Section VII. Diseases of the Head & Neck

This section deals with diseases of the head and neck—but not the brain, which is covered in the section on the nervous system (Section XV). The main rationale of including such diverse organs as the oral cavity, salivary glands, ear, nose, pharynx, and larynx in one section is that they are included in the surgical specialty of otolaryngology. Diseases of the teeth (dental pathology, Chapter 31: The Oral Cavity & Salivary Glands) and eyes (ophthalmic pathology, Chapter 33: The Eye) form the rest of this section. The oral cavity, nose, pharynx, and larynx form the common opening of the respiratory and gastrointestinal systems and are often collectively called the upper respiratory tract.

Viral infections of the upper respiratory tract, which include coryza (the common cold) and pharyngotonsillitis, are among the most common infections of humans and are responsible for the loss of many manhours of work throughout the world. The most common neoplasms in this section are squamous carcinomas of the upper respiratory tract (Chapters 31 and 32) and salivary gland neoplasms (Chapter 31: The Oral Cavity & Salivary Glands).

The oral cavity is lined by a mucosa composed of nonkeratinizing stratified squamous epithelium, continuous with the skin at the lips and with the pharyngeal mucosa posteriorly. Specialized structures in the oral cavity include the following:

1.  The taste buds, which are specialized nerve endings with afferents in the ninth (posterior tongue) and seventh (anterior tongue) cranial nerves.

2.  The teeth, which are embedded in the maxilla and mandible. The part of the mucosa that is reflected onto the bone in relation to the teeth is called the gingiva (gum).

3.  Three major pairs of salivary glands, plus numerous minor salivary glands. The parotid glands are composed almost entirely of serous cells and are situated in front of and below the ear. They secrete saliva through a duct (Stensen's duct) that opens in the cheek adjacent to the molar teeth. The seromucous submandibular gland lies beneath the mandible and opens by a duct (Warthin's duct) into the floor of the mouth. The sublingual gland, also seromucous in type, is situated in the floor of the mouth and empties through 10–20 small ducts.

4.  Lymphoid tissue, which guards the pharyngeal opening (Waldeyer's ring). The tonsils, which are situated between the faucial pillars and adenoids in the nasopharynx, are the largest collections of lymphoid tissue.

The function of the oral cavity is to accept food and begin the process of digestion. Mastication, aided by the lubricant action of the saliva, converts the food into a bolus that is propelled back by the tongue muscles into the pharynx for swallowing. Saliva contains (a) amylase, which may initiate carbohydrate digestion; (b) lysozyme, which has bactericidal properties; and (c) secretory IgA. The salivary gland epithelium synthesizes “the secretor piece,” which complexes with IgA produced by plasma cells in the gland stroma.

Pain

The oral cavity is richly supplied with sensory nerve endings, and pain is a feature of almost all diseases that affect the mucosa. Pain in diseases of the teeth occurs only when pain-sensitive fibers in the root of a tooth are involved.

Changes of the Oral Mucosa

Alterations of the mucosa include ulceration, vesicular lesions (blisters), and changes in color. Oral ulcers occur in many diseases, including infections, allergy, trauma, and neoplasms. Vesicular lesions occur in infections (eg, herpesvirus infections) and immunologic diseases such as pemphigus vulgaris and erythema multiforme that primarily affect the skin. White plaques on the mucosa (leukoplakia) occur in hyperplastic and neoplastic conditions, and melanin pigmentation occurs in many systemic diseases (Table 31-1).

Masses

Mass lesions may be solid or cystic and may be found in any part of the oral cavity. Mass lesions arising in structures outside the oral cavity (eg, bone of the mandible and maxilla) may involve the oral cavity by extension.

Dental Caries

Etiology

Dental caries is a progressive decomposition of tooth substances caused by a wide variety of bacteria and fungi but most commonly Streptococcus mutans. The microorganisms proliferate in food residue on the teeth to form a hard adherent mass of calcified debris containing bacteria and desquamated epithelial cells (plaque, tartar; calculus when calcified). Enzymes and acids produced by the microorganisms cause proteolysis, decalcification, and decay of first the enamel covering of the tooth, then the dentin, and finally the tooth pulp. Cavities are detectable with probes when there is a break in continuity of the enamel.

Several factors influence the risk of dental caries:

1. Microorganisms are essential for formation of caries. Attempts to develop vaccines against common causative organisms have not proved successful. The use of antibiotics is not feasible because of the variety of microorganisms involved and the adverse effects of these drugs.

2. Regular brushing prevents accumulation of food residue and clearly reduces the incidence of caries.

3.   Sugar, particularly in a form that sticks to the teeth, promotes dental caries because bacteria utilize carbohydrates for metabolism. The stickiness of plaque is caused by dextran, which is a product of sucrose fermentation by Streptococcus mutans.

4. Once plaque has formed, it cannot be removed by simple brushing. Removal of plaque by regular use of dental floss or by scaling decreases the incidence of caries.

5. Fluoride has a dual protective effect: It makes the enamel more resistant to bacterial degradation and has a weak microbicidal action.

6. Saliva has a mechanical cleansing action and contains microbicidal substances (eg, lysozyme, IgA). Any cause of decreased salivary secretion, such as Sjögren's syndrome or radiation, increases the risk of dental caries. Patients who undergo radiation treatment to the oral cavity need careful dental care to prevent “radiation caries.”

Clinicopathologic Effects

(Figure 31-1)

Early Caries

Early dental caries does not cause symptoms but can be recognized by clinical dental examination. Because caries is slowly progressive, regular dental examination permits effective treatment at an early stage.

Pulp Infection

Deep caries that extends through the enamel and dentin layers into the tooth pulp permits the entry of microorganisms into the tooth pulp. Acute inflammation results, leading to the formation of a localized abscess or destruction of the entire pulp. Both are associated with severe pain (toothache) and swelling.

When there is a localized pulp abscess, simple drainage and antibiotic therapy may be sufficient treatment. Total destruction of the pulp requires clearance of the entire pulp cavity followed by replacement with an inert material and sealing (root canal therapy).

Periapical Infection

Extension of pulp infection to the apical periodontium results in an inflammatory lesion that progresses through several stages:

1. An apical abscess develops around the apex of the tooth and is intensely painful due to the high tissue tension that develops in the bone. The abscess enlarges and eventually drains through the gingiva (parulis, gumboil). Rarely, the infection spreads in the floor of the mouth and neck along fascial planes, associated with extensive tissue necrosis (Ludwig's angina).

2. Periapical granuloma is a more chronic inflammatory response around the apex of the tooth, characterized by bone resorption and infiltration by lymphocytes, plasma cells, and histiocytes. Symptoms may be minor—typically mild pain when biting down or increased sensitivity of the tooth to heat and cold. X-ray reveals a well-demarcated lucent area in the bone at the apex of the tooth.

Periapical granulomas tend to undergo epithelialization from the periapical region to form a cystic structure lined by squamous epithelium and containing the fluid debris of inflammation. This is called a radicular cyst.

Periodontal Disease

Periodontal disease is also a complication of plaque formation. As the incidence of dental caries decreases, periodontal disease has become the most common cause of tooth loss in adults in the United States. Accumulation of plaque (see above) in the crevice between the gingiva and the tooth causes inflammation (gingivitis), which may progress to periodontitis, involving not only the gingival crevice but also the periodontal membrane, alveolar bone, and the outer layer of the tooth itself. The end result is instability of the tooth, resorption of the gingiva and bone, purulent discharge from the gingival crevice (pyorrhea), and eventual tooth loss. Again, multiple bacteria are involved.

Gingival hyperplasia also occurs in pregnancy, in some patients receiving phenytoin therapy, and in response to local gingival hemorrhage (in scurvy, leukemia, or thrombocytopenia). Fibrous thickening of the gingiva may also occur in chronic gingivitis resulting from low-grade chronic bacterial infection.

Cysts of the Jaw

Cysts of the jaw are very common. Many of them—eg, radicular cysts, follicular cysts, and odontogenic keratocysts—occur in relation to the teeth. Others, such as fissural and inclusion cysts, are not related to the teeth but enter the differential diagnosis.

Radicular cyst is the most common and is the result of epithelialization of a periapical granuloma.

Follicular cysts arise from the epithelium of the tooth follicle. They may be associated with failure of eruption of the involved tooth. If the unerupted tooth is present in the cyst wall, the term “dentigerous cyst” may be applied.

Odontogenic keratocysts are lined by a keratinized squamous epithelium and occur at the root of the tooth. They may be multiple, in which case they are frequently associated with basal cell carcinomas of the skin.

Fissural or inclusion cysts are derived from epithelial inclusions along lines of fusion of the embryologic facial processes; they are classified according to their site, eg, median palatine cyst, globulomaxillary cyst. A similar cyst arising in nasopalatine duct remnants is called a nasopalatine cyst. All of these are fluid-filled cysts lined by squamous or respiratory epithelium.

Bone cysts are discussed in Chapter 67: Diseases of Bones.

Neoplasms of Tooth-Forming (Odontogenic) Tissues

The most common neoplasms in this region are those derived from bone (osteoma, osteosarcoma, etc) and soft tissues (neurofibroma, vascular neoplasms, etc). Ameloblastoma, although it is the most common odontogenic tumor, is rare, comprising 1% of cysts and tumors of the jaw. Other odontogenic neoplasms (cementomas, dentinomas, etc) are very rare.

