The surgical management of the clinical negative neck node in early oral tongue squamous cell carcinoma (OTSCC) has been the topic of debate since few decades. As the occult cervical lymph node metastasis is considered to be the prime prognostic factor in early OTSCC, this meta-analysis has been carried out to find the risk of regional nodal recurrence, disease specific survival and overall survival rates in outcome of Elective neck dissection (END) versus patients under observation. The articles were electronically retrieved from Ovid Medline, PubMed, Cochrane and Scholar for comparison of END versus Observation in early OTSCC. The search strategy identified 37 relevant review articles from April 1979 to April 2020 from different search engines. A total of 11,973 patients from 32 retrospective analysis, 4 prospective and 1 randomised control trial were included in this meta-analysis. Statistical analysis revealed Overall test (OR: 5.31 95% CI: − 2.132–14.698) with t-test 1.919 and p value 0.113 which is not statistically significant but the readings says that there is always better Disease specific survival with END patients rather than patients kept on observation. Overall test revealed (OR: 13.02 95% CI: 1.360–17.154) with t test 2.382 and p value 0.023 which is statistically significant and showed that End significantly reduced the risk of regional nodal recurrence. Overall test revealed (OR: 7.93 95% CI: − 15.461–4.238) with t test − 1.347 and p value 0.220 which is statistically insignificant and but showed that to some extent Overall survival improves in patient with END than the patients kept on observation. This meta-analysis find that there is statistically significant relationship when Elective neck dissection was performed which reduced the risk of regional nodal recurrence. This analysis didn’t statistically find any significance in Disease specific survival and Overall survival with Elective neck dissection patients rather than patients kept on observation but however showed good prognosis when elective neck dissection was performed.
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Introduction
Cancer is being recognised as the leading cause of morbidity and mortality after cardiovascular disease [1, 2]. The most common type of oral cavity cancers are squamous cell carcinoma which constitute approximately 90% of all cancers [3, 4]. The most frequent sub-site of the lip oral cavity cancer is the tongue cancer [5]. The etiology of the lip oral cavity cancer is attributed to the use of tobacco and its related products, alcohol use, sedentary lifestyle, diet and nutrition, dental irritation, genetic factors and HPV infections [6]. Cervical nodal metastasis is considered as the most important prognostic factor which solely determines the survival and prognosis of patient [7, 9, 10, 16]. It is estimated that the involvement of lymph node in oral cavity cancers reduces the survival by 50% and presence of extranodal extension further decreases the survival by 50% [8].
The management of the N0 neck in early tongue cancer has been the topic of discussion since last three decades and is still an controversial topic. Surgery is the mainstay treatment of early stage oral tongue squamous cell carcinoma (OTSCC). The decision while performing the surgery is whether to address the neck at the time of excision of primary tumor or to observe the neck till clinical positive neck nodes. Various studies have been reported in literature favouring observation as well as Elective neck dissection (END). Neck dissection along with the excision of primary is thought to be benefitted in cases of subclinical occult metastasis [9]. Presence of higher incidence of occult metastasis in cases of early oral cancers is approximately 16–36% [10‐12]. The logic lies in the fact that the sub clinical occult metastasis plays the pivotal role in the early OTSCC and considered to be the key factor for the loco-regional failure in the cases where only resection of primary tumor has been performed. Meanwhile, the quality of life is compromised in END because of invasiveness of neck surgery [13]. Whereas, in the “Wait and Watch” group, the observed neck is benefitted in truly negative clinical neck as those patients experiences less extensive surgery.
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The aim of this study is to systematically review the current literature to (1) find disease specific survival patients after END versus patients kept on observation (2) find the neck nodal recurrence in END patients and patients kept on Observation (3) find the overall survival rate in END patients and patients kept on observation .
