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Solid variant of keratocystic odontogenic tumor of the mandible: report of a case with a clear cell component and review of the literature
Vol. 116 No. 5 November 2013
Solid variant of keratocystic odontogenic tumor of the mandible: report of a case with a clear cell component and review of the literature Kenji Kawano, DDS, PhD,a Kazuhiko Okamura, DDS, PhD,b Kenji Kashima, MD, PhD,c Kou Matsuo, DDS, PhD,d Yoshihiro Takahashi, DDS, PhD,e Noriaki Yamamoto, DDS, PhD,e Tatsuyuki Kono, DDS,e and Kazuhiro Kawamura, DDSf Faculty of Medicine, Oita University, Oita, Japan; Fukuoka Dental College, Fukuoka, Japan; and Kyushu Dental College, Fukuoka, Japan
This is a case report on a solid variant of keratocystic odontogenic tumor arising in the mandible, which aggressively infiltrated into the cancelous spaces and involved the periosteal connective tissue of the mandible. The patient was a 57year-old woman with an ill-defined radiolucent lesion having a moth-eaten pattern in the left molar region of the mandible. Computed tomography scans revealed that the tumor penetrated the buccal cortical plate of the mandible. Histologically, the lesion was characterized by multicystic spaces lined with a thin layer of keratinizing squamous epithelium, which contained basal cells with palisaded hyperchromatic nuclei. Lumina were filled with concentric layers of parakeratin. An additional feature was the appearance of a conspicuous clear cell component showing intraluminal papillary proliferation or forming small cord-like nests in the fibrous stroma. The patient underwent segmental mandibulectomy followed by reconstruction using a titanium plate. A 20-year follow-up revealed no recurrence of the tumor. (Oral Surg Oral Med Oral Pathol Oral Radiol 2013;116:e393-e398)
Keratocystic odontogenic tumor (KCOT), formerly termed odontogenic keratocyst, is a neoplasm defined by World Health Organization (WHO) in 2005.1 This tumor comprises a spectrum of histopathological variants, with the single typical cystic lesion at one end, through the single cystic lesion having multiple satellite microcysts and the solid or multicystic variant at the other end. The solid variant of KCOT is an extremely rare neoplasm, and to date only 6 cases have been reported in the literature obtained in English.2-7 The solid variant of KCOT exhibits a solid or multicystic architecture with a parakeratinized epithelial lining.2 This tumor shares histological features with some keratinizing odontogenic lesions, such as acanthomatous ameloblastoma, keratoameloblastoma (KA) and papilliferous KA. KA is a rare variant of ameloblastoma characterized histologically by solid tumor islands resembling follicular ameloblastoma with a
Professor and Head, Department of Dentistry and Oral-Maxillo-Facial Surgery, Faculty of Medicine, Oita University. b Associate Professor, Department of Morphological Biology, Division of Pathology, Fukuoka Dental College. c Associate Professor, Department of Diagnostic Pathology, Faculty of Medicine, Oita University. d Associate Professor, Department of Biosciences, Kyushu Dental College. e Assistant Professor, Department of Dentistry and Oral-Maxillo-Facial Surgery, Faculty of Medicine, Oita University. f PhD Student, Department of Dentistry and Oral-Maxillo-Facial Surgery, Faculty of Medicine, Oita University. Received for publication Nov 21, 2012; returned for revision Feb 18, 2013; accepted for publication Feb 25, 2013. Ó 2013 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2013.02.020
extensive keratinization. Whitt et al.8 reported that there are great histological similarities between solid KCOT and KA. Ide et al.9 suggested a histogenetic relation between these two tumors. Clear cells occur in certain odontogenic tumors such as ameloblastoma, calcifying odontogenic cyst, and calcifying epithelial odontogenic tumors,10 and some authors reported that the presence of clear cells may indicate increased tumor aggressiveness.11,12 To our knowledge, appearance of a clear cell component in KCOT have not been reported previously. The aim of this paper is to report an additional case of solid KCOT, which also presented with a histological feature previously undescribed in the spectrum of KCOT.
CASE REPORT In December 1991, a 57-year-old woman was referred to the Department of Dentistry and Oral-Maxillo-Facial Surgery of the Oita University Hospital because of a swelling in the left mandibular body. She had been aware of the swelling for 2 months. Physical examination showed a hard bony expansion of the alveolus in the left mandibular molar region. On a panoramic radiograph an ill-defined, moth-eaten radiolucent lesion extending from the left canine to the left retromolar area of the mandible was noted (Figure 1). Computed tomography demonstrated perforation of the buccal cortical plate, as well as expansion of the marrow space (Figure 2). Biopsies were performed, and the histopathological diagnosis of “an odontogenic keratocyst with ameloblastomatous proliferation” was made. In March 1992, the patient was admitted to our hospital and underwent resection of the mandible from the left lower canine to the left condyle, followed by reconstruction with a titanium plate. Macroscopically, sections cut from the resected mandible revealed a solid lesion occupying the entire bone marrow
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ORAL AND MAXILLOFACIAL PATHOLOGY e394 Kawano et al.
