Case 40-2005 — An 18-Year-Old Man with a One-Month History of Nontender Left Mandibular Swelling
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《新英格兰医药杂志》
Presentation of Case
An 18-year-old man was referred by his dentist to the oral and maxillofacial surgery clinic of this hospital because of left mandibular swelling.
One month earlier, the patient first noticed gradual left mandibular enlargement without pain, fever, malocclusion, sensory changes, or trismus. There was no history of trauma or recent dental work. He had no illnesses or allergies, took no medications, did not use tobacco or alcohol, and reported no first-degree relatives with cancer.
On physical examination, there was obvious facial asymmetry, with the left side of the jaw larger than the right (Figure 1A). A firm, nontender swelling was palpable along the ramus and posterior body of the left mandible. Neurologic examination revealed normal function of cranial nerves V and VII. He had generalized, mild-to-moderate gingivitis on intraoral examination; the mucosae and soft tissues were otherwise normal. The dentition was intact and in good repair, and there was no malocclusion. There was expansion of the bone along the left lateral alveolar ridge of the mandible, which obliterated the buccal vestibule (Figure 1C).
Figure 1. Clinical Images of the Patient.
Images of the face when the patient presented (Panel A) and 21 months after the first procedure (Panel B), showing swelling of the left mandible (Panel A, arrow), which is greatly diminished in Panel B. An intraoral photograph, also obtained at the time of presentation (Panel C), shows smooth thickening of the posterior body and ramus of the left mandible (arrows) that obliterate the buccal vestibule. Another intraoral image obtained 21 months after the first procedure (Panel D) shows substantial reduction in swelling.
A panoramic radiograph of the jaws revealed a septated radiolucent lesion in the left mandible. Four days later, a maxillofacial computed tomographic (CT) scan obtained without intravenously administered contrast material showed a unilocular, expansile, lytic lesion, 5.1 cm (superoinferior) by 2.6 cm (buccolingual) by 8 cm (mesiodistal), in the left mandible.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. Meredith August: I was involved in the care of this patient and am aware of the diagnosis. This case presents an opportunity to review the differential diagnosis and management of cystic lesions of the jaw. May we review the imaging studies?
Dr. Paul A. Caruso: A panoramic radiograph of the jaws obtained at the time of the patient's presentation (Figure 2A) revealed a large, expansile, partially septated, radiolucent lesion of the left mandible that extended from the midbody mesially to the ramus distally, involved the sigmoid notch and the base of the coronoid process, and spared the condyle. The lesion displaced the impacted left mandibular third molar mesially, inferiorly, and buccally; involved both the crown and the roots; and clearly involved the tooth beyond the cemento-enamel junction. The lesion resorbed the distal roots of the left mandibular first molar.
Figure 2. Imaging Studies of the Mandibular Lesion.
A preprocedural panoramic radiograph (Panel A) reveals an expansile, lytic lesion involving the body and ramus of the left mandible that incorporates the unerupted mandibular third molar. A panoramic radiograph obtained 13 months after the biopsy (Panel B) shows two irrigation cannulae, thick marginal sclerosis, and mineralization within the lesion but persistent central radiolucency, most notably within the ramus. A panoramic radiograph obtained three months after the second procedure (Panel C) shows marked progressive sclerosis of the entire lesion.
A non-contrast-enhanced, maxillofacial CT with three-dimensional reconstructions (Figures 1A, 1B, and 1C of the Supplementary Appendix, available with the full text of this article at www.nejm.org) showed a partially septated, otherwise homogeneous-appearing, radiolucent lesion in the left mandible that thinned and expanded but did not breach the lingual and buccal cortices, and showed no extraosseous component.
Dr. August: This 18-year-old, otherwise healthy man presented with a one-month history of swelling in the left jaw that was not associated with pain, fever, trismus, malocclusion, antecedent trauma, or neurosensory change. A physical examination ruled out an odontogenic source of infection; his teeth were in good repair. The panoramic radiograph revealed a large and loculated radiolucency of the left mandible with inferior displacement of the left mandibular third molar and evidence of root resorption of the left mandibular second molar. CT scanning showed that the buccal and lingual cortices were expanded but intact. Both odontogenic and nonodontogenic processes are included in this differential diagnosis (Table 1).
Table 1. Cystic Lesions of the Mandible.
Odontogenic Cysts and Neoplasms
Because of the regular bony contours of the radiolucency on imaging studies and the associated impacted tooth, an odontogenic cyst is the most likely problem. Dentigerous cysts are the most common odontogenic cysts in this location; they are associated with the displacement of impacted teeth and cortical expansion. The odontogenic keratocyst represents 10 percent of all cystic jaw lesions; the posterior mandibular location, seen in this case, is most common, and 50 percent of these cysts are associated with impacted teeth. Pain and paresthesias are uncommon for both dentigerous cysts and odontogenic keratocysts. Root resorption is more commonly reported with dentigerous cysts. The calcifying odontogenic cyst usually has variable amounts of radiopaque material within it but in early phases may present as a primarily lucent lesion. Less common odontogenic cysts, such as the glandular odontogenic cyst, should also be considered in the differential diagnosis.
