Unraveling the Keratin Expression in Oral Leukoplakia: A Scoping Review
Abstract
:1. Introduction
2. Methods
2.1. Eligibility Criteria
2.2. Data Sources and Search Strategy I
2.3. Study Selection and Screening I
2.4. Data Extraction and Synthesis
3. Results
4. Discussion
- Loss of expression of primary keratins normally found in oral epithelium. Specifically, K1/K10 and K4/K13 suprabasally in keratinized and non-keratinized epithelium. This is also true for K2p for keratinized mucosa. This suggests that dysplasia disrupts the terminal differentiation pathway of primary keratins.
- Suprabasal extension of primary keratins of the basal layer, which include K5/K14 and K19. However, K19 may also express atypically (suprabasal extension) in inflammatory lesions.
- The gain of K17 expression in OLK samples, which is the most studied keratin with respect to the increase in protein expression. Aside from the above, K8 and K18 have also shown increased expression, albeit in a smaller proportion of samples compared to K17.
- Nonetheless, from this review, further studies on the following keratins may be helpful in the following scenarios (high-grade vs. low-grade dysplasia):
- LOE of K1/K10.
- There is a marked loss of K1/K10 expression in severe dysplasia (regardless of original site of OLK samples, e.g., keratinized or non-keratinized).
- Suprabasal extension of K19 to the most superficial layers of epithelium indicates severe or high-grade dysplasia.
- Prognostic utility:
- GOE of K17.
- Retention of K13 expression may indicate a lower risk of MT.
- Further studies investigating the significance of GOE for K6, K7, K8, K16, and K18 in OLK. Current evidence shows that not many studies stain for these keratins in their samples, and as such, data are not hampered by the quality but rather by quantity of studies.
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Author/Year | Keratin of Interest | Tissue of Interest and Site | Normal Controls (If Any) | Dysplasia Grading System and Statistical Analysis (SA). | Analysis of CK Expression | Study Type |
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Ambatipudi et al., 2013 [26] | K76 (K2p) | 61 total: hyperplasic lesions with focal mild–moderate dysplasia Site not specified | 35 normal tissues from the gingiva-buccal tissues and 7 inflamed tissues not associated with oral malignancy or premalignant lesions | Grading system not specified No grading or detection of the absence/presence of dysplasia in their leukoplakia (OLK) samples SA completed, however not specifically between normal controls and OLK | Hematoxylin and eosin (H&E) with immunohistochemistry (IHC) immunostaining and qRT-PCR K76 protein expression—semi quantitative (0 = no staining; +1 = weak staining in <10% of cells; +2 = moderate staining and/or 10–50% of positive cells; +3 = strong staining in more than 50% of cells by pathologist For statistical analysis, stained tissues were categorized into two groups (0 and +1) and (+2 and +3). | Expression |
Barakat et al., 2015 [27] | K15 | 30 total: 10 mild, 10 moderate, and 10 severe, and 10 with oral hyperkeratosis Site not specified | 5 normal controls Site not specified No ST completed | WHO (2005) [72] Dysplasia graded No SA completed | H&E and IHC Semiquantitative 3 layers identified (stratum basale, spinosum, and corneum) Intensity was graded as mild (<25% cells stained), moderate (25–50% cells stained), and strong (>50% of cells stained) in the areas showing most intense staining at 200× magnification. | Expression |
Becker et al., 2024 [28] | K13 and K17 | 131 total: 52 differentiated dysplasia, 42 keratosis without dysplasia, 14 mild dysplasia, 12 moderate dysplasia, and 11 severe dysplasia Sites: vestibular, buccal, tongue, and floor of mouth (FOM) | No controls | WHO (2017) [73] Dysplasia graded SA completed | H&E and IHC. Keratin expression labelled as ‘normal’(positive) or ‘aberrant’ (negative); K13 loss and K17 expression (even partially) was considered aberrant | Expression and prognosis |