Ameloblastoma occurs mainly in patients between 20 and 50 years of age, most often in the molar region of the mandible. It commonly is made up of both cystic and solid areas and arises from the epithelium of the dental lamina. It is a locally invasive neoplasm that does not metastasize, with a behavior and appearance similar to those of basal cell carcinoma of the skin. Because of its tendency to local invasion, it may recur after surgical removal.

(Table 31-1)

Inflammatory Lesions

Herpes Simplex Stomatitis

Herpes simplex type 1 is a common viral infection of the oral mucosa. The primary infection occurs in children or young adults as a widespread gingivostomatitis, characterized by multiple vesicles that rupture early to form ulcers. Systemic symptoms such as fever are present. Although locally severe, the disease is self-limited, and recovery is the rule.

Herpes simplex virus passes up the nerve trunks and infects the ganglia during the acute phase, where it remains dormant for long periods. Reactivation of the infection occurs repeatedly in some patients, with the virus passing down the nerve to the oral mucosa to form isolated vesicular lesions and ulcers (herpes labialis—fever blisters and cold sores). Reactivation is often precipitated by a concurrent fever or common cold or by exposure to sunlight. About 20% of the population is affected.

Candidiasis (Oral Thrush)

Candida albicans is a normal commensal of the mouth. Clinical infection of the oral mucosa usually represents an opportunistic infection in a patient with increased susceptibility. Persons at risk are those with immunosuppression, eg, acquired immune deficiency syndrome (AIDS) patients or those receiving cancer chemotherapy; newborn infants; patients with diabetes; and sick patients who receive long-term antibiotic therapy.

Candida produces inflammation and edema of the epithelium, forming white patches that leave raw ulcerated lesions when they are rubbed off. The budding yeasts and pseudohyphae of Candida can be identified in smears, cultures, or biopsy specimens from the lesion.

Aphthous Stomatitis

Aphthous stomatitis is a common disorder characterized by recurrent episodes of painful shallow ulcers (canker sores) on the oral mucosa. The pathologic picture is of nonspecific acute inflammation. The cause is unknown—psychosomatic and allergic mechanisms have been suggested; no infectious agent has been identified. The disease is usually self-limited. Rarely, it is associated with genital and conjunctival ulcers and neurologic abnormalities (Behçet's syndrome).

Rare Infections of the Oral Cavity

Actinomyces israelii and Actinomyces bovis cause chronic suppurative inflammation in the mouth and jaw. Patients present with an indurated jaw mass that has multiple sinuses opening to the skin surface, which drain pus. The pus typically contains visible small colonies of the organism (sulfur granules). Actinomyces species are gram-positive filamentous bacteria that are part of the normal mouth flora, and actinomycosis usually follows dental extraction. The organism is sensitive to penicillin.

A wide variety of spirochetes and fusiform bacilli inhabit the mouth. In debilitated or malnourished individuals, they may cause severe ulcerative gingivitis (Vincent's angina, or trench mouth).

Syphilis may involve the mouth in all three stages. In primary syphilis, the chancre may be on the lips or tongue; in secondary syphilis, superficial mucous patches and snail track ulcers may be present; in tertiary syphilis, chronic inflammation may produce tongue ulcers or large granulomas (gummas). Congenital syphilis also produces scarring at the angles of the mouth (rhagades). Abnormalities in the permanent teeth—Hutchinson's incisors and Moon's ulcers—are described in Chapter 54: Sexually Transmitted Infections.

Skin Diseases Manifesting in the Mouth

The following skin diseases are frequently manifested in the mouth, with or without concurrent skin lesions: (1) lichen planus, (2) pemphigus vulgaris, (3) bullous pemphigoid, and (4) erythema multiforme (Stevens-Johnson syndrome). The histologic features of these lesions are characteristic and permit diagnosis (Chapter 61: Diseases of the Skin).

Benign “Tumors” of the Oral Cavity

A large number of lesions present clinically as a mass in the oral cavity. Not all are neoplasms.

Mucocele (Mucus Escape Reaction)

Mucoceles represent a localized inflammatory reaction to the escape of mucus from a ruptured minor salivary gland or duct. They are usually small white cystic structures. More rarely, they become large and stretch the overlying mucosa. Large mucoceles of the floor of the mouth resulting from damage to the submandibular or sublingual salivary ducts are called ranulas.

Pyogenic Granuloma

Pyogenic granuloma is a common oral lesion that is the result of a reactive inflammatory proliferation of granulation tissue. It presents as a small, bright red nodule with ulceration of the overlying mucosa (Figure 31-2). Pyogenic granulomas occur commonly during pregnancy (pregnancy tumor). The cause is unknown. They resolve spontaneously.

Epulis

The term epulis signifies a local reactive inflammatory lesion of the gum that presents as a mass. It includes pyogenic granuloma as well as a distinct lesion composed of multinucleated giant cells (giant cell epulis). A form of congenital epulis is characterized by the proliferation of large cells with abundant granular cytoplasm (granular cell epulis).

Lingual Thyroid

Thyroid tissue at the root of the tongue is a rare condition that represents incomplete descent of thyroid tissue in the embryo. It usually coexists with a normal thyroid but in rare cases represents the individual's only thyroid tissue.

Benign Neoplasms of the Oral Cavity

Benign neoplasms in the oral cavity may arise from the squamous epithelium (squamous papilloma), from mesenchymal cells (fibroma, lipoma, neurofibroma), or from minor salivary glands (adenomas). One benign tumor that occurs commonly in the tongue is the granular cell tumor, probably a variant of a schwannoma in which the cells have abundant granular cytoplasm.

Squamous Carcinoma of the Oral Cavity

Incidence & Etiology

Squamous carcinoma accounts for over 95% of malignant neoplasms in the oral cavity and 5% of all cancers in the United States. Cancers arising in the lower lip (40%), the tongue (20%), and the floor of the mouth (15%) account for the majority. Involvement of the upper lip, palate, gingiva, and tonsillar area (5% each) is less common. The mucosa of the cheek is rarely the primary site for squamous carcinoma.

Oral cancer is much more common in men than in women. In the United States, oral cancer is most strongly related to tobacco chewing, particularly in baseball players. Cigarette and pipe smoking and alcohol are also associated.

Oral cancer is extremely common in Sri Lanka and parts of India, where chewing betel is common—betel is a green leaf that is mixed with areca nut, limestone, and tobacco to form a cud. The carcinogenic agent is believed to be in either the limestone or the tobacco. In parts of Italy where it is customary to smoke cigars with the lighted end inside the mouth, polycyclic hydrocarbons are believed to be the agents responsible for causing squamous carcinoma.

Clinical Features

Squamous cancer begins as a painless indurated plaque on the tongue or oral mucosa that commonly ulcerates to form a malignant ulcer. The lesion is usually readily visible, and diagnosis is made by biopsy. A significant number of patients with oral cancer present first with involved cervical lymph nodes. In very advanced local disease, there may be fixation of the tongue, interfering with speech and swallowing.

Pathology

The earliest lesion is squamous epithelial dysplasia, the most severe form of which is carcinoma in situ. At this stage there may or may not be visible whitish thickening (leukoplakia) of the epithelium (see below); however, most lesions are invasive to a variable depth at the time of diagnosis. The degree of differentiation varies; most tumors are well differentiated.

Oral cancer spreads primarily by lymphatics. Cervical lymph nodes are involved early. Bloodstream metastasis occurs late.

Leukoplakia is a term applied to visible flat, white lesions of the oral or genital mucous membranes. In most instances, it is due simply to hyperkeratosis (increased thickness of keratin layer) resulting from chronic irritation. In some instances, however, epithelial dysplasia is present, and the lesion is then considered precancerous. Persistent leukoplakia should therefore be biopsied.

Treatment & Prognosis

Treatment of oral squamous carcinoma is by radical surgery, radiotherapy, and chemotherapy. Squamous carcinoma of the oral cavity is sensitive to radiation therapy. The prognosis depends on the stage of the disease and is relatively good in the absence of cervical lymph node involvement.

Other Malignant Neoplasms of the Oral Cavity

Rare malignant neoplasms in the oral cavity include malignant lymphomas and carcinomas of minor salivary gland origin. Malignant melanoma is very rare.

Inflammatory Lesions of the Salivary Glands

Salivary Duct Calculi (Sialolithiasis)

Calculi occur mainly in the duct of the submandibular gland, possibly related to the thicker mucoid secretion of this gland. Obstruction of a salivary gland duct produces acute inflammation (acute sialadenitis) followed by chronic inflammation, glandular atrophy, and fibrosis (chronic sialadenitis).

Sjögren's Syndrome

Sjögren's syndrome is an autoimmune disease in which there is immune-mediated destruction of the lacrimal and salivary glands. It is manifested clinically as dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) due to failure of gland secretion. It is commonly associated with other autoimmune diseases, notably rheumatoid arthritis. Patients with Sjögren's syndrome have an increased incidence of malignant lymphomas in the salivary gland.

About 75% of patients have rheumatoid factor in the blood, and 70% have antinuclear antibodies. Specific autoantibodies directed against ribonucleopro-teins designated anti-Ro [Sjögren's Syndrome (SS)-A] and anti-La (SS-B) have been identified in the serum of 60% of patients with Sjögren's syndrome.

Histologically, the lacrimal and salivary glands show marked lymphocytic and plasma cell infiltration with destruction of the glandular epithelium and fibrosis.

The diagnosis can be made by clinical tests to demonstrate absence of secretion of tears and by lip biopsy, which shows the typical histologic changes in the mucus glands of the lip (Figure 31-3).

