Developmental Disturbances of Oral and Paraoral Structures

Multifactorial Inheritance

In contrast to single-gene inheritance, either autosomal or sex-linked, the pedigree pattern does not afford a diagnosis of multifactorial inheritance. In multifactorial traits, the trait is determined by the interaction of a number of genes at different loci, each with a small, but additive effect, together with environmental factors (i.e., the genes are rendering the individual unduly susceptible to the environmental agents). Many congenital malformations (Table 1-6) and common diseases of adult life are inherited as multifactorial traits and these are categorized as either continuous or discontinuous.

Molecular Genetics in Dental Development

The first sign of tooth development is a local thickening of oral epithelium, which subsequently invaginates into neural crest derived mesenchyme and forms a tooth bud. Subsequent epithelial folding and rapid cell proliferation result in first the cap, and then the bell stage of tooth morphogenesis. During the bell stage, the dentine producing odontoblasts and enamel secreting ameloblasts differentiate. Tooth development, like the development of all epithelial appendages, is regulated by inductive tissue interactions between the epithelium and mesenchyme (Thesleff, 1995).

There is now increasing evidence that a number of different mesenchymal molecules and their receptors act as mediators of the epithelial-mesenchymal interactions during tooth development. Of the bone morphogenetic proteins (BMPs) 2, 4, and 7 mRNAs shift between the epithelium and mesenchyme in the regulation of tooth morphogenesis (Aberg et al, 1997). The fibroblast growth factor (FGF) family have also been localized in epithelial and mesenchymal components of the tooth by immunohistochemistry (Cam et al, 1992); and in dental mesenchyme tooth development and shape is regulated by FGF8 and FGF9 via downstream factors MSX1 and PAX9 (Kettunen and Thesleff, 1998).

Control of Tooth Development

Homeobox genes have particular implications in tooth development. Muscle specific homeobox genes Msx-1 and Msx-2 appear to be involved in epithelial mesenchymal interactions, and are implicated in craniofacial development, and in particular, in the initiation developmental position (Msx-1) and further development (Msx-2) of the tooth buds (MacKenzie et al, 1991; Jowett et al, 1993). Further evidence of the role of Msx-1 comes from gene knock-out experiments which results in disruption of tooth morphogenesis among other defects (Satokata and Maas, 1994). Pax-9 is also transcription factor necessary for tooth morphogenesis (Neubuser et al, 1997). BMPs are members of the growth factor family (TGF) and they function in many aspects of craniofacial development with tissue specific functions. BMPs have been found to have multiple roles not only in bone morphogenesis, (BMP 5, for example, induces endochondral osteogenes is in vivo), but BMP 7 appears to induce dentinogenesis (Thesleff, 1995).

Disorders in Tooth Morphogenesis

Advances in the field of molecular genetics have made great progress in the understanding of a number of dental anomalies with a genetic component.

Etiology

The cause is unknown, but the condition has been variously ascribed to vascular or lymphatic abnormalities; CNS disturbances; and chromosomal abnormalities.

Clinical Features

Patients affected by facial hemihypertrophy exhibit an enlargement which is confined to one side of the body, unilateral macroglossia and premature development, and eruption as well as an increased size of dentition. Familial occurrence has been reported on a few occasions, according to the excellent review of the condition by Rowe, who described four additional cases. Of all reported cases, females are affected somewhat more frequently than males (63% versus 37%), according to the review by Ringrose. There is an almost equal involvement of the right and left sides.

Oral Manifestations

The dentition of the hypertrophic side, according to Rowe, is abnormal in three respects: crown size, root size and shape, and rate of development. Rowe has also pointed out that not all teeth in the enlarged area are necessarily affected in a similar fashion. There is little information about the effects on the deciduous dentition, but the permanent teeth on the affected side are often enlarged, although not exceeding a 50% increase in size. This enlargement may involve any tooth, but seems to occur most frequently in the cuspid, premolars, and first molar. The roots of the teeth are sometimes proportionately enlarged but may be short.

Characteristically, the permanent teeth on the affected side develop more rapidly and erupt before their counterparts on the uninvolved side (Fig. 1-5). Coincident to this phenomenon is premature shedding of the deciduous teeth. The bone of the maxilla and mandible is also enlarged, being wider and thicker, sometimes with an altered trabecular pattern.

The tongue is commonly involved by the hemihypertrophy and may show a bizarre picture of enlargement of lingual papillae in addition to the general unilateral enlargement and contralateral displacement. In addition, the buccal mucosa frequently appears velvety and may seem to hang in soft, pendulous folds on the affected side.

Histologic Features

Tissue examination has been infrequently reported but is generally uninformative. In those cases reported, true muscular hypertrophy was not found.

Treatment and Prognosis

There is no specific treatment for this condition other than attempts at cosmetic repair. Cosmetic surgery is advised after cessation of growth. Effect on life expectancy is not certain, but in some cases patients have lived a normal life span. Periodic abdominal ultrasound/ MRI is recommended to rule out tumors.

Differential Diagnosis

There are certain diseases of the jaws, such as neurofibromatosis and fibrous dysplasia of the jaws, that may give the clinical appearance of facial hemihypertrophy, but these can usually be differentiated readily by the lack of effect on tooth size and rate of eruption.

Etiology

The etiology has been the subject of considerable debate. Wartenburg considered the primary factor to be a cerebral disturbance leading to increased and unregulated activity of sympathetic nervous system, which in turn produced the localized atrophy through its trophic functions conducted by way of sensory trunks of the trigeminal nerve. Other workers suggested extraction of teeth, local trauma, infection and genetic factors could also be a cause. In a paper published in 1973, Poswillo attributed the development of facial deformities to the disruption of the stapedial artery. Poswillo fed pregnant rats with triazine and pregnant monkeys with thalidomide and showed the consistent maldevelopment of first and second branchial arch structures. Robinson, in 1987, supported Poswillo’s theory by demonstrating carotid flow abnormalities in two and defects related to vascular disruption in a third child with craniofacial microsomia.

Clinical Features

Hemifacial atrophy is a syndrome with diverse presentation. The most common early sign is a painless cleft, the ‘coup de sabre,’ near the midline of the face or forehead. This marks the boundary between normal and atrophic tissue. A bluish hue may appear in the skin overlying atrophic fat.

The affected area extends progressively with the atrophy of the skin, subcutaneous tissue, muscles, bones, cartilages, alveolar bone and soft palate on that side of the face. In addition to facial wasting that may include the ipsilateral salivary glands and hemiatrophy of the tongue, unilateral involvement of the ear, larynx, esophagus, diaphragm, kidney and brain have been reported.

It starts in the first decade and lasts for about three years before it becomes quiescent. The final deformity varies widely, burning itself out in some patients with minimal atrophy, while in others progressing to marked atrophy.

Neurological disorders are found in 15% of patients, while ocular findings occur in 10–40%, the most common being enophthalmos.

Rarely, one half of the body may be affected. This condition may be accompanied by pigmentation disorders, vitiligo, pigmented facial nevi, contralateral Jacksonian epilepsy, contralateral trigeminal neuralgia and ocular complications.

The disease occurs more frequently in women; female to male ratio is 3 : 2. It has a slight predilection for the left side and appears in the first or second decades of life. It progresses over a period of two and 10 years, and atrophy appears to follow the distribution of one or more divisions of the trigeminal nerve. The resulting facial flattening may be mistaken for Bell’s palsy (Fig. 1-6).

Oral Manifestations

Dental abnormalities include incomplete root formation, delayed eruption and severe facial asymmetry, resulting in facial deformation and difficulty with mastication. Hemiatrophy of the lips and the tongue is reported, as are dental effects. Foster has reported that growth of the teeth may be affected just as other tissues are involved. Eruption of teeth on the affected side may also be retarded.

Differential Diagnosis

Post-traumatic fat atrophy, hemifacial microsomia (first and second branchial arch syndrome), Goldenhar’s syndrome, and partial lipodystrophy which is; however, always bilateral.

