Cytokeratins 14 and 19 in Odontogenic

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Cytokeratins 14 and 19 in odontogenic cysts and tumors: a review Nieves Sabrina*, Apellaniz Delmira*, Tapia Gabriel**, Maglia Alvaro***, Mosqueda-Taylor Adalberto****, Bologna-Molina Ronell*****.

Abstract All mammal cells include a cytoplasmic fiber system essential for cell mobility, the cytoskeleton, formed by three main structural units and associated proteins: microfilaments, microtubules and intermediate filaments. Cytokeratins are intermediate filaments forming a complex network which extends from the nucleus surface to the peripheral cell sector, where they are inserted into desmosomes and hemidesmosomes. Cytokeratins 14 and 19 have been used as diagnosis and prognosis markers in various tumors of epithelial origin, not only to identify a cell as epithelial, but also to identify different stages during epithelial differentiation and to characterize the tumor. There are numerous studies in biomedical literature that have exemplified the utility of cytokeratins 14 and 19 to identify odontogenic epithelium. This review analyzes the utility of their immunologic expression in the different cysts and odontogenic tumors.

Keywords: Cytokeratin 14, Cytokeratin 19, Odontogenic cysts, Odontogenic tumors.

* Molecular Pathology Trainee, Facultad de Odontología, UdelaR, Uruguay ** Assistant Professor, Grade 3, Department of Histology, Facultad de Odontología, UdelaR, Uruguay *** Associate Professor, Grade 5, Department of Histology, Facultad de Odontología, UdelaR, Uruguay **** Specialist in Pathology and Oral Medicine, Full-time Research Professor, Health Care Department, Universidad Autónoma Metro- politana, Mexico ***** Specialist in Pathology and Oral Medicine, Doctor in Biological Sciences (Molecular Pathology), Full-time Associate Professor, Grade 5, Molecular Pathology, Facultad de Odontología, UdelaR, Uruguay

Received on: 08.05.14 - Accepted on: 01.09.14

Odontoestomatología / Vol. XVI. Nº 24 / November 2014 45 What are cytokeratins? epithelial keratins with variable molecular weights within the 40-70 kDa range, and sub- All mammal cells include a cytoplasmic fiber sequently an additional keratin was identified: system essential for cell mobility: the cytoskel- CK20. They can be divided into low versus eton. If we try to explain it in a simple and high molecular weight, and into acid or basic colloquial way, we could compare it to the according to their isoelectric points (2). steel rods that support the structure of a build- CKs 14 and 19 are type I keratins: CK 19 is ing: the cytoskeleton plays a key role as it sup- the smallest one and it is exceptional because, ports the plasma membrane and presents paths unlike other cytokeratins, it lacks the typical along which organelles and other cytosol ele- domain (no alpha helix) (5). CK14 is found in ments can move. However, unlike the passive the keratinocytes of stratified squamous epi- frame of a building, the cytoskeleton is con- thelium, both in the epidermis and the nonke- stantly restructured, which allows for move- ratinized mucosa (4), while CK19 is expressed ment (1). The cytoskeleton is formed by three in most simple epithelia, in various ductal main structural units and associated proteins: epithelia, in intestinal epithelia, in the gastric microfilaments, microtubules and intermedi- foveolar epithelium, and in the mesothelium. ate filaments. Intermediate filaments are divid- Besides, it is present in most pseudostratified ed into six types according to their molecular epithelia and urothelial cells, as well as in basal characteristics. Cytokeratins (CK) are type I cells of nonkeratinized stratified squamous and type II intermediate filaments (2, 3). epithelium (4). Moll et al. (4) classified a total of 19 human

Fig. 1. Epithelial cells. Disposition of cytokeratins from the cytoplasmic plaque toward the nuclear periphery.

46 Nieves Sabrina, Apellaniz Delmira, Tapia Gabriel, Maglia Alvaro, Mosqueda-Taylor Adalberto, Bologna-Molina Ronell Which are their functions? Utility of cytokeratins as markers

