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The predictive value of depth of invasion and tumor size on risk of neck node metastasis in squamous cell carcinoma of the oral cavity: A prospective study


 Department of Surgical Oncology, Mahavir Cancer Sansthan, Patna, Bihar, India

Date of Submission20-Jun-2020
Date of Decision13-Aug-2020
Date of Acceptance21-Dec-2020
Date of Web Publication30-Jul-2021

Correspondence Address:
Naresh Kumar Jangir,
Department of Surgical Oncology, Mahavir Cancer Sansthan, Patna, Bihar
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_783_20

 > Abstract 


Background: Tumor depth is a reliable parameter to predict nodal metastasis in oral cancers; therefore, the authors embarked upon a prospective observational study to define the relationship between the tumor depth and the risk of cervical lymph node involvement as well to determine the optimal tumor depth cutoff point for nodal metastasis.
Aims: The aim was to study the predictive value of depth of invasion (DOI) and tumor size on risk of cervical node metastasis in squamous cell carcinoma of the oral cavity.
Materials and Methods: Biopsy-proven Stage I–Stage III oral cavity squamous cell carcinoma patients were included in this prospective, observational study. Various histopathological characteristics (DOI, tumor size, lympho-vascular invasion [LVI], perineural spread, and grade of differentiation) were analyzed to predict the cervical node metastasis.
Statistical Analysis Used: The impact of the clinical and histopathological parameters of primary tumor on cervical lymph node metastasis was analyzed by univariate as well as multivariate logistic regression analyses using NCSS 12 version 12.0.5 statistical software.
Results: The independent predictors of cervical lymph node metastasis were DOI (P = 0.0014) and LVI (P = 0.0414). The incidence of cervical metastasis increased markedly when the DOI was over 5 mm, and it was a statistically significant (P < 0001) association.
Conclusions: DOI is a significant predictor of cervical nodal metastasis and tumor depth 5 mm can be considered as a cutoff value in staging and management of early oral squamous cell carcinoma.

Keywords: Cervical node metastasis, depth of invasion, oral cancer, tumor size



How to cite this URL:
Jangir NK, Singh A, Jain P, Khemka S. The predictive value of depth of invasion and tumor size on risk of neck node metastasis in squamous cell carcinoma of the oral cavity: A prospective study. J Can Res Ther [Epub ahead of print] [cited 2021 Dec 6]. Available from: https://www.cancerjournal.net/preprintarticle.asp?id=322711




 > Introduction Top


The Indian subcontinent has a large burden of oral cancer in the world, with around 77,000 new patients detected every year. This high incidence is mainly because of habit of chewing betel nuts, tobacco, and pan.[1]

Oral squamous cell carcinoma (OSCC) is characterized by a high tendency for locally aggressive growth, early metastasis to neck lymph nodes, and variability in tumor behavior after surgical intervention. Metastasis to regional lymph nodes is the single most important prognostic factor in predicting local and distant failure as well as survival. Nodal metastasis reduces the survival by 50%.[2]

There is a consensus that large (cT3 or cT4) head and neck tumors and cN + neck disease necessitate treatment of the cervical lymph nodes. However, the treatment of patients with early stage, clinically node negative oral squamous cell cancer has been a controversial issue spanning five decades.

It is generally known that overall survival for patients with clinically negative lymph nodes is high. The main problem in the management of early-stage cancers is node involvement as a result of undetectable subclinical node metastasis.[3] In spite of the advances in the techniques for the detection of lymph node metastasis, which include imaging techniques such as ultrasonography, computed tomography (CT) scan, magnetic resonance imaging (MRI), 20%–50% of lymph node negative patients with occult node metastasis go unidentified. These patients develop a clinically evident metastatic disease, usually within 2 years of follow-up.[4]

During the evaluation of cancer patients, the tumor/node/metastasis (TNM) classification has traditionally been used as an objective, internationally accepted system. It has been proposed that a combined assessment of histological characteristic as well as clinical staging might provide a more precise measure for predicting the outcome of the neoplasms and deciding the best treatment plan for each patient.[5] The most recent staging system (American Joint Committee on Cancer [AJCC] TNM staging system 8th edition) includes depth of invasion (DOI) for staging of head and neck cancer to overcome the drawbacks of previous staging system.