Benign odontogenic tumors can also present as multiloculated radiolucent lesions. Both ameloblastomas and ameloblastic fibromas are commonly found in this location. The average age of a patient at diagnosis for ameloblastoma is in the third decade and somewhat younger for ameloblastic fibroma. Both tumors tend to expand rather than perforate bone, as does this lesion. They are seldom painful and are commonly multilocular on radiographs. Unicystic ameloblastoma accounts for about 10 percent of intraosseous ameloblastomas. Most are found in the mandible and have features that are radiographically identical to those in this case. Another possibility, the calcifying epithelial odontogenic tumor, is more common in middle-aged patients and often is first noticed as a painless swelling of the mandible. Its radiographic pattern is variable (often containing calcifications), but a loculated radiolucency with an associated impaction has been described. The odontogenic myxoma is most common in patients who are in their teens and 20s and has a slight predilection for the mandible. Swelling without pain or tooth displacement is common. Bony perforation is rare. In early stages, a myxoma as visualized by radiography can show a well-circumscribed radiolucency. The squamous odontogenic tumor may be found in patients of widely varying ages. The bicuspid and molar regions are the most common locations for this type of tumor, which is generally painless and radiographically associated with the junction of the crown and the root of an impacted tooth.
Nonodontogenic Tumors
One type of benign nonodontogenic tumor to be considered in this case is an aggressive giant-cell tumor. A loculated radiolucency on radiography is typical, and cortical thinning and displacement of teeth are common. The patient's age is consistent with this diagnosis. Ossifying and cementifying fibromas are generally found in slightly older patients. Swelling without pain is common. Bone perforation is rare. On radiographic examination, the lesions are well circumscribed and radiolucent in early stages. Aneurysmal bone cysts could also have these signs and symptoms, although pain is more frequently associated with cases of this type of tumor. Desmoplastic fibroma (an intrabony form of aggressive fibromatosis) is a rare tumor, but the patient's age and the location of the lesion, as well as the radiographic findings, make it a possibility.
Vascular malformations need to be considered. The absence of any bleeding history, bruit, or thrill and no involvement of the overlying mucosa or skin make these unlikely to be the final diagnosis. Malignant tumors (both primary and metastatic) would be far down on the list of differential diagnoses. The radiographic regularity, along with the lack of neurosensory change or pain, make these tumors unlikely to be the cause of this patient's symptoms.
The findings in this case of an 18-year-old man with painless left posterior mandibular swelling with radiographic findings of a loculated radiolucency and an associated impacted tooth favor the diagnosis of an odontogenic cyst. The dentigerous cyst is far more common than the odontogenic keratocyst. Both lesions have a predilection for this mandibular location. However, the lack of bone perforation, especially with a lesion this large, as well as the circumferential appearance of the radiolucency surrounding the impacted tooth rather than emanating from the junction of the crown and the root, slightly favor the diagnosis of odontogenic keratocyst. Nonetheless, a dentigerous cyst and some of the less common odontogenic and nonodontogenic tumors cannot be ruled out. A biopsy of the lesion is necessary to establish the diagnosis.
Standard biopsy techniques require opening the cyst cavity and removing a portion of the lining for evaluation. This procedure often converts a closed cavity into an infected and open lesion with communication to the oral cavity. It may make eventual removal of the lesion more difficult and affect the accuracy of the diagnosis on the final specimen. Fine-needle aspiration biopsy in conjunction with immunocytochemical staining for low-molecular-weight cytokeratin has proved useful in sampling cells that line the cyst and in helping to establish a preoperative diagnosis, specifically, by differentiating dentigerous from odontogenic keratocysts.1,2,3 In this patient, fine-needle aspiration with cytokeratin staining would be appropriate. Because of the high clinical likelihood that this is an odontogenic keratocyst, open biopsy with frozen-section diagnosis, followed by preparation for subsequent definitive therapy, could also be considered.
Dr. Meredith August's Diagnosis
Odontogenic keratocyst.
Pathological Discussion
Dr. Edward T. Lahey (Department of Oral and Maxillofacial Surgery): The diagnostic procedure was an incisional biopsy of the lesion. The lesion was aspirated first, yielding a cloudy yellow fluid that was not bloody; ruling out a vascular malformation is imperative before opening into a bony cavity. Electrocautery was used to incise the mucosa from the left external oblique ridge, anterior to the first molar. A full-thickness mucoperiosteal flap was then elevated to reveal perforation of the lesion through the left lateral mandibular cortex, posterior to the second molar. Bone was removed in this region, exposing a lined cavity. A portion of the lining was removed for intraoperative frozen-section evaluation.
Dr. William C. Faquin: The biopsy specimen of the left mandible was sent for intraoperative frozen-section examination. The diagnostic information obtained by frozen section would be used to guide the surgical management. Microscopical examination revealed a fragmented cystic lesion with a dense fibrous wall, lined by a stratified squamous epithelium that was approximately six to seven cells thick (Figure 3A). Occasional smaller (daughter) cysts were present within the fibrous wall (Figure 3B). The interface between the epithelium and stroma was smooth, lacking the rete pegs that characterize normal squamous mucosa. The basal layer of the epithelium consisted of a palisaded arrangement of cuboidal cells with dark nuclei, and the epithelial surface showed a wavy layer of keratinized cells with retained nuclei, known as a corrugated parakeratinized layer (Figure 3C). The cyst lumen contained sloughed parakeratotic cells and anucleated squamous cells. A diagnosis of an odontogenic keratocyst was made.