Materials and Methods
The data collected for this study was performed according to PRISMA guidelines. Electronic searches were performed using Ovid Medline, PubMed, Cochrane, Scopus and Scholar from 1970 to April 2020. Search terms used to achieve maximum data were: (“squamous cell carcinoma” OR “Cancer” OR “Carcinoma” OR “SCC”) AND (“Tongue” OR “oral tongue” OR “mobile tongue”) AND (“T1” OR “T2” OR “early stage”) AND (“elective neck dissection” OR “END”, “neck dissection” OR “no neck treatment” OR “observation” OR “wait and watch”) AND (“node-negative neck” OR “N0 neck”) as either terms or MeSH terms. The data obtained from above search results were reviewed and the relevant articles were selected based on the inclusion and exclusion criteria of our study .
Inclusion criteria: The articles with full text in English language were included in the study. Only early stage cancer as T1, T2 and N0 neck are included in the study. Randomised trials and matched Studies including the elective neck dissection versus observation were included. All patients included should be pathologically proven as Squamous cell carcinoma of the tongue without any clinically apparent lymphadenopathy or distant metastasis at the time of diagnosis. Exclusion criteria: T3 and T4 lesions of tongue, medically compromised patients, patient completed radiation therapy prior to surgery.
Data Extraction
There were 2 reviewers in this study to discuss any difference in opinion. First reviewer extracted all the data from the published articles. The information collected were type of study design, year, patient characteristics (age and sex), country and period, tumor stage distribution, data on END versus observation, follow up period and the outcome of the articles. All these Information were reviewed by the second reviewer. Three parameters were chosen as endpoints for the systemic review and meta-analysis: occult cervical lymph node metastasis, neck nodal recurrence and overall survival rate. Table 1 show demographic table with a total 37 articles were included in the study with 11,973 patients with all the data collected.
Table 1
Demographic
Article
Year
Design
Sex (M/F)
Age
Country, dates
Total patients
Patients included in analysis
No of pts (END)
Follow up time
Fakih et al.
1989
Prospective randomized
45/25
NA
India (1985–1988)
70
40
30
Median 20 months
Franceschi et al.
1993
Retrospective
NA
Median 60
America (1978–1987)
211
148
63
Minimum 5 years
Lydiatt et al.
1993
Retrospective
93/63
Median (60.5/64)
America (1970–1985)
156
102
54
Median (Obs-78 months/END-67.5 months)
Yuen et al.
1997
Retrospective
36/27
Median 57
Hong Kong (1980–1994)
63
30
33
Median 67 months
Yii et al.
1999
Retrospective
54/23
Median 57
United Kingdom (1983–1995)
71
50
13
Median 48 months
Beenken et al.
1999
Retrospective
99/70
Mean 61
United States (1956–1994)
150
135
15
Median 4.8 years
Haddadin et al.
1999
Retrospective
72/65
Mean 65.7
United Kingdom
137
90
47
NA
Kligerman et al.
2001
Retrospective
32/17
Median 59
Brazil (1985–1995)
28
17
11
Median 57 months
Kramer et al.
2001
Retrospective
55/41
NA
Canada (1985–1994)
96
75
21
Minimum 5 years
Al-Rajhi et al.
2002
Retrospective
45/48
Median 60
Saudi Arabia (1980–1997)
93
29
36
Median 62 months
Goto et al.
2005
Retrospective
55/35
Median 50
Japan (1985–2000)
90
57
33
Median 66 months
Deng et al.
2005
Retrospective
59/36
Median 50
China (1988–1997)
95
24
71
Minimum 5 years
Keski-santti et al.
2006
Retrospective
41/39
Median 57
Finland (1992–2002)
80
34
44
Minimum 2 years
Huang et al.
2008
Retrospective
325/55
Median 48
Taiwan (1995–2002)
380
56
324
Median 38 months
An et al.
2008
Retrospective
35/28
Mean 56
Korea (1987–2006)
63
43
20
Median 59 months
Yuen et al.
