CARIES (TOOTH DECAY)

Dental caries, caused by focal degradation of the tooth structure, is one of the most common diseases throughout the world and is the most common cause of tooth loss before age 35. Carious lesions are the result of mineral dissolution of tooth structure by acid metabolic end products from bacteria that are present in the oral cavity and are capable of fermenting sugars. Traditionally, the rate of caries has been higher in industrialized countries, where there is ready access to processed foods containing large amounts of carbohydrates. However, global trends may change these demographics. First of all, the rate of caries has markedly dropped in countries such as the United States, where improved oral hygiene and fluoridation of the drinking water has become a standard practice. Fluoride incorporates into the crystalline structure of enamel, forming fluoroapatite, and contributes to resistance to degradation by bacterial acids. Second, with globalization of the world’s economy, increased amounts of processed foods with high carbohydrate content are being imported into developing nations. With these trends, one can expect the rate of caries to increase dramatically in the less-developed world over the next several decades.

GINGIVITIS

Gingiva is the designation of the squamous mucosa in between the teeth and around them. Gingivitis is inflammation of the mucosa and the associated soft tissues. Typically, the development of gingivitis is the result of a lack of proper oral hygiene, leading to an accumulation of dental plaque and calculus. Dental plaque is a sticky, usually colorless, biofilm that builds in between and on the surface of the teeth. It is formed by a complex of the oral bacteria, proteins from the saliva, and desquamated epithelial cells. If plaque continues to build and is not removed, it becomes mineralized to form calculus (tartar). The bacteria in the plaque release acids from sugar-rich foods, which erode the enamel surface of the tooth. Repeated erosions lead to dental caries. Plaque build-up beneath the gumline can cause gingivitis. Chronic gingivitis is characterized by gingival erythema, edema, bleeding, changes in contour, and loss of soft-tissue adaptation to the teeth. Gingivitis occurs at any age but is most prevalent and severe in adolescence (ranging from 40% to 60%), after which the incidence tapers off. It is a reversible disease; therapy is primarily aimed at reducing the accumulation of plaque and calculus via brushing, flossing, and regular dental visits.¹

PERIODONTITIS

Periodontitis refers to an inflammatory process that affects the supporting structures of the teeth: periodontal ligaments, alveolar bone, and cementum. With progression, periodontitis can lead to serious sequelae, including the loss of attachment caused by complete destruction of the periodontal ligament and alveolar bone. Loosening and eventual loss of teeth are possible. The pathogenesis of periodontal inflammation is not entirely clear. Until the 1960s it was believed that long-standing gingivitis uniformly progressed to periodontal disease. However, this is no longer thought to be the case. Rather, the development of periodontal disease is now considered to be an independent process, which, for reasons that are still unclear, is associated with a marked shift in the types and proportions of bacteria along the gingiva.² This shift, along with other environmental conditions such as poor oral hygiene, is believed to be important in the pathogenesis of periodontitis. This view is supported by significant differences in the content of dental plaque in areas of healthy and diseased periodontium. For the most part, facultative gram-positive organisms colonize healthy sites, while plaque within areas of active periodontitis contains anaerobic and microaerophilic gram-negative flora. Although 300 types of bacteria reside in the oral cavity, adult periodontitis is associated primarily with Aggregatibacter (Actinobacillus) actinomycetemcomitans, Porphyromonas gingivalis, and Prevotella intermedia.

While it typically presents without any associated disorders, periodontal disease can also be a component of several different systemic diseases, including acquired immunodeficiency syndrome (AIDS), leukemia, Crohn’s disease, diabetes mellitus, Down syndrome, sarcoidosis, and syndromes associated with polymorphonuclear defects (Chédiak-Higashi syndrome, agranulocytosis, and cyclic neutropenia). In addition to being a component of certain systemic diseases, periodontal infections can also be etiologic factors in several important systemic diseases. These include, for example, infective endocarditis, pulmonary and brain abscesses, and adverse pregnancy outcomes.^3,4

FIBROUS PROLIFERATIVE LESIONS

The so-called irritation fibroma (Fig. 16-2) 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.

The pyogenic granuloma (Fig. 16-3) is a highly vascular pedunculated 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 red to purple in color. In some cases growth is alarmingly rapid, raising the fear of a malignant neoplasm. Histologically these lesions demonstrate a highly vascular proliferation that is similar to granulation tissue. Because of this histologic picture, pyogenic granulomas are considered by some authorities to be a form of capillary hemangioma (Chapter 11). 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. Erythematous, hemorrhagic, and exophytic mass arising from the gingival mucosa.

The peripheral ossifying fibroma is a relatively common growth of the gingiva that is considered to be reactive in nature rather than neoplastic. However, the etiology of the lesion is unknown. Some may arise as a result of the maturation of a long-standing pyogenic granuloma. 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, since these lesions have a recurrence rate of 15% to 20%.

The peripheral giant cell granuloma is a relatively common lesion of the gingiva. It is generally covered by intact gingival mucosa, but it may be ulcerated. The clinical appearance of peripheral giant-cell granuloma can be similar to that of pyogenic granuloma, but which is generally more bluish purple in color while the pyogenic granuloma is more bright red. Histologically, however, these lesions are distinct. Peripheral giant-cell granuloma is made up of a striking aggregation of multinucleate, foreign body–like giant cells separated by a fibroangiomatous stroma. Although not encapsulated, these lesions are usually well delimited and easily excised. They should be differentiated from central giant-cell granulomas found within the maxilla or the mandible and from the histologically similar but frequently multiple “brown tumors” seen in hyperparathyroidism (Chapter 24).