Fig. 1. Panoramic radiograph of the mandible of the patient at the first visit. An ill-defined, moth-eaten radiolucent lesion extending from the left canine to the left retromolar area of the mandible is observed. space (Figure 3). The cortex of the mandible was penetrated by the lesion and lost its continuity in parts. Microscopical examination of the surgical specimen demonstrated that the lesion was characterized by an admixture of multiple keratinizing cysts of varying size and solid epithelial tumor nests (Figure 4). Keratinizing cysts were lined by a thin layer of parakeratinized squamous epithelium of uniform thickness with a basal layer of palisaded columnar or cuboidal cells (Figure 5). Most cystic spaces were filled with concentric layers of parakeratin, desquamated squamous cells and necrotic material. Solid nests showed central keratinization, and were often in direct continuity with cysts (Figure 5). The epithelium frequently extended downward to the surrounding connective tissue and reached the surface of the cancelous bone. Small cysts and small solid epithelial nests invaded cancelous bone and cortical bone, and involved the periosteal connective tissue of the mandible (Figure 6). Cystic tumor nests often contacted the bone surface and produced bone compression without the appearance of a significant number of osteoclasts. There was a transition from squamous epithelial cells to clear cells in some cyst walls (Figure 7A), and the lining epithelium was composed of clear cells revealing an intraluminal papillary proliferation. In addition, small cord-like nests of clear cells, which showed reversed polarization of the nucleus and subnuclear vacuolization in basal cells, proliferated in a part of the fibrous stroma between cystic structures (Figure 7B and C). Such areas showed histological features similar to clear cell odontogenic carcinoma (CCOC).13 Furthermore, occasional mitotic figures were observed in nests of clear cells (Figure 7C). Diastase-labile Periodic acid-Schiff (PAS)-positive granules were noted in some of the clear cells (Figure 8). The clear cell component was observed only in the center of the tumor but not in the periphery, and occupied a small area of the tumor. No histological features of ameloblastoma, such as subnuclear vacuolization in basal cells or existence of stellate reticulum-like cells, were noted anywhere in the specimen. The postoperative course was uneventful with no signs of recurrence after 20 years.
DISCUSSION In 2005, the WHO Working Group recategorized odontogenic keratocyst as a neoplastic lesion and renamed it
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KCOT1 on the basis of aggressive behavior, high recurrence rate, and molecular genetic features.14,15 Characteristic histological features of KCOT include the existence of satellite cysts, mural proliferation of epithelial nests, and a tendency to extend along the cancelous bone without producing expansion of the cortical plates.14,15 The solid variant of KCOT was first described by Ide et al.2 in 2003. Since that report, only 6 additional cases including our present case have been reported in the English language literature (Table I).3-7 The age of the patients ranged from 38 years to 72 years, with an average of 52 years. Five tumors occurred in the mandible, and 2 in the maxilla. Histopathologically, solid KCOT is characterized by the following features: multiple cysts of various sizes forming a solid neoplasm; and the lining epithelium reveals the typical histological features of KCOT.6 The differential diagnosis includes subtypes of ameloblastoma with keratinization, such as acanthomatous ameloblastoma, KA, and papilliferous KA. Acanthomatous ameloblastoma exhibits squamous metaplasia with keratinization in the center of epithelial follicles. This tumors usually reveals a solid structure, and occasionally exhibits a multicystic structure due to pronounced cystic degeneration of follicles.16 KA and papilliferous KA are extremely rare variants of ameloblastoma. Whitt et al.8 reviewed 13 reported cases of KA and papilliferous KA and divided them into 4 groups: papilliferous histology, simple histology, simple histology with odontogenic keratocyst-like features, and complex histology. Tumors of the third and fourth groups exhibit a strong histological resemblance to solid KCOT. An important point to differentiate solid KCOT from KA is that stellate reticulum-like cells are found in KA but not in KCOT. In the present case, there was no evidence of amelobastic follicles with stellate reticulum-like cells even after meticulous examination of the entire specimen. Papilliferous KA was first described by Pindborg17 as a tumor consisting of keratinizing cysts and tumor islands with a papilliferous appearance. In the present case, there was no papilliferous epithelium in the cyst walls. Therefore, it does not fulfill the criteria of KA and papilliferous KA. Another unique feature of the present case was the appearance of a clear cell component in part of the lesion. Tumors with a clear cell component in the head and neck region can impose serious problems with respect to differential diagnosis. Clear cells are characteristic cellular components of the epithelial lining of lateral periodontal cysts and gingival cysts of the adult, or they may be found as clear cell remainders of dental lamina within the connective tissue of these cysts.18 Clear cells may also occur in certain odontogenic
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Fig. 2. Computed tomography show perforation of the buccal cortical plate and expansion of the marrow space. Soft tissue (A) and hard tissue (B) windows are presented.
Fig. 4. Microscopic findings of the surgically resected material. The lesion consisted of multiple keratinizing cysts of varying size and solid epithelial tumor nests. Hematoxylin and eosin staining, original magnification: 4.