Treatment and Prognosis

There is no specific treatment for the condition. It has been found that, typically, the disease will be progressive for a period of several years and then remain unchanged for the remainder of the patient’s life.

Etiology

Many theories of the etiology of congenital lip pits have been offered, but none has been universally accepted. Pits may result from notching of the lip at an early stage of development, with fixation of the tissue at the base of the notch, or from failure of complete union of the embryonic lateral sulci of the lip, which persist and ultimately develop into the typical pits.

Commissural pits are also difficult to explain, but they occur at the site of the horizontal facial cleft and may represent defective development of this embryonic fissure.

Clinical Features

The lip pit or fistula is a unilateral or bilateral depression or pit that occurs on the vermilion surface of either lip but far more commonly on the lower lip (Fig. 1-7A). In some cases a sparse mucous secretion may exude from the base of this pit. The lip sometimes appears swollen, accentuating the appearance of the pits.

Commissural pits appear as unilateral or bilateral pits at the corners of the mouth on the vermilion surface (Fig. 1-7B). An actual fistula may be present from which fluid may be expressed. Whether this tract, either in lip or commissural fistulas, represents a true duct is not clear. Interestingly, in several cases preauricular pits have been reported in association with commissural pits.

Treatment

Surgical excision of these various pits has been recommended but primarily for academic information, since the pits are harmless and seldom manifest complications.

Etiology

The most prominent and consistent feature of van der Woude syndrome is orofacial anomalies. They are due to an abnormal fusion of the palate and lips, at days 30–50 postconception. The van der Woude syndrome can be caused by deletions in chromosome band 1q32, and linkage analysis has confirmed this chromosomal locus as the disease gene site. The gene has been localized to chromosome band 1q32. Further studies have raised the possibility that the degree of phenotypic expression of a gene defect at this locus may be influenced by a second modifying gene that has been mapped to chromosome band 17p11.

Clinical Features

In general, van der Woude syndrome affects about 1 in 100,000–200,000 people. About 1–2% of patients with cleft lip or palate have van der Woude syndrome. The van der Woude syndrome affects both genders equally and no difference among them have been reported. The severity of the van der Woude syndrome varies widely, even within families. About 25% of individuals with the van der Woude syndrome have no findings or minimal ones, such as missing teeth or trivial indentations in the lower lips. Others have severe clefting of the lip or palate. The hallmark of the van der Woude syndrome is the association of cleft lip and/or palate with distinctive lower lip pits. This combination is seen in about 70% of those who are overtly affected but in less than half of those who carry the gene. The cleft lip and palate may be isolated. They may take any degree of severity and may be unilateral or bilateral. Submucous cleft palate is common and may be easily missed on physical examination. Hypernasal voice and cleft or bifid uvula are clues to this diagnosis. It is possible as well that a bifid uvula is an isolated finding in certain individuals with the van der Woude syndrome. The lower lip pits seen in this syndrome are fairly distinctive (Fig. 1-8). The pits are usually medial, on the vermilion portion of the lower lip. They tend to be centered on small elevations in infancy, but are simple depressions in adults. These pits are often associated with accessory salivary glands that empty into the pits, sometimes leading to embarrassing visible discharge. Occasionally lip pits may be the only manifestation of the syndrome. Affected individuals may have maxillary hypodontia; missing maxillary incisors or missing premolars. Again, this may be the only manifestation of the syndrome. Although infrequently reported, other oral manifestations include syngnathia (congenital adhesion of the jaws); narrow, high, arched palate; and ankyloglossia (short glossal frenulum or tongue-tie).

Extraoral Manifestations

The reported incidence of extraoral manifestations are rare but include limb anomalies, popliteal webs, and brain abnormalities. Accessory nipples, congenital heart defects, and Hirschsprung disease have also been reported. It is uncertain whether these extraoral manifestations are unassociated additional anomalies or infrequently expressed aspects of van der Woude syndrome.

Treatment

Along with a thorough orofacial examination, a thorough general physical examination helps to determine if there are other associated anomalies of the cardiovascular system, genitourinary system, limbs, or other organ systems. Examination and genetic counseling by a pediatric geneticist (dysmorphologist) is suggested for families that may be affected by the van der Woude syndrome. This should include an examination of as many potentially affected family members (probands) as possible. Surgical repair of the cleft lip and palate or other anomalies may be required, when planning surgical intervention, imaging studies of affected areas, such as CT scanning of the oropharynx, may be appropriate. Even among those less severely affected, surgical excision of lip pits is often performed, either to alleviate discomfort or for cosmetic reasons (e.g. improving the appearance of lip pits or reducing mucous discharge).

Etiology

It has been clearly established by Fogh-Andersen and confirmed by numerous other investigators that two separate and distinct entities exist:

Heredity is undoubtedly one of the most important factors to be considered in the etiology of these malformations. However, there is increasing evidence that environmental factors are important as well. According to Fogh-Andersen, slightly less than 40% of the cases of cleft lip with or without cleft palate are genetic in origin, whereas slightly less than 20% of the cases of isolated cleft palate appear to be genetically derived. Most investigations indicate that the inheritance pattern in cleft lip with or without cleft palate is different from that in isolated cleft palate. The mode of transmission of the defect is uncertain. This has been discussed by Bhatia, who pointed out that the possible main modes of transmission are either by a single mutant gene, producing a large effect, or by a number of genes (polygenic inheritance), each producing a small effect which together create this condition. It should be pointed out that cytogenetic studies have failed to reveal visible alterations in chromosomal morphology of the affected individuals.

Bixler more recently has expanded upon this concept and reiterated that there are two forms of clefts. The most common is hereditary, its nature being most probably polygenic (determined by several different genes acting together). In other words, when the total genetic liability of an individual reaches a certain minimum level, the threshold for expression is reached and a cleft occurs. Actually, it is presumed that every individual carries some genetic liability for clefting, but if this is less than the threshold level, there is no cleft. When the individual liabilities of two parents are added together in their offspring, a cleft occurs if the threshold value is exceeded. However, even though this is the most common form of cleft, the threshold value is sufficiently high that it is a low-risk type. The second form of cleft is monogenic or syndromic and is associated with a variety of other congenital anomalies. Since these are monogenic, they are of a high-risk type. Bixler has pointed out that, fortunately, the clefting syndromes are rare and probably make up only 5% of all cleft cases even though, according to Cohen, there are now over 300 clefting syndromes reported in the literature.

Although there is insufficient evidence that nutritional disturbances cause cleft palates in human beings, abnormal dietary regimens have caused developmental clefts in animals. Cleft palate has been experimentally produced in newborn rats by feeding diets either deficient or excessive in vitamin A to maternal rats during pregnancy. Riboflavin-deficient diets fed to pregnant rats have also produced offspring with a high incidence of cleft palate. The administration of cortisone to pregnant rabbits has induced similar clefts in their young.

Strean and Peer reported that physiologic, emotional, or traumatic stress may play a significant role in the etiology of human cleft palate, since stress induces increased function of the adrenal cortex and secretion of hydrocortisone. Their study, based on histories of 228 mothers of children with cleft palate, confirms the experimental findings of cleft palate in animals due to the action of stressor agents or the administration of cortisone. However, Fraser and Warburton have reported data which indicate that neither maternal emotional stress nor the lack of a prenatal nutritional supplement was causally related to the occurrence of cleft lip or cleft palate.

Other factors that have been suggested as possible causes of cleft palate include:

Despite the numerous clinical and experimental investigations, the etiology of cleft palate in the human being is still largely unknown. It must be concluded; however, that heredity is probably the most important single factor.

Clinical Features

Cleft lip with or without palate is more common in males than in females. Males have also been reported to have more severe defects, whereas the isolated cleft palate is more common in females.

Clefts can be divided into nonsyndromic and syndromic forms. Syndromic forms of clefts include those cases that have additional birth defects like lip pits or other malformations, whereas nonsyndromic clefts are those cases wherein the affected individual has no other physical or developmental anomalies and no recognized maternal environmental exposures. At present, most studies suggest that about 70% of cases of cleft lip with or without palate and 50% of isolated cleft palate are nonsyndromic. The remaining syndromic cases can be subdivided into chromosomal anomalies, teratogens and uncategorized syndromes.