Figure 3. Photomicrographs of the Biopsy Specimen of the Mandibular Lesion.
The biopsy specimen of the left mandible shows a squamous-epithelium-lined cyst with a thick fibrous wall (Panel A). Small daughter cysts were present within the fibrous wall (Panel B). The epithelium shows a prominent palisaded basal-cell layer and corrugated parakeratotic surface, typical of an odontogenic keratocyst (Panel C). (Panels A, B, and C; hematoxylin and eosin.) There is positive reactivity with an immunohistochemical stain for keratin 10 (Panel D, immunoperoxidase method).
On permanent, paraffin-embedded sections, an immunohistochemical stain for keratin 10 showed positive reactivity of the surface parakeratinized layer as well as of the cyst contents (Figure 3D). On the basis of these microscopical findings, the frozen-section diagnosis of an odontogenic keratocyst was confirmed.
The odontogenic keratocyst4 is a squamous-epithelium-lined cystic neoplasm thought to be from the dental lamina or the primordial odontogenic epithelium.5 Odontogenic keratocysts are locally destructive lesions6 that frequently recur and that rarely can be associated with epithelial dysplasia or even squamous-cell carcinoma.7 Evidence that the tumor-suppressor gene, PATCHED, is mutated in both inherited and sporadic forms of the parakeratinized type of odontogenic keratocyst supports the view that unlike other odontogenic cysts, odontogenic keratocysts are neoplasms.8,9,10
The histologic diagnosis of an odontogenic keratocyst is based primarily on the presence of specific microscopic features: a thin, stratified squamous epithelium with a prominent palisaded basal layer; a smooth interface with the stroma, lacking rete pegs; and a wavy or corrugated parakeratinized surface layer. Immunohistochemical staining for keratin 10, a low-molecular-weight cytokeratin that is expressed in a subset of keratinocytes within normal gingival mucosa, shows a characteristic strong staining of the superficial parakeratinized cells of odontogenic keratocysts and can be applied to both histologic and cytologic samples as an ancillary marker to support the diagnosis of an odontogenic keratocyst (Figure 3D).3,11,12
The entity most commonly confused clinically and microscopically with an odontogenic keratocyst is the dentigerous cyst, which is characterized by a squamous lining of variable thickness, sometimes with rete pegs; scattered mucin-containing cells; and occasionally ciliated cells — features not seen in odontogenic keratocysts. However, when an odontogenic keratocyst becomes inflamed, its epithelium may become indistinguishable from that of a dentigerous cyst. In any odontogenic cyst, thorough sampling by the surgeon and adequate sectioning of the biopsy specimen by the pathologist are essential. Apparently, dentigerous cysts that recur are typically found to have been odontogenic keratocysts whose diagnostic features have been obscured by inflammation or inadequate sampling.
Approximately 5 percent of odontogenic keratocysts are associated with the autosomal dominant basal cell nevus syndrome (Gorlin's syndrome), associated with germ-line mutations in PATCHED and characterized by multiple basal-cell carcinomas of the skin, multiple odontogenic keratocysts of the jaw, skeletal abnormalities such as bifid ribs, and occasionally by other tumors, such as medulloblastomas and ovarian fibromas.13
Discussion of Management
Dr. August: Management of an odontogenic keratocyst is a focus of investigation, because of the high recurrence rate (overall, about 30 percent).14,15,16,17 En bloc resection will prevent recurrences but results in clinical deformity and the necessity for bone-graft reconstruction.
Enucleation — removal of the cyst lining — is the most common method of treatment, but because the lining is typically thin and friable, it often fragments during the removal process. Incomplete removal of the cyst lining and associated connective tissue with microcysts is thought to predispose the patient to recurrence or persistence of the tumor.18,19 Curettage, cryotherapy, peripheral ostectomy, and application of chemical fixatives to the underlying bone all lower recurrence rates but result in increased morbidity.19,20,21
A protocol of surgical decompression of the cyst, followed by 12 months of twice-daily irrigation with hexachlorophene and, later, cystectomy, has proved to be a promising approach for large odontogenic keratocysts.22 The decompression prevents further expansion, while the irrigant causes the neoplastic epithelium to undergo squamous metaplasia and the cyst wall to become fibrotic, thus minimizing the likelihood of recurrence and facilitating subsequent removal of any residual lesion. In patients who undergo this treatment, there is often a change in the character of the cyst lining seen at eventual cystectomy; it may have become thickened and less adherent to the underlying bone, and in about 60 percent of cases, the epithelium no longer showed the features of odonotogenic keratocyst and was cytokeratin-10 negative.23 The reported recurrence rate with this treatment has been less than 10 percent.24
Dr. Lahey: After the intraoperative diagnosis of an odontogenic keratocyst was made, the cyst was explored along its entire extent to ensure that no septa remained intact. Two decompression stents were inserted into the cystic cavity and securely fastened to the reapproximated mucosal wound edges (Figure 2 of the Supplementary Appendix). The patient was discharged to his home later the same day with instructions to irrigate the cyst twice daily through the irrigation tubes using 10 ml of 0.12 percent chlorhexidine.