Bloor et al., 2001 [29] | K4, K13, K1, and K10 | 23 total: 9 mild, 7 moderate, and 7 severe from non-keratinized sites | 6 normal controls Site from the BM | Grading system not specified Dysplasia graded No SA completed | H&E, IHC, and ISH | Expression |
Bloor et al., 2003 [30] | K2e, K1, and K10 | 13 total: 6 Keratosis with no dysplasia, 2 mild dysplasia, 3 moderate dysplasia, and 2 severe dysplasia Sites from buccal mucosa (BM), lingual mucosa dorsal tongue, lateral tongue, ventral tongue, floor of mouth (FOM), labial mucosa, and lateral tongue soft palate | 6 normal controls Sites from BM ventral tongue and gingiva | Grading system not specified Dysplasia graded No SA completed | H&E, IHC, and PCR (−) no immunostaining for protein (+/−) <5% cells positive (+) 10–30% cells positive (++) 40–70% cells positive (+++) 80–100% cells positive | Expression |
Cema et al., 998 [31] | K10, K10/13,K5/6, K17, K18, and K19 | 6 total: 1 mild dysplasia, 2 moderate dysplasia, 2 severe, and 1 carcinoma in situ Sites from: FOM, BM, ventral and lateral surface of tongue | Normal oral mucosa, epithelial hyperplasia, and atrophy Numbers not discussed Site from FOM, BM, ventral and lateral surface of tongue | WHO (1978) [65] Dysplasia graded No SA completed | H&E and IHC Epithelium was divided into stratum basal, stratum suprabasal (spinosum and granulosum) and stratum superficial, semi-quantitatively measured using as follows: (−) no expression (1+) <5% positive cells (2+) 5–20% cells (3+) 21–50% (4+) 51–80% cells (5+) >80% cells | Expression |
Cintorino et al., 990 [32] | K1 and K19 | 20 total: 14 cases of OLK with no dysplasia. Sites from BM vestibular mucosa, FOM, soft palate, gingiva, and dorsal tongue 6 cases of OLK with mild to severe dysplasia Sites from vestibular mucosa, soft palate, hard palate, pilastrum, and dorsal tongue. | Normal controls presented in results, but not discussed in materials and methods Site and number of controls not specified | WHO (1978) [65] Dysplasia graded No SA completed | H&E and IHC Semiquantitative: (−) negative (−/+) weak and/or irregular (+) strong and regular | Expression |
Ermich et al., 989 [33] | K1, K2, K3, K4, K5,K6/K11, K7/K13, K8, K9, K10, K12, K14/15, K16, K17, K18, and K19 | 20 total: 4 degree I dysplasia, 2 degree II dysplasia, and the remining 14 samples had no dysplasia 14 from non-keratinizing and 6 from keratinizing sites | 31 normal controls in total. 10 from non-keratinized mucosa, 12 from keratinized tissues (8 gingiva and 4 hard palate) and 9 from specialized mucosa (5 from lip and 4 dorsal tongue) | WHO (1978) [65] Dysplasia graded No SA completed | H&E and SDS PAGE and MABs to keratins | Expression |
Farrar et al., 2004 [34] | AE1, AE3, and K14 | 40 total: 10 samples from 4 tissue types: oral tissues showing benign oral lesions (squamous papillomas) or inflammatory changes; oral tissue displaying evidence of mild, moderate, and severe dysplasia Site not specified | 10 normal controls Site not specified | Grading system not specified. Dysplasia graded No SA completed specifically for expression of keratins | H&E and IHC Qualitative analysis of intensity and location of staining (basal layer, lower 1/3, middle 1/3, and upper 1/3) Intensity of staining graded at 0, + (1–50 +ve cells), ++ (51–150 +ve cells), and +++ (>150 +ve cells) | Expression |
Farrukh et al., 2015 [35] | K13 | 37 total: 21 hyperplastic, 16 severely dysplastic tissue Sites from BM, tongue, FOM, and lip | 19 normal controls Site from BM | Grading system not specified However, presence/absence of dysplasia was identified; dysplasia was not graded SA completed | H&E and IHC. Qualitative analysis using different categories, including the following: strong diffuse +ve, extensive or near complete loss, complete loss with focal reactivity in keratin pearls, complete loss with focal strong reactivity in keratin pearls, complete loss with focal weak reactivity in keratin pearls, loss except in superficial granular layer, complete loss | Expression |
