| Abstract|| |
Background: Histologic grading has been used as a prognostic factor and for clinical behavior evaluation of oral squamous cell carcinoma for the past several decades. At the same time, the prognostic value of different grading classifications remains controversial. A major problem for most histopathological grading systems is the intraobserver and interobserver disagreement.
Aims and Objectives: To validate the prognostic efficiency of the histologic assessment of the primary tumor in predicting cervical metastasis, to identify those histologic features in the tumor most closely associated with cervical metastasis and to evaluate the reliability of the multifactorial grading (MFG) system by measuring intraobserver and interobserver agreement using kappa statistic.
Materials and Methods: A set of 60 cases were chosen at random out of the 292 squamous cell carcinoma cases reported in our institution from 2007 to 2010. All cases were graded according to: Modified Broders' descriptive system and Anneroth et al., MFG system. Two Pathologists independently graded the tumor forefront blinded to the node metastasis.
Results: The MFG showed a significant relation between the degree of histologic malignancy and presence of metastasis in the nodes. Among the components of grading, a significant difference was observed in the nuclear polymorphism and the pattern of invasion between the metastatic and non-metastatic patients. Intraobserver and interobserver agreement was acceptable and satisfactory.
Conclusions: Moderate to good agreement between observers greatly increases the validity of the MFG system. The multifactorial malignancy grading could serve as a predictor for metastasis in the cervical lymph nodes.
Keywords: Lymph node metastasis, malignancy grading, oral squamous cell carcinoma
|How to cite this article:|
Acharya S, Sivakumar AT, Shetty S. Cervical lymph node metastasis in oral squamous cell carcinoma: A correlative study between histopathological malignancy grading and lymph node metastasis. Indian J Dent Res 2013;24:599-604
The presence of cervical lymph node metastasis in patients with head and neck carcinomas leads to poor prognosis. In patients with nodal metastasis, the 5-year survival rate has been reported to be 20-36% after surgical treatment as compared to 63-86% in patients with no lymph node involvement. Many investigators have studied clinical and histopathologic features of the primary tumor, such as size of tumor, degree of differentiation, host immune response and pattern of invasion (PI), to determine the propensity for lymph node metastasis. Although surface size, histologic grade of malignancy and growth pattern have been related to metastasis, evaluation of these factors in predicting metastatic propensity varies among studies. ,
|How to cite this URL:|
Acharya S, Sivakumar AT, Shetty S. Cervical lymph node metastasis in oral squamous cell carcinoma: A correlative study between histopathological malignancy grading and lymph node metastasis. Indian J Dent Res [serial online] 2013 [cited 2019 Aug 17];24:599-604. Available from: http://www.ijdr.in/text.asp?2013/24/5/599/123385
Histologic grading has been used as a prognostic factor and for clinical behavior evaluation of oral squamous cell carcinoma (OSCC) for the past several decades.  The prognostic value of histopathologic grading of OSCC has varied from not any to highly significant.  A major problem for most histopathological grading systems is the disagreement. The kappa (k) statistic is presently considered the best test of reproducibility in grading systems of this kind. 
The biological activity OSCC is evaluated and descriptively categorized as highly, moderately and poorly differentiated. This system was primarily developed by Broder, based on the differentiation of the tumor cell population alone, is of limited value as a basis for choice of treatment as well as for prediction of the outcome of the disease. , Subjective nature of assessment; small biopsies from tumors showing histologic heterogeneity and insufficient sampling; evaluation of tumor cells in isolation from the supporting stroma and host tissues; reliance on structural characteristics of the tumor cells rather than functional ones have all been mentioned as possible justifications for the unsatisfactory results.  Since Broders' initial classification, multifactorial grading (MFG) systems were introduced which were mainly based on different parameters of tumor cells as well as the tumor-host relationship. It is uncertain as to which of the histologic parameters that are assessed in MFG schemes are the most accurate predictors of lymph nodal metastasis.  Hence the aims of this study were to assess the correlation between the lymph node metastasis and histological malignancy grading system - i.e. MFG proposed by Anneroth et al.,  to define the histopathologic parameters that could be correlated with lymph node metastasis in OSCC patients and to evaluate the reliability of the MFG by measuring intraobserver and interobserver agreement using kappa statistic.
| Materials and Methods|| |
A group of 60 OSCC patients were selected randomly out of the 292 OSCC cases reported in our institution from 2007 to 2010, to analyze the relationship between selected histologic features of the primary tumor of the oral mucosa and the actual metastatic status in these OSCC cases.
