- Email: [email protected]
Intraosseous ameloblastoma
Intraosseous ameloblastoma Candice C. Black, DO,a Rocco R. Addante, MD, DMD,b and Carrie A. Mohila, MD, PhD,c Lebanon, New Hampshire DARTMOUTH HITCHCOCK MEDICAL CENTER
Ameloblastomas are benign slow-growing aggressive neoplasms with a poorly understood potential for rare metastasis. They are capable of reaching large sizes with extensive local bone erosion and destruction. They are composed of a mixture of ameloblastic epithelium and mesenchyme and arise from rests of outer and inner enamel epithelium and dental lamina. Microscopically, ameloblastomas are recognizable from their recapitulation of embryologic ameloblasts and stellate reticulum. There are 3 subtypes: the conventional or solid-multicystic variant, the unicystic variant, and the desmoplastic variant. Treatment planning for a given tumor includes consideration of location, primary versus recurrent, size, presence of cortical perforation, and age and health of the patient. Complete excision is recommended for conventional and desmoplastic variants. The unicystic variant requires additional subtyping to determine the best treatment approach. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;110:585-592)
Ameloblastoma is a benign but potentially aggressive tumor composed of a mixture of ameloblastic epithelium and mesenchyme. Excluding cysts, ameloblastoma represents 13%-54% of all jaw tumors.1 It affects males and females somewhat equally, peaking in the third decade, with a first-to-ninth decade range.1 The ratio of mandibular to maxillary tumors is 1:5.4.1 Ameloblastoma arises from rests of outer and inner enamel epithelium and dental lamina. Microscopically, ameloblastomas are recognizable from their recapitulation of embryologic ameloblasts and stellate reticulum. BRIEF EMBRYOLOGIC REVIEW At ⬃6 weeks of gestation the mesenchyme of the developing tooth induces epithelial proliferation forming the dental lamina. Small pockets of epithelium grow into the underlying mesenchyme and are known as the bud phase, which will give rise to the primary teeth. The mesenchyme proliferates and condenses around the bud, which then invaginates to form a cap shape, known as the cap phase, at ⬃9-11 weeks. The cap phase marks the start of the enamel organ. At week 14, the enamel organ further differentiates into an outer and inner epithelial layer, separated by a loose mesenchyme, the stellate reticulum, imparting a bell shape, known as the bell phase. Ameloblasts arise from the a
Associate Professor, Department of Pathology. Professor, Department of Maxillofacial Surgery. c Resident, Department of Pathology. Received for publication Nov 27, 2009; returned for revision Feb 9, 2010; accepted for publication Feb 24, 2010. 1079-2104/$ - see front matter © 2010 Mosby, Inc. All rights reserved. doi:10.1016/j.tripleo.2010.02.040 b
inner epithelium. Ameloblastomas express amelogenin, the precursor of enamel, which further supports this theory.2 Ameloblastic epithelium shows nuclear polarization toward the underlying reticulum surface, known as the stratum intermedium. The stratum intermedium (embryologically sandwiched between the ameloblast and stellate reticulum), thought to aid enamel production, is not present in ameloblastomas and, therefore, no enamel is produced. This polarization is recapitulated in ameloblastic tumors and marks the formation of the preameloblast cell. Preameloblasts work in concert with odontoblasts in the dental papillae to induce further differentiation of both cell lines and the eventual formation of enamel and dentin, respectively. AMELOBLASTOMA VARIANTS Our understanding of ameloblastomas has proved to be historically challenging. In their 1930 paper titled “The need of a standardized surgical and pathological classification of tumors . . . of dental origin,” Ivey and Churchill proposed the term “ameloblastoma” to replace various prevailing terms such as adamantinoma and adamantoblastoma.3 There have been many classification schemes for intraosseous ameloblastomas, with many early clinical reports lumping all comers into a single category, which has largely hampered efforts of clinicians to form meaningful evidence-based treatment guidelines. Published recurrence rates may over- or underestimate the actual recurrence for certain types of ameloblastoma. Ameloblastomas are benign aggressive slow-growing neoplasms with a poorly understood potential for rare metastasis.4 They are capable of reaching large sizes with extensive local bone erosion and destruction. Although some surgeons urge conservative treatment for ameloblastomas to avoid the potential 585
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morbidity associated with larger resections, others favor more definitive procedures to reduce recurrence risk.5-8 Conservative treatments include enucleation and curettage. Enucleation is the surgical removal of the whole lesion intact, including the capsular/pseudocapsular surface. Curettage is the scraping of the lesion out in a piecemeal fashion, as with friable lesions and lesions without capsules. A radical approach is a surgical resection of the lesion with some amount of surrounding bone9 with or without a continuity defect. The separation of ameloblastoma into meaningful subtypes and the individual features of a given tumor (location, primary vs. recurrent, size, presence of cortical perforation, and age and health of the patient) are best weighed case by case for deciding the appropriate treatment.5,10 Three types of intraosseous ameloblastoma are currently agreed upon: the solid-multicystic or conventional variant, the unicystic variant, and the desmoplastic variant. The solid-multicystic variant is the most common, comprising 92% in one large series.1 A peripheral (soft tissue) variant also exists without apparent connection to bone. Intraosseous lesions predominate over peripheral tumors by a ratio of 9:1.1,11 The peripheral type may actually represent a mixed bag of tumors, a few of which may arise from oral surface epithelium.12 Each of the subtypes of intraosseous ameloblastoma, including treatments, will be considered next. Conventional ameloblastoma (solid-multicystic) Conventional follicular ameloblastomas occur in patients mainly in their third to fifth decades with ⬍2% in children ⬍10 years old. The majority arise in the mandible (85%), with most in the molar and ramus regions. Small tumors are usually incidental findings on routine radiographs, and larger lesions produce local symptoms of pain, swelling, malocclusion, and paresthesia. Intraosseous ameloblastomas are classically periapical. A panoramic radiographic is a good scout film for all ameloblastic lesions. It demonstrates the entire extent of the lesion and its relationship to the adjacent teeth, nerves and sinuses as well as any displacement or erosion of adjacent roots. In panoramic films, conventional ameloblastomas appear as multilocular or “soapbubble” radiolucencies.13 Computerized tomography (CT) scans are useful to show the whole tumor volume and the relationship of the tumor to surrounding structures including soft tissue structures (Fig. 1). Data from a 3-dimensional CT scan may be used to create a working acrylate model of the patient’s facial bones that is perfectly accurate in scale and can be
Fig. 1. A panoramic radiograph showing a radiolucent conventional ameloblastoma of the right posterior mandible at a periapical position (A) and a computerized tomographic scan showing the full extent of the cortical erosion (B).
