|Ahead of print publication
Histopathological prognosticators and their clinicopathological correlation in oral squamous cell carcinomas of the tongue
Kriti Pallavi1, Ankita Tandon2, Nikita Gulati1, Saurabh Juneja1, Devi Charan Shetty1
1 Department of Oral Pathology and Microbiology, ITS-CDSR, Ghaziabad, Uttar Pradesh, India
2 Department of Oral Pathology, Microbiology and Forensic Odontology, Dental Institute, RIMS, Ranchi, Jharkhand, India
|Date of Submission||30-Mar-2020|
|Date of Decision||31-May-2020|
|Date of Acceptance||10-Sep-2020|
|Date of Web Publication||03-Aug-2021|
Department of Oral Pathology and Microbiology, ITS-CDSR, Muradnagar, Ghaziabad, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Background: Tongue carcinomas account for 25%–40% of intraoral squamous cell carcinomas (OSCCs). Although TNM staging systems is an international standard for cancer reporting, prognosis evaluation, and treatment planning, multiple histopathological risk assessment predictors such as tumor thickness (TT), tumor shape, tumor growth pattern, and invasive malignancy grading scoring systems have been studied and should form a basis for prediction and prognostication of such aggressive carcinomas.
Aim: To evaluate and characterize the histomorphological prognostic indicators in OSCCs of tongue and compare it with OSCCs of other anatomic sites within the oral cavity. Furthermore, to elucidate the significance of histopathological indicators in predicting prognosis of tongue squamous cell carcinomas (SCCs).
Materials and Methods: Forty SCC cases with 20 each of tongue and 20 from other intraoral sites were retrieved from department archives. Clinical data and staging were obtained for each case. Histomorphological parameters including pattern of invasion (POI), tumor budding (TB), depth of invasion (DOI), TT, lymphocytic host response, tumor-associated tissue eosinophilia (TATE), vascular invasion, perineural invasion (PNI), and muscular invasion were assessed. The results were statistically evaluated.
Results: TB, DOI, and sarcolemmal spread were significant histologic predictors in tongue SCC. Upon correlation of histomorphological parameters with clinical staging, TT, POI, and TATE were observed to be significantly correlated (P ≤ 0.05).
Conclusion: The histomorphological risk assessment model may serve as important addition to the existing prognosticators and may be used as a prognostic index to help plan and individualize treatment protocol in cases with aggressive high-risk disease for whom the use of multimodality treatment seems beneficial.
Keywords: Histopathology, prognosticators, squamous cell carcinoma, tongue
|How to cite this URL:|
Pallavi K, Tandon A, Gulati N, Juneja S, Shetty DC. Histopathological prognosticators and their clinicopathological correlation in oral squamous cell carcinomas of the tongue. J Can Res Ther [Epub ahead of print] [cited 2022 Jun 25]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=322904
| > Introduction|| |
Oral squamous cell carcinoma (OSCC) is the eighth most common cancer worldwide and poses a significant health burden, with <60% of patients surviving more than 5 years. These may arise from the oral tongue, floor of mouth, buccal mucosa, alveolar mucosa, and hard palate. A recent increase in the number of tongue and oropharyngeal cancers in younger patients, women , and individuals with no exposure to the traditional risk factors such as tobacco has made this intraoral subsite the most common and also one of the worst anatomical locations in terms of prognosis.
The tongue is the most common site for OSCC, particularly the oral (mobile) portion (OTSCC), where the tumor tends to show a more aggressive behavior due to the high frequency of regional lymph node metastasis. The tongue has characteristic structural features including a high content of muscle bundles and a rich lymphatic network that may influence the properties of tumor spread in it. Locoregional recurrences are the main cause of treatment failures of oral tongue carcinoma. Nodal recurrence as a result of undetectable subclinical nodal metastasis is, however, the main management problem of early stage I and II carcinomas.