Infections of the Salivary Glands

The parotid gland is the most common site of involvement in mumps virus infection. The gland is painfully enlarged in the acute phase. Mumps is a self-limited illness.

Bacterial parotitis occurred commonly in the past in debilitated patients with dehydration and poor oral hygiene. It was characterized by painful enlargement of the gland, frequently complicated by abscess formation. Improvement in oral hygiene in patients at risk has made bacterial parotitis uncommon.

Neoplasms of the Salivary Glands

(Table 31-2)

Salivary gland neoplasms are common and varied. About 80% occur in the parotids, 15% in the submandibular gland, and 5% in minor salivary glands. All present as a mass causing enlargement of the affected gland. Computerized tomography is helpful in assessment of the location and extent of salivary gland neoplasms. Diagnosis requires cytologic (fine-needle aspiration) or histologic examination.

Benign Neoplasms

Pleomorphic Adenoma (Mixed Tumor)

Pleomorphic adenoma accounts for over 50% of salivary gland tumors. Although the lesion is benign and well circumscribed, encapsulation is incomplete, and simple enucleation is followed by a high rate of local recurrence due to regrowth of residual tumor. Wide excision is necessary for cure.

Pleomorphic adenoma is a firm, solid mass. Histologically, the tumor presents a greatly varied appearance. Uniform epithelial and myoepithelial cells are distributed in cords, nests, and strands within a matrix of mucoid material (Figure 31-4A), which frequently resembles cartilage (hence the mistaken notion that this was a mixed mesenchymal and epithelial tumor).

Warthin's Tumor (Adenolymphoma)

Most Warthin tumors occur in the parotid gland. They may rarely be multicentric and bilateral. The histologic appearance is distinctive (Figure 31-4B), with cystic spaces lined by a uniform double-layered epithelium that is frequently thrown into papillary folds. The neoplastic epithelial cells are large, with abundant pink cytoplasm, and are surrounded by a dense lymphocytic infiltrate.

Malignant Salivary Gland Neoplasms

Malignant neoplasms of the salivary glands are of several different pathologic types (Table 31-2).

Most of these neoplasms are slow growing. The exceptions are the rare undifferentiated carcinomas and the high-grade mucoepidermoid carcinomas. Low-grade mucoepidermoid carcinoma (Figure 31-4C) is a well-circumscribed neoplasm with variable solid and cystic areas that is cured in over 90% of cases by surgical removal. Adenoid cystic carcinoma (Figure 31-4D) is a highly infiltrative neoplasm with a tendency to invade along nerves. It is very rarely cured by surgery because of its invasiveness, and local recurrences and metastases often occur many (5–25) years after original treatment. Carcinomas arising in mixed tumors and acinic cell carcinoma have variable clinical courses.

The ear (Figure 32-1) is divided into (1) the external ear; (2) the middle ear, which is separated from the external auditory meatus by the tympanic membrane and is in communication anteriorly with the pharynx via the auditory tube (eustachian tube) and posteriorly with the mastoid air cells; and (3) the inner ear, consisting of the semicircular canals, which are part of the vestibular system, and the cochlea, which is the hearing sense organ. The vestibular and auditory nerves arise in the inner ear and pass to the brain stem in the internal auditory meatus.

The External Ear

The external ear consists of the pinna (or auricle) and the external auditory meatus. The pinna is composed of cartilage covered by skin. The meatus is lined by stratified squamous epithelium and contains wax-secreting ceruminous glands between the epithelium and the bony wall.

Preauricular Sinus & Cyst

This is a developmental anomaly associated with abnormal fusion of the facial folds. A blind-ending epithelium-lined tract opens as a small pit anterior to the meatus. Obstruction of the opening may lead to the development of an epidermal cyst; infection may cause an abscess and discharging sinus.

Otitis Externa

Inflammation of the external auditory canal is commonly caused by saprophytic fungi, commonly Aspergillus spp. This causes pain and a thick discharge. A foreign body or excessive exposure to water (swimmer's ear) predisposes to infection by low-grade pathogens.

Herpes Zoster

Herpes zoster involving the facial nerve ganglion (Ramsay Hunt syndrome) results in typical viral vesicles in the external ear, commonly associated with severe pain.

Chondrodermatitis Nodularis Helicis

This is a common lesion characterized clinically by the occurrence of a painful nodule in the helix. It is thought to result from trauma and is more common in males. Microscopically, there is ulceration of the skin and a chronic inflammatory infiltrate involving the perichondrium of the underlying cartilage. Surgical excision is curative.

Cauliflower Ear

This is the result of trauma and is most commonly seen in professional boxers. It is caused by thickening due to multiple organized and contracted hematomas.

Neoplasms of the External Ear

The skin of the external ear is a common site for basal cell and squamous carcinoma. Nevi and malignant melanoma also occur in the skin of the ear.

Neoplasms of the external auditory meatus, such as osteoma and ceruminous gland adenoma, are very rare.

The Middle Ear

Otitis Media

Incidence & Etiology

Otitis media is a common disease characterized by acute or chronic suppurative inflammation of the middle ear. Common causes are Streptococcus pyogenes and the pneumococcus. The middle ear is usually infected by pharyngeal organisms that reach the middle ear via the auditory tube. It usually occurs in children as a complication of viral and bacterial infections of the pharynx. Edema obstructing the pharyngeal opening of the auditory tube predisposes to infection.

Pathologic Features

In acute otitis media, the middle ear is filled with purulent exudate. The reddened tympanic membrane bulges into the external auditory meatus and may rupture, leading to a purulent discharge from the ear. Adequate and early treatment results in resolution with the middle ear reverting to normal.

In cases that are not properly treated, chronic suppuration occurs with fibrosis of the ossicles, leading to hearing loss. Chronic otitis media is associated with ingrowth of keratinizing squamous epithelium from the tympanic membrane, forming a pearly-white keratinized mass with acute and chronic inflammation known as a cholesteatoma.

Clinical Features

In acute otitis media there is earache and fever. The diagnosis is made by noting the outward-bulging, tense, reddened tympanic membrane. In cases where the membrane has ruptured, there is a purulent discharge from the ear. Impairment of hearing is common in these cases. Culture of the exudate is necessary to identify the causative bacterium.

Chronic suppurative otitis media may produce a chronic serous or purulent ear discharge, commonly associated with hearing loss of varying degree. Systemic symptoms are usually not prominent. The tympanic membrane may show evidence of rupture. Granulation tissue in the middle ear may protrude from the external auditory meatus as a polypoid mass (aural polyp). A cholesteatoma may be present in the middle ear.

Complications

Complications usually result from spread of the infection:

Mastoiditis

The mastoid air cells often become involved, leading to both localized and extensive bone inflammation and necrosis (osteomyelitis).

Epidural Abscess, Meningitis, and Brain Abscess

Spread of infection through the thin roof of the middle ear may result in epidural abscess, meningitis, or brain abscess in the cerebellum or temporal lobes.

Thrombophlebitis

Thrombophlebitis of the lateral and sigmoid venous sinuses follows local spread. This is characterized by high fever, severe headache, and bacteremia. Septic embolization from affected sinuses may result in lung abscess.

Otosclerosis

Otosclerosis is a disease of uncertain cause characterized by sclerosis of the middle ear ossicles. The bone becomes abnormally vascular; abnormal trabeculae develop and lead to increased bone density, often with fusion of the foot process of the stapes. Bony ankylosis impairs transmission of sound waves to the cochlea, leading to deafness. The disease is usually bilateral and has a strong familial tendency, with about 40% of patients giving a positive family history.

Clinically, otosclerosis is characterized by progressive deafness, usually beginning in the third decade. Low tones are lost first, followed by failure of high tone perception.

Glomus Jugulare Tumor

The jugular glomus lies in the adventitia of the internal jugular vein at the base of the skull just below the bony floor of the middle ear. Glomus jugulare tumor is a paraganglioma that arises in this structure. It frequently erodes into the middle ear, forming a red nodular mass and causing conduction deafness. When large, it causes bulging under and then through the tympanic membrane into the external auditory meatus. Glomus jugulare tumors are extremely vascular and bleed profusely when handled. The diagnosis is established by histologic examination. Glomus jugulare tumors are locally aggressive but do not usually metastasize.

The Inner Ear

Acute Labyrinthitis

Acute inflammation of the inner ear is a common cause of sudden unilateral hearing loss. It may also cause acute vertigo.

Viral infection is the most common cause of acute labyrinthitis. It may be part of a systemic viral infection, as occurs in mumps and measles, or it may be an isolated infection of the inner ear. Viral labyrinthitis is usually a self-limited illness, but a significant number of patients have permanent hearing loss.

Bacterial labyrinthitis is a rarer, more serious infection that is usually due to extension of suppurative otitis media. It causes suppurative necrosis of the inner ear and commonly results in permanent deafness.

Meniere's Disease (Hydrops of the Labyrinth)

Meniere's disease is an uncommon lesion involving the cochlea. The cause is not known; infection, allergy, and vascular disturbance have all been suggested. Meniere's disease occurs mainly in middle age, is more common in men than in women, and is bilateral in 20% of cases.

Pathology

Attacks of Meniere's disease are characterized by an imbalance in secretion and absorption of endolymphatic fluid that favors accumulation of fluid in the cochlea. This results in increased endolymphatic pressure in the cochlear duct. Initially, the process is reversible, but with repeated attacks there is degeneration of the cochlear hair cells that are the end organ for hearing.