APHTHOUS ULCERS (CANKER SORES)

These extremely common superficial ulcerations of the oral mucosa affect up to 40% of the population in the United States.⁶ They are more common in the first two decades of life, are extremely painful and often recurrent, and tend to be prevalent within certain families.

The lesions appear as single or multiple, shallow, hyperemic ulcerations covered by a thin exudate and rimmed by a narrow zone of erythema (Fig. 16-4). The underlying inflammatory infiltrate is at first largely mononuclear, but secondary bacterial infection introduces numerous neutrophils. The lesions may spontaneously resolve in 7 to 10 days or be stubbornly persistent for weeks. The causation of these lesions is obscure. Most ulcers are more painful than serious and require only symptomatic treatment. Recurrent apthous ulcers may be associated with celiac disease and inflammatory bowel disease.

FIGURE 16-4 Aphthous ulcer. Single ulceration with an erythematous halo surrounding a yellowish fibrinopurulent membrane.

GLOSSITIS

Although the designation glossitis implies inflammation of the tongue, it is sometimes applied to the beefy-red tongue encountered in certain deficiency states; this change results from atrophy of the papillae of the tongue and thinning of the mucosa, exposing the underlying vasculature. In some instances the atrophic changes do indeed lead to inflammation and even shallow ulcerations. Such changes may be encountered in deficiencies of vitamin B₁₂ (pernicious anemia), riboflavin, niacin, or pyridoxine. Similar alterations are sometimes encountered with sprue and iron-deficiency anemia, possibly complicated by deficiency in one of the B vitamins. The combination of iron-deficiency anemia, glossitis, and esophageal dysphagia usually related to webs is known as the Plummer-Vinson or Paterson-Kelly syndrome. Glossitis, characterized by ulcerative lesions (sometimes along the lateral borders of the tongue), may also be seen with jagged carious teeth, ill-fitting dentures, and, rarely, with syphilis, inhalation burns, or ingestion of corrosive chemicals.

HERPES SIMPLEX VIRUS INFECTIONS

Most orofacial herpetic infections are caused by herpes simplex virus type 1 (HSV-1). However, because of changes in sexual habits, an increase in HSV-2 (genital herpes) has been observed in the oral cavity. Primary HSV infection typically occurs in children age 2 to 4 years, is often asymptomatic, and does not cause significant morbidity. Approximately 10% to 20% of the time, primary infection presents as acute herpetic gingivostomatitis, in which there is an abrupt onset of vesicles and ulcerations throughout the oral cavity, especially in the gingiva. These lesions are also accompanied by lymphadenopathy, fever, anorexia, and irritability.

The great preponderance of adults harbor latent HSV-1, but in some individuals, usually young adults, the virus becomes reactivated to produce the common but usually mild cold sore. The influences predisposing to activation are poorly understood but are thought to include trauma, allergies, exposure to ultraviolet light, upper respiratory tract infections, pregnancy, menstruation, immunosuppression, and exposure to extremes of temperature.

Recurrent herpetic stomatitis (in contrast to acute gingivostomatitis) occurs either at the site of primary inoculation or in adjacent mucosal areas that are associated with the same ganglion; it takes the form of groups of small (1–3 mm) vesicles. The lips (Herpes labialis), nasal orifices, buccal mucosa, gingiva, and hard palate are the most common locations for recurrent lesions. They resemble those already described in the primary infections but are much more limited in duration, are milder, usually dry up in 4 to 6 days, and heal within a week to 10 days.

OTHER VIRAL INFECTIONS

Additional viral infections that can be seen in the oral cavity as well as the head and neck region include herpes zoster, Epstein-Barr virus (EBV; mononucleosis), cytomegalovirus, enterovirus (herpangina, hand-foot-and-mouth disease, acute lymphonodular pharyngitis), and rubeola (measles).

ORAL CANDIDIASIS (THRUSH)

The many localizations of candidal infection are fully described in Chapter 8, and so this discussion is limited to presentation in the oral cavity. Candidiasis is by far the most common fungal infection in the oral cavity. Candida albicans is a normal component of the oral flora in approximately 50% of the population. Three factors seem to influence the likelihood of a clinical infection: (1) immune status of the individual; (2) the strain of C. albicans present; and (3) the composition of an individual’s oral flora. There are three major clinical forms of oral candidiasis, including pseudo-membranous (thrush), erythematous, and hyperplastic, with several different variations within these groups. Only the pseudo-membranous form, the most common of these, is discussed here. Also known as “thrush,” pseudo-membranous candidiasis typically takes the form of a superficial, curdy, gray to white inflammatory membrane composed of matted organisms enmeshed in a fibrinosuppurative exudate that can be readily scraped off to reveal an underlying erythematous inflammatory base. This fungus causes mischief only in individuals who have some form of immunosuppression, as occurs in patients with diabetes mellitus, organ or bone marrow transplant recipients, those with neutropenia, chemotherapy-induced immunosuppression, or AIDS. In addition, broad-spectrum antibiotics that eliminate or alter the normal bacterial flora of the mouth can also result in the development of oral candidiasis.

DEEP FUNGAL INFECTIONS

In addition to their more common sites of infection, certain deep fungal infections have a significant predilection for the oral cavity and the head and neck region. Such fungi include histoplasmosis, blastomycosis, coccidioidomycosis, cryptococcosis, zygomycosis, and aspergillosis. With an increasing number of patients who are immunocompromised due to diseases such as AIDS or therapies for cancer and organ transplantation, the prevalence of fungal infections of the oral cavity has also increased in recent years.

