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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 8  |  Issue : 4  |  Page : 139-147

Histologic characteristics of invasive oral carcinoma and the role of epithelial-mesenchymal transition in cancer progression


1 Department of Pathology, HIMSR and Associated HAH Centenary Hospital, New Delhi, India
2 Department of Oto-Rhino-Laryngology, HIMSR and Associated HAH Centenary Hospital, New Delhi, India

Date of Submission23-Mar-2021
Date of Decision25-Jul-2021
Date of Acceptance27-Jul-2021
Date of Web Publication3-Dec-2021

Correspondence Address:
Dr. Zeeba S Jairajpuri
Department of Pathology, Hamdard Institute of Medical Sciences and Research, Hamdard Nagar, New Delhi - 110 062
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JCRP.JCRP_25_21

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  Abstract 


Background: To find the association of tumor budding, depth of invasion (DOI), and epithelial-to-mesenchymal transition (EMT) markers (E-cadherin and smooth muscle actin [SMA] expression) with prognostic factors of oral squamous cell carcinoma (OSCC). Materials and Methods: A cross-sectional study conducted on 50 cases of histologically proven OSCC were selected for the assessment of TNM staging, tumor budding, DOI, and EMT markers (E-cadherin and SMA expression). Associations were evaluated between established clinical prognostic factors and histological parameters. Statistical analysis was performed using SPSS version 21.0. (IBM, Chicago, Illinois, USA) and P < 0.05 was considered statistically significant. Results: In the study, the median age of distribution was 48.5 years with 86% of males. Tobacco consumption was seen among 90% of patients. A significant association of pathological TNM staging with tumor budding and DOI (P < 0.05). There was a loss of E-cadherin expression with loss of tumor differentiation, progressive TNM stage, increasing DOI and more tumor budding (P < 0.05). On the contrary, α-SMA (% stained cells) expression showed an increase with increasing pathological T stage, N stage, tumor budding, and DOI (P < 0.0001). However, the tumor differentiation showed no significant association with SMA expression (P = 0.44). Conclusion: It can be concluded that EMT has a strong association with OSCC demonstrated by loss of E-cadherin and increased expression of α-SMA at the invasive front in higher grade carcinomas, in tumors with increased DOI, high-risk tumor budding, and increased pathological T and cases showing lymph node metastasis. Hence, SMA can be used in conjunction with loss of E-cadherin expression for determining the aggressive nature of OSCC and predicting the survival rates of the patients.

Keywords: Depth of invasion, epithelial-mesenchymal transition, tumor budding


How to cite this article:
Jetley S, Sultan B, Rana S, Khetrapal S, Sharma AP, Naseeruddin K, Jairajpuri ZS. Histologic characteristics of invasive oral carcinoma and the role of epithelial-mesenchymal transition in cancer progression. J Cancer Res Pract 2021;8:139-47

How to cite this URL:
Jetley S, Sultan B, Rana S, Khetrapal S, Sharma AP, Naseeruddin K, Jairajpuri ZS. Histologic characteristics of invasive oral carcinoma and the role of epithelial-mesenchymal transition in cancer progression. J Cancer Res Pract [serial online] 2021 [cited 2022 Jan 25];8:139-47. Available from: https://www.ejcrp.org/text.asp?2021/8/4/139/331654




  Introduction Top


Oral cancer is one of the most highly prevalent cancers worldwide accounting for over 30% of all cancers in India.[1] As per the GLOBOCAN report of the IARC 2012, these cancers accounted for 300,000 cases in 2012 (2.1% of the world total), with two-thirds occurring in men.[2] Despite the continuing evolution of diagnostic and therapeutic methods used in oncology, the histopathological factors with definite prognostic value for oral carcinoma that might aid in more precise selection of patients for various treatment strategies are not well defined.[3]

Tumor progression is a multifactorial and multistep process, and the biological behavior of oral carcinoma has been objectively assessed in many studies.[4],[5] Tumor thickness is an important prognostic factor in head and neck cancers. It is now accepted that tumor thickness reflects the depth of invasion (DOI) within the oral cavity and that it is a more accurate predictor of nodal metastasis, local recurrence, and survival than tumor size/diameter.[6]

