- Email: [email protected]
Keratocyst of the buccal mucosa: is it odontogenic?
Keratocyst of the buccal mucosa: is it odontogenic? Fumio Ide, DDS, PhD,a Kentaro Kikuchi, DDS, PhD,b Yuji Miyazaki, PhD,c Kenji Mishima, DDS, PhD,d Ichiro Saito, DDS, PhD,e and Kaoru Kusama, DDS, PhD,f Sakado and Yokohama, Japan MEIKAI UNIVERSITY AND TSURUMI UNIVERSITY
Odontogenic keratocyst (OKC) of the buccal mucosa, the diagnosis of which is based on subjective histologic evaluation, is a controversial entity of questionable existence. This report describes 2 rare cases of parakeratinized cyst arising from the buccal mucosa. Case 1 was a 60-year-old man with a 3-cm cyst and case 2 was a 16-year-old boy with a microcyst incidentally discovered on histology. Both lesions were essentially identical in histologic appearance and immunophenotype to intraosseous and gingival OKC, but they were clearly different from orthokeratinized odontogenic cysts and buccal mucosal epidermoid cysts. Step sections failed to reveal any kind of odontogenic tissue or skin adnexa in the cyst wall. These microscopic characteristics reflexively lead to the diagnosis of OKC, if the extragingival occurrence in the buccal mucosa cannot be considered. An alternative nonodontogenic origin includes a keratocyst of the skin, ie, an unusual mucosal presentation of cutaneous keratocyst. Because its true nature, either odontogenic or epidermal, cannot be conclusively proven at this time, we propose a more descriptive and noncommittal term, “mucosal keratocyst,” for a particular cyst in a buccal location that is morphologically indistinguishable from OKC. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;110:e42-e47)
Cysts and tumors arising from epithelial structures and remnants associated with the development of teeth are conceptualized as “odontogenic.” In addition to the ordinary central processes, uncommon lesions that occur solely in the soft tissues overlying the alveolar bone are referred to as “peripheral.” According to these definitions, odontogenic cysts/tumors are exclusive to 2 anatomic areas: intraosseous in the jaws and extraosseous in the gingiva. There are, however, a few reports of peripheral lesions of ameloblastoma,1-5 odontogenic keratocyst (OKC),6-9 and odontoma1,10 in extragnathic locations, and the buccal mucosa is by far the most common site.1 No rationale for this peculiar topoa
Associate Professor, Division of Pathology, Department of Diagnostic and Therapeutic Sciences, Meikai University School of Dentistry; and Department of Pathology, Tsurumi University School of Dental Medicine. b Assistant Professor, Division of Pathology, Department of Diagnostic and Therapeutic Sciences, Meikai University School of Dentistry. c Research Associate, Division of Pathology, Department of Diagnostic and Therapeutic Sciences, Meikai University School of Dentistry. d Associate Professor, Department of Pathology, Tsurumi University School of Dental Medicine. e Professor and Chairman, Department of Pathology, Tsurumi University School of Dental Medicine. f Professor and Chairman, Division of Pathology, Department of Diagnostic and Therapeutic Sciences, Meikai University School of Dentistry. Received for publication Apr 7, 2010; returned for revision May 19, 2010; accepted for publication May 31, 2010. 1079-2104/$ - see front matter © 2010 Published by Mosby, Inc. doi:10.1016/j.tripleo.2010.05.073
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graphic predilection can be offered other than a general theory of embryonic mishap of odontogenesis.1 With the exception of rare odontomas in which the formation of dental hard tissues takes place,1,10 what can be considered to be good evidence of an odontogenic origin is open to speculation, and an extragingival peripheral ameloblastoma is regarded by some to be a nonentity.11 In the present study, 2 examples of mucosal “parakeratinized cyst,” abbreviated “keratocyst,” are presented originating within the buccal mucosa; they mimicked OKC in their histologic and immunohistochemical features but not in location. Confronting this debatable entity prompted us to review and discuss the origin and nature of a buccal mucosal keratocyst. CASE REPORTS Case 1 A 60-year-old man, fit and well, appeared with an 8-year history of a painless swelling of the left buccal mucosa. Posterior to the parotid papilla was a 3 ⫻ 2 ⫻ 2 cm cystic tumor in the mucosal side of the buccinator muscle. The surface erythematous area coincided with the occlusal line when his upper denture was inserted (Fig. 1, a). The mass was removed in 1988 and histologically reported as an epidermoid cyst. Recurrence has not been observed. Microscopically, a multilocular cyst had the conventional OKC lining (Fig. 1, b and c). Focally, a small keratin granuloma was present. Mucous salivary lobules and striated muscle bundles were also sampled.
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Fig. 1. Mucosal keratocysts of case 1 (a-c) and case 2 (d-f). a, Intraoral photograph of case 1, showing a mass in the left buccal mucosa. b, Whole-mount section of a collapsed multilocular cyst (arrows), containing mucous salivary lobules (arrowheads) (hematoxylin and eosin stain [HE], original magnification ⫻3). c, Epithelial lining diagnostic of odontogenic keratocyst (HE, original magnification ⫻400). d, Scanning view of case 2, showing a rounded microcyst, mucous salivary glands (arrowhead) and a foreign body granuloma (arrow) (HE, original magnification ⫻3.5). e, Epithelial lining suggestive of odontogenic keratocyst (HE, original magnification ⫻400). f, Cholesterol clefts forming part of a keratin granuloma (HE, original magnification ⫻100).