2009
Prospective, randomised
43/28
Mean, Obs-58; END-56
Hong Kong (1996–2004)
71
35
36
Median 34 months
D Cruz et al.
2009
Retrospective
239/120
Median 59
India (1997–2001)
359
200
159
NA
Lin et al.
2011
Retrospective
47/34
Median 63
Australia (1991–2009)
81
47
29
Median 34 months
Liu et al.
2011
Retrospective
79/52
Median 52
China (1991–2003)
92
43
49
NA
Li et al.
2011
Retrospective
78/54
Mean 61/59
China (1997–2007)
132
61
71
Median (END-4 years/Obs-3 years)
Ryott et al.
2011
Retrospective
NA
NA
Sweden
74
40
33
Mean 74 months
Pugazhendi et al.
2012
Retrospective
15 male/6 female
NA
India (2009–2011)
21
10
11
Median 8.2 months
Jantharapatta et al.
2012
Retrospective
54/55
Median 64
Thailand (1992–2000)
109
68
41
Median 64 months
Feng et al.
2014
Retrospective
104/125
Mean 58.1
China (1993–2010)
229
73
156
Median 58 months
Kelner et al.*
2014
Retrospective
160/61
Median 58
Brazil (1980–2010)
222
61
161
Median 68.7 months
Peng et al.
2014
Retrospective
64/59
Mean 56
United States (1990–2009)
123
35
88
Median 29 months
Zhang et al.
2014
Retrospective
33/32
Mean 60.7
America (1999–2007)
65
29
36
Median 56.8 months
Yeh et al.
2014
Retrospective
NA
Mean 54.2
Taiwan (2001–2009)
253
77
176
Median 61.9 months
Mirea et al.
2014
Prospective
69/17
Mean 54
Romania
86
38
48
Minimum 2 years
D cruz et al.
2015
Prospective, randomised
374/122
Mean 48
India (2004–2014)
496
253
243
Median 39 months
Patel et al.
2016
Retrospective
3951/3059
Mean 62.1
United States (1998–2011)
7010
4279
2720
NA
Otsura et al.
2016
Retrospective
97/65
Mean 61.1
Japan (1996–2006)
152
136
26
NA
Orabona et al.
2016
Retrospective
59/68
Mean 59.4
Italy
127
61
66
Mean 41.6 months
Sung et al.
2017
Retrospective
56/42
Mean 57
Korea (2005–2014)
98
84
14
Mean 33.7 months
Loganathan et al.
2017
Retrospective
50/31
Median 57
United Kingdom (2000–2006)
81
65
16
Median 32 months
Gad ZS et al.
2018
Retrospective
44/44
Mean 59.2%
Egypt (2007–2013)
88
13
75
54 months
Yang et al.
2018
RCT
122/99
Mean (51.8/54.5)
China (2008–2014)
221
110
111
Mean 44.3 months
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Statistics
To evaluate heterogeneity of studies, Chi-square test (χ2) was done. The level of significance was determined for heterogeneity at p = 0.05. I2 value determined the percentage of variation across the studies. Values < 50% show less variability. For comparison between two parameters end and observed values, t test was applied and level of significance was determined, along with confidence interval at 95% level.
Results
The search strategy identified 37 relevant review articles from April 1979 to April 2020 from different search engines. A total of 11,973 patients from 32 retrospective analysis, 4 prospective and 1 randomised control trial were included in this meta-analysis.
Out of 37 articles, 11 articles (Table 2) were included in meta-analysis to find Disease specific survival for Elective neck dissection patients versus Observation. The HR test revealed that χ2 IS 30.0, I2 is 42% with p value 0.224. Overall test revealed (OR: 5.31 95% CI: − 2.132–14.698) with t test 1.919 and p value 0.113 which is not statistically significant but the readings says that there is always better Disease specific survival with END patients rather than patients kept on observation (Fig. 1).