The patient was initially seen in the clinic weekly for a physical examination and to obtain panoramic radiographs. Three weeks after he went home, there was a purulent discharge from the posterior stent. The patient admitted that he had not adhered to the prescribed irrigation regimen. Penicillin was prescribed for one week, and he was counseled regarding the irrigation protocol. After the first four weeks, the patient was followed monthly.
After 21 months, a physical examination showed vastly reduced facial asymmetry, with only a slight fullness on the left (Figure 1B). Intraoral examination showed the resolution of the left mandibular vestibular swelling (Figure 1D). Reexploration and enucleation of the residual lesion was performed according to the protocol. The patient was discharged to his home on the day of the cystectomy. At three-month and six-month follow-ups, he had only mild, residual facial swelling on the lower left side.
Dr. Faquin: Microscopical examination of the resection specimen revealed inflamed, dense fibrotic stroma and a small, 1.0-cm squamous-epithelium-lined cyst (Figure 3 of the Supplementary Appendix). Focal areas of the cyst lining revealed classic features of an odontogenic keratocyst, whereas other areas of the epithelial lining were thicker, without a distinct basal layer or parakeratotic surface.
Dr. Caruso: A panoramic radiograph obtained 13 months after the first procedure (Figure 2B) showed progressive sclerosis of the lesion, most notably along the margins of the mesial component of the lesion nearest the irrigation cannulae; there was a persistent radiolucency in the center, most conspicuous within the distal components of the lesion. A panoramic radiograph obtained three months after the second procedure (Figure 2C) showed marked sclerosis and new bone formation within the mesial and distal components of the lesion, indicating essentially complete resolution of the lesion.
A Physician: Is it possible to use keratin 10 to distinguish between a dentigerous cyst and an inflamed odontogenic keratocyst?
Dr. Faquin: Immunohistochemical staining of odontogenic keratocysts using keratin 10 works best when you have well-defined histologic features of an odontogenic keratocyst, so that in an inflamed lesion, the keratin-10 staining is less likely to give a definitive result. I think that the best application for keratin 10 is in a fine-needle aspiration in which there are only squamous cells, which could be either from a dentigerous cyst or from an odontogenic keratocyst. If the cells are keratin-10–positive, that would support the diagnosis of an odontogenic keratocyst.
Dr. Leonard B. Kaban (Department of Oral and Maxillofacial Surgery): Dr. August, are there any factors that appear to contribute to either the success or the failure of this procedure of decompression and irrigation?
Dr. August: Case selection is important, and the radiographic features help in planning. If there are a lot of loculations, we try to identify them and break them up if possible or, as in this patient, place two stents in a very large lesion. It is important to make sure that the whole cyst receives the effect of treatment, so loculations within the cavity must be recognized and removed, if possible. Finally, the patient must be able to understand the irrigation instructions and be willing to comply with the procedure.
Anatomical Diagnosis
Odontogenic keratocyst.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Department of Oral and Maxillofacial Surgery (M.A.) and the Department of Pathology (W.C.F.), Massachusetts General Hospital; the Department of Radiology , Massachusetts Eye and Ear Infirmary (P.A.C.); and the Departments of Oral and Maxillofacial Surgery (M.A.), Radiology (P.A.C.), and Pathology (W.C.F.), Harvard Medical School — all in Boston.
References
August M, Faquin WC, Ferraro NF, Kaban LB. Fine-needle aspiration biopsy of intraosseous jaw lesions. J Oral Maxillofac Surg 1999;57:1282-1286.
MacDonald AW, Fletcher A. Expression of cytokeratin in the epithelium of dentigerous cysts and odontogenic keratocysts: an aid to diagnosis. J Clin Pathol 1989;42:736-739.
Matthews JB, Mason GI, Browne RM. Epithelial cell markers and proliferating cells in odontogenic jaw cysts. J Pathol 1988;156:283-290.
Philipsen HP. Om keratocysts (Kolesteatomer) I Kaeberne. Tandlaegebladet 1956;60:963-980.
Sciubba JJ, Fantasia JE, Kahn LB. Tumors and cysts of the jaw. Atlas of tumor pathology. 3rd series. Fascicle 29. Washington, D.C.: Armed Forces Institute of Pathology, 2001.
Shear M. The aggressive nature of the odontogenic keratocyst: is it a benign cystic neoplasm? 1. Clinical and early experimental evidence of aggressive behaviour. Oral Oncol 2002;38:219-226.
Anand VK, Arrowood JP Jr, Krolls SO. Malignant potential of the odontogenic keratocyst. Otolaryngol Head Neck Surg 1994;111:124-129.
Lench NJ, High AS, Markham AF, Hume WJ, Robinson PA. Investigation of chromosome 9q22.3-q31 DNA marker loss in odontogenic keratocysts. Eur J Cancer B Oral Oncol 1996;32:202-206.
Shear M. The aggressive nature of the odontogenic keratocyst: is it a benign cystic neoplasm? 3. Immunocytochemistry of cytokeratin and other epithelial cell markers. Oral Oncol 2002;38:407-415.
Ohki K, Kumamoto H, Ichinohasama R, Sato T, Takahashi K, Ooya K. PTC gene mutations and expression of SHH, PTC, SMO, and GLI-1 in odontogenic keratocysts. Int J Oral Maxillofac Surg 2004;33:584-592.
Shuler CF, Shriver BJ. Identification of inermediate filament keratin proteins in parakeratinized odontogenic keratocysts: a preliminary study. Oral Surg Oral Med Oral Pathol 1987;64:439-444.
