6
Benign Lesions of the Oral Cavity and the Jaws
A. Ross Kerr, DDS, MSD
Denise A. Trochesset, DDS
This chapter provides an overview of the etiology and pathogenesis, epidemiology, clinical and histopathologic manifestations, differential diagnosis, applicable laboratory findings, and management of nonmalignant growths and tumors of the oral cavity and the jaws. Prevalence data for these entities is variable and based on population screening studies1,2,3 or large case series, and many of the entities described occur at a sufficiently low prevalence to be reported as rare. Most entities are not true neoplasms, and therefore a variety of miscellaneous etiologies are discussed. If left untreated, some of the entities considered in this chapter can lead to extensive tissue destruction and deformity, whereas others may have a lesser impact, albeit they negatively affect oral function. Regardless, one of the major clinical considerations in the management of these growths and tumors is to identify their benign nature and to distinguish them from potentially life-threatening malignant neoplasms. Identification can only be established with certainty by microscopic examination of excised tissue; therefore, biopsy is often an essential step in their diagnosis and management.
VARIANTS OF NORMAL
Structural variations of the oral cavity and the jaws are sometimes mistakenly identified as pathologic, but they are usually easily recognized as being within the range of normal findings, and biopsy is rarely indicated. One cannot appreciate the abnormal before understanding the range of normal. Examples of such structural variants are tori, enlarged papillae associated with the opening of Stensen’s duct, Fordyce spots, and sublingual varicosities in older individuals.
Tori/Exostoses
Etiology and Pathogenesis
Tori and exostoses are considered to be normal structural variants. Their etiology is multifactorial and poorly defined, although genetics is a dominant factor.4 There is no strong evidence to either support or refute bruxism or other parafunctional habits as causes. The growth of tori and exostoses is highly variable and their negligible growth after an initial slow but steady period of development suggests that they are unlikely to be inflammatory hyperplasias or neoplasms.
Epidemiology
The prevalence of tori is highly variable, ranging from <5% to almost 30% in different studies and populations. Smaller studies using dental casts to determine the presence of any torus or exostosis demonstrate significantly higher prevalence, >50%. Their onset is at any age, but most commonly during the third decade, and with no consistent sex predilection.
Clinical and Histologic Manifestations
Exostoses manifest as localized nodular enlargements of the cortical bone of the midline of the palate (torus palatinus),5 the lingual aspect of the mandible (torus mandibularis), and the buccal aspects of either jaws (Figure 6-1). Other than the torus palatinus, exostoses have a bilateral presentation. They are typically small, although rarely they may become sufficiently large to interfere with oral function. Histologically, tori consist of layers of dense cortical bone covered by periosteum and a thin overlying layer of epithelium with minimal rete peg development.
Figure 6‐1 (A) Mandibular tori (tori mandibularis). (B) Mandibular tori. Note traumatic keratosis on the left side due to the large size of the tori. (C) Maxillary torus (torus palatinus). (D) Maxillary torus. Note the large size with a “pedunculated base.”
Differential Diagnosis
Similar nodular growths or exostoses arising on the buccal aspect of the maxillary and mandibular alveolae must be differentiated from bony enlargement secondary to bone diseases such as fibrous dysplasia or Paget’s disease.
Management
No management is required unless tori pose a functional problem such as a mechanical problem in the construction of dentures, or if they become frequently traumatized as a result of their prominent position and the resulting traumatic ulcers are slow to heal. In such cases, surgical removal is indicated.
Unencapsulated Lymphoid Aggregates
Etiology and Pathogenesis
These are normal structures, distinct from the palatine and lingual tonsils, and comprise part of Waldeyer’s ring, They may increase in size as a result of benign (reactive) processes 6 or due to lymphoid neoplasms (i.e., lymphomas).
Clinical Manifestations
They may be located on the posterolateral aspects of the tongue (Figure 6-2), anterior tonsillar pillar, posterior pharyngeal wall, soft palate, and dorsal tongue. Histologic criteria based on architectural, cytologic, and immunologic features of the lymphoid aggregate have been described.
Differential Diagnosis
These may masquerade clinically as a malignancy.
Management
No management is required unless these aggregates demonstrate unilateral and progressive enlargement, in which case a biopsy is indicated to rule out malignancy.
Fordyce Spots
Etiology and Pathogenesis
These are ectopic sebaceous glands and it is unclear why some individuals develop them. The link between hyperlipidemia and Fordyce spots has not been substantiated.
Epidemiology
Fordyce spots are common and have been reported to occur in up to 80% of patients.7
Figure 6‐2 Right posterolateral tongue revealing a prominent foliate papilla region containing unencapsulated lymphoid aggregates. A similar presentation was seen on the left side.
Clinical Manifestations
The most common locations for Fordyce spots are the buccal mucosae and lip vermillion.
Management
Typically no treatment is required. There are surgical options for patients with a high concentration of labial Fordyce spots deemed esthetically obtrusive.
BENIGN SOFT TISSUE LESIONS
INFLAMMATORY/REACTIVE EXOPHYTIC SOFT TISSUE LESIONS
The term inflammatory/reactive soft tissue tumors is used to describe a large range of commonly occurring exophytic lesions of the oral mucosa that histologically represent inflamed fibrous and granulation tissue. The majority of these occur peripherally on the oral mucosal surfaces that may be subject to masticatory trauma (i.e., as the result of chronic trauma from ill-fitting dentures, biting, or contact with fractured teeth), related to the chronic inflammatory stimuli (i.e., overhanging restorations, calculus), or in some lesions the levels of circulating hormones or medications play a role. The number and size of these reactive hyperplastic lesions vary depending on the degree to which one or more of the components of the inflammatory reaction and healing response are exaggerated. Some are predominantly epithelial overgrowths with only scanty connective tissue stroma; others are fibromatous, with a thin epithelial covering, and may exhibit either angiomatous, desmoplastic (collagenous), or fibroblastic features. In many lesions, examples of each of these histologic patterns is revealed. Like scar tissue, some inflammatory hyperplasias appear to mature and become less vascular (paler and less friable) and more collagenous (firmer and smaller) with time. Others appear to have a high proliferative ability for exophytic growth until they are excised. This variability of histologic appearance is reflected in the wide range of clinical characteristics exhibited by inflammatory hyperplasias.8 If the chronic irritant is eliminated when the lesion is excised, the majority of inflammatory hyperplasias will not recur, thus confirming the benign nature of these lesions.