Fig. 3. Macroscopic findings of the surgically resected material. The resected mandible was longitudinally sliced after decalcification (A). Cut sections revealed a solid lesion occupying the entire bone marrow space (B). Large cavities in the #3 and #4 slices are tissue defects produced by biopsies.
tumors such as ameloblastoma, calcifying odontogenic cyst, and calcifying epithelial odontogenic tumor.10 CCOC is histologically characterized by solid sheets or nests of tumor cells comprising biphasic mixtures of 2 distinct cell types, i.e., clear cells and eosinophilic polygonal cells.13 In the present case, the clear cell component formed small cord-like nests without the biphasic pattern, and showed slightly elevated mitotic activity. Tumor nests with clear cells were apparently transformed from the typical components of KCOT, and
exhibited occasional PAS-positive granules in their cytoplasm. Existence of diastase-labile PAS-positive materials indicative of glycogen supported that clear cells were of odontogenic origin.10,12 However, we are uncertain whether the clear cell component of the present case represents a CCOC deriving from a solid KCOT, because clear cells were distributed in only a small area of the histological specimen. Neither local recurrence nor distant metastasis was observed during the 20-year postoperative follow-up. There was no evidence of malignancy in the CCOC-like area, at least on the basis of the clinical outcome of the present case. Since the dominant histological component of the present case was KCOT, we finally diagnosed this lesion as solid variant of KCOT with a clear cell component. Radiologically, most cases of KCOT appear as unilocular radiolucent lesion with a well-defined border, which is frequently scalloped.19 Multilocular
ORAL AND MAXILLOFACIAL PATHOLOGY e396 Kawano et al.
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Fig. 5. Keratinizing cysts were lined by a layer of parakeratinized squamous epithelium with a basal layer of palisaded columnar cells (inset). Solid nests showed central keratinization, and were in direct continuity with cysts. Hematoxylin and eosin staining, original magnification: 40 (inset: 200).
radiolucencies are common in large lesions. Tumors showing multilocular ill-defined radiolucencies with a honeycomb appearance have been reported previously (Table I).2,3 The cases with this unique radiological feature demonstrated aggressive, infiltrative growth into the cancelous bone similar to that seen in ameloblastomas. However, the present case showed an illdefined radiolucency with a moth-eaten pattern, an undescribed variation of the radiographic findings in KCOT. These radiological features may suggest that the present case was a malignant tumor, such as primary intraosseous carcinoma or ameloblastic carcinoma.20 However, histological examination revealed infiltrating tumor nests with characteristics of benign keratinizing cysts even at the periphery of the tumor and marked resorption of cortical bone by direct infiltration of the cystic tumor component. This finding suggested that the radiographically moth-eaten resorption seen in the present case was attributable to the biological nature of the cystic tumor component itself and not to the infiltrating cord-like nests seen in the regions containing the clear cell component. Interestingly, cystic tumor nests produced bone compression without the appearance of a significant number of osteoclasts, suggestive of rapid, aggressive growth of the tumor. Previous laboratory data revealed that KCOT secrets larger amounts of interleukin 1a and pro-matrix metalloproteinase-9 (proMMT-9) than dentigerous and radicular cysts, leading to increased bone resorption.14,15 The solid counterparts of other cystic odontogenic lesions represent more aggressive entities. For example, calcifying odontogenic cyst was renamed calcifying cystic odontogenic tumor (CCOT) by WHO in 2005,21
Fig. 6. Cystic tumor nests contacted the bone surface and produced bone compression without an obvious increase in osteoclasts. Small cystic and solid tumor nests invaded intraosseous spaces of the mandibular cortex, and reached the periosteal connective tissue (+: periostium). Hematoxylin and eosin staining, original magnification: 20.
and the solid variant of this lesion was categorized as a separate more aggressive entity called the dentinogenic ghost cell tumor. Since only seven cases of the solid variant of KCOT have been documented in the literature to date including the present case, it is unknown whether solid KCOT should be categorized as a separate entity different from cystic KCOT. Although solid KCOT showed more aggressive and infiltrative growth into the cortical jaw bone on microscopic observation, some reports described nonaggressive cases of solid KCOT without recurrence even after conservative surgery.5,7 Surgical treatment of solid KCOT includes “shelledout”, enucleation, en-bloc resection, and hemimandibulectomy, depending on the extent of the tumor (Table I). Follow-up records were obtained in 6 cases, including the present case, and recurrence was reported only in one case after conservative surgery.2 Following surgery with resection of adjacent hard tissues, no recurrence was noted during the follow-up periods, which ranged from 6 months to 20 years. Since the solid variant of KCOT has been considered to be more aggressive than the conventional cystic KCOT2-4 and lacks a capsule, conservative enucleation or curettage is not recommended for those tumors showing an ill-
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Fig. 7. A transition from squamous epithelial cells to clear cells was noted in the cyst wall (A). Small cord-like nests of clear cells proliferated in the fibrous stroma between cystic structures (B). These nests showed reversed polarization of nucleus and subnuclear vacuolization in basal cells (C). A mitotic figure can be seen in the clear cell nest (arrow). Hematoxylin and eosin staining, original magnification: (A): 200, (B): 200; (C): 400.
Fig. 8. Diastase-labile PAS-positive granules were seen in clear cells. (A) PAS staining without diastase digestion, (B) PAS staining with diastase digestion, original magnification: (A) and (B): 400.
Table I. Solid variant of keratocystic odontogenic tumor in the English language literature Authors
Age, sex
Site
Radiogram
Ide et al.