Cleft lip can occur as a unilateral (on the left or right side) or as a bilateral anomaly. The line of cleft always starts on the lateral part of the upper lip and continues through the philtrum to the alveolus between the lateral incisor and the canine tooth. The clefting anterior to the incisive foramen (i.e. lip and alveolus) is also defined as a cleft of primary palate. Cleft lip may occur with a wide range of severity, from a notch located on the left or right side of the lip to the most severe form, bilateral cleft lip and alveolus that separates the philtrum of the upper lip and premaxilla from the rest of the maxillary arch. When cleft lip continues from the incisive foramen further through the palatal suture in the middle of the palate, a cleft lip with palate (either unilateral or bilateral) is present (Figs. 1-9, 1-10). A wide range of severity may be observed. The cleft line may be interrupted by skin or mucosa bridges, hard (bone) bridges, or both, corresponding to a diagnosis of an incomplete cleft. This occurs in unilateral and bilateral CLP.

Isolated cleft palate is etiologically and embryologically different from cleft lip with or without cleft palate. Several subtypes of isolated cleft palate can be diagnosed based on severity. The uvula is the place where the minimal form of clefting of the palate is observed (Fig. 1-11). A more severe form is a cleft of the soft palate. A complete cleft palate constitutes a cleft of the hard palate, soft palate, and cleft uvula. The clefting posterior to the incisive foramen is defined as a cleft of secondary palate.

A median maxillary anterior alveolar cleft is a relatively common defect, occurring in approximately 1% of the population, according to Stout and Collett, but this is unrelated to cleft lip or cleft palate. This type of cleft has been discussed by Gier and Fast, who suggested that it might be due to precocious limitation of the growth of the primary ossification centers on either side of the midline at the primary palate, or to their subsequent failure to fuse. In addition, Miller and his coworkers have suggested that at least some cases may represent an incomplete manifestation of the median cleft-face syndrome (hypertelorism, median cleft of the premaxilla and palate, and cranium bifidum occultum). This syndrome has no clinical manifestations and is usually detected only on routine intraoral radiographic examination (Fig. 1-12).

Clinical Significance

Most cases of cleft lip can be surgically repaired with excellent cosmetic and functional results. It is customary to operate before the patient is one month old or when he has regained his original birth weight and is still gaining.

Both the physical and psychologic effects of cleft palate on the patient are of considerable concern. Eating and drinking are difficult because of regurgitation of food and liquid through the nose. The speech problem is also serious and tends to increase the mental trauma suffered by the patient.

Most individuals with CL, CP, or both, require the coordinated care of providers in many fields of medicine and dentistry, as well as those in speech pathology, otolaryngology, audiology, genetics, nursing, mental health, and social medicine.

Treatment

Treatment of CLP anomalies requires years of specialized care. Although successful treatment of the cosmetic and functional aspects of orofacial cleft anomalies is now possible, it is still challenging, lengthy, costly, and dependent on the skills and experience of a medical team. This especially applies to surgical, dental, and speech therapies. Undoubtedly, closure of the CL is the first major procedure that tremendously changes children’s future development and ability to thrive. Variations occur in timing of the first lip surgery; however, the most usual time occurs at approximately three months of age. Pediatricians used to strictly follow a rule of ‘three 10s’ as a necessary requirement for identifying the child’s status as suitable for surgery (i.e. 10 lb, 10 mg/L of hemoglobin, and age 10 weeks). Although pediatricians are presently much more flexible, and some surgeons may well justify a neonatal lip closure, the rule of three 10s is still very useful.

Anatomical differences predispose children with CLP and with isolated CP to ear infections. Therefore, ventilation tubes are placed to ventilate the middle ear and prevent hearing loss secondary to otitis media with effusion (OME). In multidisciplinary teams with significant participation of an otolaryngologist, the tubes are placed at the initial surgery and at the second surgery routinely. The hearing is tested after the first placement when ears are clear with tubes. If no cleft surgery is planned early, placing the tubes by age six months and monitoring hearing with repeated testing is recommended. Complications include eardrum perforation and otorrhea, particularly in patients with open secondary palates in which closure is planned for a later date.

Etiology

CG is an unusual clinical manifestation of cheilitis that evolves in response to one or more diverse sources of chronic irritation. Lip enlargement is attributable to inflammation, hyperemia, edema, and fibrosis. Surface keratosis, erosion, and crusting develop consequent to longstanding actinic exposure, unusual repeated manipulations that include self-inflicted biting or other factitial trauma, excessive wetting from compulsive licking, drying (sometimes associated with mouth-breathing, atopy, eczema, and asthma), and any other repeated stimulus that could serve as a chronic aggravating factor.

Clinical Features

In 1870, von Volkman introduced the term cheilitis glandularis. He described a clinically distinct, deeply suppurative, chronic inflammatory condition of the lower lip characterized by mucopurulent exudates from the ductal orifices of the labial minor salivary glands. In 1914, Sutton proposed that the characteristic lip swelling was attributable to a congenital adenomatous enlargement of the labial salivary glands. This remained the prevailing hypothesis until 1984 when Swerlick and Cooper reported five new cases and a retrospective analysis of all cases of CG reported until that time. Their studies revealed no evidence to support the assertion that salivary gland hyperplasia is responsible for CG.

Cheilitis glandularis is a chronic progressive condition. Patients typically present for diagnostic consultation within 3–12 months of onset. Complaints vary according to the nature and the degree of pain, the enlargement and the loss of elasticity of the lip, and the extent of evident surface change. Asymptomatic lip swelling initially occurs with clear viscous secretion expressible from dilated ductal openings on the mucosal surface. Some patients report periods of relative quiescence interrupted by transient or persistent painful episodes associated with suppurative discharge. A burning discomfort or a sensation of rawness referable to the vermilion border may be reported. This is associated with atrophy, speckled leukoplakic change, erosion, or frank ulceration with crusting. CG affects the lower lip almost exclusively. In more suppurative cases, application of gentle pressure can elicit mucopurulent exudate. Prolonged exposure to the external environment results in desiccation and disruption of the labial mucous membrane, predisposing it to inflammatory, infectious, and actinic influences. This is an uncommon condition. CG has been associated with a heightened risk for the development of squamous cell carcinoma. In many cases, dysplastic (premalignant) surface epithelial change is evident, and frank carcinomas have been reported in 18–35% of cases. The disorder appears to favor adult males; however, cases have been reported in both genders. The condition most frequently occurs between the fourth and seventh decades of life; however, the age range is wide. The risk of dysplasia and carcinoma increases with age, especially in fair-skinned individuals with sun-damaged skin. This is because the characteristic eversion of the lower lip results in long-term chronic exposure of the thinner, more vulnerable labial mucosa to actinic influence.

Classification

CG had historically been subclassified into three types, now believed to represent evolving stages in the severity of a single progressive disorder.

The latter two types of CG have the highest association with dysplasia and carcinoma, respectively.

Histologic Findings

Lip biopsy is indicated to rule out specific granulomatous diseases that predispose to lip enlargement and aid in establishing a definitive diagnosis. A representative incisional biopsy specimen should consist of a wedge (or punch) of lip tissue that includes surface epithelium and is of adequate depth to ensure inclusion of several submucosal salivary glands. The term cheilitis glandularis is a provisional descriptive designation rather than a definitive diagnosis. It refers to a constellation of clinical findings that can reflect a broad scope of possible histologic changes; therefore, no consistent or pathognomonic features of this disorder are seen at the microscopic level. Instead, a diverse array of possible alterations can be seen in both the surface epithelium and the submucosal tissues. These findings best enable the clinician to presumptively determine the etiology and the nature of individual cases.

The minor salivary glands may appear normal under the microscope, or they may exhibit various changes indicative of nonspecific sialadenitis. These changes can include atrophy or distention of acini, ductal ectasia with or without squamous metaplasia, chronic inflammatory infiltration and replacement of glandular parenchyma, and interstitial fibrosis. Suppuration and sinus tracts may be present in cases that involve bacterial infection. Other possible histologic findings include stromal edema, hyperemia, surface hyperkeratosis, erosion, or ulceration.