Clinical and histopathological parameters are widely used for the selection of treatment strategies and for the determination of prognosis in oral cancer patients. A multitude of parameters have been reported to influence the survival of OSCC patients, such as the mode of invasion, presence of lymph node metastasis, extracapsular spread, surgical margins, and invasive tumor front grade. Other clinicopathological prognosticators of significance are pTNM, tumor volume, depth of invasion (DOI), tumor budding (TB), vascular and perineural invasion, medullary bone invasion, and the presence of distant metastasis.
The purpose of this study is to evaluate and characterize the histomorphological prognostic indicators in OSCCs of tongue and to correlate these with clinicopathologic features.
| > Materials and Methods|| |
The study was conducted using archival tissues for histopathological evaluation and records of the patients were evaluated for assessing clinical parameters and staging of the neoplasm after gaining consent from the institutional review board of ITS-CDSR, Muradnagar, Ghaziabad.
The study sample comprised a total 40 OSCC cases with 20 each of tongue and 20 from other intraoral sites. Patients with other simultaneous primary tumors, patients with a history of previous chemotherapy or radiotherapy, and tumors with extensive necrosis and/or superadded infection were excluded from the study sample.
Histopathological analysis (hematoxylin and eosin stain)
The evaluation of the histopathological parameters was done using light microscope (BX 41), Olympus EPL 3 Camera and Magnus Pro software for morphometric analysis.
In the study groups, multiple histomorphological parameters were evaluated which included pattern of invasion (POI), TB, DOI, tumor thickness (TT), lymphocytic host response (LHR), tumor-associated tissue eosinophilia (TATE), vascular invasion (VI), perineural invasion (PI), and muscular invasion (MI). The AJCC and UICC TNM staging systems were followed where the stages were categorized as I-IV.
The resulting data were analyzed using SPSS software version 16 (Armonk, New York). Pearson's Chi-square test was carried out to determine the level of association between the groups under study and P ≤ 0.05 was considered significant.
| > Results|| |
Upon comparison of POI and TB with other histomorphological parameters, TB significantly correlated with DOI (P = 0.012), LHR (P = 0.022), VI (P = 0.044), and TATE (P = 0.024), whereas the correlation of POI with other histomorphological parameters was nonsignificant (P > 0.05). Similarly, comparison of DOI and TT with other histomorphological parameters showed that the TT significantly correlated with LHR (P = 0.001), whereas DOI significantly correlated with TB (P = 0.012). Furthermore, the comparison of LHR and TATE with other histomorphological parameters showed that LHR significantly correlated with TB (P = 0.022) and TT (P = 0.001), whereas TATE significantly correlated with TB (P = 0.024). The comparison of perineural invasion, VI, and sarcolemmal spread with other histomorphological parameters demonstrated that the VI significantly correlated with TB (P = 0.044), whereas the correlation of sarcolemmal spread and perineural invasion with other histomorphological parameters was nonsignificant (P > 0.05).
Comparison of invasive front characteristics, i.e., POI, TB, DOI, and TT in the study groups (TSCC and OSCC), reveals that 15% of cases showed Type 1 POI [Figure 1]a whereas majority of cases, i.e., 75%, showed Type 2 POI [Figure 1]b and only 10% cases revealed Type 3 POI in TSCC (Group 1). Similarly, in TB, Type 1 was shown in 35% of cases and 65% of cases showed type 2 in Group 1 (TSCC). 55% of the cases showed Type 1 DOI, whereas 45% of the cases showed Type 2 DOI in Group 1 (TSCC) (P ≤ 0.05). Type 1 TT was shown in 35% of cases and 65% of cases showed type 2 in TSCC cases (Group 1), whereas 25% of cases showed Type 1 TT and 75% showed Type 2 in OSCC cases (Group 2) (P ≤ 0.05). 55% of the cases showed Type 1 DOI, whereas 45% of the cases showed Type 2 DOI in Group 1 (TSCC). However, in Group 2 (OSCC), 85% of cases showed Type 1 DOI and 15% of cases showed Type 2 DOI. Type 1 TT was shown in 35% of cases and 65% of cases showed type 2 in TSCC cases (Group 1), whereas 25% of cases showed Type 1 TT and 75% showed Type 2 in OSCC cases (Group 2) [Table 1].