HAIRY LEUKOPLAKIA

Hairy leukoplakia is a distinctive oral lesion that is usually seen in immunocompromised patients. Approximately 80% of patients with hairy leukoplakia are infected with the human immunodeficiency virus (HIV); the presence of this lesion sometimes calls attention to the existence of HIV infection. However, 20% of lesions are seen in patients who are immunocompromised for other reasons, such as cancer therapy or transplant immunosuppression. Hairy leukoplakia takes the form of white, confluent patches of fluffy (“hairy”), hyperkeratotic thickenings, almost always situated on the lateral border of the tongue. Unlike thrush, the lesion cannot be scraped off. The distinctive microscopic appearance consists of hyperparakeratosis and acanthosis with “balloon cells” in the upper spinous layer. Sometimes there is koilocytosis of the superficial, nucleated epidermal cells, suggesting human papillomavirus (HPV) infection, and HPV transcripts have occasionally been found within the cells. However, EBV is present in most cells and is now accepted as the cause of the condition.⁷ Sometimes there is superimposed candidal infection on the surface of the lesions, adding to the “hairiness.” In HIV-positive individuals, with hairy leukoplarkia, symptoms of AIDS follow in 2 to 3 years.

LEUKOPLAKIA AND ERYTHROPLAKIA

As is discussed in more detail below, oral cancers are common worldwide, with a fairly high mortality. Screening and early detection in populations at risk have been proposed to decrease the morbidity and mortality associated with oral cancer.^8,9 However, the visual detection of definitive premalignant oral lesions is problematic. This is in stark contrast to skin lesions, where visual screening for melanomas of the skin has been shown to have sensitivity and specificity rates of 93% and 98%.^10,11 One explanation for this discrepancy is that the early lesions frequently do not demonstrate any of the clinical characteristics observed in advanced oral cancer such as ulceration, induration, pain, or cervical lymphadenopathy.¹² In addition, the clinical presentation of potentially premalignant lesions in the oral cavity is highly heterogeneous. We begin our discussion with two premalignant lesions: leukoplakia and erythroplakia.

The term leukoplakia is defined by the World Health Organization as “a white patch or plaque that cannot be scraped off and cannot be characterized clinically or pathologically as any other disease.” Simply put, if a white lesion in the oral cavity can be given a specific diagnosis it is not a leukoplakia. This clinical term is reserved for lesions that are present in the oral cavity for no apparent reason. As such, white patches caused by entities such as lichen planus and candidiasis are not leukoplakias. Approximately 3% of the world’s population have leukoplakic lesions, and somewhere between 5% and 25% of these lesions are premalignant.¹³ Thus, until it is proved otherwise via histologic evaluation, all leukoplakias must be considered precancerous.

Related to leukoplakia, but much less common and much more ominous, is erythroplakia. It represents a red, velvety, possibly eroded area within the oral cavity that usually remains level with or may be slightly depressed in relation to the surrounding mucosa (Fig. 16-5). The epithelium in such lesions tends to be markedly atypical, incurring a much higher risk of malignant transformation than that seen with leukoplakia. Intermediate forms are occasionally encountered that have the characteristics of both leukoplakia and erythroplakia, termed speckled leukoerythroplakia.

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.

Both leukoplakia and erythroplakia may be seen in adults at any age, but they are usually found between ages 40 and 70, with a 2 : 1 male preponderance. Although these lesions have multifactorial origins, the use of tobacco (cigarettes, pipes, cigars, and chewing tobacco) is the most common antecedent.

Morphology. Leukoplakias may occur anywhere in the oral cavity (favored locations are buccal mucosa, floor of the mouth, ventral surface of the tongue, palate, and gingiva). They appear as solitary or multiple white patches or plaques, often with sharply demarcated borders. They may be slightly thickened and smooth or wrinkled and fissured, or they may appear as raised, sometimes corrugated, verrucous plaques (Fig. 16-6). On histologic examination they present a spectrum of epithelial changes ranging from hyperkeratosis overlying a thickened, acanthotic but orderly mucosal epithelium to lesions with markedly dysplastic changes sometimes merging into carcinoma in situ (Fig. 16-7). The more dysplastic or anaplastic the lesion, the more likely that a subjacent inflammatory infiltrate of lymphocytes and macrophages will be present.

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, to (D) diffuse and corrugated.

(Courtesy of Drs. Neville, Damm, Allen, Bouquot [eds], Oral and Maxillofacial Pathology. Philadelphia, WB Saunders, 2008.)

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. CIS, carcinoma in situ; SCC, squamous cell carcinoma.

(Clinical photographs courtesy of Sol Silverman, MD, from Silverman S: Oral Cancer. Hamilton, Ontario, Canada, BD Dekker, 2003.)

The histologic changes in erythroplakia only rarely consist of orderly epidermal maturation; virtually all (approximately 90%) disclose superficial erosions with dysplasia, carcinoma in situ, or already developed carcinoma in the surrounding margins. Often, an intense subepithelial inflammatory reaction with vascular dilation is seen that likely contributes to the reddish clinical appearance.

SQUAMOUS CELL CARCINOMA

At least 95% of cancers of the head and neck are squamous cell carcinomas (HNSCCs), arising most commonly in the oral cavity. The remainder includes adenocarcinomas (of salivary gland origin), melanomas, various carcinomas, and other rarities. Biologically, squamous cell carcinomas in the oral cavity are fairly similar to those elsewhere in the head and neck, hence they are described together here. Features that apply to squamous cell cancer at specific sites in the head and neck are mentioned in the following discussion. Laryngeal squamous cell cancers are described later.