Differential Diagnosis

Differential diagnoses of this condition include actinic keratosis, atopic dermatitis, cheilitis granulomatosa (Miescher-Melkersson-Rosenthal syndrome), sarcoidosis and squamous cell carcinoma.

Treatment

The approach to treatment is based on diagnostic information obtained from histopathologic analysis, the identification of likely etiologic factors responsible for the condition, and attempts to alleviate or eradicate those causes. In cases with acute or chronic suppuration, bacterial culture and sensitivity testing is indicated for selection of appropriate antibiotic therapy. Given the relatively small number of reported cases of CG, neither sufficient nor reliable data exist with regard to medical approaches to the condition. Therefore, treatment varies accordingly for each patient. In cases where a history of chronic sun exposure exists (especially if the patient is fair skinned or the everted lip surface is chronically eroded, ulcerated, or crusted), biopsy is strongly recommended to rule out actinic cheilitis or carcinoma.

Etiology

The cause is unknown. A genetic predisposition may exist in Melkersson-Rosenthal syndrome; siblings have been affected, and a plicated tongue may be present in otherwise unaffected relatives. Crohn’s disease, sarcoidosis, and orofacial granulomatosis may present in a similar clinical fashion, and with identical histologic findings. Dietary or other antigens are the most common identified causes of orofacial granulomatosis. Contact antigens are sometimes implicated.

Clinical Features

Cheilitis granulomatosa is episodic with nontender swelling and enlargement of one or both lips (Fig. 1-13). Occasionally, similar swellings involve other areas, including the periocular region. The first episode of edema typically subsides completely in hours or days. After recurrent attacks, swelling may persist and slowly increase in degree, eventually becoming permanent. Recurrences can range from days to years. Attacks sometimes are accompanied by fever and mild constitutional symptoms (e.g. headache, visual disturbance).

The earliest manifestation is sudden diffuse or occasionally nodular swellings of the lip or the face involving (in decreasing order of frequency) the upper lip, the lower lip, and one or both cheeks. The forehead, the eyelids, or one side of the scalp may be involved (less common). The upper lip is involved slightly more often than the lower lip, and it may feel soft, firm, or nodular on palpation. Once chronicity is established, the enlarged lip appears cracked and fissured with reddish brown discoloration and scaling. The fissured lip becomes painful and eventually acquires the consistency of firm rubber. Swelling may regress very slowly after some years. Regional lymph nodes are enlarged (usually minimally) in 50% of patients. A fissured or plicated tongue is seen in 20–40% of patients. Its presence from birth (in some patients) may indicate a genetic susceptibility. Patients may lose the sense of taste and have decreased salivary gland secretion. Facial palsy of the lower motor-neuron type occurs in about 30% of patients. Facial palsy may precede attacks of edema by months or years, but it more commonly develops later. Facial palsy is intermittent at first, but it may become permanent. It can be unilateral or bilateral, partial or complete. Other cranial nerves (e.g. olfactory, auditory, glossopharyngeal, hypoglossal) are occasionally affected. Poorly defined association of psychiatric and neurologic features are reported. Autonomic disturbances may occur. In granulomatous cheilitis, normal lip architecture is eventually altered by the presence of lymphedema and noncaseating granulomas in the lamina propria. The frequency is unknown; the condition is rare. Morbidity depends on whether underlying organic disease, such as Crohn’s disease or sarcoidosis, is present. There is no racial and sexual predilection. The age of onset is usually young adulthood.

Differential Diagnosis

Differential diagnoses include insect bites and sarcoidosis. Serum angiotensin-converting enzyme test, chest radiography or gallium or positron emission tomography (PET) scanning may be performed to help exclude sarcoidosis. Gastrointestinal tract endoscopy and radiography may be used to help exclude Crohn’s disease.

Histologic Features

The histologic features of cheilitis granulomatosa and the swellings of the syndrome are rather characteristic, consisting of a chronic inflammatory cell infiltrate—particularly peri- and para-vascular aggregations of lymphocytes, plasma cells, and histiocytes—and focal noncaseating granuloma formation with epithelioid cells and Langhans type giant cells. The microscopic findings are suggestive of sarcoidosis, but as yet there is insufficient evidence to relate cheilitis granulomatosa with sarcoid.

Treatment

Patch tests may be used to help exclude reactions to metals, food additives, or other oral antigens. Some cases may be associated with such sensitivities. If found, avoidance of the implicated allergen is recommended. This condition can be conservatively managed by intralesional corticosteroid injections, nonsteroidal anti-inflammatory agents, mast cell stabilizers, clofazimine and tetracycline (used for antiinflammatory activity). Surgery and radiation have been reported to be used.

Etiology

The cause of the Peutz-Jeghers syndrome appears to be a germline mutation of the STK11 (serine threonine kinase 11) gene in most cases, located on band 19p13.3. Penetrance of the gene is variable, causing varied phenotypic manifestations among patients with Peutz-Jeghers syndrome (e.g. inconsistent number of polyps, differing presentation of the macules) and allowing for a variable presentation of cancer. Because the signaling pathway of the STK11 gene product currently is not identified, the mechanism of hamartomatous polyp formation and mucocutaneous pigmentation is not known. In cancer formation, STK11 inactivation appears to occur early and might be followed by interruption of the APC/β catenin and p53 pathways, but this has not been fully elucidated. STK11 may be a tumor suppressor gene in that its overexpression can induce a growth arrest of a cell at the G1 phase of the cell cycle and that somatic inactivation of the unaffected allele of STK11 often is observed in polyps and cancers from patients with the Peutz-Jeghers syndrome.

Clinical Features

The Peutz-Jeghers syndrome has been described in all races. The occurrence of cases in males and females is about equal. The average age at diagnosis is 23 years in men and 26 years in women. The affected individuals usually have a positive family history of the Peutz-Jeghers syndrome. The principal causes of morbidity stem from the intestinal location of the polyps (i.e. small intestine, colon, stomach). Morbidity includes small intestinal obstruction and intussusception (43%), abdominal pain (23%), hematochezia (14%), and prolapse of a colonic polyp (7%), and these typically occur in the second and third decades of life.

The presenting complaints include repeated bouts of abdominal pain in patients younger than 25 years, unexplained intestinal bleeding in a young patient, or menstrual irregularities in females (due to hyperestrogenism from sex cord tumors with annular tubules). Cutaneous pigmentation (1–5 mm macules) of the perioral region crossing the vermilion border (94%), perinasal, and perioral areas is seen; pigmentation may also be present on the fingers and toes, on the dorsal and ventral aspects of the hands and feet, and around the anus and genitalia. This pigmentation may fade after puberty. Mucous membrane pigmentation primarily affects the buccal mucosa (66%) and the intestinal mucosa rarely. Other manifestations of this syndrome include precocious puberty, prolapse of tissue from the rectum, rectal mass (rectal polyp), testicular mass, gynecomastia and growth acceleration (due to Sertoli cell tumor).

Histologic Features

Characteristic pathology of Peutz-Jeghers polyps includes extensive smooth muscle arborization throughout the polyp, with the appearance of pseudoinvasion because some of the epithelial cells, usually from benign glands, are surrounded by the smooth muscle.

Treatment

Surgical treatment for cancers detected by surveillance has been recommended.

Clinical Features

The oral melanotic macule has a 2:1 female predilection with an average age of 43 years at the time of diagnosis, although it can develop at any age. One-third of lesions occur on the vermilion border of the lower lip, but the buccal mucosa, gingiva and palate are other sites of common occurrence. Almost one fifth of the lesions are multiple.

The typical macule is a well-demarcated, uniformly tan to dark brown, asymptomatic, round or oval discoloration less than 7 mm in diameter. The lesion is not thickened and has the same consistency as surrounding mucosa. It tends to have an abrupt onset and seldom enlarges after diagnosis.