49 y, F
LT mandible
Vered et al.3
72 y, M
RT maxilla
Daley et al.4 Iezzi et al.5 Geng et al.6 Shuster et al.7
52 52 38 47
LT mandible LT mandible LT maxilla RT mandible
Multilocular RL Honeycombed RL Multilocular, ill-defined RL Honeycombed appearance Unilocular RL Well-demarcated RL Multilocular ill-defined RL Scalloped, well-defined RL
Present case
57 y, F
LT mandible
Ill-defined, moth-eaten RL
2
y, y, y, y,
M M F M
Treatment
Follow-up
Clear cell
Enucleation En-bloc resection Hemimaxillectomy
R, 3 times NR, 4 y NR, 2 y
No No
”Shelled-out” “Shelled-out” Segmental resection Enucleation, followed by peripheral resection Hemimandibulectomy
ND NR, 6 y NR, 3 y NR, 6 mo
No No No No
NR, 20 y
Yes
Ide’s case showed recurrence 3 times after enucleation, and then no recurrence for 4 years after en-bloc resection. M, male; F, female; y, years; mo, months; LT, left; RT, right; RL, radiolucency; ND, not described; R, recurrence; NR, no recurrence.
ORAL AND MAXILLOFACIAL PATHOLOGY e398 Kawano et al.
defined radiolucency. We believe that resection with a surgical margin in adjacent normal bone, which is usually performed in the case of ameloblastomas, is necessary for the solid variant of KCOT. Identification and characterization of further cases is needed to evaluate the biological behavior of this rare variant of KCOT and to establish appropriate treatment for this tumor. The authors would like to thank Enago (www.enago.jp) for the English language review. REFERENCES 1. Philipsen HP. Keratocystic odontogenic tumour. In: Barnes L, Eveson JW, Reichart PA, Sidransky D, eds. World Health Organization Classification of Tumours. Pathology and Genetics of Head and Neck Tumours. Lyon: IARC Press; 2005:306-307. 2. Ide F, Mishima K, Saito I. Solid-cystic tumor variant of odontogenic keratocyst: an aggressive but benign lesion simulating keratoameloblastoma. Virchows Arch. 2003;442:501-503. 3. Vered M, Buchner A, Dayan D, Shteil M, Laurian A. Solid variant of odontogenic keratocyst. J Oral Pathol Med. 2004;33: 125-128. 4. Daley TD, Multari J, Darling MR. A case report of a solid keratocystic odontogenic tumor: is it the missing link? Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007;103:512-515. 5. Iezzi G, Rubini C, Zizzi A, Aspriello SD, Fioroni M, Piattelli A. Solid variant of keratocystic odontogenic tumour: report of a case. Minerva Stomatol. 2011;60:133-138. 6. Geng N, Ly D, Chen Q-M, et al. Solid variant of keratocystic odontogenic tumor with ameloblastomatous transformation: a case report and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;114:223-229. 7. Shuster A, Shlomi B, Reiser V, Kaplan I. Solid keratocystic odontogenic tumor e report of a nonaggressive case. J Oral Maxillofac Surg. 2012;70:865-870. 8. Whitt JC, Dunlap CL, Sheets JL, Thompson ML. Keratoameloblastoma: a tumor sui generis or a chimera? Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007;104:368-376. 9. Ide F, Ito Y, Muramatsu T, Saito I, Abiko Y. Histogenetic relations between keratoameloblastoma and solid variant of odontogenic keratocyst. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;114:812-813.
OOOO November 2013 10. Hansen LS, Eversole LR, Green TL, Powell NB. Clear cell odontogenic tumor e a new histological variant with aggressive potential. Head Neck Surg. 1985;8:115-123. 11. Waldron CA, Small IA, Silverman H. Clear cell ameloblastoma e an odontogenic carcinoma. J Oral Maxillofac Surg. 1985;43:707-717. 12. Anavi Y, Kaplan I, Citir M, Calderon S. Clear-cell variant of calcifying epithelial odontogenic tumor: clinical and radiological characteristics. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2003;95:331-339. 13. Gnepp DR, ed. Diagnostic Surgical Pathology of the Head and Neck. Philadelphia: Saunders; 2009:814-815. 14. Shear M. The aggressive nature of the odontogenic keratocyst: is it a benign cystic neoplasm? Part 1. Clinical and early experimental evidence of aggressive behaviour. Oral Oncol. 2002;38: 219-226. 15. Shear M. The aggressive nature of the odontogenic keratocyst: is it a benign cystic neoplasm? Part 2. Proliferation and genetic studies. Oral Oncol. 2002;38:323-331. 16. Anneroth G, Hansen LS. Variations in keratinizing odontogenic cysts and tumors. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1982;54:530-546. 17. Pindborg JJ, ed. Pathology of the Dental Hard Tissues. Copenhagen: Munksgaard; 1970:371-376. 18. Wysocki GP, Brannon RB, Gardner DG, Sapp P. Histogenesis of the lateral periodontal cyst and the gingival cyst of the adult. Oral Surg Oral Med Oral Pathol. 1980;50:327-334. 19. Partridge M, Towere JF. The primordial cyst (odontogenic keratocyst): its tumour-like characteristics and behaviour. Br J Oral Maxillofac Surg. 1987;25:271-279. 20. Suei Y, Tanimoto K, Taguchi A, Wada T. Primary intraosseous carcinoma: review of the literature and diagnostic criteria. J Oral Maxillofac Surg. 1994;52:580-583. 21. Praetorius F, Ledesma-Montes C. Calcifying cystic odontogenic tumour. In: Barnes L, Eveson JW, Reichart PA, Sidransky D, eds. World Health Organization Classification of Tumours. Pathology and Genetics of Head and Neck Tumours. Lyon: IARC Press; 2005:313.