Fillies et al., 2007 [36] | K5/K6, K8/18, K1, K10, K14, and K19 | 140 total: 117 OLK with no dysplasia, 23 leukoplakia (OLK) with dysplasia Site not specified | No controls | Squamous intraepithelial neoplasia (SIN) system [72] Dysplasia graded SA completed | HE and IHC Positive cells in each core (0 = no expression; 1 = >1% positive expression) | Expression |
Gires et al., 2006 [37] | K8 | 8 OLK total Site not specified | 9 normal controls Site not specified | Grading system not specified However, presence/absence of dysplasia was identified; dysplasia was not graded No SA completed | H&E, IHC, and AMIDA system (autoantibody-mediated identification of antigens) | Expression |
Heyden et al., 992 [38] | K10, K13, and K14 | 30 OLK total Site from FOM and ventral surface of tongue | 10 autopsy specimens of non-keratinized normal mucosa, from forensic cases 8–24 h after death caused by myocardial infarction or accident, and 5 biopsies from buccal mucosa containing metaplastic keratinized epithelium with no dysplastic changes were examined | WHO (1978) [65] Dysplasia graded SA completed | H&E and IHC Differences in staining intensity between cell layers of normal mucosa, dysplastic lesions, and carcinomas; keratin staining was recorded twice by the same investigator (AH), applying a semi-quantitative scoring system (negative (−), heterogeneous (−/+), homogenously intense (+++)) for each cell layer | Expression |
Ida-Yonemochi et al., 2012 [39] | K13 and K16 | 23 total CIS samples from the tongue | 10 foci of normal controls Site not specified | Grading system not specified Dysplasia graded No SA completed | H&E, IHC, RT-PCR, and ISH | Expression |
Ikeda, 2020 [40] | K13 and K17 | 200 total: Dysplasia samples include 9 from the palate, 60 from the gingiva, 99 from the tongue, and 32 from the buccal mucosa | Normal controls used Site and sample size not discussed | WHO (2017) [73] Dysplasia graded SA completed | H&E and IHC IHC marker patterns for K13 (opposite true for K17): 1 = Normal expression pattern 2 = Heterogenous positivity with high intensity 3 = Heterogenous positivity with low intensity 4 = No positivity as a homogenous decrease with a border separating the normal area | Expression |
Kannan et al., 994 [41] | K 10/11, K19, K18, and K14 | 60 total: 30 non-dysplastic OLK, 15 mild, 8 moderate, 7 severe All from non-keratinizing sites | 10 normal controls 5 from keratinizing and another 5 from non-keratinizing sites | WHO (1978) [65] Dysplasia graded SA completed | H&E and IHC | Expression |
Kannan et al., 994 [42] | K10 and K11 | 60 total: 30 non-dysplastic OLK, 15 mild, 8 moderate, 7 severe All from non-keratinizing sites | 10 normal controls 5 from keratinizing and another 5 from non-keratinizing sites | WHO (1978) [65] Dysplasia graded SA completed | H&E and IHC Qualitative analysis—intensity of staining in basal, lower, and upper third; intensity rated from 0–6 | Expression |
Kannan et al., 996 [43] | K10/11, K13, K14, K16, K19, and K18 | 60 total: 30 non-dysplastic OLK, 15 mild, 8 moderate, 7 severe All from non-keratinizing sites | 5 normal controls Site from non-keratinizing epithelium | WHO (1978) [65] Dysplasia graded SA completed | H&E and IHC Grade of staining (negative: 0, mild: 2, moderate: 4 and intense: 6) and layers (basal, lower spinal, upper spinal) were also scored. | Expression |
Kiani et al., 2020 [44] | K13 and K17 | 85 dysplasia total Site not specified | No normal controls | Grading system not specified However, presence/absence of dysplasia was identified; dysplasia was not graded SA completed | H&E and IHC. Case was considered negative or positive depending on the intensity of staining of the cells; 10 high power fields in each slide were evaluated for K13 and K17 positivity | Expression |