Tumor budding is an independent prognostic factor linked with epithelial-to-mesenchymal transition (EMT), and it represents two properties of malignancy: loss of cellular cohesion and active invasion. It has been associated with aggressive behavior and is correlated with lymph node metastasis, recurrence, distant metastasis, and decreased survival in several cancers as well as in oral carcinoma.[7] Loss of epithelial morphology and acquisition of mesenchymal characteristics, known as the EMT, are typical in carcinoma cells and are correlated with the local invasiveness and metastatic potential of the tumor.[8] Cancer-associated fibroblasts (CAF) represents myofibroblastic differentiation at the invasive front, and it is associated with higher mortality.[9],[10]

This study evaluated the histologic characteristics at the invasive front (tumor budding, tumor thickness) along with selected immunohistochemical (IHC) studies to assess cancer progression in 50 cases of invasive oral carcinoma.


  Materials and Methods Top


The present study was conducted at Hakeem Abdul Hameed Centenary Hospital, New Delhi over a 3-year period. A total of 50 cases of histologically proven oral carcinoma with radical neck dissection were evaluated. Ethical approval was obtained from the Jamia Hamdard Institutional Ethical Committee (approval date October 25, 2017, approval number 13/17). Data on age, personal history and presenting clinical features were retrieved from the accompanying laboratory request forms and the patients' medical records.

All hematoxylin and eosin (H and E) stained pathology slides from the resection specimens were retrieved and uniformly reviewed. The histologic parameters DOI, tumor budding, lymph node status, and lymphovascular invasion were assessed in all of the cases.

DOI was used to assess the invasiveness of a carcinoma, regardless of any exophytic component. It was measured by establishing a horizontal line at the level of the basement membrane of the intact adjacent squamous mucosa. The deepest point of tumor invasion, which represents DOI is then calculated by dropping a perpendicular plumb line to the deepest point [Figure 1]. The DOI was recorded in millimeters.[11] Tumor budding was defined as a single cancer cell or a cluster of <5 cancer cells in the stroma of the invasive front. Tumor budding of <5/HPF was defined as low risk, and >5/HPF as high risk. Highest tumor budding was the score of budding.[12],[13] The universally acknowledged American Joint Committee on Cancer which uses the TNM scoring system to describe the extent of disease progression in cancer patients was adopted in this study.[11]
Figure 1: Microphotograph of measurement of DOI. Horizontal line joining the basement membrane of intact adjacent squamous mucosa with ulcerated mucosa. Vertical, perpendicular plumbline till the deepest point of invasion. DOI calculated in mm (H&E, 4X)

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The IHC markers assessed in this study were E-cadherin for evidence of EMT and smooth muscle actin (SMA) to identify CAF. IHC staining was done by the biotin-avidin technique with DAB as the chromogen. In parallel, poly-l-lysine-coated slides of sections of appendix were used as positive controls for both E-cadherin and SMA immunostaining and negative controls (by omitting the primary antibody) to ensure correct staining procedure.

Quantitative variables were compared using the independent t-test or Mann–Whitney test (when the datasets were not normally distributed) between two groups, and the Kruskal–Wallis test was used for comparisons between more than two groups. Qualitative variables were analyzed using the Chi-square test, and potential associations between the histological characteristics at the invasive front with histological type and grade, DOI, tumor budding, lymphovascular invasion, lymph node status, and the role of EMT by studying the expression of E-cadherin and SMA were investigated.


  Results Top


Fifty patients with oral squamous cell carcinoma (OSCC) who underwent radical surgery (glossectomy, radical mandibulectomy with radical neck dissection) at our institution during the study period of 3 years were the subjects of this study. The age of the patients ranged between 50 and 70 years, and 43 (86%) were male and 7 (14%) were female. The demographic details are depicted in [Table 1].
Table 1: Distribution of demographic characteristics

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OSCC can affect multiple subsites in the oral mucosa, the most common being the tongue, floor of the mouth, and gingiva. The most common primary subsites in the present study were the tongue (21/50), gingivo-buccal sulcus (14/50), buccal mucosa (7/50), and retromolar trigone (3/50) [Figure 2]. The tumor characteristics are depicted in [Table 2].
Figure 2: Representative clinical photograph of (a) An ulceroproliferative growth, right side of buccal mucosa (Arrow); (b) MRI face with neck, post contrast sagittal view showing heterogeneous intense enhancing lesion in posterior third of tongue (Arrow). (c) Composite resection specimen consisting of total soft paletectomy with bilateral inferior maxillectomy, and the soft palate shows ulcerated, fungating, grey white friable tumor (Arrows)

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Table 2: Distribution of tumour characteristics

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Conventional histological grading of OSCCs consists of well, moderately, and poorly differentiated tumors according to the degree of differentiation. In this study, 36 (72%) patients had well-differentiated histological grade, 12 (24%) had moderately differentiated, and only 2 (4%) had poorly differentiated OSCC [Table 2].