August M, Faquin WC, Troulis M, Kaban LB. Differentiation of odontogenic keratocysts from nonkeratinizing cysts by use of fine-needle aspiration biopsy and cytokeratin-10 staining. J Oral Maxillofac Surg 2000;58:935-940.
Gorlin RJ. Nevoid basal cell carcinoma syndrome. Dermatol Clin 1995;13:113-125.
Zachariades N, Papanicolaou S, Triantafyllou D. Odontogenic keratocysts: review of the literature and report of sixteen cases. J Oral Maxillofac Surg 1985;43:177-182.
Chow HT. Odontogenic keratocyst: a clinical experience in Singapore. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;86:573-577.
Bataineh A, al Qudah M. Treatment of mandibular odontogenic keratocysts. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;86:42-47.
Dammer R, Niederdellmann H, Dammer P, Nuebler-Moritz M. Conservative or radical treatment of keratocysts: a retrospective review. Br J Oral Maxillofac Surg 1997;35:46-48.
el-Hajj G, Anneroth G. Odontogenic keratocysts -- a retrospective clinical and histologic study. Int J Oral Maxillofac Surg 1996;25:124-129.
Stoelinga PJ. Long-term follow-up on keratocysts treated according to a defined protocol. Int J Oral Maxillofac Surg 2001;30:14-25.
Schmidt BL, Pogrel MA. Neurosensory changes following cryotherapy. J Oral Maxillofac Surg 1999;57:Suppl 1:46-46. abstract.
Voorsmit RACA. The incredible keratocyst: a retrospective and prospective study. (Ph.D. thesis. Nijmegen, the Netherlands: University of Nijmegen, 1984.)
Brondum N, Jensen VJ. Recurrence of keratocysts and decompression treatment: a long-term follow-up of forty-four cases. Oral Surg Oral Med Oral Pathol 1991;72:265-269.
August M, Faquin WC, Troulis MJ, Kaban LB. Dedifferentiation of odontogenic keratocyst epithelium after cyst decompression. J Oral Maxillofac Surg 2003;61:678-683.
Marker P, Brondum N, Clausen PP, Bastian HL. Treatment of large odontogenic keratocysts by decompression and later cystectomy: a long-term follow-up and a historical study of 23 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;82:122-131.(Meredith August, M.D., D.)
An 18-year-old man was referred by his dentist to the oral and maxillofacial surgery clinic of this hospital because of left mandibular swelling.
One month earlier, the patient first noticed gradual left mandibular enlargement without pain, fever, malocclusion, sensory changes, or trismus. There was no history of trauma or recent dental work. He had no illnesses or allergies, took no medications, did not use tobacco or alcohol, and reported no first-degree relatives with cancer.
On physical examination, there was obvious facial asymmetry, with the left side of the jaw larger than the right (Figure 1A). A firm, nontender swelling was palpable along the ramus and posterior body of the left mandible. Neurologic examination revealed normal function of cranial nerves V and VII. He had generalized, mild-to-moderate gingivitis on intraoral examination; the mucosae and soft tissues were otherwise normal. The dentition was intact and in good repair, and there was no malocclusion. There was expansion of the bone along the left lateral alveolar ridge of the mandible, which obliterated the buccal vestibule (Figure 1C).
Figure 1. Clinical Images of the Patient.
Images of the face when the patient presented (Panel A) and 21 months after the first procedure (Panel B), showing swelling of the left mandible (Panel A, arrow), which is greatly diminished in Panel B. An intraoral photograph, also obtained at the time of presentation (Panel C), shows smooth thickening of the posterior body and ramus of the left mandible (arrows) that obliterate the buccal vestibule. Another intraoral image obtained 21 months after the first procedure (Panel D) shows substantial reduction in swelling.
A panoramic radiograph of the jaws revealed a septated radiolucent lesion in the left mandible. Four days later, a maxillofacial computed tomographic (CT) scan obtained without intravenously administered contrast material showed a unilocular, expansile, lytic lesion, 5.1 cm (superoinferior) by 2.6 cm (buccolingual) by 8 cm (mesiodistal), in the left mandible.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. Meredith August: I was involved in the care of this patient and am aware of the diagnosis. This case presents an opportunity to review the differential diagnosis and management of cystic lesions of the jaw. May we review the imaging studies?
Dr. Paul A. Caruso: A panoramic radiograph of the jaws obtained at the time of the patient's presentation (Figure 2A) revealed a large, expansile, partially septated, radiolucent lesion of the left mandible that extended from the midbody mesially to the ramus distally, involved the sigmoid notch and the base of the coronoid process, and spared the condyle. The lesion displaced the impacted left mandibular third molar mesially, inferiorly, and buccally; involved both the crown and the roots; and clearly involved the tooth beyond the cemento-enamel junction. The lesion resorbed the distal roots of the left mandibular first molar.
Figure 2. Imaging Studies of the Mandibular Lesion.
A preprocedural panoramic radiograph (Panel A) reveals an expansile, lytic lesion involving the body and ramus of the left mandible that incorporates the unerupted mandibular third molar. A panoramic radiograph obtained 13 months after the biopsy (Panel B) shows two irrigation cannulae, thick marginal sclerosis, and mineralization within the lesion but persistent central radiolucency, most notably within the ramus. A panoramic radiograph obtained three months after the second procedure (Panel C) shows marked progressive sclerosis of the entire lesion.