Irritation Fibroma
Etiology and Pathogenesis
Irritation fibromas develop following trauma, such as a cheek or lip bite.
Epidemiology
They are the most common exophytic soft tissue lesion, with a prevalence of approximately 1%, and they comprise 10–15% of exophytic soft tissue lesions submitted for histopathologic examination.
Clinical Manifestations
Irritation fibromas are usually asymptomatic and may occur as either pedunculated or sessile (broad-based) pink nodules on any surface of the oral mucosa, but most commonly involving the buccal or labial mucosae (Figure 6-3). The majority are rarely >1 cm in diameter.
Differential Diagnosis
These include giant cell fibroma, neurofibroma, schwannoma, granular cell tumor, leiomyoma, rhabdomyoma, mucocele, or malignant minor salivary gland neoplasms.
Figure 6‐3 Irritation fibroma (traumatic fibroma). Patient reported a daily habit of biting this lesion for several months.
Management
An excisional biopsy is indicated except when the procedure would produce marked deformity; in such a case, incisional biopsy to establish the diagnosis is mandatory. The irritant, if present, should also be eliminated when the lesion is excised to reduce the risk for recurrence.
Other Solitary Fibrous Lesions
Pulp polyps (aka chronic hyperplastic pulpitis) are analogous to a fibroma. They occur when the pulpal connective tissue proliferates through a large carious pulpal exposure and fills the cavity in the tooth with a mushroom-shaped polyp that is connected by a stalk to the pulp chamber (Figure 6-4). Masticatory pressure may lead to keratinization of the epithelium covering these lesions. Pulp polyps contain few sensory nerve fibers and are remarkably insensitive. The crowns of teeth affected by pulp polyps are usually so badly destroyed by caries that endodontic treatment is not feasible.
Giant cell fibromas comprise a small subset (<5%) of solitary fibrous lesions. Their etiology is unknown, and these exophytic lesions are typically smaller than the irritation fibroma.9 They most often involve the gingivae, exhibit a nodular surface, and are histologically distinguished from other fibromas by the presence of stellate-shaped and multinucleated cells in the connective tissue.
Although they are nonreactive, it is worth mentioning that fibromas are part of the manifestations in two rare syndromes: Cowden syndrome and tuberous sclerosis complex. Cowden syndrome (multiple hamartoma and neoplasia syndrome) is an autosomal dominant disorder affecting multiple organ systems10 and caused by mutations in the phosphatase and tensin homolog gene (PTEN). Oral and perioral findings include multiple papules on the lips and gingivae, papillomatosis (benign fibromatosis) of the buccal, palatal, faucial, and oropharyngeal mucosae often producing a “cobblestone” effect, and the tongue may also present as pebbly or fissured. Multiple papillomatous nodules (histologically inverted follicular keratoses or trichilemmomas) are often present on the perioral, periorbital, and perinasal skin, the pinnae of the ears, and the neck. These nodules are often accompanied by lipomas, hemangiomas, neuromas, vitiligo, café au lait spots, and acromelanosis elsewhere on the skin. A variety of neoplastic changes occur in the organs exhibiting hamartomatous lesions, with an increased rate of breast and thyroid carcinoma and gastrointestinal malignancy. Squamous cell carcinoma of the tongue and basal cell tumors of the perioral skin have also been reported.
Tuberous sclerosis complex is an inherited disorder11 caused by mutations in the tuberous sclerosis complex (TSC1 or TSC2) genes that is characterized by seizures and intellectual disability, associated with hamartomatous glial proliferations and neuronal deformity in the central nervous system. Fine wart-like lesions (adenoma sebaceum) occur in a butterfly distribution over the cheeks and forehead (Figure 6-5A), and histologically similar lesions (vascular fibromas) have been described intraorally (Figure 6-5B). Characteristic hypoplastic enamel defects (pitted enamel hypoplasia) occur in 40–100% of those affected. Rhabdomyoma of the heart and other hamartomas of the kidney, liver, adrenal glands, pancreas, and jaw have been described.
Figure 6‐4 (A) Young male with tuberous sclerosis. There are extensive wart-like lesions (adenoma sebaceum) in a butterfly distribution over the face. (B) Same patient as in (A) showing intraoral fibromas. Generalized hypoplastic pitted enamel changes are absent.
Fibrous Inflammatory Hyperplasias/Epulis Fissuratum
Etiology and Pathogenesis
These are reactive inflammatory lesions associated with the periphery of ill-fitting dentures.12 They have no malignant potential.
Epidemiology
The prevalence is <0.5% in the general population and comprises <2% of exophytic soft tissue lesions submitted for histopathologic examination.
Clinical and Histologic Manifestations
The growth is often split by the edge of the denture, resulting in a fissure, one part of the lesion lying under the denture and the other part lying between the lip or cheek and the outer denture surface (Figure 5-6). Histologically they resemble the irritation fibroma.
Differential Diagnosis
The rolled border, albeit nonindurated, can resemble some squamous cell carcinomas.
Management
Many such hyperplastic growths will become less edematous and inflamed following the removal of the associated chronic irritant, but they rarely resolve entirely. In the preparation of the mouth to receive dentures, these lesions are excised (i.e., by conventional scalpel or laser excision) to prevent further irritation and to ensure a soft tissue seal for the denture periphery. Recurrence following excision is almost always a result of a failure to eliminate the source of irritation. The occasional report of squamous cell carcinoma arising in an area of chronic denture irritation, however, underlines the importance of microscopic examination of the excised tissue.
Inflammatory Papillary Hyperplasia
Etiology and Pathogenesis
The exact pathogenesis is unclear, but this condition is usually associated with chronic denture irritation and denture stomatitis due to chronic candidal infection.12
Epidemiology
Inflammatory papillary hyperplasia is a common lesion in approximately 3–4% of denture wearers. Old and ill-fitting complete maxillary dentures appear to be the strongest stimuli, but the lesion may also be seen under partial maxillary dentures.
Figure 6‐5 Fibrous hyperplasia (epulis fissuratum) secondary to a poorly fitting mandibular complete denture.
Figure 6-6 Pulp polyp (hyperplastic pulpitis) within a carious maxillary premolar.
Clinical Manifestations
This condition develops on the central hard palate, with a characteristic red to scarlet lesion demonstrating swollen and tightly packed projections resembling the surface of an overripe berry (Figure 6-7). Such lesions are friable, and often bleed with minimal trauma.
