. The overall 5-year survival rates after surgery and adjuvant radiation and chemotherapy are about 40% for cancers of the base of the tongue, pharynx, and floor of the mouth without lymph node metastasis, compared with less than 20% for those with lymph node metastasis. When these cancers are discovered at an early stage, 5-year survival can exceed 90%

Morphology The three predominant sites of origin of oral cavity carcinomas are (in order of frequency) the (1) vermilion border of the lateral margins of the lower lip, (2) floor of the mouth, and (3) lateral borders of the mobile tongue. Early lesions appear as pearly white to gray, circumscribed thickenings of the mucosa closely resembling leukoplakic patches. They then may grow in an exophytic fashion to produce readily visible and palpable nodular and eventually fungating lesions, or they may assume an endophytic, invasive pattern with central necrosis to create a cancerous ulcer.

Figure 16-8 Schematic representation of the sites of origin of squamous cell carcinoma of the oral cavity, in numerical order of frequency. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 16 February 2009 07:18 PM) © 2007 Elsevier 49

Morphology The squamous cell carcinomas are usually moderately to well-differentiated keratinizing tumors Before the lesions become advanced it may be possible to identify epithelial atypia, dysplasia, or carcinoma in situ in the margins, suggesting origin from leukoplakia or erythroplakia. Spread to regional nodes is present at the time of initial diagnosis only rarely with lip cancer, in about 50% of cases of tongue cancer, and in more than 60% of those with cancer of the floor of the mouth. More remote spread to tissues or organs in the thorax or abdomen is less common than extensive regional spread.

NECK Most of the conditions that involve the neck are described elsewhere (e.g., squamous cell and basal cell carcinomas of the skin, melanomas, lymphomas), or they are only a component of a systemic disorder (e.g., generalized rashes, the lymphadenopathy of infectious mononucleosis or tonsillitis). What remains for consideration here are a few uncommon lesions unique to the neck.

Branchial Cyst (Lymphoepithelial Cyst) These benign cysts, usually appearing on the anterolateral aspect of the neck, arise either from remnants of the branchial arches or, as many believe, from developmental salivary gland inclusions within cervical lymph nodes. They are circumscribed cysts, 2 to 5 cm in diameter, with fibrous walls usually lined by stratified squamous or pseudostratified columnar epithelium underlain by an intense lymphocytic infiltrate or, more often, well-developed lymphoid tissue with reactive follicles. The cysts enlarge only slowly, are rarely the site of malignant transformation, and generally are readily excised. Similar lesions sometimes appear in the parotid gland or in the oral cavity beneath the tongue.

Thyroglossal Tract Cyst Embryologically, the thyroid anlage begins in the region of the foramen cecum at the base of the tongue; as the gland develops, it descends to its definitive location in the anterior neck. Remnants of this developmental tract may persist, producing cysts, 1 to 4 cm in diameter, that may be lined by stratified squamous epithelium, when the cyst is near the base of the tongue, or by pseudostratified columnar epithelium in lower locations. The connective tissue wall of the cyst may harbor lymphoid aggregates or remnants of recognizable thyroid tissue. The treatment is excision, but if it is not complete, stubborn recurrence can be expected. Malignant transformation within the lining epithelium has been reported but is rare.

Paraganglioma (Carotid Body Tumor) Paraganglia are clusters of neuroendocrine cells dispersed throughout the body, some connected with the sympathetic nervous system and others with the parasympathetic nervous system. The largest collection of these cells is found in the adrenal medulla, where they give rise to pheochromocytomas . Tumors arising in extra-adrenal paraganglia are not surprisingly referred to as paragangliomas.

Figure 16-14 Carotid body tumor Figure 16-14 Carotid body tumor. A, Low-power view showing tumor clusters separated by septa (zellballen). B, High-power view of large, eosinophilic, slightly vacuolated tumor cells with elongated sustentacular cells in the septa. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 16 February 2009 07:18 PM) © 2007 Elsevier 55

Figure 16-14 Carotid body tumor Figure 16-14 Carotid body tumor. A, Low-power view showing tumor clusters separated by septa (zellballen). B, High-power view of large, eosinophilic, slightly vacuolated tumor cells with elongated sustentacular cells in the septa. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 16 February 2009 07:18 PM) © 2007 Elsevier 56

SALIVARY GLAND DISEASES Although diseases primary to the major salivary glands are in general uncommon, the parotids bear the brunt of these involvements. Among the many possible disorders, attention is restricted here to sialadenitis and salivary gland tumors.

Sialadenitis Inflammation of the major salivary glands may be of traumatic, viral, bacterial, or autoimmune origin. The most common lesion of the salivary glands is mucocele, resulting from blockage or rupture of a salivary gland duct, with consequent leakage of saliva into the surrounding tissues. Mucoceles are most often found in the lower lip, as a consequence of trauma.

