|Year : 2021 | Volume
| Issue : 1 | Page : 20-24
Lymph node metastasis in cT1/T2 buccal mucosa squamous cell carcinoma: A subsite-specific study
Siddharth Mahesh Vyas1, Rajesh Arvind Kantharia1, Shehnaz Rajesh Kantharia1, Zahoor Ahmad Teli1, Yogesh Matadin Mistry2
1 Kailash Cancer Hospital and Research Centre, Muni Seva Ashram, Vadodara, Gujarat, India
2 Department of Onco-Pathology, Kailash Cancer Hospital and Research Centre, Muni Seva Ashram, Vadodara, Gujarat, India
|Date of Submission||26-Dec-2020|
|Date of Decision||11-Feb-2021|
|Date of Acceptance||14-Feb-2021|
|Date of Web Publication||14-Apr-2021|
Rajesh Arvind Kantharia
Kailash Cancer Hospital and Research Centre, Muni Seva Ashram, Goraj, Waghodiya, Vadodara - 391 761, Gujarat
Source of Support: None, Conflict of Interest: None
Objectives: To analyze the incidence of cervical lymph node metastasis in cT1/T2 buccal mucosa cancers, correlate it with the depth of invasion and study the percentage of occult metastasis. Through this study, we also attempt to look into subsite-specific buccal mucosa data which are lacking in literature and will help us improve the understanding of the disease. Materials and Methods: Retrospective analysis of the prospectively collected data of 109 patients with cT1/T2 buccal mucosa cancer operated from January 2018 to August 2019 was done. Information regarding the pathological T stage, depth of invasion, presence or absence of cervical node metastasis, occult metastasis, size of the metastatic lymph nodes, and the presence of extracapsular extension was collected from the final histopathology reports. Results: Twenty-five out of 109 (22.94%) patients had cervical node metastasis. Nine out of 93 (9.68%) clinically N0 patients had occult metastasis. No metastasis was observed for the patients with depth of invasion <4 mm. Of these 25 patients, 17 were pathologically staged T2 (68%), whereas 8 were staged T1 (32%). P value obtained by the Fisher's exact test was 0.003 and validated the hypothesis generated by our results. Conclusion: Through this study, we can conclude that the possibility of cervical node metastasis in cT1/T2 buccal mucosa cancers with depth of invasion <4 mm is negligible and the percentage of occult metastasis stands low. Our study also reflects the lack of robust data in context to early-stage buccal mucosa cancers and offers an insight on the importance of subsite specific research.
Keywords: Cervical node metastasis, depth of invasion, early-stage buccal mucosa squamous cell carcinoma, occult metastasis
|How to cite this article:|
Vyas SM, Kantharia RA, Kantharia SR, Teli ZA, Mistry YM. Lymph node metastasis in cT1/T2 buccal mucosa squamous cell carcinoma: A subsite-specific study. Oncol J India 2021;5:20-4
|How to cite this URL:|
Vyas SM, Kantharia RA, Kantharia SR, Teli ZA, Mistry YM. Lymph node metastasis in cT1/T2 buccal mucosa squamous cell carcinoma: A subsite-specific study. Oncol J India [serial online] 2021 [cited 2021 Oct 23];5:20-4. Available from: https://www.ojionline.org/text.asp?2021/5/1/20/313672
| Introduction|| |
Lip and oral cavity cancer was the most common cancer among males in India in 2016. It was the first or second leading cause of cancer deaths in seven Indian states for males in 2016. Lymphatic dissemination of the disease and resulting cervical lymph node metastasis is one of the most important prognostic factors in oral squamous cell carcinoma. The inclusion of the depth of invasion in the 8th edition of the AJCC staging manual is the testimony of its prognostic significance. Literature is rich in the studies demonstrating the correlation between the depth of invasion and cervical node metastasis and its prognostic implications for early oral tongue squamous cell carcinoma. However, there is a lack of exclusive studies on buccal mucosa squamous cell carcinoma in literature. Furthermore, the studies looking at nodal metastasis for different sub sites of the oral cavity have a smaller number of patients with buccal mucosa cancer.