Case 2 A 16-year-old boy in good health had a 5 mm nodule in the right buccal mucosa near the parotid papilla which appeared after accidentally biting his cheek. The histologic diagnosis in 1996 was traumatic fibroma with a salivary duct cyst. The patient declined subsequent follow-up. A chance microscopic finding of interest was a unilocular microcyst (⬍3 mm), the lining of which showed features similar to those described in case 1, with the exception of a mildly palisaded basal layer (Fig. 1 d and e). Likewise, a granulomatous response to keratin and cholesterol was seen (Fig. 1, f). This latent lesion mimicked a satellite microcyst in the wall of OKC.
Immunohistochemical findings Immunoprofiles were compared among keratocysts (cases 1 and 2), central and peripheral OKC (n ⫽ 3 each),12 orthokeratinized odontogenic cysts (OOC; n ⫽ 3),13 and buccal mucosal epidermoid cysts (EC; n ⫽ 3). Normal adult skin and sebaceous hyperplasia of the buccal mucosa were included as reference tissues. Cytokeratin (CK) 10 (DE-K10; DakoCytomation, Carpinteria, CA; 1:50), CK16 (LL026; Santa Cruz, Santa Cruz, CA; 1:50), CK17 (E3; Dako; 1:20), CK19 (RCK108, Dako; 1:20), hard ␣-keratin (polyclonal antibody against human hair keratins; 1:400),14 Bcl-2 (124; Dako; 1:50), D2-40 (Dako; 1:50), and Ki-67 (MIB-1; Dako; 1:20) were used. Details of immunohistochemical staining appear in our previous reports.14-16
There was no difference in the CK pattern (CK17 positive and CK10 negative) between keratocysts and OKC,8,17 and OOC and EC had the opposite staining results.8,17-19 In keratocysts and OKC, whole epithelial layers in the thin lining of ⬍5 cells were intensely positive for CK17, whereas the basal and sometimes parabasal layers in the thick lining of ⬎6-8 cells looked faintly stained with CK17 (Fig. 2). The CK10 stainability in OOC and EC never included the basal cells. CK16 reacted with the suprabasal layers of keratocyst, OOC, and EC in general, and in OKC the positive staining was confined to the parakeratin surface. CK19 left all types of cysts unstained. Similarly, hard ␣-keratin that is present in hair shafts as well as in shadow and ghost cells14 was absent. There was an impressive basal cell expression for Bcl-2 and D2-40 in keratocyst and OKC.12,16,17,20 Also, both cysts revealed a unique parabasal onset of the Ki-67 labeling (Fig. 3). In marked contrast, these 3 markers were essentially negative in the lining of OOC and EC, either thin or thick (data not shown).16,17 As a result of the present study, OOC and EC are equal in immunophenotype. Because CK16 is a minor member of the CK set of OKC, keratocyst and OKC cannot be differentiated by their expression patterns of antibodies used. In sections of control skin, the isthmus of a hair follicle and the sebaceous duct opening into a follicle showed a refractile parakeratotic surface and a distinguished basal layer (Fig. 4, a). They had the CK17-positive (in the suprabasal layer; Fig.
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Fig. 2. Cytokeratin (CK) profile of mucosal keratocysts (cases 1 and 2), central (cOKC) and peripheral (pOKC) odontogenic keratocysts, and orthokeratinized odontogenic cysts (OOC) (immunostaining, original magnifications ⫻400).
Fig. 3. Comparative immunohistochemistry of D2-40, Bcl-2, and Ki-67 between mucosal keratocysts (cases 1 and 2), and central (cOKC) and peripheral (pOKC) odontogenic keratocysts (immunostaining, original magnifications ⫻400).
4, b) and CK10-negative phenotype.18,19,21 Both areas expressed none of the remaining antibodies tested. The same profile was apparent in the lobular side of the ducts of hyperplastic sebaceous glands in the buccal mucosa (Fig. 4, c and d). Referring to cutaneous keratinous cysts,17-19 CK10 is linked to the epidermal or infundibular keratinization and CK17 belongs to the isthmic or sebaceous duct CK subset. The presence of CK17 and the absence of CK10 in keratocysts are in keeping with the CK composition of keratinous cysts differentiating toward the follicular isthmus or the short sebaceous duct.18,19
REVIEW OF THE LITERATURE A careful review of published reports of buccal mucosal epidermoid cysts disclosed 1 earlier example of keratocyst.22 We made exception to the acceptance of 2 unconvinced cases.23,24 The previous 3 lesions in the literature plus the present case 1 occurred in middleaged men (average 59 years, range 43-72 years) who had a 3 cm fluctuant mass around the parotid papilla, 2 of each side.8,9,22 Our case 2 was a latent form. A
submucosal cyst was confined to the oral aspect of the buccinator muscle and unrelated to the parotid gland. Excluding case 2, there was no history of trauma. The patients did not fulfill the diagnostic criteria for nevoid basal cell carcinoma syndrome (NBCCS). After simple enucleation, none experienced recurrence. Histologically, a collapsed and folded unilocular cyst lacked the formation of the opening pore. All lesions revealed features of OKC, but satellite microcysts, solid epithelial rests, and basal budding were absent. The present case 1 is the first polycystic variety. The fibrous wall was uninflamed and often included mucous salivary glands which were not truly a part of the lesion.8,9 Skin elements, such as pigmented epidermis, pilosebaceous structure, and sweat glands, were not present. DISCUSSION The diagnosis of OKC is based purely on its specific histologic criteria.20 This warrants the designation of peripheral OKC in a rare subset of gingival cyst of the
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Fig. 4. Follicular isthmus of the skin, showing the isthmic-type keratinization (a) and expressing CK17 suprabasally (b). Gland side of a sebaceous duct of the buccal mucosa, showing an undulated parakeratin surface (c) and a suprabasal expression of CK17 (d). Note a palisaded basal layer. a, c, Hematoxylin and eosin stain, original magnifications ⫻400; b, d, immunostaining, original magnifications ⫻400.