Figure 16-15 Mucocele. A, Fluctuant fluid-filled lesion on the lower lip subsequent to trauma. B, Cystlike cavity filled with mucinous material and lined by organizing granulation tissue. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 16 February 2009 07:18 PM) © 2007 Elsevier 59

Figure 16-15 Mucocele. A, Fluctuant fluid-filled lesion on the lower lip subsequent to trauma. B, Cystlike cavity filled with mucinous material and lined by organizing granulation tissue. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 16 February 2009 07:18 PM) © 2007 Elsevier 60

Sialadenitis Dominant among other causations of sialadenitis is the infectious viral disease mumps, which may produce enlargement of all the major salivary glands but predominantly the parotids. Although several viruses may cause mumps, the most important cause is a paramyxovirus, an RNA virus related to the influenza and parainfluenza viruses. It usually produces a diffuse, interstitial inflammation marked by edema and a mononuclear cell infiltration and, sometimes, by focal necrosis. Although childhood mumps is self-limited and rarely creates residual problems, mumps in adults may be accompanied by pancreatitis or orchitis; the latter sometimes causes permanent sterility.

Sialadenitis Bacterial sialadenitis most often occurs secondary to ductal obstruction resulting from stone formation (sialolithiasis), but it may also arise after retrograde entry of oral cavity bacteria under conditions of severe systemic dehydration such as the postoperative state. The most common bacteria causing the infection are Staphylococcus aureus and Streptococcus viridans. Persons with chronic, debilitating medical conditions, compromised immune function, or on medications contributing to oral or systemic dehydration are at increased risk for acute bacterial sialadenitis. The sialadenitis may be largely interstitial, or it may cause focal areas of suppurative necrosis or even abscess formation.

Sialadenitis Chronic sialadenitis arises from decreased production of saliva with subsequent inflammation. The dominant cause is autoimmune sialadenitis, which is almost invariably bilateral. This is seen in Sjögren syndrome. All of the salivary glands (major and minor), as well as the lacrimal glands, may be affected in this disorder, which presents with dry mouth (xerostomia) and dry eyes (keratoconjunctivitis sicca).

Sialadenitis The combination of salivary and lacrimal gland inflammatory enlargement, which is usually painless, and xerostomia, is sometimes referred to as Mikulicz syndrome. The causes include sarcoidosis, leukemia, lymphoma, and idiopathic lymphoepithelial hyperplasia.

Salivary Gland Tumors The salivary glands give rise to a diversity of tumors. About 80% of tumors occur within the parotid glands and most of the others in the submandibular glands. Males and females are affected about equally, usually in the sixth or seventh decade of life. In the parotids 70% to 80% of these tumors are benign, whereas in the submaxillary glands only half are benign. Thus, it is evident that a neoplasm in the submaxillary glands is more ominous than one in the parotids. The dominant tumor arising in the parotids is the benign pleomorphic adenoma, which is sometimes called a mixed tumor of salivary gland origin. Much less frequent is the papillary cystadenoma lymphomatosum (Warthin tumor). Collectively, these two types account for three-fourths of parotid tumors.

Salivary Gland Tumors Whatever the type, they present clinically as a mass causing a swelling at the angle of the jaw. The most malignant tumor of the salivary gland is mucoepidermoid carcinoma, which occurs mainly in the parotids. When primary or recurrent benign tumors are present for many (10-20) years, malignant transformation may occur, referred to then as a malignant mixed salivary gland tumor. Malignancy is less common in the parotid gland (15%) than in the submandibular glands (40%).

Pleomorphic Adenoma (Mixed Tumor of Salivary Glands) This tumor accounts for more than 90% of benign tumors of the salivary glands. It is a slow-growing, well-demarcated, apparently encapsulated lesion rarely exceeding 6 cm in greatest dimension. Most often arising in the superficial parotid, it usually causes painless swelling at the angle of the jaw and can be readily palpated as a discrete mass. It is nonetheless often present for years before being brought to medical attention.

Pleomorphic Adenoma (Mixed Tumor of Salivary Glands) Despite the tumor's encapsulation, histologic examination often reveals multiple sites where the tumor penetrates the capsule. Adequate margins of resection are thus necessary to prevent recurrences. This may require sacrifice of the facial nerve, which courses through the parotid gland. On average, about 10% of excisions are followed by recurrence.

Figure 16-16 Pleomorphic adenoma Figure 16-16 Pleomorphic adenoma. A, Slowly enlarging neoplasm in the parotid gland of many years duration. B, The bisected, sharply circumscribed, yellow-white tumor can be seen surrounded by normal salivary gland tissue. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 16 February 2009 07:18 PM) © 2007 Elsevier 69

Figure 16-16 Pleomorphic adenoma Figure 16-16 Pleomorphic adenoma. A, Slowly enlarging neoplasm in the parotid gland of many years duration. B, The bisected, sharply circumscribed, yellow-white tumor can be seen surrounded by normal salivary gland tissue. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 16 February 2009 07:18 PM) © 2007 Elsevier 70

Morphology The characteristic histologic feature of pleomorphic adenoma is heterogeneity. The tumor cells form ducts, acini, tubules, strands, or sheets of cells. The epithelial cells are small and dark and range from cuboidal to spindle forms. These epithelial elements are intermingled with a loose, often myxoid connective tissue stroma sometimes containing islands of apparent cartilage or, rarely, bone. Immunohistochemical evidence suggests that all of the diverse cell types within pleomorphic adenoma, including those within the stroma, are of myoepithelial derivation.