Oral cancer in India is different compared to the western countries. The high incidence of carcinoma of the buccal mucosa in our country is attributable to the extensive use of chewable tobacco in various forms. Placing these carcinogenic substances in the gingivobuccal complex region accounts for the higher incidence of oral cavity cancers in this subsite. Furthermore, 70% of the cases are advanced at the time of presentation. Hence, in the current Indian literature, very few studies exclusively look into the early-stage buccal mucosa squamous cell carcinoma. Even the review of the existing data in the consensus document for the management of buccal mucosa cancers, published by the Indian Council for Medical Research showed only one study, done by Mishra et al. in 1999 which focused exclusively on buccal mucosa squamous cell carcinoma.
With this background, we have retrospectively analyzed the prospectively collected data and made an attempt to quantify the rate of cervical lymph node metastasis and correlate it with the depth of invasion in T1 and T2 (AJCC 8th edition) buccal mucosa squamous cell carcinoma.
| Materials and Methods|| |
A total of 1000 head and neck cancer cases were operated in the Department of Head and Neck Surgical Oncology at Kailash Cancer Hospital and Research center in the timespan of 20 months (January, 2018 to August 2019). Of these 1000 cases, 921 were oral squamous cell carcinoma, of which 405 (44%) were buccal mucosa primary, 295 (32%) were oral tongue primary, and 221 (24%) were squamous cell carcinoma of other subsites. The patients suffering from the buccal mucosa squamous cell carcinoma were segregated. They were further divided into the early-stage disease and advanced stage disease. Finally, we retrieved 115 patients having primary T1/T2 disease. Of these 115 patients, six patients having superficial lesions were treated with per oral LASER wide excision and were spared from neck dissection. Of the 109 patients included in this study [Figure 1], modified radical neck dissection (MRND) was performed in 36 patients, whereas 73 patients underwent selective neck dissection (SND). SND (Level I to III) was performed in patients with clinically N0 neck. Level IV was dissected in case of level I having clinically suspicious lymph node. MRND was performed in patients having multiple clinically suspicious lymph nodes, metastatic lymph node at level II, for lymph node suspicious for extracapsular extension or in cases with multi-station disease. Intraoperative frozen section analysis was not performed in any case to detect nodal metastasis. All these patients were operated either by a senior head and neck surgical oncologist or by surgical fellows under supervision. Histopathological analysis and reporting were done by a single senior oncopathologist. Recurrent cases or patients who had primary radiotherapy or neoadjuvant chemotherapy were excluded. On retrospective analysis of the histopathology reports, details on the pathologic staging, presence or absence of cervical node metastasis, depth of invasion, size of the metastatic lymph nodes, and presence of extracapsular extension were retrieved. Depth of invasion was noted for each case and an attempt to set a cut off point for nodal metastasis was made. Fisher's exact test was carried out to derive the correlation between the depth of invasion and cervical node metastasis.
|Figure 1: Flowchart depicting the segregation of cases included in this study. BM – buccal mucosa, GBS – gingiva-buccal sulcus, MRND – modified radical neck dissection, SND – selective neck dissection|
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| Results|| |
Out of 109 cases analyzed in this study, 37 cases were pathologically T1 (pT1) disease and 72 cases were pathologically T2 (pT2) disease. The final histopathology reports of 109 neck dissection specimen showed the presence of nodal metastasis in 25 patients. Of the 25 node positive patients, 16 were clinically node positive (cN+), whereas 9 patients were clinically node negative (cN0). Seventeen patients were pT2 and 8 were pT1.
Of the 109 neck dissections, 36 underwent MRND; 6 for stage T1 and 30 for stage T2. Of the 36 MRND, 6 cases were pathologically N+ (pN+) while 30 were pathologically N0 (pN0). Of the 6 pN + cases, 5 were cN + while one was cN0. MRND was done in cN0 patients considering the trismus, paramandibular spread, edentulous mandible in whom marginal mandibulectomy was not possible and the need for reconstruction. [Figure 2] shows the distribution of the cases with MRND based on the depth of invasion and number of pathologically N + cases.
|Figure 2: Distribution of the modified radical neck dissection cases based on the depth of invasion and pathological node positive (pN+) or node negative cases (pN0)|
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Seventy-three patients were treated with SND (Levels I to III or I to IV); 31 for stage T1 and 42 for stage T2. Of the 73 SND, 19 cases were pN + and 54 were pN0. Of the 19 pN + cases, 11 were cN + while 8 were cN0. Distribution of the cases with SND based on the depth of invasion and number of pathologically N + cases is shown in [Figure 3].