Lymphovascular invasion is a histological feature which is associated with a likelihood of regional and distant metastases. It was seen in 12 of our 50 cases who underwent radical resection, and 10 of these cases were high-risk tumors in the pT3 stage.

Tumor budding is defined as the presence of either isolated single cells or small cell clusters (up to four) scattered in the stroma ahead of the invasive tumor front [Figure 3]. Budding represents two malignant features: cellular discohesion and active invasion, and it is associated with a poor prognosis. Budding was classified as being high risk or low risk depending on the number of tumor cells or small clusters seen at the invasive front (>5/HPF- high grade, <5/HPF- low grade). Forty-four of the 50 patients had high-risk tumor budding, and only six patients had low-risk tumor budding.
Figure 3: Microphotograph of SCC at the invasive front showing high risk tumor budding.(H&E, 10X)

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In all 50 cases of radical resection, TNM staging was done according to AJCC. T1/T2 tumors are generally referred to as low-risk tumors, and T3/T4 tumors are referred to as high-risk tumors. In our study, most of the cases belonged to the high-risk category. Similarly, nodal involvement is associated with a poor prognosis. In this study, most of the patients had N2 (60%) followed by N1 (24%). Eight of the 50 patients had N0 pathological N stage [Table 2].

DOI assesses the invasiveness of a carcinoma regardless of any exophytic component, and it is an independent risk factor for assessing disease-free survival. It is calculated by establishing a horizon at the level of the basement membrane and dropping a plumbline from the horizon to the deepest point of invasion.[11] The height of the plumbline represents the DOI. A DOI >4 mm has been associated with a poor prognosis. The mean DOI of the patients in this study was 1.47 ± 0.88 cm, including 36% with a DOI >15 mm, 28% with 11–15 mm, and 24% with 6–10 mm, with only a few patients having a DOI ≤5 mm [Table 2].

A significant association was seen between DOI and tumor budding. All of the patients with low-risk tumor budding had a DOI between 0 and 5 mm, whereas the majority of the patients with high-risk tumor budding had a DOI >15 mm. Thus, the patients with high-risk tumor budding had a higher DOI compared to the patients with low-risk tumor budding, and the difference was significant (P < 0.05) [Table 3].
Table 3: Association of tumour budding and depth of invasion with pathological T stage

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The cases were then evaluated immunohistochemically for the expressions of E cadherin and α-SMA. E-cadherin was used to study the role of EMT and to predict invasiveness. [Table 4] shows the associations of various prognostic variables with E cadherin expression among the 50 cases with OSCC in this study. The results showed that 31 of the 50 (62%) patients showed 1+ (<10% staining) E-cadherin expression and six (12%) showed 2+ (10–20% staining) and 4+ (>50% staining), respectively. E-cadherin expression was absent in 2/50 patients. The location of staining of E-cadherin was also examined. Of the 50 cases, 29 showed membranous staining, 12 showed membranous and cytoplasmic E-cadherin expression, seven showed the cytoplasmic location of E-cadherin expression, and two did not show an expression of E-cadherin staining. The intensity of staining was also evaluated, and most cases showed weak and homogeneous staining intensity (28/50 cases), followed by strong intensity (20/50 cases) and an absent expression (2/50 cases).
Table 4: Association of prognostic variables with E-cadherin

