10.59987/ads/2017.3.104-109
Aims. Cytokeratin 19 (CK-19) is an epitheliumspecific intermediate filament protein that has been investigated in oral lichen planus (OLP) lesions but has not been compared with the expression of CK-19 in the OLP-related oral squamous cell carcinoma (OSCC). The aim of the present study has been to objectively compare the immunohistochemical expression of the CK-19 in OLP lesions and subsequent OSCC lesions that developed over time, to evaluate the change of the staining pattern among OLP and the grades of differentiation in OSCC.
Methods. Thirty-six formalin-fixed tissues of 18 OLP patients (18 samples from OLP lesion and 18 samples from OLP-related OSCC lesion) were included. The monoclonal antibody for CK-19 was used at 1:100 dilution for the immuno-staining on 4-μm thick sections. Staining pattern of CK-19 was graded into a 4-point scale: (1) no staining, (2) only few cells staining, (3) less than 50% of the cells stained, and (4) 50% or more of the cells stained. Microslides were examined under the light microscope using objective lenses magnifications of 4×, 10×, and 20×.
Results. The CK19 positive rate in OLP tissues was 33% (6 out of 18) and 56% (10 out of 18) in OSCC tissues. The CK19 positive score in OSCC tissues was significantly higher than that in the corresponding OLP tissues (Mann-Whitney test, P=0.02). Well-differentiated OSCC showed significantly lower of C-K19 scores than those moderately differentiated grades (Mann-Whitney, P=0.007).
Conclusions. The quantity and distribution of CK-19 staining in OSCCs showed relevant difference in comparison with OLP lesions. The increased of CK19 protein expression in OSCC tissues correlates significantly with the pathologic differentiation grade.
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Annali di stomatologia
head and neck cancer
Immunoexpression of cytokeratin-19 in the oral lichen planus and related oral squamous cell carcinoma
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Immunoexpression of cytokeratin-19 in the oral lichen planus and related oral squamous cell carcinoma
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                                                                                                  Original article


    Immunoexpression of cytokeratin-19 in the oral
    lichen planus and related oral squamous cell
    carcinoma




                                                                                               li
                                                                                             na
    Gian Paolo Bombeccari DDS, PD, MS                       corresponding OLP tissues (Mann-Whitney test,
    Aldo Bruno Giannì MD                                    P=0.02). Well-differentiated OSCC showed signifi-
    Francesco Spadari MD                                    cantly lower of C-K19 scores than those moder-




                                                                                           io
                                                            ately differentiated grades (Mann-Whitney,

    Maxillo-Facial and Dental Unit (Head Prof. AB Giannì)
                                                            P=0.007).

    Fondazione Ca’ Granda IRCCS Ospedale Maggiore
                                                            Conclusions. The quantity and distribution of CK-




                                                                      az
    Policlinico Milan, Italy - Department of Biomedical,
                                                            19 staining in OSCCs showed relevant difference

    Surgical and Dental Sciences, University of Milan,
                                                            in comparison with OLP lesions. The increased of

    Italy
                                                            CK19 protein expression in OSCC tissues corre-
                                                            lates significantly with the pathologic differentia-




                                                                    rn
                                                            tion grade.


    Gian Paolo Bombeccari
    Corresponding author:                                   Key words: cytokeratin, oral cancer, oral squa-

    Department of Biomedical, Surgical, and Dental Sci-
                                                            mous cell carcinoma, oral lichen planus, head




                                                       te
    ences, Unit of Oral Pathology and Medicine, Universi-
                                                            and neck cancer.

    ty of Milan
    Via Della Commenda 10
    20122 Milan, Italy
                                                            Introduction
                                                     In
    E-mail: gpbombeccari@libero.it                          Oral lichen planus (OLP) is a chronic inflammatory
                                                            disorder with a prevalence accepted to be approxi-
                                                            mately 1% of the general population (1).
                                                            The alleged potentially malignant character of the
                            ni

                                                            oral lichen planus has been matter of debate for sev-
                                                            eral decades. In a seven-year follow-up study of 327
    Summary

                                                            OLP patients the annual malignant transformation
                          io


                                                            rate amounted to less than 0.5% (2).
    Aims. Cytokeratin 19 (CK-19) is an epithelium-

                                                            However, when the incidence of oral cancer is set at
    specific intermediate filament protein that has

