Oral Oncology (2004) 40 545–551
http://intl.elsevierhealth.com/journals/oron/
Cytokeratin expression in central mucoepidermoid carcinoma and glandular odontogenic cyst bio Ramo ^a Piresa, Sow-Yeh Chenb, Danyel Elias da Cruz Perezc, Fa Oslei Paes de Almeidac, Luiz Paulo Kowalskid,* a
Oral Pathology, School of Dentistry, State University of Rio de Janeiro (UERJ), Boulevard 28 de Setembro, 157 Vila Isabel, CEP: 21550-030, Rio de Janeiro/RJ, Brazil b Department of Pathology and Laboratory Medicine, Temple University School of Medicine, 3401 North Broad Street, Philadelphia, PA 19140, USA c Oral Pathology, School of Dentistry of Piracicaba, State University of Campinas (UNICAMP), ~o, CEP: 13414-900, Piracicaba/SP, Brazil Av. Limeira, 901, Areia d Department of Head and Neck Surgery and Otorhinolaryngology, AC Camargo Cancer Hospital, ^nio Prudente, 211 Liberdade, CEP: 01509-900, Sa ~o Paulo/SP, Brazil Rua Prof. Anto
Received 19 November 2003; accepted 21 November 2003
KEYWORDS
Summary Central mucoepidermoid carcinoma (MEC) is an entity whose origin is still controversial. Glandular odontogenic cyst (GOC) is a recently described lesion whose relationship to low-grade central MEC has been reported in the literature. Our aim was to assess the cytokeratin (CK) profile of central MEC and GOC, and compare the results with CK expression in salivary gland MEC and odontogenic cysts and tumors. Eighty-five cases, including 6 central MECs, 23 salivary gland MECs, 10 GOCs, 34 odontogenic cysts and 12 ameloblastomas, were studied through immunohistochemistry using eleven monoclonal anti-CK antibodies. All central MECs expressed CKs 5, 7, 8, 14, and 18 and all GOCs expressed CKs 5, 7, 8, 13, 14, and 19. Comparing CK expression from GOC and central MEC we found differences in CKs 18 (30% vs 100%) and 19 (100% vs 50%). Central MEC and GOC are probably distinct entities with CK profiles similar to lesions of glandular and odontogenic origins, respectively, and expression of CKs 18 and 19 could be useful in their differential diagnosis. c 2003 Elsevier Ltd. All rights reserved.
Mucoepidermoid carcinoma; Central; Intraosseous; Glandular odontogenic cyst; Cytokeratins
Introduction * Corresponding author. Tel.: +55-11-33410325/32725125; fax: +55-11-32776789. E-mail addresses:
[email protected](F.R. Pires); schen@ astro.temple.edu(S.-Y. Chen);
[email protected](O.P. de Almeida);
[email protected](L.P. Kowalski).
Mucoepidermoid carcinoma (MEC) is the most common malignant salivary gland tumor, usually affecting the parotid and minor salivary glands of adults.1 Its origin is thought to be from
1368-8375/$ - see front matter c 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2003.11.007
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F.R. Pires et al.
pluripotential cells of the excretory ducts of glandular structures.2 MEC arising centrally within the mandible or maxilla is extremely uncommon, representing about 1–4% of all MECs.1–5 Several sources of histogenic origin have been proposed for central MEC, including: (1) mucous metaplasia of odontogenic cyst epithelium; (2) entrapment of salivary tissues from the submandibular, sublingual, or minor salivary glands from the retromolar area during embryonic development; (3) maxillary sinus epithelium; (4) iatrogenic entrapment of minor salivary glands (e.g. chronic osteomyelitis and sinusitis); (5) remnants of the dental lamina. However, none of these possibilities is universally accepted.3–9 Glandular odontogenic cyst (GOC) is a recently described uncommon lesion, whose origin is still debatable, and it has many histological features similar to low-grade central MEC.8;10 In fact, it has been suggested that many cases formerly diagnosed as central MEC can be examples of GOC, and also some low-grade central MECs would have originated from GOCs.3;5;8 Cytokeratins (CKs) are a group of intermediate filaments mostly expressed by epithelial cells, which includes a wide range of proteins, varying in molecular weight, acid/basic composition, and affinity.11 Immunohistochemical expression of CKs has been regarded as an useful tool in identifying different epithelial types and origins, however few studies have described the CK profile of central MEC and GOC.2;12–18 The aim of this study was to analyze the immunohistochemical expression of CKs in central MECs and GOCs, and to compare the results with CK profiles in salivary gland MECs, and odontogenic cysts and tumors.