HNSCC is an aggressive epithelial malignancy that is the sixth most common neoplasm in the world today. At current rates, approximately 45,000 cases in the United States and more than 650,000 cases worldwide will be diagnosed each year.^14,15-17 Despite numerous advances in treatment taking advantage of the most recent protocols for surgery, radiation therapy, and chemotherapy, the overall long-term survival has remained at less than 50% for the past 50 years.¹⁶ The 5-year survival rate of early-stage oral cancer is approximately 80%, while survival drops to 19% for late-stage disease. This dismal outlook is due to several factors, including the fact that oral cancer is often diagnosed when the disease has already reached an advanced stage. In addition, the frequent development of multiple primary tumors markedly decreases survival. The rate of second primary tumors in these patients has been reported to be 3% to 7% per year, which is higher than for any other malignancy.^18,19 This observation has led to the concept of “field cancerization.” It is postulated that multiple individual primary tumors develop independently in the upper aerodigestive tract as a result of years of chronic exposure of the mucosa to carcinogens.^20,21 Because of such field cancerization, an individual who is fortunate to live 5 years after the initial primary tumor has up to a 35% chance of developing at least one new primary tumor within that period of time. The occurrence of new primary tumors can be particularly devastating for individuals whose initial lesions were small. The 5-year survival rate for the first primary tumor is considerably better than 50%, but in such individuals, second primary tumors are the most common cause of death.²² Therefore, the early detection of all premalignant lesions is critical for the long-term survival of these patients.

Pathogenesis.

The pathogenesis of squamous cell carcinoma is multifactorial. Within North America and Europe it has classically been considered to be a disease of middle-aged men who have been chronic abusers of smoked tobacco and alcohol. The risk is magnified in those who smoke as well as consume alochol. Not unexpectedly, therefore, and concurrent with increased cigarette usage, the incidence of oral cancer in women is on the rise.

It is now known that at least 50% of oropharyngeal cancers, particularly those involving the tonsils, the base of the tongue, and the oropharynx harbor oncogenic variants of HPV.²³ It is predicted that the incidence of HPV-associated HNSCC will surpass that of cervical cancer in the next decade, in part because the anatomic sites of origin (tonsillar crypts, base of tongue, and oropharynx) are not readily accessible or amenable to cytologic screening (unlike the cervix). It should be noted, however, that patients with HPV-positive HNSCC do better than those with HPV-negative tumors. The HPV vaccine, which is protective against cervical cancer, offers hope to stem the tide of HPV-associated HNSCC, although it is not yet approved for this use.

There is increasing epidemiologic evidence that a family history of head and neck cancer is a risk factor for the disease, thought to be due to inherited genomic instability.²⁴ Finally, actinic radiation (sunlight) and, particularly, pipe smoking are known predisposing influences for cancer of the lower lip. Outside of North America and Europe, a major regional predisposing influence is the chewing of betel quid and paan in India and parts of Asia. The betel quid is a “witches’ brew” that contains several ingredients such as areca nut, slaked lime, and tobacco, which are wrapped in a betel leaf. While protracted irritation from ill-fitting dentures, jagged teeth, or chronic infections is no longer thought to be a direct antecedent to oral cancer, chronic irritation of the mucosa could act as a “promoter” of cancer in much the same way as alcohol does.

The incidence of oral cancer in individuals under age 40 who have no known risk factors has been on the rise for the past several years.^25-27 The pathogenesis of this group of patients who are nonsmokers and not infected with HPV is unknown.

Molecular Biology of Squamous Cell Carcinoma.

Like all epithelial neoplasms, the development of squamous cell carcinoma is thought to be a multi-step process involving the sequential activation of oncogenes and inactivation of tumor suppressor genes in a clonal population of cells. Several genetic alterations, some definitively identified and some inferred from tumor-specific chromosomal alterations, have been found in HNSCC. While not all of the specific mutations required for progression have been delineated, a working molecular model has been established (see Fig. 16-7). The first change is the loss of chromosomal regions of 3p and 9p21.²⁸ Loss of heterozygosity (LOH) in conjunction with promoter hypermethylation at this locus results in the inactivation of the p16 gene, an inhibitor of cyclin-dependent kinase (Chapter 7). This alteration is associated with the transition from normal to hyperplasia/hyperkeratosis and occurs before the development of histologic atypia, thus underscoring the histologic limitations for early diagnosis. Subsequent LOH at 17p with mutation of the p53 tumor suppressor gene is associated with progression to dysplasia.²⁹ Recently it has been demonstrated that gross genomic alterations as well as deletions on 4q, 6p, 8p, 11q, 13q, and 14q may act as predictors of progression to frank malignancy.³⁰ Ultimately, amplification and overexpression of the cyclin D1 gene (located on chromosome 11q13), which constitutively activates cell cycle progression, is a common late event. Data suggest that alterations of this gene confer the ability to invade in certain clones.^31,32

However, while this model is a good working draft of the molecular changes involved in development of HNSCC, it is incomplete. First, while some of the gross genomic alterations correlate with genes known to be important in HNSCC (such as p16, p53, and CyclinD1), many of the specific genes are still unknown. Second, this model does not take into account alterations in genes such as the epidermal growth factor receptor (EFGR), which is overexpressed in a high percentage of HNSCC and has been successfully targeted in the treatment of this disease. Finally, as indicated above, it is increasingly clear that HNSCC is a heterogeneous disease in terms of etiology and its molecular mechanisms of development.