Clinical Features

Clinically, Meniere's disease is characterized by fluctuating hearing loss and tinnitus, episodic vertigo, and a sensation of fullness in the ear. After several years, permanent and progressive hearing loss develops. No effective treatment is available. Treatment with diuretics is of value in some patients; otherwise, surgery may be used in an attempt to relieve the pressure.

The upper respiratory tract includes the nose, the paranasal sinuses, the pharynx, and the upper part of the larynx above the level of the true vocal cords. It is concerned with ventilation and speech. The nasal cavity and sinuses are lined by respiratory epithelium, which is continuous with the skin at the anterior nares and with the squamous epithelium of the pharynx posteriorly.

The Nose, Paranasal Sinuses, & Pharynx

Inflammatory Diseases

(Table 32-1)

Acute Rhinitis (Coryza, Common Cold)

Acute infectious rhinitis (coryza) is almost always the result of viral infection and is one of the most common infections of humans. It is caused by many different viruses, commonly rhinoviruses, influenza viruses, myxoviruses, paramyxoviruses, and adenoviruses.

Acute inflammation of the nasal mucosa is accompanied by markedly increased mucous secretion (catarrhal inflammation). The watery nasal discharge may be accompanied by sore throat due to pharyngeal involvement, fever, and muscle aches. Coryza is a self-limited infection. Although it is an innocuous infection, the common cold is responsible for the loss of many hours in the work force with considerable economic loss.

Allergic Rhinitis

Type I hypersensitivity (atopy) is also a common cause of acute rhinitis (hay fever). Susceptible patients are affected by a variety of allergens, most commonly pollens and dust. Patients who suffer from allergic rhinitis commonly have a positive family history and an increased frequency of developing other atopic diseases such as bronchial asthma and atopic dermatitis.

Acute Pharyngotonsillitis

Over 90% of cases of pharyngotonsillitis are the result of viral infections; influenza, parainfluenza, myxo- and paramyxoviruses, adenovirus, respiratory syncytial virus, and enteroviruses are the usual causes. Epstein-Barr virus (infectious mononucleosis) and cytomegalovirus produce pharyngotonsillitis as part of a distinctive systemic illness. Bacterial infection, most commonly with Streptococcus pyogenes, is responsible for less than 10% of cases. Neisseria gonorrhoeae, Mycoplasma pneumoniae, and Corynebacterium diphtheriae are rare causes.

Clinically, acute pharyngotonsillitis is characterized by hyperemia and erythema of the mucosa with pain (sore throat). Fever and enlargement of cervical lymph nodes are commonly present. The various etiologic agents cannot be distinguished from one another clinically, and culture of a throat swab is essential for diagnosis. It is important to identify cases caused by bacteria because they require specific antibiotic therapy. Early treatment of streptococcal infections is important because it decreases the risk of poststreptococcal glomerulonephritis and acute rheumatic fever, which occur as complications of streptococcal pharyngotonsillitis. A quick (< 30-minute) nonculture test is now available for the rapid diagnosis of streptococcal sore throat.

Viral infections are usually self-limited. Bacterial infections may lead to suppuration, particularly around the tonsil to cause peritonsillar abscess (quinsy), which presents as a fluctuant red mass in the region of the tonsil that causes intense pain on swallowing and inability to open the mouth (trismus) due to spasm of the masseter muscle. Abscesses may also occur in the retropharyngeal space and rarely involve the vertebral bone. Tonsils subject to recurring inflammation may be advantageously removed; the enlarged tonsils and adenoids that do not become infected should not be removed because they represent reactive hyperplasia of the lymphoid tissue of Waldeyer's ring, part of the body's defense mechanism.

Inflammatory & Allergic Nasal Polyps

Repeated episodes of acute rhinitis result in the development of nasal polyps. These common nasal “tumors” occur mainly in young adults and are usually multiple. Similar polyps may occur in the sinuses. Microscopically, they are composed of edematous stroma in which are found numerous neutrophils, eosinophils, lymphocytes, and plasma cells. Eosinophils are more numerous in allergic than in inflammatory polyps. Nasal polyps may cause nasal obstruction and frequently need to be removed surgically.

Chronic Rhinitis

Chronic inflammation of the nasal cavity occurs in leprosy, leishmaniasis, and syphilis, with marked destruction of the nose. Nonspecific inflammation also occurs with cocaine sniffing, in which septal perforation may occur. Histologically, foreign body granulomas due to substances used to adulterate cocaine may be seen in the submucosa.

Nonspecific chronic bacterial infection of the nose often leads to atrophy of the nasal epithelium, accompanied by crusting and an offensive odor (ozena, or chronic atrophic rhinitis).

Rhinoscleroma is an uncommon infection in the United States but occurs more often in eastern Europe and Central America. It is caused by Klebsiella rhinoscleromatis, which multiplies in macrophages in the nasal mucosa. Accumulation of foamy macrophages (Mikulicz cells) filled with bacteria (see Chapter 13: Infectious Diseases: I. Mechanisms of Tissue Changes in Infection) and lymphoplasmacytic infiltration result in nodular polypoid masses and ulceration (Hebra nose). The diagnosis is made by demonstration of the organism in histologic sections and culture.

Rhinosporidiosis occurs in South India and Sri Lanka but is rare elsewhere. It is caused by the fungus Rhinosporidium seeberi, which appears in the nasal submucosa as large spherules containing endospores. The inflammation results in nasal polyps. The diagnosis is made by demonstrating the organism in histologic sections; Rhinosporidium cannot be cultured.

Paranasal Sinusitis

Inflammation of the maxillary, ethmoid, and frontal sinuses is a common complication of acute rhinitis and results from obstruction of the nasal openings of these sinuses by the nasal inflammatory edema. Chronic suppurative inflammation may occur. Haemophilus influenzae and Streptococcus pneumoniae are the organisms found most commonly in chronic suppurative sinusitis.

Sinusitis causes headache, sometimes accompanied by fever and cervical lymph node enlargement. Extension of the inflammation to adjacent structures may lead to serious complications such as osteomyelitis, orbital cellulitis, cavernous sinus thrombophlebitis, meningitis, and brain abscess. These are rare.

Fungal Infections

Phycomycosis (mucormycosis) is an infection caused by fungi of the class Phycomycetes, most commonly Mucor species. Mucor (bread mold) is a saprophytic fungus commonly found in nature, and infection occurs only in a host with increased susceptibility. Patients with diabetic ketoacidosis and patients being treated for cancer with immunosuppressive anticancer drugs are those usually affected.

The fungus causes an acute nasal inflammation with extensive tissue necrosis due to invasion of blood vessels with thrombosis, frequently spreading to the adjacent orbit and the cranial cavity. Death is common unless emergent treatment is instituted. Irregularly branching nonseptate hyphae can be identified by microscopy and culture.

Aspergillus causes a similar necrotizing inflammation of the nasal cavity in immunocompromised patients. Aspergillus is distinguished from Mucor by culture and recognition of the thinner, dichotomously branching, septate hyphae.

Aspergillus spp may also cause a noninvasive infection in the nasal sinuses, particularly in the presence of chronic sinusitis. In these cases, the fungus forms an intracavitary mass (“fungus ball”).

Wegener's Granulomatosis

Wegener's granulomatosis is a rare disease that in its fully expressed form involves the upper and lower respiratory tract and the renal glomeruli (Chapters 35: The Lung: II. Toxic, Immunologic, & Vascular Diseases and 48: The Kidney: II. Glomerular Diseases). Nasal and paranasal sinus lesions occur in 60% of patients and are characterized clinically by destructive mass lesions. Biopsies of the nasal lesions may show necrotizing granulomas and a severe vasculitis.

Neoplasms

Neoplasms of the Nasal Cavity

Nasal neoplasms are uncommon but display great variety (Table 32-2). They commonly present as polypoid masses obstructing the nasal cavity. Both benign and malignant tumors may ulcerate and bleed, producing epistaxis. The most common benign neoplasm is sinonasal papilloma. A variant of sinonasal papilloma known as inverted papilloma has a locally infiltrative growth pattern (Figure 32-2) with a tendency to recur locally after surgical excision. The malignant neoplasms, such as squamous carcinoma and embryonal rhabdomyosarcoma, infiltrate extensively and tend to metastasize via lymphatics to the cervical lymph nodes. Diagnosis of the specific type is made by biopsy.

Malignant lymphoma of the nasal cavityis most frequently a high-grade, rapidly growing T cell lymphoma. It is characterized by the presence of a polymorphous cell population among which are found the malignant T cells. The lesion is characterized by extensive necrosis; patients commonly present with a severe, progressive destructive lesion of the midline nasal cavity and palate (Figure 32-3). This clinical presentation is sometimes designated lethal midline granuloma—an obsolete term that should be discarded. The diagnosis is made by biopsy; special studies to demonstrate the malignant T cell population are often necessary.

Neoplasms of the paranasal sinuses (Table 32-2) tend to remain silent clinically until they are large.

Carcinoma of the Nasopharynx

Carcinoma of the nasopharynx is of special interest because it has a striking geographic distribution, being very common in the Far East and eastern Africa. In addition, it has been linked etiologically to epstein-barr virus (EBV). Affected individuals show evidence of EBV infection, and the viral genome has been identified in the tumor cells. EBV-associated nasopharyngeal carcinoma tends to occur in young patients. The mechanism of EBV carcinogenesis is unknown. Cigarette smoking is also an important etiologic factor in nasopharyngeal carcinoma, especially in cases in the United States, where there is no strong association with EBV.