adult.12 These lesions probably influenced the respective authors to automatically consider an extragingival keratocyst in the buccal mucosa with the morphology of OKC to be “odontogenic.”8,9 However, the buccal mucosa can be problematic to permit the definitive diagnosis of OKC in the absence of other evidence of an odontogenic origin. The site of predilection of keratocysts is apparently unrelated to lines of closure of embryonic fusion planes, thus precluding a buccal mucosal manifestation of a common dermoid-epidermoid cyst spectrum. Interestingly enough, Greene25 in 1965 theorized that epidermoid cysts of the buccal mucosa may be derived from the entrapment of odontogenic epithelium. This “odontogenic inclusion cyst” concept merits consideration in the pathogenesis of keratocyst. As proposed in OKC,20 the dental lamina rests that are displaced and persist in the buccal mucosa during odontogenesis may be a candidate. There is an important finding in the embryologic literature that the vestibular lamina reiteratively integrates into the dental lamina in the upper molar areas distal to the parotid duct.26 In concert with the fact that the vestibular lamina is involved in the formation of the buccal sulcus and mucosa,1,26,27 this observation could explain why keratocysts are uniformly centered around the parotid papilla.7,8,22 Al-
though the onset in late-middle-aged and elderly patients argues against a developmental anomaly, the available data, combined with the evidence from the clinically occult nature of present case 2, suggest that keratocysts were growing slowly and have been present but unnoticed for several decades. This also appears to hold true for peripheral ameloblastomas of the buccal mucosa.1 Taken all together, a buccal mucosal keratocyst seems to be analogous to OKC despite heterotopia. It is not surprising that keratocysts of epidermal origin may occur ectopically in the buccal mucosa. Three dermatologic conditions in the adults are most telling: Sebaceous glands are a variation of normal,28 sebaceous pathoses are not uncommon,28 and hair follicles are a rare but well documented phenomenon.29,30 An even more interesting buccal mucosal lesion is an epidermal choristoma composed of melanin-laden epidermis and dermal adnexal structures.31 Basal cell carcinomas could also be included in this setting.1,15 Exclusive of sebaceous cells of the latter, keratocyst and steatocystoma simplex28,32 share many histologic characteristics in common. Both cysts are similar in the CK pattern (CK17 positive, CK10 negative).19 Of further importance is a cutaneous keratocyst (CKC) that is more prevalent in a patient with NBCCS than in a patient without.7,12,33-36 The clinical behavior
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of keratocysts at 2 sites (skin vs. jawbone) is quite different, but CKC, either congenital or acquired, is acknowledged as a cutaneous counterpart of OKC in the dermatologic literarture.35,36 By analogy, a revised interpretation would be that CKC has its parallel in the buccal mucosal keartocyst. Taking all of these findings into consideration, a sporadic keratocyst of the buccal mucosa with a typical morphology of OKC is not necessarily “odontogenic.” As proposed in CKC,35 keratocysts may have an origin from the isthmus of an abortive hair follicle or from the associated short sebaceous duct in the buccal mucosa. If so, the almost universal absence of pilosebaceous units undoubtedly accounts for the rarity of keratocyst in a buccal mucosal location.29-31 In conclusion, any attempt to explain whether an enigmatic keratocyst of the buccal mucosa represents a true equivalent to OKC or a mucosal analogue of CKC would be sheer conjecture. There are not enough cases of CKC in the literature for valid comparative analysis.35,36 For these reasons, we favor a common name of “mucosal keratocyst.” The buccal mucosa is a unique site where the questionable odontogenic lesions may be encountered: Just as peripheral ameloblastoma versus basal cell carcinoma is a subject of protracted controversy,1,11 so OKC versus CKC is a newcomer of diagnostic dilemma. REFERENCES 1. Ide F. Peripheral ameloblastoma of the buccal mucosa. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;109:653-4. 2. Ramnarayan K, Nayak RG, Kavalam AG. Peripheral ameloblastoma. Int J Oral Surg 1985;14:300-1. 3. Bonfils P, Aubert P, Garnault M, Trotoux J. Ameloblastoma of the pterygomaxillary fossa. Apropos of a case and review of the literature. Ann Otolaryngol 1988;105:477-9. French with English abstract. 4. Takahashi Y, Tanaka K, Kayano T, Iida O, Miyazawa M, Enomoto S. Tumor mass showing the histological findings of ameloblastoma of the submandibular region: report of a case. Jpn J Oral Maxillofac Surg 1989;35:415-22. Japanese with English abstract. 5. Sanada E, Hasegawa T, Koyama M, Mabuchi K, Fujita S, Hyo Y, et al. A case of peripheral ameloblastoma in the pterygomandibular space. Immunohistochemical investigations. Jpn J Oral Maxillofac Surg 1989;35:1599-605. Japanese with English abstract. 6. Satoh H, Fukuta Y, Izumisawa M, Ohya T, Kudo K, Takeda Y. A case of epidermoid cyst in the pterygomandibular space. Jpn J Oral Maxillofac Surg 1998;44:76-8. Japanese with English abstract. 7. Valter K, Pavelic B, Katanec D, Sokler K, Galic N, Segovic S, et al. Evaluation of sporadic cases of odontogenic keratocysts in multicentric study. Coll Antropol 2002;26S:177-82. 8. Tanaka K, Yunoki H, Muroi Y, Haeniwa H, Horii K, Kakudo K. A case of a lesion of the cheek histopathologically resembling keratocystic odontogenic tumor. Jpn J Oral Maxillofac Surg 2008;54:440-4. Japanese with English abstract.