                                                            5 per 100.000 per year, then an annual risk of malig-
    been investigated in oral lichen planus (OLP) le-

                                                            nant transformation in oral lichen planus patients of
                        iz



    sions but has not been compared with the expres-

                                                            0.5% is a hundred times increased risk (1).
    sion of CK-19 in the OLP-related oral squamous

                                                            Cytokeratins (CKs) are epithelium-specific intermedi-
    cell carcinoma (OSCC). The aim of the present

                                                            ate filament proteins that maintain cellular integrity
          Ed




    study has been to objectively compare the im-

                                                            and participate in cell-to-cell attachments (3).
    munohistochemical expression of the CK-19 in

                                                            Cytokeratins are the main differentiation markers of
    OLP lesions and subsequent OSCC lesions that

                                                            the stratified epithelium, and 19 subclasses of CKs
    developed over time, to evaluate the change of

                                                            can be classified in according to their molecular
    the staining pattern among OLP and the grades of

                                                            weights, and distinguished by the site-specific distrib-
    differentiation in OSCC.

                                                            ution in the epithelium (4).
    Methods. Thirty-six formalin-fixed tissues of 18
 IC




                                                            Cytokeratin-19 (CK-19) has been identified as a use-
    OLP patients (18 samples from OLP lesion and 18

                                                            ful marker of cellular atypia, associated with pre-ma-
    samples from OLP-related OSCC lesion) were in-

                                                            lignant lesions in the oral epithelium (5).
    cluded. The monoclonal antibody for CK-19 was

                                                            Also, CK-19 expression has been regarded as an im-
    used at 1:100 dilution for the immuno-staining on
C




                                                            portant clue in the initial events during oral carcino-
    4-µm thick sections. Staining pattern of CK-19

                                                            genesis (6).
    was graded into a 4-point scale: (1) no staining,

                                                            Although a few studies demonstrated positive CK-19
    (2) only few cells staining, (3) less than 50% of the

                                                            staining in the basal layer of some dysplastic and ma-
    cells stained, and (4) 50% or more of the cells
©




                                                            lignant oral lesions (5, 7, 8), other studies have not
    stained. Microslides were examined under the

                                                            shown changes in the CK-19 expression in presence
    light microscope using objective lenses magnifi-

                                                            of oral dysplastic lesions, and/or any correlation be-
    cations of 4×, 10×, and 20×.

                                                            tween the histological parameters and CK-19 staining
    Results. The CK19 positive rate in OLP tissues

                                                            pattern in OLP lesions (9-11).
    was 33% (6 out of 18) and 56% (10 out of 18) in

                                                            Since the available data are discordant and the pro-
    OSCC tissues. The CK19 positive score in OSCC
    tissues was significantly higher than that in the

    104                                                                      Annali di Stomatologia 2017;VIII(3):104-109
    CK 19 and oral lichen planus


    duction of Ck-19 in the suprabasal cells of the oral
    mucosa – usually produced by cells in the basal lay-
                                                               Immunohistochemistry and evaluation of

    er- may- indicate alteration in cell behavior and prob-    For immunohistochemical staining 4-μm thick sec-
                                                               immunostaining

    able premalignant changes (5, 12, 13), more data are       tions from formalin-fixed, paraffin-embedded tissue
    needed to establish a correlation between CK-19 ex-        blocks were cut. The monoclonal antibody for CK-19
    pression pattern and the oral malignant transforma-        (DAB-Ventana-Roche, Benchmark-XT system, Tuc-
    tion.                                                      son, AZ, USA) were used at 1:100 dilution. The incu-




                                                                                                 li
    The aim of the present study is to objectively analyze     bation period for antibody was 12 hours. The expres-




                                                                                               na
    the immunohistochemical expression of the CK-19 in         sion level of CK-19 was analyzed using Biotin free
    OLP lesions undergoing malignant transformation            Multimer Ultraview. As regard CK-19, a positive reac-
    and subsequent OLP-related oral squamous cell car-         tion was considered as clear staining within the ep-
    cinoma (OSCC), and to compare the change of the            ithelium (basal and/or suprabasal) of OLPs and OS-
    staining pattern among OLP and the grades of differ-       CCs sections. The staining pattern of CK-19 was




                                                                                             io
    entiation in OSCC.                                         graded into a 4-point scale: (1) no staining, (2) stain-
                                                               ing of only few cells, (3) less than 50% of the cells
                                                               stained, and (4) 50% or more of the cells stained. All