Sections obtained from surgical specimens of 30 non-metastasizing tumors (pN(0)) were compared with 30 tumors, which had metastasized (pN(+)). Paraffin sections for the analysis of histopathological features were obtained from the archives of our department. Sections of all tissue blocks of 60 OSCC were reviewed and the section containing the whole tumor area, including the connective tissue stroma (most anaplastic areas at its invasive front) was selected for grading. The selected hematoxylin and eosin stained slide were assigned with random numbers and the observer was blinded to the lymph node metastasis status. The order in which the cases were examined was randomized.
Each case was graded according to: Modified Broder's system.  For MFG, three parameters reflecting tumor cell features including degree of keratinization (DK), nuclear polymorphism (NP) and mitosis (M) were evaluated in the whole thickness of the tumor and each scored from 1 to 4. Host response (HR) and PI representing the tumor-host relationship were graded in the most invasive areas and scored from 1 to 4. , Then the sum of scores i.e. total malignancy score (TMS) was grouped as follows: 5-10: Grade I, 11-15: Grade II, 16-20: Grade III  and the results were then compared in the (pN(+)) and (pN(0)) groups.
Before the commencement of the principal study, a pilot study was carried out to assess observer's consistency. To assess intra-observer agreement, the same slides were reassigned with random numbers and were re-examined by observers, who were blinded to the results of the first assessment and lymph node metastasis after an interval of 8-10 weeks.
Details related to the cervical lymph node status of these cases were obtained from the department records.
Frequency tables of categorical data were analyzed using the Chi-square test. Data from the two independent groups were compared using the Mann-Whitney U test for non-parametric data. The relations between two variables were assessed by Spearman's rank correlation test for non-parametric data. The relationship between multiple variables and metastasis were assessed by multiple logistic regressions. Interobserver and intraobserver agreement for each of the components of the MFG system was examined with the kappa statistic.
| Results|| |
[Table 1] shows demographic and clinical data of 60 OSCC cases. [Table 2] illustrates the relation between the growth patterns of OSCC versus lymph node status. 23 tumors in the pN(+) were exophytic and 7 endophytic; in the pN(0), 15 were exophytic and 15 endophytic. Thus, exophytic lesions were significantly (P = 0.03) more common in the pN(+) group than in the pN(0). Overall exophytic presentations were more in number than the endophytic lesions.
|Table 2: Relation between the growth pattern of OSCC versus lymph node status |
Click here to view
Statistical analysis failed to detect any relationship between Broder's grades and lymph node metastasis. The MFG was performed at tumor forefront. The distribution of the TMS is shown in [Figure 1]. Of the 60 OSCC cases, TMS of 46 OSCC were in the range of 9-14. The TMS in relation to the cervical node status is shown in [Figure 2]. Observation shows that the number of patients with a TMS ≥12 (18 cases vs. 8 cases) was higher in pN(+) cases than in pN(0) cases.
|Figure 1: Distribution of total malignancy score in 60 oral squamous cell carcinoma patients|
Click here to view
|Figure 2: Total malignancy score in patients with and without lymph node metastasis|
Click here to view
When the degree of histologic malignancy (TMS) was examined in relation to metastasis in the cervical nodes, significant difference was observed in the degree of histologic malignancy (TMS) between the pN(+) and pN(0) cases (P = 0.007) as shown in [Table 3].
|Table 3: Comparison of degree of histologic malignancy and lymph node metastasis |
Click here to view
The relationships between grading parameters and cervical node metastasis are summarized in [Table 4]. The occurrence of metastasis is significantly and positively associated with DK (P = 0.04), NP (P = 0.01), M (P = 0.008), PI (P = 0.0061) and TMS (P = 0.006). The occurrence of lymph node metastasis and the parameters of the MFG are dependent on each other.
|Table 4: SR correlations between grading parameters and lymph node metastasis |
Click here to view
Statistical comparison of the scores of each of the component features MGF in the two groups of patients is shown in [Table 5]. Among the components of MFG, a significant difference was observed in the parameters like NP (P = 0.02) and the PI (P = 0.01) between the pN(+) and pN(0) cases.
|Table 5: Comparison of parameters of the histologic malignancy and lymph node metastasis |
Click here to view
The aim of the regression in the present study was to identify the important predictor variable. The five histologic features most of which showed nearly significant or significant association with metastasis were entered into the initial logistic regression model. Our results based logistic regression analysis failed to come up with the best predictor variable for the presence cervical lymph node metastasis as shown in [Table 6].