Reprint requests: Kenji Kawano, DDS, PhD Department of Dentistry and Oral-Maxillo-Facial Surgery Faculty of Medicine, Oita University 1 Idaigaoka, Hasama-machi, Yufu-shi Oita 879-5593, Japan [email protected]
Solid variant of keratocystic odontogenic tumor of the mandible: report of a case with a clear cell component and review of the literature Kenji Kawano, DDS, PhD,a Kazuhiko Okamura, DDS, PhD,b Kenji Kashima, MD, PhD,c Kou Matsuo, DDS, PhD,d Yoshihiro Takahashi, DDS, PhD,e Noriaki Yamamoto, DDS, PhD,e Tatsuyuki Kono, DDS,e and Kazuhiro Kawamura, DDSf Faculty of Medicine, Oita University, Oita, Japan; Fukuoka Dental College, Fukuoka, Japan; and Kyushu Dental College, Fukuoka, Japan
This is a case report on a solid variant of keratocystic odontogenic tumor arising in the mandible, which aggressively infiltrated into the cancelous spaces and involved the periosteal connective tissue of the mandible. The patient was a 57year-old woman with an ill-defined radiolucent lesion having a moth-eaten pattern in the left molar region of the mandible. Computed tomography scans revealed that the tumor penetrated the buccal cortical plate of the mandible. Histologically, the lesion was characterized by multicystic spaces lined with a thin layer of keratinizing squamous epithelium, which contained basal cells with palisaded hyperchromatic nuclei. Lumina were filled with concentric layers of parakeratin. An additional feature was the appearance of a conspicuous clear cell component showing intraluminal papillary proliferation or forming small cord-like nests in the fibrous stroma. The patient underwent segmental mandibulectomy followed by reconstruction using a titanium plate. A 20-year follow-up revealed no recurrence of the tumor. (Oral Surg Oral Med Oral Pathol Oral Radiol 2013;116:e393-e398)
Keratocystic odontogenic tumor (KCOT), formerly termed odontogenic keratocyst, is a neoplasm defined by World Health Organization (WHO) in 2005.1 This tumor comprises a spectrum of histopathological variants, with the single typical cystic lesion at one end, through the single cystic lesion having multiple satellite microcysts and the solid or multicystic variant at the other end. The solid variant of KCOT is an extremely rare neoplasm, and to date only 6 cases have been reported in the literature obtained in English.2-7 The solid variant of KCOT exhibits a solid or multicystic architecture with a parakeratinized epithelial lining.2 This tumor shares histological features with some keratinizing odontogenic lesions, such as acanthomatous ameloblastoma, keratoameloblastoma (KA) and papilliferous KA. KA is a rare variant of ameloblastoma characterized histologically by solid tumor islands resembling follicular ameloblastoma with a
Professor and Head, Department of Dentistry and Oral-Maxillo-Facial Surgery, Faculty of Medicine, Oita University. b Associate Professor, Department of Morphological Biology, Division of Pathology, Fukuoka Dental College. c Associate Professor, Department of Diagnostic Pathology, Faculty of Medicine, Oita University. d Associate Professor, Department of Biosciences, Kyushu Dental College. e Assistant Professor, Department of Dentistry and Oral-Maxillo-Facial Surgery, Faculty of Medicine, Oita University. f PhD Student, Department of Dentistry and Oral-Maxillo-Facial Surgery, Faculty of Medicine, Oita University. Received for publication Nov 21, 2012; returned for revision Feb 18, 2013; accepted for publication Feb 25, 2013. Ó 2013 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2013.02.020
extensive keratinization. Whitt et al.8 reported that there are great histological similarities between solid KCOT and KA. Ide et al.9 suggested a histogenetic relation between these two tumors. Clear cells occur in certain odontogenic tumors such as ameloblastoma, calcifying odontogenic cyst, and calcifying epithelial odontogenic tumors,10 and some authors reported that the presence of clear cells may indicate increased tumor aggressiveness.11,12 To our knowledge, appearance of a clear cell component in KCOT have not been reported previously. The aim of this paper is to report an additional case of solid KCOT, which also presented with a histological feature previously undescribed in the spectrum of KCOT.
CASE REPORT In December 1991, a 57-year-old woman was referred to the Department of Dentistry and Oral-Maxillo-Facial Surgery of the Oita University Hospital because of a swelling in the left mandibular body. She had been aware of the swelling for 2 months. Physical examination showed a hard bony expansion of the alveolus in the left mandibular molar region. On a panoramic radiograph an ill-defined, moth-eaten radiolucent lesion extending from the left canine to the left retromolar area of the mandible was noted (Figure 1). Computed tomography demonstrated perforation of the buccal cortical plate, as well as expansion of the marrow space (Figure 2). Biopsies were performed, and the histopathological diagnosis of “an odontogenic keratocyst with ameloblastomatous proliferation” was made. In March 1992, the patient was admitted to our hospital and underwent resection of the mandible from the left lower canine to the left condyle, followed by reconstruction with a titanium plate. Macroscopically, sections cut from the resected mandible revealed a solid lesion occupying the entire bone marrow
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ORAL AND MAXILLOFACIAL PATHOLOGY e394 Kawano et al.