A special case of oral melanosis, called smoker’s melanosis is found on the gingival or buccal mucosa in heavy smokers. It has an adult onset and is often associated with a concomitant superficial white/gray keratosis. The keratosis may become thick enough to mimic leukoplakia, although it is not known whether or not it is a true precancer. Both the pigmentation and the keratosis diminish or disappear once the tobacco habit is stopped.

While the melanotic macule is an innocuous lesion, it must be remembered that focal oral and oropharyngeal pigmentation might represent an internal malignancy (usually lung), an oral manifestation of a systemic disease or one facet of a genetic syndrome.

Histologic Features

The oral melanotic macule is characterized by an otherwise normal stratified squamous epithelium with abundant melanin deposits within the keratinocytes of the basal and parabasal layers. Deposits may also be seen within subepithelial stroma (melanin incontinence), perhaps within macrophages or melanophages. There is no underlying inflammatory response. The melanin can be distinguished from iron deposits with melanin stains or by the loss of brown color after bleaching. Brown formalin deposits can be differentiated by their association with erythrocytes rather than with basal layer epithelial cells.

Treatment and Prognosis

No treatment is required for oral melanotic macule except for esthetic considerations. The intraoral melanotic macule has no malignant transformation potential, but an early melanoma could have a similar clinical appearance. For this reason, pigmented macular lesions of recent onset, large size, irregular pigmentation, unknown duration, or with a history of recent enlargement should be excised and examined histopathologically.

Clinical Features

Fordyce’s granules appear as small yellow spots, either discretely separated or forming relatively large plaques, often projecting slightly above the surface of the tissue (Fig. 1-14). They are found most frequently in a bilaterally symmetrical pattern on the mucosa of the cheeks opposite the molar teeth but also occur on the inner surfaces of the lips, in the retromolar region lateral to the anterior faucial pillar, and occasionally on the tongue, gingiva, frenum, and palate. Ectopic sebaceous glands have been discussed in an excellent review by Guiducci and Hyman and are recognized to occur, besides in the oral cavity, in the esophagus, the female genitalia including the cervix uteri, the male genitalia, the nipples, the palms and soles, the parotid gland, the larynx, and the orbit.

Studies by Halperin and coworkers, confirmed by Miles, have indicated that the oral condition is present in approximately 80% of the population, with apparently no significant differences in occurrence between the genders or races. Fewer children than adults exhibit Fordyce’s granules, probably because the sebaceous glands and hair system do not reach maximal development until puberty. Nevertheless, Miles has reported that large numbers of sebaceous glands in the cheeks and lips may sometimes be found in children long before the age of puberty. Because of the high incidence of these glands in the oral cavity, Knapp has suggested that they be regarded as sebaceous nevi rather than ectopic glandular tissue.

Histologic Features

These heterotopic collections of sebaceous glands are identical with those seen normally in the skin, but are unassociated with hair follicles, although a single hair follicle and hair shaft growing from the gingiva—an extremely rare occurrence—has been reported recently by Baughman (Fig. 1-15). The glands are usually superficial and may consist of only a few or a great many lobules, all grouped around one or more ducts which open on the surface of the mucosa. These ducts may show keratin plugging.

Treatment

These glands are innocuous, have no clinical or functional significance, and require no treatment. However, very rarely a benign sebaceous gland adenoma may develop from these intraoral structures, such as in the case involving the buccal mucosa reported by Miller and McCrea. Sewerin has also reported the occasional development of keratin-filled pseudocysts from the ducts of these sebaceous glands.

Clinical Features

Heck’s disease primarily occurs in children, but lesions may occur in young and middle-aged adults. There is no gender predilection. Sites of greatest involvement include the labial, buccal and lingual mucosa, but gingival and tonsillar lesions have also been reported.

Individual lesions are broad-based or so slightly elevated as to present as well demarcated plaques. Lesions are frequently papillary in nature, but relatively smooth-surfaced, flat-topped lesions are more commonly seen. Papules and plaques are usually the color of normal mucosa, but may be pale or, rarely, white. Hyperplastic lesions are small (0.3–1.0 cm), discrete, and well-demarcated, but they frequently cluster so closely together that the entire mucosal area takes on a cobblestone or fissured appearance.

Histologic Features

Epithelial hyperplasia in this disease presents microscopically as an abrupt and sometimes considerable focal acanthosis of the oral epithelium. The thickened mucosa extends upward, not down into underlying connective tissues, hence the lesional rete ridges are at the same depth as the adjacent normal rete ridges. The ridges themselves are widened, often confluent and sometimes club-shaped; they are not long and thin as in psoriasis and other diseases. Some superficial keratinocytes show a koilocytic change similar to that seen in other HPV infections, while occasionally others demonstrate a collapsed nucleus which resembles a mitotic figure (mitosoid cell). These presumably result from viral alteration of the cells. Virus-like particles have been noted ultrastructurally within both cytoplasm and nuclei of cells within the spinous layer, and this layer is positive for HPV antigen with in situ hybridization.

The lesion is usually easily differentiated from squamous papilloma, verruca vulgaris and condyloma by its lack of pronounced surface projections; the presence of mitosoid cells, and the lack of connective tissue cores in the surface projections, when present. The sessile nature of focal epithelial hyperplasia also serves to separate it from the former two lesions, although this is not a guaranteed distinction.

Focal epithelial hyperplasia also tends to lack the pronounced elongation of thin rete ridges seen in keratoacanthoma and pseudoepitheliomatous hyperplasia, and it lacks the central keratin-filled core of the keratoacanthoma. It also lacks the subepithelial foamy or granular histiocyte-like cells required for the diagnosis of verruciform xanthoma.

Treatment and Prognosis

Conservative excisional biopsy may be required to establish the proper diagnosis, but additional treatment is unnecessary, except perhaps for esthetic reasons relating to visible labial lesions. Spontaneous regression has been reported after months or years, and the disease is rather rare in adults. No case of focal epithelial hyperplasia has been reported to transform into carcinoma. It should be remembered that focal epithelial hyperplasia may be an oral manifestation of AIDS.

Clinical Features

This condition is manifested as a dense, diffuse, smooth, or nodular overgrowth of the gingival tissues of one or both arches, usually appearing about the time of eruption of the permanent incisors. It has been reported; however, in even very young children and, in a few instances, at birth (Fig. 1-16A). The tissue is usually not inflamed, but is of normal or even pale color, and it is often so firm and dense that it may prevent the normal eruption of teeth. It is not painful and shows no tendency for hemorrhage. The extent of the tissue overgrowth may be such that the crowns of the teeth are nearly hidden even though they are fully erupted with respect to the alveolar bone (Fig. 1-17).

Histologic Features

The microscopic picture of the tissue in fibromatosis gingivae is similar to that of any fibrous hyperplasia. The epithelium may be somewhat thickened with elongated rete pegs, although the bulk of the tissue is composed of dense fibrous connective tissue. The bundles of collagen fibers are coarse and show few interspersed fibroblasts or blood vessels. Inflammation is an unrelated and variable finding (Fig. 1-16B).

Treatment and Prognosis

When tooth eruption is impeded, surgical removal of the excessive tissue and exposure of the teeth are indicated. The cosmetic appearance may also require surgical excision. The lesion sometimes recurs. It has been reported that tooth extraction alone will cause the tissues to shrink almost to normal and that recurrences can be prevented by this means.

Clinical Features

This soft, well-circumscribed, sessile, mucosal nodule, commonly bilateral, is located lingual to the mandibular cuspid, between the free gingival margin and the mucogingival junction.

It is exceedingly common in children, occurring in 99% of those between the ages of eight and 16 years, according to the original report of Hirshfeld, but decreases in incidence with age, occurring in 38% of those between the ages of 25 and 39 years and in 19% of those between the ages of 60 and 80 years. Thus there appears to be regression of the structure with maturity. In addition, most studies have found a greater occurrence bilaterally than unilaterally. A study by Berman and Fay, who have reviewed the studies dealing with the retrocuspid papilla, reported from their own data that the structure was consistently more common in females than in males.

