|Year : 2012 | Volume
| Issue : 4 | Page : 591-597
A comparative analysis of langerhans cell in oral epithelial dysplasia and oral squamous cell carcinoma using antibody CD-1a
Juhi Upadhyay1, Nirmala N Rao2, Ram B Upadhyay1
1 Department of Oral and Maxillofacial Pathology, KD Dental College and Hospital, Mathura, Uttar Pradesh, India
2 Department of Oral and Maxillofacial Pathology, Manipal College of Dental Sciences, Manipal, Karnataka, India
|Date of Web Publication||29-Jan-2013|
Ram B Upadhyay
Department of Oral and Maxillofacial Pathology, KD Dental College and Hospital, Nh-2, Post - Chatikara, Mathura, Pin- 281001, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Background: The integrity of the immune system is necessary to control tumor progression and a compromised state contributes to tumor escape.
Aims: The study intends to evaluate the presence and distribution pattern of Langerhans cells (LC) in Oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC) oral epithelial dysplasia and oral squamous cell carcinoma and elucidate their role. The study analyses LC in histological zones of the epithelium and connective tissue, which has seldom been attempted previously.
Materials and Methods: Forty-five microscopic sections (i.e. 5 normal, 15 OED and 25 OSCC) were examined for expression of LC marker CD1a using immunohistochemistry. LCs were counted in zones of epithelium and connective tissue.
Statistical Analysis Used: Results were analyzed using SPSS Version 16.0 and subjected to one-way ANOVA comparison and Student's t-test and Wilcoxon Z test.
Results: Significant decline in LC count was observed with progressing grade of OED and OSCC. The basal and suprabasal zones in OED and superficial zone in OSCC exhibited the highest density of LCs. The low LC count in severe dysplasia was attributed to paucity in the basal zone. There was a significant paucity of LCs in the sub-epithelial zone of all the grades of OSCC, with high influx of LCs within the tumor stroma. Also, poorly differentiated OSCC exhibited a significant decrease in the LC count within the overlying epitheilium as well as the tumor stroma.
Conclusion: The present study suggests that there is a recruitment of LCs in the neoplastic process. Changes observed in LC distribution within the zones of dysplastic epithelium and tumor stroma can be interpreted as their pathophysiologic function.
Keywords: CD1a, Langerhans cells, oral epithelial dysplasia, oral squamous cell carcinoma, oral epithelial dysplasia and oral squamous cell carcinoma
|How to cite this article:|
Upadhyay J, Rao NN, Upadhyay RB. A comparative analysis of langerhans cell in oral epithelial dysplasia and oral squamous cell carcinoma using antibody CD-1a. J Can Res Ther 2012;8:591-7
|How to cite this URL:|
Upadhyay J, Rao NN, Upadhyay RB. A comparative analysis of langerhans cell in oral epithelial dysplasia and oral squamous cell carcinoma using antibody CD-1a. J Can Res Ther [serial online] 2012 [cited 2019 Dec 6];8:591-7. Available from: http://www.cancerjournal.net/text.asp?2012/8/4/591/106565
| > Introduction|| |
Oral squamous cell carcinoma (OSCC) is known to arise from non-invasive lesions of the mucosa, which encompasses a histological continuum between normal mucosa at one end to high-grade oral epithelial dysplasia (OED) at the other, finally evolving into frank carcinoma. During the initiation, promotion, and progression of multi-step carcinogenesis changes in host immunological factors have been observed.  Inadequate presentation of tumor antigens by host Langerhans cells (LCs) is one potential mechanism that allows tumor progression.
First discovered in 1868,  LCs remained enigmatic for over a century, until they were described in contact dermatitis as "the most peripheral outpost of the immune system".  A rapidly growing body of literature suggests a pivotal role for LCs in various immune and inflammatory responses, including anti-tumor immunity. LCs were first reported in human tumors and have been elaborated extensively since then.  In tumor-bearing sites LCs uptake, process, and present tumor-associated antigens to naive or memory T-cells, which leads to generation of tumor-specific effector T-cells capable of recognizing and eliminating tumor cells. Immune tolerance develops due to altered function of LCs,which subsequently allow proliferation of aberrant cells. 