OOOOE November 2010 9. Precheur HV, Krolls SO. An unusual presentation of an odontogenic keratocyst in the buccal space: case report. J Oral Maxillofac Surg 2009;67:2513-5. 10. Gopalakrishnan R, Koutlas IG, Schauer GM, Schnitker G. Dental (odontogenic) choristoma of the tongue. J Oral Maxillofac Surg 2009;67:1135-8. 11. Philipsen HP, Reichart PA, Nikai H, Takata T, Kudo Y. Peripheral ameloblastoma: biological profile based on 160 cases from the literature. Oral Oncol 2001;37:17-27. 12. Ide F, Mishima K, Saito I, Kusama K. Rare peripheral odontogenic tumors: report of 5 cases and comprehensive review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;106:e22-8. 13. Ide F, Saito I, Horie N, Shimoyama T. Orthokeratinized odontogenic cyst of the mandible with heterotopic cartilage. Head Neck Pathol 2009;3:150-2. 14. Kusama K, Katayama Y, Oba K, Ishige T, Kebusa Y, Okazawa J, et al. Expression of hard ␣-keratins in pilomatrixoma, craniopharyngioma, and calcifying odontogenic cyst. Am J Clin Pathol 2005;123:376-81. 15. 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. 16. Okamoto E, Kikuchi K, Miyazaki Y, Gonzalez-Alva P, Oku Y, Tanaka A, et al. Significance of podoplanin expression in keratocystic odontogenic tumor. J Oral Pathol Med 2010;39:110-4. 17. Koizumi Y. Odontogenic keratocyst, orthokeratinized odontogenic cyst and epidermal cyst: an immunohistochemical study including markers of proliferation, cytokeratin and apoptosis related factors. Int J Oral Med Sci 2004;2:14-22. 18. Ohnishi T, Watanabe S. Immunohistochemical observation of cytokeratins in keratinous cysts including plantar epidermoid cyst. J Cutan Pathol 1999;26:424-9. 19. Kurokawa I, Nishimura K, Hakamada A, Isoda K, Yamanaka K, Mizutani H, et al. Cutaneous dermoid cyst: cytokeratin and filaggrin expression suggesting differentiation toward follicular infundibulum and mature sebaceous gland. Oncol Rep 2006; 16:295-9. 20. Ide F, Horie N, Shimoyama T, Saito I, Tanaka A, Kusama K. Infrequent clinicopathologic features of keratocystic odontogenic tumour: a 29-year multi-institutional retrospective review. Oral Surg 2009;2:1-9. 21. Schirren CG, Burgdorf WHC, Sander CA, Plewig G. Fetal and adult hair follicle. An immunohistochemical study of anticytokeratin antibodies in formalin-fixed and paraffin-embedded tissue. Am J Dermatopathol 1997;19:334-40. 22. Imai T, Ohsawa M, Ohkubo T, Okamoto K, Shibata T. A case of epidermoid cyst in the oral buccal mucosa. Proc Takayama Red Cross Hosp 2006;30:40-3. Japanese with English abstract. 23. Gutmann J, Cifuentes C, Gandulfo P, Guesalaga F. Intradermal nevus associated with epidermoid cyst in the mucous membrane of the cheek. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1978;45:76-82. 24. Sakamoto H, Hayashi K, Asakura A, Suzuki K, Otozura N, Kamiyama T, et al. [A case of two epidermoid cysts in the cheek]. Jpn J Oral Surg 1981;27:1061-5. Japanese. 25. Greene GW. Dental granuloma, odontogenic cysts, and nonodontogenic cysts. In: Tiecke RW, editor. Oral pathology. New York: McGraw-Hill; 1965. p. 193-212. 26. Hovorakova M, Lesot H, Peterka M, Peterkova R. The developmental relationship between the deciduous dentition and the oral vestibule in human embryos. Anat Embryol 2005;209:303-13.
OOOOE Volume 110, Number 5 27. Hovorakova M, Lesot H, Vonesch J-L, Peterka M, Peterkova R. Early development of the lower deciduous dentition and oral vestibule in human embryos. Eur J Oral Sci 2007;115:280-7. 28. Daley T. Pathology of intraoral sebaceous glands. J Oral Pathol Med 1993;22:241-5. 29. Miles AEW. A hair follicle in human cheek mucosa. Proc R Soc Med 1960;53:527-8. 30. Saku T, Dohhara Y, Yamashita S, Hashimoto K. [Buccal polyp associated with heterotopic dermal appendages: report of a case]. Jpn J Oral Surg 1978;24:957-60. Japanese. 31. Chi AC, Mapes IL, Javed T, Neville BW. Epidermal choristoma of the oral cavity: report of 2 cases of an extremely rare entity. J Oral Maxillofac Surg 2010;68:451-5. 32. Olsen DB, Mostofi RS, Lagrotteria LB. Steatocystoma simplex in the oral cavity: a previously undescribed condition. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1988;66:605-7. 33. Lehnert K. [Multiple cysts of the jaws in athermoa of the oral mucosa and hyperkeratotic skin changes: case reports on the etiology of the cysts of the jaws]. Dtsch Zahnarztl Z 1955;10: 214-9. German.
Ide et al. e47 34. Sekimoto K, Oguchi T, Fujita T, Takimoto A, Nakanishi K, Shimada K. [A case of multiple epidermoid cysts of the skin including the jawbone]. J Jpn Stomatol Soc 1972;21:781-9. Japanese. 35. Fernandez-Flores A. Cutaneous keratocyst: a renaming as isthmic-anagenic cyst proposal. Am J Dermatopathol 2008;30:87-9. 36. Motegi S, Nagai Y, Tamura A, Ishikawa O. Multiple skin cysts in nevoid basal cell carcinoma syndrome: a case report and review of the literature. Dermatology 2008;216:159-62.