Histologic Features

The structure appears as an elevated mucosal tag often showing mild hyperorthokeratosis or hyperparakeratosis, with or without acanthosis. The underlying connective tissue is sometimes highly vascularized and may exhibit large stellate fibroblasts as well as occasional epithelial rests.

Treatment

Because of its frequency of occurrence, the retrocuspid papilla is often considered to be a ‘normal’ anatomic structure which regresses with age and requires no treatment.

Treatment

The goal of nearly all surgery is to return the patient to an anatomically and physiologically normal condition; and this applies to macroglossia as well. The goal is to reduce tongue size and thereby improve function. Those main functions include articulation, mastication, deglutition, protection of the airway, and gustation. Of these, only gustation is not often improved with surgical intervention.

Treatment

Frenulectomy is recommended.

Clinical Features

The prevalence worldwide varies by geographic location and has been reported to be as high as 21%. Fissured tongue is a totally benign condition and is considered by most to be a variant of normal tongue architecture. No predilection for any particular race appears to exist. Some reports have shown a slight male predilection. Although fissured tongue may be diagnosed initially during childhood, it is diagnosed more frequently in adulthood. The prominence of the condition appears to increase with increasing age.

The lesions are usually asymptomatic unless debris is entrapped within the fissure or when it occurs in association with geographic tongue (a common finding). On clinical examination, fissured tongue affects the dorsum and often extends to the lateral borders of the tongue. The depth of the fissures varies but has been noted to be up to 6 mm in diameter. When particularly prominent, the fissures or grooves may be interconnected, separating the tongue dorsum into what may appear to be several lobules. Although a specific etiology has not been elicited, a polygenic or autosomal dominant mode of inheritance is suspected because this condition is seen with increased frequency in families with an affected proband.

Histologic Features

A biopsy is rarely performed on a fissured tongue because of its characteristic diagnostic clinical appearance; however, histologic examination has shown an increase in the thickness of the lamina propria, loss of filiform papillae of the surface mucosa, hyperplasia of the rete pegs, neutrophilic microabscesses within the epithelium, and a mixed inflammatory infiltrate in the lamina propria.

Treatment

No definitive therapy or medication is required.

Clinical Features

Median rhomboid glossitis presents in the posterior midline of the dorsum of the tongue, just anterior to the V-shaped grouping of the circumvallate papillae (Fig. 1.23A, B). The long axis of the rhomboid or oval area of red depapillation is in the anteroposterior direction. Most cases are not diagnosed until the middle age of the affected patient, but the entity is, of course, present in childhood. There appears to be a 3 : 1 male predilection.

Those lesions with atrophic candidiasis are usually more erythematous but some respond with excess keratin production, and therefore, show a white surface change. Infected cases may also demonstrate a midline soft palate erythema in the area of routine contact with the underlying tongue involvement; this is commonly referred to as a kissing lesion.

Lesions are typically less than 2 cm in greatest dimension and most demonstrate a smooth, flat surface, although it is not unusual for the surface to be lobulated. Occasional lesions are located somewhat anterior to the usual location. None have been reported posterior to the circumvallate papillae.

Prior to biopsy, the clinician should be certain that the midline lesion does not represent a lingual thyroid, as it may be the only thyroid tissue present in the patient’s body. Differential diagnoses include the gumma of tertiary syphilis, the granuloma of tuberculosis, deep fungal infections, and granular cell tumor.

Histologic Features

Median rhomboid glossitis shows a smooth or nodular surface covered by atrophic stratified squamous epithelium overlying a moderately fibrosed stroma with somewhat dilated capillaries. Fungiform and filiform papillae are not seen, although surface nodules may mimic or perhaps represent anlage of these structures. A mild to moderately intense chronic inflammatory cell infiltrate may be seen within subepithelial and deeper fibrovascular tissues.

Chronic candida infection may result in excess surface keratin or extreme elongation of rete processes and premature keratin production with individual cells or as epithelial pearls (dyskeratosis) deep in the processes. Silver staining for fungus will often reveal candida hyphae and spores in the superficial layers of the epithelium. This pseudoepitheliomatous hyperplasia may be quite pronounced, and the tangential cutting of such a specimen may result in the artifactual appearance of cut rete processes as unconnected islands of squamous epithelium, leading to a mistaken diagnosis of well differentiated squamous cell carcinoma. Because of this difficulty, it is recommended that the patient be treated with topical antifungals prior to biopsy of a suspected median rhomboid glossitis.

Treatment and Prognosis

No treatment is necessary for median rhomboid glossitis, but nodular cases are often removed for microscopic evaluation. Recurrence after removal is not expected, although those cases with pseudoepitheliomatous hyperplasia should be followed closely for at least a year after biopsy to be certain of the benign diagnosis. Antifungal therapy (topical troches or systemic medication) will reduce clinical erythema and inflammation due to candida infection. This therapy, as stated earlier, should ideally be given prior to the biopsy, in order to reduce the candida-induced pseudoepitheliomatous hyperplasia features. Some lesions will disappear entirely with antifungal therapy.

Histologic Features

All of the microscopic features of psoriasis are present in benign migratory glossitis and migratory stomatitis, but these will not be obvious unless the biopsy is taken from a prominent serpiginous line at the periphery of a depapillated patch. A thickened layer of keratin is infiltrated with neutrophils, as are lower portions of the epithelium to a lesser extent. These inflammatory cells often produce small microabscesses, called Monro's abscesses, in the keratin and spinous layers. Rete ridges are typically thin and considerably elongated, with only a thin layer of epithelium overlying connective tissue papillae. When rete ridges are not elongated, the pathologist should consider Reiter's syndrome as a diagnostic possibility. Chronic inflammatory cells can be seen in variable numbers within the stroma and silver or PAS staining will often demonstrate candida hyphae or spores in the superficial layers of the epithelium. There is no liquefactive degeneration of basal cells, as seen in lichenoid lesions, and there is no ulceration except in cases of Reiter’s syndrome.

Treatment and Prognosis

No treatment is usually necessary for benign migratory glossitis and stomatitis. Symptomatic lesions can be treated with topical prednisolone and a topical or systemic antifungal medication can be tried if a secondary candidiasis is suspected. Occasional symptomatic cases respond well to topical tetracycline or systemic, broadspectrum antibiotics, but this should not be expected.

Etiology

The basic defect in hairy tongue is the hypertrophy of filiform papillae on the dorsal surface of the tongue, usually due to a lack of mechanical stimulation and debridement. This condition often occurs in individuals with poor oral hygiene (e.g. lack of toothbrushing, eating a soft diet with no roughage that would otherwise mechanically debride the dorsal surface of the tongue). Contributory factors for hairy tongue are numerous and include tobacco use and coffee or tea drinking. These factors account for the various colors associated with the condition.

Clinical Features

Normal filiform papillae are approximately 1 mm in length, whereas filiform papillae in hairy tongue are more than 15 mm in length. Hairy tongue has been reported with greater frequency in males, patients infected with human immunodeficiency virus (HIV), and those who are HIV negative and use intravenous drugs. Hairy tongue is rarely symptomatic, although overgrowth of Candida albicans may result in glossopyrosis (burning tongue). Patients frequently complain of a tickling sensation in the soft palate and the oropharynx during swallowing. In more severe cases, patients may actually complain of a gagging sensation. Retention of oral debris between the elongated papillae may result in halitosis. No racial predilection is associated with hairy tongue. Because hairy tongue is usually asymptomatic, the history is often irrelevant. In most cases, lesions are noted as part of an intraoral examination, although patients may complain of a tickling or gagging sensation. The tongue has a thick coating in the middle, with a greater accentuation towards the back. Bacterial and fungal overgrowth play a role in the color of the tongue. The only complication associated with hairy tongue is an occasional candidal overgrowth, which often results in an uncomfortable glossopyrosis (burning tongue). Altered taste sensation is a rare complication.