Several studies focused on tumor depth as new parameter to predict regional metastasis.[6],[7]

In this article, we describe our study to define the relationship between the tumor depth and the risk of cervical lymph node involvement as well as to determine the optimal tumor depth cutoff point for nodal metastasis; furthermore, additional four clinical parameters (patient sex and age, tumor site, and size) and three pathological parameters (degree of differentiation, perineural invasion (PNI), and lymphovascular invasion [LVI]) were evaluated for nodal metastasis.


 > Materials and Methods Top


This prospective, single-arm, observational study was conducted from June 2016 to March 2018 at the Department of Surgical Oncology, Mahavir Cancer Sansthan, Patna, Bihar, after approval of scientific and ethical committee of our institute.

In patients with oral lesions which were clinically suspicious of malignancy, blood investigations (complete blood count, random blood sugar, liver function test, kidney function test, and viral markers) were done. This was followed by incisional biopsy or punch biopsy from the oral cavity lesion. After biopsy, radiological (OPG when proximity or direct extension of a primary tumor of the oral cavity to the mandible/CT scan when primary tumors of the mandible, lesions where soft-tissue extension from tumors involving the ascending ramus of the mandible and midline tumors near symphysis menti, MRI in the tongue, and floor of mouth lesions) investigations were done.

Patients with biopsy-proven Stage I to Stage III squamous cell carcinoma of the oral cavity with Eastern Cooperative Oncology Group Performance level 0 and 1 were selected for the study. All patients were categorized as per AJCC TNM Staging System 7th Edition for oral cavity cancer. They were primarily treated with wide excision of the tumor and simultaneous bilateral or unilateral neck dissection, depending on the tumor location and the status of the neck. Surgery was followed by radiotherapy and/or chemotherapy if necessary. Patients who had been previously treated with radiotherapy or chemotherapy were excluded. Patients with distant metastasis, recurrent tumor, unknown primary, multiple primary tumors, and nonsquamous histology were also excluded from the study. The study pro forma was filled, and informed consents were taken.

Sample size

For sample size calculation, following formula was used: N = Za2 P (1−P)/D2

P = True proportion of factor in the population or the expected frequency value

D = Expected frequency value minus (−) worst acceptable value

Z = Area under normal curve corresponding to the desired confidence level

Confidence level/value for Z

90%/1.645

95%/1.960

99%/2.575

Previous studies–Trehan et al. showed positive neck node metastasis in 54% of patients.[8]

Expected difference (D) is taken as 10%

Z was taken for a confidence level of 95%

N = (1.96)2 × 0.54 × (1−0.54)/(0.1)2 = 95.42.

In order to achieve robust results from this observational study, the authors considered a sample size of 120.

Histopathologic examination

After surgery, surgical specimen were oriented and labeled by surgeons and fixed in 10% buffered formalin by pathologists. The specimens were then processed and examined under microscopic vision. In order to assess the depth of the tumor optimally, it was ensured that a part of the adjacent normal mucosa had been included in the sections.

In the specimens of node dissection, the number of nodes dissected and the maximum dimension of the largest excised node were noted. Multiple histopathological characteristics were analyzed: LVI, perineural spread, tumor size, DOI, grade of differentiation, pattern of invasion, and cervical node metastasis.

The DOI is calculated as the distance between the basal membrane and the deepest point of the invaded stromal tissue by an ocular micrometer. The magnification of microscope to assess the DOI was ×4.

In the cases of exophytic tumor growth, the measurement was made from the height of the surface of adjacent normal mucosa to the deepest-reaching front of infiltration.