                                                                         az
                                                               immunostained microslides were examined under the
                                                               light microscope (Olympus model U-MDO10B, USA)
    Materials and methods

                                                               equipped with objective lenses magnifications of 4×,
    The study was conducted using the oral mucosa              10×, and 20×.
    Specimen selection




                                                                       rn
    biopsy samples of 18 Caucasian patients that devel-
    oped an oral squamous cell carcinoma (OSCC), with-
    in a group of 683 subjects with clinical and pathologic    Frequency tables were analyzed using the Chi-
                                                               Statistical analysis

    diagnosis of OLP. The entire cohort of OLP patients        square test in order to assess the relevance of the




                                                        te
    has been followed from March 2001 through Novem-           correlation among the categorical variables. Mann-
    ber 2015, with a frequency established on the basis        Whitney U test were applied with the objective of
    of the clinical features and need for topical OLP ther-    comparing the means of the grades of immunoex-
                                                      In
    apy.                                                       pression of CK-19 for each diagnostic group (OLP
    The OLP diagnosis was defined according to revised         group and OSCC group). In each analyze the proba-
    and modified World Health Organization diagnostic          bility values less than 0.05 (p< 0.05) were regarded
    criteria (14).                                             as significant. Statistical calculations were performed
    For each of the 18 OLP-OSCC patients 2 tissue sam-         with the use of STATA 11.1 (College Station, TX,
                               ni

    ples were taken: the first sample from OLP lesion and      USA).
    second sample from OLP-related OSCC lesion. Clini-
    cal criteria for biopsy sampling in OLP-OSCC sus-
                             io


    pected lesions were the evidence of a loss of keratot-
    ic homogeneity associated with red areas of granular
                                                               Results

    appearance and an increased consistency of the OLP         Out of 683 OLP patients prospectively followed for
                           iz



    lesions. The criteria of the American Joint Committee      19-128 months in the mean observation period of
    on Cancer (AJCC) have been adopted to determine            89.7 months (SD 13.9), 18 of them developed an OS-
    the clinical cancer stage (15). The Local Ethical Com-     CC. The group of 18 OLP-OSCC patients was com-
            Ed




    mittee approval was obtained by the Institutional          posed of 12 women (67%) and 6 men (33%), with the
    Board, and each of the patients, once thoroughly in-       women’s mean age of 65 years (range 60-71) and the
    formed, provided oral and written (signed) informed        men’s mean age of 62 years (range 55-68). The
    consent.                                                   length of follow-up period before malignant transfor-
                                                               mation event ranged from 24 to 78 months [mean val-
                                                               ue 47.3 months (SD 12.90)].
 IC




    The oral biopsy samples of OLP-OSCC group pa-              The anatomic sites most commonly involved in sub-
    Histological examination

    tients were fixed in 10% formalin, paraffin-embedded       sequent malignant transformations of the OLP lesions
    and processed. Haematoxilin and eosin stained              were the tongue [8/18 patients, (44%)] and oral buc-
    slides of 6 μm were cut for diagnostic procedures.         cal mucosa [6/18 patients, (33%)].
C




    The OLP biopsies were reviewed by an expert oral           The observed clinical form of OLP that more fre-
    pathologist and were deemed to be eligible when the        quently underwent malignant transformation was the
    following histopathologic features were observed: 1)       atrophic and/or erosive form, with erosive OLP being
    the presence of one or more well defined band-like         detected in 9 out of the 18 cases (50.0%) of OSCC
©




    zone of cellular infiltration, which was confined to the   and the keratotic form in 6 out of 18 patients (33%).
    superficial part of connective tissue; 2) evidence of      Histologically, 13 out of 18 cases (72.0%) of OSCC
    liquefaction degeneration in the basal cell layer; and     presented a well differentiated grade with a microin-
    3) absence of epithelial dysplasia. The localization of    vasive pattern of infiltration. The remaining 5 out of
    the OLP lesions in the oral mucosa and site of prima-      18 cases (28.0%) displayed a moderate degree of dif-
    ry OSCC arising from OLP were recorded.                    ferentiation.

    Annali di Stomatologia 2017;VIII(3):104-109                                                                    105
    G.P. Bombeccari et al.