Differential Diagnosis
Squamous cell carcinoma.
Management
Mild cases may be treated successfully by topical or systemic antifungals alone; otherwise, papillary hyperplasia may be surgically excised or removed by electrocautery, cryosurgery, or laser surgery. The old denture or a palatal splint can be used as a postoperative surgical dressing, followed by fabrication of a new denture.
Figure 6‐7 Papillary hyperplasia under a poorly fitting maxillary complete denture.
Pyogenic Granuloma and Pregnancy Tumor
Etiology and Pathogenesis
The etiology of pyogenic granulomas is thought to be in response to chronic irritation.13 Their propensity for involving the gingival margin supports this etiology and suggests that calculus, food materials, and overhanging dental restoration margins are important irritants that should be eliminated when the lesion is excised. Hormones play a role in the etiology of the lesion in the setting of pregnancy (where the lesion is named a pregnancy tumor), although local irritation is also an important etiologic factor.
Epidemiology
Fewer than 5% of exophytic soft tissue lesions submitted for histopathologic examinations are pyogenic granulomas. They have a female predilection (>2:1 ratio). Pregnancy tumors occur toward the end of pregnancy (when levels of circulating estrogens are highest), and they tend to shrink after delivery (when there is a precipitous drop in circulating estrogens).
Clinical and Histologic Manifestations
Pyogenic granulomas typically present as solitary hemorrhagic, often pedunculated, nodules of variable size that occur most frequently on the gingiva (Figure 6-8), although they may occur on any mucosal surface. Their friable, hemorrhagic, and frequently ulcerated appearance correlates with their histologic structure, demonstrating proliferating endothelial tissue, much of which is canalized into a rich vascular network with minimal collagenous support. Neutrophils, as well as chronic inflammatory cells, are consistently present throughout the edematous stroma, and form into microabscesses. These histologic features resemble hemangiomas. Despite the common name for the lesion, a frank discharge of pus is not present, and when such a discharge does occur it is likely a sinus tract emanating from an underlying periodontal or periapical abscess, the opening of which is often marked by a nodule of granulation tissue (parulis).
Differential Diagnosis
When involving the gingiva, the differential includes other reactive gingival lesions, including peripheral ossifying fibroma and peripheral giant cell granuloma. Hemangiomas may appear similar clinically. Malignant neoplasms may also be included in the differential (e.g., squamous cell carcinoma, or other rarer entities).
Figure 6‐8 Pyogenic granuloma associated with a periodontal defect on the distal aspect of the maxillary left third molar. There is radiographic evidence of subgingival calculus, a likely etiologic factor.
Management
Surgical excision and successful removal of the associated irritant are associated with a low rate of recurrence. Scrupulous oral hygiene can prevent pregnancy tumors.
Peripheral Ossifying or Cementifying Fibroma
Etiology and Pathogenesis
This is a reactive lesion of unclear etiology, most likely related to local trauma/irritation.
Epidemiology
These lesions occur in teenagers and young adults and are more common in women.
Clinical/Histologic Manifestations
They occur exclusively on the gingiva, typically located in the interdental papilla region (Figure 6-9), and vary in presentation from pale pink to cherry red. This reactive proliferation is named because of the histologic evidence of calcifications that are seen in the context of a hypercellular fibroblastic stroma.
Differential Diagnosis
The differential includes other reactive gingival lesions, including pyogenic granuloma and peripheral giant cell granuloma. Malignant neoplasms may also be included in the differential (e.g., squamous cell carcinoma, or other rarer entities).
Management
Treatment should include the elimination of subgingival irritants and periodontal pockets, as well as excision of the gingival growth.
Figure 6‐9 Peripheral ossifying fibroma in a teenage male associated with the maxillary buccal gingiva. The lesion was pedunculated.
Peripheral Giant Cell Granuloma
Etiology and Pathogenesis
This is a reactive lesion of unclear etiology, most likely related to local trauma/irritation. It is the soft tissue counterpart to the central giant cell granuloma.
Epidemiology
Peripheral giant cell granulomas are five times as common as the central lesions.
Clinical and Histologic Manifestations
Giant cell granulomas are solitary and occur either as a peripheral exophytic lesion found exclusively on the gingiva or as a centrally located lesion within the jaw, skull, or other facial bones (described in the section that includes bone lesions).
Differential Diagnosis
The differential includes other reactive gingival lesions, including pyogenic granuloma and peripheral ossifying or cementifying fibroma. Malignant neoplasms may also be included in the differential (e.g., squamous cell carcinoma, or other rarer entities).
Management
Peripheral giant cell granuloma is treated identically to the other reactive gingival lesions, by surgical excision and the elimination of local factors contributing to gingival/periodontal disease.
Nodular Fasciitis
Etiology and Pathogenesis
This is a reactive proliferation of myofibroblasts and although the etiology is unknown, trauma is a likely factor. Growth rates are variable but can be rapid.
Epidemiology
Oral nodular fasciitis is rare and occurs at all ages, with the majority during the fourth and fifth decades, with no sex predilection.
Clinical and Histopathologic Manifestations
The most common oral site is the buccal mucosa and most have an exophytic presentation. Nodular fasciitis has distinctive microscopic features revealing the myofibroblast as the predominant cell type. The microscopic features can resemble a sarcoma, and may present a diagnostic challenge for the pathologist.
Differential Diagnosis
Benign or malignant soft tissue growths.
Management
Conservative surgical excision and submission for histology.
Proliferative Myositis and Focal Myositis
Etiology and Pathogenesis
These entities are reactive fibroblastic lesions that infiltrate around individual muscle fibers.
Epidemiology
They are exceedingly rare.
Clinical Manifestations
Lesions most frequently involve the tongue and other neck and jaw muscles. Despite the nomenclature, these lesions do not show histologic signs of inflammation.
Differential Diagnosis
Lesions of skeletal muscle that have similar clinical features and are differentiated by histopathologic findings.
Management
Conservative surgical excision and submission for histopathology.
Reactive Gingival Enlargement
Gingival enlargement or overgrowth is usually caused by local inflammatory conditions such as poor oral hygiene, food impaction, or mouth breathing.14 Systemic conditions such as hormonal changes or drug therapy may also cause or contribute to the severity of gingival enlargement. Histologically, there are a number of explanations for gingival enlargement: hypertrophy (an increase in cell size), hyperplasia (an actual increase in cell number), edema, vascular engorgement, the presence of an inflammatory cell infiltrate, or an increase in dense fibrous connective tissue. One or more of these explanations may predominate depending on the underlying cause.