drilled and cut to aid in the surgical resection and reconstruction planning. Evidence from CT studies show that the term multicystic may be a misnomer in many conventional ameloblastomas. The radiographic spaces show scalloping resorption of the delimiting cortical plates, giving the illusion of multicystic spaces rather than truly septated compartments.14 Impacted teeth are associated with 15%-40% of all cases.14 Assessment of anatomic barriers is the most important preoperative information to be gleaned from the radiographs. Once the bone barrier, cortex, or cortical bone is violated, the periosteum will soon be invaded by tumor. Soft tissue extension removes curettage and enucleation from the treatment options. Microscopically, conventional ameloblastomas are solid infiltrating tumors that frequently undergo sec-
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Fig. 2. Conventional follicular ameloblastoma showing loose central stellate reticulum nests lined by typical reverse-polarized ameloblastic epithelium.
ondary cystic change. The 2 most frequent histologic patterns are the follicular and the plexiform. The follicular pattern is most easily recognized, with tumor islands of epithelial nests lined by characteristic ameloblastic epithelium with central stellate reticulum in a collagenized stromal background. This is considered to be a classic or conventional morphology (Fig. 2). The plexiform growth pattern shows interconnecting strands and cords of cells. Both follicular and plexiform patterns are associated most with a multilocular soap-bubble radiographic appearance. Less common variant patterns of conventional ameloblastoma include the cellular variant, the acanthomatous variant with squamoid features, a basal cell variant with peripheral palisaded nuclei, and the granular cell variant with abundant granular cytoplasm. More than 1 histologic growth pattern can be seen in a single tumor, and patterns within a tumor have no clinical significance. Treatment planning for a conventional ameloblastoma includes consideration of location and extent of local growth. A complete resection is required to control recurrence; however, achieving complete resection without excessive surgery remains the main area of debate in this field. Recurrence rates for conventional mandibular tumors with initial radical surgery approach zero when negative margins are achieved, whereas in one study they ranged up to 70%-80% recurrence with initial conservative therapy (8 out of 10 patients).10 Recurrence ranged up to 14 years. All of the recurrence cases were subsequently treated with radical surgery. One rerecurrence was deemed to be inoperable due to base of skull invasion.10 The others were disease free with 3-15 years of follow-up.
Fig. 3. The resection (A) and the specimen radiograph (B), confirming the adequacy of the radiographic margins (same patient as in Fig. 1).
Ameloblastoma invades into the trabecular spaces of surrounding bone. Bony margins with microscopic disease may appear to be uninvolved by gross inspection and radiography.15 In a series presentation of 82 cases, the tumor was found to extend 2-8 mm beyond the radiographic extent of the tumor, with an average of 4.5 mm.16 Radiographic margins of 1-1.5 cm are considered to be acceptable by many surgeons. Long-term follow-up reveals disease-free patients with these recommended margins, assuming the soft tissue margins are negative as well. Bone margins can take a long time to be reported in a final pathology report, owing to the required decalcification and fixation processes. Intraoperative radiographs of the resected specimen may be used to confirm the radiographic margin adequacy (Fig. 3). Soft tissue margins must also be negative, although there are no recommended clearance distances, and frozen sections are recommended for tumors with soft tissue extension. Good intraoperative pathologist-radiologist-surgeon communication can prevent repeated surgeries for unexpected positive margins. If a tumor can be excised completely with preservation of the inferior border of the mandibular bone, then there is usually a significant regeneration of bone, es-
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pecially in younger patients. If the attainment of adequate margins around the tumor results in a compromise in the stability of the jaw and raises the likelihood of a pathologic fracture, then segmental resection with reconstruction is favored.9,17 Late recurrences up to 20-30 years after curettage have been reported in conventional ameloblastomas.7,15,18 Long-term follow-up is warranted. The terms recurrence and persistence of disease have been debated, and the latter is probably more accurate for incomplete excisions. Radiation therapy alone is not warranted, because ameloblastoma is considered to be a radioresistant tumor. Early radiotherapy failures were documented back in the 1970s by Sedhev et al.19 with 100% failure rates (persistent or recurrent disease in all). Of the recurrent patients eligible for radical surgery, 25% have serious complications, such as osteomyelitis leading to death. These data likely influenced subsequent care providers leading to little additional information about this treatment modality. “Megadoses” of radiation were attempted in the 1980s for primary treatment and salvage therapy, which showed greater affect on the tumor, but they also demonstrated greater side effects.16,20 Other attempts of primary radiotherapy treatment have demonstrated recurrence of 42% in one series for cases treated with radiotherapy alone.21 There was a 25% rate of fatal radiation-induced sarcoma in the same series. Cryotherapy after conservative treatment has also been examined as a way of bolstering the effect of conservative therapy and reducing recurrence. In a series of cases22 of solid ameloblastomas treated with curettage and cryotherapy (3 freeze-thaw cycles), there was a 31% recurrence rate, an 11% pathologic fracture rate, and 30% wound dehiscence. The extent of the nonneoplastic tissue death from the freeze cycles is likely not well enough controlled and/or is too nonspecific to control the residual tumor. There may be less morbidity with an initial radical surgery than multiple repeated conservative therapies with recurrence.5 Unicystic ameloblastoma Unicystic ameloblastoma is a subtype of ameloblastoma that is a unique de novo neoplasm and not due simply to secondary cystic change in a conventional ameloblastoma. It was first described by Robinson and Martinez in 1977.23 Unicystic ameloblastoma represents 5%-15% of ameloblastoma cases. Unicystic ameloblastoma occurs in younger patients in the first through third decades, with an average age of 22 years. It typically occurs in the mandible in association with an impacted tooth, usually the third molar. Radiographically, the unicystic ameloblastoma is sharply demarcated unicystic radiolucency with a scalloped or lobulated border. More than half of the cases
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Fig. 4. A panoramic radiograph showing a unicystic ameloblastoma of the posterior mandible associated with an impacted tooth and erosion of the apical aspect of the distal root of the first molar.
Fig. 5. The simple ameloblastic lining of a unicystic ameloblastoma.
are associated with impacted teeth, and the tumor is usually surrounding the crown of the impacted tooth as is seen with dentigerous cysts13 (Fig. 4). Unicystic ameloblastomas are unilocular intraosseous cysts lined by characteristic ameloblastic epithelium (Fig. 5). In addition to the simple luminal unicystic ameloblastoma, showing a flat ameloblastic cyst lining, there are 2 subtype growth patterns of clinical significance. The intraluminal pattern, characterized by tumor growth into the cyst lumen, usually has soft luminal projections and microscopically resembles conventional ameloblastoma. The mural subtype exhibits infiltrating growth into the wall of the cyst and possibly beyond into the surrounding bone. The full extent of the tumor invasion into soft tissue and/or bone may not be evident until microscopic examination. In cystic lesions with a flat bland epithelial lining with only focal areas of diagnostic “ameloblastic” epithelium, the pathologist might be unsure of the best diagnosis. Secondary inflammation or areas of epithelial denudation and sloughing can be troublesome for the
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Fig. 6. Resection for a mural unicystic variant ameloblastoma, the diagnosis made before surgery (same patient as in Fig. 4): a computerized tomography– derived acrylate model (A), a plaster cast derived from the acrylate model fitted with a metal bridge (B), intraoperative placement of the bridge after tumor resection (C), and the resection specimen (D); note the similarity to the radiographic appearance with molar root erosion (E).