Grade of differentiation was divided into well differentiated, moderately differentiated, and poorly differentiated. Tumors were considered to be well differentiated when good stratification, clear formation of keratin, presence of intercellular bridges, absence or near absence of cellular pleomorphism, and low presence of mitosis (<10 mitosis/10 fields) were present. Tumors were considered to be poorly differentiated when the latter criteria were difficult to achieve with an undifferentiated cell pattern, high cellular pleomorphism, marked nuclear atypia, absence of keratinization, and high rate of mitosis (>20 mitosis/10 fields). Tumors were considered to be moderately differentiated when criteria are between both good and poor differentiation.

LVI was defined when a clear pattern of tumor cells within lymphatic, venous, or arterial vessels were evident.

Perineural spread was defined as a clear perineural or neural invasion by tumor cells.

Statistical analysis

All the primary data were initially recorded in the format of MS Excel worksheets (Excel 2013; Microsoft Corp, Washington). Microsoft word and Excel were used to generate graphs and tables. The statistical analysis was performed using a software program, NCSS 12 version 12.0.5 (NCSS, LLC, Kaysville, Utah, USA).The impact of the clinical and histopathological parameters of primary tumor site on cervical lymph node metastasis was analyzed by univariate as well as multivariate logistic regression analyses using NCSS 12 version 12.0.5 statistical software. P < 0.05 was considered to be statistically significant.


 > Results Top


A total of 120 consecutive patients presenting in Surgical Oncology Outdoor Patient Department of Mahavir Cancer Sansthan, Patna, India, who fulfilled the inclusion and exclusion criteria were evaluated.

Demography

The mean age of presentation was 47.2 years. Majority of the patients were male and predominantly from lower socioeconomical status. Most of the patients (91.66%) were addicted to tobacco chewing either alone or combined with smoking/alcohol or both [Table 1].
Table 1: Demographic variables, tumor site, and clinical stage

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In our study, the most common site of oral cavity cancer was the tongue, and most of the patients presented with clinically Stage III [Table 1].

Histopathological characteristics

Tumor size

Evaluation of tumor size in pathological specimen revealed that 36 patients (30%) were classified as pTl, 72 (60%) as pT2, and 12 as pT3 [Table 2].
Table2:Histopathologicalvariablesaffectingcervicallymphnodemetastasisinoralcavitycancers

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Depth of invasion

DOI was 5 mm or less in 47 (39.17%) patients, 5.1–10 mm in 53 (44.17%) patients, and more than 10 mm in 20 patients (16.67%) [Table 2].

Degree of differentiation

Well-differentiated tumors were seen in majority of patients (58.66% of cases), and poorly differentiated were seen in only 8.33% of cases in our study [Table 2].

LVI was seen in 28% patients and PNI was present in 15% patients [Table 2].

Cervical lymph node involvement

Metastatic cervical lymph nodes (pN+) were present in 36 (30%) patients in our study. On preoperative examination, 50 patients were node-positive (cN+) and 70 were node-negative (cN0). On postoperative pathology, however, 36 patients were found to be pN+, including 15 of the 70 patients who had been classified as cN0. Therefore, the prevalence of occult neck metastasis was 21.42% [Table 3].
Table 3: Comparison of preoperative and postoperative N status

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Factors affecting cervical lymph node metastasis in oral cavity cancers

Factors such as age, sex, socioeconomic status, cancer subsite, tumor size, DOI, histological grade of tumor, PNI, and LVI were used to compare their association with cervical lymph node metastasis.

Correlation of tumor size with cervical lymph node metastasis

Neck metastases (pN+) were found in 8 out of the 36 pT1 patients (22.22%), in 24 of the 72 pT2 patients (33.33%), and in 4 of the 12 patients of pT3 Stage (33.33%). The difference was not statistically significant [Table 4].
Table4:Factorsaffectingcervicallymphnodemetastasisinoralcavitycancers

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Correlation of depth of invasion with cervical lymph node metastasis

DOI ranged from 0 to 14 mm, with an average of 7.08 mm. No cervical metastasis was found in patients with a tumor depth <4 mm. Node metastases were present in 4 out of 47 patients with a DOI of 5 mm or less (8.50%), in 20 of 53 patients whose DOI was between 5.1 and 10 mm (37.73%), and in 12 of 20 patients with invasion more than 10 mm (60%). There was a statistically significant association between a higher prevalence of lymph node metastasis and a greater depth of tumor (P < 0.00003) [Table 1].