Reprint requests: Fumio Ide, DDS, PhD Division of Pathology Department of Diagnostic and Therapeutic Sciences Meikai University School of Dentistry 1-1 Keyakidai, Sakado, Saitama 350-0283 Japan [email protected]
Odontogenic keratocyst (OKC) of the buccal mucosa, the diagnosis of which is based on subjective histologic evaluation, is a controversial entity of questionable existence. This report describes 2 rare cases of parakeratinized cyst arising from the buccal mucosa. Case 1 was a 60-year-old man with a 3-cm cyst and case 2 was a 16-year-old boy with a microcyst incidentally discovered on histology. Both lesions were essentially identical in histologic appearance and immunophenotype to intraosseous and gingival OKC, but they were clearly different from orthokeratinized odontogenic cysts and buccal mucosal epidermoid cysts. Step sections failed to reveal any kind of odontogenic tissue or skin adnexa in the cyst wall. These microscopic characteristics reflexively lead to the diagnosis of OKC, if the extragingival occurrence in the buccal mucosa cannot be considered. An alternative nonodontogenic origin includes a keratocyst of the skin, ie, an unusual mucosal presentation of cutaneous keratocyst. Because its true nature, either odontogenic or epidermal, cannot be conclusively proven at this time, we propose a more descriptive and noncommittal term, “mucosal keratocyst,” for a particular cyst in a buccal location that is morphologically indistinguishable from OKC. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;110:e42-e47)
Cysts and tumors arising from epithelial structures and remnants associated with the development of teeth are conceptualized as “odontogenic.” In addition to the ordinary central processes, uncommon lesions that occur solely in the soft tissues overlying the alveolar bone are referred to as “peripheral.” According to these definitions, odontogenic cysts/tumors are exclusive to 2 anatomic areas: intraosseous in the jaws and extraosseous in the gingiva. There are, however, a few reports of peripheral lesions of ameloblastoma,1-5 odontogenic keratocyst (OKC),6-9 and odontoma1,10 in extragnathic locations, and the buccal mucosa is by far the most common site.1 No rationale for this peculiar topoa
Associate Professor, Division of Pathology, Department of Diagnostic and Therapeutic Sciences, Meikai University School of Dentistry; and Department of Pathology, Tsurumi University School of Dental Medicine. b Assistant Professor, Division of Pathology, Department of Diagnostic and Therapeutic Sciences, Meikai University School of Dentistry. c Research Associate, Division of Pathology, Department of Diagnostic and Therapeutic Sciences, Meikai University School of Dentistry. d Associate Professor, Department of Pathology, Tsurumi University School of Dental Medicine. e Professor and Chairman, Department of Pathology, Tsurumi University School of Dental Medicine. f Professor and Chairman, Division of Pathology, Department of Diagnostic and Therapeutic Sciences, Meikai University School of Dentistry. Received for publication Apr 7, 2010; returned for revision May 19, 2010; accepted for publication May 31, 2010. 1079-2104/$ - see front matter © 2010 Published by Mosby, Inc. doi:10.1016/j.tripleo.2010.05.073
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graphic predilection can be offered other than a general theory of embryonic mishap of odontogenesis.1 With the exception of rare odontomas in which the formation of dental hard tissues takes place,1,10 what can be considered to be good evidence of an odontogenic origin is open to speculation, and an extragingival peripheral ameloblastoma is regarded by some to be a nonentity.11 In the present study, 2 examples of mucosal “parakeratinized cyst,” abbreviated “keratocyst,” are presented originating within the buccal mucosa; they mimicked OKC in their histologic and immunohistochemical features but not in location. Confronting this debatable entity prompted us to review and discuss the origin and nature of a buccal mucosal keratocyst. CASE REPORTS Case 1 A 60-year-old man, fit and well, appeared with an 8-year history of a painless swelling of the left buccal mucosa. Posterior to the parotid papilla was a 3 ⫻ 2 ⫻ 2 cm cystic tumor in the mucosal side of the buccinator muscle. The surface erythematous area coincided with the occlusal line when his upper denture was inserted (Fig. 1, a). The mass was removed in 1988 and histologically reported as an epidermoid cyst. Recurrence has not been observed. Microscopically, a multilocular cyst had the conventional OKC lining (Fig. 1, b and c). Focally, a small keratin granuloma was present. Mucous salivary lobules and striated muscle bundles were also sampled.
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Fig. 1. Mucosal keratocysts of case 1 (a-c) and case 2 (d-f). a, Intraoral photograph of case 1, showing a mass in the left buccal mucosa. b, Whole-mount section of a collapsed multilocular cyst (arrows), containing mucous salivary lobules (arrowheads) (hematoxylin and eosin stain [HE], original magnification ⫻3). c, Epithelial lining diagnostic of odontogenic keratocyst (HE, original magnification ⫻400). d, Scanning view of case 2, showing a rounded microcyst, mucous salivary glands (arrowhead) and a foreign body granuloma (arrow) (HE, original magnification ⫻3.5). e, Epithelial lining suggestive of odontogenic keratocyst (HE, original magnification ⫻400). f, Cholesterol clefts forming part of a keratin granuloma (HE, original magnification ⫻100).
Case 2 A 16-year-old boy in good health had a 5 mm nodule in the right buccal mucosa near the parotid papilla which appeared after accidentally biting his cheek. The histologic diagnosis in 1996 was traumatic fibroma with a salivary duct cyst. The patient declined subsequent follow-up. A chance microscopic finding of interest was a unilocular microcyst (⬍3 mm), the lining of which showed features similar to those described in case 1, with the exception of a mildly palisaded basal layer (Fig. 1 d and e). Likewise, a granulomatous response to keratin and cholesterol was seen (Fig. 1, f). This latent lesion mimicked a satellite microcyst in the wall of OKC.