|Figure 1: (a) Type 1 pattern of invasion (pushing, well-delineated infiltrating borders) in squamous cell carcinoma of tongue (H and E, ×10), (b) Type 2 pattern of invasion (infiltrating, solid cords, bands and/or strands) in squamous cell carcinoma of tongue (H and E, ×10), (c) Type 1 lymphocytic host response showing dense complete host response rimming tumor) (H and E, ×10), (d) Type 2 lymphocytic host response (patches of dense lymphoid infiltrate but the inflammation was discontinuous) (H and E, ×10), (e) Type 1 tumor budding (<s5 buds/field) in squamous cell carcinoma of tongue (H and E, ×10), (f) Type 2 tumor budding (≥5 buds/field) in squamous cell carcinoma of tongue (H and E, ×10)|
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|Table 1: Comparison of invasive front characteristics in study groups (tongue squamous cell carcinoma and oral squamous cell carcinoma)|
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Perineural invasion was present in 20% of cases in Group 1 (TSCC) and absent in Group 2 (OSCC) (P ≤ 0.05). However, perivascular invasion was present in 30% of cases of TSCC (Group 1) and 15% of cases of OSCC (Group 2) (P > 0.05). Sarcolemmal spread was present in 80% of cases in Group 1 (TSCC) and 15% of cases in Group 2 (OSCC) (P ≤ 0.05) [Table 2].
|Table 2: Comparison of local invasion in study groups (tongue squamous cell carcinoma and oral squamous cell carcinoma)|
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65% of cases depicted pattern 1 of LHR, whereas 35% of cases showed pattern 2 LHR in TSCC (Group 1) whereas in OSCC (Group 2) 60% of cases showed Pattern 2 LHR and pattern 1 was shown in 40% of cases (P > 0.05). TATE showed major cases of Type 1, i.e., 50%, Type 2 was shown in 35% of cases, Type 3 by 10% of cases, and 5% by Type 4 in Group 1. However, in Group 2 (OSCC), 45% of cases showed Type 1 as well as Type 2 TATE, 10% of cases of Type 3, whereas no cases were reported for Type 4 TATE in OSCC cases [Table 3].
|Table 3: Characterization of inflammatory host response in study groups (tongue squamous cell carcinoma and oral squamous cell carcinoma)|
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On correlation of clinicopathological and histopathological parameters using multinomial regression analysis in which the histopathological grading is predictive of clinical staging; the findings of our study reveals that T (Tumor size) correlates with POI (P < 0.05) and TT (P = 0.016), similarly N (nodal status) correlates with LHR (P = 0.021). Furthermore, TNM stage correlates with POI (P < 0.000), TATE (P = 0.015), and TT (P < 0.000) [Table 4].
|Table 4: Correlation of histopathological parameters with Tumor size, Nodal status and TNM Stage of the disease in Group 1 (tongue squamous cell carcinoma)|
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Odds ratio of histopathological parameters in tongue squamous cell carcinoma (SCC) depicts that the histopathological parameters including DOI, TB, perineural invasion, and sarcolemmal spread have statistically significant values (P ≤ 0.05) [Table 5].
|Table 5: Odds ratio of histopathological parameters in tongue squamous cell carcinoma|
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| > Discussion|| |
OSCC entails quite noteworthy morbidity and mortality rates instead of immense amount of research and advances. The incidence varies worldwide, with India and Southeast Asia showing the highest rates. The global incidence accounts for over 50,000 new cases annually worldwide and more than 50% of all patients have advanced disease at the time of diagnosis. The tongue is the most common and deadliest site for OSCC, particularly its mobile portion, where the tumor tends to show a more aggressive behavior due to the high frequency of locoregional spread.