The present study intends to compare the distribution pattern of LC in the neoplastic process from normal to dysplasia to frank carcinoma. Further, an attempt has been made for the first time to evaluate the distribution of LCs by dividing the epithelium and the connective tissue of OED and OSCC into various zones. The critical analysis made provides a better system for evaluation of the immunologic changes, i.e. LCs in potentially-neoplastic and neoplastic tissues.
| > Materials and Methods|| |
Twenty-five 10% formalin-fixed paraffin-embedded tissue samples of OSCC (10 of well-differentiated, 10 of moderately differentiated; 5 of poorly differentiated OSCC), 15 of OED (5 of mild, moderate and severe dysplasia each) and five of normal mucosa distributed among 25 males and 20 females, with mean age of 48.5 years were collected. The control tissues were obtained from areas adjacent to the biopsied mucocele cases. -. All samples were preferably collected from region of non-keratinized mucosa. The diagnosis, grading and tissue selection was with the consent of two reviewing oral pathologists.
Patients with history of radiotherapy and immunosuppressive/corticosteroid treatment were excluded from the sample group.
Two sections, of 4-μm thickness were prepared from each of the tissue blocks. The first section was stained with hematoxylin and eosin for histological confirmation and grading of lesions. The second section was stained with rabbit anti-human CD-1a (pre-diluted) monoclonal antibody and super sensitive polymer-HRP IHC detection system for the immunohistochemical detection of CD-1a from Biogenex Life Sciences Pvt. Ltd.
The sections were deparaffinized, hydrated and brought to water. Antigen retrieval was done with pressure cooker method, using Tris-EDTA buffer (pH 9.2). Endogenous peroxidase activity was abolished with hydrogen peroxide treatment for 30 min, and sections were then treated with 0.1% trypsin solution at 37°C for 1 h. Slides were incubated for 2 h at 37°C with primary antibody CD1a and were visualized using freshly prepared diaminobenzidine tetrachloride chromogen. The slides were then counterstained with Harris hematoxylin and cover-slipped. For each batch of staining, a negative control was performed, where the tissue sections were treated with goat serum in phosphate-buffered saline instead of the primary antibody. Sections of thymus were taken as positive control.
Identification and quantification
The cells were typified as Langerhans cells under the following criteria: (a) CD1a staining found localized which appeared brownish in color, (b) Round/ovoid brown stained cell body which must be visible completely; (c) at least one dendritic process must be present from the cell surface.
The LCs were counted in three zone of the epithelium i.e., along the basal layers, suprabasal layer and the superficial epithelium. Within the underlying connective tissue stroma the zones were divided as papillary portion of lamina propria, reticular lamina propria and submucosa of the deeper connective tissue. This method was followed to assess LCs in normal oral mucosa and OED. The criteria followed were the same as mentioned above for counting cells in the overlying epithelium in sections of OSCC. And for assessment of cells in the tumor stroma, the cells were counted in two zones divided as subepithelial connective tissue and tumor stroma. For each zone ten continuous non-overlapping high-power fields at 400x magnifications were selected. LCs were assessed for each selected field by manual counting performed by two observers.
The scores of both observers were subjected to Wilcoxon Z test, and the interobserver variation was found to be minimal. Further analyses were done using the mean of the number of LCs counted by both the observers. Results were further analyzed using SPSS Version 16.0 (Statistical Package for Social Sciences, Chicago, Illinois, USA) and subjected to one-way ANOVA comparison and Student's t-test.
| > Results|| |
Under light microscope the CD1a-positive LCs exhibited a uniform staining intensity of brown color, round to oval morphology, with dendritic cytoplasmic processes extending onto adjacent epithelial cells [Figure 1].