Inflammatory Gingival Enlargement
Etiology and Pathogenesis
Inflammatory gingival enlargement occurs in sites where there has been chronic suboptimal oral hygiene with heavy biofilm accumulation, supragingival calculus formation, impaction of food, or the presence of aggravating factors such as orthodontic appliances, mouth breathing, hormonal changes, or other systemic diseases. Gingival enlargement primarily affecting the maxillary anterior region may be observed in mouth breathers, and hormonal changes (such as during pregnancy or puberty) may exaggerate the local immune response to local factors and contribute to gingival enlargement.
Epidemiology
Gingivitis is highly prevalent (>90%), particularly in a pediatric and adolescent population, but conservative estimates of severe gingivitis associated with gingival enlargement are <5%.
Clinical and Histologic Manifestations
The clinical diagnosis of inflammatory gingival enlargement is straightforward, with tissues exhibiting a glossy edematous bright red or purplish color, pitting edema, and a tendency to hemorrhage on slight provocation (Figure 6-10). A malodor may result from the decomposition of food debris and accumulation of bacteria. Pseudopockets formed by gingival enlargement make the maintenance of good oral hygiene difficult, perpetuating a cycle of inflammation. Longstanding inflammatory gingival enlargement may demonstrate relatively firm, resilient, and pink gingivae that do not bleed readily. This is due to a greater fibrous component with an abundance of fibroblasts and collagen fibers. Chronic inflammatory gingival enlargement is a risk factor for periodontal disease. Histologically, the exudative and proliferative features of chronic inflammation are seen: a preponderance of inflammatory cells, vascular engorgement, new capillary formation, and associated degenerative changes.
Figure 6‐10 Inflammatory gingival enlargement secondary to local factors.
Differential Diagnosis
Drug-induced gingival enlargement, other systemic diseases (including acute myelogenous leukemia, von Recklinghausen’s neurofibromatosis [neurofibromatosis 1], Wegener’s granulomatosis, sarcoidosis, Crohn’s disease, primary amyloidosis, Kaposi’s sarcoma, acromegaly, and lymphoma), and hereditary gingivofibromatosis.
Management
Treatment of inflammatory gingival enlargement begins with the establishment of excellent oral hygiene, together with the elimination of all local and/or systemic predisposing factors if possible. This includes a professional debridement (supragingival scaling or subgingival root planing) and prophylaxis, and correction of faulty restorations, carious lesions, or food impaction sites. Close follow-up after initial therapy is required to assess improvements in home care and tissue response that will dictate subsequent treatment options.
For refractory cases, adjunctive topical or systemic antimicrobials or surgical options may be indicated. The successful treatment of gingival enlargement in mouth breathers depends primarily on the elimination of the habit. Patients should be referred to an otolaryngologist to determine if there is any obstruction of the upper air passages and/or to an orthodontist to assess the potential for treatment to permit the normal closure of the lips during sleep. A tissue biopsy should be considered whenever the cause is unclear, when there is a poor response to local therapy, or to rule out rare systemic diseases that may present with gingival enlargement (e.g., acute myelogenous leukemia).
Drug-Induced Gingival Enlargement
Etiology and Pathogenesis
Drug-induced gingival enlargement is most commonly associated with the administration of anticonvulsants (principally phenytoin), cyclosporine, and calcium channel blocking agents (principally nifedipine).15 Contributing local factors aside, the extent of inflammation and fibrosis is largely influenced by the drug type, dosing, and duration. Phenytoin-induced gingival enlargement exhibits the most fibrosis, and in contrast cyclosporine induces the least fibrosis, but in both the gingivae are enlarged and highly inflamed. The blend of fibrosis versus inflammation falls between these two extremes for calcium channel blocker–induced enlargement. These drugs likely exert their influence by the dysregulation of cytokines and growth factors, and also differentially affect the response of innate and adaptive immune systems.
Epidemiology
Phenytoin-induced gingival enlargement (Figure 6-11) is the most prevalent, affecting approximately 50% of patients who use the drug for longer than three months. Although rare, gingival enlargement has also been reported in patients taking other anticonvulsants, namely valproic acid, phenobarbital, and vigabatrin. The immunosuppressant agent cyclosporine causes gingival enlargement in 25–30% of adults and, notably, in more than 70% of children (Figure 6-12). Nifedipine and dilitiazem are responsible for most cases of calcium channel blocker–induced gingival enlargement, with a prevalence of 5–20%. There are also reports of gingival enlargement following use of verapamil, felodipine, and amlodipine.
Figure 6‐11 Gingival enlargement secondary to longstanding phenytoin use.
Clinical Manifestations
There is a characteristic clinical appearance of drug-induced gingival enlargement. After approximately one month of use of the drug, interdental papillae enlargement begins, usually in the anterior regions, and enlargement may become more extensive, leading to gingival disfigurement and associated esthetic and functional complications.
Differential Diagnosis
Inflammatory gingival enlargement, other systemic diseases (including acute myelogenous leukemia, von Recklinghausen’s neurofibromatosis [neurofibromatosis 1], Wegener’s granulomatosis, sarcoidosis, Crohn’s disease, primary amyloidosis, Kaposi’s sarcoma, acromegaly, and lymphoma), and hereditary gingivofibromatosis.
Management
Prevention through optimal oral hygiene is essential to minimize the severity of enlargement. For patients treated for epilepsy, medications must be reviewed before orthodontic treatment begins. There are several treatment options for drug-induced gingival enlargement. The most predictable treatment is either the withdrawal or change of medication and there are a variety of new-generation anticonvulsants, immunosuppressants, and antihypertensives available. Tacrolimus has been shown to be an effective replacement for cyclosporine and does not seem to cause gingival enlargement.
Figure 6‐12 Gingival enlargement secondary to longstanding cyclosporine use.
Nonsurgical treatments such as professional gingival debridement and topical or systemic antimicrobials may ameliorate gingival enlargement. Surgical management is reserved for severe cases, although recurrence is common. Conventional gingivectomy is commonly performed, although periodontal flap surgery may be indicated if there are mucogingival considerations, or in pediatric patients in whom tooth eruption might be affected. Laser ablation gingivectomy may offer an advantage over conventional surgery since procedures are faster and there is improved hemostasis and more rapid healing.