Fig. 1. Panoramic radiograph of the mandible of the patient at the first visit. An ill-defined, moth-eaten radiolucent lesion extending from the left canine to the left retromolar area of the mandible is observed. space (Figure 3). The cortex of the mandible was penetrated by the lesion and lost its continuity in parts. Microscopical examination of the surgical specimen demonstrated that the lesion was characterized by an admixture of multiple keratinizing cysts of varying size and solid epithelial tumor nests (Figure 4). Keratinizing cysts were lined by a thin layer of parakeratinized squamous epithelium of uniform thickness with a basal layer of palisaded columnar or cuboidal cells (Figure 5). Most cystic spaces were filled with concentric layers of parakeratin, desquamated squamous cells and necrotic material. Solid nests showed central keratinization, and were often in direct continuity with cysts (Figure 5). The epithelium frequently extended downward to the surrounding connective tissue and reached the surface of the cancelous bone. Small cysts and small solid epithelial nests invaded cancelous bone and cortical bone, and involved the periosteal connective tissue of the mandible (Figure 6). Cystic tumor nests often contacted the bone surface and produced bone compression without the appearance of a significant number of osteoclasts. There was a transition from squamous epithelial cells to clear cells in some cyst walls (Figure 7A), and the lining epithelium was composed of clear cells revealing an intraluminal papillary proliferation. In addition, small cord-like nests of clear cells, which showed reversed polarization of the nucleus and subnuclear vacuolization in basal cells, proliferated in a part of the fibrous stroma between cystic structures (Figure 7B and C). Such areas showed histological features similar to clear cell odontogenic carcinoma (CCOC).13 Furthermore, occasional mitotic figures were observed in nests of clear cells (Figure 7C). Diastase-labile Periodic acid-Schiff (PAS)-positive granules were noted in some of the clear cells (Figure 8). The clear cell component was observed only in the center of the tumor but not in the periphery, and occupied a small area of the tumor. No histological features of ameloblastoma, such as subnuclear vacuolization in basal cells or existence of stellate reticulum-like cells, were noted anywhere in the specimen. The postoperative course was uneventful with no signs of recurrence after 20 years.
DISCUSSION In 2005, the WHO Working Group recategorized odontogenic keratocyst as a neoplastic lesion and renamed it
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KCOT1 on the basis of aggressive behavior, high recurrence rate, and molecular genetic features.14,15 Characteristic histological features of KCOT include the existence of satellite cysts, mural proliferation of epithelial nests, and a tendency to extend along the cancelous bone without producing expansion of the cortical plates.14,15 The solid variant of KCOT was first described by Ide et al.2 in 2003. Since that report, only 6 additional cases including our present case have been reported in the English language literature (Table I).3-7 The age of the patients ranged from 38 years to 72 years, with an average of 52 years. Five tumors occurred in the mandible, and 2 in the maxilla. Histopathologically, solid KCOT is characterized by the following features: multiple cysts of various sizes forming a solid neoplasm; and the lining epithelium reveals the typical histological features of KCOT.6 The differential diagnosis includes subtypes of ameloblastoma with keratinization, such as acanthomatous ameloblastoma, KA, and papilliferous KA. Acanthomatous ameloblastoma exhibits squamous metaplasia with keratinization in the center of epithelial follicles. This tumors usually reveals a solid structure, and occasionally exhibits a multicystic structure due to pronounced cystic degeneration of follicles.16 KA and papilliferous KA are extremely rare variants of ameloblastoma. Whitt et al.8 reviewed 13 reported cases of KA and papilliferous KA and divided them into 4 groups: papilliferous histology, simple histology, simple histology with odontogenic keratocyst-like features, and complex histology. Tumors of the third and fourth groups exhibit a strong histological resemblance to solid KCOT. An important point to differentiate solid KCOT from KA is that stellate reticulum-like cells are found in KA but not in KCOT. In the present case, there was no evidence of amelobastic follicles with stellate reticulum-like cells even after meticulous examination of the entire specimen. Papilliferous KA was first described by Pindborg17 as a tumor consisting of keratinizing cysts and tumor islands with a papilliferous appearance. In the present case, there was no papilliferous epithelium in the cyst walls. Therefore, it does not fulfill the criteria of KA and papilliferous KA. Another unique feature of the present case was the appearance of a clear cell component in part of the lesion. Tumors with a clear cell component in the head and neck region can impose serious problems with respect to differential diagnosis. Clear cells are characteristic cellular components of the epithelial lining of lateral periodontal cysts and gingival cysts of the adult, or they may be found as clear cell remainders of dental lamina within the connective tissue of these cysts.18 Clear cells may also occur in certain odontogenic
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Fig. 2. Computed tomography show perforation of the buccal cortical plate and expansion of the marrow space. Soft tissue (A) and hard tissue (B) windows are presented.
Fig. 4. Microscopic findings of the surgically resected material. The lesion consisted of multiple keratinizing cysts of varying size and solid epithelial tumor nests. Hematoxylin and eosin staining, original magnification: 4.
Fig. 3. Macroscopic findings of the surgically resected material. The resected mandible was longitudinally sliced after decalcification (A). Cut sections revealed a solid lesion occupying the entire bone marrow space (B). Large cavities in the #3 and #4 slices are tissue defects produced by biopsies.