Table 2
Disease specific survival for END versus patients kept on observation
Article
END (%)
Observation (%)
Al-Rajhi et al.
79
59
Goto et al.
Observation vs END, HR, 0.271 (95% CI, 0.026–2.854, NS)
Keski-santti et al.
82
77
Yuen et al.
89
87
Jantharapatta et al.
DSS-2.20 (0.20–19.92) 95% Cl
Feng et al.
79.2
61.9
Kelner et al.*
74
79
Yeh et al.
DSS-0.83 (0.11–6.45) 95% Cl
Patel et al.
Obs (T1-0.8193, T2-0.5735); END (T1-0.816, T2-0.8015)
Sung et al.
70.7
65.3
Yang et al.
DSS-1.75 (0.88–3.49) 95% Cl
Results
Heterogeneity Test
Odd ratio
OR
SE
95% CI
Overall test
χ2
df
p-value
I2
t-test
p-value
DSS
30.0
25
0.224
42%
5.31
3.27378
− 2.13218–14.69884
1.919
0.113
*p-value > 0.05 is in sig
Fig. 1
Tabulation of HR of all 11 articles to find disease specific survival for END versus patients kept on observation
×
All the 37 articles with 11,973 patients (Table 3) were included in meta-analysis to find the nodal recurrence in END patients versus patients kept on observation. The HR test revealed that χ2 IS 394.917, I2 is 40% with p value 0.506. Overall test revealed (OR: 13.02 95% CI: 1.360–17.154) with t test 2.382 and p value 0.023 which is statistically significant and showed that End significantly reduced the risk of regional nodal recurrence (Fig. 2).
Table 3
Nodal recurrence in END versus observation
Article
Observation (%)
END
Fakih et al.
23 (57.5%)
9 (30%)
Franceschi et al.
39 (26.4%)
10 (15.9%)
Lydiatt et al.
17 (16.7%)
10 (18.5%)
Yuen et al.
14 (46.7%)
3 (9.1%)
Yii et al.
22 (44%)
1 (7.7%)
Beenken et al.
32 (23.7%)
0
Haddadin et al.
38 (42.2%)
8 (17%)
Kligerman et al.
6 (35.3%)
0
Kramer et al.
24 (32%)
2 (9.5%)
Al-Rajhi et al.
11 (38%)
4 (11%)
Goto et al.
15 (26.3%)
5 (15.1%)
Deng et al.
6 (25%)
5 (7.0%)
Keski-santti et al.
8 (23.5%)
4 (8.7%)
Huang et al.
16 (28.6%)
40 (12.3%)
An et al.
5 (11.6%)
5 (25%)
Yuen et al.
11 (31.4%)
2 (5.5%)
D Cruz et al.
94 (47%)
9 (5.7%)
Lin et al.
20 (42.5%)
5 (17.2%)
Liu et al.
10 (23.2%)
8 (16.3%)
Li et al.
10 (14.1%)
23 (37.7%)
Ryott et al.
16 (36%)
3 (10%)
Pugazhendi et al.
2 (20%)
0
Jantharapatta et al.
12 (17.6%),
23 (56.1%)
Feng et al.
14 (19.2%)
15 (9.6%)
Kelner et al.*
16
21
Peng et al.
2 (5.7%)
7 (7.9%)
Zhang et al.
4 (13.8%)
5 (13.9%)
Yeh et al.
10 (24.7%)
16 (9.1%)
Mirea et al.
8 (16.7%)
18 (47.4%)
D cruz et al.
108 (42.7%)
25 (10.3%)
Otsura et al.
30 (22.1%)
3 (11.5%)
Orabona et al.
5 (8.2%)
8 (12.2%)
Loganathan et al.
4 (25%)
6 (9.2%)
Gad ZS et al.
2 (15.4%)
16 (21.3%)
Yang et al.