Differential Diagnosis

This condition has to be differentiated from candidiasis, leukoplakia, oral lichen planus and oral hairy leukoplakia. Culture of the tongue’s dorsal surface may be taken if a superimposed oral candidiasis or other specific oral infection is suspected. Distinguishing between oral hairy leukoplakia and hairy tongue is important if patients are found or suspected to be HIV positive. This can be accomplished by a simple mucosal punch biopsy and appropriate immunostaining of the specimen for the presence of Epstein-Barr virus, the causative agent of oral hairy leukoplakia. However, in most cases, the diagnosis is made retrospectively on the basis of the clinical response to mechanical debridement.

Histologic Features

Histopathologic findings in hairy tongue consist of elongated filiform papillae, with mild hyperkeratosis and occasional inflammatory cells. Debris accumulation among the papillae and candidal pseudohyphae is not unusual finding. No other specific microscopic findings are associated with this entity.

Treatment

The treatment of hairy tongue is variable. In many cases, brushing of the tongue with a toothbrush or using a commercially available tongue scraper is sufficient to remove elongated filiform papillae and retard the growth of additional ones. Surgical removal of the papillae by using electrodesiccation, carbon dioxide laser, or even scissors is the treatment of last resort when less complicated therapies prove ineffective. The prognosis for hairy tongue is excellent. If the precipitating factors cannot be adequately controlled or compensated for, patients may have to make tongue brushing or scraping part of their daily oral hygiene regimen.

Etiology

The benign enlargement of lingual thyroid tissue is thought to be due in some cases to functional insufficiency of the chief thyroid gland in the neck, since some patients with such a lingual lesion are without a demonstrable main thyroid gland. Other cases of lingual thyroid nodules occur in patients residing in goitrous areas, but it is not certain that the condition is a form of goiter. In addition, it has been suggested that the failure of the primitive thyroid anlage to descend is the cause of the majority of cases of nongoitrous sporadic cretinism.

Clinical Features

The incidence of this benign condition is not known, since a routine autopsy seldom includes an examination of the base of the tongue. Montgomery, in an exceptionally complete and thorough review of the entire subject of the lingual thyroid, analyzed 144 acceptable previously reported cases, pointing out that these represented only cases showing hypertrophy of the lingual thyroid tissue. Though information is inadequate about racial and geographic distribution of lingual thyroid nodules, a difference in gender incidence does appear to be significant. Of 135 cases in which the gender was recorded, 118 patients were female and only 17 were male. The majority of patients had their onset of symptoms relatively early in life, chiefly during puberty, adolescence, and early maturity, though cases have been recorded as early as birth and as late as the seventh decade.

In contrast, Sauk carried out a study to determine the frequency with which ectopic thyroid tissue occurred in the tongue of ‘normal’ persons, i.e. those without a definite symptomatic mass for which treatment was sought. In a series of 200 consecutive necropsies, ectopic thyroid tissue was found in 10% of the cases, with an equal distribution between the sexes. Nearly identical data have been reported by Baughman in his own investigation of 184 tongues from human cadavers. Since the condition is more often clinically apparent in females, Sauk suggested that hormonal factors may be involved in the genesis of symptoms. Most cases appear to arise in females during puberty, adolescence, pregnancy, or menopause.

The lingual thyroid may be manifested clinically as a nodular mass in or near the base of the tongue in the general vicinity of the foramen caecum and often, but not always, in the midline (Fig. 1-26). This mass, which more commonly appears as deeply situated rather than as a superficial exophytic lesion, tends to have a smooth surface. In some cases it may appear vascular, while in others the color of the mucosa is not atypical. The size of the lesion in many of the reported cases has been approximated 2–3 cm in diameter. The chief symptoms of the condition may vary, but the presenting complaint is often dysphagia, dysphonia, dyspnea, hemorrhage with pain, or a feeling of tightness or fullness in the throat.

Histologic Features

The benign lingual thyroid nodules may present a variety of microscopic patterns, but in the majority of cases they resemble either normal thyroid tissue or thyroid tissue of an embryonal or fetal type. In some instances the nodules exhibit colloid degeneration or goiter.

Great care must be taken to distinguish these lesions from lesions derived from accessory salivary glands in the same location. Both the lingual thyroid and these salivary glands may give rise to adenomas and adenocarcinomas in the tongue.

Treatment

Care must be exercised in handling the lingual thyroid lesion. It has been emphasized by Hung and his associates that a careful physical examination should be performed to demonstrate the presence of a normally located thyroid gland in patients presenting with midline masses in the lingual or sublingual area. If the thyroid gland cannot be palpated, a scintiscan with a tracer dose of radioactive iodine, ¹³¹I, should be carried out to determine whether there is a normally located thyroid gland and if the lingual mass is ectopic thyroid. It is usually recommended that a patient with an ectopic thyroid gland should have a trial of replacement thyroid hormone therapy before excision is contemplated, since this will often decrease the size of the lesion and make surgery unnecessary. Occasionally, the clinical manifestations of the lesion and its size necessitates surgical excision.

Etiology

ALHE is idiopathic. Whether this condition is a neoplastic or reactive state is uncertain; a reactive cause is favored.

Clinical Features

Although ALHE may be a benign tumor numerous factors suggest that it is an unusual reactive process. The condition may be multifocal. ALHE has occurred following various forms of trauma or infection. Hyperestrogenic states (e.g. pregnancy, oral contraceptive use) may foster lesion growth. Additionally, the distinctive inflammatory infiltrate in ALHE appears to be an intrinsic (not secondary) component of the lesion. Approximately 20% of patients have blood eosinophilia. Although frequency is unknown, cases have been reported worldwide. ALHE is uncommon but not rare; it may be more common in Japan than in other countries. ALHE can persist for years, but serious complications (e.g. malignant transformation) do not occur. ALHE is seen most commonly in Asians, followed by Caucasians. Although less commonly, blacks too can develop ALHE. ALHE is somewhat more common in females; however, a male predominance has been noted in selected Asian studies. ALHE presents most commonly in patients aged 20–50 years, with mean onset of 30–33 years. This condition is rare in elderly patients and in the non-Asian pediatric population.

Patients with ALHE typically present with an expanding nodule or group of nodules, usually in the vicinity of the ear. The lesion(s) may be associated with pain or pruritus. Uncommon symptoms include pulsation and spontaneous bleeding.

ALHE typically appears as dome-shaped, smooth-surfaced papules or nodules. Approximately 85% of lesions occur in the skin of the head and neck; most of them are on or near the ear or on the forehead or scalp. The lesions range from erythematous to brown in color and may be eroded or crusted. Approximately 80% of patients present with isolated lesions, while the remaining patients usually demonstrate grouped papules or nodules in a single region. Rarely, the lesions may be pulsatile. Most lesions are 0.5–2 cm in diameter, with a range of 0.2–8 cm. Larger nodules tend to be deeply centered within the subcutis.

Differential Diagnosis

Granuloma faciale, insect bites, pyogenic granuloma (lobular capillary hemangioma), angiosarcoma, hemangioendothelioma and hemangioma.

Histologic Features

The clinical presentation of papules around the ears may suggest ALHE, but a biopsy is required to establish the diagnosis. ALHE shows characteristic histologic features, including a proliferation of small blood vessels, many of which are lined by enlarged endothelial cells with uniform ovoid nuclei and intracytoplasmic vacuoles. These distinctive endothelial cells have been described as having a cobblestone appearance. In addition, a perivascular and interstitial infiltrate composed primarily of lymphocytes and eosinophils is present. Eosinophils typically comprise 5–15% of the infiltrate. Rarely, they can account for as much as 50% of the infiltrate. Occasionally, the infiltrate is devoid of eosinophils. Lymphoid aggregates with or without follicle formation are typical.

Treatment

Treatment is not mandatory. Intralesional corticosteroids and irradiation have been employed but are not very effective. Surgical removal of the lesions has demonstrated the best results, however, they may recur.