|Figure 1: Microphotograph showing CD1a-positive LCs in the epithelium of normal oral mucosa (20x) (marked with arrow)|
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The LC count was compared among the three groups, i.e. normal oral mucosa (1.55 ± 1.10), OED (4.55 ± 4.37) and OSCC (6.41 ± 5.33), and was found to be statistically significant (P-value 0.000, one-way ANOVA) [Table 1]. LC count within the epithelial compartment of OED (5.88 ± 5.01) and OSCC (6.00 ± 3.87) was similar, whereas within the connective tissue a significant influx was observed in OED (3.00 ± 2.83) compared to control (0.88 ± 0.67) (P value < 0.05), with further increase in OSCC (7.00 ± 6.89), suggesting recruitment of LCs with progression of the neoplastic process.
|Table 1: Mean cell count of Langerhans cells in the three groups as per grades and zones|
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The mean number of LCs counted in mild, moderate and severe dysplasia was 5.98 ± 4.77 (epithelium: 6.32 ± 4.38; connective tissue: 3.82 ± 3.28:), 7.60 ± 6.7 (epithelium: 7.94 ± 6.35; connective tissue: 3.21 ± 3.00) and 3.69 ± 2.4 (epithelium: 3.40 ± 2.86; connective tissue: 1.76 ± 1.52) respectively [Table 1]. The LC count in the epithelium of the three grades of dysplasia was found to be significant (P value < 0.05, one-way ANOVA) with the least count in severe dysplasia [Table 1]; [Figure 2], [Figure 3].
|Figure 2: Microphotograph showing the distribution of CD1a-positive Langerhans cells in dysplastic epithelium (moderate dysplasia), with predominant distribution in the basal and supra-basal zones of the epithelium (marked with black arrow) (10x)|
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|Figure 3: Microphotograph showing poor distribution of CD1a-positive LCs in the dysplastic epithelium (severe dysplasia) (marked with black arrow), (10x)|
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Within the zones of dysplastic epithelium LCs exhibited a significantly higher count in basal and supra-basal zones in all specimens when compared to control [Figure 1], [Figure 2]; [Figure 7]. However, on intra-group comparison, basal zone of the epithelium and papillary zone of the connective tissue in severe dysplasia exhibited a significantly low LC count when compared to mild/moderate dysplasia (P value < 0.05) [Table 1]; [Figure 2], [Figure 3], [Figure 7]; [Figure 8] thus indicating a depletion of LCs in severe dysplasia.
The mean number of LCs in well-differentiated, moderately differentiated and poorly differentiated OSCC was 7.54 ± 6.24 (epithelium: 6.26 ± 2.71; connective tissue: 9.47 ± 9.10), 6.02 ± 4.50 (epithelium: 5.86 ± 4.75; connective tissue: 6.23 ± 4.28), and 4.51 ± 3.80 (epithelium: 5.60 ± 4.58; connective tissue: 3.06 ± 1.78) respectively [Table 1], [Figure 4], [Figure 5]; [Figure 6]. A significant increase in the LC count was observed in the superficial zone of the epithelium in all the grades of OSCC [Figure 6]. Further, it is interesting to observe that the increase in the LC count corresponded with the advancing grade of OSCC [Table 1]; [Figure 7]. Abundant LCs were also observed within tumor connective tissues, often at the periphery of tumor islands. On the contrary, LCs were minimal in the sub-epithelial zone [Table 1]; [Figure 4], [Figure 8]. Interestingly, tumor stroma exhibited a gradual decline in the LC count with the advancing grade of OSCC. Poorly differentiated OSCC showed a significant paucity of LCs within the zones of the epithelium as well as connective tissue [Table 1]; [Figure 5]; [Figure 8].