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A significant association was seen between E-cadherin expression and DOI as depicted in [Table 4]. Most of the patients with a DOI >10 mm had an E-cadherin expression of 1+, whereas most of the patients with a DOI <10 mm had an E-cadherin expression >1+. None of the patients with a DOI of 0–5 mm, 33.33% of the patients with a DOI of 6–10 mm, 78.57% of the patients with a DOI of 11–15 mm, and 88.89% of the patients with a DOI of >15 mm had an E-cadherin expression 1+. Therefore, a lower DOI was associated with a higher E-cadherin expression of >1+, and the association was significant (P < 0.05) [Figure 4].
Figure 4: (a)Well Differentiated SCC with strong, membranous, 3+ E-cadherin expression(Arrow)(IHC,40X). (b)Microphotograph of Well Differentiated SCC with strong, membranous, 3+E-cadherin expression (Arrow)(IHC, 40X). (c) Microphotograph of Moderately Differentiated SCC with weak, membranous, 1+ E-cadherin expression (Arrows) (IHC, 40X). (d) Microphotograph of Poorly Differentiated SCC with heterogeneous/absent E-cadherin expression (IHC, 40X)

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In OSCC, the cells of the activated stroma (i.e., fibroblasts with smooth muscle properties) play an important role in tumor progression. Myofibroblasts are distinctive fibroblasts expressing α-SMA. CAFs have been described in association with parameters that worsen the prognosis in OSCC. In the present study, 23/50 patients had a spindled distribution pattern, followed by 18/50 patients with an interwoven network distribution pattern, and focal Myofibroblasts were seen in only a few patients. According to the percentage of cells stained, the expression of α-SMA in this study showed that most of the patients (33, 66%) had a score of 3++ (abundant/ >50%), followed by nine patients with a score of 2+ (scanty/ >1%<50%), and eight with a score of 1- score (negative/<1%) [Figure 5].
Figure 5: (a) Microphotograph showing Poorly Differentiated SCC with 3++, spindle distribution pattern of α-SMA expression (Arrows) (IHC, 40X). (b) Microphotograph of 2+, focal distribution pattern of staining of α-SMA in Well Differentiated SCC. (IHC, 40X). (c) Microphotograph of 2+, network distribution pattern of staining expression of α-SMA in Poorly Differentiated SCC (Arrows). (IHC, 40X). (d) Microphotograph of Moderately Differentiated SCC showing 3++, spindle distribution pattern of distribution of α-SMA (IHC, 10X)

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A significant association was seen between α-SMA expression (percentage staining) and DOI as shown in [Table 5]. Most of the patients with a DOI >10 mm had a 3++ (abundant) expression of α-SMA; 100% of the patients with a DOI 11–15 mm and 94.44% of the patients with a DOI >15 mm showed α-SMA expression, on the other hand, most of the patients with a DOI <10 mm had 1− (negative) or 2+ (scanty) α-SMA expressions; 100% of the patients with a DOI 0–5 mm and 83.34% of the patients with a DOI 6–10 mm. This inferred that the patients with a lower DOI had a lower α-SMA expression (percentage staining); while the patients with a higher DOI had a significantly higher expression of α-SMA (percentage staining) (P < 0.05).
Table 5: Association of prognostic variables with alpha smooth muscle actin (percentage stained cells)

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  Discussion Top


Oral carcinoma is a major health problem in developing countries, and also a leading cause of death. The biological behavior of OSCC is uncertain and this uncertainty in tumor progression has led researchers to seek factors that might alter the prognosis. A wide range of tumor features, including size and site, histologic malignant grade, tumor thickness, tumor budding, and lymphovascular invasion. have been reported to be major risk factor that adversely affect the prognosis of patients with OSCC.[12]

In this study, we enrolled 50 cases with OSCC who underwent radical neck dissection. They were assessed for prognostic indicators such as DOI and tumor budding. EMT and the density of CAFs at the invasive front of the oral carcinoma as measured by E-cadherin and α-SMA staining were also assessed and correlations were analyzed between the expressions of these markers and various prognostic indicators.

In current practice, information obtained from clinical examinations and radiologic imaging are used to assign a clinical stage (cTNM), which is then used to stratify patients for selection of therapy and to report outcomes of treatment. In cases with positive lymph nodes during surgery, postoperative radiation is recommended to improve loco-regional control.[14] The pathologic stage (pTNM) after surgical resection as derived from histopathologic examinations of the tumor and/or regional lymph nodes is useful in selecting postoperative adjuvant therapy and for estimating prognosis.[15] T1/T2 tumors are generally referred to as low-risk tumors, and T3/T4 tumors are referred to as high-risk tumors. The survival rate and outcomes have been closely related to the stage of tumor at the time of diagnosis. The prognosis also depends or varies with tumor primary site, nodal involvement, tumor thickness, and the status of the surgical margins.[6] In our study, most cases belonged to the high-risk category (i.e., pathological T3 stage - 64% of the cases and pathological T4 stage - 10% of the cases). Regional lymph node metastases were seen in 42 of the 50 patients (84% cases) in this study.