|Figure 3: Distribution of the selective neck dissection cases based on the depth of invasion and pathological node positive (pN+) or node negative cases (pN0)|
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Of the 109 patients, 93 patients were cN0. Of these 93 patients, 9 had occult metastasis (9.68%); 4 patients were pT2 and 5 were pT1 disease. Important finding noted was, none of the patient with depth of invasion <4 mm showed metastatic cervical lymphadenopathy. This held true even for the cases demonstrating occult metastasis. The percentage of occult metastasis for T1 and T2 stage disease was 13.51% (5/37) and 5.56% (4/72) while the percentage of cN + for T1 and T2 cases were 8.11% (3/37) and 18.06% (13/72), respectively. Depth of invasion for the cases segregated on the basis of occult metastasis and clinically positive neck is shown in the [Table 1].
|Table 1: Distribution of clinical/pathological node positive (N+) cases and occult node metastasis based on depth of invasion|
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Of the total 25 pN + patients; 11 were N1 (44%), 6 were N2a (24%), and 4 patients were N2b (16%) and N3b (16%) each. Macroscopic extranodal extension was present in nine patients and one patient had microscopic extracapsular spread. The smallest lymph node having macroscopic extracapsular spread was 8 mm in dimension. The smallest lymph node having metastatic deposit was 8 mm in the short axis while the largest one was 45 mm.
Fisher's exact test was performed to evaluate the significance of the cutoff value of 4 mm depth of invasion for cervical node metastasis. The results demonstrated the P value of 0.003 which has high statistical significance and validates our hypothesis.
| Discussion|| |
In 2018, De Silva et al. proposed a model to predict nodal metastasis in oral squamous cell carcinoma. This study showed statistically significant associations between status of the nodal metastasis and tumor (T), site, pattern of invasion, and depth of invasion. They predicted the probability of nodal metastasis when the depth was dichotomised as <4 mm and 4+ mm. They demonstrated that T1 lesions were at low risk even when the depth of invasion was >4 mm. T2 lesions demonstrated low risk and moderate risk when the depth was <4 mm and >4 mm, respectively, with the pattern of infiltration Type 4. Our analysis coincided with this observation for T2 lesions. 23.61% of all T2 cases were pathologic N + in our analysis and all these demonstrated type 4 pattern of infiltration. However, 21.62% of the total T1 lesions too demonstrated nodal metastasis which does not correlate with the low-risk stratification proposed by De Silva et al. The difference in the percentage of T1 lesions (21.62%) and T2 lesions demonstrating nodal metastasis (23.61%) was insignificant. Of the 8 T1 lesions that had nodal metastasis, 7 had type 4 and 1 had type 5 pattern of infiltration.
It is noteworthy that the long-standing contentious issue of elective neck node dissection has been put to rest post publication of the landmark paper by D'Cruz et al. in the New England Journal of Medicine. This seminal paper also states that the node positivity increased substantially when the depth of invasion increased from 3 mm to 4 mm. However, in this study, 85.2% of the patients were oral tongue cancers and with buccal mucosa cancers constituting only 13.6% of the total cases. Furthermore, in the arms of elective neck dissection and therapeutic neck dissection, the number of buccal mucosa cancer cases having occult metastasis or the nodal recurrence was not specified. The authors had also stated the 3 mm cutoff point is just a hypothesis generated at best. Our study consolidates the observation of the aforementioned study in context to the buccal mucosa cancers.
However, an interesting observation made is the percentage of occult node metastasis in our paper is just 9.68% (9 patients were N + out of 93 patients having clinical/radiographic N0 neck). Weiss et al. and Okura et al. opined to observe the patient instead of performing prophylactic neck dissection when the probability of occult metastasis goes below 20% and 44.4%, respectively.,
The study by Hakeem et al. in 2012 represents the largest series of previously untreated patients with early (T1-2 N0) cancer of buccal mucosa treated only with per oral wide excision and no prophylactic neck dissection. Out of 156 patients, 24 patients developed nodal recurrence (16.9%). Median follow-up period was 48 months. Of these, only nine patients (9.6%) with nodal recurrence had depth of invasion less than or equal to 5 mm. Furthermore, the number of patients with depth of invasion >10 mm was not described. Hence, as per current TNM staging, few of these patients may get upstaged. The authors concluded prophylactic neck dissection is not warranted in T1 stage buccal mucosa cancer. Iyer et al., in their study of 147 cases with early cancer of buccal mucosa, do not recommend elective neck dissection due to only 14.68% occult metastases in their series.
