Most pathologic lesions of the jaws or of oral mucosa are treated successfully by surgical interventions. For treatment of the central giant cell lesion, aneurysmal bone cysts, histiocytosis of the mandible, hemangioma, odontogenic keratocyst, Paget disease, oral submucous fibrosis, and oral lichen planus, medical management consisting of intralesional injections, sclerosing agents, and systemic bisphosphonates is as successful as surgical procedures with fewer complications. Pharmacology of agents used and protocols are presented.
Key points
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Most pathologic lesions of the jaws or of oral mucosa are treated successfully by surgical interventions.
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For treatment of the central giant cell lesion, aneurysmal bone cysts (ABC), histiocytosis of the mandible, hemangioma, odontogenic keratocyst, Paget disease, oral submucous fibrosis (OSF), and oral lichen planus (OLP), medical management consisting of intralesional injections, sclerosing agents, and systemic bisphosphonates is as successful as surgical procedures with fewer complications.
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Medication management of jaw lesions involves the use of pharmacologic agents to modify, slow, or eradicate a pathologic process that is affecting the jaw.
Medication management of jaw lesions involves the use of pharmacologic agents to modify, slow, or eradicate a pathologic process that is affecting the jaw. For a majority of pathologic lesions seen in the jaws, surgical procedures are indicated and are curative. For large lesions, however, surgical procedures may have poor neurologic, functional, or esthetic results. Several alternative nonsurgical therapies, such as intralesional injections, the use of sclerosing agents, and bisphosphonates, have been described for the management of certain intrabony or mucosal diseases. This article discusses the treatment of jaw lesions that are amenable to localized drug treatment and the pharmacology of the agents used most frequently used ( Table 1 ). Drugs that require systemic administration are only briefly presented. For completion, a few soft tissue lesions are also discussed.
| Disease | Agents Used |
|---|---|
| Central giant cell lesion | Corticosteroids, calcitonin, interferon alfa, bisphosphonates |
| ABCs | Ethibloc, calcitonin, aqueous calcium sulfate. |
| Histiocytosis of the mandible | Corticosteroids |
| Low-flow VM | Absolute ethanol, sodium morrhuate, sodium tetradecyl sulfate, ethanolamine oleate |
| Hemangioma | Corticosteroids, bleomycin, sodium morrhuate |
| Odontogenic keratocyst | Carnoy solution |
| Paget disease | Calcitonin, bisphosphonates |
| OLP | Corticosteroids |
| OSF | Corticosteroids, interferon gamma |
The methods used to treat jaw lesions by pharmaceutical or chemical agents involve
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Intralesional injection
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Topical application
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Systemic administration
Intralesional injection
Intralesional injection is the direct delivery of medication into the body of the lesion. The purpose is to obtain a high concentration of the drug at the diseased site, with minimal systemic absorption. Intralesional injections are easily performed and are relatively safe. The operator must take into consideration, however, the anatomy of the area. Adjacent nerves should not be compromised and intravascular injections should be avoided.
Intralesional injection
Intralesional injection is the direct delivery of medication into the body of the lesion. The purpose is to obtain a high concentration of the drug at the diseased site, with minimal systemic absorption. Intralesional injections are easily performed and are relatively safe. The operator must take into consideration, however, the anatomy of the area. Adjacent nerves should not be compromised and intravascular injections should be avoided.
Central giant cell lesion
The central giant cell granuloma (CGCG) was classified by the World Health Organization in 2005 as an aggressive idiopathic benign intraosseous lesion that occurs almost exclusively in the jaws. It is most frequently seen in young women (women:men ratio = 2:1) and typically presents in the second and third decades. The lesion is osteolytic and histologically consists of multinucleated giant cells throughout a fibroblastic stroma that are often clustered around areas of hemorrhage. Surgery (ranging from aggressive curettage to peripheral ostectomy to en bloc resection) is the most common treatment, but because of a high recurrence rate, alternative medical treatments have been introduced. The most widely used agents are corticosteroids, calcitonin, and interferon alfa. Both steroids and calcitonin affect the giant cells rather than the stromal cells, even though it may be the stromal cells (fibroblasts) that are the etiologic cells of CGCG and the giant cells only secondary or reactive. Glucocorticoid receptors and calcitonin receptors have been identified on both multinucleated giant cells and mononuclear spindle-shaped cells.