Kitamura et al., 2012 [45] | K17 and K13 | 108 total: 74 OLK without dysplasia and 34 OLK with dysplasia Site not specified | 10 normal controls Site not specified | WHO (2005) [72] Dysplasia graded SA completed | H&E and IHC | Expression |
Lindberg and Rheinwald, 1989 [46] | K19 | 19 OLK total Site from 9 FOM, 4 ventral tongue, 3 retromolar pad, 3 gingivae | Normal controls from keratinizing and non-keratinizing mucosa; did not specify number | Kramer (1980) [74] Dysplasia graded SA completed | H&E and IHC K19 expression was recorded for its presence or absence, in basal and/or suprabasal layers; no quantification of staining | Expression |
Nanda et al., 2012 [47] | K8 and K18 | 10 OLK total Site from BM | 10 normal controls Site from the BM | Grading system not specified Presence/absence of dysplasia was not identified; dysplasia was not graded SA completed | H&E and IHC The intensity of staining of epithelium (basal and suprabasal) was assessed as on a 4-point scale from -ve to +++ intense | Expression |
Nobusawa et al., 2014 [48] | K13, K14, and K17 | 146 total: 43 mild, 63 moderate, and 40 CIS Site from tongue, gingiva, BM, FOM, hard palate, and soft palate | 21 normal epithelial foci from surgical excisions Sites from tongue, gingiva, BM, and FOM | WHO (2005) [72] Dysplasia graded SA completed | H&E and IHC Staining for each keratin was assessed as positive when more than 10% of cells showed intracytoplasmic staining | Expression |
Okada et al., 2010 [49] | K13, K14, and K17 | 30 total: 10 hyperkeratosis with no dysplasia, 10 hyperkeratosis with dysplasia, and 10 CIS Site from tongue | No controls | Grading system not specified However, presence/absence of dysplasia was identified; dysplasia was not graded No SA completed | H&E and IHC Qualitative analysis of intensity of staining—strong, intermediate, weak, negative | Expression |
Rajeswari et al., 2021 [50] | K19 | 40 total: 10 cases of hyperplasia 10 mild, 10 moderate, and 10 severe Site not specified | Normal controls. Number and sites not specified | WHO (2005) [72] Dysplasia graded SA completed | H&E and IHC Sections initially scanned at lower power, if positive, ×40 zoom used for three microscopic fields; Allred score used for scoring; system as follows: Proportion score: 0 = no cells + 1 = ≤1% cells + 2 = 1–10% of cells + 3 = 11–33% of cells + 4 = 34–66% of cells + 5 = >66% of cells + Intensity score: 0 = none 1 = weak 2 = intermediate 3 = strong | Expression |
Ram Prassad, 2005 [51] | K19 | 18 total: 6 mild, 6 moderate, and 6 severe dysplasia Site not specified | 6 normal controls 4 non-keratinized and 2 keratinized sites | Grading system not specified However, presence/absence of dysplasia was identified; dysplasia was not graded SA completed | H&E and IHC 500 cells counted at 40× magnification in 3 layers—basal, suprabasal and spinous layer | Expression |
Safadi et al., 2010 [52] | K19 | 43 total: 23 mild, 8 moderate, and 12 severe Site not specified | Polypoid fibrous hyperplasia to represent normal oral epithelium Site and number of controls not specified | WHO (1978) [65] Dysplasia graded SA completed | H&E and IHC Staining for K19 measured via ImageJ computer program—measured using color deconvolution plug in. | Expression |
Sakamoto et al., 2011 [53] | K1, K2e, K4, K5, K6, K7, K8, K9, K10, K13, K14, K15, K16, K17, K18, K19, K20, and hair keratins | 100 total Site not specified | Normal cells adjacent to OSCC specimens; for IHC, normal epithelium adjacent to OSCC and OED (100 sample) Sites not specified | WHO (2005) [72] Dysplasia graded No SA completed | H&E and IHC Assessment by comparing immunoreactivity in the lesion with that in normal epithelium of the same specimen | Expression |
Sanguansin et al., 2021 [54] | K17 | 91 total: 33 OLK without dysplasia and 58 OLK with dysplasia Site not specified | 12 normal controls Site not specified | WHO (2017) [73] Dysplasia graded SA completed | H&E and IHC Number of positive cases in a group calculated and also staining intensity graded on 0–3 score depending on number of cells that stained positive (semiquantitative—0 = ≤5% of immunoreactive cells; 1 = 6–25%, 2 = 26–50% and 3 = ≥51%). | Expression |