tumors such as ameloblastoma, calcifying odontogenic cyst, and calcifying epithelial odontogenic tumor.10 CCOC is histologically characterized by solid sheets or nests of tumor cells comprising biphasic mixtures of 2 distinct cell types, i.e., clear cells and eosinophilic polygonal cells.13 In the present case, the clear cell component formed small cord-like nests without the biphasic pattern, and showed slightly elevated mitotic activity. Tumor nests with clear cells were apparently transformed from the typical components of KCOT, and
exhibited occasional PAS-positive granules in their cytoplasm. Existence of diastase-labile PAS-positive materials indicative of glycogen supported that clear cells were of odontogenic origin.10,12 However, we are uncertain whether the clear cell component of the present case represents a CCOC deriving from a solid KCOT, because clear cells were distributed in only a small area of the histological specimen. Neither local recurrence nor distant metastasis was observed during the 20-year postoperative follow-up. There was no evidence of malignancy in the CCOC-like area, at least on the basis of the clinical outcome of the present case. Since the dominant histological component of the present case was KCOT, we finally diagnosed this lesion as solid variant of KCOT with a clear cell component. Radiologically, most cases of KCOT appear as unilocular radiolucent lesion with a well-defined border, which is frequently scalloped.19 Multilocular
ORAL AND MAXILLOFACIAL PATHOLOGY e396 Kawano et al.
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Fig. 5. Keratinizing cysts were lined by a layer of parakeratinized squamous epithelium with a basal layer of palisaded columnar cells (inset). Solid nests showed central keratinization, and were in direct continuity with cysts. Hematoxylin and eosin staining, original magnification: 40 (inset: 200).
radiolucencies are common in large lesions. Tumors showing multilocular ill-defined radiolucencies with a honeycomb appearance have been reported previously (Table I).2,3 The cases with this unique radiological feature demonstrated aggressive, infiltrative growth into the cancelous bone similar to that seen in ameloblastomas. However, the present case showed an illdefined radiolucency with a moth-eaten pattern, an undescribed variation of the radiographic findings in KCOT. These radiological features may suggest that the present case was a malignant tumor, such as primary intraosseous carcinoma or ameloblastic carcinoma.20 However, histological examination revealed infiltrating tumor nests with characteristics of benign keratinizing cysts even at the periphery of the tumor and marked resorption of cortical bone by direct infiltration of the cystic tumor component. This finding suggested that the radiographically moth-eaten resorption seen in the present case was attributable to the biological nature of the cystic tumor component itself and not to the infiltrating cord-like nests seen in the regions containing the clear cell component. Interestingly, cystic tumor nests produced bone compression without the appearance of a significant number of osteoclasts, suggestive of rapid, aggressive growth of the tumor. Previous laboratory data revealed that KCOT secrets larger amounts of interleukin 1a and pro-matrix metalloproteinase-9 (proMMT-9) than dentigerous and radicular cysts, leading to increased bone resorption.14,15 The solid counterparts of other cystic odontogenic lesions represent more aggressive entities. For example, calcifying odontogenic cyst was renamed calcifying cystic odontogenic tumor (CCOT) by WHO in 2005,21
Fig. 6. Cystic tumor nests contacted the bone surface and produced bone compression without an obvious increase in osteoclasts. Small cystic and solid tumor nests invaded intraosseous spaces of the mandibular cortex, and reached the periosteal connective tissue (+: periostium). Hematoxylin and eosin staining, original magnification: 20.
and the solid variant of this lesion was categorized as a separate more aggressive entity called the dentinogenic ghost cell tumor. Since only seven cases of the solid variant of KCOT have been documented in the literature to date including the present case, it is unknown whether solid KCOT should be categorized as a separate entity different from cystic KCOT. Although solid KCOT showed more aggressive and infiltrative growth into the cortical jaw bone on microscopic observation, some reports described nonaggressive cases of solid KCOT without recurrence even after conservative surgery.5,7 Surgical treatment of solid KCOT includes “shelledout”, enucleation, en-bloc resection, and hemimandibulectomy, depending on the extent of the tumor (Table I). Follow-up records were obtained in 6 cases, including the present case, and recurrence was reported only in one case after conservative surgery.2 Following surgery with resection of adjacent hard tissues, no recurrence was noted during the follow-up periods, which ranged from 6 months to 20 years. Since the solid variant of KCOT has been considered to be more aggressive than the conventional cystic KCOT2-4 and lacks a capsule, conservative enucleation or curettage is not recommended for those tumors showing an ill-
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CASE REPORT Kawano et al. e397
Fig. 7. A transition from squamous epithelial cells to clear cells was noted in the cyst wall (A). Small cord-like nests of clear cells proliferated in the fibrous stroma between cystic structures (B). These nests showed reversed polarization of nucleus and subnuclear vacuolization in basal cells (C). A mitotic figure can be seen in the clear cell nest (arrow). Hematoxylin and eosin staining, original magnification: (A): 200, (B): 200; (C): 400.
Fig. 8. Diastase-labile PAS-positive granules were seen in clear cells. (A) PAS staining without diastase digestion, (B) PAS staining with diastase digestion, original magnification: (A) and (B): 400.
Table I. Solid variant of keratocystic odontogenic tumor in the English language literature Authors
Age, sex
Site
Radiogram
Ide et al.
49 y, F
LT mandible
Vered et al.3
72 y, M
RT maxilla
Daley et al.4 Iezzi et al.5 Geng et al.6 Shuster et al.7
52 52 38 47
LT mandible LT mandible LT maxilla RT mandible
Multilocular RL Honeycombed RL Multilocular, ill-defined RL Honeycombed appearance Unilocular RL Well-demarcated RL Multilocular ill-defined RL Scalloped, well-defined RL
Present case
57 y, F
LT mandible
Ill-defined, moth-eaten RL
2
y, y, y, y,
M M F M
Treatment
Follow-up
Clear cell
Enucleation En-bloc resection Hemimaxillectomy
R, 3 times NR, 4 y NR, 2 y
No No
”Shelled-out” “Shelled-out” Segmental resection Enucleation, followed by peripheral resection Hemimandibulectomy
ND NR, 6 y NR, 3 y NR, 6 mo
No No No No
NR, 20 y
Yes
Ide’s case showed recurrence 3 times after enucleation, and then no recurrence for 4 years after en-bloc resection. M, male; F, female; y, years; mo, months; LT, left; RT, right; RL, radiolucency; ND, not described; R, recurrence; NR, no recurrence.