When we evaluated DOI in the 70 cN0 cases, the corresponding rates of neck node metastasis were 6.66%, 35.8%, and 55.55%. The association of node metastasis with the DOI in the cN0 group was also statistically significant (P = 0.00535) [Figure 1].
Figure 1: Correlation of depth of invasion with cervical lymph node metastasis

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Taking into consideration previously reported literature, a cutoff value of 5 mm was applied. In the group in which tumor depth was equal or <5 mm, the metastatic rate was 8.55% (4/47). In contrast, when the DOI exceeded 5 mm, the metastatic rate was 43.83% (32/73).The incidence of cervical metastasis increased markedly when the DOI was over 5 mm, and it was a statistically significant (P < 0001) association. Hence, we can consider 5 mm as a cutoff value for DOI at which cervical metastasis is probable.

Nodal metastasis being nominal variable and DOI (DOI mm) we have plotted the receiver operating characteristic (ROC) curve. With the help of ROC curve, the cutoff value having maximum sensitivity and specificity was determined. At 0.55 cm, the sensitivity and specificity of the DOI were 88.1% and 52.4%. The area under curve = 0.772 and P < 0.001 are indicative of test being useful of diagnosing/screening nodal metastasis [Figure 2] and [Table 5].
Figure 2: Receiver operating characteristic curve to determine the cutoff value for depth of invasion as a marker of nodal metastasis

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Table5:Areaunderthecurveforcutoffvalueofdepthofinvasion

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Correlation between depth of invasion and cervical lymph node metastasis according to cancer subsite

When all three groups of DOI were compared for cervical lymph node metastasis according to cancer subsite, there was statistically significant (P < 0.05) increase in cervical lymph node metastasis with increase in DOI for the tongue (P = 0.011) and buccal mucosa (P = 0.004) in our study. However, this association was not statistically significant in gingivobuccal sulcus (P = 0.230) and lip (P = 0.379) [Table 6].
Table 6: Correlation between depth of invasion and cervical lymphnodemetastasisaccordingtocancersubsite

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On univariate analysis, factors significantly associated (P < 0.05) with cervical lymph node metastasis were DOI, cancer subsite, histological grade of tumor, PNI, and LVI [Table 4].

By using multivariate logistic regression analysis, the independent predictors of cervical lymph node metastasis were DOI (P = 0.0014) and LVI (P = 0.0414) [Table 7].
Table7:Multivariateanalysisofvariousfactorsaffectingcervicallymphnodemetastasis

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 > Discussion Top


Since cervical lymph node status is the most important prognostic factor in patients with head and neck carcinoma,[2],[9] prediction of nodal metastasis become important factor and identifying a reliable parameter that predict the risk of cervical lymph node involvement is of great value.

Of the different histopathological variables that are related to neck metastasis, the most important is DOI. Many studies have demonstrated that DOI is an appropriate factor on which to base predictions of cervical metastasis in OSCC.[3],[10],[11],[12]

The association of tumor depth with lymph node metastasis is believed to reflect the aggressiveness of tumor growth[13] and/or is an objective indicator for the proximity of the tumor to lymphovascular structures.[9] Another theory for the positive relationship between tumor thickness and the presence of lymph node involvement is that tumor emboli may be more difficult to form in the small-caliber lymphatics of superficial areas than in the wider lymphatics of deeper tissue.[9]

DOI was an independent predictor (P = 0.0014) of cervical node metastasis in our study. Pentenero et al. reviewed of the studies analyzing DOI in predicting regional metastases and survival. They found DOI is a reliable parameter for predicting regional nodal involvement and survival in OSCC.[9]