Sawant et al., 2014 [55] | K1, K5, K8, and K18 | 52 OLK total Site from BM | 10 normal controls Site from the BM | WHO (1997) [66] Dysplasia graded SA completed | H&E and IHC. IHC was quantified by visual assessment under x200 magnification; three fields (1 field = 100 cells) were counted by two pathologists Immunoreactivity was graded as follows: −/no = <10%; +/low = 11–30%; ++/moderate = 31–50%; +++/intense = >51% | Expression |
Schaaij-Visser et al., 2010 [56] | K4 and K13 | 48 OLKs total Site not specified | No controls | WHO (1978) [65] Dysplasia graded SA completed | H&E and IHC semi quantitative—estimated % of stained cells x staining intensity (0 = absent; 1 = weak; and 2 = strong). | Expression and prognostic |
Schulz et al., 992 [57] | K1, K2, K3, K4, K5, K6/11, K7/13, K8, K9, K10, K12, K14–15, K16, K17, K18, and K19 | 20 OLK total Site not specified | 22 normal controls 10 from non-keratinized and 12 from keratinized gingiva | Grading system not specified Presence/absence of dysplasia was not identified; dysplasia was not graded No SA completed | H&E and IHC, SDS page, and Western blotting | Expression |
Shahabinejad et al., 2021 [58] | K7 and K20 | 38 dysplasia total Site not specified | No controls | Grading system not specified Dysplasia graded SA completed | H&E and qRT-PCR | mRNA expression |
Sihmar et al., 2022 [59] | K8 and K18 | 30 OLK total Site not specified | 10 normal controls Site not specified | Grading system not specified However, presence/absence of dysplasia was identified; dysplasia was not graded SA completed | H&E and IHC Semi-quantitative assessment: the number of K8- and K18-positive cells was counted in 50 cells of each field by two observers; the scoring was as follows: (−) no color; (+) yellow; (++) light brown; and (+++) dark brown Cases were assigned to one of the following categories: 0% positive cells (−); 10% positive cells (+); 10–25% positive cells (++); 26–50% positive cells (+++); or more than 50% positive cells (++++) | Expression |
Su et al., 994 [60] | K7, K8, and C18 | 9 severe dysplasia total Sites not specified | 10 normal controls Site from BM, labial FOM hard palate dorsum of tongue and gingival sites | Grading system not specified Dysplasia was graded; however, all dysplasia samples was combined into 1 group for analysis No SA completed | H&E, IHC, and ISH | Expression |
Su et al., 996 [61] | K14 and K19 | 9 moderate-to-severe dysplasias Site from non-keratinized sites | 10 normal controls Site from BM, labial, FOM, hard palate, dorsum tongue, and gingival sites | Kramer (1980) [74] Dysplasia was graded However, all dysplasia samples was combined into 1 group for analysis No SA completed | H&E, IHC, and ISH | Expression |
Takeda et al., 2006 [62] | K19 | 62 total: 10 hyperplasia, 10 mild dysplasia, 10 moderate, 13 severe, and 10 CIS, 9 two phase dysplasia classified as moderate dysplasia Sites from tongue, gingiva, BM, hard palate, FOM, and lip. | 10 normal controls Sites from tongue, gingiva, BM, hard palate, FOM and lip | WHO (2005) [72] Dysplasia graded No ST completed for keratins | H&E and IHC Qualitative—assessed via layers—BM, parabasal layer (two layers above BM and next to basal layer, supra basal layer—above the parabasal layer) using microscope at ×400 zoom | Expression |
Vaidya et al., 998 [63] | K1/K2, K4, K5, K6, K7, K8, K10, K11, K13, K14, K16, K17, and K18 | 20 OLK total Site from buccal mucosa | Normal controls taken from adjacent to three of the OLK samples | Grading system not specified Presence/absence of dysplasia was not identified; dysplasia was not graded. No SA completed | Gel electrophoresis and immunoblotting for K1–19 | Expression |
Vigneswaran et al., 989 [64] | K1, K2, K5, K7, K8, K10, K11, K18, and K19 | 150 OLK total Site not specified | 15 normal controls Sites from labial, BM, lingual, gingival, and palatal tissue | Grassel-Pietrusky and Hornsein (1982) [75] Dysplasia graded No SA completed | H&E and IHC Semiquantitative 0 to +4 with regard to extent (1/3 s) of epithelium involved | Expression |