|Table 6: Logistic regression analysis to assess the relationship between variables and lymph node metastasis |
Click here to view
Interobserver agreement was calculated from the first assessment of the first observer and that of the second observer. The findings for interobserver agreement are shown in the [Table 7]. The K scores in the data ranged from 0.551 for "NP" to 0.681 for "HR", from what might be considered "moderate agreement" to what might be regarded as 'good agreement'. The k scores for intraobserver were generally higher than those of the interobserver scores. The k scores for intraobserver agreement ranged from 0.631 for 'DK' to 0.840 for 'HR', from what might be considered 'good agreement' to what might be regarded as 'very good agreement'. Intraobserver and interobserver agreement was acceptable and satisfactory. Value of (k) represented a moderate to good agreement. 
|Table 7: Interobserver and intraobserver agreements for the histological features of MFG for the 60 OSCC patients |
Click here to view
| Discussion|| |
Among 292 cases of primary squamous cell carcinoma (SCC) of the oral cavity reported in our department from 2007 to 2010, 90 cases underwent radical neck dissection out of which, 60 cases were selected randomly for the study. As for the site of the primary lesion, the buccal mucosa and retromolar trigone was affected in 40 cases, gingiva and alveolus in 17 cases and lateral border of tongue in 3 cases. Fifty percent of OSCC (age aside) in India occur in the buccal mucosa, supported by this study, in contrast to less than 5% in many western countries pointing to a salient effect of chewing tobacco on risk.  The proportion of young patients in the present study was quite large (mean age: 49 years, range: 27-70 years, 24 cases ≤45 years) primarily because of early and habitual exposure to the chewing tobacco products (pan masala and gutkha) in this region. It also reported that oral cancer is increasing in India due to young people chewing pan masala products often containing tobacco, which is responsible for the carcinogenicity of the betel quid. ,
Oral cancer has a varied clinical appearance. Most of the lesions can be described as exophytic or ulceroproliferative, ulcerative or infiltrative or endophytic and verrucous carcinoma. Such distinction also serves as a prognostic marker for this disease.  Kuriakose et al., reported the significant difference in the morphological type of tumor.  Tumors in young patients (<35 years) were predominantly endophytic lesions affecting the tongue with an early spread to lymph nodes. Tumors in older patients (>60 years) presented as exophytic lesions of the buccal mucosa or gingiva and spread late to the lymph nodes. Majority of tumors in this study were from buccal mucosa, with an exophytic presentation. But most of the pN cases showed an exophytic growth pattern rather than endophytic presentation.
Cervical node metastasis have variable incidence and are widely accepted as one of major prognostic factors in OSCC patients.  The rate of metastasis in the cervical nodes was reported to be 35.3-60% in OSCC patients.  Metastasis in the cervical nodes was detected in 43% of the cases (90 radical neck dissection (RND) = 51 pN(0) and 39 pN(+)) reported between 2007 and 2010, which was in accordance with the results illustrated by other authors. 
Most decisions for cancer patients are now made on the basis of prognostic and predictive factors. , Cervical nodes metastasis is well known to be an indicator of poor prognosis in patients with oral cancer.  There is an ongoing debate about the predictive value of histopathological parameters in oral cancer. In the past decades, the emphasis was on the possible added value of the so called malignancy grading system.  Histologic grading has been used as a prognostic factor and for clinical behavior evaluation of OSCC for past several decades. At the same time, the prognostic value of different grading classifications remains controversial.  Malignancy grading studies are complicated by the heterogeneity between subtypes of oral carcinomas and the different behavior of carcinomas arising in localized but distinct areas of the mucosa. 
A possible relation of the degree of malignancy judged by histopathological findings to its prognosis has been examined since Broders reported the DK of cancer cells in relation to its prognosis in 1920.  Odell et al., in a study of small lingual SCC's, found a relationship between local recurrence and metastasis with Broders' grades  The present study failed to observe any relation between Broder's system of grading and lymph node metastasis.
Many more complex grading systems for oral carcinoma have been described.  Most are variations on the MFG, which has the advantage of scoring tumor host interactions and tumor characteristics.  Anneroth et al.,  proposed a grading system based on the DK, NP, PI, HR and M activity. Their system has been shown to have the best prognostic value when applied to the least differentiated tumor at the deep invasive front of oral carcinomas. , This grading system has been validated using carcinomas from mixed oral sites, floor of mouth and buccal and maxillary alveolar carcinomas  and has proved reproducible between observers.  Cases analyzed here were heterogeneous w.r.t to site, size and stage. This study also confirms the usefulness of MFG and demonstrates significant relation between the degree of histologic malignancy and metastasis in the cervical nodes, indicating that the MFG could serve as a predictor for metastasis in the cervical nodes.