|Figure 4: Microphotograph showing the distribution of CD1a-positive Langerhans cells in tumor stroma of well-differentiated OSCC (marked with red arrow), also showing the relative paucity of Langerhans cells in the sub-epithelial zone (marked with black arrow) (10x)|
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|Figure 5: Microphotograph showing the distribution of CD1a-positive Langerhans cells in tumor stroma (marked with red arrow) and overlying epithelium (marked with black arrow) of well-differentiated OSCC (10x)|
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|Figure 6: Microphotograph showing an increase in the number of CD1a-positive Langerhans cells within the superfi cial zone of the overlying epithelium of poorly differentiated OSCC (marked with black arrow) (10x)|
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|Figure 7: Bar diagram showing distribution of Langerhans cells in epithelial zones|
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|Figure 8: Bar diagram showing distribution of Langerhans cells in connective tissue zones|
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The analysis of mean LC count showed no correlation between the density of LCs and patient age and sex in the present study.
| > Discussion|| |
Altered immune, inflammatory, and angiogenesis responses are observed in patients with head and neck squamous cell carcinoma. LCs as sentinels of immune response, have been investigated in several oral mucosal diseases, including OED and OSCC.
In the control tissues [Figure 1] of the present study the LCs were found to be restricted mainly in the intra-epithelial compartment [Table 1], which is a consistent and characteristic feature with supra-basal distribution. ,, The study observed a significant recruitment of LCs in OED compared to controls which can be attributed to the uptake of new antigens produced by the dysplastic cells. A further increase is contributed in response to the various other factors like oral carcinogens, secondary infection of the lesion and trauma. , Although a concurrent increase in LCs with hyperplasia cannot be ruled out, further studies are required with comparisons between epithelial hyperplasia and OED.
Three mechanisms that could have led to an increase in the LC infiltration of the dysplastic tissues are: (a) increased mitosis, (b) reduced migration to the lymph nodes; and/or (c) increased recruitment into the epidermis.  However, it is widely believed that LCs are end-cells and incapable of cell division,but increased mitotic figures have been demonstrated and confirmed by electron microscopy incorporation of 3H-thymidine and DNA densitometric analysis. ,,, Although LCs exhibit a low level of mitotic activity, their contribution to the increase in LC count within the epithelial compartment cannot be excluded. 
It has also been suggested that the factors released by the dysplastic/neoplastic cells inhibit the LC migration to lymph nodes leading to accumulation of LCs within the epithelial compartment.  Furthermore various oral carcinogens are known to induce production of cytokines, like PGE2, IL-6, and TNF-α, by oral epithelial cells which are immuno-suppressive and known to inhibit LC differentiation, maturation and function. , Thus, the local environment of the dysplastic epithelium may further modulate the LC distribution.
The increase in LC count within the connective tissue stroma of OED, with predominant distribution within the papillary zone was in accordance to previous studies. , However, the decrease in LCs with the progression to severe dysplasia [Table 1]; [Figure 3] was contradictory to previous studies. , This can be explained by the observation that all the patients of the study group gave a positive history of tobacco.  A dose-dependent response has been demonstrated with the number of cigarettes smoked and the depletion of the LCs. LCs recognize the antigenic products released by the tobacco and the neo-antigens generated by the dysplastic cells and migrate out to sensitize the T-cell in lymph nodes.  Previous studies have concluded similar findings and suggest that it is this LC depletion, rather than carcinogenic treatment that is a critical factor which leaves skin immunologically compromised and favors progression of the dysplastic process.  A similar phenomenon could be applicable to the observation of the present study. However, if such a view was to be true, papillary and reticular zones of lamina propria should have demonstrated increase in LC with the grade of dysplasia. On the contrary, a gradual decrease of LCs was seen [Table 1]; [Figure 8]. Thus inferring from the observations of the present study, two more mechanisms can be considered, (a) dysplastic epithelium was inhibiting the recruitment of LCs, and (b) interaction with the dysplastic and inflammatory cells was causing death of LCs. The present study supports the above view based on two main observations, i.e. a decrease in the LC count in the basal zone of the epithelium as well as the connective tissue stroma of severe dysplasia [Table 1]; [Figure 3] and [Figure 7], indicating a lack of migration as well as recruitment of LCs.