Morphology. Squamous cell carcinoma may arise anywhere in the oral cavity, but the favored locations are the ventral surface of the tongue, floor of the mouth, lower lip, soft palate, and gingiva (Fig. 16-8). The malignancies themselves are typically preceded by the presence of premalignant lesions that can be very heterogeneous in presentation (see above).

FIGURE 16-8 Schematic representation of the sites of origin of squamous cell carcinoma of the oral cavity, in numerical order of frequency.

In the early stages, cancers of the oral cavity appear either as raised, firm, pearly plaques or as irregular, roughened, or verrucous areas of mucosal thickening, possibly mistaken for leukoplakia. Either pattern may be superimposed on a background of apparent leukoplakia or erythroplakia. As these lesions enlarge, they typically create ulcerated and protruding masses that have irregular and indurated (rolled) borders.

On histologic examination, these cancers begin as dysplastic lesions, which may or may not progress to full-thickness dysplasia (carcinoma in situ) before invading the underlying connective tissue stroma (Fig. 16-7). This difference in progression should be contrasted with cervical cancer (Chapter 22), in which, typically, full-thickness dysplasia, representing carcinoma in situ, develops before invasion. Squamous cell carcinomas range from well-differentiated keratinizing neoplasms to anaplastic, sometimes sarcomatoid, tumors, and from slowly to rapidly growing lesions. However, the degree of histologic differentiation, as determined by the relative degree of keratinization, is not correlated with behavior. As a group these tumors tend to infiltrate locally before they metastasize to other sites. The routes of extension depend on the primary site. The favored sites of local metastasis are the cervical lymph nodes, while the most common sites of distant metastasis are mediastinal lymph nodes, lungs, liver, and bones. Unfortunately, such distant metastases are often occult at the time of discovery of the primary lesion.

INFLAMMATIONS

Infectious Rhinitis.

Infectious rhinitis, the more elegant way of saying “common cold,” is in most instances caused by one or more viruses. Major offenders are adenoviruses, echoviruses, and rhinoviruses. They evoke a profuse catarrhal discharge that is familiar to all and the bane of the kindergarten teacher. During the initial acute stages, the nasal mucosa is thickened, edematous, and red; the nasal cavities are narrowed; and the turbinates are enlarged. These changes may extend, producing a concomitant pharyngotonsillitis. Secondary bacterial infection enhances the inflammatory reaction and produces an essentially mucopurulent or sometimes frankly suppurative exudate. But as all have learned from experience, these infections soon clear up—as the saying goes, in a week if treated but in 7 days if ignored.

Allergic Rhinitis.

Allergic rhinitis (hay fever) is initiated by hypersensitivity reactions to one of a large group of allergens, most commonly the plant pollens, fungi, animal allergens, and dust mites.³⁴ It affects 20% of the US population. As is the case with asthma, allergic rhinitis is an IgE–mediated immune reaction with an early- and late-phase response (see “Immediate (Type I) Hypersensitivity” in Chapter 6). The allergic reaction is characterized by marked mucosal edema, redness, and mucus secretion, accompanied by a leukocytic infiltration in which eosinophils are prominent.

Nasal Polyps.

Recurrent attacks of rhinitis may eventually lead to focal protrusions of the mucosa, producing so-called nasal polyps, which may reach 3 to 4 cm in length. On histologic examination these polyps consist of edematous mucosa having a loose stroma, often harboring hyperplastic or cystic mucous glands, infiltrated with a variety of inflammatory cells, including neutrophils, eosinophils, and plasma cells with occasional clusters of lymphocytes (Fig. 16-9). In the absence of bacterial infection, the mucosal covering of these polyps is intact, but with chronicity it may become ulcerated or infected. When multiple or large, the polyps may encroach on the airway and impair sinus drainage. Although the features of nasal polyps point to an allergic etiology, most people with nasal polyps are not atopic, and only 0.5% of atopic patients develop polyps.³⁵

FIGURE 16-9 A, Nasal polyps. Low-power magnification showing edematous masses lined by epithelium. B, High-power view showing edema and eosinophil-rich inflammatory infiltrate.

Chronic Rhinitis.

Chronic rhinitis is a sequel to repeated attacks of acute rhinitis, either microbial or allergic in origin, with the eventual development of superimposed bacterial infection. A deviated nasal septum or nasal polyps with impaired drainage of secretions contribute to the likelihood of microbial invasion. Frequently, there is superficial desquamation or ulceration of the mucosal epithelium and a variable inflammatory infiltrate of neutrophils, lymphocytes, and plasma cells subjacent to the epithelium. These suppurative infections sometimes extend into the air sinuses.

Sinusitis.

Acute sinusitis is most commonly preceded by acute or chronic rhinitis, but maxillary sinusitis occasionally arises by extension of a periapical infection through the bony floor of the sinus. The offending agents are usually inhabitants of the oral cavity, and the inflammatory reaction is entirely nonspecific. Impairment of drainage of the sinus by inflammatory edema of the mucosa is an important contributor to the process and, when complete, may impound the suppurative exudate, producing empyema of the sinus. Obstruction of the outflow, most often from the frontal and less commonly from the anterior ethmoid sinuses, occasionally leads to an accumulation of mucous secretions in the absence of direct bacterial invasion, producing a so-called mucocele. Acute sinusitis may, in time, give rise to chronic sinusitis, particularly when there is interference with drainage. There is usually a mixed microbial flora, largely of normal inhabitants of the oral cavity. Particularly severe forms of chronic sinusitis are caused by fungi (e.g., mucormycosis), especially in diabetics. Uncommonly, sinusitis is a component of Kartagener syndrome, which also includes bronchiectasis and situs inversus (Chapter 15). All these features are secondary to defective ciliary action. Although most instances of chronic sinusitis are more uncomfortable than disabling or serious, the infections have the potential of spreading into the orbit or of penetrating into the surrounding bone to give rise to osteomyelitis or spreading into the cranial vault, causing septic thrombophlebitis of a dural venous sinus.