Other Causes of Gingival Enlargement
Although not strictly reactive, gingival enlargement may rarely be the result of genetic predisposition. Hereditary gingivofibromatosis (Figure 6-13), is linked to both autosomal dominant and recessive patterns of inheritance, and genetic heterogeneity and variable expressivity contribute to the difficulty encountered in assigning this diagnosis to a specific syndrome.16 Putative inherited mutations are in the SOS1 or CAMK4 genes. In contrast, there are a number of syndromes in which gingival enlargement is one of the manifestations. Enlargement may be present at birth or may become apparent only with the eruption of the deciduous or permanent dentitions. Tooth migration, prolonged retention of the primary dentition, and diastemata are common, and enlargement may completely cover the crowns of the teeth, resulting in compromised oral function.
Patients with acute myelogenous leukemia (principally acute monocytic [M4] or acute myelomonocytic [M5] leukemia) may present with gingival leukemic infiltrates (Figure 6-14). Others include von Recklinghausen’s neurofibromatosis (neurofibromatosis 1), Wegener’s granulomatosis, sarcoidosis, Crohn’s disease, primary amyloidosis, Kaposi’s sarcoma, acromegaly, and lymphoma.
Figure 6‐13 Hereditary gingival fibromatosis. Note the severity, with almost complete coverage of teeth in some locations.
Figure 6‐14 Gingival enlargement associated with acute myelogenous leukemia.
BENIGN SOFT TISSUE TUMORS
Oral mucosal benign tumors comprise lesions that are formed from epithelium, fibrous connective tissue, adipose tissue, nerve, and muscle. Benign proliferations of blood vessels and lymphatic vessels resemble neoplasms, but do not have unlimited growth potential and therefore are more appropriately considered hamartomatous proliferations.
Epithelial Tumors
Human Papillomavirus-Induced Growths
Etiology and Pathogenesis
These growths are not true neoplasms, but rather virally induced tissue proliferations.17 There are almost 200 human papillomavirus (HPV) genotypes, of which at least 30 have been detected in oral lesions. Much attention has been focused on the relationship between oncogenic genotypes (predominantly HPV 16) and oropharyngeal carcinogenesis (see Chapter 7, “Head and Neck Cancer”). Benign HPV-induced lesions are not routinely genotyped, and in case series where such lesions were genotyped, HPV positivity was variable (ranging from 13 to 100%), suggesting methodologic inconsistencies. In those lesions that are HPV positive, nononcogenic genotypes predominate. The virus infects the basal cell layer of the epithelium following mucosal trauma, there is integration of the viral genome, and proliferation of the epithelium leading to the development of a clinically visible lesion or lesions. The virus is most often transmitted by direct contact with another infected person, although such a history may not be evident, suggesting transmission by autoinoculation or casual contact. Lesions associated with sexual contact (referred to as condyloma acuminatum) or vertical transmission are also covered in Chapter 21, “Infectious Diseases.”
Epidemiology
HPV-induced growths are estimated to have a prevalence of <0.4% and comprise <5% of all oral biopsy specimens submitted for histology. Current effective vaccines for HPV may be expected to result in a decrease in prevalence of HPV-induced lesions. Patients living with HIV infection are at higher risk for developing HPV-induced growths than immunocompetent patients. Viral papillomas (also called squamous papilloma), largely associated with HPV 6 and 11, are the most commonly appearing of the HPV-induced growths (Figure 6-15) and they usually occur in the third to fifth decades. Verruca vulgaris is predominantly cutaneous (associated with HPV 2 and 57), and condyloma accuminatum, similar to genital warts, is associated with HPV 6 and 11. Heck’s disease is endemic in some Eskimo and Native American communities and associated with HPV 13 and 32.
Clinical and Histologic Manifestations
Viral papillomas most commonly present as an isolated small growth (<1 cm diameter) on the palate, ranging in color from white to pink, their surface is papillary/verrucous, and they are pedunculated more often than sessile. Condyloma accuminata are typically larger in size than viral papillomas, are often flat-topped, and may present as a single main growth associated with smaller satellite lesions. The common wart, verruca vulgaris, is generally found on the skin (sometimes in association with similar skin lesions, often on the fingers). When involving the oral cavity, these warts are similar in appearance to viral papillomas and they tend to involve the lips, gingivae, and hard palate.
Focal epithelial hyperplasia (Heck’s disease) is characterized by numerous soft, well-circumscribed, comparatively flat, and sessile papules distributed throughout the oral mucosa. Histologically, FEH is characterized by nondyskeratotic nodular acanthosis, which forms the basis of the papules, and a subepithelial lymphocytic infiltration. Intraoral papillomatosis, often florid, has been found in a small subset of HIV-infected patients (Figure 6-16), particularly since the advent of active antiretroviral therapy, and may be associated with numerous HPV genotypes. Florid papillomatosis may also occur in patients with conditions such as ichthyosis hystrix (a congenitally acquired deforming skin papillomatosis) and Down syndrome.
Figure 6‐15 (A) Viral papilloma involving the right buccal mucosa. Note the papillary and highly keratinized surface, presumably related to the location (see inset). (B) Viral papilloma with a pebbled surface (inset) involving the right maxillary alveolar ridge. (C) Viral papilloma with a papillary surface (inset) involving the soft palate.
Differential Diagnosis
Verruciform xanthoma, giant cell fibroma, or a verrucous leukoplakia or papillary squamous cell carcinoma can mimic solitary benign HPV-induced growths. White sponge nevus, or proliferative verrucous leukoplakia, may mimic florid benign HPV-induced growths.
Management
Oral viral papillomas and warts are clinically similar, and local excision is desirable. Care should be exercised when removing HPV-induced oral growths with electrocautery or laser, as there exists the possibility of aerosolizing viral particles. Due to the widespread manifestations, florid disease is challenging to manage surgically, and there is no current evidence-based medical management.
Keratoacanthoma
Etiology and Pathogenesis
The rapid growth of a keratoacanthoma may be quite frightening, to the point where it is often mistakenly diagnosed as squamous or basal cell carcinoma.
Epidemiology
They are exceedingly rare.