A non-contrast-enhanced, maxillofacial CT with three-dimensional reconstructions (Figures 1A, 1B, and 1C of the Supplementary Appendix, available with the full text of this article at www.nejm.org) showed a partially septated, otherwise homogeneous-appearing, radiolucent lesion in the left mandible that thinned and expanded but did not breach the lingual and buccal cortices, and showed no extraosseous component.
Dr. August: This 18-year-old, otherwise healthy man presented with a one-month history of swelling in the left jaw that was not associated with pain, fever, trismus, malocclusion, antecedent trauma, or neurosensory change. A physical examination ruled out an odontogenic source of infection; his teeth were in good repair. The panoramic radiograph revealed a large and loculated radiolucency of the left mandible with inferior displacement of the left mandibular third molar and evidence of root resorption of the left mandibular second molar. CT scanning showed that the buccal and lingual cortices were expanded but intact. Both odontogenic and nonodontogenic processes are included in this differential diagnosis (Table 1).
Table 1. Cystic Lesions of the Mandible.
Odontogenic Cysts and Neoplasms
Because of the regular bony contours of the radiolucency on imaging studies and the associated impacted tooth, an odontogenic cyst is the most likely problem. Dentigerous cysts are the most common odontogenic cysts in this location; they are associated with the displacement of impacted teeth and cortical expansion. The odontogenic keratocyst represents 10 percent of all cystic jaw lesions; the posterior mandibular location, seen in this case, is most common, and 50 percent of these cysts are associated with impacted teeth. Pain and paresthesias are uncommon for both dentigerous cysts and odontogenic keratocysts. Root resorption is more commonly reported with dentigerous cysts. The calcifying odontogenic cyst usually has variable amounts of radiopaque material within it but in early phases may present as a primarily lucent lesion. Less common odontogenic cysts, such as the glandular odontogenic cyst, should also be considered in the differential diagnosis.
Benign odontogenic tumors can also present as multiloculated radiolucent lesions. Both ameloblastomas and ameloblastic fibromas are commonly found in this location. The average age of a patient at diagnosis for ameloblastoma is in the third decade and somewhat younger for ameloblastic fibroma. Both tumors tend to expand rather than perforate bone, as does this lesion. They are seldom painful and are commonly multilocular on radiographs. Unicystic ameloblastoma accounts for about 10 percent of intraosseous ameloblastomas. Most are found in the mandible and have features that are radiographically identical to those in this case. Another possibility, the calcifying epithelial odontogenic tumor, is more common in middle-aged patients and often is first noticed as a painless swelling of the mandible. Its radiographic pattern is variable (often containing calcifications), but a loculated radiolucency with an associated impaction has been described. The odontogenic myxoma is most common in patients who are in their teens and 20s and has a slight predilection for the mandible. Swelling without pain or tooth displacement is common. Bony perforation is rare. In early stages, a myxoma as visualized by radiography can show a well-circumscribed radiolucency. The squamous odontogenic tumor may be found in patients of widely varying ages. The bicuspid and molar regions are the most common locations for this type of tumor, which is generally painless and radiographically associated with the junction of the crown and the root of an impacted tooth.
Nonodontogenic Tumors
One type of benign nonodontogenic tumor to be considered in this case is an aggressive giant-cell tumor. A loculated radiolucency on radiography is typical, and cortical thinning and displacement of teeth are common. The patient's age is consistent with this diagnosis. Ossifying and cementifying fibromas are generally found in slightly older patients. Swelling without pain is common. Bone perforation is rare. On radiographic examination, the lesions are well circumscribed and radiolucent in early stages. Aneurysmal bone cysts could also have these signs and symptoms, although pain is more frequently associated with cases of this type of tumor. Desmoplastic fibroma (an intrabony form of aggressive fibromatosis) is a rare tumor, but the patient's age and the location of the lesion, as well as the radiographic findings, make it a possibility.
Vascular malformations need to be considered. The absence of any bleeding history, bruit, or thrill and no involvement of the overlying mucosa or skin make these unlikely to be the final diagnosis. Malignant tumors (both primary and metastatic) would be far down on the list of differential diagnoses. The radiographic regularity, along with the lack of neurosensory change or pain, make these tumors unlikely to be the cause of this patient's symptoms.
The findings in this case of an 18-year-old man with painless left posterior mandibular swelling with radiographic findings of a loculated radiolucency and an associated impacted tooth favor the diagnosis of an odontogenic cyst. The dentigerous cyst is far more common than the odontogenic keratocyst. Both lesions have a predilection for this mandibular location. However, the lack of bone perforation, especially with a lesion this large, as well as the circumferential appearance of the radiolucency surrounding the impacted tooth rather than emanating from the junction of the crown and the root, slightly favor the diagnosis of odontogenic keratocyst. Nonetheless, a dentigerous cyst and some of the less common odontogenic and nonodontogenic tumors cannot be ruled out. A biopsy of the lesion is necessary to establish the diagnosis.