Nasopharyngeal carcinoma is a squamous carcinoma of varying differentiation. One subtype consists of poorly differentiated squamous carcinoma associated with a prominent lymphocytic reaction (sometimes called lymphoepithelioma, although this designation is not favored because the lymphoid cells are not neoplastic). This variety occurs in younger patients, is associated with EBV, disseminates to lymph nodes at an early stage, and is more sensitive to radiation.

Nasopharyngeal carcinoma often presents with enlarged cervical lymph nodes resulting from metastasis. A few cases infiltrate the skull base, involving cranial nerves at the base of the brain. Obstruction of the opening of the auditory tube may result in otitis media. Only rarely is the primary tumor responsible for early symptoms. The diagnosis is made by examination of the nasopharynx and biopsy; in infiltrative lesions, blind biopsies may be positive even when no gross lesion is visualized.

Malignant Lymphoma of the Oropharynx

The ring of lymphoid tissue in the oropharynx (Waldeyer's ring) is a common site for occurrence of extranodal malignant lymphoma. Most are of B cell origin; intermediate- and high-grade lymphomas are most common.

Malignant lymphoma presents as a nodular or ulcerative mass that resembles carcinoma grossly. Diagnosis is made by histologic examination with immunologic confirmation that the neoplastic cells bear lymphocytic markers such as common leukocyte antigen. Frozen sections stained for immunoglobulin light chains and gene rearrangement studies permit monoclonality of the lymphocytic proliferation to be established and are important in differentiating a malignant lymphoma from a reactive lymphoid proliferation.

The Larynx

Inflammatory Conditions

Acute Laryngitis

Acute laryngitis frequently accompanies viral and bacterial infections of the upper respiratory tract, causing pain and hoarseness. It is usually self-limited.

Acute epiglottitis is a common, important, and dangerous infection in very young children. It is caused either by Haemophilus influenzae or by viruses. The site of maximal involvement is the epiglottis, although in severe cases the entire larynx and trachea may be affected (acute laryngotracheobronchitis). The acute inflammation and its attendant swelling result in narrowing of the air passages, causing respiratory obstruction. Croup is acute respiratory difficulty with cyanosis in a child due to epiglottitis, laryngeal spasm, or both.

Diphtheria

Incidence

Diphtheria is caused by the gram-positive bacillus Corynebacterium diphtheriae. It has become rare in the United States and other developed countries because of effective immunization in childhood [the “D” in diphtheria-pertussis-tetanus (DPT) vaccine represents diphtheria toxoid], but it still occurs frequently in underdeveloped countries, where it is predominantly a disease of young children.

Pathology

(Figure 32-4)

Diphtheria is transmitted by droplet infection. Nasal, faucial, and laryngeal forms of diphtheria are recognized depending on the site of maximum involvement. Laryngeal diphtheria is the most common form as well as the most dangerous. The bacterium infects the mucosa, causing acute inflammation with exudation and necrosis. The necrotic mucosa and exudate remain adherent to the surface as a yellowish membrane (acute membranous inflammation), characteristic of diphtheria. Detachment of the membrane and impaction in the trachea may cause sudden death (Figure 32-5). Respiratory obstruction is a common cause of death in diphtheria and may require emergency tracheostomy.

The bacterium remains localized to the surface of the upper respiratory tract and does not invade deep tissues or the bloodstream. However, some strains produce an exotoxin that enters the bloodstream and causes myocardial and nerve damage (Figure 32-4).

Clinical Features & Treatment

Laryngeal diphtheria is characterized by pain and hoarseness. High fever and marked enlargement of cervical lymph nodes (“bull neck”) is common. Physical examination reveals acute inflammation with the typical membrane. The diagnosis is made by clinical examination and culture (requires special media). Patients with nasal diphtheria may have a very mild illness with nasal discharge only, and they represent an important source of infection.

Treatment includes antibiotics to kill the organisms as well as high doses of antitoxin to neutralize any exotoxin that has been absorbed into the bloodstream. With adequate treatment, mortality rates of diphtheria are low.

Laryngeal Nodule

Laryngeal nodule is a common lesion that occurs in the middle third of the true vocal cord. It is related to excessive use of the voice and occurs in singers (“singer's nodule”), teachers, and preachers. It is believed to be the result of trauma.

It appears grossly as a firm, rounded nodule covered by mucosa. Microscopically, dilated vascular spaces, fibrosis, and myxomatous degeneration are present to varying degrees.

Clinically, patients present with hoarseness and loss of ability to speak. Excision is curative. However, unless the patient stops overusing the voice, the lesion may recur.

Laryngeal Neoplasms

Squamous Papilloma

Laryngeal squamous papilloma is a common benign neoplasm that usually presents with hoarseness. Laryngeal papillomas occur in two distinct forms: (1) solitary papillomas occurring in adults, cured by local excision; and (2) juvenile papillomatosis, which occurs mainly in children and is characterized by the development of multiple papillomas and a high incidence of local recurrence after surgical removal. Juvenile papillomatosis is caused by infection with papillomavirus. In many patients, the lesions regress after puberty. Very rarely, malignant transformation may occur.

Squamous Carcinoma

Incidence & Etiology

Squamous carcinoma is the most common malignant neoplasm of the larynx. Most cases occur after the age of 50 years. Men are affected 7 times more frequently than women. Cigarette smoking and exposure to asbestos have a statistical association with laryngeal carcinoma.

Pathologic Features

Laryngeal carcinomas are classified anatomically as (1) glottic (Figure 32-6), arising in the vocal cord; (2) supraglottic, arising in the aryepiglottic folds and epiglottis; and (3) subglottic, below the vocal cords.

Laryngeal carcinoma often begins as an area of squamous epithelial dysplasia progressing to carcinoma in situ before invasive carcinoma occurs. The noninvasive lesions appear as white areas of thickened plaque-like mucosa. Invasion is associated with nodularity and ulceration.

Microscopically, the majority are well-differentiated squamous carcinomas (Figure 32-7). A highly differentiated form of squamous carcinoma is characterized by a wart-like exophytic growth pattern with little invasion. This type, called verrucous carcinoma, is successfully treated by surgery.

Clinical Features

Laryngeal carcinoma commonly presents with hoarseness, and it is a good rule that carcinoma must be excluded in any patient with persistent hoarseness. Large masses may cause respiratory obstruction and hemoptysis. Metastasis to cervical lymph nodes occurs early. Distant metastases occur late. Diagnosis is established by laryngoscopy and biopsy. Surgical removal of laryngeal carcinoma is highly successful when the patient has an early neoplasm restricted to the vocal cord. When there is subglottic or supraglottic extension, total laryngectomy and removal of cervical lymph nodes is frequently necessary, and survival rates are much lower. Radiation therapy is effective because squamous carcinoma is a radiosensitive neoplasm.

The eyes are complex vision receptors situated in a pair of bony cavities in the skull—the orbits—which open anteriorly to the exterior and posteriorly for the entry and exit of nerves and blood vessels. The main nerve—the optic nerve—carries visual impulses from the retina to the brain.

The anterior covering of the eyeball is the transparent cornea, which permits entry of light into the eyeball through the lens, which is the focusing mechanism. The cornea is continuous at the limbus with the sclera. The conjunctiva lines the inner surface of the eyelids (palpebral conjunctiva) and is reflected onto the sclera (bulbar conjunctiva). When the eyelids are closed, the conjunctiva forms a sac that is lubricated by tears, the secretion of the lacrimal gland, situated in the lateral part of the orbit.

The eyeball is separated from orbital bone by connective tissue, muscles, nerves, and blood vessels. The eyelids, which protect the front of the eye, are covered with skin on the outside and conjunctiva on the inside.

Pain

Many different types of pain may occur in eye diseases. In conjunctival and corneal inflammation, burning or itching of the eye is commonly associated with increased sensitivity to light (photophobia). Deep aching pain occurs in angle-closure glaucoma and inflammation of the uveal tract. Pain in acute glaucoma may be so severe as to cause vomiting. Headache may accompany conditions of disturbed vision.

Visual Disturbances

Decreased visual acuity (amblyopia) is a feature of many ocular diseases. Spots and halos before the eyes occur in early cataract. Halos may also occur in glaucoma. Diminution of the visual field may signify disease of the retina, the optic disk, or the visual neural pathways, which include the optic nerve, chiasm, radiation, and visual cortex. Night blindness may result from vitamin A deficiency and retinal degenerative diseases. Double vision (diplopia) is a feature of eye muscle dysfunction.

Discharge

Eye discharge may represent increased tearing (eg, in allergy) or inflammation of the conjunctiva. Microscopic examination of the discharge shows the type of inflammatory cells present and the presence of viral and chlamydial inclusions when these agents are involved. The presence of numerous eosinophils is typical of allergic conjunctivitis, while neutrophils dominate in acute infectious conjunctivitis. Gram stain for bacteria and potassium hydroxide preparations for fungi are of value in some cases.

Change in Appearance

Inspection of the eyes may disclose evidence of strabismus (muscle imbalance), hemorrhage, congestion, jaundice, swelling, displacements of the eye such as proptosis (forward displacement), and the presence of tumors. Ophthalmoscopic examination may reveal abnormalities of the anterior chamber (eg, hypopyon and hyphema—pus and blood, respectively, in the anterior chamber), lens (eg, early cataract, dislocation), vitreous (eg, hemorrhage), retina (eg, diabetic and hypertensive retinopathy, retinal degenerative diseases, detachment, hemorrhages, exudates, changes in retinal vessels), and optic disk (eg, optic atrophy, papilledema).