NECROTIZING LESIONS OF THE NOSE AND UPPER AIRWAYS

Necrotizing ulcerating lesions of the nose and upper respiratory tract may be produced by

INFLAMMATIONS

Pharyngitis and tonsillitis are frequent in the usual viral upper respiratory infections. Most commonly implicated are the multitudinous rhinoviruses, echoviruses, and adenoviruses, and, less frequently, respiratory syncytial viruses and the various strains of influenza virus. In the usual case, there is reddening and slight edema of the nasopharyngeal mucosa, with reactive enlargement of the related lymphoid structures. Bacterial infections may be superimposed on these viral involvements, or may be primary invaders. The most common offenders are the β-hemolytic streptococci, but sometimes Staphylococcus aureus or other pathogens may be implicated. The inflamed nasopharyngeal mucosa may be covered by an exudative membrane (pseudo-membrane), and the nasopalatine and palatine tonsils may be enlarged and covered by exudate. A typical appearance is of enlarged, reddened tonsils (due to reactive lymphoid hyperplasia) dotted by pinpoints of exudate emanating from the tonsillar crypts, so-called follicular tonsillitis.

The major importance of streptococcal “sore throats” lies in the possible development of late sequelae, such as, rheumatic fever (Chapter 12) and glomerulonephritis (Chapter 20). Whether recurrent episodes of acute tonsillitis favor the development of chronic tonsillitis (true chronic tonsillitis is extremely rare) is open to debate, but the result is residual enlargement of the lymphoid tissue, inviting the tender mercies of the otolaryngologist.

INFLAMMATIONS

Laryngitis may occur as the sole manifestation of allergic, viral, bacterial, or chemical insult, but it is more commonly part of a generalized upper respiratory tract infection or the result of heavy exposure to environmental toxins such as tobacco smoke. It may also occur in association with gastroesophageal reflux due to the irritating effect of gastric contents. The larynx may also be affected in systemic infections, such as tuberculosis and diphtheria. Although most infections are self-limited, they may at times be serious, especially in infancy or childhood, when mucosal congestion, exudation, or edema may cause laryngeal obstruction. In particular, laryngoepiglottitis, caused by respiratory syncitial virus, Haemophilus influenzae, or β-hemolytic streptococci in infants and young children with their small airways, may induce such sudden swelling of the epiglottis and vocal cords that a potentially lethal medical emergency is created. This form of disease is uncommon in adults because of the larger size of the larynx and the stronger accessory muscles of respiration. Croup is the name given to laryngotracheobronchitis in children, in which the inflammatory narrowing of the airway produces the inspiratory stridor so frightening to parents. The most common form of laryngitis, encountered in heavy smokers, predisposes to squamous epithelial metaplasia and sometimes overt carcinoma.

REACTIVE NODULES (VOCAL CORD NODULES AND POLYPS)

Reactive nodules, also called polyps, sometimes develop on the vocal cords, most often in heavy smokers or in individuals who impose great strain on their vocal cords (singers’ nodules) (Fig. 16-12). By convention, singers’ nodules are bilateral lesions and polyps are unilateral. Adults, predominantly men, are most often affected. These nodules are smooth, rounded, sessile or pedunculated excrescences, generally only a few millimeters in the greatest dimension, located usually on the true vocal cords. They are typically covered by squamous epithelium that may become keratotic, hyperplastic, or even slightly dysplastic. The core of the nodule is a loose myxoid connective tissue that may be variably fibrotic or punctuated by numerous vascular channels. When nodules on opposing vocal cords impinge on each other, the mucosa may undergo ulceration. Because of their strategic location and accompanying inflammation, they characteristically change the character of the voice and often cause progressive hoarseness. They virtually never give rise to cancers.

FIGURE 16-12 Diagrammatic comparison of a benign papilloma and an exophytic carcinoma of the larynx to highlight their quite different appearances.

SQUAMOUS PAPILLOMA AND PAPILLOMATOSIS

Laryngeal squamous papillomas are benign neoplasms, usually located on the true vocal cords, that form soft, raspberry-like excrescences rarely more than 1 cm in diameter (Fig. 16-12). On histologic examination, the papillomas are made up of multiple slender, finger-like projections supported by central fibrovascular cores and covered by an orderly stratified squamous epithelium. When the papillomas are on the free edge of the vocal cord, trauma may lead to ulceration that can be accompanied by hemoptysis.

Papillomas are usually single in adults but are often multiple in children, in whom they are referred to as juvenile laryngeal papillomatosis.⁴² However, multiple recurring papillomas also occur in adults. The lesions are caused by HPV types 6 and 11. They do not become malignant, but frequently recur. They often spontaneously regress at puberty, but some affected patients endure numerous surgeries before this occurs. Cancerous transformation is rare.

CARCINOMA OF THE LARYNX

Sequence of Hyperplasia-Dysplasia-Carcinoma.