ORAL AND MAXILLOFACIAL PATHOLOGY e398 Kawano et al.
defined radiolucency. We believe that resection with a surgical margin in adjacent normal bone, which is usually performed in the case of ameloblastomas, is necessary for the solid variant of KCOT. Identification and characterization of further cases is needed to evaluate the biological behavior of this rare variant of KCOT and to establish appropriate treatment for this tumor. The authors would like to thank Enago (www.enago.jp) for the English language review. REFERENCES 1. Philipsen HP. Keratocystic odontogenic tumour. In: Barnes L, Eveson JW, Reichart PA, Sidransky D, eds. World Health Organization Classification of Tumours. Pathology and Genetics of Head and Neck Tumours. Lyon: IARC Press; 2005:306-307. 2. Ide F, Mishima K, Saito I. Solid-cystic tumor variant of odontogenic keratocyst: an aggressive but benign lesion simulating keratoameloblastoma. Virchows Arch. 2003;442:501-503. 3. Vered M, Buchner A, Dayan D, Shteil M, Laurian A. Solid variant of odontogenic keratocyst. J Oral Pathol Med. 2004;33: 125-128. 4. Daley TD, Multari J, Darling MR. A case report of a solid keratocystic odontogenic tumor: is it the missing link? Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007;103:512-515. 5. Iezzi G, Rubini C, Zizzi A, Aspriello SD, Fioroni M, Piattelli A. Solid variant of keratocystic odontogenic tumour: report of a case. Minerva Stomatol. 2011;60:133-138. 6. Geng N, Ly D, Chen Q-M, et al. Solid variant of keratocystic odontogenic tumor with ameloblastomatous transformation: a case report and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;114:223-229. 7. Shuster A, Shlomi B, Reiser V, Kaplan I. Solid keratocystic odontogenic tumor e report of a nonaggressive case. J Oral Maxillofac Surg. 2012;70:865-870. 8. Whitt JC, Dunlap CL, Sheets JL, Thompson ML. Keratoameloblastoma: a tumor sui generis or a chimera? Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007;104:368-376. 9. Ide F, Ito Y, Muramatsu T, Saito I, Abiko Y. Histogenetic relations between keratoameloblastoma and solid variant of odontogenic keratocyst. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;114:812-813.
OOOO November 2013 10. Hansen LS, Eversole LR, Green TL, Powell NB. Clear cell odontogenic tumor e a new histological variant with aggressive potential. Head Neck Surg. 1985;8:115-123. 11. Waldron CA, Small IA, Silverman H. Clear cell ameloblastoma e an odontogenic carcinoma. J Oral Maxillofac Surg. 1985;43:707-717. 12. Anavi Y, Kaplan I, Citir M, Calderon S. Clear-cell variant of calcifying epithelial odontogenic tumor: clinical and radiological characteristics. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2003;95:331-339. 13. Gnepp DR, ed. Diagnostic Surgical Pathology of the Head and Neck. Philadelphia: Saunders; 2009:814-815. 14. Shear M. The aggressive nature of the odontogenic keratocyst: is it a benign cystic neoplasm? Part 1. Clinical and early experimental evidence of aggressive behaviour. Oral Oncol. 2002;38: 219-226. 15. Shear M. The aggressive nature of the odontogenic keratocyst: is it a benign cystic neoplasm? Part 2. Proliferation and genetic studies. Oral Oncol. 2002;38:323-331. 16. Anneroth G, Hansen LS. Variations in keratinizing odontogenic cysts and tumors. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1982;54:530-546. 17. Pindborg JJ, ed. Pathology of the Dental Hard Tissues. Copenhagen: Munksgaard; 1970:371-376. 18. Wysocki GP, Brannon RB, Gardner DG, Sapp P. Histogenesis of the lateral periodontal cyst and the gingival cyst of the adult. Oral Surg Oral Med Oral Pathol. 1980;50:327-334. 19. Partridge M, Towere JF. The primordial cyst (odontogenic keratocyst): its tumour-like characteristics and behaviour. Br J Oral Maxillofac Surg. 1987;25:271-279. 20. Suei Y, Tanimoto K, Taguchi A, Wada T. Primary intraosseous carcinoma: review of the literature and diagnostic criteria. J Oral Maxillofac Surg. 1994;52:580-583. 21. Praetorius F, Ledesma-Montes C. Calcifying cystic odontogenic tumour. In: Barnes L, Eveson JW, Reichart PA, Sidransky D, eds. World Health Organization Classification of Tumours. Pathology and Genetics of Head and Neck Tumours. Lyon: IARC Press; 2005:313.
Reprint requests: Kenji Kawano, DDS, PhD Department of Dentistry and Oral-Maxillo-Facial Surgery Faculty of Medicine, Oita University 1 Idaigaoka, Hasama-machi, Yufu-shi Oita 879-5593, Japan [email protected]