19 (17.3%)
30 (27.0%)
Results
Heterogeneity test
Odd ratio
OR
SE
95% CI
Overall test
χ2
df
p-value
I2
t-test
p-value
NR
394.917
396
0.506
40%
13.02
3.886
1.360–17.154
2.382
0.023*
*p-value < 0.05 is sig
Fig. 2
Tabulation of HR of all 37 articles to find nodal recurrence in END versus observation
×
Out of 37 articles, 16 articles (Table 4) were included in meta-analysis to find the overall survival in END patients versus patients kept on observation. The HR test revealed that χ2 is 56, I2 is 43% with p value 0.229. Overall test revealed (OR: 7.93 95% CI: − 15.461–4.238) with t test − 1.347 and p value 0.220 which is statistically insignificant and but showed that to some extent Overall survival improves in patient with END than the patients kept on observation (Figure 3).
Table 4
Overall survival for END and observation
Article
Observation (%)
END (%)
Yii et al.
65
75
Haddadin et al.
53.6
80.5
Deng et al.
OS-0.33 (0.16–0.67) 95% CI
Keski-santti et al.
66
63
Huang et al.
75.1
87.2
D Cruz et al.
62
69
Liu et al.
75.9
83.9
Li et al.
OS-0.73 (0.31–1.71) 95% CL
Jantharapatta et al.
OS-1.33 (0.33–5.40) 95% Cl
Kelner et al.*
77
70
Yeh et al.
OS-1.01 (0.99–1.03) 95%Cl
D cruz et al.
END vs OBSERVATION, HR 0.64 (95% CI, 0.45–0.92), P = 0.01
Patel et al.
Obs (T1-77.1%, T2-45.2%); END (T1-77.8%, T2-68.8%)
Otsura et al.
OS-0.61 (0.27–1.35) 95% Cl
Orabona et al.
Overall relapse free survival-Obs 34.2 ± 16.4 months and END 37.9 ± 15
Sung et al.
92.4
83.3
Loganathan et al.
OS-0.26 (0.01–5.24) 95% Cl
Results
Heterogeneity test
Odd ratio
OR
SE
95% CI
Overall test
χ2
df
p-value
I2
t-test
p-value
OS
56
49
0.229
43%
7.93
4.16582
− 15.46311–4.23811
− 1.347
0.220
*p-value > 0.05 is insig
Fig. 3
Tabulation of HR of all the 16 articles to find overall survival for END and observation
×
Discussion
OTSCC is a challenging entity when compared to other sub-sites of oral cavity because of its unpredictable nature of lymphatic involvement. The lymphatic spread of the OTSCC can be sub-clinical at the time of diagnosis and it can be presented as unilateral or bilateral Involvement. The lymph node metastasis depends on various factors such as tumor growth type, size, differentiation, mode of Invasion, pattern of Invasion, tumor thickness, histological grading and staging [14, 15].