Steroids
The rationale for using corticosteroids to treat CGCC was based on its histologic resemblance to sarcoid. Because corticosteroids have been effective in the treatment of sarcoid, it was thought that they may have a similar therapeutic effect on the CGCC. In addition, corticosteroids may act by suppressing the angiogenic component of the lesion. Steroids seem to inhibit the extracellular production of bone resorption mediating lysosomal proteases in multinucleated giant cells and by inducing apoptosis of osteoclastic cells.
The drugs used are triamcinolone acetonide (10 mg/mL or 40 mg/mL) or triamcinolone hexacetonide (20 mg/mL). The injections are administered weekly or biweekly.
Triamcinolone acetonide
Triamcinolone acetonide is a more potent derivative of triamcinolone. It is a synthetic glucocorticoid corticosteroid with marked anti-inflammatory action and no mineralocorticoid action. Its potency is 5 times that of cortisol. It is packaged as a sterile aqueous suspension suitable for intralesional injection, in doses of 10 mg/mL or 40 mg/mL. It should be injected directly into the jaw lesion.
The general protocol is to start with triamcinolone acetonide, 10 mg/mL, and inject 2 mL of the drug for every 2 cm of radiolucency noted on the standard panoramic jaw radiograph (panorex). The drug is mixed 50/50 with 2% lidocaine, with 1:100,000 epinephrine and injected into the body of the lesion. The site of injection is determined by clinically selecting the site where cortical bone is most expanded and is thinnest and, once inside the lesion, small amounts are injected into different areas. At times, several spots may have to be selected. The injections are repeated weekly for 6 weeks.
Allergic reactions are rare and dose independent. Systemic side effects are not likely to follow these intralesional injections because the doses are confined locally and the actual systemic absorbed dose is small. Intralesional steroids should not be injected at the site of active infection – including the presence of herpes labialis – nor where there is previous history of triamcinolone hypersensitivity. Side effects include pain at the injection site, bleeding, bruising, infection, and impaired wound healing.
Triamcinolone hexacetonide
Triamcinolone hexacetonide (Aristospan [Sandoz Inc., Princeton, NJ]) is the hexacetonide (containing 6 acetonide groups) ester of triamcinolone and is practically insoluble. When injected intralesionally, it is absorbed slowly from the injection site. The pharmacologic action of triamcinolone hexacetonide is less intense but more prolonged. Its activity is due to the slow release of triamcinolone acetonide through hydrolysis. After this reaction, the pharmacology is identical to triamcinolone acetonide. Its use in CGCC is that using triamcinolone hexacetonide, 20 mg/mL, allows for a biweekly interval of injections.
Calcitonin
Similar to the use of steroids, the rationale for using calcitonin to treat CGCC was that its histology appears similar to brown tumor of hyperparathyroidism and only blood calcium levels can distinguish between the two. For this reason, calcitonin—the antagonist for parathormone—was introduced, although parathyroid hormone has never been identified in the CGCG. Calcitonin receptors, however, have been identified on the giant cells of the lesion, antagonizing osteoclastic bone resorption.
Calcitonin takes longer than steroids to affect CGCGs and is, therefore, not suitable for treating patients with aggressive lesions (especially in a younger age group) or those with associated pain or paraesthesia where a quick result would be beneficial.
Calcitonin is commercially available as human calcitonin and salmon calcitonin but salmon calcitonin is the one most widely used. Salmon calcitonin is approximately 50 times more potent than human calcitonin. Its high potency in human is due to its high affinity (40 times that of human calcitonin) for the human calcitonin receptor and its slow rate of clearance. It inhibits osteoclastic bone resorption, altering both the number and/or resorptive activity of osteoclasts, and decreases the rate of bone turnover in conditions with an increased rate of bone resorption and formation, such as active Paget disease and CGCG. The bioavailability of salmon calcitonin is approximately 70% after injection. It is supplied as ready-for-injection ampules of 100 IU, where each ampule of 1 mL contains 100 IU, and as 50 IU, where each ampule of 1 mL contains 50 IU.