The cutoff points of 4 mm derived in our analysis are similar to that observed in the meta-analysis of 16 studies conducted by Huang et al. in 2009. However, tumor thickness was evaluated in the analysis instead of depth of invasion. This meta-analysis also included the study of Mishra et al. and was the only study that exclusively dealt with early-stage buccal mucosa cancers. In other studies, cases of oral tongue cancer dominated the number in the meta-analysis. In another review, Borges et al. studied in detail the pathologic outcomes in 79 patients with buccal mucosa cancer. Tumor thickness of 5 mm was found to be associated with nodal metastases even in clinical N0 neck.
In 2005, Pentenero et al. performed a review of literature explaining the importance of the tumor thickness and depth of invasion in cervical lymph node metastasis and prognosis in oral squamous cell carcinoma. Twenty-five studies included in that review exclusively included T1/T2 oral cancers. Majority of these studies were for oral tongue cancers and few others involved floor of the mouth, lip, and other oral cavity subsites. The meta-analysis of 5 high-quality randomized control trials by Ren et al. in 2015 suggest that elective neck dissection at the time of resection of the primary tumor confers a disease-free survival and overall survival benefit in patients with clinically node-negative oral cancer. Again, most of the patients in the randomized controlled trials included in this meta-analysis had tumors involving only oral tongue and floor of the mouth.
In 2017, for the first time, Brockhoff et al. correlated the depth of invasion of squamous cell carcinomas in different subsites of the oral cavity with the risk of cervical node metastasis. Out of 286 patients analyzed, 63% of the total cases were T1/T2 cancers. They proposed different cutoff values for different subsites ranging from 2 mm to 4 mm. Oral tongue cancers dominated the number followed by alveolus/hard palate, floor of the mouth, and retromolar trigone. The number of buccal mucosa cancers was very low.
[Table 2] provides brief detail of the studies discussed above and demonstrates the heterogeneity of the current literature and lack of data specific to early-stage buccal mucosa cancers.,,,
|Table 2: Comparison of the present study with current literature demonstrating the lack of data on early-stage buccal mucosa cancers|
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Evaluating the current scientific literature, it was noted that the lack of uniformity in the methods of measuring thickness of the tumor or depth of invasion has resulted in varying cutoff values. Some authors have used the technique proposed by Breslow where they have measured vertically, starting from the surface of the tumor or from the base of the ulcer to the deepest point of invasion. While others have measured by constructing an imaginary line indicating the level of the adjacent intact oral mucosa or the basement membrane up to the deepest point of invasion.,, Pentenero et al. 2005 also recommended to consider the actual mass beneath the basement membrane rather than measuring the entire thickness of the tumour. We too have measured the depth of invasion from the intact basement membrane up to the point of deepest invasion.
We did not study the patterns of lymph node metastasis as it has already been elegantly reported by Pantvaidya et al. in 2014. We observed the similar pattern of spread for our patients and hence did not analyze it in this study.
In the Indian subcontinent, buccal mucosa and gingivobuccal complex squamous cell carcinoma forms the majority while in the western world, they are not common. However, almost 70% of these patients present in the advanced stage of the disease. This contributes to the scarcity of literature on early-stage buccal mucosa cancers. Hence, we focussed our efforts and analyzed our data on cT1/T2 buccal mucosa cancers. Through this study, we have made an attempt to emphasize the significance of subsite-based research in oral squamous cell carcinoma. Generalizing the biologic behavior of different subsites and extrapolation of information may not be justified. We intended to analyze the pattern and rate of cervical node metastasis for cT1/T2 buccal mucosa and tried correlating it with the depth of invasion. Our analysis also describes the rate of occult metastasis for this group of buccal mucosa cancers, hence paving the way for further studies and randomised trials specifically designed for buccal mucosa cancers.