Standard biopsy techniques require opening the cyst cavity and removing a portion of the lining for evaluation. This procedure often converts a closed cavity into an infected and open lesion with communication to the oral cavity. It may make eventual removal of the lesion more difficult and affect the accuracy of the diagnosis on the final specimen. Fine-needle aspiration biopsy in conjunction with immunocytochemical staining for low-molecular-weight cytokeratin has proved useful in sampling cells that line the cyst and in helping to establish a preoperative diagnosis, specifically, by differentiating dentigerous from odontogenic keratocysts.1,2,3 In this patient, fine-needle aspiration with cytokeratin staining would be appropriate. Because of the high clinical likelihood that this is an odontogenic keratocyst, open biopsy with frozen-section diagnosis, followed by preparation for subsequent definitive therapy, could also be considered.
Dr. Meredith August's Diagnosis
Odontogenic keratocyst.
Pathological Discussion
Dr. Edward T. Lahey (Department of Oral and Maxillofacial Surgery): The diagnostic procedure was an incisional biopsy of the lesion. The lesion was aspirated first, yielding a cloudy yellow fluid that was not bloody; ruling out a vascular malformation is imperative before opening into a bony cavity. Electrocautery was used to incise the mucosa from the left external oblique ridge, anterior to the first molar. A full-thickness mucoperiosteal flap was then elevated to reveal perforation of the lesion through the left lateral mandibular cortex, posterior to the second molar. Bone was removed in this region, exposing a lined cavity. A portion of the lining was removed for intraoperative frozen-section evaluation.
Dr. William C. Faquin: The biopsy specimen of the left mandible was sent for intraoperative frozen-section examination. The diagnostic information obtained by frozen section would be used to guide the surgical management. Microscopical examination revealed a fragmented cystic lesion with a dense fibrous wall, lined by a stratified squamous epithelium that was approximately six to seven cells thick (Figure 3A). Occasional smaller (daughter) cysts were present within the fibrous wall (Figure 3B). The interface between the epithelium and stroma was smooth, lacking the rete pegs that characterize normal squamous mucosa. The basal layer of the epithelium consisted of a palisaded arrangement of cuboidal cells with dark nuclei, and the epithelial surface showed a wavy layer of keratinized cells with retained nuclei, known as a corrugated parakeratinized layer (Figure 3C). The cyst lumen contained sloughed parakeratotic cells and anucleated squamous cells. A diagnosis of an odontogenic keratocyst was made.
Figure 3. Photomicrographs of the Biopsy Specimen of the Mandibular Lesion.
The biopsy specimen of the left mandible shows a squamous-epithelium-lined cyst with a thick fibrous wall (Panel A). Small daughter cysts were present within the fibrous wall (Panel B). The epithelium shows a prominent palisaded basal-cell layer and corrugated parakeratotic surface, typical of an odontogenic keratocyst (Panel C). (Panels A, B, and C; hematoxylin and eosin.) There is positive reactivity with an immunohistochemical stain for keratin 10 (Panel D, immunoperoxidase method).
On permanent, paraffin-embedded sections, an immunohistochemical stain for keratin 10 showed positive reactivity of the surface parakeratinized layer as well as of the cyst contents (Figure 3D). On the basis of these microscopical findings, the frozen-section diagnosis of an odontogenic keratocyst was confirmed.
The odontogenic keratocyst4 is a squamous-epithelium-lined cystic neoplasm thought to be from the dental lamina or the primordial odontogenic epithelium.5 Odontogenic keratocysts are locally destructive lesions6 that frequently recur and that rarely can be associated with epithelial dysplasia or even squamous-cell carcinoma.7 Evidence that the tumor-suppressor gene, PATCHED, is mutated in both inherited and sporadic forms of the parakeratinized type of odontogenic keratocyst supports the view that unlike other odontogenic cysts, odontogenic keratocysts are neoplasms.8,9,10
The histologic diagnosis of an odontogenic keratocyst is based primarily on the presence of specific microscopic features: a thin, stratified squamous epithelium with a prominent palisaded basal layer; a smooth interface with the stroma, lacking rete pegs; and a wavy or corrugated parakeratinized surface layer. Immunohistochemical staining for keratin 10, a low-molecular-weight cytokeratin that is expressed in a subset of keratinocytes within normal gingival mucosa, shows a characteristic strong staining of the superficial parakeratinized cells of odontogenic keratocysts and can be applied to both histologic and cytologic samples as an ancillary marker to support the diagnosis of an odontogenic keratocyst (Figure 3D).3,11,12
The entity most commonly confused clinically and microscopically with an odontogenic keratocyst is the dentigerous cyst, which is characterized by a squamous lining of variable thickness, sometimes with rete pegs; scattered mucin-containing cells; and occasionally ciliated cells — features not seen in odontogenic keratocysts. However, when an odontogenic keratocyst becomes inflamed, its epithelium may become indistinguishable from that of a dentigerous cyst. In any odontogenic cyst, thorough sampling by the surgeon and adequate sectioning of the biopsy specimen by the pathologist are essential. Apparently, dentigerous cysts that recur are typically found to have been odontogenic keratocysts whose diagnostic features have been obscured by inflammation or inadequate sampling.