When individual component of MFG were taken into consideration, in agreement with several other reports , we found that assessment of the DK has not materialized as an independent foretelling indicator. In the present study, NP had significant independent value in predicting metastasis, in contrast with others , we found that nuclear features had predictive value in relation to cervical node metastasis.
Although Crissman et al.,  reported that the frequency of M was a good predictor of survival, this feature has not emerged as an independent prognostic factor in the present report. In the present study, the PI had significant independent value in predicting metastasis, in agreement with other reports, ,,, hence an essential component of MFG scheme. In agreement with the other reports , HR did not have significant independent value in predicting metastasis.
Improved reproducibility was one of aims of MFG and several workers have reported good levels of intraobserver agreement, but interobserver agreement are less satisfactory.  Suggestions to improve reproducibility include simplification of the categories, clarification of definitions and omission of less reproducible feature which were applied  in the present study and found that both intraobserver and interobserver agreement was acceptable and satisfactory.
It is the opinion of the authors that the MFG can be taken as a predictive factor of lymph node metastasis, has a value in developing countries owing to economic feasibility and practical constraint. 
But according to Martínez-Gimeno et al., the assessment of neck metastasis is an unsettled issue still. No clinical exploration or imaging techniques are able to show micro metastasis in the neck nodes.  Carlos Martínez-Gimeno et al., has designed Martínez-Gimeno scoring system (MGSS) based on clinical and histologic criteria.  According to these authors this system is very useful and safe in identifying a group of patients with almost null risk for cervical metastasis. The risk predicted by MGSS includes macro and micro metastases.  Furture studies should aim at assessing the accuracy in predicting nodal metastasis by applying MGSS.
| Conclusions|| |
The relationship of degree of histologic malignancy with lymph node metastasis was analyzed in this study. A significant relation was noticeable between the degree of histologic malignancy (TMS) and metastasis in the lymph nodes, indicating that the histological malignancy could serve as a predictor for metastasis in the cervical nodes. Its value could be enhanced by the removal of features of uncertain value (like HR). The clinical value of grading system will increase by improving reproducibility. Moderate to good agreement between observers greatly increases the validity of the MFG.
In conclusion, this study confirms the validity of MFG for OSCC. Although grading correlates well with metastasis, it is the NP and PI elements of the system that are of most value because they closely correlated with metastasis.
| Acknowledgments|| |
Authors express their thanks to ICMR STS - 2011.
| References|| |
|1.||Shingaki S, Suzuki I, Nakajima T, Kawasaki T. Evaluation of histopathologic parameters in predicting cervical lymph node metastasis of oral and oropharyngeal carcinomas. Oral Surg Oral Med Oral Pathol 1988;66:683-8. |
|2.||Yamamoto E, Miyakawa A, Kohama G. Mode of invasion and lymph node metastasis in squamous cell carcinoma of the oral cavity. Head Neck Surg 1984;6:938-47. |
|3.||Yazdi I, Khalili M. Grading of oral cancer: Comparison of different systems with respect to lymph node metastasis in tongue squamous cell carcinoma. Arch Iran Med 1999;2:87-92. |
|4.||Bryne M, Koppang HS, Lilleng R, Stene T, Bang G, Dabelsteen E. New malignancy grading is a better prognostic indicator than Broders' grading in oral squamous cell carcinomas. J Oral Pathol Med 1989;18:432-7. |
|5.||Sawair FA, Irwin CR, Gordon DJ, Leonard AG, Stephenson M, Napier SS. Invasive front grading: Reliability and usefulness in the management of oral squamous cell carcinoma. J Oral Pathol Med 2003;32:1-9. |
|6.||Anneroth G, Batsakis J, Luna M. Review of the literature and a recommended system of malignancy grading in oral squamous cell carcinomas. Scand J Dent Res 1987;95:229-49. |