A spectrum of epithelial alterations is seen in the larynx. They range from hyperplasia, atypical hyperplasia, dysplasia, carcinoma in situ, to invasive carcinoma.⁴³ Macroscopically, the epithelial changes vary from smooth, white or reddened focal thickenings, sometimes roughened by keratosis, to irregular verrucous or ulcerated white-pink lesions that are similar in appearance to carcinoma.

There are all gradations of epithelial hyperplasia of the true vocal cords, and the likelihood of the development of an overt carcinoma is directly proportional to the level of atypia when the lesion is first seen. Orderly hyperplasias have almost no potential for malignant transformation, but the risk rises to 1% to 2% during the span of 5 to 10 years with mild dysplasia and 5% to 10% with severe dysplasia. Only histologic evaluation can determine the gravity of the changes.

The various changes described are most often related to tobacco smoke, the risk being proportional to the level of exposure. Indeed, up to the point of frank cancer, the changes often regress after cessation of smoking. Alcohol is also clearly a risk factor. Together smoking and alochol increase the risk substantially. Other factors that may contribute to increased risk include nutritional factors, exposure to asbestos, irradiation, and infection with HPV.^44,45

Morphology. About 95% of laryngeal carcinomas are typical squamous cell tumors. The tumor usually develops directly on the vocal cords, but it may arise above or below the cords, on the epiglottis or aryepiglottic folds, or in the pyriform sinuses. Those confined within the larynx proper are termed intrinsic, whereas those that arise or extend outside the larynx are called extrinsic. Squamous cell carcinomas of the larynx follow the growth pattern of other squamous cell carcinomas. They begin as in situ lesions that later appear as pearly gray, wrinkled plaques on the mucosal surface, ultimately ulcerating and fungating (Fig. 16-13). The degree of anaplasia of the laryngeal tumors is highly variable. Sometimes massive tumor giant cells and multiple bizarre mitotic figures are seen. As expected with lesions arising from recurrent exposure to environmental carcinogens, adjacent mucosa may demonstrate squamous cell hyperplasia with foci of dysplasia or even carcinoma in situ.

FIGURE 16-13 A, Laryngeal carcinoma. Note the large, ulcerated, fungating lesion involving the vocal cord and pyriform sinus. B, Histologic appearance of laryngeal squamous cell carcinoma. Note the atypical lining epithelium and invasive keratinizing cancer cells in the submucosa.

Carcinoma of the larynx manifests itself clinically by persistent hoarseness. At presentation, about 60% of these cancers are confined to the larynx. The prognosis for these is better than for those tumors that have spread into adjacent structures. Later, laryngeal tumors may produce pain, dysphagia, and hemoptysis. Patients are also extremely vulnerable to secondary infection of the ulcerating lesion. With surgery, irradiation, or combination therapy, many patients can be cured, but about one third die of the disease. The usual causes of death are infection of the distal respiratory passages or widespread metastases and cachexia.

PLEOMORPHIC ADENOMA

Because of their remarkable histologic diversity, these neoplasms have also been called mixed tumors. They represent about 60% of tumors in the parotid, are less common in the submandibular glands, and are relatively rare in the minor salivary glands. They are benign tumors that consist of a mixture of ductal (epithelial) and myoepithelial cells, and therefore they show both epithelial and mesenchymal differentiation. They reveal epithelial elements dispersed throughout the matrix along with varying degrees of myxoid, hyaline, chondroid (cartilaginous), and even osseous tissue. In some tumors the epithelial elements predominate; in others they are present only in widely dispersed foci.

Little is known about the origins of these neoplasms, except that radiation exposure increases the risk. Equally uncertain is the histogenesis of the various components. A currently popular view is that all neoplastic elements, including those that appear mesenchymal, are of either myoepithelial or ductal reserve cell origin (hence the designation pleomorphic adenoma).

Morphology. Most pleomorphic adenomas present as rounded, well-demarcated masses rarely exceeding 6 cm in the greatest dimension (Fig. 16-16). Although they are encapsulated, in some locations (particularly the palate) the capsule is not fully developed, and expansile growth produces protrusions into the surrounding gland, rendering enucleation of the tumor hazardous. The cut surface is gray-white with myxoid and blue translucent areas of chondroid (cartilage-like).

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.

The dominant histologic feature is the great heterogeneity mentioned. The epithelial elements resembling ductal cells or myoepithelial cells are arranged in duct formations, acini, irregular tubules, strands, or sheets of cells. These elements are typically dispersed within a mesenchyme-like background of loose myxoid tissue containing islands of chondroid and, rarely, foci of bone (Fig. 16-17). Sometimes the epithelial cells form well-developed ducts lined by cuboidal to columnar cells with an underlying layer of deeply chromatic, small myoepithelial cells. In other instances there may be strands or sheets of myoepithelial cells. Islands of well-differentiated squamous epithelium may also be present. In most cases there is no epithelial dysplasia or evident mitotic activity. There is no difference in biologic behavior between the tumors composed largely of epithelial elements and those composed largely of seemingly mesenchymal elements.

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.

WARTHIN TUMOR (PAPILLARY CYSTADENOMA LYMPHOMATOSUM)

This curious benign neoplasm with its intimidating histologic name is the second most common salivary gland neoplasm. It arises almost exclusively in the parotid gland (the only tumor virtually restricted to the parotid) and occurs more commonly in males than in females, usually in the fifth to seventh decades of life. About 10% are multifocal and 10% bilateral. Smokers have eight times the risk of nonsmokers for developing these tumors.