Cytokeratins form a complex network which Not all keratins are synthesized simultane- extends from the nucleus surface to the pe- ously by a cell, but rather different subsets of ripheral cell sector, where they are inserted keratins are expressed during terminal differ- into desmosomes and hemidesmosomes. entiation in different stages of development, (Figure 1). As they connect the nucleus sur- as well as in different epithelia. Therefore, all face with the plasma membrane, they provide epithelia (simple and complex) can be clas- a permanent link that can have important sified according to cytokeratin expression. implications for cytoplasm organization, cell Simple or monostratified epithelia generally communication, and perhaps for the trans- express keratins 7, 18, 19 and 20, while com- portation of information inside and outside plex (stratified) epithelia express keratins 5, the nucleus (2, 4). Additionally, as they are 6, 10, 14 and 15. When an epithelium un- inserted into desmosomes and hemidesmo- dergoes malignant transformation, its keratin somes, they contribute not only to the stabil- profile usually remains constant (2). There- ity of epithelial cells, but to their union with fore, patterns of keratin expression allow us the basal membrane and the underlying con- not only to identify a cell as epithelial, but nective tissue (4, 6). also to determine the phases of epithelial dif- In recent years there has been agreement re- ferentiation and to characterize the tumor. garding the fact that keratins have two funda- This is why antibodies against several keratins mental roles in epithelial cells: are used routinely at immunohistochemistry a) structural support, without which physical labs to diagnose carcinoma, especially unclear trauma leads to loss of integrity, and b) regulation of metabolic processes and their metastases (4). growth, proliferation, migration and apopto- Another clinical application is the detection of sis. protein fragments of CK8, CK18 and CK19 These two general roles involve regulated in- in the bloodstream of cancer patients. These teractions with a diverse group of fragments are increasingly used to monitor proteins (2, 7), which include signaling mol- tumor burden and the progression of the dis- ecules such as 14-3-3 proteins, apoptosis-re- ease in certain carcinomas such as lung cancer lated proteins, kinases and phosphatases (8). (15, 16). Besides, it has been observed that Oriolo et al. (9) say that they can also have a over 95% of lung carcinoma squamous cells role in epithelial polarity and membrane traf- are positive for CK14 (13, 17). fic. CK19 is one of the most frequently studied Cytokeratins have also been linked to wound immunohistochemical markers in thyroid pa- healing, as they provide a more pliable cyto- thology, which could make it a useful diagno- skeleton to the cell, which favors the migra- sis and prognosis tool, as it can be determined tion of keratinocytes for wound closure (10). before the therapeutic procedure in cytologic As for CK14, mutations in the CK genes are findings (14). responsible for epidermolysis bullosa simplex Immunohistochemical staining for CK19 (11, 12), a hereditary disease, considered im- facilitates the differential diagnosis between portant for the physical stability of the epi- papillary carcinoma, which presents strong dermis (4). In turn, CKs 15 and 20 have been and diffuse staining, and other thyroid can- used as diagnosis and prognosis markers in cers, which present weak and focal staining. various tumors of epithelial origin (13, 14). It has also been suggested that it could be a

Cytokeratins 14 and 19 in odontogenic cysts and tumors: a review 47 useful predictor of the progression of thyroid nign or malignant myoepithelioma, adenoid carcinoma (14). cystic carcinoma and pleomorphic adenoma Tsuruba et al. (18) showed that CK8 and (13, 26, 27). CK14 can be useful to diagnose tumors in skin appendices. In general, the following tu- Cytokeratins and odontogenesis mors test negative for CK8 and positive for CK14: epidermis, sebaceous glands and hair Patterns of expression of cytokeratins in the follicles, while tumors derived from eccrine odontogenic epithelium have been described glands and apocrine sweat glands are CK8 in a very general way. Domingues et al. (28), positive and CK14 negative. in their immunohistochemical study, showed Squamous cells carcinoma, as well as malig- that epithelial cells of the tooth germ and in nant mesothelioma, show a strong expression the remnants of the dental lamina are posi- of CK14, while adenocarcinomas show none tive for CK14 and CK19 with slight changes or very little (2, 4, 19). Studies have suggested in their expression pattern, depending on the that the expression of certain keratins of sim- phase of odontogenesis. For example, they ple epithelia (like CK19) in squamous cells state that at the inner epithelium of the enam- carcinomas may indicate a poorly differenti- el organ the expression of CK14 and CK19 ated carcinoma (4). CK19 is detected in the varies in the follicle and bell stages (early bell epithelium near squamous cells carcinomas, stage according to the author). They observed which suggests that it could be used as a fun- a strong positive for CK14 while CK 19 had damental biological agent of the malignant weak staining, which was the opposite at the progression (20). Clearly these findings can late bell or follicle stage. CK19 has a strong be applied in the case of oral cavity squamous positive, while the expression of CK14 de- cells, which shows the utility of these cytoker- creases. Additionally, the most prevalent cy- atins in the diagnosis and as a possible prog- tokeratin in the remnants of the dental lami- nosis factor in diverse neoplasms that affect na was CK14, which strongly stained all cells, the maxillofacial region (21), as well as lesions while CK19 appeared only in some cells of of the oral mucosa considered potentially ma- the dental lamina, with a non-homogeneous lignant (22, 23). pattern. CK14 was also observed in the stel- late reticulum, which was stronger at the early As for salivary glands tumors, they can be bell phase. CK19 was also expressed but more divided into two large categories: tumors weakly. The outer epithelium of the enamel derived from stratified epithelium (pleomor- organ was marked for CK14 and for CK19. phic adenoma, myoepithelioma, basaloid Crivelini et al. (20), Ferreira Lopes et al. (29), squamous cells carcinoma, adenoid cystic Leon et al. (30), Kasper et al. (31), Heikin- carcinoma and mucoepidermoid carcinoma), heimo et al. (32), and Gao et al. (33) also and tumors that arise from simple epithelia studied the expression of CK14 and CK19 in (adenocarcinoma NOS, monomorphic ad- tooth germ, although in less detail. enocarcinoma and acinar cell carcinoma). They found CK14 and CK19 in the enamel The former express CK14 and CK19, while organ (20, 29–33) and in the dental lamina the latter do not (24, 25). CK14 is a myoepi- (20, 30, 31). thelial cells marker, therefore, salivary glands Crivelini et al. and Leon et al. agree with the tumors with myoepithelial cells are usually findings of Domingues et al. As for CK14, it positive for CK14. These tumors include be- is gradually replaced by CK19 in the inner