pathologist. Review of the case by a seasoned oromaxillofacial pathologist may help. The clinical suggestion for pathologists to avoid vague terms such as “preameloblastic” and “focal ameloblastic change” in the final pathology report of difficult and histologically borderline cases in preference to “histologic changes suggestive of but not diagnostic for ameloblastoma” has been made to ensure adequate patient follow-up.3
More than 1 growth pattern can be seen in a single unicystic tumor. The presence of a mural component would change the treatment modality if known before surgery. Ackerman et al.8 suggested a more aggressive approach to the treatment of this tumor. Curettage is acceptable for unicystic and intraluminal unicystic ameloblastomas in certain patients if the tumor does not extend beyond the basement membrane of
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the cyst. Curettage is not effective for the complete surgical removal of mural unicystic ameloblastoma, which has recurrence rates closer to the conventional type when curetted only.10,24 If tumor invades into the wall of the cyst, then it technically has a solid component which outweighs the cystic component regarding treatment planning. A radical surgical approach is required with careful microscopic evaluation of the margins. A preoperative biopsy may be of aid in surgical planning; however, the mural component of the tumor can be missed with a biopsy. This presents a clinical dilemma, because curettage, if selected as treatment, would miss mural invasion and promote recurrence, and there is no way to be certain before surgery. We have encountered a case of radiographic unicystic ameloblastoma for which the biopsy showed a conventional follicular-pattern tumor. In the context of the radiograph, this was interpreted as an invasive mural component. A complete surgical resection was planned with the use of a CT scan– derived anatomic acrylate mold. Histologic examination of the tumor after resection confirmed the diagnosis (Fig. 6). The suggestion that there is lower postcurettage recurrence for unicystic ameloblastomas is best understood when the subtype of unicystic ameloblastoma is detailed. When a mural subtype is lumped into the category of all unicystic ameloblastomas, the recurrence can be as high as 50%-80%.10 We recommend preoperative biopsies of cases with radiographically suspected mural invasion, with definitive surgery after the final pathology report of the biopsy. Rarely, a second surgery is necessary. A small completely intraosseus lesion of 1-2 cm may be a candidate for conservation if complete histologic sampling is performed and close clinical follow-up over many years is possible.5,10 A marginal resection that allows for 1-2 cm of bone margin may be an alternative for unicystic tumors with a mural component. This is the same approach as with conventional ameloblastoma surgical planning. Desmoplastic ameloblastoma Desmoplastic ameloblastoma, described in 1984 By Eversole et al.,25 represents ⬍10% of ameloblastomas and occurs in patients ranging from the third to the seventh decade. This tumor deserves separation from the group of conventional ameloblastomas, based on its tendency to involve the maxilla and anterior jaw and owing to its unique appearance. Radiographically, desmoplastic ameloblastoma shows a mixed radiolucent-radiopaque pattern in 25% of cases. New bone formation results in the mixed radiographic appearance. The remainder of cases are radiolucent. Unlike other ameloblastoma variants, desmoplastic ameloblastoma has poorly demarcated borders. It
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Fig. 7. A computerized tomographic scan of a left maxillary ameloblastoma with extension through the posterior maxillary sinus wall.
Fig. 8. The resection (same patient as in Fig. 7) showed a histologic desmoplastic variant ameloblastoma characterized by thin cords of tumor embedded in dense collagenized stroma.
may be mistaken for a benign fibro-osseous lesion.26 A CT scan is secondarily obtained to gain a 3-dimensional view of the lesion and to better examine the soft tissues and lesion volume (Fig. 7). Desmoplastic ameloblastomas appear as compressed islands and thin cords of ameloblastic or bland basaloid epithelial cells embedded in a dense collagenized stroma. Areas of stellate reticulum are rare to absent (Fig. 8). A complete resection is required to remove a desmoplastic ameloblastoma, which results in complex resec-
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Table I. Characteristics of Intra Osseous Ameloblastoma with Standard Treatments Conventional Age (y) Location Radiographic features
Histologic features
Treatment
20-50 Mandible Posterior Radiolucent Soap-bubble Follicular Plexiform Acanthomatous Granular Other variants Complete resection
Unicystic 10-30 Mandible Posterior Radiolucent Unicystic Impacted tooth Luminal Intraluminal Mural
Maxillary ameloblastoma The most feared anatomic location of any intraosseous ameloblastoma is in the maxilla, owing to its proximity to the orbit, skull base, and intracranial contents, as well as the fragility of the maxillary bone. The potential for widespread destruction and death due to local disease is high, because of the thin bone plates and lack of a dense cortex as in the mandible. Unimpeded growth in this area can render complete resection impossible, and therefore a maxillary ameloblastoma of any size is a potentially lethal tumor. It has been argued by some that this location of an ameloblastoma is so important that the current classification of ameloblastoma should be amended to include maxillary ameloblastoma as its own unique group, regardless of the microscopic growth pattern.27 Men and women have nearly equal occurrence of maxillary ameloblastomas; however, 10.6% of men versus 5.9% of women have aggressive maxillary sinus involvement at presentation.1 The sinus spaces in the anterior face region contribute to delayed symptoms in this location, leading to delay of diagnosis and treatment.20 Intraoral swelling with or without pain is the most common complaint. Facial deformity is rare, because of the potential spaces for growth. Radical surgery is always recommended. In one series,20 13 patients with maxillary tumors after surgical resection with curative intent had a 31% rate of death from the disease. In 1 of the patients, inoperability due to intracranial extension was discovered intraoperatively. In a separate case, 1 patient was disease free for 13 years
20-70 Maxilla Anterior Radiolucent-radiopaque
Cords of cells Dense collagenized stroma
Luminal and intraluminal: enucleation/curettage possible with patient follow-up Mural: complete resection
tions when located in the delicate maxillary region, often with need for prosthetic reconstruction to restore function. The invasive growth pattern with lack of smooth borders removes this type of ameloblastoma from conservative therapy consideration.