Clinical and Histologic Manifestations
The usual location is on the upper lip, where they are dome-like, sharply demarcated, appear fixed to the surrounding tissue, and are usually capped by thick keratin.18 The proliferating epithelium consists of masses of well-differentiated squamous cells that often produce keratin pearls, yet show little cellular atypia.
Differential Diagnosis
Squamous cell or basal cell carcinoma.
Management
Occasionally, the lesion matures, exfoliates, and heals spontaneously. In most cases, however, treatment of this lesion is conservative excision, although some believe that it is not clearly separable from squamous cell carcinoma and advocate wide excision to prevent recurrence.
Other Benign Epithelial Growths
Molluscum contagiosum is a dermatologic infection caused by a poxvirus that is acquired by direct skin contact. Both intraoral and labial lesions of molluscum contagiosum occur, predominantly in HIV-infected patients, and these are characterized by clusters of tiny firm papules. Histologically, these papules are composed of clumps of proliferating epithelial cells with prominent eosinophilic molluscum inclusion bodies that are commonly associated with poxvirus infections.
Vascular Anomalies
These entities have been classified using standardized terminology developed by the International Society for the Study of Vascular Anomalies and may be subdivided into vascular tumors and vascular malformations.19
Hemangiomas
Etiology and Pathogenesis
Hemangiomas of the head and neck are vascular tumors and true endothelial cell neoplasms. They appear a few weeks after birth and grow rapidly, and in most cases undergo involution over time, with residual telangiectatic, fatty, or scar tissue apparent in approximately 50% of patients.
Figure 6‐16 (A) HIV-associated florid papillomatosis involving free marginal gingivae. (B) HIV-associated florid papillomatosis involving buccal mucosa. Note coalescing papules, which are flat. (C) HIV-associated florid papillomatosis involving the lips.
Epidemiology
Hemangiomas are present in approximately 4–5% of infants. The majority (approximately 70%) involve the head and neck.
Clinical and Histologic Manifestations
They have been described in almost all head and neck locations in a variety of presentations: superficial and deep, small and large, most commonly as solitary lesions but also as multiple lesions. Small lesions may be clinically and histologically indistinguishable from pyogenic granulomas and superficial venous varicosities.
Differential Diagnosis
Oral hemangiomas may be similar in appearance to vascular malformations, or pyogenic granulomas.
Management
Given the propensity for involution, surgery should only be considered for those that do not involute, are esthetically obtrusive, or bleed easily.
Capillary, Venous, and Arterial/Arteriovenous Vascular Malformations
Etiology and Pathogenesis
These malformations are classified depending on the vessel type involved or flow types: arterial and arteriovenous (high flow), capillary (Figure 6-17), or venous (low flow). They are structural aberrations in components of the vascular apparatus and may be clinically apparent at birth, grow slowly proportional to the growth of the child (characterized by hypertrophy), and never involute. Centrally located malformations must be distinguished from the many osteolytic tumors and cyst-like lesions that affect the jaws (see later). Arterial and arteriovenous malformations may first develop following hormonal changes (such as puberty), infections, or trauma. Venous malformations can sometimes appear first in early adulthood.
Figure 6‐17 Vascular malformation involving the tongue, which developed two months before in a 25-year-old female.
Epidemiology
It is challenging to estimate the prevalence of vascular malformations because of the older classification systems for vascular anomalies implemented in large screening studies. However, the prevalence of oral vascular malformations is approximately 0.2–0.5%.
Clinical Manifestations
Arterial or arteriovenous malformations may be firm, pulsatile, and warm. Venous malformations are soft and easily compressible. Diascopy is the technique of applying pressure to a suspected vascular lesion to visualize the evacuation of coloration (Figure 6-18) and may facilitate the differentiation of a small vascular lesion from ot her nonblanchable red or pigmented lesions.
Differential Diagnosis
The diagnosis of malignant neoplasms must always be entertained if lesions demonstrate progressive enlargement.
Figure 6‐18 Diascopy of a small capillary malformation on the lateral border of the tongue. Note blanching of the lesion.
Management
Care should be taken in performing biopsies or excising all vascular lesions, as they have a tendency for uncontrolled hemorrhage and the extent of the lesion is unknown, since only a small portion may be evident in the mouth. Therefore, identification of the precise anatomic location and depth of tissue extent is warranted before treatment, particularly for the high-flow lesions. A number of imaging modalities may be indicated, including ultrasound, contrast-enhanced magnetic resonance imaging or computed tomography (CT), and dynamic MR angiography. Treatment modalities (alone or in combination) for peripheral vascular malformations depend on the type of malformation and include sirolimus, sclerotherapy, embolization, or surgical excision/resection using electrocoagulation.
Other Angiomatous Syndromes
A number of syndromes are associated with vascular malformations, including Osler–Weber–Rendu syndrome (hereditary hemorrhagic telangiectasia; Figure 6-19), blue rubber bleb nevus syndrome, Bannayan–Zonana syndrome, Sturge–Weber syndrome (Figure 6-20),20 Klippel–Trénaunay syndrome, Servelle–Martorell syndrome, von Hippel–Lindau syndrome, and Maffucci syndrome.
Lymphatic Malformations
Etiology and Pathogenesis
Macrocystic, microcystic, or mixed cystic lymphatic malformations may be localized or regional, and they are characterized by an abnormal proliferation of lymphatic vessels. The most common extraoral and intraoral sites are the neck (predominantly in the posterior triangle) and tongue, respectively. The vast majority (80–90%) of lymphangiomas arise within the first two years of life and are an important cause of congenital macroglossia.
Figure 6‐19 Osler–Wendu–Rendu syndrome (hereditary hemorrhagic telangiectasia). Note discrete multiple red papules associated with dilated vessels. Patient has similar papules distributed on his labial mucosae and finger tips.
Figure 6‐20 Sturge–Weber syndrome. Hypervascular changes are unilateral, which is consistent with a trigeminal nerve distribution, in this case following the second (maxillary) branch of the left trigeminal nerve.
Epidemiology
Lymphatic malformations are rare.
Clinical and Histologic Manifestations
Clinically, lymphangiomas are a slow-growing and painless soft tissue mass. Frequently they are without a clear anatomic outline, dissecting tissue planes, and can be more extensive than anticipated. Intraosseous lymphangiomas have been reported. Occasionally, they may undergo a rapid increase in size secondary to inflammation from an infection or hemorrhage from trauma. Large lymphangiomas may become life-threatening if they compromise the airway or vital blood vessels, and those spreading into and distending the neck are macrocystic and are referred to as cystic hygromas. Abnormalities of the tongue mucosa overlying a lymphatic malformation may give the appearance of a localized glossitis and may draw attention to the presence of a lesion buried deep in the tongue. The typical oral lymphatic malformation has a racemose or pebbly surface.