                                                                more marked in the OSCC samples versus the OLP
                                                                specimens (Mann-Whitney, P=0.02). Of the OLP pos-
    Microscopic evaluation of the immunostained

    Thirty-six biopsy samples (18 OLP samples and 18            itive samples, 6/18 (33%) were classified in category
    sections

    OLP-related OSCC) were studied for CK-19 im-                2 (only few cells staining), with CK-19 staining con-
    munostaining (Figs. 1-3). For each patient, the stain-      fined to the basal cell layer of the oral epithelium. Of
    ing pattern of CK-19 is shown in Table 1. Cytokeratin-      the 10/18 OSCC samples, 5/10 (50%) were catego-
    19 expression was positive in 6/18 of the OLP biopsy        rized of grade 2 and 5/10 (50%) of grade 3 (less than




                                                                                                   li
                                                                                                 na
                                                                                  Figure 1. Oral lichen planus immuno-
                                                                                  histochemistry: complete negativity for
                                                                                  CK-19 staining in the basal and
                                                                                  suprabasal layer (10x, CK19).




                                                                                               io
                                                                          az
                                                                        rn
                                                         te
                                                       In
                             ni

                                                                                  Figure 2. Well-differentiated OSCC:
                                                                                  positivity for CK-19 in the basal and
                                                                                  suprabasal layer with a score of 3 in the
                           io


                                                                                  staining pattern (10x, CK19).
                         iz
           Ed
 IC
C
©




    samples (33%), and 10/18 of the OLP-related OSCC            50% of the cells stained), with CK-19 expressed in
    biopsy samples (56%), with no significant difference        basal-parabasal layer and focally on the superficial
    between the samples of OLP and OSCC (Mann-Whit-             epithelium (Tab. 2). In the paired comparisons of CK-
    ney, P>0,10).                                               19 staining scoring, well-differentiated OSCC showed
    Concerning to the grading of the tissues staining into      significantly lower C-K19 scores than those moder-
    a 4-point scale CK-19, it was statistically significantly   ately differentiated grades (Mann-Whitney, P=0.007)

    106                                                                          Annali di Stomatologia 2017;VIII(3):104-109
    CK 19 and oral lichen planus


                                                                                             Figure 3. Moderate-differentiated OS-
                                                                                             CC: positivity for CK-19 in the basal
                                                                                             layer and superficial layer with a score
                                                                                             of 3 in the staining pattern (10x, CK19).




                                                                                                               li
                                                                                                             na
                                                                                                           io
                                                                                 az
                                                                               rn
                                                                te
                                                              In
    Table 1. Clinical-epidemiological data, oral localization of the lesions and comparative values of CK-19 score for each patient:
    (1) no staining, (2) only few cells staining, (3) less than 50% of the cells stained, and (4) 50% or more of the cells stained.

     Sample          sex      age                  Lesions site           Clinical form of OLP             Expression of CK-19
                               ni

                                                                                                            OLP             OSCC
    BS           F          60              Dorsum of the tongue            Atrophic, Erosive          2                3
                             io


    CN           F          67           Lateral margin of the tongue            Keratotic             1                1
    DD           M          55           Lateral margin of the tongue       Atrophic, Erosive          1                1
                           iz



    FF           F          69                    Maxillary gingiva         Atrophic, Erosive          2                3
    PS           M          67                    Buccal mucosa                  Keratotic             1                1
            Ed




    PM           M          58           Lateral margin of the tongue           Mixed form             1                2
    RA           F          71                    Buccal mucosa                  Keratotic             1                1
    ZL           F          63                    Buccal mucosa             Atrophic, Erosive          1                2
    TV           F          61                    Buccal mucosa             Atrophic, Erosive          1                2
    BM           F          67           Lateral margin of the tongue            Keratotic             1                1
 IC




    BT           F          62             Ventral tongue mucosa            Atrophic, Erosive          2                3
    CS           M          68                    Buccal mucosa                  Keratotic             1                1
    BG           M          64           Lateral margin of the tongue       Atrophic, Erosive          2                3
C




    CA           F          68           Lateral margin of the tongue       Atrophic, Erosive          1                1
    PG           M          60              Dorsum of the tongue                 Keratotic             2                3
    PE           F          64           Lateral margin of the tongue           Mixed form             2                2
©




    LM           F          70                    Buccal mucosa             Atrophic, Erosive          1                1
    SE           F          61                Mandibular gingiva                Mixed form             1                2
                P-value                           0.045 (Tongue)                   0.11                     0.10 (OLP VS OSCC)
         (Expression of CK-19)                                                                             0.02 (OSCC+ VS OLP+)
    CK-19, cytokeratin 19; OLP Oral Lichen Planus; OSCC, Oral Squamous Cell Carcinoma


    Annali di Stomatologia 2017;VIII(3):104-109                                                                                   107
    G.P. Bombeccari et al.