Tumor thickness was first reported as a prognostic factor in cutaneous melanoma in 1970 by the pathologist Alexander Breslow at George Washington University. He reported a significant link between tumor thickness and both tumor-free survival and metastatic disease.[16] Since then, many authors have tested this parameter in OSCC.[12],[17],[18] Tumor thickness differs from DOI, although many clinicians use the two terms interchangeably. DOI is defined as the extent of cancer invasion into the tissue beneath the epithelial basement membrane, and it is regarded to be a better predictive parameter than tumor thickness. The 8th Edition of the AJCC recommendations proposes that DOI should be recorded in all pathological staging of oral carcinomas. It is now recognized as one of the independent risk factors for assessing disease-free survival. Increased DOI has been associated with a poor prognosis. In our study, the mean DOI across all groups was 1.47 ± 0.88 cm; which carried a good prognosis overall. Previous studies have shown that DOI is associated with increasing stage (T) and nodal involvement (N).[12],[17],[18] Ebrahimi et al. in a multicenter retrospective study assessed a modified staging system for oral cancer which integrated the DOI into the T categories and concluded that it had a greater prognostic value compared with the current AJCC T staging. They proposed an improved oral cancer T staging system based on incorporation of DOI that should be considered in future versions of the AJCC staging system after external validation.[19]

Tumor budding is a specific type of invasive growth in carcinomas which is characterized by the invasion of single tumor cells or small clusters of tumor cells (<5 cells) at the invasive front leading to dissemination of the tumor and poor prognosis. This is due to the loss of cellular cohesion and active invasive movement with a definitive role in EMT. Its role as an independent prognostic factor was utilized by Brandwein-Gensler et al., who developed a novel histologic risk assessment system to evaluate the aggressiveness of head and neck SCC.[20] The advantages of a tumor budding-based index as a prognostic indicator are the simplicity and reproducible measurements of the budding. It is readily adaptable to routine H and E staining-based histopathological examinations without the need for additional cost-demanding techniques. In our study, most of the cases (88%) had high-risk tumor budding (>5 cells at the invasive front/HPF) and 12% had low-risk tumor budding (<5 cells at the invasive front/HPF). We also found a significant association of tumor budding with increasing T and N stages of the tumor. All of the patients with pathological T stages including T2, T3, and T4 had associated high-risk tumor budding, whereas all of the patients with T1 pathological T stage had low-risk tumor budding; and most of the patients with pathological N stage N1 and N2 had high-risk tumor budding compared to those with N0. Our results are similar to those of the study by Angadi et al.[7] Tumor budding is a readily detectable histopathological feature, and it has been recognized to be an adverse prognostic factor in several human cancers including oral cancers. Recent research has confirmed the association of tumor budding with increasing grade and stage of OSCC and decreased survival.[12] Both the additional prognostic factors of tumor budding and DOI showed strong associations among themselves as well. All of the patients with low-risk tumor budding had a DOI between 0 and 5 mm, whereas most of the patients with high-risk tumor budding had a DOI >15 mm (P < 0.05). Thus, the two parameters had a synergistic effect in predicting the prognosis of the patients.