Clinical Features

Oral lymphoepithelial cyst presents as a movable, painless submucosal nodule with a yellow or yellow-white discoloration. Occasional cysts are transparent. Almost all cases are less than 0.6 cm in diameter at the time of diagnosis, which is usually during the teen years or the third decade of life. Approximately half of all intraoral examples are found on the oral floor (Fig. 1-28A), but the lateral and ventral tongue are not uncommon sites of occurrence, nor is the soft palate, especially the mucosa above the pharyngeal tonsil. Of course, this cyst may also occur within the pharyngeal tonsils themselves. Occasional superficial cysts rupture to release a foul-tasting, cheesy, keratinaceous material.

This cyst has a clinical appearance similar to that of an epidermoid cyst or a dermoid cyst of the oral/pharyngeal mucosa, but its growth potential is much less than the other cysts. The lymphoepithelial cyst never occurs on the alveolar mucosa, hence, can easily be distinguished from a gingival cyst of adults or from an unruptured parulis or ‘pus pocket’ at the terminus of a fistula (extending from the apical or lateral region of an abscessed tooth).

Histologic Features

The lymphoepithelial cyst is lined by atrophic and often degenerated stratified squamous epithelium, usually lacking rete processes and usually demonstratinga minimal granular cell layer. Orthokeratin is seen to be sloughing from the epithelial surface into the cystic lumen, often completely filling the lumen and sometimes showing dystrophic calcification. Rarely, mucus-filled goblet cells may be seen within the superficial layers of the epithelium, and occasional cysts will demonstrate an epithelium-lined communication with the overlying mucosal surface. The cyst is entrapped within a well-demarcated aggregate of mature lymphocytes. The aggregate or ‘tonsil’ will have a variable number of germinal centers, sometimes none at all. The lymphoid aggregate may be hyperplastic.

This combination of epithelium-lined cyst with lymphoid aggregates is unique enough to make the diagnosis an easy one (Fig. 1-28B), but the pathologist must differentiate this lesion from the Warthin tumor (papillary cystadenoma lymphomatosum). The latter lesion is lined not by squamous epithelium but by a bilayered cuboidal, columnar or oncocytic ductal epithelium. It is almost always found in the parotid gland, but rare oral examples have been reported.

Occasional cysts have very small lumina with degenerated epithelial linings and may mimic metastatic deposits of well differentiated squamous cell carcinoma. Deeper sections will reveal the true nature of the benign lesion.

Treatment and Prognosis

No treatment is usually necessary for the oral lymphoepithelial cyst unless its location is such that it is constantly being traumatized. Most lesions are, however, removed by conservative surgical excision in order to arrive at a definitive diagnosis. There is no malignant potential to this lesion but the lymphoid stroma, as with all lymphoid tissues, can become involved with an extranodal lymphoma.

Treatment

Treatment for salivary gland agenesis is support-ive and directed at relieving xerostomia and its effects. Salivary substitutes, frequent mouth washes, comprehensive dental care, fluoride therapy, and good oral hygiene all play a role in successful management.

Etiology

A convenient way of classifying the causes of xerostomia is as temporary or permanent.

Temporary Causes

Permanent Causes

Clinical Features

It is important to establish whether the dryness is continual or intermittent, whether it is accompanied by pain or swelling, if unilateral or bilateral and whether there is any relevant history of anxiety, stress or depression, a systemic disorder, irradiation, trauma, surgery or medication. The patient’s occupation, diet and domestic situation are often relevant.

Unilateral dryness with pain or discomfort and swelling in the affected gland on stimulation is often an indication of a duct calculus. Sjögren’s syndrome commonly produces bilateral swelling, often constant and accompanied by the other symptoms of the syndrome, and in many cases lymph node enlargement. A punch biopsy of labial glands and by serological tests may be needed to confirm the diagnosis. As well as looking for evidence of enlargement of salivary glands and lymph nodes and unilateral dryness, the palpation of the floor of the mouth for evidence of submandibular duct calculi and examination of the major duct openings, as inflammation or swelling of the orifice may indicate the presence of a distally placed calculus. These are often revealed by simple radiography.

While the more dramatic forms of xerostomia are not common, a more typical case of nonspecific xerostomia is a postmenopausal woman, living alone with few family or other social contacts, surviving on a low income and a marginally inadequate diet, and wearing old ill-fitting dentures. The combination of atrophy of the oral mucosa due to hormonal changes and a mild chronic candidosis and reduced salivary flow due to age and depression for which she might have medication, together with a marginal iron deficiency anemia, is sufficient to produce a degree of discomfort which a cursory oral examination will not reveal.

All degrees of xerostomia exist. In some cases, the patient complains of a dry or burning sensation but the mucosa appears normal. In other cases there is a complete lack of saliva.

When the deficiency of saliva is pronounced, there may be severe alterations in the mucous membranes, and the patient may have extreme discomfort. The mucosa will appear dry and atrophic, sometimes inflamed or, more often, pale and translucent. The tongue may manifest the deficiency by atrophy of the papillae, inflammation, fissuring, and cracking and in severe cases by areas of denudation. Soreness, burning, and pain of the mucous membrane and tongue are common symptoms. Xerostomia, in all its aspects, has been discussed by Bertram.

Clinical Significance

Aside from annoyance to the patient, there is one feature of the condition that is serious. In many cases, chronic xerostomia predisposes to rampant dental caries and subsequent loss of teeth. Moreover, patients with xerostomia have difficulty with artificial dentures. Dental appliances are extremely disagreeable against dry mucosa and cannot be tolerated by some patients.

Treatment

The basic principles of management are first to eliminate or address any etiological factors such as drugs, calculi and emotional problems. It is also advisable to promote salivary stimulation by using sugar-free chewing gum which is effective and convenient. Salivary substitutes can also be given. The relief that can be given to many sufferers is limited. However, patience and consideration, especially towards the elderly, is as important as clinical intervention. Regular review to monitor the condition of teeth, gingivae and mucosa and to give support and reinforcement of preventive measures is advised.

Clinical Features

Palatal gland hyperplasia presents as a small localized swelling, measuring from several millimeters to 1 cm or more in diameter, usually on the hard palate or at the junction of the hard and soft palates. The lesion has an intact surface and is firm, sessile, and normal in color. It is usually asymptomatic and the patient may be unaware of the lesion. Too few cases have been reported to determine whether there is any age or gender predilection.

Histologic Features

The mass appears microscopically as closely packed collections of normal-appearing mucous acini with the usual intermingling of normal ducts. There is no inflammation, no spillage of mucin, and no fibrosis.

Treatment

Because hyperplasia of palatal glands cannot be differentiated clinically from a small salivary gland neoplasm in this area, it is essential that they be excised for microscopic examination. No further treatment is necessary and the condition is not reported to recur.

Complications

A complication occasionally reported in the literature is the development of a true central salivary gland neoplasm from the included salivary gland tissue, but this is rare. This has been discussed in Chapter 3 on Tumors of the Salivary Glands (q.v.) in the section on mucoepidermoid carcinoma.

Treatment

These lesions generally represent benign developmental anomalies that normally do not require any treatment. A complication occasionally reported in the literature is the development of a true salivary gland neoplasm in the tissue associated with one of the cortical defects. Therefore, re-cording the finding of these lesions and periodically observing them radiographically seem prudent. Clinical or radiographic changes may indicate the need for further investigation.

Clinical Features

Taurodontism may affect either the deciduous or permanent dentition, although permanent tooth involvement is more common. The teeth involved are almost invariably molars, sometimes only a single tooth, at other times several molars in the same quadrant. The condition may be unilateral or bilateral or may exhibit any combination of quadrant involvement. The teeth themselves have no remarkable or unusual morphologic clinical characteristics.

Radiographic Features

The unusual nature of this condition is best visualized on the radiograph. Involved teeth frequently tend to be rectangular in shape rather than taper toward the roots. The pulp chamber is extremely large with a much greater apico-occlusal height than normal. In addition, the pulp lacks the usual constriction at the cervical of the tooth and the roots are exceedingly short. The bifurcation o trifurcation may be only a few millimeters above the apices of the roots (Fig. 1-41). This radiographic picture is quite striking and characteristic.

Treatment

No special treatment is necessary for this anomaly.