The present study suggests that, in severe dysplasia in spite of the presence of the epithelial pathology, the lesion is not immunologically equipped with adequate LCs. Thus, the tissue is unable to elicit a protective immune response to aberrant cells, allowing carcinogenic transformation.  Such a finding may also validate the higher risk of malignant transformation associated with severe dysplasia. However, evidence in the literature for such views is scanty and requires further investigation.
The abundance of LCs in the overlying epithelium of OSCC observed in the present study is compatible with the observations of a previous study.  Similar LC count in the epithelium of OSCC and OED was observed in the present study [Table 1]; [Figure 7] and supported with the fact that the overlying epithelium of OSCC also exhibits dysplastic features and is exposed to oral carcinogens.
Decrease LC count in poorly differentiated OSCC in the present study [Table 1]; [Figure 7] and [Figure 8], draws support from previous studies, thus reaffirms that LC distribution in overlying epithelium were influenced by the underlying tumor microenvironment.  Although there is lack of literature describing the reasons for the increase in the LCs in the superficial zones of OSCC [Table 1]; [Figure 6] and [Figure 7], it is tempting to speculate that such an alteration may stem from secondary infection or ulceration of the overlying epithelium associated with OSCC.
Presence of LCs within the tumor stroma of OSCC [Table 1]; [Figure 4] and [Figure 5] has often been simply explained as that being associated with invading malignant epithelial cells. However, the literature holds substantial evidence that increase in LCs within the tumor stroma is organized recruitment. Significant paucity of LCs in the sub-epithelial zone indicates that these LCs have not migrated from the overlying epithelium, thus Agreeing with the view that LCs are recruited in response to the tumor microenvironment.  It has been suggested that the greater influx of LCs in the invasive lesions reflects the increased tumor bulk, and concomitant increase in the production of the putative 'chemotactic factors'. Chemokine MIP-3α/CCL20 produced by tumor cells are selectively chemotactic to LCs  whereas IL-10, TGF-β, VEGF could regulate the recruitment and migration in the tumor microenvironment.  Furthermore, a study  suggested that tumor-derived factors can induce dendritic cell apoptosis. The present study thus indicates diminishing immune responses with progression of tumor, which are in accordance with other researchers. ,,
The authors agree with a previous study that the diminished infiltration of LCs within the tumor stroma might result as a consequence of the immunosuppressive effect of the tumor micro-environment.  Another possibility could be that the LCs in the tumor stroma exhibited a lack of CD1a expression under the influence of tumor-derived factors thereby providing an erroneous result.  In the present study CD1a antibody was used as the sole immunohistochemical marker and could have served as a drawback in the detection of those LCs which failed to express CD1a.
An interesting question that may arise with this standpoint is that, in spite of such an increase in the number of infiltrating LCs and claims of its role in tumor immunity  there is still progression of the tumor.  A previous study suggested that the ability of tumor cells to evade host immune system control could be attributed to the fact that the tumor cells themselves may manifest low immunogenicity, and thus escape detection by LCs. Further, it seems that not only the number, but also the functional capability of LCs may be compromised within the tumor stroma. ,,
The present study suggests that there is an alteration in the number and distribution pattern of LCs. Further investigation for the association between LCs and presence/severity of inflammation in connective tissue could offer better understanding of the immunologic alterations.
| > Conclusion|| |
Several questions yet remain unanswered and it is unclear if the alteration in the density and distribution pattern of LCs is a cause or a result of the neoplastic process. The present study analyzed only one aspect of the multi-directional alterations that take place in pathogenesis of the neoplastic processes. The present study critically analyzed the distribution pattern of LCs in the zones of dysplastic as well as neoplastic tissue, which has not been attempted in previous studies for OED and OSCC. Further, the LCs within severe dysplasia and poorly-differentiated OSCC could be therapeutically modified for better prognosis. Although the present study mandates further validation and confirmation with larger samples, it provides a better stage for analysis of the versatile LC.
| > Acknowledgments|| |
We sincerely thank Manipal University, Manipal, Karnataka, India for giving financial assistance for the study.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]