The AJCC and UICC TNM staging systems are international standards for cancer reporting, prognosis evaluation, and treatment planning. Besides, the literature also witnesses multiple histopathological risk assessment predictors such as TT, tumor shape, tumor growth pattern, and invasive malignancy grading scoring systems for prediction and prognostication. However, due to limitation in depth and size of biopsy specimens, a reliable method of assessment of histopathological parameters is necessary. Therefore, assessment of these histomorphological parameters clubbed with clinical staging would propose a novel stepwise evaluation of course and outcome of the disease as a more reliable and objective guide.
The present study was designed to assess the effectiveness of histomorphological parameters in predicting the aggressiveness in OTSCC (Group 1) as compared to SCC reported at other oral sites (Group 2). In our study, upon comparison of POI between Group 1 and 2, 75% showed type 2 POI [Figure 1]b in Group 1, whereas 30% of cases in Group 2 showed type 2 POI which is in agreement with the findings of Sinha et al. and Lundqvist et al., who suggested that POI in OSCCs is a significant predictive parameter for locoregional recurrence and disease specific survival. The ability of neoplastic cells to infiltrate, invade, and penetrate adjacent tissues can ultimately result in distant and local metastases, which is a distinctive feature of cancers and a determinant of prognosis in malignancies. It has been suggested that neoplastic microenvironment and the structure/arrangement of stromal elements can affect the POI. According to previous studies, tumor stromas that are more organized have been seen to support collective migration of tumor cells. Tissues with higher muscle fiber content and thick collagen bundles tend to promote invasion, while fatty tissues and those with less-organized short collagen fibers and muscle bundles are in favor of single-cell migration such as in tongue OSCCs.
Furthermore, at the invasive front Type 1[Figure 1]e and Type 2 [Figure 1]f tumor budding (TB) were assessed between Group 1 and 2 and it was observed that 60% of cases showed type 2 TB, i.e., ≥5 buds/field [Figure 1]f in comparison to Group 2 where only 20% of cases revealed the same (P ≤ 0.05). Our findings were similar to the study conducted by Almangush et al., who proposed a novel prognostic model for early stage oral tongue carcinomas and stated that TB is actually a sign of epithelial to mesenchymal transition of carcinoma cells, reflecting the powerful invasive growth of tongue carcinomas. TB resides ahead of the invasive front and characterizes poor prognosis. It is marker of discohesion and active invasion of tumor cells. The evaluation of tumor 'budding' could improve the grading system with particular reference to potential aggressiveness, as a marker of prognostic significance, and furthermore, has the merits of simplicity and reproducibility and has been proven in other carcinomas.
55% of cases showed Type 1 DOI, whereas 45% of cases showed Type 2 DOI in Group 1 (TSCC); however, in Group 2 (OSCC), 85% of cases showed Type 1 DOI and 15% by Type 2 (P ≤ 0.05) [Figure 2]b. DOI [Figure 3]b has been expressed as a microscopic depth structure rather than an objective measurement of a micrometer on a millimeter scale. It is determined microscopically by detecting the deepest invasive cells in the underlying tissues and the most reliable measurement is from the basement membrane to the deepest point of invasion. It is important to know that literature does not warrant use of DOI as a single reliable prognosticator in tongue SCCs rather from a biological point of view both TB and DOI model indicates efficacy of tumor cells for tissue penetration and reflect EMT along with tumor dissociation at invasive front.