Immunohistochemical findings Immunoprofiles were compared among keratocysts (cases 1 and 2), central and peripheral OKC (n ⫽ 3 each),12 orthokeratinized odontogenic cysts (OOC; n ⫽ 3),13 and buccal mucosal epidermoid cysts (EC; n ⫽ 3). Normal adult skin and sebaceous hyperplasia of the buccal mucosa were included as reference tissues. Cytokeratin (CK) 10 (DE-K10; DakoCytomation, Carpinteria, CA; 1:50), CK16 (LL026; Santa Cruz, Santa Cruz, CA; 1:50), CK17 (E3; Dako; 1:20), CK19 (RCK108, Dako; 1:20), hard ␣-keratin (polyclonal antibody against human hair keratins; 1:400),14 Bcl-2 (124; Dako; 1:50), D2-40 (Dako; 1:50), and Ki-67 (MIB-1; Dako; 1:20) were used. Details of immunohistochemical staining appear in our previous reports.14-16
There was no difference in the CK pattern (CK17 positive and CK10 negative) between keratocysts and OKC,8,17 and OOC and EC had the opposite staining results.8,17-19 In keratocysts and OKC, whole epithelial layers in the thin lining of ⬍5 cells were intensely positive for CK17, whereas the basal and sometimes parabasal layers in the thick lining of ⬎6-8 cells looked faintly stained with CK17 (Fig. 2). The CK10 stainability in OOC and EC never included the basal cells. CK16 reacted with the suprabasal layers of keratocyst, OOC, and EC in general, and in OKC the positive staining was confined to the parakeratin surface. CK19 left all types of cysts unstained. Similarly, hard ␣-keratin that is present in hair shafts as well as in shadow and ghost cells14 was absent. There was an impressive basal cell expression for Bcl-2 and D2-40 in keratocyst and OKC.12,16,17,20 Also, both cysts revealed a unique parabasal onset of the Ki-67 labeling (Fig. 3). In marked contrast, these 3 markers were essentially negative in the lining of OOC and EC, either thin or thick (data not shown).16,17 As a result of the present study, OOC and EC are equal in immunophenotype. Because CK16 is a minor member of the CK set of OKC, keratocyst and OKC cannot be differentiated by their expression patterns of antibodies used. In sections of control skin, the isthmus of a hair follicle and the sebaceous duct opening into a follicle showed a refractile parakeratotic surface and a distinguished basal layer (Fig. 4, a). They had the CK17-positive (in the suprabasal layer; Fig.
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Fig. 2. Cytokeratin (CK) profile of mucosal keratocysts (cases 1 and 2), central (cOKC) and peripheral (pOKC) odontogenic keratocysts, and orthokeratinized odontogenic cysts (OOC) (immunostaining, original magnifications ⫻400).
Fig. 3. Comparative immunohistochemistry of D2-40, Bcl-2, and Ki-67 between mucosal keratocysts (cases 1 and 2), and central (cOKC) and peripheral (pOKC) odontogenic keratocysts (immunostaining, original magnifications ⫻400).
4, b) and CK10-negative phenotype.18,19,21 Both areas expressed none of the remaining antibodies tested. The same profile was apparent in the lobular side of the ducts of hyperplastic sebaceous glands in the buccal mucosa (Fig. 4, c and d). Referring to cutaneous keratinous cysts,17-19 CK10 is linked to the epidermal or infundibular keratinization and CK17 belongs to the isthmic or sebaceous duct CK subset. The presence of CK17 and the absence of CK10 in keratocysts are in keeping with the CK composition of keratinous cysts differentiating toward the follicular isthmus or the short sebaceous duct.18,19
REVIEW OF THE LITERATURE A careful review of published reports of buccal mucosal epidermoid cysts disclosed 1 earlier example of keratocyst.22 We made exception to the acceptance of 2 unconvinced cases.23,24 The previous 3 lesions in the literature plus the present case 1 occurred in middleaged men (average 59 years, range 43-72 years) who had a 3 cm fluctuant mass around the parotid papilla, 2 of each side.8,9,22 Our case 2 was a latent form. A
submucosal cyst was confined to the oral aspect of the buccinator muscle and unrelated to the parotid gland. Excluding case 2, there was no history of trauma. The patients did not fulfill the diagnostic criteria for nevoid basal cell carcinoma syndrome (NBCCS). After simple enucleation, none experienced recurrence. Histologically, a collapsed and folded unilocular cyst lacked the formation of the opening pore. All lesions revealed features of OKC, but satellite microcysts, solid epithelial rests, and basal budding were absent. The present case 1 is the first polycystic variety. The fibrous wall was uninflamed and often included mucous salivary glands which were not truly a part of the lesion.8,9 Skin elements, such as pigmented epidermis, pilosebaceous structure, and sweat glands, were not present. DISCUSSION The diagnosis of OKC is based purely on its specific histologic criteria.20 This warrants the designation of peripheral OKC in a rare subset of gingival cyst of the
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Fig. 4. Follicular isthmus of the skin, showing the isthmic-type keratinization (a) and expressing CK17 suprabasally (b). Gland side of a sebaceous duct of the buccal mucosa, showing an undulated parakeratin surface (c) and a suprabasal expression of CK17 (d). Note a palisaded basal layer. a, c, Hematoxylin and eosin stain, original magnifications ⫻400; b, d, immunostaining, original magnifications ⫻400.