Loss of epithelial morphology and acquisition of mesenchymal characteristics, known as the EMT, are typical for carcinoma cells and are correlated with the invasiveness and metastatic potential of the tumor.[8] EMT has been shown to be a reversible biologic process that is important during prenatal development (Type I EMT) and in adults. It can be found in several pathophysiological conditions, inflammatory process, and normal wound healing in adults (Type II EMT).[21] EMT is also a well-known event during cancer metastasis. The step-wise accumulation of genetic mutations during carcinogenesis leads to a reduction/loss of E-cadherin in epithelial cells, with the eventual loss of cell-to-cell adhesion and separation of tumor cells. Thus, the epithelial cells lose their apico-basal polarity, gain motility and acquire the mesenchymal phenotype which heralds metastasis.[22] One of the best-studied processes of EMT is the breakdown of intercellular adhesion between epithelial cells by inhibiting the expression of E-cadherin, and aberrantly expressing higher levels of N-cadherin: termed “cadherin switching.”[21] In our study, we used E-cadherin to study the role of EMT and to predict invasiveness. Most of the patients (31/50 patients) had a 1+ (<10%) E-cadherin expression, and it was absent in two patients – signifying a loss of E-cadherin expression. We found a significant association between E-cadherin expression and histologic grade (poorly differentiated tumors had an absent expression of E-cadherin, well-differentiated tumors had a strong expression); pathological T stage: (higher pathological T stage [T3/T4] had either an absent or low E-cadherin expression); pathological N stage (loss of E-cadherin was seen in lymph node-positive cases); tumor budding (high-risk tumor budding patients had a low E-cadherin expression); and DOI (increased DOI was seen in the patients with a low E-cadherin expression). Our study results are in agreement with Kaur et al.[23] The main observations of this study were that well-differentiated OSCC expressed E-cadherin often as strongly as normal stratified squamous epithelium, while in poorly differentiated OSCC the expression of E cadherin was lost or cytoplasmic, and in moderately differentiated tumors it was expressed in a heterogeneous fashion. Our results are similar to those of Tanaka et al.,[24] who observed a significant relationship between reduced E-cadherin and invasiveness of OSCC. E-cadherin showed a significant association with all prognostic factors and decreased or loss of E-cadherin expression was found in the advanced stage/grade of OSCC. Thus, E-cadherin can be used as a useful adjunct IHC marker to differentiate well and poorly differentiated tumors in cases of the diagnostic dilemma; and in addition, its loss of expression may predict the invasiveness of oral cancers.

Vimentin is an intermediate filament normally expressed by cells presenting a mesenchymal phenotype. Its expression by epithelial malignant tumors cells is associated with high invasiveness, and some studies have described it as a reliable EMT marker.[25] Other studies have demonstrated differences in the expression of this protein at the invasive front and in the central/superficial areas of the tumor. They concluded that although vimentin was also an EMT marker, its expression was neither limited to the invasive front nor related to histological invasiveness.[26]

Apart from cadherin switching, activated fibroblasts around cancer cells affect cancer invasion and metastasis in OSCC, thereby continuing the process of EMT. The activation of CAFs results in the expression of several molecular markers, such as α-SMA, fibroblast activation protein α, and fibroblast-specific protein-1. α-SMA-expressing MFs are representative of activated CAFs.[27] Tumors cells admixed with blood capillaries, fibroblasts, extracellular matrix, inflammatory cells, and occasionally MFs pooled in the tumor stroma comprise the neoplastic tissue. In OSCC, the cells of the activated stroma that are responsible for the progression and metastasis of the tumor are fibroblasts with smooth muscle properties (SMA positive).[28] These MFs are thought to secrete numerous inflammatory mediators and factors which play a crucial role in tumor progression. The expression and intensity of SMA play a key role in prognosis assessment.[27]

The distribution pattern of MFs, the arrangement of positive-stained cells is classified into three groups, focal, spindle, and network. Understanding the pattern of arrangement in OSCC is also of importance as it has been shown that a network pattern represents higher invasive characteristics and poorer prognosis. In our study, we noted three patterns of SMA arrangement: focal, spindle, and network. The spindle and network distribution patterns were significantly more common among the high T and N stages, and high-risk tumor budding and >5 mm DOI whereas focal arrangement was seen in low tumor T and N0, low-risk tumor budding, and <5 mm DOI. In addition, with regards to SMA intensity, a 3++ score (abundant/ >50%) or 2+ score (scanty/ >1% <50%) was significantly more common among the high T and N stages, and high-risk tumor budding and >5 mm DOI, whereas a 1+ score (negative/ <1%) was seen in low tumor T and N0, low-risk tumor budding and <5 mm DOI. Our results are in agreement with various Indian and international studies.[29],[30],[31] These studies suggest that MF proliferation facilitates tumor invasion, the occurrence of occult neck disease, and distant metastasis. Worse survival rates in patients with abundant MFs have also been reported.[31]

From our results and various other studies, we conclude that MFs might provide a permissive environment for the invasion of OSCC, and SMA in conjunction with cadherin testing is a useful investigation to establish the aggressive nature of OSCC.