The skin covering of the eyelids is subject to a wide variety of diseases, the most important of which is basal cell carcinoma. Low-grade inflammation of the lid margins is termed blepharitis. More specific diseases of the eyelids are discussed below.

Sty (Hordeolum)

A sty is an acute suppurative inflammation of the hair follicle or associated glandular structures—the sebaceous glands of Zeis and the apocrine glands of Moll. It is usually caused by Staphylococcus aureus and produces a painful localized abscess (Figure 33-1), which is cured by rupture or extraction of the involved eyelash to effect drainage.

Chalazion

A chalazion is a common chronic inflammatory process involving the meibomian glands. It is believed to be caused by duct obstruction, leading to retention of secretions, infection, and chronic inflammation with macrophages, lymphocytes, and plasma cells. Clinically, it produces an indurated mass that may be mistaken for a neoplasm.

Xanthelasma

Xanthelasma, a small yellow plaque composed of collections of lipid-laden foamy macrophages in the subepithelial zone, occurs in some hyperlipidemic conditions. There are usually multiple lesions.

Cysts

Several types of cyst occur in the eyelid. Congenital dermoid cysts occur along the lines of fusion of the facial skin folds, most often at the external angle of the upper eyelid. Microscopically, the cysts are lined by skin containing dermal glands. Acquired cysts arising in ducts of glands (eg, eccrine and apocrine hydrocystomas) and epidermal inclusions (epidermal cysts) are common.

Malignant Neoplasms

Basal cell carcinoma is the most common malignant neoplasm of the eyelid. It occurs much more commonly in the lower than in the upper lid. The skin about the eye is the most common location for basal cell carcinoma. These tumors begin as small nodules that grow and ulcerate, forming an enlarging ulcer with an elevated pearly margin (Figure 33-2). Microscopically, they are composed of nests of small hyperchromatic cells resembling basal cells. They invade locally and may extend deeply into the orbit, but they do not metastasize. Squamous carcinoma is uncommon in the eyelids.

Meibomian gland carcinoma (sebaceous carcinoma) occurs chiefly in the upper eyelid, which is the predominant location of meibomian glands. These tumors appear as slowly growing yellowish masses that may resemble a chalazion. Progression causes erosion of the lid margin or conjunctiva and the appearance of a large lobulated mass. Microscopically, the tumor forms large invasive nests and sheets of cells with abundant cytoplasm. The diagnostic feature is the presence of large cells with vacuolated cytoplasm that contain lipid (demonstrable with lipid stains on frozen sections). Like other adenocarcinomas, meibomian gland carcinoma may spread laterally in pagetoid fashion into the epidermis of the eyelid. Meibomian gland carcinoma is important to distinguish from squamous and basal cell carcinoma because it has a more aggressive biologic behavior. Lymph node metastasis is common.

The conjunctiva is lined by a thin, transparent, nonkeratinizing stratified squamous epithelium in which are found scattered mucous cells. The cornea is composed of nonkeratinizing stratified squamous epithelium, Bowman's layer, an avascular stroma, Descemet's membrane, and an underlying endothelium lining the anterior chamber.

Keratoconjunctivitis

Definition & Etiology

Inflammation of the conjunctiva is called conjunctivitis and inflammation of the cornea is called keratitis; when both are involved, as is frequently the case, the term keratoconjunctivitis is used.

Conjunctivitis is common and has many causes (Table 33-1).

Pathology & Clinical Features

Acute bacterial conjunctivitis is characterized by pain, hyperemia appearing as vascular injection (red eye), and a purulent discharge in which numerous neutrophils are present. Neisseria species, pneumococcus, and Haemophilus aegyptius infections are common. Ophthalmia neonatorum results from infection of the fetus with Neisseria gonorrhoeae during delivery through the birth canal. Ulceration occurs in severe cases, and when this involves the cornea visual impairment may occur.

Viral keratoconjunctivitis is most frequently caused by adenoviruses and herpes simplex virus (Figure 33-3).

Inclusion conjunctivitis (“swimming pool conjunctivitis”) is common worldwide. It is characterized clinically by acute inflammation with pain, red eye, and discharge and histologically by accumulation of lymphocytes in the conjunctiva. It is caused by chlamydiae, which may be demonstrated as cytoplasmic inclusions in infected cells in the exudate. The disease is transmitted via contaminated hands, shared towels, and infection of the fetus during delivery through an infected birth canal. It is self-limited, with recovery occurring in all cases after a few days of discomfort.

Trachoma is a much more serious chlamydial infection in which there is long-term destruction of the cornea, leading to blindness in cases that are not treated early. The acute conjunctival inflammation progresses to a chronic phase in which there may be epithelial hyperplasia, lymphocytic infiltration, and pannus formation—the last an inflamed mass of granulation tissue that replaces the superficial layers of the cornea and results in blindness. Trachoma is the most common cause of blindness in underdeveloped tropical countries.

Acanthamoeba keratoconjunctivitis. Epidemics of keratoconjunctivitis caused by amebae of the species Acanthamoeba have been traced to the use of contaminated contact lens cleaning fluids.

Allergic conjunctivitis. Allergic conjunctivitis—also called vernal (“spring”) conjunctivitis—is typically seasonal in occurrence due to pollens in the environment and is associated with hay fever. Histologically, it shows goblet cell hyperplasia and infiltration by lymphocytes and eosinophils.

Phlyctenular conjunctivitis is a delayed hypersensitivity response to antigens of bacteria such as Mycobacterium tuberculosis and Staphylococcus aureus. It is characterized by an elevated, hard, red triangular plaque at the limbus, which ulcerates and then heals in about 2 weeks. Corneal involvement may cause scarring and visual disturbances.

Diagnosis

The diagnosis of conjunctivitis can be made clinically based on the presence of conjunctival injection and discharge. Keratitis is diagnosed by examination; invisible epithelial lesions may be outlined by fluorescein staining. The etiologic agent is identified by culture and microscopic examination of conjunctival discharge and scrapings from corneal lesions. A finding of chlamydial or viral inclusions is diagnostic. Amebic trophozoites are present, often in large numbers, in Acanthamoeba keratoconjunctivitis.

Degenerative Conjunctival & Corneal Conditions

Pinguecula

Pinguecula is a common degenerative disease caused by ultraviolet solar radiation and is similar to solar-induced changes in the skin, with epithelial atrophy, degeneration of collagen, and hyalinization of elastic tissue (see Chapter 61: Diseases of the Skin). The exposed interpalpebral part of the conjunctiva is chiefly affected. The atrophic epithelium may show precancerous dysplastic changes.

Pinguecula appears clinically as a thickened, yellowish area in the conjunctiva. It may become secondarily infected and ulcerate. The risk of squamous carcinoma is small.

Pterygium

Pterygium is pathologically similar to pinguecula but differs in that it affects the sclerocorneal junction (limbus) and may extend into the cornea as a layer of vascularized connective tissue, producing corneal opacification and visual impairment. In the cornea, there is replacement of Bowman's layer by collagen and elastic tissue. Pterygia also have a greater tendency to recur after excision. The incidence of secondary infection, ulceration, and epithelial dysplasia is low.

Squamous Metaplasia

In squamous metaplasia, the normally thin, transparent nonkeratinized squamous epithelium is replaced by a thick, opaque, keratinized squamous type. This appears as a pearly white plaque on the conjunctiva, sometimes called leukoplakia. Areas of squamous metaplasia are more often subject to infection and ulceration but are not precancerous.

Squamous metaplasia may be caused by (1) insufficiency of tears, as occurs in Sjögren's syndrome, which causes frictional damage of the conjunctiva; (2) protrusion of the eyeball (exophthalmos), which prevents eyelid closure and results in excessive irritation; (3) neuromuscular disorders in which paralysis of the eyelid muscles is a feature (facial nerve paralysis), leading to inability to close the eyes, again increasing irritation; and (4) vitamin A deficiency, which causes a basic abnormality of squamous epithelium, leading to thickening. The areas of squamous metaplasia in vitamin A deficiency are called Bitot's spots and commonly extend to involve the cornea; they may become infected, causing softening of the cornea (keratomalacia) and visual impairment.

Arcus Senilis

Arcus senilis is a ring of fatty infiltration at the outer margin of the cornea, common in elderly individuals. A similar lesion occurs in younger patients with hyperlipidemia.

Neoplasms of the Conjunctiva

Benign Neoplasms

Benign neoplasms such as squamous papilloma, melanocytic nevus, hemangioma, and neurofibroma occur rarely on the conjunctiva as small masses of various colors. Benign lymphoid hyperplasia may also occur, leading to a conjunctival mass.

Squamous Carcinoma

Squamous carcinoma of the conjunctiva is also rare. Most cases are believed to be the result of exposure to ultraviolet radiation, complicating the actinic lesions pinguecula and pterygium. The neoplastic process progresses through increasing grades of dysplasia to carcinoma in situ and then invasive squamous carcinoma.

Conjunctival squamous carcinoma usually invades superficially and almost never metastasizes. It has an excellent prognosis and is treated by limited local excision.

Malignant Melanoma

Conjunctival malignant melanoma is rare. It may occur (1) de novo, (2) in relation to a preexistent melanocytic nevus, or (3) in relation to an acquired melanocytic hyperplasia (lentigo). It presents clinically as a nodule that may or may not be pigmented. The more superficial lesions can be treated by local excision and have a good prognosis. With deeper invasion, lymphatic and vascular involvement commonly occurs, and the prognosis is guarded even following radical exenteration of orbital contents.