Wils et al., 2020 [65] | K13 and K17 | 84 OLK total Site not specified | 8 normal controls Site not specified | WHO (2017) [73] with the addition of differentiated dysplasia. Presence/absence of dysplasia was identified. Dysplasia was not graded. SA completed | H&E and IHC | Expression and prognostic |
Wils et al., 2023 [66] | K13 and K17 | 176 OLK total Site not specified | No controls | WHO (2017) [73] with the addition of differentiated dysplasia. Dysplasia graded SA completed | H&E and IHC K13 was negative when staining was even partly absent K17 was scored positive when epithelium showed detectable levels | Expression and prognostic |
Yagyuu et al., 2015 [67] | K13 and K17 | 94 total High-grade dysplasia (HGD) and low-grade dysplasia (LGD) Site not specified | No controls | WHO (2005) [72] and their expanded SIN system Dysplasia graded SA completed | H&E and IHC K13: 0 = strong diffuse expression; 1 = weak or patchy expression; 2 = no expression. The reverse of this scale was used for K17 Discrepant slides were re-evaluated using dual vision microscope to achieve a consensus | Expression, and prognostic |
Yoshida et al., 2015 [68] | K14 and K19 | 17 total: 9 LGD and 8 HGD Site not specified | 15 normal controls from Tissue from surgical margins | WHO (1997) [66] Dysplasia graded SA completed | H&E and IHC and RT PCR. >500 epithelial cells in each slide—percentage of +ve cells calculated in addition with the mean for all 44 samples; values were used as labelling indices | Expression |
Keratin | Studies That Investigated the Keratins of Interest | Expression in Oral Leukoplakia (OLK) | Overall Impressions for Utility |
---|---|---|---|
K1 and/or K10 | 12 studies in total: | General trend:
|
|
K2p (K76) and K2e | 4 studies in total: | K2p: General trend of LOE of K2p (K76) in dysplastic samples.
|
|
K3 | 1 study in total:
|
|
|
K4 and/or K13 | 17 studies in total: | Expression studies: General trend:
General trend:
|
|
K5 and/or K14 | 12 studies in total: |
General trend:
|
|
K6 | 3 studies in total: |
|
|
K7 | 3 studies in total: | General trend: A small amount of OLK +/− dysplasia samples gain expression of K7.
|
|
K8 and or K18 | 12 studies in total: | General trend: |
|
K9 | 3 studies in total: |
|
|
K12 | 2 studies in total: |
|
|
K15 | 3 studies in total: |
|
|
K16 | 4 studies in total: | General trend: GOE of K16 in a small proportion of OLK or dysplasia samples.
|
|
K17 | 15 studies in total: | Expression studies: General trend:
|
|
K19 | 15 studies in total: | General trend:
|
|
K20 | 2 studies:
|
|
Keratin | Studies That Investigated the Keratins of Interest | Expression in Oral Leukoplakia (OLK) | Overall Impressions for Utility |
K1 and/or K10 | 1 study in total:
|
|
|
K2e | 1 study in total:
|
|
|
K4 and/or K13 | 2 studies in total: |
|
|
K5 and/or K14 | 2 studies in total: |
|
|
K7 | 2 studies in total: |
|
|
K8 and/or K18 | 1 study in total:
|
|
|
K16 | 1 study in total:
|
|
|
K19 | 1 study in total: |
|
|
K20 | 1 study in total:
|
|
|
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Murthy O, G.; Lau, J.; Balasubramaniam, R.; Frydrych, A.M.; Kujan, O. Unraveling the Keratin Expression in Oral Leukoplakia: A Scoping Review. Int. J. Mol. Sci. 2024, 25, 5597. https://doi.org/10.3390/ijms25115597
Murthy O G, Lau J, Balasubramaniam R, Frydrych AM, Kujan O. Unraveling the Keratin Expression in Oral Leukoplakia: A Scoping Review. International Journal of Molecular Sciences. 2024; 25(11):5597. https://doi.org/10.3390/ijms25115597
Chicago/Turabian StyleMurthy O, Guru, Jeremy Lau, Ramesh Balasubramaniam, Agnieszka M. Frydrych, and Omar Kujan. 2024. "Unraveling the Keratin Expression in Oral Leukoplakia: A Scoping Review" International Journal of Molecular Sciences 25, no. 11: 5597. https://doi.org/10.3390/ijms25115597