The prime etiology of treatment failure and poor prognosis in early OTSCC is neck nodal recurrence [8]. According to various studies, it has been concluded that the recurrence rate of cervical lymph nodes are higher in tongue compared to other sub-site, because of rich vascular supply, lymphatic drainage and frequent mechanical movement of the tongue [18, 19]. After reviewing the literature the chances of neck node recurrence is less in END when compared with the observation. Yuen et al. has concluded that elective neck dissection has significantly reduced neck nodal recurrence [15‐17]. A study was carried out by Tsang et al. suggesting that END is suitable for T2 lesions of tongue and patients kept under wait and watch policy was only considered when the tumor thickness is less than 4 mm, G2 grading and patients are ready to be in close follow up [20]. The concept of Elective neck dissection in early stage OTSCC is followed worldwide and has gained popularity because of increased rate of nodal recurrence in cases of observed neck. Although, END gives more morbidity such as shoulder dysfunction, neck pain and keloids. Disadvantage of END occurs in case of true N0 neck which comprises of approximately 70% has to undergo morbidity to prevent neck node recurrence. Benefit of observation over END is that the patients with truly subclinical nodal metastasis (30–40%) have to undergo surgery but with a increased risk of morbidity [17]. Wong et al. described the effectiveness of salvage surgery in neck nodal recurrence to be only moderately effectively with 32% of 5-year survival rate [21]. In cases of cervical metastasis, early diagnosis and management is of utmost importance, as in delayed cases the risk of extracapsular spread and multiple involvement of nodes are increased. So, it can be said that the reduced survival rate could be seen in cases of observation group [22]. Van den Berkel et al. showed that the occurrence of the neck nodal recurrence arise in less than 18 months after the first treatment. He suggested that the reason to neck nodal recurrence is the previous presence of micro-metastasis of the lymph node which went undetected clinically. With the improvement in the technology, USG-guided FNAC has high positive and negative predictive values which is proved to be better diagnostic aids in detecting the lymph node metastasis [23]. Similarly Sentinel lymph node biopsy is also considered to be alternative for detecting the nodal metastasis [24]. A study carried out on 10 patients with early OTSCC by Sagheb et al., comparing the histopathological findings from END group to the SLNB specimen. His results showed the sensitivity and specificity rates of 75 and 100% respectively [25]. Many surgeons believe that SLNB is an alternative option for END. In present meta-analysis p value 0.023 which is statistically significant and showed that END significantly reduced the risk of regional nodal recurrence.
In our study, we have calculated overall survival rate of patients undergoing END and kept under observation. Our meta-analysis shows p value 0.220 which is statistically insignificant and but showed that to some extent Overall survival improves in patient with END than the patients kept on observation. Overall survival rate is stated as a five year survival rate, which is the percentage of people in a study or treatment group who are alive 5 years after their diagnosis. D’Cruz and his colleagues conducted a randomised trial in 2015 comparing the rates of overall survival and disease free survival of END versus therapeutic neck dissection in node-negative oral cancer patients. His study included 596 patients of oral cavity cancer with the maximum of 85.3% cases of tongue cancer. He suggested that END showed significantly better overall survival rate by 12.5%. They also reported more advanced nodal disease in cases of observed neck cases [26]. Ren et al. conducted a meta-analysis comparing the results END and observation with therapeutic neck dissection for nodal repalse including 5 randomised trials. 4 studies had reported on Overall survival rate. The result showed higher OS in the END group as compared to observation with a significant inter-group difference [27]. In a meta-analysis done by Abu Ghanem et al., he demonstrated less recurrence and better disease-specific survival rate in END group compared to observation. However, they reported no significant improvement in overall survival rates [16]. Keski-Santti et al., in his study included 80 patients of early OTSCC with clinically N0 neck demonstrated that there is no significant improvement in the overall survival rate and disease free survival rate after undergoing END [28]. In the study of Kligerman, he showed better 3 year survival rates from 49 to 72% in END group [22]. In 2006, Yu et al. reported 100% 5 year survival rate in END group whereas only 68.7% in patients kept under observation [29]. Yuen et al. achieved 89% survival rate after END and 87% survival rate in observation group which is insignificant [17]. Fakih et al. also reported insignificant difference in overall survival rate between the hemiglossectomy group and hemiglossectomy and radical neck dissection group [30].
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In our study we also found that p-value 0.113 which is not statistically significant but the readings says that there is always better Disease specific survival (DSS) with END patients rather than patients kept on observation. There are many studies done in literature, the one from Yookyeong Carolyn Sim et al. [31] concluded that the survival rate is lower in poor-grade or advanced TNM stages. In their study, patients with stage I and II disease showed DSS of 100%. It could be concluded that early-stage OSCC is curable, and therefore early detection is critical.
This meta-analysis find that there is statistically significant relationship when END was performed which reduced the risk of regional nodal recurrence. This analysis didn’t statistically find any significance in DSS and OS with Elective neck dissection patients rather than patients kept on observation but however showed good prognosis when END was performed.
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