Mass lesions of the orbit cause forward displacement of the eyeball (proptosis). Because the lesion is behind the conjunctival sac, special techniques are required to obtain tissue for diagnosis.

Inflammatory Pseudotumor

Inflammatory pseudotumor is characterized by forward protrusion of the eyeball (proptosis), pain, swelling, and restriction of ocular movement. Histologically, there is edema, hyperemia, and infiltration of the orbital soft tissue with neutrophils, eosinophils, lymphocytes, and plasmacytes. The diagnosis is usually made when orbital exploration in a patient suspected clinically of having a neoplasm shows only nonspecific chronic inflammation and fibrosis. The cause is unknown.

Graves' Disease

Graves' disease (primary autoimmune hyperthyroidism) is commonly associated with exophthalmos as a result of edema and increased accumulation of mucopolysaccharides in the orbital soft tissues. The orbital muscles show marked myxoid change and weakness. The condition is usually bilateral and is believed to be caused by an autoantibody (exophthalmos-producing factor) that may persist even after the hyperthyroidism is treated (Chapter 58: The Thyroid Gland).

Lacrimal Gland Diseases

The lacrimal gland is situated in the lateral wall of the orbit and is rarely the site of pathologic processes. Sjögren's syndrome (see Chapter 31: The Oral Cavity & Salivary Glands) is characterized by autoimmune destruction of the gland associated with dry eyes due to failure of tear production. The autoimmune process usually causes atrophy of the gland; more rarely, the lymphocytic infiltration may produce a mass lesion (benign lymphoepithelial lesion). Primary neoplasms of the lacrimal glands are very rare and are similar to salivary gland neoplasms.

Primary Neoplasms of the Orbit

Malignant Lymphoma

Malignant lymphoma is the most common malignant neoplasm of the orbit in adults. Most orbital lymphomas are low-grade B cell lymphomas (Chapter 29: The Lymphoid System: II. Malignant Lymphomas). An exception is Burkitt's lymphoma, an aggressive B cell lymphoma that occurs in children in Africa and often involves the orbit.

The diagnosis is established by histologic examination. Inflammatory lymphoid proliferations (pseu-dotumors) may be distinguished from lymphomas by immunologic methods (polyclonal versus monoclonal; Chapter 29: The Lymphoid System: II. Malignant Lymphomas).

Embryonal Rhabdomyosarcoma

Embryonal rhabdomyosarcoma is a rare orbital primary tumor, occurring mainly in children. It is highly malignant, with a rapid growth rate. The diagnosis is made by demonstrating an undifferentiated neoplasm in which primitive rhabdomyoblasts may be identified. Untreated, it is rapidly fatal. With chemotherapy and radiation, orbital embryonal rhabdomyosarcomas can be controlled and sometimes cured.

Optic Nerve Glioma

Optic nerve glioma is a rare neoplasm of the optic nerve, usually affecting the intraorbital part of the nerve. It is commonly a well-differentiated, very low grade, fibrillary astrocytoma that grows slowly over several years. Most cases occur in children, often in association with generalized neurofibromatosis (von Recklinghausen's disease).

Neoplasms of Bone

Primary neoplasms of bone such as osteoma and histiocytosis X (Hand-Schüller-Christian disease and eosinophilic granuloma) and metastatic neoplasms such as neuroblastoma in children and metastatic carcinoma in adults may present as orbital masses.

The eyeball itself is composed of several layers and compartments. The retina is the inner light-sensitive layer and is composed of modified neurons, the axons of which form the optic nerve. The choroid, which is pigmented, and the fibrous sclera are the outer layers of the eyeball.

The lens is attached to the sclera by the ciliary muscle, contraction of which controls the focal length of the lens. The lens and ciliary muscle separate the anterior part of the eyeball, filled with aqueous humor, from the posterior part, which is filled with vitreous. The iris projects into the aqueous humor in front of the lens, partially separating the aqueous humor into anterior and posterior chambers. The iris, by its contraction, controls the amount of light entering the eye and also gives the eyes their color. The circular black opening in the center of the iris through which light passes into the eye is the pupil. The choroid, iris, and ciliary body comprise the uveal tract.

Inflammatory Conditions of the Eyeball

Inflammations of the eye may involve one or more—or all—components of the eyeball.

Bacterial Infections

Pyogenic bacteria such as staphylococci gain entry into the eyeball following penetrating injuries to the eye or, less often, from orbital cellulitis or via the bloodstream from an infective focus elsewhere in the body. Acute endophthalmitis or panophthalmitis results, with swelling and a severe neutrophil infiltration. Untreated, there may be severe destruction with softening and collapse of the eyeball (phthisis bulbi).

Toxoplasma Chorioretinitis

Toxoplasma gondii infection involves the choroid and retina and occurs either as a congenital transplacental infection or as an acquired infection.

Congenital toxoplasmosis may cause neonatal or intrauterine death from encephalitis; survivors frequently show chorioretinitis, sometimes as the only manifestation of congenital toxoplasmosis. The organism persists in the choroid as pseudocysts, causing symptoms in childhood and early adult life.

Acquired toxoplasmosis occurs in adults. Ocular involvement is common, and the eye may be the only clinical site of involvement.

Pathologically, there is focal coagulative necrosis of the retina and choroid, with granulomatous inflammation and fibrosis. Toxoplasma can be identified as small crescent-shaped trophozoites and as larger pseudocysts.

Ocular Larva Migrans

Ocular larva migrans is usually caused by larvae of Toxocara canis (a dog nematode) that reach the interior of the eye through the uveal or retinal blood vessels. Children exposed to dog feces are chiefly affected. It causes a granulomatous endophthalmitis with large numbers of eosinophils around the larvae. Marked fibrosis frequently causes retinal detachment and visual loss.

Noninfectious Inflammatory Conditions

Sarcoidosis produces both an acute iridocyclitis, with fever and pain, and a chronic granulomatous disease, with corneal opacification and visual impairment.

Rheumatoid arthritis typically produces scleritis and uveitis, in which foci of necrotic collagen surrounded by palisading histiocytes resemble ill-defined rheumatoid nodules.

Both ulcerative colitis and Crohn's disease are associated with nonspecific chronic iritis.

Ankylosing spondylitis is associated with anterior uveitis in 20–50% of cases.

Sympathetic ophthalmia is an uncommon diffuse granulomatous uveitis that affects both eyes after a penetrating injury (or surgery) to one eye. It is believed to be the result of an immunologic reaction against antigens released or altered in some unknown way by the injury. The entire uveal tract is infiltrated by lymphocytes and plasma cells and may show ill-defined epithelioid cell granulomas. Severe visual loss commonly occurs.

Behet's syndrome (uveitis plus oral and genital lesions) and Reiter's syndrome (conjunctivitis, uveitis, arthritis, and urethritis) probably represent postinfectious autohypersensitivity responses.

Miscellaneous Diseases of the Eyeball

Cataract

Opacification of the lens, irrespective of cause (Table 33-2), is called a cataract (Figure 33-4). The lens is derived from surface ectoderm and consists of a mass of modified epithelial cells. It has no blood supply and derives its nutrition from the aqueous humor of the anterior chamber. Despite the fact that the oldest epithelial cells become compressed centrally throughout life, the lens normally remains transparent. Most individuals develop some lens opacification in later life (senile cataract). Whether this is an aging phenomenon or disease has not been elucidated.

Pathologically, visible cataracts may occur with minimal changes in water content of cortical cells. With advanced or mature cataracts, the epithelial cells break down, fragment, and undergo dissolution. In diabetes, high glucose levels cause excess production of sorbitol within the lens. Sorbitol is not diffusible and exerts a strong osmotic effect, leading to water imbibition and ultimately to cell degeneration. In galactosemia, galactose is metabolized in the lens to dulcitol with similar results.

Clinically, cataracts cause progressive loss of visual acuity. Halos or spots in the visual field are early symptoms. Current treatment methods, which include extraction of the cataract and implantation of a prosthetic lens, are very successful.

Glaucoma

Glaucoma is defined as an increase in intraocular pressure sufficient to cause degeneration of the optic disk and optic nerve fibers. Normal intraocular pressure as measured by tonometry (which measures the pressure required to cause flattening of the cornea to a specified amount) is 10–20 mm Hg; elevations in pressure are thought to have a dual effect, inducing deformational changes in the optic disk plus decreased retinal blood flow. However, the correlation between intraocular pressure and optic nerve damage is not exact.

Glaucoma is the result of an abnormality in the dynamics of aqueous humor circulation. Aqueous humor production occurs at the ciliary body, partly by diffusion from plasma and partly by active secretion by the epithelium of the ciliary processes. The fluid passes from the posterior chamber through the pupil to the anterior chamber and then peripherally to the angle between the iris and cornea. Absorption of aqueous humor occurs at the iridocorneal angle by the trabecular meshwork and canal of Schlemm.

Glaucoma is a common disorder, with about 2% of all people over 40 years of age affected. Visual loss is the most common effect. Of the many causes (Table 33-3), obstruction to the outflow of aqueous humor from the anterior chamber is most common (Figure 33-5). Glaucoma may occur as a complication of other diseases affecting the eye (secondary glaucoma) or as a primary disease.