Desmoplastic
Complete resection
after initial en bloc resection, but the late recurrence was large and inoperable at presentation and rapidly fatal. Long-term follow-up for recurrent disease is important, as is microscopic margin evaluation. As with other tumors, soft tissue margins can be evaluated intraoperatively with frozen section as needed, but bone margins, not able to be frozen, must be taken with adequate clearance and possible radiographic assistance. CONCLUSION Intraosseous ameloblastoma is a benign but aggressive tumor with 3 clinically distinct variants. The surgical approach to treatment includes clinical-pathologic and radiographic correlation. An algorithmic approach is sensible given the variability of tumor types and locations (Table I). Whereas complete eradication of the tumor is the correct treatment, debate about the risks and benefits of a conservative approach is ongoing. Most tumors require resection, but a select group can be spared the morbidity of extensive resection and reconstruction.5,20 Curettage and clinical follow-up may work best for simple unicystic mandibular tumors without a mural solid component of growth. Solid multicystic ameloblastomas recur in 60%-90% of cases with curettage,10,20 and radical mandibular surgery is associated with 8.7% recurrence.28 Despite high recurrence rates, some surgeons still advocate a conservative approach, especially for young patients in whom growth and development is still occurring to prevent future problems with function and esthetics28 and for elderly patients to avoid surgical complications.15 A recurrence or complication from initial undertreatment may prove to be more complex than initial radical surgery. A more definitive surgery would then be reserved for a recurrence. One note of caution is that most cases of metastasizing ameloblastoma are preceded by local re-
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currence. No histologic predictors of metastatic potential have been determined.4,29 The median survival time after treatment of the metastasis is only 2 years in a review of these rare cases.4 A series aimed at prognostic factors, reviewing all types of intraosseous ameloblastoma treated surgically, found that unilocular histology and a younger patient age (⬍20 years old) were associated with significantly less recurrence than older patients with radiographic solid multicystic tumors. In 23 cases, plexiform histology fared better than follicular pattern with 56.8% versus 32.2% recurrence rates, respectively,28 although in our experience, it is rare to find cases with a pure histologic pattern. Many of the early conclusions on ameloblastoma treatment from Sedhev et al19 remain valid today. Curettage would likely lead to recurrence for conventional tumors, maxillary location requires a full initial radical resection, metastasis is rare but associated with high mortality, and radiation therapy is not effective and may potentially lead to long-term risk of second malignancy. Through the years, these statements have been validated, and new conservative therapy attempts, such as cryotherapy, have been tried and some have failed. Our understanding of the different varieties of unicystic tumors has expanded. A simple unicystic tumor being the only tumor for a conservative approach is still supported by most authorities. REFERENCES 1. Reichart PA, Philipsen HP, Sonner S. Ameloblastoma: biological profile of 3677 cases. Eur J Cancer B Oral Oncol 1995;31B: 86-99. 2. Snead ML, Luo W, Hsu DD, Melrose RJ, Lau EC, Stenman G. Human ameloblastoma tumors express the amelogenin gene. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1992: 74:64-72. 3. Ivey RH, Churchill HR. The need of a standardized surgical and pathological classification of tumors and anomalies of dental origin. Am Assoc Dental School Trans 1930;7:240-5. 4. Laughlin EH. Metastasizing amleoblastoma. Cancer 1989;64: 776-80. 5. Sampson DE, Pogrel MA. Management of mandibular ameloblastoma: the clinical basis for a treatment algorithm. J Oral Maxillofac Surg 1999;57:1074-7. 6. Hayward JR. Recurrent ameloblastoma 30 years after surgical treatment. J Oral Surg 1973;31:368-70. 7. Robinson L, Martinez M. Unicystic ameloblastoma: a prognostically unique entity. Cancer 1977;40:2278-85. 8. Ackermann GL, Altini M, Shear M. The unicystic ameloblastoma: a clinicopathologic study of 57 cases. J Oral Pathol 1988;17:541-6. 9. Feinberg SE, Steinberg B. Surgical management of ameloblasoma. Current status of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;81:383-8. 10. Ghandi D, Ayoub AF, Pogrel MA, MacDonald G, Brocklebank LM, Moos KF. Ameloblastoma: a surgeon’s dilemma. J Oral Maxillofac Surg 2006;64:1010-4.
11. Wetten HL, Patella PA, Freedman PD. Peripheral ameloblastoma: review of the literature and report of recurrence as severe dysplasia. J Oral Maxillofac Surg 2001;59:811-5. 12. Ide F, Mishima K, Miyazaki Y, Saito I, Kusama K. Peripheral ameloblastoma in-situ: an evidential fact of surface epithelium origin. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;108:763-7. 13. Nakamura US, Mushimoto K, Shirasu R. A clinicopathologic study of ameloblastoma. J Oral Maxillofac Surg 1986;44:361-5. 14. Kessler HP. Intraosseous ameloblastoma. Oral Maxillofac Surg Clin North Am 2004;16:309-22. 15. Gardner DG, Pecak AM. The treatment of ameloblastoma based on pathologic and anatomic principles. Cancer 1980;46:2514-9. 16. Carlson ER. Ameloblastoma. Symposium on odontogenic tumors. Presented at AAOMS 82nd annual meeting and scientific sessions. San Francisco, CA; September 23, 2000. 17. Carlson ER, Marx RE. The ameloblastoma: primary, curative surgical management. J Oral Maxillofac Surg 2006;64:484-94. 18. Daramola JO, Ajagbe HA, Oluwasanmni JO. Recurrent ameloblastoma of the jaws—a review of 22 cases. Plast Reconstr Surg 1980;65:577-9. 19. Sedhev MK, Huvos AG, Strong EW, Gerold FP, Willis GW. Ameloblastoma of the maxilla and mandible. Cancer 1974;33: 324-33. 20. Atkinson CH, Harwood AR, Cummings BJ. Ameloblastoma of the jaw. A reappraisal of the role of megavoltage irradiation. Cancer 1984;53:869-73. 21. Nastri AL, Weisenfeld D, Radden BG, Evenson J, Scully C. Maxillary ameloblastoma:a retrospective study of 13 cases. Br J Oral Maxillofac Surg 1995;33:28-32. 22. Curi MM, Dib LL, Pinto DS. Management of solid ameloblastoma of the jaws with liquid nitrogen spray cryosurgery. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;84:339-44. 23. Robinson L, Martinez MG. Unicystic Ameloblastoma. A prognostically distinct entity. Cancer 1977;40:2278-85. 24. Pogrel MA, Montes DM. Is ther a role for enucleation in the management of ameloblastoma? Int J Oral Maxillofac Surg 2009;38:807-12. 25. Eversole LR, Leider AS, Hansen LS. Ameloblastomas with pronounced desmoplasia. J Oral Maxillofac Surg 1984;42: 735-40. 26. Waldron CA, el-Mofty SK. A Histopathologic study of 116 ameloblastomas with special reference to the desmoplastic variant. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1987;63:441-51. 27. Jackson IT, Callan PP, Forte RA. An anatomical classification of maxillary ameloblastoma as an aid to surgical treatment. J Craniomaxillofac Surg 1996;24:230-36. 28. Uneo S, Mushimoto K, Shirasu R. Prognostic evaluation of ameloblastoma based on histologic and radiographic typing. J Oral Maxillofac Surg 1989;47:11-5. 29. Kunze E, Donath K, Luhr HG, Englehardt W De Vivie R. Biology of metastasizing ameloblastoma. Pathol Res Pract 1985;180:526-35. Reprint requests: Candice C. Black, DO Associate Professor Department of Pathology Dartmouth Hitchcock Medical Center One Medical Center Drive Lebanon NH 03756 [email protected]