adult.12 These lesions probably influenced the respective authors to automatically consider an extragingival keratocyst in the buccal mucosa with the morphology of OKC to be “odontogenic.”8,9 However, the buccal mucosa can be problematic to permit the definitive diagnosis of OKC in the absence of other evidence of an odontogenic origin. The site of predilection of keratocysts is apparently unrelated to lines of closure of embryonic fusion planes, thus precluding a buccal mucosal manifestation of a common dermoid-epidermoid cyst spectrum. Interestingly enough, Greene25 in 1965 theorized that epidermoid cysts of the buccal mucosa may be derived from the entrapment of odontogenic epithelium. This “odontogenic inclusion cyst” concept merits consideration in the pathogenesis of keratocyst. As proposed in OKC,20 the dental lamina rests that are displaced and persist in the buccal mucosa during odontogenesis may be a candidate. There is an important finding in the embryologic literature that the vestibular lamina reiteratively integrates into the dental lamina in the upper molar areas distal to the parotid duct.26 In concert with the fact that the vestibular lamina is involved in the formation of the buccal sulcus and mucosa,1,26,27 this observation could explain why keratocysts are uniformly centered around the parotid papilla.7,8,22 Al-
though the onset in late-middle-aged and elderly patients argues against a developmental anomaly, the available data, combined with the evidence from the clinically occult nature of present case 2, suggest that keratocysts were growing slowly and have been present but unnoticed for several decades. This also appears to hold true for peripheral ameloblastomas of the buccal mucosa.1 Taken all together, a buccal mucosal keratocyst seems to be analogous to OKC despite heterotopia. It is not surprising that keratocysts of epidermal origin may occur ectopically in the buccal mucosa. Three dermatologic conditions in the adults are most telling: Sebaceous glands are a variation of normal,28 sebaceous pathoses are not uncommon,28 and hair follicles are a rare but well documented phenomenon.29,30 An even more interesting buccal mucosal lesion is an epidermal choristoma composed of melanin-laden epidermis and dermal adnexal structures.31 Basal cell carcinomas could also be included in this setting.1,15 Exclusive of sebaceous cells of the latter, keratocyst and steatocystoma simplex28,32 share many histologic characteristics in common. Both cysts are similar in the CK pattern (CK17 positive, CK10 negative).19 Of further importance is a cutaneous keratocyst (CKC) that is more prevalent in a patient with NBCCS than in a patient without.7,12,33-36 The clinical behavior
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of keratocysts at 2 sites (skin vs. jawbone) is quite different, but CKC, either congenital or acquired, is acknowledged as a cutaneous counterpart of OKC in the dermatologic literarture.35,36 By analogy, a revised interpretation would be that CKC has its parallel in the buccal mucosal keartocyst. Taking all of these findings into consideration, a sporadic keratocyst of the buccal mucosa with a typical morphology of OKC is not necessarily “odontogenic.” As proposed in CKC,35 keratocysts may have an origin from the isthmus of an abortive hair follicle or from the associated short sebaceous duct in the buccal mucosa. If so, the almost universal absence of pilosebaceous units undoubtedly accounts for the rarity of keratocyst in a buccal mucosal location.29-31 In conclusion, any attempt to explain whether an enigmatic keratocyst of the buccal mucosa represents a true equivalent to OKC or a mucosal analogue of CKC would be sheer conjecture. There are not enough cases of CKC in the literature for valid comparative analysis.35,36 For these reasons, we favor a common name of “mucosal keratocyst.” The buccal mucosa is a unique site where the questionable odontogenic lesions may be encountered: Just as peripheral ameloblastoma versus basal cell carcinoma is a subject of protracted controversy,1,11 so OKC versus CKC is a newcomer of diagnostic dilemma. REFERENCES 1. Ide F. Peripheral ameloblastoma of the buccal mucosa. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;109:653-4. 2. Ramnarayan K, Nayak RG, Kavalam AG. Peripheral ameloblastoma. Int J Oral Surg 1985;14:300-1. 3. Bonfils P, Aubert P, Garnault M, Trotoux J. Ameloblastoma of the pterygomaxillary fossa. Apropos of a case and review of the literature. Ann Otolaryngol 1988;105:477-9. French with English abstract. 4. Takahashi Y, Tanaka K, Kayano T, Iida O, Miyazawa M, Enomoto S. Tumor mass showing the histological findings of ameloblastoma of the submandibular region: report of a case. Jpn J Oral Maxillofac Surg 1989;35:415-22. Japanese with English abstract. 5. Sanada E, Hasegawa T, Koyama M, Mabuchi K, Fujita S, Hyo Y, et al. A case of peripheral ameloblastoma in the pterygomandibular space. Immunohistochemical investigations. Jpn J Oral Maxillofac Surg 1989;35:1599-605. Japanese with English abstract. 6. Satoh H, Fukuta Y, Izumisawa M, Ohya T, Kudo K, Takeda Y. A case of epidermoid cyst in the pterygomandibular space. Jpn J Oral Maxillofac Surg 1998;44:76-8. Japanese with English abstract. 7. Valter K, Pavelic B, Katanec D, Sokler K, Galic N, Segovic S, et al. Evaluation of sporadic cases of odontogenic keratocysts in multicentric study. Coll Antropol 2002;26S:177-82. 8. Tanaka K, Yunoki H, Muroi Y, Haeniwa H, Horii K, Kakudo K. A case of a lesion of the cheek histopathologically resembling keratocystic odontogenic tumor. Jpn J Oral Maxillofac Surg 2008;54:440-4. Japanese with English abstract.