Material and methods Six cases of central MEC and 10 cases of GOC were reviewed from the files of the AC Camargo ~o Paulo, Brazil, the Oral Cancer Hospital, Sa Pathology Laboratory, School of Medicine, Temple University, Philadelphia, USA, and the Oral Pathology Laboratory, School of Dentistry of Piracicaba, State University of Campinas (UNICAMP), Piracicaba, Brazil. The criteria for selecting MEC cases with central (intraosseous) origin was the one proposed by Alexander et al.,6 modified by Browand and Waldron7 and Brookstone and Huvos,4 and include: (1) presence of a radiographic distinct osteolytic lesion; (2) positive mucicarmine staining; (3) absence of rupture of one or more cortical plates; (4) clinical and histological exclusion of a metastasis or an odontogenic lesion; (5) exclusion of the origin from a soft tissue salivary gland; (6) histologic confirmation. GOC cases were diagnosed based on the criteria described by the World Health Organization Histological Typing of Odontogenic Cysts and Tumors,19 and include: an usually multi-cystic lesion lined by nonkeratinized epithelia containing focal plaque-like thickenings; surface epithelial layer containing eosinophilic cuboidal cells; mucous cells and mucin pools in microcystic areas. Twenty-three cases of MEC from parotid (10 cases), palate (5 cases), submandibular (4 cases) and retromolar area (4 cases), and 46 odontogenic lesions including 10 dentigerous cysts, 14 keratocysts, 10 periapical cysts, and 12 ameloblastomas were used for study of CK profile, to compare with those of central MEC and GOC. Clinical data were obtained from the patients’ records. H&E stained histological slides from all
Table 1 Monoclonal antibodies against CKs used in the immunohistochemical evaluation of 6 central and 23 salivary gland MECs, 10 GOCs, and 46 odontogenic cysts and tumors Antibodies
Clone
Source
Dilution
Anti-CK Anti-CK Anti-CK Anti-CK Anti-CK Anti-CK Anti-CK Anti-CK Anti-CK Anti-CK Anti-CK
34bB4 XM26 LHK6B OV-TL 12/30 35H11 DE-K10 KS-1A3 LL002 LL025 DC10 RCK108
Novocastraa Novocastra Novocastra Dakob Dako Dako Novocastra Novocastra Novocastra Dako Dako
1:200 1:400 1:200 1:400 1:200 1:200 1:400 1:200 1:200 1:400 1:200
a b
1 5 6 7 8 10 13 14 16 18 19
Novocastra Laboratories, United Kingdom. Dako A/S Denmark.
Cytokeratin expression cases were reviewed to confirm the diagnosis, and PAS and mucicarmine stained slides were also used when necessary. CKs used in this study are shown in Table 1. Immunohistochemical reactions were performed as follows: slides were deparaffinized, hydrated in alcohol and washed in 10% hydrogen peroxide for 30 min to inhibit endogenous peroxidase. Microwave antigen retrieval using citrate buffer and overnight incubation with the primary monoclonal antibodies were performed in all cases. Secondary antibodies conjugated to a streptavidin–biotin–peroxidase system (Strept AB Complex/HRP Duet, Mouse/Rabbit, Dako A/S, Denmark) were used, followed by diaminobenzidine as the chromogen. Slides were counterstained with hematoxylin, mounted and analyzed by the same author (FRP). Expression of CKs was classified as negative (0–5% of positive cells) or positive (>5% of positive cells), based on the average number of positively stained cells in 10 high-power fields of each specimen under light microscopy.