Ameloblastomas are benign slow-growing aggressive neoplasms with a poorly understood potential for rare metastasis. They are capable of reaching large sizes with extensive local bone erosion and destruction. They are composed of a mixture of ameloblastic epithelium and mesenchyme and arise from rests of outer and inner enamel epithelium and dental lamina. Microscopically, ameloblastomas are recognizable from their recapitulation of embryologic ameloblasts and stellate reticulum. There are 3 subtypes: the conventional or solid-multicystic variant, the unicystic variant, and the desmoplastic variant. Treatment planning for a given tumor includes consideration of location, primary versus recurrent, size, presence of cortical perforation, and age and health of the patient. Complete excision is recommended for conventional and desmoplastic variants. The unicystic variant requires additional subtyping to determine the best treatment approach. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;110:585-592)
Ameloblastoma is a benign but potentially aggressive tumor composed of a mixture of ameloblastic epithelium and mesenchyme. Excluding cysts, ameloblastoma represents 13%-54% of all jaw tumors.1 It affects males and females somewhat equally, peaking in the third decade, with a first-to-ninth decade range.1 The ratio of mandibular to maxillary tumors is 1:5.4.1 Ameloblastoma arises from rests of outer and inner enamel epithelium and dental lamina. Microscopically, ameloblastomas are recognizable from their recapitulation of embryologic ameloblasts and stellate reticulum. BRIEF EMBRYOLOGIC REVIEW At ⬃6 weeks of gestation the mesenchyme of the developing tooth induces epithelial proliferation forming the dental lamina. Small pockets of epithelium grow into the underlying mesenchyme and are known as the bud phase, which will give rise to the primary teeth. The mesenchyme proliferates and condenses around the bud, which then invaginates to form a cap shape, known as the cap phase, at ⬃9-11 weeks. The cap phase marks the start of the enamel organ. At week 14, the enamel organ further differentiates into an outer and inner epithelial layer, separated by a loose mesenchyme, the stellate reticulum, imparting a bell shape, known as the bell phase. Ameloblasts arise from the a
Associate Professor, Department of Pathology. Professor, Department of Maxillofacial Surgery. c Resident, Department of Pathology. Received for publication Nov 27, 2009; returned for revision Feb 9, 2010; accepted for publication Feb 24, 2010. 1079-2104/$ - see front matter © 2010 Mosby, Inc. All rights reserved. doi:10.1016/j.tripleo.2010.02.040 b
inner epithelium. Ameloblastomas express amelogenin, the precursor of enamel, which further supports this theory.2 Ameloblastic epithelium shows nuclear polarization toward the underlying reticulum surface, known as the stratum intermedium. The stratum intermedium (embryologically sandwiched between the ameloblast and stellate reticulum), thought to aid enamel production, is not present in ameloblastomas and, therefore, no enamel is produced. This polarization is recapitulated in ameloblastic tumors and marks the formation of the preameloblast cell. Preameloblasts work in concert with odontoblasts in the dental papillae to induce further differentiation of both cell lines and the eventual formation of enamel and dentin, respectively. AMELOBLASTOMA VARIANTS Our understanding of ameloblastomas has proved to be historically challenging. In their 1930 paper titled “The need of a standardized surgical and pathological classification of tumors . . . of dental origin,” Ivey and Churchill proposed the term “ameloblastoma” to replace various prevailing terms such as adamantinoma and adamantoblastoma.3 There have been many classification schemes for intraosseous ameloblastomas, with many early clinical reports lumping all comers into a single category, which has largely hampered efforts of clinicians to form meaningful evidence-based treatment guidelines. Published recurrence rates may over- or underestimate the actual recurrence for certain types of ameloblastoma. Ameloblastomas are benign aggressive slow-growing neoplasms with a poorly understood potential for rare metastasis.4 They are capable of reaching large sizes with extensive local bone erosion and destruction. Although some surgeons urge conservative treatment for ameloblastomas to avoid the potential 585
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morbidity associated with larger resections, others favor more definitive procedures to reduce recurrence risk.5-8 Conservative treatments include enucleation and curettage. Enucleation is the surgical removal of the whole lesion intact, including the capsular/pseudocapsular surface. Curettage is the scraping of the lesion out in a piecemeal fashion, as with friable lesions and lesions without capsules. A radical approach is a surgical resection of the lesion with some amount of surrounding bone9 with or without a continuity defect. The separation of ameloblastoma into meaningful subtypes and the individual features of a given tumor (location, primary vs. recurrent, size, presence of cortical perforation, and age and health of the patient) are best weighed case by case for deciding the appropriate treatment.5,10 Three types of intraosseous ameloblastoma are currently agreed upon: the solid-multicystic or conventional variant, the unicystic variant, and the desmoplastic variant. The solid-multicystic variant is the most common, comprising 92% in one large series.1 A peripheral (soft tissue) variant also exists without apparent connection to bone. Intraosseous lesions predominate over peripheral tumors by a ratio of 9:1.1,11 The peripheral type may actually represent a mixed bag of tumors, a few of which may arise from oral surface epithelium.12 Each of the subtypes of intraosseous ameloblastoma, including treatments, will be considered next. Conventional ameloblastoma (solid-multicystic) Conventional follicular ameloblastomas occur in patients mainly in their third to fifth decades with ⬍2% in children ⬍10 years old. The majority arise in the mandible (85%), with most in the molar and ramus regions. Small tumors are usually incidental findings on routine radiographs, and larger lesions produce local symptoms of pain, swelling, malocclusion, and paresthesia. Intraosseous ameloblastomas are classically periapical. A panoramic radiographic is a good scout film for all ameloblastic lesions. It demonstrates the entire extent of the lesion and its relationship to the adjacent teeth, nerves and sinuses as well as any displacement or erosion of adjacent roots. In panoramic films, conventional ameloblastomas appear as multilocular or “soapbubble” radiolucencies.13 Computerized tomography (CT) scans are useful to show the whole tumor volume and the relationship of the tumor to surrounding structures including soft tissue structures (Fig. 1). Data from a 3-dimensional CT scan may be used to create a working acrylate model of the patient’s facial bones that is perfectly accurate in scale and can be
Fig. 1. A panoramic radiograph showing a radiolucent conventional ameloblastoma of the right posterior mandible at a periapical position (A) and a computerized tomographic scan showing the full extent of the cortical erosion (B).