|7.||Woolgar JA. Histopathological prognosticators in oral and oropharyngeal squamous cell carcinoma. Oral Oncol 2006;42:229-39. |
|8.||Woolgar JA, Scott J. Prediction of cervical lymph node metastasis in squamous cell carcinoma of the tongue/floor of mouth. Head Neck 1995;17:463-72. |
|9.||Siriwardena BS, Tilakaratne A, Amaratunga EA, Udagama MN, Ogawa I, Kudo Y, et al. Analysis of histopathological and immunohistochemical differences of oral squamous cell carcinoma in young and old patients in Sri Lanka. J Oral Pathol Med 2007;36:357-62. |
|10.||Llewellyn CD, Johnson NW, Warnakulasuriya KA. Risk factors for squamous cell carcinoma of the oral cavity in young people: A comprehensive literature review. Oral Oncol 2001;37:401-18. |
|11.||Gupta PC, Pindborg JJ, Mehta FS. Comparison of carcinogenicity of betel quid with and without tobacco: An epidemiological review. Ecol Dis 1982;1:213-9. |
|12.||Mehta FS, Hamner JE III. Tobacco-Related Oral Mucosal Lesions and Conditions in India. A Guide for Dental Students, Dentists and Physicians. 1 st ed. Bombay: Tata Institute of Fundamental Research, Tata Press, Jaypee Brothers Medical Publishers; 1993. p. 2. |
|13.||Kuriakose M, Sankaranarayanan M, Nair MK, Cherian T, Sugar AW, Scully C, et al. Comparison of oral squamous cell carcinoma in younger and older patients in India. Eur J Cancer B Oral Oncol 1992;28B: 113-20. |
|14.||Massano J, Regateiro FS, Januário G, Ferreira A. Oral squamous cell carcinoma: Review of prognostic and predictive factors. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;102:67-76. |
|15.||Okada Y, Mataga I, Katagiri M, Ishii K. An analysis of cervical lymph nodes metastasis in oral squamous cell carcinoma. Relationship between grade of histopathological malignancy and lymph nodes metastasis. Int J Oral Maxillofac Surg 2003;32:284-8. |
|16.||Bànkfalvi A, Piffkò J. Prognostic and predictive factors in oral cancer: The role of the invasive tumour front. J Oral Pathol Med 2000;29:291-8. |
|17.||Weijers M, Snow GB, Bezemer PD, van der Waal I. Malignancy grading is no better than conventional histopathological grading in small squamous cell carcinoma of tongue and floor of mouth: Retrospective study in 128 patients. J Oral Pathol Med 2009;38:343-7. |
|18.||Odell EW, Jani P, Sherriff M, Ahluwalia SM, Hibbert J, Levison DA, et al. The prognostic value of individual histologic grading parameters in small lingual squamous cell carcinomas. The importance of the pattern of invasion. Cancer 1994;74:789-94. |
|19.||Bryne M, Koppang HS, Lilleng R, Kjaerheim A. Malignancy grading of the deep invasive margins of oral squamous cell carcinomas has high prognostic value. J Pathol 1992;166:375-81. |
|20.||Bryne M, Nielsen K, Koppang HS, Dabelsteen E. Reproducibility of two malignancy grading systems with reportedly prognostic value for oral cancer patients. J Oral Pathol Med 1991;20:369-72. |
|21.||Crissman JD, Gluckman J, Whiteley J, Quenelle D. Squamous-cell carcinoma of the floor of the mouth. Head Neck Surg 1980;3:2-7. |
|22.||Okamoto M, Ozeki S, Watanabe T, Iida Y, Tashiro H. Cervical lymph node metastasis in carcinoma of the tongue. Correlation between clinical and histopathological findings and metastasis. J Craniomaxillofac Surg 1988;16:31-4. |
|23.||Akhter M, Hossain S, Rahman QB, Molla MR. A study on histological grading of oral squamous cell carcinoma and its co-relationship with regional metastasis. J Oral Maxillofac Pathol 2011;15:168-76. |
|24.||Martínez-Gimeno C, Rodríguez-Delgado LE, Perera-Molinero A, Trujillo Mdel C, Chivite A, Maeso MC, et al. A new method for the prediction of cervical node metastases in squamous cell carcinoma of the oral cavity: A combination of Martínez-Gimeno scoring system and clinical palpation. J Craniomaxillofac Surg 2011;39:534-7. |
|25.||Martínez-Gimeno C, Rodríguez EM, Vila CN, Varela CL. Squamous cell carcinoma of the oral cavity: A clinicopathologic scoring system for evaluating risk of cervical lymph node metastasis. Laryngoscope 1995;105:728-33. |
Department of Oral Pathology and Microbiology, Rajiv Gandhi University of Health Sciences, SDM College of Dental Sciences and Hospital, Dharwad, Karnataka
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]