1. Introduction
Globacan 2020 data places the gastric cancer on the 6. most common and 5. most deadly malignancy among all cancers.[ 1 ] Despite the new efforts as well as the improvement in management of the disease, it still represents itself with an unpleasant course with a low prognostic expectation affecting more than 1 million people.[ 2 ] Particularly in cases which are being diagnosed in an advanced stage, the prognosis is remarkably low despite chemotherapy and targeted therapies.[ 3 ] There are studies claiming that the advanced staged tumors having lower rates of 5-year survival in comparison with T1 tumors which are limited to mucosa.[ 4 ] Early stage gastric cancer achieves a 5-year survival rate of more than 90%.[ 5 , 6 ] Nevertheless, there is an increasing amount of gastric cancer cases in early ages of life and the younger age is associated with increased mortality.[ 7 , 8 ]
Management of the cases with gastric carcinoma includes surgery, chemotherapy and radiotherapy. Extended lymph node dissection surgery is the mainstay treatment of local advanced gastric carcinoma.[ 9 ] Metastatic status of the lymph nodes, defined by D2-dissection, is an important prognostic factor not only in that it helps to evaluate the pathological staging and therefore help managing the systemic chemotherapy, but also in that it helps predicting the survival outcomes.[ 10 ] Surgically dissected lymph nodes contribute to gastric cancer staging.[ 11 ] On the other hand, the suboptimal dissection of lymph nodes or despite the efforts unsatisfactory numbers of lymph nodes to dissect following a neoadjuvant therapy might deteriorate the validity of this method to identify the actual stage of the cancer.[ 12 ] In order to optimize this process, studies focus on identifying the effective parameters to adequately stage the gastric cancer .
There is an increase in the amount of studies concluding that the positive lymph node ratio (LNR) is a more plausible parameter when compared to TNM staging.[ 13–15 ] Nevertheless, positive lymph node ratio is recently being discussed as an independent risk factor in current literature.[ 16 , 17 ] This survey aims to evaluate the metastatic lymph node ratio in local advanced gastric tumors and to compare the prognostic significance of LNR with the number of lymph nodes.
2. Materials and methods
A total of 193 gastric cancer cases treated with curative gastrectomy between January 2011 and December 2015 have been recruited retrospectively into this survey. The data regarding the duration of life, body-mass-index (BMI), pathological stages, whether or not neoadjuvant therapy was applied, the localization of the tumor, as well as the postoperative complications were recorded. The studies involving human participants were reviewed and approved by Institutional Review Board of University of Health Sciences Turkey, Sisli Hamidiye Etfal Training and Research Hospital (Date: 25.05.2022/No:3268). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.
2.1. Statistical analysis
For the statistical analysis NCSS (Number Cruncher Statistical System, 2007, Utah) was utilized. While evaluating the data, complementary statistical methods were used (mean, standard deviation, median, frequency, percentage, minimum and maximum). The Shapiro–Wilk test as well as the graphical assessments were used to evaluate the normality in frequentist statistics.
In order to compare the means of two independent groups with normal distribution the Independent Samples t Test and Mann–Whitney U test to compare two groups of quantitative parameters without normal distribution. Pearson chi-square test, Fisher’s exact test, Fisher–Freeman–Halton exact test were used to compare qualitative data. cutoff values of the parameters were determined by using diagnostic tests (accuracy and precision, positive and negative predictive value) and ROC analysis. Statistical significance is defined by P < .05.
3. Results
This survey includes 138 male (71.5%) and 55 female (28.5%) patients treated between 2011 and 2015 in our clinic. The average age of the population was 63.41 ± 12.56, patients ranging between 27 and 91 years. The BMI measures of cases are ranging between 17.7 and 49.9, and the average BMI was 32.97 ± 6.68. Demographic features of the population are represented in Table 1 .