    Table 2. Distribution and statistical comparison of CK-19 scores between OLP lesions and OLP-related OSCCs.

           CK-19 staining pattern             Specimens          OLP          OSCC            W-D OSCC            M-D OSCC
                                                No (%)          No (%)       No (%)             No (%)             No (%)




                                                                                                           li
    No staining (grade 1)                       20 (56)         12 (67)       8 (44)             8 (62)               0
    Only few stained cells (grade 2)            11 (30)         6 (33)        5 (28)             4 (30)             1 (20)




                                                                                                         na
    <50% of the cells stained (grade 3)         5 (14)            0           5 (28)             1 (8)              4 (80)
    >50% of the cells stained (grade 4)            0              0             0                  0                  0
    Total number of specimens                     36              18            18                 13                 5




                                                                                                       io
    P-value (CK19- VS CK19+)                     0.12            0.15          0.7                        0.007
                                                                                                  (W-D vs M-D OSCC)
    CK-19, cytokeratin 19; OLP Oral Lichen Planus; OSCC, Oral Squamous Cell Carcinoma; W-D, Well-Differentiated OSCC;




                                                                             az
    M-D, Moderately-Differentiated OSCC



    (Tab. 2). The CK-19 staining pattern was significantly         - between 2 and 3 - of the observed staining pattern
    more frequent in the tongue tissues than in other lo-          in the tissue sections. Furthermore, a significantly




                                                                           rn
    calizations of the oral mucosa (Chi-square test                higher CK-19 score in moderately differentiated OS-
    P=0.045). Regarding the different types of OLP, the            CCs than well-differentiated ones was reported. Pre-
    CK-19 expression has not been statistically signifi-           vious studies examined the rate of CK-19 expression




                                                            te
    cant in relation with any clinical form of OLP among           in relation to the grades of pathological differentiation
    those reported in Table 1 (Chi-square test P=0.11).            in the OSCCs, detecting a positive association (6, 8,
                                                                   13, 17, 18). The achieved findings are consistent with
                                                                   the results of those studies and could be related to
                                                          In
                                                                   the progressive increased expression of precursor-
                                                                   cell keratin – as cytokeratin-19 – in less-differentiated
    Discussion

    The purpose of the present study was to examine the            grades of OSCCs (6, 8, 13). The staining pattern of
    expression of cytokeratin 19 (CK-19) in both oral              CK-19 was detected as significantly more frequent in
                                ni

    lichen planus (OLP) biopsy samples and those of oral           the tongue of the OLP and OSCC patients than in other
    squamous cell carcinoma (OSCC) developed in the                sites of the oral mucosa. This trend is in line with a pre-
    OLP lesions. Outcomes showed that CK-19 staining               vious study by Mattila et al. concerning the topographic
                              io


    was heterogeneously expressed in the 33% of the                expression of CK-19 in OLP lesions (10). As a matter of
    OLP lesions and the 56% of the OLP-related OSCCs.              fact, the tongue appears to be the preferential site of
    Data collected on the immunostaining OLP lesions               primary neoplasia OLP-related, in accordance with pre-
    are consistent with the results of the study by Mattila        viously reported in literature (2, 19).
                            iz



    et al., which reported a 29% rate of CK-19 marked              Although the data achieved in the present study are
    OLP specimens (10). As for the findings of CK-19               consistent with other reports, the most significant limi-
    positivity in the OSCC samples our data are coherent           tation of this single-center study is the relatively small
           Ed




    with a previous study by Safadi et al. which reports           number of investigated cases, also due to the low
    an overall percentage of 66,7% of stained sections             rate of malignant transformation that occurring on av-
    (8). Also, additional evidence showed that the grading         erage in the OLP patients. Another limitation can be
    of CK-19 staining in the OSCC sections was signifi-            considered the absence in our cases of poorly differ-
    cantly more marked in comparison with the OLP sec-             entiated OSCCs, that has not made possible a CK-19
    tions. In the current study, the aberrant expression           staining comparison on all histopathological differenti-
 IC