Morphology. Most Warthin tumors are round to oval, encapsulated masses, 2 to 5 cm in diameter, usually arising in the superficial parotid gland, where they are readily palpable. Transection reveals a pale gray surface punctuated by narrow cystic or cleftlike spaces filled with a mucinous or serous secretion. On microscopic examination these spaces are lined by a double layer of neoplastic epithelial cells resting on a dense lymphoid stroma sometimes bearing germinal centers (Fig. 16-18). The spaces are frequently narrowed by polypoid projections of the lymphoepithelial elements. The double layer of lining cells is distinctive; it consists of a surface palisade of columnar cells having an abundant, finely granular, eosinophilic cytoplasm, that imparts an oncocytic appearance, which rests on a layer of cuboidal to polygonal cells. Oncocytes are epithelial cells stuffed with mitochondria, which impart the granular appearance to the cytoplasm. Secretory cells are dispersed in the columnar cell layer, accounting for the secretions within the cystically dilated lumens. On occasion, there are foci of squamous metaplasia.

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.

The histogenesis of these tumors has long been disputed. The occasional finding of small salivary gland rests in lymph nodes in the neck suggests that these tumors arise from the aberrant incorporation of similar inclusion-bearing lymphoid tissue in the parotids. Indeed, rarely, Warthin tumors have arisen within cervical lymph nodes, a finding that should not be mistaken for metastases. These neoplasms are benign, with recurrence rates of only 2% after resection.

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. In more than half the cases, this tumor is associated with a balanced (11;19) (q21;p13) chromosomal translocation that creates a fusion gene composed of portions of the MECT1 and MAML2 genes. The MECT1-MAML2 gene is believed to play a key role in the genesis of this tumor, possibly by perturbing the notch and cAMP-dependent signaling pathways.^54,55 Overall, they are the most common form of primary malignant tumor of the salivary glands.

Morphology. Mucoepidermoid carcinomas can grow as large as 8 cm in diameter and although they are apparently circumscribed, they lack well-defined capsules and are often infiltrative at the margins. Pale and gray-white on transection, they frequently contain small, mucin-containing cysts. The basic histologic pattern is that of cords, sheets, or cystic configurations of squamous, mucous, or intermediate cells. The hybrid cell types often have squamous features, with small to large mucus-filled vacuoles, best seen when highlighted with mucin stains (Fig. 16-19). The tumor cells may be regular and benign appearing or, alternatively, highly anaplastic and unmistakably malignant. Accordingly, mucoepidermoid carcinomas are subclassified into low, intermediate, or high grade.

FIGURE 16-19 A, Mucoepidermoid carcinoma growing in nests composed of squamous cells as well as clear vacuolated cells containing mucin. B, Mucicarmine stains the mucin reddish pink.

(Courtesy of Dr. James Gulizia, Brigham and Women’s Hospital, Boston, MA.)

The clinical course and prognosis depend on the grade of the neoplasm. Low-grade tumors may invade locally and recur in about 15% of cases, but only rarely do they metastasize and so yield a 5-year survival rate of more than 90%. By contrast, high-grade neoplasms and, to a lesser extent, intermediate-grade tumors are invasive and difficult to excise and so recur in about 25% to 30% of cases and, in 30% of cases, metastasize to distant sites. The 5-year survival rate in patients with these tumors is only 50%.

OTHER SALIVARY GLAND TUMORS

Two less common neoplasms merit brief description: adenoid cystic carcinoma and acinic cell tumor.

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.

Morphology. In gross appearance, they are generally small, poorly encapsulated, infiltrative, gray-pink lesions. On histologic evaluation, they are composed of small cells having dark, compact nuclei and scant cytoplasm. These cells tend to be disposed in tubular, solid, or cribriform patterns reminiscent of cylindromas arising in the adnexa of the skin. The spaces between the tumor cells are often filled with a hyaline material thought to represent excess basement membrane (Fig. 16-20A). Other less common histologic patterns have been designated as tubular and solid variants.

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.

Although slow growing, adenoid cystic carcinomas are relentless and unpredictable tumors with a tendency to invade perineural spaces (Fig. 16-20B), and they are stubbornly recurrent. Eventually, 50% or more disseminate widely to distant sites such as bone, liver, and brain, sometimes decades after attempted removal. Thus, although the 5-year survival rate is about 60% to 70%, it drops to about 30% at 10 years and 15% at 15 years. Neoplasms arising in the minor salivary glands have, on average, a poorer prognosis than those primary in the parotids.

The acinic cell tumor is composed of cells resembling the normal serous acinar cells of salivary glands. They are relatively uncommon, representing only 2% to 3% of salivary gland tumors. Most arise in the parotids; the remainder arise in the submandibular glands. They rarely involve the minor glands, which normally have only a scant number of serous cells. Like Warthin tumor, they are sometimes bilateral or multicentric. They are generally small, discrete lesions that may appear encapsulated. On histologic examination, they reveal a variable architecture and cell morphology. Most characteristically, the cells have clear cytoplasm but the cells are sometimes solid and at other times vacuolated. The cells are disposed in sheets or microcystic, glandular, follicular, or papillary patterns. There is usually little anaplasia and few mitoses, but some tumors are occasionally slightly more pleomorphic.

The clinical course of these neoplasms is somewhat dependent on the level of pleomorphism. Overall, recurrence after resection is uncommon, but about 10% to 15% of these neoplasms metastasize to lymph nodes. The survival rate is in the range of 90% at 5 years and 60% at 20 years.