drilled and cut to aid in the surgical resection and reconstruction planning. Evidence from CT studies show that the term multicystic may be a misnomer in many conventional ameloblastomas. The radiographic spaces show scalloping resorption of the delimiting cortical plates, giving the illusion of multicystic spaces rather than truly septated compartments.14 Impacted teeth are associated with 15%-40% of all cases.14 Assessment of anatomic barriers is the most important preoperative information to be gleaned from the radiographs. Once the bone barrier, cortex, or cortical bone is violated, the periosteum will soon be invaded by tumor. Soft tissue extension removes curettage and enucleation from the treatment options. Microscopically, conventional ameloblastomas are solid infiltrating tumors that frequently undergo sec-
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Fig. 2. Conventional follicular ameloblastoma showing loose central stellate reticulum nests lined by typical reverse-polarized ameloblastic epithelium.
ondary cystic change. The 2 most frequent histologic patterns are the follicular and the plexiform. The follicular pattern is most easily recognized, with tumor islands of epithelial nests lined by characteristic ameloblastic epithelium with central stellate reticulum in a collagenized stromal background. This is considered to be a classic or conventional morphology (Fig. 2). The plexiform growth pattern shows interconnecting strands and cords of cells. Both follicular and plexiform patterns are associated most with a multilocular soap-bubble radiographic appearance. Less common variant patterns of conventional ameloblastoma include the cellular variant, the acanthomatous variant with squamoid features, a basal cell variant with peripheral palisaded nuclei, and the granular cell variant with abundant granular cytoplasm. More than 1 histologic growth pattern can be seen in a single tumor, and patterns within a tumor have no clinical significance. Treatment planning for a conventional ameloblastoma includes consideration of location and extent of local growth. A complete resection is required to control recurrence; however, achieving complete resection without excessive surgery remains the main area of debate in this field. Recurrence rates for conventional mandibular tumors with initial radical surgery approach zero when negative margins are achieved, whereas in one study they ranged up to 70%-80% recurrence with initial conservative therapy (8 out of 10 patients).10 Recurrence ranged up to 14 years. All of the recurrence cases were subsequently treated with radical surgery. One rerecurrence was deemed to be inoperable due to base of skull invasion.10 The others were disease free with 3-15 years of follow-up.
Fig. 3. The resection (A) and the specimen radiograph (B), confirming the adequacy of the radiographic margins (same patient as in Fig. 1).
Ameloblastoma invades into the trabecular spaces of surrounding bone. Bony margins with microscopic disease may appear to be uninvolved by gross inspection and radiography.15 In a series presentation of 82 cases, the tumor was found to extend 2-8 mm beyond the radiographic extent of the tumor, with an average of 4.5 mm.16 Radiographic margins of 1-1.5 cm are considered to be acceptable by many surgeons. Long-term follow-up reveals disease-free patients with these recommended margins, assuming the soft tissue margins are negative as well. Bone margins can take a long time to be reported in a final pathology report, owing to the required decalcification and fixation processes. Intraoperative radiographs of the resected specimen may be used to confirm the radiographic margin adequacy (Fig. 3). Soft tissue margins must also be negative, although there are no recommended clearance distances, and frozen sections are recommended for tumors with soft tissue extension. Good intraoperative pathologist-radiologist-surgeon communication can prevent repeated surgeries for unexpected positive margins. If a tumor can be excised completely with preservation of the inferior border of the mandibular bone, then there is usually a significant regeneration of bone, es-
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pecially in younger patients. If the attainment of adequate margins around the tumor results in a compromise in the stability of the jaw and raises the likelihood of a pathologic fracture, then segmental resection with reconstruction is favored.9,17 Late recurrences up to 20-30 years after curettage have been reported in conventional ameloblastomas.7,15,18 Long-term follow-up is warranted. The terms recurrence and persistence of disease have been debated, and the latter is probably more accurate for incomplete excisions. Radiation therapy alone is not warranted, because ameloblastoma is considered to be a radioresistant tumor. Early radiotherapy failures were documented back in the 1970s by Sedhev et al.19 with 100% failure rates (persistent or recurrent disease in all). Of the recurrent patients eligible for radical surgery, 25% have serious complications, such as osteomyelitis leading to death. These data likely influenced subsequent care providers leading to little additional information about this treatment modality. “Megadoses” of radiation were attempted in the 1980s for primary treatment and salvage therapy, which showed greater affect on the tumor, but they also demonstrated greater side effects.16,20 Other attempts of primary radiotherapy treatment have demonstrated recurrence of 42% in one series for cases treated with radiotherapy alone.21 There was a 25% rate of fatal radiation-induced sarcoma in the same series. Cryotherapy after conservative treatment has also been examined as a way of bolstering the effect of conservative therapy and reducing recurrence. In a series of cases22 of solid ameloblastomas treated with curettage and cryotherapy (3 freeze-thaw cycles), there was a 31% recurrence rate, an 11% pathologic fracture rate, and 30% wound dehiscence. The extent of the nonneoplastic tissue death from the freeze cycles is likely not well enough controlled and/or is too nonspecific to control the residual tumor. There may be less morbidity with an initial radical surgery than multiple repeated conservative therapies with recurrence.5 Unicystic ameloblastoma Unicystic ameloblastoma is a subtype of ameloblastoma that is a unique de novo neoplasm and not due simply to secondary cystic change in a conventional ameloblastoma. It was first described by Robinson and Martinez in 1977.23 Unicystic ameloblastoma represents 5%-15% of ameloblastoma cases. Unicystic ameloblastoma occurs in younger patients in the first through third decades, with an average age of 22 years. It typically occurs in the mandible in association with an impacted tooth, usually the third molar. Radiographically, the unicystic ameloblastoma is sharply demarcated unicystic radiolucency with a scalloped or lobulated border. More than half of the cases
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Fig. 4. A panoramic radiograph showing a unicystic ameloblastoma of the posterior mandible associated with an impacted tooth and erosion of the apical aspect of the distal root of the first molar.
Fig. 5. The simple ameloblastic lining of a unicystic ameloblastoma.
are associated with impacted teeth, and the tumor is usually surrounding the crown of the impacted tooth as is seen with dentigerous cysts13 (Fig. 4). Unicystic ameloblastomas are unilocular intraosseous cysts lined by characteristic ameloblastic epithelium (Fig. 5). In addition to the simple luminal unicystic ameloblastoma, showing a flat ameloblastic cyst lining, there are 2 subtype growth patterns of clinical significance. The intraluminal pattern, characterized by tumor growth into the cyst lumen, usually has soft luminal projections and microscopically resembles conventional ameloblastoma. The mural subtype exhibits infiltrating growth into the wall of the cyst and possibly beyond into the surrounding bone. The full extent of the tumor invasion into soft tissue and/or bone may not be evident until microscopic examination. In cystic lesions with a flat bland epithelial lining with only focal areas of diagnostic “ameloblastic” epithelium, the pathologist might be unsure of the best diagnosis. Secondary inflammation or areas of epithelial denudation and sloughing can be troublesome for the
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Fig. 6. Resection for a mural unicystic variant ameloblastoma, the diagnosis made before surgery (same patient as in Fig. 4): a computerized tomography– derived acrylate model (A), a plaster cast derived from the acrylate model fitted with a metal bridge (B), intraoperative placement of the bridge after tumor resection (C), and the resection specimen (D); note the similarity to the radiographic appearance with molar root erosion (E).