  Conclusion Top


This study investigated the individual histopathological parameters at the invasive front including tumor budding and DOI, which were predictive of an adverse prognosis, and their inclusion in routine pathology reporting of OSCC was also highlighted. The role of EMT in the progression of OSCC as demonstrated by loss of E-cadherin and increased expression of α-SMA was also observed. Further studies, including other IHC markers, may provide better insights into the occurrence of EMT.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Elango JK, Gangadharan P, Sumithra S, Kuriakose MA. Trends of head and neck cancers in urban and rural India. Asian Pac J Cancer Prev 2006;7:108-12.  Back to cited text no. 1
    
2.
GLOBOCAN: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. International Agency for Research on Cancer [online] 2012. Available from: http://globocan.iarc.fr/Pages/fact_sheets_population.aspx. [Last accessed on 2021 Mar 22].  Back to cited text no. 2
    
3.
Bundgaard T, Rossen K, Henriksen SD, Charabi S, Søgaard H, Grau C. Histopathologic parameters in the evaluation of T1 squamous cell carcinomas of the oral cavity. Head Neck 2002;24:656-60.  Back to cited text no. 3
    
4.
Bryne M, Jenssen N, Boysen M. Histological grading in the deep invasive front of T1 and T2 glottic squamous cell carcinomas has high prognostic value. Virchows Arch 1995;427:277-81.  Back to cited text no. 4
    
5.
Chang YC, Nieh S, Chen SF, Jao SW, Lin YL, Fu E. Invasive pattern grading score designed as an independent prognostic indicator in oral squamous cell carcinoma. Histopathology 2010;57:295-303.  Back to cited text no. 5
    
6.
Omar EA. The outline of prognosis and new advances in diagnosis of oral squamous cell carcinoma (OSCC): Review of the literature. J Oral Oncol 2013;28:1-13.  Back to cited text no. 6
    
7.
Angadi PV, Patil PV, Hallikeri K, Mallapur MD, Hallikerimath S, Kale AD. Tumor budding is an independent prognostic factor for prediction of lymph node metastasis in oral squamous cell carcinoma. Int J Surg Pathol 2015;23:102-10.  Back to cited text no. 7
    
8.
Hollier BG, Evans K, Mani SA. The epithelial-to-mesenchymal transition and cancer stem cells: A coalition against cancer therapies. J Mammary Gland Biol Neoplasia 2009;14:29-43.  Back to cited text no. 8
    
9.
Bello IO, Vered M, Dayan D, Dobriyan A, Yahalom R, Alanen K, et al. Cancer-associated fibroblasts, a parameter of the tumor microenvironment, overcomes carcinoma-associated parameters in the prognosis of patients with mobile tongue cancer. Oral Oncol 2011;47:33-8.  Back to cited text no. 9
    
10.
Marsh D, Suchak K, Moutasim KA, Vallath S, Hopper C, Jerjes W, et al. Stromal features are predictive of disease mortality in oral cancer patients. J Pathol 2011;223:470-81.  Back to cited text no. 10
    
11.
Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, et al. In: AJCC Cancer Staging Manual. 8th edn. Chicago,Springer International Publishing: American Joint Commission on Cancer. 2017. p. 85-7.  Back to cited text no. 11
    
12.
Almangush A, Bello IO, Keski-Säntti H, Mäkinen LK, Kauppila JH, Pukkila M, et al. Depth of invasion, tumor budding, and worst pattern of invasion: Prognostic indicators in early-stage oral tongue cancer. Head Neck 2014;36:811-8.  Back to cited text no. 12
    
13.
Wang C, Huang H, Huang Z, Wang A, Chen X, Huang L, et al. Tumor budding correlates with poor prognosis and epithelial-mesenchymal transition in tongue squamous cell carcinoma. J Oral Pathol Med 2011;40:545-51.  Back to cited text no. 13
    
14.
Fang QG, Shi S, Li ZN, Zhang X, Liua FY, Xu ZF, et al. Squamous cell carcinoma of the buccal mucosa: Analysis of clinical presentation, outcome and prognostic factors. Mol Clin Oncol 2013;1:531-4.  Back to cited text no. 14
    
15.
Patel SG, Shah JP. TNM staging of cancers of the head and neck: Striving for uniformity among diversity. CA Cancer J Clin 2005;55:242-58.  Back to cited text no. 15
    
16.
Breslow A. Problems in the measurement of tumor thickness and level of invasion in cutaneous melanoma. Hum Pathol 1977;8:1-2.  Back to cited text no. 16
    