OOOOE November 2010 9. Precheur HV, Krolls SO. An unusual presentation of an odontogenic keratocyst in the buccal space: case report. J Oral Maxillofac Surg 2009;67:2513-5. 10. Gopalakrishnan R, Koutlas IG, Schauer GM, Schnitker G. Dental (odontogenic) choristoma of the tongue. J Oral Maxillofac Surg 2009;67:1135-8. 11. Philipsen HP, Reichart PA, Nikai H, Takata T, Kudo Y. Peripheral ameloblastoma: biological profile based on 160 cases from the literature. Oral Oncol 2001;37:17-27. 12. Ide F, Mishima K, Saito I, Kusama K. Rare peripheral odontogenic tumors: report of 5 cases and comprehensive review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;106:e22-8. 13. Ide F, Saito I, Horie N, Shimoyama T. Orthokeratinized odontogenic cyst of the mandible with heterotopic cartilage. Head Neck Pathol 2009;3:150-2. 14. Kusama K, Katayama Y, Oba K, Ishige T, Kebusa Y, Okazawa J, et al. Expression of hard ␣-keratins in pilomatrixoma, craniopharyngioma, and calcifying odontogenic cyst. Am J Clin Pathol 2005;123:376-81. 15. 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. 16. Okamoto E, Kikuchi K, Miyazaki Y, Gonzalez-Alva P, Oku Y, Tanaka A, et al. Significance of podoplanin expression in keratocystic odontogenic tumor. J Oral Pathol Med 2010;39:110-4. 17. Koizumi Y. Odontogenic keratocyst, orthokeratinized odontogenic cyst and epidermal cyst: an immunohistochemical study including markers of proliferation, cytokeratin and apoptosis related factors. Int J Oral Med Sci 2004;2:14-22. 18. Ohnishi T, Watanabe S. Immunohistochemical observation of cytokeratins in keratinous cysts including plantar epidermoid cyst. J Cutan Pathol 1999;26:424-9. 19. Kurokawa I, Nishimura K, Hakamada A, Isoda K, Yamanaka K, Mizutani H, et al. Cutaneous dermoid cyst: cytokeratin and filaggrin expression suggesting differentiation toward follicular infundibulum and mature sebaceous gland. Oncol Rep 2006; 16:295-9. 20. Ide F, Horie N, Shimoyama T, Saito I, Tanaka A, Kusama K. Infrequent clinicopathologic features of keratocystic odontogenic tumour: a 29-year multi-institutional retrospective review. Oral Surg 2009;2:1-9. 21. Schirren CG, Burgdorf WHC, Sander CA, Plewig G. Fetal and adult hair follicle. An immunohistochemical study of anticytokeratin antibodies in formalin-fixed and paraffin-embedded tissue. Am J Dermatopathol 1997;19:334-40. 22. Imai T, Ohsawa M, Ohkubo T, Okamoto K, Shibata T. A case of epidermoid cyst in the oral buccal mucosa. Proc Takayama Red Cross Hosp 2006;30:40-3. Japanese with English abstract. 23. Gutmann J, Cifuentes C, Gandulfo P, Guesalaga F. Intradermal nevus associated with epidermoid cyst in the mucous membrane of the cheek. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1978;45:76-82. 24. Sakamoto H, Hayashi K, Asakura A, Suzuki K, Otozura N, Kamiyama T, et al. [A case of two epidermoid cysts in the cheek]. Jpn J Oral Surg 1981;27:1061-5. Japanese. 25. Greene GW. Dental granuloma, odontogenic cysts, and nonodontogenic cysts. In: Tiecke RW, editor. Oral pathology. New York: McGraw-Hill; 1965. p. 193-212. 26. Hovorakova M, Lesot H, Peterka M, Peterkova R. The developmental relationship between the deciduous dentition and the oral vestibule in human embryos. Anat Embryol 2005;209:303-13.
OOOOE Volume 110, Number 5 27. Hovorakova M, Lesot H, Vonesch J-L, Peterka M, Peterkova R. Early development of the lower deciduous dentition and oral vestibule in human embryos. Eur J Oral Sci 2007;115:280-7. 28. Daley T. Pathology of intraoral sebaceous glands. J Oral Pathol Med 1993;22:241-5. 29. Miles AEW. A hair follicle in human cheek mucosa. Proc R Soc Med 1960;53:527-8. 30. Saku T, Dohhara Y, Yamashita S, Hashimoto K. [Buccal polyp associated with heterotopic dermal appendages: report of a case]. Jpn J Oral Surg 1978;24:957-60. Japanese. 31. Chi AC, Mapes IL, Javed T, Neville BW. Epidermal choristoma of the oral cavity: report of 2 cases of an extremely rare entity. J Oral Maxillofac Surg 2010;68:451-5. 32. Olsen DB, Mostofi RS, Lagrotteria LB. Steatocystoma simplex in the oral cavity: a previously undescribed condition. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1988;66:605-7. 33. Lehnert K. [Multiple cysts of the jaws in athermoa of the oral mucosa and hyperkeratotic skin changes: case reports on the etiology of the cysts of the jaws]. Dtsch Zahnarztl Z 1955;10: 214-9. German.
Ide et al. e47 34. Sekimoto K, Oguchi T, Fujita T, Takimoto A, Nakanishi K, Shimada K. [A case of multiple epidermoid cysts of the skin including the jawbone]. J Jpn Stomatol Soc 1972;21:781-9. Japanese. 35. Fernandez-Flores A. Cutaneous keratocyst: a renaming as isthmic-anagenic cyst proposal. Am J Dermatopathol 2008;30:87-9. 36. Motegi S, Nagai Y, Tamura A, Ishikawa O. Multiple skin cysts in nevoid basal cell carcinoma syndrome: a case report and review of the literature. Dermatology 2008;216:159-62.
Reprint requests: Fumio Ide, DDS, PhD Division of Pathology Department of Diagnostic and Therapeutic Sciences Meikai University School of Dentistry 1-1 Keyakidai, Sakado, Saitama 350-0283 Japan [email protected]