Approximately 5 percent of odontogenic keratocysts are associated with the autosomal dominant basal cell nevus syndrome (Gorlin's syndrome), associated with germ-line mutations in PATCHED and characterized by multiple basal-cell carcinomas of the skin, multiple odontogenic keratocysts of the jaw, skeletal abnormalities such as bifid ribs, and occasionally by other tumors, such as medulloblastomas and ovarian fibromas.13
Discussion of Management
Dr. August: Management of an odontogenic keratocyst is a focus of investigation, because of the high recurrence rate (overall, about 30 percent).14,15,16,17 En bloc resection will prevent recurrences but results in clinical deformity and the necessity for bone-graft reconstruction.
Enucleation — removal of the cyst lining — is the most common method of treatment, but because the lining is typically thin and friable, it often fragments during the removal process. Incomplete removal of the cyst lining and associated connective tissue with microcysts is thought to predispose the patient to recurrence or persistence of the tumor.18,19 Curettage, cryotherapy, peripheral ostectomy, and application of chemical fixatives to the underlying bone all lower recurrence rates but result in increased morbidity.19,20,21
A protocol of surgical decompression of the cyst, followed by 12 months of twice-daily irrigation with hexachlorophene and, later, cystectomy, has proved to be a promising approach for large odontogenic keratocysts.22 The decompression prevents further expansion, while the irrigant causes the neoplastic epithelium to undergo squamous metaplasia and the cyst wall to become fibrotic, thus minimizing the likelihood of recurrence and facilitating subsequent removal of any residual lesion. In patients who undergo this treatment, there is often a change in the character of the cyst lining seen at eventual cystectomy; it may have become thickened and less adherent to the underlying bone, and in about 60 percent of cases, the epithelium no longer showed the features of odonotogenic keratocyst and was cytokeratin-10 negative.23 The reported recurrence rate with this treatment has been less than 10 percent.24
Dr. Lahey: After the intraoperative diagnosis of an odontogenic keratocyst was made, the cyst was explored along its entire extent to ensure that no septa remained intact. Two decompression stents were inserted into the cystic cavity and securely fastened to the reapproximated mucosal wound edges (Figure 2 of the Supplementary Appendix). The patient was discharged to his home later the same day with instructions to irrigate the cyst twice daily through the irrigation tubes using 10 ml of 0.12 percent chlorhexidine.
The patient was initially seen in the clinic weekly for a physical examination and to obtain panoramic radiographs. Three weeks after he went home, there was a purulent discharge from the posterior stent. The patient admitted that he had not adhered to the prescribed irrigation regimen. Penicillin was prescribed for one week, and he was counseled regarding the irrigation protocol. After the first four weeks, the patient was followed monthly.
After 21 months, a physical examination showed vastly reduced facial asymmetry, with only a slight fullness on the left (Figure 1B). Intraoral examination showed the resolution of the left mandibular vestibular swelling (Figure 1D). Reexploration and enucleation of the residual lesion was performed according to the protocol. The patient was discharged to his home on the day of the cystectomy. At three-month and six-month follow-ups, he had only mild, residual facial swelling on the lower left side.
Dr. Faquin: Microscopical examination of the resection specimen revealed inflamed, dense fibrotic stroma and a small, 1.0-cm squamous-epithelium-lined cyst (Figure 3 of the Supplementary Appendix). Focal areas of the cyst lining revealed classic features of an odontogenic keratocyst, whereas other areas of the epithelial lining were thicker, without a distinct basal layer or parakeratotic surface.
Dr. Caruso: A panoramic radiograph obtained 13 months after the first procedure (Figure 2B) showed progressive sclerosis of the lesion, most notably along the margins of the mesial component of the lesion nearest the irrigation cannulae; there was a persistent radiolucency in the center, most conspicuous within the distal components of the lesion. A panoramic radiograph obtained three months after the second procedure (Figure 2C) showed marked sclerosis and new bone formation within the mesial and distal components of the lesion, indicating essentially complete resolution of the lesion.
A Physician: Is it possible to use keratin 10 to distinguish between a dentigerous cyst and an inflamed odontogenic keratocyst?
Dr. Faquin: Immunohistochemical staining of odontogenic keratocysts using keratin 10 works best when you have well-defined histologic features of an odontogenic keratocyst, so that in an inflamed lesion, the keratin-10 staining is less likely to give a definitive result. I think that the best application for keratin 10 is in a fine-needle aspiration in which there are only squamous cells, which could be either from a dentigerous cyst or from an odontogenic keratocyst. If the cells are keratin-10–positive, that would support the diagnosis of an odontogenic keratocyst.
Dr. Leonard B. Kaban (Department of Oral and Maxillofacial Surgery): Dr. August, are there any factors that appear to contribute to either the success or the failure of this procedure of decompression and irrigation?
Dr. August: Case selection is important, and the radiographic features help in planning. If there are a lot of loculations, we try to identify them and break them up if possible or, as in this patient, place two stents in a very large lesion. It is important to make sure that the whole cyst receives the effect of treatment, so loculations within the cavity must be recognized and removed, if possible. Finally, the patient must be able to understand the irrigation instructions and be willing to comply with the procedure.
Anatomical Diagnosis
Odontogenic keratocyst.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Department of Oral and Maxillofacial Surgery (M.A.) and the Department of Pathology (W.C.F.), Massachusetts General Hospital; the Department of Radiology , Massachusetts Eye and Ear Infirmary (P.A.C.); and the Departments of Oral and Maxillofacial Surgery (M.A.), Radiology (P.A.C.), and Pathology (W.C.F.), Harvard Medical School — all in Boston.
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