Being a polypeptide, calcitonin may give rise in rare cases to localized or generalized hypersensitivity reactions. Antibody formation can limit its effectiveness. Allergic-type reactions, including single cases of anaphylactic shock, have been reported. Side effects are rare and generally mild.
A suggested treatment regimen is 100 IU of calcitonin per day, until it is ascertained radiographically that there is no further resolution of the disease. Radiographically, resolution does not normally commence until 6 to 9 months of treatment, and treatment is continued for up to 24 months to see the maximum resolution.
Interferon
The use of interferon alfa derives its rationale from the hypothesis that the central giant cell lesion is an angiogenic tumor that is characterized by vascular proliferation and bone resorption. Antiangiogenic activity is a known property of interferon alfa. It directly interferes with the ability of endothelial cells to form new capillary blood vessels. Interferon also seems to encourage bone formation, through stimulation of osteoblasts and preosteoblasts, and to inhibit bone resorption.
Interferon alfa is a biologic response modifier and is classified as a pleiotropic cytokine. This drug has multiple serious side effects and patients need to be followed closely. Hematocrit, hemoglobin, white blood cell and platelet counts, and liver function tests should be performed every 6 weeks. Side effects include headache, fatigue, diarrhea, upset stomach, loss of appetite, dizziness, xerostomia, dysgeusia, nausea/vomiting, anemia, neutropenia, and thrombocytopenia. Tooth and gum problems may sometimes occur during treatment. Having a dry mouth can worsen the periodontal side effects. Contraindications are hypersensitivity to interferon alfa, autoimmune hepatitis, decompensated liver disease, and pregnancy.
The protocol for using interferon to treat the CGCG is a combination of surgery and medical treatment. After enucleation, interferon alfa-2a or interferon alfa-2b is started on postoperative day 3 at a once-daily dose of 2,000,000 units to 3,000,000 units subcutaneously. The daily doses are continued until the defect seems to be filled in with bone on a panoramic radiograph or on a confirmatory CT scan. The mean duration of treatment was reported to be 7.3 ± 0.8 months.
Aneurysmal bone cysts
The ABC is a benign cystic type lesion of bone, composed of blood-filled spaces separated by connective tissue septa containing fibroblasts, osteoclast-type giant cells, and reactive woven bone. The lesion, however, is neither an aneurysm nor a cyst. It is characterized by a rapid growth pattern with resultant bony expansion and facial asymmetry. It affects young individuals under 20 years of age, with no gender predilection, and is seen more frequently in the mandible than the maxilla (3:1) with preponderance for the body, ramus, and angle region. ABC can be classified into 3 types: vascular cystic type (95%), a solid noncystic type (5%), and a rare mixed variant that demonstrates features of both the vascular and solid types.
Treatment of ABC is usually the complete surgical removal of the lesion. This may prove difficult at times because the lesions are often multilocular and may be divided by multiple bony septae. In addition to curettage or block resection, pharmaceutical management includes intralesional injection of calcitonin in combination with methylprednisolone, intralesional fibrosing Ethibloc (Ethicon), and aqueous calcium sulfate.
Intralesional injection of calcitonin in combination with methylprednisolone requires long-term repeated multiple injections and the response is unpredictable and has not been consistent. Methylprednisolone has an antiangiogenesis and fibroblastic effect whereas calcitonin has an osteoclastic inhibitory effect and promotes trabecular bone formation.
Methylprednisolone
Methylprednisolone sodium succinate (Medrol and Solu-Medrol [Pfizer Inc., NY]) is a synthetic glucocorticoid that is typically used for its anti-inflammatory effects. It is an intermediate-acting steroid that can stay active for 12 to 36 hours. Methylprednisolone at very low doses can inhibited angiogenesis. For the treatment of ABC, 125 mg of methylprednisolone is injected with 200 IU of calcitonin into the center of the lesion. Side effects are rare.
Ethibloc (Ethicon, Norderstedt, Germany) is an emulsion of zein, alcohol, oleum papaveris, propylene glycol, and a contrast medium, which thickens immediately when in contact with aqueous solution. As the alcohol dissolves in blood, zein precipitates and forms a filler with chewing gum–like consistency. The gelatinous material that is formed is biodegradable. Ethibloc injection is a simple, minimally invasive alternative procedure for the treatment of ABC and makes open operation unnecessary by stopping the expansion of the cyst and inducing endosteal new bone formation. It is not currently available in the United States but it has been used successfully in Europe and Canada. It is applied as a single injection and basically acts as a fibrosing agent.