Similarly, Huang et al. conducted a meta-analysis to assess the relationship between DOI and the risk of cervical lymph node involvement and tried to establish an optimal cutoff point for elective neck dissection. They concluded that a cutoff point of 4 mm in DOI is a strong predictor for cervical lymph node involvement (positive lymph node disease of 16.6% DOI >4 mm, compared with 4.5% for DOI <4 mm group.[14]

In our study, we found that the cutoff point is most strongly associated with neck metastasis when tumor depth categorized >5 mm, in conversion N0-N1 group. Kane et al.[3] and Fukano et al.[10] concluded that the optimal cutoff point is 5 mm for the consideration of neck management, this coincides with our study.

Although there is no doubt about the importance of tumor depth, no consensus has yet been reached on a valid cutoff point.[15] The fact that different authors report different thresholds might be attributable to the factors such as individual definitions of tumor depth and differences in oblique sectioning during the processing of surgical specimens.

We hope that future multicenter studies will include a large number of cases and standardized measurements of DOI, which might lead to the identification of an ideal cutoff value. However, some important issues must be addressed. One is that the DOI is usually measured postoperatively in a pathologic specimen. Hence, most of the time, we do not know what the DOI is preoperatively, so we obviously cannot use it as a basis for deciding whether or not to operate. The role of radiologic techniques such as MRI (preoperative) and frozen section (intra-operative) for assessment of tumor depth need to be studied for better implication of DOI for the management of early stage oral cancer.

Another parameter that we used in our study was the surface size of tumor. We found that the surface size of a tumor does not correlate with the incidence of cervical nodal metastasis in OSCC (P = 0.476). Many previous studies concluded that as tumor size increases, the rate of node metastasis does not significantly increase. A similar result was reported by Chen et al.[11] Haksever et al. found that there is no significant association between neck node metastasis and tumor size.[2] On the other hand, it has been shown that T category tends to be more advanced in N + groups. These conflicting findings might be attributable to several histopathologic factors, such as DOI, degree of differentiation, and type of growth pattern (i.e., exophytic or endophytic). Therefore, consideration of a patient's T category might not be sufficient for making optimal treatment decisions.

Another independent predictor of cervical node metastasis in our study was LVI. Tumor invasion into lymphatic and/or blood vessels has long been postulated to be an important pathologic factor. We found statistically significant association between LVI and lymph node positivity (P < 0.00056). This finding is consistent with some other basic study on oral cavity squamous cell carcinoma such as Goldson et al.[16] (P = 0.02) and Sparano et al.[17] (P = 0.01).


 > Conclusions Top


DOI and LVI were the only independent predictor of cervical lymph node metastasis and optimal cutoff value for tumor depth for cervical lymph node metastases was 5 mm in our study. Patients with early cancers with a tumor depth of more than 5 mm are at greater risk of harboring neck node metastasis.

We find it relevant that tumor size was not correlated with metastasis, which is significant because the TNM system is so widely used to evaluate patients preoperatively. There is also a need for determining an optimal DOI for early squamous carcinomas of the oral cavity, preoperatively by the use of imaging techniques or intraoperatively by the use of frozen-section analysis, which would permit the surgeon to address the neck nodes optimally at the time of first surgery.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Available from:http://cancerindia.org.in/wp content/uploads/2018/09/GATS__2_India report.pdf. [Last accessed on 02 May 2020].  Back to cited text no. 1
    
2.
Haksever M, Inançlı HM, Tunçel U, Kürkçüoğlu SS, Uyar M, Genç O, et al. The effects of tumor size, degree of differentiation, and depth of invasion on the risk of neck node metastasis in squamous cell carcinoma of the oral cavity. Ear Nose Throat J 2012;91:130-5.  Back to cited text no. 2
    
3.
Kane SV, Gupta M, Kakade AC, D' Cruz A. Depth of invasion is the most significant histological predictor of subclinical cervical lymph node metastasis in early squamous carcinomas of the oral cavity. Eur J Surg Oncol 2006;32:795-803.  Back to cited text no. 3
    