Differential Diagnosis
Includes other vascular malformations, amyloidosis, neurofibromatosis, and other causes of macroglossia.
Management
The treatment of lymphatic malformations is dictated by their type, anatomic site, and extent of infiltration into surrounding structures. Sclerotherapy (with chemotherapeutic agents such as picabinil [OK-432], bleomycin, or doxycycline) is advocated over surgical excision in most cases. Recurrence of oral lymphangiomas has been reported, presumably because the lesion is interwoven between muscle fibers, preventing complete removal.
Other Vascular Growths
An unusual abnormality, glomus tumor (glomangioma), develops as a small, painful, unencapsulated nodule. It represents a proliferation of the modified smooth muscle pericytic cells found in the characteristic type of peripheral arteriovenous anastomosis known as the glomus. In addition to having a distinctive histology, these lesions also may secrete various catecholamines. The glomus tumor is rare in the mouth and occurs more often around the carotid body, in the jugulotympanic region, and in the vagus nerve. Glomus tumors arising in the carotid bodies may produce neck masses and are referred to as chemodectomas or paragangliomas.
Neurogenic Tumors21
Traumatic Neuroma
Etiology and Pathogenesis
A traumatic neuroma is a reactive lesion caused by injury to a peripheral nerve. When a nerve and its sheath are damaged, the proximal end of the damaged nerve proliferates into a mass of nerve and Schwann cells mixed with dense fibrous scar tissue.22 In the oral cavity, injury to a nerve may occur from injection of local anesthesia, surgery, or other sources of trauma.
Epidemiology
Traumatic neuromas are rare and tend to occur in adults.
Clinical Manifestations
Traumatic neuromas in the oral cavity may occur in any location where a nerve is damaged, and the mental foramen area, tongue, and lower lip are the most common sites. Traumatic neuromas may lead to either reduced sensation or, in approximately 20% of cases, elicit discomfort.22 The discomfort may range from pain on palpation or pressure from an overlying denture (in the case of a neuroma involving the mental foramen area) to severe and constant pain.
Differential Diagnosis
Any smooth-surfaced submucosal exophytic lesion may be included in a differential diagnosis, including the palisaded encapsulated neuroma, neurofibroma, schwannoma, irritation fibroma, tumors of muscles, and minor salivary gland neoplasms.
Management
Traumatic neuromas are treated by surgical excision and recurrence is rare.
Palisaded Encapsulated Neuroma
Etiology and Pathogenesis
This is considered a reactive neoplasm, likely in response to trauma.
Epidemiology
This lesion is rare and most often occurs in older adults.
Clinical and Histologic Manifestations
The lesions are solitary, a feature that distinguishes them from the neuromas in MEN syndrome (see later). They are typically painless and the most common location is the hard palate.23 Histologically, there is a well-circumscribed, partially encapsulated nodule composed of spindle-shaped cells exhibiting areas of nuclear palisading, often admixed with axons. They contain Schwann cells, perineural cells, and axons, and can be distinguished from neurofibromas and schwannomas both by their light microscopic appearance and by immunohistochemical stain that is positive for EMA and S-100.
Differential Diagnosis
Any smooth-surfaced submucosal exophytic lesion may be included in a differential diagnosis, including the palisaded encapsulated neuroma, neurofibroma, neurilemmoma, irritation fibroma, tumors of muscle tissue, and minor salivary gland neoplasms.
Management
Palisaded encapsulated neuromas are treated by surgical excision and recurrence is rare.
Oral Mucosal Neuromas and Multiple Endocrine Neoplasia Syndrome 2B (MEN 2B)
MEN 2B is caused by inherited mutations in the Met918Thr RET gene and characterized by tumors or hyperplasias of neuroendocrine tissues.24 Patients with MEN 2B present with a characteristic phenotype that includes medullary thyroid carcinoma, pheochromocytoma, prominent corneal nerve fibers, a “Marfanoid” body habitus, enlarged lips, and neuromas on the eyelids and oral mucosal tissues. Identification of mucosal neuromas may precede other components of the syndrome. Management includes prophylactic total thyroidectomy, ideally before the age of 1 year.
Neurofibroma and Schwannoma (aka Neurilemmoma)
Etiology and Pathogenesis
These are benign tumors derived from the tissue that envelops nerves and includes Schwann cells and fibroblasts.25 Although distinct tumors microscopically, they are quite similar in their clinical presentation and behavior.
Epidemiology
These benign tumors are rare and may occur at any age, without any sex predilection.
Clinical and Histologic Manifestations
They are typically asymptomatic and the tongue is the most common intraoral location (Figure 6-21). Microscopic examination of a neurofibroma reveals a fairly well-delineated but diffuse proliferation of spindle-shaped Schwann cells. A schwannoma is encapsulated and exhibits varying amounts of two different microscopic patterns. One pattern consists of cells in a palisaded arrangement around eosinophilic areas, and the other consists of less cellular spindle-shaped cells in a loose myxoid-appearing stroma. Differences in immunohistochemical staining have been demonstrated and may be helpful in establishing the definitive diagnosis.
Differential Diagnosis
Any smooth-surfaced submucosal exophytic lesion may be included in a differential diagnosis, including the palisaded encapsulated neuroma, irritation fibroma, tumors of muscle tissue, and minor salivary gland neoplasms.
Figure 6‐21 Neurogenic tumor involving the right lateral tongue.
Management
The treatment for a neurofibroma or schwannoma is surgical excision. They generally do not recur.
Multiple neurofibromas occur in a genetically inherited disorder known as neurofibromatosis 1 (NF1) or von Recklinghausen’s disease. This disease is transmitted as an autosomal dominant trait, and a germline mutation in the NF1 gene has been identified. Oral neurofibromas are a common feature of the disease. The presence of numerous neurofibromas or a plexiform-type neurofibroma is pathognomonic of NF1. Patients with NF1 are at increased risk of the development of a number of malignant tumors, especially malignant peripheral nerve sheath tumor, leukemia, and rhabdomyosarcoma.