Figure 15-5 Pleomorphic adenoma Figure 15-5 Pleomorphic adenoma. A, A well-demarcated tumor in the parotid gland. B, Low-power view showing a well-demarcated tumor with normal parotid acini below. C, High-power view showing amorphous myxoid stroma resembling cartilage, with interspersed islands and strands of myoepithelial cells. (Courtesy of Dr. E. Lee, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas.) Downloaded from: StudentConsult (on 13 February 2009 05:34 PM) © 2005 Elsevier

Figure 16-17 Pleomorphic adenoma Figure 16-17 Pleomorphic adenoma. A, Low-power view showing a well-demarcated tumor with adjacent normal salivary gland parenchyma. B, High-power view showing epithelial cells as well as myoepithelial cells found within a chondroid matrix material. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 16 February 2009 07:18 PM) © 2007 Elsevier 73

Figure 16-17 Pleomorphic adenoma Figure 16-17 Pleomorphic adenoma. A, Low-power view showing a well-demarcated tumor with adjacent normal salivary gland parenchyma. B, High-power view showing epithelial cells as well as myoepithelial cells found within a chondroid matrix material. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 16 February 2009 07:18 PM) © 2007 Elsevier 74

Warthin Tumor (Papillary Cystadenoma Lymphomatosum, Cystadenolymphoma) This infrequent benign tumor occurs virtually only in the region of the parotid gland and is thought to arise from heterotopic salivary tissue trapped within a regional lymph node during embryogenesis. This tumor is generally a small, well-encapsulated, round to ovoid mass that on transection often reveals mucin-containing cleftlike or cystic spaces within a soft gray background.

Warthin Tumor (Papillary Cystadenoma Lymphomatosum, Cystadenolymphoma) Microscopically, it exhibits two characteristic features: (1) a two-tiered epithelial layer lining the branching, cystic, or cleftlike spaces; and (2) an immediately subjacent, well-developed lymphoid tissue sometimes forming germinal centers. A recurrence rate of about 10% is attributed to incomplete excision, multicentricity, or a second primary tumor. Malignant transformation is rare; about half of reported cases have had prior radiation exposure.

Figure 16-18 Warthin tumor. A, Low-power view showing epithelial and lymphoid elements. Note the follicular germinal center beneath the epithelium. B, Cystic spaces separate lobules of neoplastic epithelium consisting of a double layer of eosinophilic epithelial cells based on a reactive lymphoid stroma. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 16 February 2009 07:18 PM) © 2007 Elsevier 77

Figure 16-18 Warthin tumor. A, Low-power view showing epithelial and lymphoid elements. Note the follicular germinal center beneath the epithelium. B, Cystic spaces separate lobules of neoplastic epithelium consisting of a double layer of eosinophilic epithelial cells based on a reactive lymphoid stroma. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 16 February 2009 07:18 PM) © 2007 Elsevier 78

Adenoid cystic carcinoma Adenoid cystic carcinoma is a relatively uncommon tumor, which in approximately 50% of cases is found in the minor salivary glands (in particular the palate). Among the major salivary glands, the parotid and submandibular glands are the most common locations. Similar neoplasms have been reported in the nose, sinuses, and upper airways and elsewhere.

Figure 16-20 Adenoid cystic carcinoma in a salivary gland Figure 16-20 Adenoid cystic carcinoma in a salivary gland. A, Low-power view. The tumor cells have created a cribriform pattern enclosing secretions. B, Perineural invasion by tumor cells. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 16 February 2009 07:18 PM) © 2007 Elsevier 80

Figure 16-20 Adenoid cystic carcinoma in a salivary gland Figure 16-20 Adenoid cystic carcinoma in a salivary gland. A, Low-power view. The tumor cells have created a cribriform pattern enclosing secretions. B, Perineural invasion by tumor cells. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 16 February 2009 07:18 PM) © 2007 Elsevier 81

MUCOEPIDERMOID CARCINOMA These neoplasms are composed of variable mixtures of squamous cells, mucus-secreting cells, and intermediate cells. They represent about 15% of all salivary gland tumors, and while they occur mainly (60% to 70%) in the parotids, they account for a large fraction of salivary gland neoplasms in the other glands, particularly the minor salivary glands. Overall, they are the most common form of primary malignant tumor of the salivary glands

Figure 16-19 A, Mucoepidermoid carcinoma showing islands having squamous cells as well as clear cells containing mucin. B, Mucicarmine stains the mucin reddish-pink. (Courtesy of Dr. James Gulizia, Brigham and Women's Hospital, Boston.) Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 16 February 2009 07:18 PM) © 2007 Elsevier 83

Figure 16-19 A, Mucoepidermoid carcinoma showing islands having squamous cells as well as clear cells containing mucin. B, Mucicarmine stains the mucin reddish-pink. (Courtesy of Dr. James Gulizia, Brigham and Women's Hospital, Boston.) Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 16 February 2009 07:18 PM) © 2007 Elsevier 84

THE END