Results All 6 central MEC cases affected the posterior mandible of females, with mean age of 54 years, ranging from 24 to 78 years (Fig. 1). GOCs affected 7 females and 3 males. The mean age of the patients was 48 years (range 31–72 years). The mandible was affected in 9 cases (5 in the posterior and 4 in the anterior portion), and the anterior maxilla in one case (Fig. 2). Table 2 shows the results of CK expression in central MECs, GOCs, salivary gland MECs, and odontogenic lesions. All central MECs expressed CKs 5, 7, 8, 14, and 18, a pattern very similar to that of the salivary gland MECs, only two cases out
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Figure 2 Glandular odontogenic cyst of the mandible showing a stratified squamous epithelial lining containing clear cells, mucous cells and microcystic structures (H&E, 120).
of 23 salivary MECs did not express CK7 and another two cases did not express CK14. All GOCs expressed CKs 5, 7, 8, 13, 14 and 19. All odontogenic cysts expressed CKs 5, 13 and 14, and 91% also expressed CK19. Only 7% of odontogenic lesions expressed CK18, which was expressed by all MECs of the central and salivary gland types (Fig. 3). Practically there were no differences of CK expression in central MECs and salivary gland MECs. Comparing salivary gland MECs with all odontogenic lesions, we observed that there were differences in the expression of CKs 7 (91% vs 39%), 16 (17% vs 57%) and 18 (100% vs 7%). Comparing central MECs with odontogenic lesions, these differences remained similar for CKs 7 (100% vs 39%) and 18 (100% vs 7%), and we also found difference for CK19 (50% vs 91%). Comparing GOCs with odontogenic lesions, we observed 100% conformity in the expression of CKs 5, 13, and 14 in GOCs and in other types of odontogenic cysts, but differences in the expression of CKs 7 (100% vs 39%) and 18 (30% vs 7%) between GOCs and odontogenic lesions. Comparing CK expression in GOCs and salivary gland MECs, we observed 100% conformity in the expression of CKs 5 and 8, but differences in the expression of CKs 1 (50% vs 9%), 16 (50% vs 17%) and 18 (30% vs 100%). In regard to GOCs and central MECs, we found 100% conformity in the expression of CKs 5, 7, 8, and 14, but differences in CKs 18 (30% vs 100%) and 19 (100% vs 50%) (Fig. 4).
Discussion Figure 1 Low-grade central MEC of the mandible showing cystic areas infiltrating bone (H&E, 40).
Central MEC is a well-recognized entity with more than 170 cases reported in the literature, but
548
Table 2
Immunohistochemical expression of CKs in 6 central MECs, 23 salivary gland MECs, 10 GOCs and 46 odontogenic cysts and tumors
Lesion (n)
CKs (number of positive cases/% of positive cases) CK1
CK5
CK6
CK7
CK8
CK10
CK13
CK14
CK16
CK18
CK19
Central MEC (6)
2 (33)
6 (100)
4 (67)
6 (100)
6 (100)
3 (50)
5 (83)
6 (100)
2 (33)
6 (100)
3 (50)
GOC (10)
5 (50)
10 (100)
8 (80)
10 (100)
10 (100)
6 (60)
10 (100)
10 (100)
5 (50)
3 (30)
10 (100)
Salivary gland MEC Parotid (10) Palate (5) Submandibular (4) Retromolar (4) Total (23)
2 0 0 0 2
(20) (0) (0) (0) (9)
10 5 4 4 23
(100) (100) (100) (100) (100)
5 2 2 3 12
(50) (40) (50) (75) (52)
10 5 2 4 21
(100) (100) (50) (100) (91)
10 5 4 4 23
(100) (100) (100) (100) (100)
10 0 1 2 13
(100) (0) (25) (50) (57)
9 5 2 3 19
(90) (100) (50) (75) (83)
10 5 3 3 21
(100) (100) (75) (75) (91)
4 0 0 0 4
(40) (0) (0) (0) (17)
10 5 4 4 23
(100) (100) (100) (100) (100)
8 5 3 4 20
(80) (100) (75) (100) (87)
3 (30) 7 (50) 0 (0) 1 (8) 11 (24)
10 14 10 12 46
(100) (100) (100) (100) (100)
6 14 2 8 30
(60) (100) (20) (67) (65)
7 3 6 2 18
(70) (21) (60) (17) (39)
8 11 8 10 37
(80) (79) (80) (83) (80)
2 13 1 3 19
(20) (93) (10) (25) (41)
10 14 10 8 42
(100) (100) (100) (67) (91)