Aqueous Calcium Sulfate
Aqueous calcium sulfate (BonePlast [Biomet, Warsaw, Indiana]) is another agent suggested for the treatment of ABC. The contents of the lesion is first aspirated. It may take a few attempts to aspirate the cavity, but the aspiration should be done until there is no return of aspirant from the cavity. After aspiration is completed, aqueous calcium sulfate is injected into the cavity. The aqueous calcium sulfate completely fills the cystic cavity and solidifies, thus preventing refill. The material is osteoconductive and has been used as a bone graft substitute in bony cavities. The calcium sulfate cement is reportedly absorbed completely within 8 weeks and replaced with new bone. Limited data exist, however, regarding the use of calcium sulfate for the treatment of ABC in the jaw.
Histiocytosis
Histiocytosis refers to a group of rare disorders of the reticuloendothelial system. Specifically, Langerhans cell disease (LCD), formerly known as histiocytosis X or idiopathic histiocytosis, is a rare disorder characterized by a proliferation of cells exhibiting phenotypic characteristics of Langerhans cells. The term, Langerhans cell histiocytosis , comprises 3 morphologically similar lesions: eosinophilic granuloma, Hand-Schüller-Christian syndrome, and Abt-Letterer-Siwe syndrome. The localized LCH (monostatic or multifocal eosinophilic granuloma) refers to a form of the disease typified by solitary or multiple skeletal lesions without extraskeletal involvement; it commonly affects children and young adults. The disseminated, chronic form, named Hand-Schüller-Christian syndrome, consists of skeletal and extraskeletal lesions with a progressive chronic course and usually affects children older than 3 years. The disseminated, acute, or subacute form, named Abt-Letterer-Siwe syndrome, refers to the form of the disease that is most often fatal because of the extensive skeletal and extraskeletal lesions; this form usually affects infants and children younger than 3 years. The skull, mandible, ribs, vertebrae, and long bones are often involved. Typically, Langerhans cell histiocytosis that affects many body systems occurs in children younger than 2, whereas single-site disease occur in people of any age and is the type dentists encounter. The disease peaks in the first 3 decades and boys and men are affected twice as often as girls and women.
The most common oral findings are localized pain and swelling, mucosal ulceration, gingival necrosis, and destruction of alveolar bone with tooth mobility and exfoliation. Many lesions, however, remain asymptomatic and are discovered accidentally during routine dental radiological examination. Radiologically, the lesions are localized radiolucencies with no sclerosis or reactive borders. With severe alveolar bone resorption there is an appearance of teeth floating in space.
Treatment options for LCD of the jaws are surgery (curettage), radiotherapy, chemotherapy, and intralesional injection of corticosteroids. Surgical curettage is the principal treatment modality, but its success is dependent on the extent and accessibility of the lesion. Extensive or radical surgery leading to loss of function and disfigurement is contraindicated. Local injection of corticosteroids is an effective treatment in localized disease. In children with mandibular LCD, 1 dose of methylprednisolone succinate injection has proved adequate. Prednisone and triamcinolone acetonide have also been used.
Steroids
It is postulated that a transient immune dysfunction stimulates the cytokine-mediated proliferation of pathologic Langerhans cells within the hematopoietic marrow of the bone. Stimulated histiocytes (monocytes/macrophages) are a source of mediators, such as tumor necrosis factor α, interleukin 1, and prostaglandin E2, which can cause osteolysis. Corticosteroids have the ability to inhibit the production of such mediators. Glucocorticoids inhibit monocyte/macrophage tumor necrosis factor α and interleukin 1p production at the transcriptional and post-transcriptional levels whereas the suppression of the production of prostanoids occurs by blocking phospholipase A2 activity. The injected steroid also serves to inhibit additional inflammatory cells and impede fibrosis, which produces better bone formation.
Methylprednisolone
Intralesional injections of 165 mg to 200 mg of methylprednisolone to mandibular lesion in which complete resolution was achieved have been reported. Complete resolution of the lesion reportedly occurs in 8 to 17 months after a single injection of methylprednisolone.
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