| Conclusion|| |
Tumor thickness and the depth of invasion have long been associated with the cervical nodal involvement in oral squamous cell carcinomas. However, there is a lack of exclusive literature on buccal mucosa squamous cell carcinoma. Our study demonstrates that buccal mucosa lesions with depth of invasion <4 mm have negligible chance of having metastatic cervical lymphadenopathy. We conclude that even cT1/T2 buccal mucosa cancers can be aggressive in terms of cervical lymph node metastasis, but the rate of occult node metastasis stands low compared to those described for the oral tongue cancers in the literature. Furthermore, the metastatic deposits with extracapsular extension can be present in sub-centimetric lymph nodes. Our study reflects the lack of robust data in context to early-stage buccal mucosa cancers and offers an insight on the importance of subsite-specific research.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
India State-Level Disease Burden Initiative Cancer Collaborators. The burden of cancers and their variations across the states of India: The Global Burden of Disease Study 1990-2016. Lancet Oncol 2018;19:1289-306.
Amin MB, Greene FL, Edge SB, Compton CC, Gershenwald JE, Brookland RK, et al
. The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin 2017;67:93-9.
Rath GK, Parikh PM, Hukku S, Rajan B, Kumar S, Malhotra H, et al
. Indian Council of Medical Research consensus document for the management of buccal mucosa cancer. Indian J Med Paediatr Oncol 2014;35:136-9.
] [Full text]
Mishra RC, Parida G, Mishra TK, Mohanty S. Tumour thickness and relationship to locoregional failure in cancer of the buccal mucosa. Eur J Surg Oncol 1999;25:186-9.
De Silva RK, Siriwardena BS, Samaranayaka A, Abeyasinghe WAMUL, Tilakaratne WM. A model to predict nodal metastasis in patients with oral squamous cell carcinoma. PLoS One 2018;13:e0201755.
D'Cruz AK, Vaish R, Kapre N, Dandekar M, Gupta S, Hawaldar R, et al
. Elective versus therapeutic neck dissection in node-negative oral cancer. N Engl J Med 2015;373:521-9.
Weiss MH, Harrison LB, Isaacs RS. Use of decision analysis in planning a management strategy for the stage N0 neck. Arch Otolaryngol Head Neck Surg 1994;120:699-702.
Okura M, Aikawa T, Sawai NY, Iida S, Kogo M. Decision analysis and treatment threshold in a management for the N0 neck of the oral cavity carcinoma. Oral Oncol 2009;45:908-11.
Hakeem AH, Pradhan SA, Tubachi J, Kannan R. Outcome of per oral wide excision of T1-2 N0 localized squamous cell cancer of the buccal mucosa–analysis of 156 cases. Laryngoscope 2013;123:177-80.
Iyer SG, Pradhan SA, Pai PS, Patil S. Surgical treatment outcomes of localized squamous carcinoma of buccal mucosa. Head Neck 2004;26:897-902.
Huang SH, Hwang D, Lockwood G, Goldstein DP, O'Sullivan B. Predictive value of tumour thickness for cervical lymph-node involvement in squamous cell carcinoma of the oral cavity. Cancer 2009;115:1489-97.
Borges AM, Shrikhande SS, Ganesh B. Surgical pathology of squamous carcinoma of the oral cavity: Its impact on management. Semin Surg Oncol 1989;5:310-7.
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.
Ren ZH, Xu JL, Li B, Fan TF, Ji T, Zhang CP. Elective versus therapeutic neck dissection in node-negative oral cancer: Evidence from five randomized controlled trials. Oral Oncol 2015;51:976-81.
Brockhoff HC 2nd
, Kim RY, Braun TM, Skouteris C, Helman JI, Ward BB. Correlating the depth of invasion at specific anatomic locations with the risk for regional metastatic disease to lymph nodes in the neck for oral squamous cell carcinoma. Head Neck 2017;39:974-9.
Breslow A. Prognostic factors in the treatment of cutaneous melanoma. J Cutan Pathol 1979;6:208-12.
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.
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.
O-charoenrat P, Pillai G, Patel S, Fisher C, Archer D, Eccles S, et al
. Tumour thickness predicts cervical nodal metastases and survival in early oral tongue cancer. Oral Oncol 2003;39:386-90.
Pantvaidya GH, Pal P, Vaidya AD, Pai PS, D'Cruz AK. Prospective study of 583 neck dissections in oral cancers: Implications for clinical practice. Head Neck 2014;36:1503-7.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]