48 Nieves Sabrina, Apellaniz Delmira, Tapia Gabriel, Maglia Alvaro, Mosqueda-Taylor Adalberto, Bologna-Molina Ronell epithelium of the enamel organ: immunoex- toma and in peripheral ameloblastoma. They pression of CK19 is very positive in pream- conclude that CK19 expression can be used as a eloblasts (32). tool to differentiate both neoplasms since in the Given the changes in the expression of CK14 cases of central ameloblastomas studied, CK19 and CK19 in the inner epithelium of the is positive in all the cells, while in peripheral am- enamel, some researchers have suggested that eloblastoma, there are CK19 negative cells. Gao CK19 could be considered an effective mark- et al. (33) studied the expression of CK14 and er of ameloblast differentiation (20, 28). CK19 in the odontogenic epithelium of normal dental follicles, as well as in the epithelium of Odontogenic cysts and tumors dentigerous cysts and keratocystic odontogenic tumors, as they all derive from the odontogenic The presence of these cytokeratins in tooth de- epithelium of the dental organ. These patterns velopment suggests that they participate in the were compared with cysts of different origins, embryonic development of the dental organ, like nasopalatine cysts and epidermoid cysts. which is why various authors have studied their The results obtained confirmed the prediction expression in odontogenic cysts and tumors (20, that development cysts from the odontogenic 29, 30, 32–47). Patterns of expression of kera- epithelium shared the expression of CK14 and tins allow us to identify a cell as epithelial and CK19, but they were different from the cysts also to identify different stages during epithelial originated in non-odontogenic epithelium. differentiation (4). Antibodies against these cy- Therefore, odontogenic epithelium and its de- tokeratins have been used to elucidate histogen- rivates (cysts and tumors) show certain similari- esis and to characterize the tumor. Numerous ties in their patterns of expression of CK, but biomedical studies have illustrated the utility of they differ from nasopalatine cysts for example, these two cytokeratins to identify odontogenic which derive from epithelial remnants of the epithelium, and therefore they have been use- nasopalatine duct, and from epidermoid cysts, ful in the diagnosis of some neoplasms or cysts which arise from the epithelium during embry- where an odontogenic origin is suspected. They onic development. have also been useful to determine the possible In Table 1 we summarize the studies which histogenesis of several cystic or tumoral lesions have focused on the expression of CK14 and/or of the maxillofacial region that are known to be CK19 in various odontogenic cysts and tumors. of odontogenic origin (20, 29, 30, 32–34, 37, 40–45, 47). An example of this are the studies conducted in ameloblastomas (20, 29, 34–36), where the expression of CK14 and CK19 was studied to elucidate its possible origin (20, 29). Other authors have studied these same cytokeratins to differentiate them from other lesions, for example Yoon et al., who studied the expression of CK14 and CK19 to differentiate it from ameloblastic carcinoma. They found that in both tumors the expression of both cytokeratins is strong and diffuse. Another interesting study is that of Pal et al. (35), who studied the expression of these same cytokeratins in central ameloblas-

Cytokeratins 14 and 19 in odontogenic cysts and tumors: a review 49 Table 1.- Expression of CK14/CK19 in odontogenic cysts and tumors. 1989–2013 literature review.