|Figure 2: (a) Tumor-associated tissue eosinophilia at the invasive front of Squamous Cell Carcinoma of tongue (H and E, ×40), (b) vascular invasion seen in squamous cell carcinoma of tongue (H and E, ×40), (c) Sarcolemmal spread seen in squamous cell carcinoma of tongue (H and E, ×40), (d) Perineural invasion - Tumor cells circumferencing the epineurium of a nerve bundle in squamous cell carcinoma of tongue (H and E, ×40)|
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|Figure 3: (a) Tumor thickness from the surface of tumor to the deepest point of invasion in tongue squamous cell carcinoma, (b) depth of invasion from the basement membrane of the adjacent normal epithelium to the deepest point of tumor invasion in tongue squamous cell carcinoma|
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Similarly, Type 1 (up to 3 mm) TT was seen in 35% of cases and 65% of cases showed type 2 (3-9 mm) in Group 1 [Figure 3]a, whereas 25% of cases showed Type 1 TT and 75% showed Type 2 in Group 2 cases. The findings are supported by Pentenero et al., where authors are in substantial agreement regarding the reliability of TT in OSCCs. Furthermore, TT has been found to be a reliable prognostic marker for subclinical nodal metastasis, local recurrence, and survival. A study conducted by Yuen et al. suggested TT to be a superior prognostic factor in prediction of subclinical nodal metastasis and also proposed a revised T staging system based on TT to replace the tumor diameter of the present UICC/AJCC system. The revised T1 is TT up to 3 mm, revised T2 is thickness more than 3 mm up to 9 mm, and T3 is TT more than 9 mm. The aforementioned revised system has been followed in our study.
It has been proposed that the histological risk model (HRM) significantly correlates with disease progression and survival for patients with primary head and neck SCC when adjusted for clinical confounders. The HRM and more specifically lymphocyte host response significantly correlates with disease progression and survival for patients. We therefore evaluated the host response and observed that 65% of cases of Group 1 showed Type 1 LHR [dense, complete host response rimming the tumor, [Figure 1]c], whereas in Group 2, majority of cases (60%) showed Type 2 LHR [patches of dense lymphoid infiltrate but the inflammation was discontinuous, [Figure 1]d]. None of the cases in either study groups revealed type 3 host response (limited response, that neither form lymphocytic patches nor showed lymphocytic response).
TATE can be defined as “eosinophilic stromal infiltration of a tumor not associated with tumor necrosis or ulceration.” It is characterized by the presence of eosinophils as a component of peritumoral and intratumoral inflammatory infiltrate. In our study, TATE [Figure 2]a was evaluated in order to characterize the inflammatory host response in study groups and it was observed that 50% of Group 1 cases showed Type 1 TATE (2–10 eosinophils/cu mm), followed by 35% of cases of type 2 response (10–20 eosinophils/cu mm) as compared to Group 2 cases where both Type 1 and 2 TATE was observed in 45% of cases (P ≥ 0.05). The findings of our study are similar to that of Dorta et al., and Yellapurkar et al., who observed that under the impact of appropriate stimuli (e.g., infections, tumors, etc.), the eosinophils release several mediators such as interleukin-1 (IL-1), IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-18, interferon-γ, transforming growth factor (TGF)-α, TGF-β, eosinophil cationic protein, major basic protein, eosinophil peroxidase, eosinophil-derived neurotoxin, tumor necrosis factor-α, Chemokines (RANTES, endotaxin-1), platelet-activating factor, leukotriene C4, neuromediators, and indoleamine 2,3-dioxygenase. These molecules may cause cell death and initiation of inflammatory symptoms as well as contribute to tumor regulation. Thus, the eosinophils are postulated to have direct tumoricidal activity with the release of cytotoxic proteins and they also act indirectly by enhancing the permeability into tumor cells facilitating penetration of tumor-killing cytokines. Furthermore, the eosinophils are said to promote tumor angiogenesis by the production of several angiogenic factors.
Among the various parameters used to predict the outcome of malignant diseases in OSCC, perivascular invasion, perineural invasion, and sarcolemmal spread are widely used as indicators of aggressive behavior. Perineural invasion (PNI) is a tropism of tumor cells for nerve bundles in the surrounding tissues. It is well known as an independent predictor of poor outcome in colorectal carcinomas and salivary gland malignancies. In our study, 20% of cases in Group 1 showed perineural invasion [Figure 2]d in comparison to Group 2 where none of the cases revealed perineural invasion (P ≤ 0.05), which is supported by the findings of Cracchiolo et al., suggesting that the presence of PNI in oral tongue SCC predicts worse disease-specific survival with distant recurrence as the most common pattern of failure.