pathologist. Review of the case by a seasoned oromaxillofacial pathologist may help. The clinical suggestion for pathologists to avoid vague terms such as “preameloblastic” and “focal ameloblastic change” in the final pathology report of difficult and histologically borderline cases in preference to “histologic changes suggestive of but not diagnostic for ameloblastoma” has been made to ensure adequate patient follow-up.3
More than 1 growth pattern can be seen in a single unicystic tumor. The presence of a mural component would change the treatment modality if known before surgery. Ackerman et al.8 suggested a more aggressive approach to the treatment of this tumor. Curettage is acceptable for unicystic and intraluminal unicystic ameloblastomas in certain patients if the tumor does not extend beyond the basement membrane of
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the cyst. Curettage is not effective for the complete surgical removal of mural unicystic ameloblastoma, which has recurrence rates closer to the conventional type when curetted only.10,24 If tumor invades into the wall of the cyst, then it technically has a solid component which outweighs the cystic component regarding treatment planning. A radical surgical approach is required with careful microscopic evaluation of the margins. A preoperative biopsy may be of aid in surgical planning; however, the mural component of the tumor can be missed with a biopsy. This presents a clinical dilemma, because curettage, if selected as treatment, would miss mural invasion and promote recurrence, and there is no way to be certain before surgery. We have encountered a case of radiographic unicystic ameloblastoma for which the biopsy showed a conventional follicular-pattern tumor. In the context of the radiograph, this was interpreted as an invasive mural component. A complete surgical resection was planned with the use of a CT scan– derived anatomic acrylate mold. Histologic examination of the tumor after resection confirmed the diagnosis (Fig. 6). The suggestion that there is lower postcurettage recurrence for unicystic ameloblastomas is best understood when the subtype of unicystic ameloblastoma is detailed. When a mural subtype is lumped into the category of all unicystic ameloblastomas, the recurrence can be as high as 50%-80%.10 We recommend preoperative biopsies of cases with radiographically suspected mural invasion, with definitive surgery after the final pathology report of the biopsy. Rarely, a second surgery is necessary. A small completely intraosseus lesion of 1-2 cm may be a candidate for conservation if complete histologic sampling is performed and close clinical follow-up over many years is possible.5,10 A marginal resection that allows for 1-2 cm of bone margin may be an alternative for unicystic tumors with a mural component. This is the same approach as with conventional ameloblastoma surgical planning. Desmoplastic ameloblastoma Desmoplastic ameloblastoma, described in 1984 By Eversole et al.,25 represents ⬍10% of ameloblastomas and occurs in patients ranging from the third to the seventh decade. This tumor deserves separation from the group of conventional ameloblastomas, based on its tendency to involve the maxilla and anterior jaw and owing to its unique appearance. Radiographically, desmoplastic ameloblastoma shows a mixed radiolucent-radiopaque pattern in 25% of cases. New bone formation results in the mixed radiographic appearance. The remainder of cases are radiolucent. Unlike other ameloblastoma variants, desmoplastic ameloblastoma has poorly demarcated borders. It
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Fig. 7. A computerized tomographic scan of a left maxillary ameloblastoma with extension through the posterior maxillary sinus wall.
Fig. 8. The resection (same patient as in Fig. 7) showed a histologic desmoplastic variant ameloblastoma characterized by thin cords of tumor embedded in dense collagenized stroma.
may be mistaken for a benign fibro-osseous lesion.26 A CT scan is secondarily obtained to gain a 3-dimensional view of the lesion and to better examine the soft tissues and lesion volume (Fig. 7). Desmoplastic ameloblastomas appear as compressed islands and thin cords of ameloblastic or bland basaloid epithelial cells embedded in a dense collagenized stroma. Areas of stellate reticulum are rare to absent (Fig. 8). A complete resection is required to remove a desmoplastic ameloblastoma, which results in complex resec-
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Table I. Characteristics of Intra Osseous Ameloblastoma with Standard Treatments Conventional Age (y) Location Radiographic features
Histologic features
Treatment
20-50 Mandible Posterior Radiolucent Soap-bubble Follicular Plexiform Acanthomatous Granular Other variants Complete resection
Unicystic 10-30 Mandible Posterior Radiolucent Unicystic Impacted tooth Luminal Intraluminal Mural
Maxillary ameloblastoma The most feared anatomic location of any intraosseous ameloblastoma is in the maxilla, owing to its proximity to the orbit, skull base, and intracranial contents, as well as the fragility of the maxillary bone. The potential for widespread destruction and death due to local disease is high, because of the thin bone plates and lack of a dense cortex as in the mandible. Unimpeded growth in this area can render complete resection impossible, and therefore a maxillary ameloblastoma of any size is a potentially lethal tumor. It has been argued by some that this location of an ameloblastoma is so important that the current classification of ameloblastoma should be amended to include maxillary ameloblastoma as its own unique group, regardless of the microscopic growth pattern.27 Men and women have nearly equal occurrence of maxillary ameloblastomas; however, 10.6% of men versus 5.9% of women have aggressive maxillary sinus involvement at presentation.1 The sinus spaces in the anterior face region contribute to delayed symptoms in this location, leading to delay of diagnosis and treatment.20 Intraoral swelling with or without pain is the most common complaint. Facial deformity is rare, because of the potential spaces for growth. Radical surgery is always recommended. In one series,20 13 patients with maxillary tumors after surgical resection with curative intent had a 31% rate of death from the disease. In 1 of the patients, inoperability due to intracranial extension was discovered intraoperatively. In a separate case, 1 patient was disease free for 13 years
20-70 Maxilla Anterior Radiolucent-radiopaque
Cords of cells Dense collagenized stroma
Luminal and intraluminal: enucleation/curettage possible with patient follow-up Mural: complete resection
tions when located in the delicate maxillary region, often with need for prosthetic reconstruction to restore function. The invasive growth pattern with lack of smooth borders removes this type of ameloblastoma from conservative therapy consideration.