    and localization – basal and suprabasal cells layer –          ation grades in the OSCCs. Despite of the all above
    of CK-19 staining observed in the OSCCs could be               mentioned, it could be stated that the positive stain-
    interpreted as a potential increased progression cor-          ing of CK-19 has resulted to be intermittent within
    related with disturbed stem cells distributions, which         both OLP and OSCCs lesions. The marking pattern
C




    are normally present in the basal cell layer (6, 16). In       for CK-19 in OLP lesions has been categorized as
    a previous study of 33 OSCCs cases, Zhong et al. re-           scarce and confined to the basal cell layer of the ep-
    ported that the CK-19 protein expression in OSCCs              ithelium in comparison to what observed in OSCCs
    tissues correlate significantly with a pathologic differ-      lesions. The supplementary immunostaining with
©




    entiation grade of the malignant lesions, with an in-          monoclonal antibody for CK-19 in the OLP-related
    creasing m-RNA CK-19 level from well-differentiated            OSCCs could contribute to better define their
    cancerous tissues in comparison with those with                histopathological differentiation grade.
    poorly grade of differentiation (13). In the present           The findings obtained in the present study suggest
    study, the high prevalence (72%) of well-differentiat-         that the amount and distribution of CK-19 staining
    ed OSCCs lesions could explain the medium scoring              have significantly increased in OSCCs in comparison

    108                                                                                Annali di Stomatologia 2017;VIII(3):104-109
    CK 19 and oral lichen planus


    with OLP-related lesions.                                             7.    Schulz J, Ermich T, Kasper M, Raabe G, Schumann D. Cy-
    This CK-19 staining pattern is significantly more                           tokeratin pattern of clinically intact and pathologically
    marked in moderately-differentiated OSCCs than                              changed oral mucosa. Int J Oral Maxillofac Surg. Feb 1992;
    well-differentiated ones.                                                   21(1):35-39.
                                                                          8.    Safadi RA, Musleh AS, Al-Khateeb TH, Hamasha AA.
                                                                                Analysis of immunohistochemical expression of k19 in oral
                                                                                epithelial dysplasia and oral squamous cell carcinoma us-




                                                                                                                      li
    Conflict of interest statement                                              ing color deconvolution-image analysis method. Head Neck
                                                                                Pathol. Dec 2010;4(4):282-289.
    We have no conflicts of interest connected with this




                                                                                                                    na
                                                                          9.    Jacques CM, Pereira AL, Maia V, Cuzzi T, Ramos-e-Silva
    work. We declare that we have no competing finan-                           M. Expression of cytokeratins 10, 13, 14 and 19 in oral lichen
    cial interest.                                                              planus. J Oral Sci. Sep 2009;51(3):355-365.
                                                                          10.   Mattila R, Alanen K, Syrjänen S. Immunohistochemical study
                                                                                on topoisomerase IIalpha, Ki-67 and cytokeratin-19 in oral




                                                                                                                  io
                                                                                lichen planus lesions. Arch Dermatol Res. Jan 2007;298
                                                                                (8):381-388.
    Funding
                                                                          11.   Maeda H, Reibel J, Holmstrup P. Keratin staining pattern in
    None.                                                                       clinically normal and diseased oral mucosa of lichen planus




                                                                                      az
                                                                                patients. Scand J Dent Res. Aug 1994;102(4):210-215.
                                                                          12.   Michel M, Torok N, Godbout MJ, et al. Keratin 19 as a bio-
                                                                                chemical marker of skin stem cells in vivo and in vitro: Ker-
                                                                                atin 19 expressing cells are differentially localized in func-
    Authors’ contributions

    GPB has conceived and drafted the manuscript. FS                            tion of anatomic sites, and their number varies with donor




                                                                                    rn
    and ABG have participated in the design and coordi-                         age and culture stage. J Cell Sci. 1996;109(Pt5):1017-1070.
    nation of this study.                                                 13.   Zhong LP, Chen WT, Zhang CP, et al. Increased CK19 ex-
                                                                                pression correlated with pathologic differentiation grade and
    All Authors read and approved the final manuscript.
                                                                                prognosis in oral squamous cell carcinoma patients. Oral Surg




                                                                  te
                                                                                Oral Med Oral Pathol Oral Radiol Endod. 2007;104(3):377-
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    Annali di Stomatologia 2017;VIII(3):104-109                                                                                               109