Primary Open-Angle Glaucoma

Primary open-angle glaucoma, also called simple or chronic glaucoma, is a slowly progressive bilateral disease of insidious onset. It occurs in individuals over 40 years of age and is responsible for over 90% of cases of primary glaucoma. It is characterized by a slow rise in intraocular pressure with subtle microscopic abnormalities in the canal of Schlemm. There is progressive degeneration of the optic disk, an increase in size of the blind spot (scotoma), and peripheral visual field loss, ultimately causing blindness. Examination of the optic fundus shows deepening and enlargement of the optic cup. Patients usually present at a late stage with severe loss of vision.

Treatment with pupillary constrictors such as pilocarpine and laser trabeculoplasty produce temporary improvement. Surgical treatment, which is indicated in severe cases, is successful in about 75% of cases in arresting visual loss.

Primary Angle-Closure Glaucoma

Angle-closure (closed-angle) glaucoma usually presents acutely. Many patients have a genetically determined anatomic variation that results in a shallow anterior chamber and a narrow anterior chamber angle (Figure 33-5). Increasing lens size, a normal occurrence with increasing age, causes forward displacement of the lens, further narrowing the angle. Acute attacks may be precipitated by dilation of the pupil (as in preparation for funduscopy), which further narrows the angle by thickening the periphery of the iris during pupillary dilation. Rapid increase of intraocular pressure causes severe pain, often accompanied by vomiting and rapid visual impairment. The optic disk is swollen, and complete blindness can occur within days.

Acute angle-closure glaucoma is an ophthalmologic emergency. Treatment with osmotic agents and pupillary constrictors such as pilocarpine is effective in interrupting the acute attack. Peripheral iridectomy by laser is effective both in the acute relief of symptoms and in preventing further episodes.

Dislocation of the Lens

The lens is connected to the ciliary body by a bundle of collagen fibers called the zonular ligament and may be dislocated by trauma. Patients with abnormal collagen, as in Marfan's syndrome and homocystinuria, have weak zonular fibers that predispose to dislocation.

Anterior lens dislocation often causes obstruction to aqueous flow, leading to acute secondary glaucoma. Posterior dislocation of an intact lens does not cause severe symptoms except visual impairment. If the lens capsule is ruptured, lens protein may enter the bloodstream and stimulate antibody formation (lens protein contains antigens sequestered from the immune system during fetal life and is therefore regarded as foreign). This may result in immunologic endophthalmitis, with lymphocytic infiltration around the ruptured lens.

Retinitis Pigmentosa

Retinitis pigmentosa is a group of degenerative disorders with variable inheritance, most often recessive. Expression is variable, but retinal degeneration usually begins in early life and progresses slowly to blindness at age 50–60 years. The degeneration begins in the peripheral part of the retina, causing progressive loss of the peripheral visual field. Central vision, including macular vision, is spared until the very late stage.

Pathologically, there is disappearance of the rod and cone layer and loss of ganglion cells. Loss of night vision is an early symptom. The fundus becomes slate-gray in color (Figure 33-6). There is no treatment at present.

Retrolental Fibroplasia of Prematurity

Retrolental fibroplasia is caused by excessive oxygen, usually given for therapy of respiratory distress syndrome in premature infants. The immature retina is exquisitely sensitive to increased partial pressure of oxygen, responding with vasospasm and proliferation of small retinal vessels into the vitreous. Edema and leakage of blood leads to organization, fibrous traction on the retina, retinal detachment, and blindness. Careful control of oxygen therapy in the premature newborn has reduced the incidence of retrolental fibroplasia.

Vascular Diseases of the Retina

The retina is commonly affected in diseases of small vessels such as the microangiopathy of diabetes mellitus (Chapter 46: The Endocrine Pancreas (Islets of Langerhans)) and hypertension (Chapter 20: The Blood Vessels).

Vascular lesions causing occlusion of the central artery of the retina result in pale retinal infarction. Hemorrhagic infarction occurs when the central vein of the retina is occluded. Arterial emboli—either cholesterol emboli, derived from atheromatous plaques in the carotid circulation, or septic emboli in septicemic states such as infective endocarditis—may produce microinfarcts in the retina.

Retinal Detachment

Detachment of the retina is separation of the neuroepithelial layer of the retina from the pigment layer, due either to fibrous contraction or to fluid collection between the two layers. Detachment deprives the neuroepithelial layer of its choroidal blood supply and causes degeneration within 4–6 weeks.

Retinal detachment may result from (1) extravasation of fluid from the choroid or retina in inflammations, neoplasms, and venous obstruction; (2) contraction of vitreous fibrous bands that have been formed by organization of vitreous hemorrhage, inflammation, or neovascularization (as occurs in retrolental fibroplasia and diabetic retinopathy); or (3) a hole in the retina, permitting passage of liquefied vitreous. Such holes are present in about 7% of individuals over 40 years. Trauma and severe myopia contribute to the occurrence of retinal detachment. Approximately 1% of myopic patients develop retinal detachment.

Clinically, retinal detachment causes sudden loss of part of the field of vision. The field defect depends on the site of detachment. Untreated, the detachment progresses, ultimately involving the entire retina and causing blindness. Laser treatment is effective in stopping the progression of retinal detachment and reversing the visual loss.

Optic Atrophy

The term optic atrophy is applied to extreme pallor of the optic disk (optic nerve head). It usually reflects degeneration of optic nerve fibers and has many causes (Table 33-4). Primary optic atrophy—resulting from diseases of the optic disk—is distinguished from secondary optic atrophy, which is due to long-standing edema of the disk caused by increased intracranial pressure. Loss of vision follows unless the cause is treatable.

Neoplasms of the Eyeball

Malignant Melanoma

Malignant melanoma occurs almost exclusively in white adults. In the United States and Europe, it is the most common intraocular malignant neoplasm. It is uncommon in Asia, Africa, and South America.

Pathology

Intraocular malignant melanomas arise in the uveal tract (85% in the choroid, 10% in the ciliary body, 5% in the iris). They are composed of proliferating, invasive melanocytes, with several morphologic subtypes. Spindle cell type A tumor, composed of slender cells with elongated nuclei and no nucleoli, has the best prognosis (85% 10-year survival). Spindle cell type B tumors, composed of more ovoid spindle cells with nucleoli, have a slightly worse prognosis (80% 10-year survival). Epithelioid cell tumors, composed of large pleomorphic round cells with hyperchromatic nuclei, nucleoli, and a high mitotic rate, have a bad prognosis (35% 10-year survival). Over 50% of melanomas of the uveal tract contain mixtures of the above cell types.

Clinical Features

Melanomas arising in the iris become visible as a black mass in the front of the eye and usually present at an early stage. Most melanomas of the iris are spindle cell type A tumors. The combination of early presentation and favorable histologic type gives iris melanomas a high survival rate (nearly 100%) after local surgical removal. Note that benign pigmented nevi also occur in the iris and are difficult to distinguish from melanoma clinically (Figure 33-7).

Melanomas arising in the ciliary body and choroid generally attain a large size before they are detected. They grow inward into the vitreous, producing detachment of the retina and visual impairment, which is the usual presenting feature. Such melanomas are usually treated by enucleation of the eye. Their prognosis depends mainly on the histologic type. In epithelioid melanomas, death is commonly due to distant metastases.

Retinoblastoma

Retinoblastoma has a worldwide distribution and occurs in two forms: an inherited form (30%) and a sporadic form (70%). It occurs almost exclusively in children under 5 years of age, with a frequency of about 1:20,000.

Genetic Features

(Chapter 18: Neoplasia: II. Mechanisms & Causes of Neoplasia)

Inherited cases commonly have bilateral retinoblastoma. More than 90% of sporadic cases have unilateral disease. Retinoblastoma is associated with a constant karyotypic abnormality (deletion of 13q−). Molecular studies show that a pair of recessive genes is involved, both of which must have undergone mutation to produce the disease. In the sporadic form of the disease, both mutations are acquired. In the hereditary form, one recessive gene is inherited in mutant form; the other suffers an acquired mutation, after which the tumor develops.

Pathology

Retinoblastoma arises in the retina from primitive neural cells. It is an aggressive neoplasm, infiltrating the retina, extending into the vitreous (Figure 33-8) and along the optic nerve into the cranial cavity. Seeding of the cerebrospinal fluid may result in widespread dissemination in the subarachnoid space. Hematogenous spread also occurs. Microscopically, retinoblastoma is composed of undifferentiated small cells with a high nuclear to cytoplasmic ratio and hyperchromatic nuclei. Mitotic figures are frequent. The presence of Flexner-Winter-steiner rosettes composed of the neoplastic cells arranged in an orderly fashion around a central lumen is a diagnostic feature.

Clinical Features

The parent usually notices some peculiarity in the child's eye, commonly a white spot in the pupil (Figure 33-9; leukocoria—caused by the reflection of light entering the pupil by the retinal tumor). Increased size of the orbit due to the mass effect is a late sign. Fundal examination shows the presence of the neoplasm.

Without treatment, retinoblastoma causes rapid death in most cases. Patients with tumors restricted to the eyeball are treated by removal of the eye; if there is no scleral or optic nerve involvement, these patients have a good prognosis. Treatment with radiation and chemotherapy has improved the prognosis somewhat in more advanced cases. A significant number (1–2%) of retinoblastomas undergo spontaneous regression—the most frequent human neoplasm to demonstrate this phenomenon. Regression is associated with cessation of proliferation of the neoplasm followed by fibrosis. Patients with inherited retinoblastomas that have regressed represent a source of transmission of the abnormal gene to the next generation. Examination of the parents of a child with the inherited form of retinoblastoma commonly shows the presence of regressed tumor in one parent's retina.