Perivascular invasion is classified according to presence or absence of neoplastic cells located in the wall or lumen of blood or lymphatic vessels and has been found to be correlated with low rates of survival and high risk of recurrence. In our study, perivascular invasion was present in 30% of cases belonging to Group 1 [Figure 2]b and only 15% of cases of Group 2 and was not statistically significant (P > 0.05), suggesting that in relation to oral carcinomas, VI does not appear to have a strong correlation with disease prognosis and hence this parameter has been omitted from many grading systems.
Sarcolemmal spread represents another simple histologic landmark of risk assessment and aggressiveness. Skeletal muscle invasion within tongue presents greater reproducibility. In tongue SCCs, muscle invasion has been proposed as a surrogate marker for DOI. Similar to vascular and perineural invasion, the neoplastic cells might spread along the sarcolemmal sheath of muscle fibers. The involvement of muscle tissue by tumor cells is usually observed at late stages of cancer probably due to deeper location. However, in our study, it has been observed that 80% of cases in Group 1 revealed sarcolemmal spread [Figure 2]c, depicting an involvement of tongue musculature in early stages of tongue SCCs in comparison to Group 2 where only 15% of cases revealed sarcolemmal spread (P ≤ 0.05). Tongue SCCs are usually characterized by infiltrative growth into the stroma rather than exophytic growth associated with other sites. Sarcolemmal spread indicates the locally infiltrative nature of the tongue SCC at the tumor–host interface. Furthermore, one of the critical aspects in the growth of tongue tumor is its deep invasion into the tongue musculature, in which the VI and metastatic spread are more likely to occur.
Upon evaluation of risk assessment of histopathological parameters based on odds ratio [Table 4] in the present study, histomorphological features such as DOI, TB, perineural invasion, and sarcolemmal spread in OTSCC were found to be statistically significant (P ≤ 0.05). Among all the factors, sarcolemmal spread (22.667 times higher) has been the most confounding factor for spread of Group 1 SCCs and compared to Group 2. Hence, taking into consideration the aforementioned histomorphological features, cases with tongue SCCs may be considered at higher risk for disease progression and therefore must be considered for more aggressive protocols for the disease control.
The present study also supports the correlation between histopathological parameters and clinical staging (TNM) of tongue SCC. Bryne proposed the invasive front grading system in which the features at most invasive part of tumor include degree of keratinization, nuclear polymorphism, POI, and host inflammatory response. In our study, POI, TATE, and TT correlated with clinical staging of the disease, which is in accordance with Hasegawa et al., where they found a strong correlation between various patterns of invasion and clinical stages. Furthermore, Razack et al. had hypothesized that tumor size is not a relevant criterion for determining prognosis due to predominant endophytic nature of tongue carcinomas. Hence, they have proposed that TT, DOI and POI are more reliable prognostic indicators in tongue carcinomas. Furthermore, out of the aforementioned parameters, primary TT ≥4 mm is the most predictive factor for occult metastasis and is also associated with poor histologic grade. The findings are in corroboration with a meta-analysis conducted by Huang et al.
| > Conclusion|| |
Based on the aforementioned findings, it may be proposed that prediction of biologic behavior of tongue SCCs may be facilitated through use of multiple histopathological parameters and these may also address the treatment protocols in such cases for inducing better measures of disease control and disease outcome. It can be stated that TB, DOI, perineural invasion, and sarcolemmal spread were significant histologic predictors in OTSCC. They may serve as important addition to the existing prognosticators and may be used as a prognostic index to help plan and individualize treatment protocol in cases with aggressive high-risk disease for whom the use of multimodality treatment would be beneficial regardless of individual treatment approaches. However, upon correlation of histomorphological parameters with clinical staging, TT, POI, and TATE were observed to be significantly correlated. These parameters could therefore be used to augment existing staging systems to effectively help in accurate treatment planning and in determination of prognosis.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]