Granular Cell Tumor
Etiology and Pathogenesis
The pathogenesis of this tumor has not been established, but most evidence suggests that it is reactive and arises from Schwann cells or their primitive mesenchymal precursors.
Epidemiology
These are rare, and the majority of cases occur in adults, with a female predilection.
Clinical and Histologic Manifestations
The granular cell tumor most often occurs on the dorsal tongue (Figure 6-22A), followed by the buccal and labial mucosae. Other intraoral sites include the palate (Figure 6-22B), gingiva, and floor of the mouth. The tumor appears as a painless, often yellowish, nonulcerated nodule. The granular cell tumor is a benign tumor composed of large oval-shaped cells with a granular cytoplasm.26 The granular cells are found in the connective tissue and the overlying surface epithelium exhibits pseudoepitheliomatous hyperplasia. Immunocytochemical staining reveals reactivity to S-100 protein, vimentin, CD-68, calretinin, NKI/C3, Inhibin-α, p75, and PGP9.5.
Figure 6‐22 (A) Granular cell tumors of the tongue, the most common site for this benign lesion. (B) Granular cell tumor involving the palate, an unusual site.
Differential Diagnosis
Any smooth-surfaced submucosal exophytic lesion may be included in a differential diagnosis, including the palisaded encapsulated neuroma, neurofibroma, schwannoma, irritation fibroma, verruciform xanthoma, tumors of muscle tissue, and minor salivary gland neoplasms.
Management
This tumor is treated by conservative surgical excision and does not recur.
The congenital epulis of the newborn is a very rare benign neoplasm composed of cells that closely resemble those seen in the granular cell tumor that occurs in adults. It is present at birth and usually presents as a smooth-surfaced, sessile, or pedunculated mass on the anterior maxillary alveolar ridge. It almost always occurs in girls. The ultrastructural and immunohistochemical features are distinct from the granular cell tumor, confirming that this lesion is a separate entity. The congenital epulis is treated by surgical excision and does not recur, and occasionally it will regress without treatment.
Melanotic Neuroectodermal Tumor of Infancy
Etiology and Pathogenesis
Melanotic neuroectodermal tumor of infancy is a benign neoplasm originating from neural crest cells that almost always occurs during the first year of life.
Epidemiology
This entity is exceedingly rare.
Clinical and Histologic Manifestations
The tumor most commonly occurs in the maxilla, followed by the skull, mandible, and brain. The tumor presents as a rapidly enlarging mass that destroys bone and may exhibit blue-black pigmentation. Histologically, the tumor is composed of collections of cells that resemble melanocytes, admixed with smaller round cells and variable amounts of melanin.
Differential Diagnosis
Given the rapid growth, malignant neoplasms must be considered, including sarcomas, and lymphomas.
Laboratory Findings
High levels of urinary vanillylmandelic acid are often found in patients with this tumor.
Management
Conservative surgical removal is usually adequate, but this tumor has a high recurrence rate and malignant transformation has been reported rarely.
Lipoma
Etiology and Pathogenesis
The lipoma is a benign mesenchymal tumor of mature adipocytes.
Epidemiology
Lipomas involving the oral cavity are rare (<3% of all lipomas). They occur in individuals over 40 years of age, and without any sex predilection.
Clinical and Histologic Manifestations
The majority of oral lipomas are found on the buccal mucosa and tongue. When occurring in the superficial soft tissue, the lipoma appears as a yellow/orange mass with a thin epithelial surface, demonstrating a delicate pattern of blood vessels (Figure 6-23). There are several microscopic variants of the lipoma. The classic description is of a well-delineated tumor composed of lobules of mature fat cells that are uniform in size and shape.27 The most common variants are fibrolipomas (i.e., those with a significant fibrous connective tissue component), followed by spindle cell lipomas (i.e., those with an admixture of uniform spindle cells), rarely sialolipomas, angiolipomas, myxoid lipomas, and an intramuscular lipoma.
Differential Diagnosis
The yellow/orange color is pathognomic. Other yellowish entities include abscess, sialolith, lymphoepithelial cyst, or granular cell tumor.
Figure 6‐23 Lipoma involving the buccal mucosa. Note the yellow color.
Management
The lipoma is treated by conservative surgical excision and generally does not recur. Intramuscular lipomas have a somewhat higher recurrence rate because they are more difficult to remove completely.
Tumors of Muscle
Etiology and Pathogenesis
These are benign neoplasms of striated (rhabdomyoma) and smooth (leiomyoma) muscle.
Epidemiology
Tumors of muscle are exceedingly rare in the oral cavity.
Clinical Manifestations
Oral rhabdomyomas have been reported to occur almost exclusively on the tongue. The vascular leiomyoma (angioleiomyoma) is the least rare of the leiomyoma variants and solitary lesions have been reported to involve multiple oral sites.28
Differential Diagnosis
Any smooth-surfaced submucosal exophytic lesion may be included in a differential diagnosis, including the palisaded encapsulated neuroma, neurofibroma, schwannoma, irritation fibroma, granular cell tumor, and minor salivary gland neoplasms.
Management
Treatment is local surgical excision, and recurrence is rare.
BENIGN HARD TISSUE LESIONS
BENIGN FIBRO-OSSEOUS LESIONS
The term “benign fibro-osseous lesion” (BFOL) is a generic histologic designation for a diverse group of bone lesions that are named for the similarity of their histopathologic morphology (see classification in Box 6-1). They are composed of cellular fibrous connective tissue admixed with either osteoid matrix, woven new bone and bone trabeculae, or rounded small to large calcified masses that have traditionally been described as cementoid material. BFOLs of the jaws include fibrous dysplasia, ossifying fibroma, and the cemento-osseous dysplasias. Since the histopathology is so similar in these lesions, imaging with radiographic correlation is critical for the diagnosis.
Fibrous Dysplasia
Fibrous dysplasia is a condition that is characterized by the replacement of normal bone with fibro-osseous tissue. The well-vascularized and cellular fibrous tissue contains trabeculae or spherules (small spheres) of poorly calcified nonlamellar bone that are formed by osseous metaplasia.
Etiology and Pathogenesis
The pathogenesis is related to GNAS (guanine nucleotide binding protein, alpha stimulating) gene mutation. The most widely accepted theory is that fibrous dysplasia results from an abnormality in the development of bone-forming mesenchyme.
Epidemiology
Fibrous dysplasia presents in childhood, typically with a slowly progressive enlargement of bone that generally slows or ceases with puberty.
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