17.
Pentenero M, Gandolfo S, Carrozzo M. Importance of tumor thickness and depth of invasion in nodal involvement and prognosis of oral squamous cell carcinoma: A review of the literature. Head Neck 2005;27:1080-91.  Back to cited text no. 17
    
18.
Ghazi N, Ghazi A, Shafiee S, Fayyazi M. Importance of depth of invasion in patients with oral squamous cell carcinoma: A review article. J Orofac Sci 2018;10:3-6.  Back to cited text no. 18
  [Full text]  
19.
International Consortium for Outcome Research (ICOR) in Head and Neck Cancer, Ebrahimi A, Gil Z, Amit M, Yen TC, Liao CT, et al. Primary tumor staging for oral cancer and a proposed modification incorporating depth of invasion: An international multicenter retrospective study. JAMA Otolaryngol Head Neck Surg 2014;140:1138-48.  Back to cited text no. 19
    
20.
Brandwein-Gensler M, Teixeira MS, Lewis CM, Lee B, Rolnitzky L, Hille JJ, et al. Oral squamous cell carcinoma: Histologic risk assessment, but not margin status, is strongly predictive of local disease-free and overall survival. Am J Surg Pathol 2005;29:167-78.  Back to cited text no. 20
    
21.
Krisanaprakornkit S, Iamaroon A. Epithelial-mesenchymal transition in oral squamous cell carcinoma. ISRN Oncol 2012;2012:681469.  Back to cited text no. 21
    
22.
Patil S, Rao RS, Ganavi BS. Mesenchymal-epithelial transition in oral cancer. J Int Oral Health 2015;7:i-ii.  Back to cited text no. 22
    
23.
Kaur G, Carnelio S, Rao N, Rao L. Expression of E-cadherin in primary oral squamous cell carcinoma and metastatic lymph nodes: An immunohistochemical study. Indian J Dent Res 2009;20:71-6.  Back to cited text no. 23
[PUBMED]  [Full text]  
24.
Tanaka N, Odajima T, Ogi K, Ikeda T, Satoh M. Expression of E-cadherin, alpha-catenin, and beta-catenin in the process of lymph node metastasis in oral squamous cell carcinoma. Br J Cancer 2003;89:557-63.  Back to cited text no. 24
    
25.
Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transitions. J Clin Invest 2009;119:1429-37.  Back to cited text no. 25
    
26.
Costa LC, Leite CF, Cardoso SV, Loyola AM, Faria PR, Souza PE, et al. Expression of epithelial-mesenchymal transition markers at the invasive front of oral squamous cell carcinoma. J Appl Oral Sci 2015;23:169-78.  Back to cited text no. 26
    
27.
Son GM, Kwon MS, Shin DH, Shin N, Ryu D, Kang CD. Comparisons of cancerassociated fibroblasts in the intratumoral stroma and invasive front in colorectal cancer. Medicine (Baltimore) 2019;98:e15164.  Back to cited text no. 27
    
28.
Prasad BV, Kakatkar GS, Jain P, Jain M, Patel M, Khan J. Expression of myofibroblasts in oral squamous cell carcinoma: An immunohistochemical study. J Contemp Dent Pract 2016;17:857-60.  Back to cited text no. 28
    
29.
Bhattacharjee K, Girish HC, Murgod S, Alshame AM, Shyamala K, Nayak VN. A comparative immunohistochemical study of presence and distribution pattern of stromal myofibroblast in oral dysplasia and in different grades of oral squamous cell carcinoma. J Int Soc Prev Community Dent 2018;8:451-6.  Back to cited text no. 29
    
30.
Dourado MR, Guerra EN, Salo T, Lambert DW, Coletta RD. Prognostic value of the immunohistochemical detection of cancer-associated fibroblasts in oral cancer: A systematic review and meta-analysis. J Oral Pathol Med 2018;47:443-53.  Back to cited text no. 30
    
31.
Luksic I, Suton P, Manojlovic S, Virag M, Petrovecki M, Macan D. Significance of myofibroblast appearance in squamous cell carcinoma of the oral cavity on the occurrence of occult regional metastases, distant metastases, and survival. Int J Oral Maxillofac Surg 2015;44:1075-80.  Back to cited text no. 31
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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