4.
Aksoy F, Veyseller B, Binay O, Apuhan T, Yıldırım YS, Ozturan O. Patterns of cervical metastasis from squamous cell carcinoma of the head and neck. Kulak Burun Bogaz Ihtis Derg 2010;20:249-54.  Back to cited text no. 4
    
5.
Sandu K, Nisa L, Monnier P, Simon C, Andrejevic-Blant S, Bron L. Clinicobiological progression and prognosis of oral squamous cell carcinoma in relation to the tumor invasive front: Impact on prognosis. Acta Otolaryngol 2014;134:416-24.  Back to cited text no. 5
    
6.
Pinto FR, de Matos LL, Palermo FC, Kulcsar MA, Cavalheiro BG, de Mello ES, et al. Tumor thickness as an independent risk factor of early recurrence in oral cavity squamous cell carcinoma. Eur Arch Otorhinolaryngol 2014;271:1747-54.  Back to cited text no. 6
    
7.
Fawzy A, Sabry M, Sabry A, El Fol H, El Kased A. The relationship between primary tumour thicknesses in cancers of the oral cavity to subsequent lymph node metastasis. Int Surg J 2017;4:2957-66.  Back to cited text no. 7
    
8.
Trehan SS, Patel K, Shukla HK, Tripathi U, Tadaiya M. The effect of depth of invasion and tumour size on risk of neck node metastasis in squamous cell carcinoma of oral cavity: retrospective analysis. Journal of Research in Medical and Dental Science 2017;3:213-8.  Back to cited text no. 8
    
9.
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. 9
    
10.
Fukano H, Matsuura H, Hasegawa Y, Nakamura S. Depth of invasion as a predictive factor for cervical lymph node metastasis in tongue carcinoma. Head Neck 1997;19:205-10.  Back to cited text no. 10
    
11.
Chen YW, Yu EH, Wu TH, Lo WL, Li WY, Kao SY. Histopathological factors affecting nodal metastasis in tongue cancer: Analysis of 94 patients in Taiwan. Int J Oral Maxillofac Surg 2008;37:912-6.  Back to cited text no. 11
    
12.
Lim SC, Zhang S, Ishii G, Endoh Y, Kodama K, Miyamoto S, et al. Predictive markers for late cervical metastasis in Stage I and II invasive squamous cell carcinoma of the oral tongue. Clin Cancer Res 2004;10:166-72.  Back to cited text no. 12
    
13.
Moore C, Kuhns JG, Greenberg RA. Thickness as prognostic aid in upper aerodigestive tract cancer. Arch Surg 1986;121:1410-4.  Back to cited text no. 13
    
14.
Huang SH, Hwang D, Lockwood G, Goldstein DP, O'sullivan B. Predictive value of tumor thickness for cervical lymph-node involvement in squamous cell carcinoma of the oral cavity. Cancer 2009;115:1489-97.  Back to cited text no. 14
    
15.
Po Wing Yuen A, Lam KY, Lam LK, Ho CM, Wong A, Chow TL, et al. Prognostic factors of clinically Stage I and II oral tongue carcinoma-A comparative study of stage, thickness, shape, growth pattern, invasive front malignancy grading, Martinez-Gimeno score, and pathologic features. Head Neck 2002;24:513-20.  Back to cited text no. 15
    
16.
Goldson TM, Han Y, Knight KB, Weiss HL, Resto VA. Clinicopathological predictors of lymphatic metastasis in HNSCC: Implications for molecular mechanisms of metastatic disease. J Exp Ther Oncol 2010;8:211-21.  Back to cited text no. 16
    
17.
Sparano A, Weinstein G, Chalian A, Yodul M, Weber R. Multivariate predictors of occult neck metastasis in early oral tongue cancer. Otolaryngol Head Neck Surg 2004;131:472-6.  Back to cited text no. 17
    


    Figures

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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

 
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