Desmoplastic
Complete resection
after initial en bloc resection, but the late recurrence was large and inoperable at presentation and rapidly fatal. Long-term follow-up for recurrent disease is important, as is microscopic margin evaluation. As with other tumors, soft tissue margins can be evaluated intraoperatively with frozen section as needed, but bone margins, not able to be frozen, must be taken with adequate clearance and possible radiographic assistance. CONCLUSION Intraosseous ameloblastoma is a benign but aggressive tumor with 3 clinically distinct variants. The surgical approach to treatment includes clinical-pathologic and radiographic correlation. An algorithmic approach is sensible given the variability of tumor types and locations (Table I). Whereas complete eradication of the tumor is the correct treatment, debate about the risks and benefits of a conservative approach is ongoing. Most tumors require resection, but a select group can be spared the morbidity of extensive resection and reconstruction.5,20 Curettage and clinical follow-up may work best for simple unicystic mandibular tumors without a mural solid component of growth. Solid multicystic ameloblastomas recur in 60%-90% of cases with curettage,10,20 and radical mandibular surgery is associated with 8.7% recurrence.28 Despite high recurrence rates, some surgeons still advocate a conservative approach, especially for young patients in whom growth and development is still occurring to prevent future problems with function and esthetics28 and for elderly patients to avoid surgical complications.15 A recurrence or complication from initial undertreatment may prove to be more complex than initial radical surgery. A more definitive surgery would then be reserved for a recurrence. One note of caution is that most cases of metastasizing ameloblastoma are preceded by local re-
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currence. No histologic predictors of metastatic potential have been determined.4,29 The median survival time after treatment of the metastasis is only 2 years in a review of these rare cases.4 A series aimed at prognostic factors, reviewing all types of intraosseous ameloblastoma treated surgically, found that unilocular histology and a younger patient age (⬍20 years old) were associated with significantly less recurrence than older patients with radiographic solid multicystic tumors. In 23 cases, plexiform histology fared better than follicular pattern with 56.8% versus 32.2% recurrence rates, respectively,28 although in our experience, it is rare to find cases with a pure histologic pattern. Many of the early conclusions on ameloblastoma treatment from Sedhev et al19 remain valid today. Curettage would likely lead to recurrence for conventional tumors, maxillary location requires a full initial radical resection, metastasis is rare but associated with high mortality, and radiation therapy is not effective and may potentially lead to long-term risk of second malignancy. Through the years, these statements have been validated, and new conservative therapy attempts, such as cryotherapy, have been tried and some have failed. Our understanding of the different varieties of unicystic tumors has expanded. A simple unicystic tumor being the only tumor for a conservative approach is still supported by most authorities. REFERENCES 1. Reichart PA, Philipsen HP, Sonner S. Ameloblastoma: biological profile of 3677 cases. Eur J Cancer B Oral Oncol 1995;31B: 86-99. 2. Snead ML, Luo W, Hsu DD, Melrose RJ, Lau EC, Stenman G. Human ameloblastoma tumors express the amelogenin gene. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1992: 74:64-72. 3. Ivey RH, Churchill HR. The need of a standardized surgical and pathological classification of tumors and anomalies of dental origin. Am Assoc Dental School Trans 1930;7:240-5. 4. Laughlin EH. Metastasizing amleoblastoma. Cancer 1989;64: 776-80. 5. Sampson DE, Pogrel MA. Management of mandibular ameloblastoma: the clinical basis for a treatment algorithm. J Oral Maxillofac Surg 1999;57:1074-7. 6. Hayward JR. Recurrent ameloblastoma 30 years after surgical treatment. J Oral Surg 1973;31:368-70. 7. Robinson L, Martinez M. Unicystic ameloblastoma: a prognostically unique entity. Cancer 1977;40:2278-85. 8. Ackermann GL, Altini M, Shear M. The unicystic ameloblastoma: a clinicopathologic study of 57 cases. J Oral Pathol 1988;17:541-6. 9. Feinberg SE, Steinberg B. Surgical management of ameloblasoma. Current status of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;81:383-8. 10. Ghandi D, Ayoub AF, Pogrel MA, MacDonald G, Brocklebank LM, Moos KF. Ameloblastoma: a surgeon’s dilemma. J Oral Maxillofac Surg 2006;64:1010-4.
11. Wetten HL, Patella PA, Freedman PD. Peripheral ameloblastoma: review of the literature and report of recurrence as severe dysplasia. J Oral Maxillofac Surg 2001;59:811-5. 12. Ide F, Mishima K, Miyazaki Y, Saito I, Kusama K. Peripheral ameloblastoma in-situ: an evidential fact of surface epithelium origin. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;108:763-7. 13. Nakamura US, Mushimoto K, Shirasu R. A clinicopathologic study of ameloblastoma. J Oral Maxillofac Surg 1986;44:361-5. 14. Kessler HP. Intraosseous ameloblastoma. Oral Maxillofac Surg Clin North Am 2004;16:309-22. 15. Gardner DG, Pecak AM. The treatment of ameloblastoma based on pathologic and anatomic principles. Cancer 1980;46:2514-9. 16. Carlson ER. Ameloblastoma. Symposium on odontogenic tumors. Presented at AAOMS 82nd annual meeting and scientific sessions. San Francisco, CA; September 23, 2000. 17. Carlson ER, Marx RE. The ameloblastoma: primary, curative surgical management. J Oral Maxillofac Surg 2006;64:484-94. 18. Daramola JO, Ajagbe HA, Oluwasanmni JO. Recurrent ameloblastoma of the jaws—a review of 22 cases. Plast Reconstr Surg 1980;65:577-9. 19. Sedhev MK, Huvos AG, Strong EW, Gerold FP, Willis GW. Ameloblastoma of the maxilla and mandible. Cancer 1974;33: 324-33. 20. Atkinson CH, Harwood AR, Cummings BJ. Ameloblastoma of the jaw. A reappraisal of the role of megavoltage irradiation. Cancer 1984;53:869-73. 21. Nastri AL, Weisenfeld D, Radden BG, Evenson J, Scully C. Maxillary ameloblastoma:a retrospective study of 13 cases. Br J Oral Maxillofac Surg 1995;33:28-32. 22. Curi MM, Dib LL, Pinto DS. Management of solid ameloblastoma of the jaws with liquid nitrogen spray cryosurgery. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;84:339-44. 23. Robinson L, Martinez MG. Unicystic Ameloblastoma. A prognostically distinct entity. Cancer 1977;40:2278-85. 24. Pogrel MA, Montes DM. Is ther a role for enucleation in the management of ameloblastoma? Int J Oral Maxillofac Surg 2009;38:807-12. 25. Eversole LR, Leider AS, Hansen LS. Ameloblastomas with pronounced desmoplasia. J Oral Maxillofac Surg 1984;42: 735-40. 26. Waldron CA, el-Mofty SK. A Histopathologic study of 116 ameloblastomas with special reference to the desmoplastic variant. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1987;63:441-51. 27. Jackson IT, Callan PP, Forte RA. An anatomical classification of maxillary ameloblastoma as an aid to surgical treatment. J Craniomaxillofac Surg 1996;24:230-36. 28. Uneo S, Mushimoto K, Shirasu R. Prognostic evaluation of ameloblastoma based on histologic and radiographic typing. J Oral Maxillofac Surg 1989;47:11-5. 29. Kunze E, Donath K, Luhr HG, Englehardt W De Vivie R. Biology of metastasizing ameloblastoma. Pathol Res Pract 1985;180:526-35. Reprint requests: Candice C. Black, DO Associate Professor Department of Pathology Dartmouth Hitchcock Medical Center One Medical Center Drive Lebanon NH 03756 [email protected]