10 14 10 12 46
(100) (100) (100) (100) (100)
3 13 3 7 26
(30) (93) (30) (58) (57)
2 0 0 1 3
(20) (0) (0) (8) (7)
9 13 9 11 42
(90) (93) (90) (92) (91)
Odontogenic lesions Dentigerous cysts (10) Keratocysts (14) Periapical cysts (10) Ameloblastomas (12) Total (46)
F.R. Pires et al.
Figure 3 Immunohistochemical expression of CK18 in central MEC (Streptavidin–biotin–peroxidase method, 200).
Figure 4 Immunohistochemical expression of CK19 in GOC (Streptavidin–biotin–peroxidase method, 160).
its origin is still controversial.3;4;9 Its similarity to MECs affecting the salivary glands in the expression of CKs 5, 7, 8, and 18 revealed in this study indicates its histogenesis from salivary gland tissue, but its localization within the jawbones and eventual association to odontogenic cysts and tumors suggest an odontogenic origin.4;5;7;9;20;21 In fact, some central MECs were described in association with dentigerous cysts, radicular cysts, and ameloblastomas.4;5;20;21 In addition, as in odontogenic cysts and tumors, the most common aspect of central MEC is an uni- or multi-locular radiolucence in the posterior mandible, frequently associated with impacted teeth.3;5;20 The possible relationship of central MECs with odontogenic lesions is also reenforced by the fact that central MECs outnumber by far intraosseous salivary tumors such as central
Cytokeratin expression pleomorphic adenoma and adenoid cystic carcinoma.9 Some studies have claimed that it is possible to establish the origin of a cyst or tumor by means of immunohistochemical expression of CKs. However, this is not easily applicable to odontogenic and glandular lesions, as CK expression varies according to different stages of differentiation, from embryonic to adult and specialized tissues.16;22 In fact, immunohistochemistry is not widely used at the present time for the diagnosis of odontogenic and salivary gland tumors. It has been shown that salivary gland excretory ducts can show a wide CK expression profile, including CKs 4, 5, 6, 7, 8, 13, 14, 16, 18 and 19, and MECs shows a similar wide profile.2;12;13;16–18 CK10 is usually absent in these tumors, reflecting that true keratinization is an uncommon finding in MECs,2 however, it was positive in about half of our cases. CK13 is frequently expressed by MECs and seems to be useful in differentiating them from other salivary gland tumors.17 However, its utility in identifying central MECs is limited due to its frequent expression in odontogenic epithelium and odontogenic lesions.23 Our results support this notion. Our findings regarding the almost 100% conformity in the expression of CKs 7, 8 and 18 in central and salivary MECs suggest that central MEC, which presumably arises from the odontogenic epithelium, may have attained the biologic nature of salivary MECs. These findings are comparable to the similarity of histomorpho differentiation between central and salivary MECs. It is difficult to relate the immunohistochemical CK profile and the origin of central MEC since all central and salivary MECs showed similar CK profile. CK expression in odontogenic epithelia depends on its embryological stage, but CKs 4, 5, 6, 7, 8, 13, 14, 15, 16, 17, 18 and 19 have been reported in several embryonic odontogenic structures.13;16;22;24–26 However, three specific subtypes (5, 14 and 19) seem to be specially important in odontogenesis.22;24–26 Odontogenic lesions can show a wide spectrum of CK expression. Dentigerous cysts can express CKs 1, 7, 8, 9, 10, 11, 13, 16, 17, 18 and 19 and keratocysts can express CKs 7, 8, 10, 11, 13, 16, 17 and 19.13;23;25;27 Although inflammation can alter CK expression pattern, periapical/radicular cysts have a similar wide spectrum of expression of CKs 4, 5, 7, 8, 10, 13, 14, 16, 17, 18 and 19.24;27 Ameloblastomas show frequent expression of CKs 1, 4, 5, 6, 7, 8, 9, 11, 14, 17, 18 and 19, and have variable expression of CKs 10, 13, and 16.13;16;23;26–30 GOC is an uncommon lesion first described in 1987, whose origin is still controversial.8;10;14;31 Its