ODONTOGENIC TUMORS AND AUTHOR YEAR CK14 expression CK19 expression Origin CYSTS

Crivelini et al. Remnants of 2003 CK14 positive CK 19 positive (20) dental lamina

Ferreira Lopes CK14 positive in the CK 19 positive, 2005 cells of the periphery of in central and Remnants of et al. (29) tumoral nests peripheral cells dental lamina

CK14 positive in the CK 19 positive, Ferreira Lopes Remnants of 2005 cells of the periphery of in central and et al. (29) dental lamina tumoral nests peripheral cells Remnants of Yoon et al. 2011 Strong positive for CK14 Positive for CK19 dental lamina (34) (enamel organ) Follicular: Positive for CK14 in all basal cells and in most internal cells Follicular: Positive Plexiform: Positive for for CK19 in all cells CK14 in all basal cells Plexiform: Positive and in most internal for CK19 in all cells cells Microcystic: Positive Microcystic: Positive for for CK19 in all cells Solid ameloblastoma Pal et al. (35) 2013 ------CK14 in all basal cells Acanthomatous: and in most internal Positive for CK19 in cells all cells Acanthomatous: Positive Granular: Weak for CK14 in all basal cells positive for CK19 and weak positive in internal cells Granular: Negative for CK14 Follicular: Positive for CK19 in all cells Plexiform: Positive for CK19 in all cells Acanthomatous: Positive for CK19 in Fukumashi et 2002 ------all cells ------al. (36) Granular: Positive for CK19 in basal cells and weak positive in suprabasal and internal cells. Kishino et al. 2007 Positive for CK14 Positive for CK19 Remnants of (37) odontogenic epithelium

Peripheral ameloblastoma Pal et al. (35) 2013 ------Positive for CK19, ------although some negative cells were found at internal and basal levels.

50 Nieves Sabrina, Apellaniz Delmira, Tapia Gabriel, Maglia Alvaro, Mosqueda-Taylor Adalberto, Bologna-Molina Ronell Pal et al. (35) 2013 ------Positive for CK19, ------although some negative cells were found at internal and basal levels. Desmoplastic ameloblastoma Fukumashi et 2002 ------Positive for CK 19 ------al. (36) in all internal and suprabasal cells Bologna- 2010 Positive for CK14 in Negative for CK19 ------Molina et al. some suprabasal cells (38) and in central cells

Calcifying epithelial odontogenic tumor Crivelini et al. 2003 Positive for CK14 in all Weak positive for Remnants of (20) cells CK19 Hertwig's sheath Crivelini et al. 2003 Positive for CK14 in all Negative for CK19. Reduced enamel (20) tumoral epithelial cells epithelium Leon et al. 2005 Positive for CK14 in all Positive for CK19 Reduced enamel (30) cells Some negative less intense than epithelium cases for clear cells positive for CK14 Adenomatoid odontogenic (cells in the center of Negative in fusiform tumor nodes) cells (peripheral to the nodes) Ferreira Lopes 2005 Positive for CK14 Positive for CK 19 in Reduced enamel et al. (29) positive in duct and duct cells epithelium plexiform cells Martínez- 2008 Positive for CK14 Partially positive for ------Odontogenic myxoma Mata et al. CK19 (39) Crivelini et al. 2003 Positive for CK14 in all Negative for CK19 Remnants of Ameloblastic fibroma (20) the epithelium dental lamina Bologna- 2013 ------Strong positive for Odontogenic Ameloblastic fibrodentinoma Molina et al. CK19 epithelium (40) Gao et al. (33) 1989 Positive for CK14. Positive for CK 19 Remnants of (irregular staining in dental lamina suprabasal cells and in some basal cells) Dos Santos et 2009 Positive for CK14 in all Strong positive for Remnants of Keratocystic odontogenic tumor al. (41) epithelial layers CK19 (in suprabasal dental lamina and intermediate cells) Aragaki et al. 2010 ------Strong positive for From remnants (42) CK19 (in basal and of the dental suprabasal cells) lamina Gao et al. (33) 1989 Positive for CK14 Strong positive for Reduced enamel CK19 epithelium Tsuji et al. 2013 ------Positive for CK 19 Odontogenic (43) (in the basal layer of epithelium Dentigerous cysts squamous epithelial cells) Stoll et al. (44) 2005 ------Positive for CK19 Odontogenic epithelium

Cytokeratins 14 and 19 in odontogenic cysts and tumors: a review 51 Lukinmaa et 1997 Strong positive for CK14 Strong positive for Odontogenic al. (45) CK19 (cells of the epithelium basal layer of the epithelium) Calcifying epithelial odontogenic Murakami et 2003 ------Positive for CK19 (in ------cyst al. (46) basal cells of oral mucosa). Fregnani et 2003 Positive for CK14 (in Positive for CK19 (in Odontogenic al. (47) basal cells of lining suprabasal cells of epithelium epithelium) epithelium) In conclusion, various studies and recent research increasingly ascribe cytokeratins a role which goes well beyond the mere construction of the cytoskeleton. Several groups are current- ly studying the influence of their structural and regulatory functions in various diseases, and the molecular interactions of these proteins in various normal and pathological processes are becoming increasingly clear. These new findings highlight the importance of this family of intermediate filaments as useful biomarkers for the prognosis and diagnosis of various human tumors, including those in the oral maxillofacial region.

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Cytokeratins 14 and 19 in odontogenic cysts and tumors: a review 55