549 histological features strongly suggest an odontogenic origin, but it is sometimes very difficult to distinguish GOC from low-grade central MEC.3;5;8;10;14;15;31 Koppang et al. 31 reported that its immunohistochemical profile includes expression of CKs 5, 6, 7, 8, 13 and 19, and absence of CK18. Sousa et al. 15 reported two cases of GOC that expressed CKs 7, 13, 14 and 19, but not CKs 8 and 18, and suggested that the lack of expression of the last two CKs should be important in differentiating GOC from low-grade MEC. Nevertheless, all our GOCs expressed CK8, suggesting that this CK is not useful in distinguishing them from central MEC. On the other hand, only 30% of GOCs expressed CK18, while MECs were 100% positive. Therefore, we confirmed that this CK can be very important in distinguishing these two lesions. Koppang et al. 31 reported that expression of CK13 in GOC does not support glandular origin, however, 83% of our central and salivary MECs also showed positive staining for this CK. The same authors have suggested that expression of CKs 8, 13 and 19 in GOC support an odontogenic origin, and our data are in agreement with this opinion. Semba et al. 14 also reported expression of several pools of CKs (1/2/5, 1/2/10/11, 10/11, 8/18/19 and 14/16/19) in GOC, but it is difficult to assess its individual importance. Comparing CKs expression in central MECs and GOCs, we observed that CK7 was expressed by all central MECs, all GOCs, and 91% of salivary MECs, but it was expressed by only 39% of all odontogenic lesions. This CK is frequently expressed in salivary glands 17 and should indicate glandular differentiation in these GOCs. CK18 was expressed by all MECs, but it was only expressed by 30% of the GOCs and 7% of the odontogenic lesions, therefore this CK seems to be an useful indicator of a glandular differentiation of the central MEC. GOCs showed more frequent CK18 expression than odontogenic lesions, probably also related to its morphological glandular differentiation. CK19 was expressed by 91% of odontogenic lesions, all GOCs, 79% of all MECs, and only 50% of the central MECs. Taking into consideration that CK19 is a frequent marker of odontogenic differentiation, the low frequency of CK19 expression in central MECs suggests that they may lose their CK19 expression during neoplastic transformation or they are of non-odontogenic origin. Our results are based on only 6 central MECs and 10 GOCs, studies on larger numbers of cases may provide a better understanding on this subject. It can be difficult to establish the origin and pathogenetic relationship of odontogenic and glandular lesions based solely on CK expression. However, CK profiles can be useful adjunctive tools
550 to the histological and morphological features to establish a definitive final diagnosis. Our results suggest that the central MEC and the GOC are distinct entities with different CK profiles, and that expression of CKs 18 and 19 could be useful adjunctive tools in differentiating these two entities. Our data also indicate that the central MEC has a CK profile similar to that of the MEC of glandular origin (CKs 7, 8, and 18) and the GOC shows a CK profile overlapping that of odontogenic lesions (CK19) and that of MECs (CKs 7, 8, and 18).
Acknowledgements This work was supported by CNPq and FAPESP, Brazil.
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