Table 1 -
Demographic features of the cases and their distributions.
n (%)
Sex
Male
138 (71.5)
Female
55 (28.5)
Age
Mean ± SD
63.41 ± 12.56
Median (Min–Max)
65 (27-91)
BMI
Mean ± SD
32.97 ± 6.68
Median (Min–Max)
32.4 (17.7–49.9)
Survey (mo)
Mean ± SD
23.24 ± 16.99
Median (Min–Max)
24 (0.2–72)
Survey
Deceased
76 (39.4)
Living
117 (60.6)
Neo adjuvant
No
136 (70.5)
Yes
57 (29.5)
Surgical method
Proximal gastrectomy
1 (0.5)
Total gastrectomy
138 (71.5)
Distal gastrectomy
54 (28.0)
Tumor localisation
Upper
41 (21.2)
Middle
113 (58.5)
Distal
21 (10.9)
Mixed
18 (9.4)
Anastomotic leakage
No
182 (94.3)
Yes
11 (5.7)
The survey follow-up duration of the cases range between 0,2 and 72 months, corresponding an average of 23.24 ± 16.99 months. Seventy six patients (39.4%) died and 117 (60.6%) has been living.
Neoadjuvant therapy has been applied in 57 (29.5%) of the patients. One patient has undergone proximal gastrectomy (0.5%), 138 patients had total gastrectomy (71.5%) and 57 patients had distal subtotal gastrectomy (29.5%).
In terms of tumor localization, 41 of the cases (21.2%) were upper, 113 of them (58.5%) were middle and 21 of them (10.9%) were distal tumors.
Comorbid clinical conditions were accompanying the gastric cancer in 67 of the cases (34.7%). In thirty nine (20.2%) of the cases resection of another organ was necessarily performed. Spleen (33.3%), liver (12.8%), colon (15.4%), pancreas (17.9%), gallbladder (15.4%), and small intestines (5.2%) were resected as concomitant organs with gastrectomy (Table 2 ).
Table 2 -
Comorbidities and additional organ resections.
n (%)
Comorbidities
No
126 (65.3)
Yes
67 (34.7)
DM
9 (13.4)
HT
27 (40.4)
CHF
21 (31.3)
COPD
8 (11.9)
CRF
2 (3.0)
Additional organ resection
No
154 (79.8)
Yes
39 (20.2)
Spleen
13 (33.3)
Liver
5 (12.8)
Colon
6 (15.4)
Pancreas
7 (17.9)
Gall bladder
6 (15.4)
Small intestine
2 (5.2)
CHF = chronic heart failure, COPD = chronic obstructive pulmonary disease, CRF = chronic renal failure, DM = diabetes mellitus, HT = hypertension.
The staging of the cases found to be significantly different amongst the groups of different survey outcomes (P = .005; P < .01). Survey groups did not found to be statistically different in terms of sex, age, BMI measures, whether or not neoadjuvant was applied, the type of surgical intervention, localization of tumor and the presence of a leakage from the site of the anastomosis (P > .05) (Table 3 ). Comorbidities or resection of another organ was not found to have a significant impact on survey outcomes (P > .05) (Table 4 ).
Table 3 -
Demographic features according to survey outcomes.
Survey
P
Dead (n = 76)
Alive (n = 117)
Sex
Male
53 (69.7)
85 (72.6)
.661†
Female
23 (30.3)
32 (27.4)
Age
Mean ± SD
65.58 ± 12.87
61.98 ± 12.21
.052‖
BMI
Mean ± SD
31.91 ± 6.75
33.67 ± 6.58
.404¶
Stage
I
9 (11.8)
26 (22.2)
.005**
§
II
12 (15.8)
41 (35.0)
III
47 (61.8)
48 (41.0)
IV
8 (10.5)
2 (1.7)
Neo Adjuvant
No
51 (67.1)
85 (72.6)
.409†
Yes
25 (32.9)
32 (27.4)
Operation type
Proximal gastrectomy
0 (0)
1 (0.9)
.388§
Total gastrectomy
59 (77.6)
79 (67.5)
Distal gastrectomy
17 (22.4)
37 (31.6)
Tumor localization
Upper
20 (26.3)
21 (17.9)
.564†
Middle
42 (55.3)
71 (60.7)
Distal
8 (10.5)
13 (11.1)
Mixed
6 (7.9)
12 (10.3)
Anastomotic leakage
No
72 (94.7)
110 (94.1)
1.000‡
Yes
4 (5.3)
7 (5.9)
BMI = body-mass-index.
** P < .01.
† Pearson chi-square test.
‡ Fisher exact test.
§ Fisher Freeman Halton test.
‖ Student t test.
¶ Mann–Whitney U test.
Table 4 -
Comorbidities and additional organ resections according to survey outcomes.
Survey
P
Dead (n = 76)
Alive (n = 117)
Comorbidity
No
47 (61.8)
79 (67.5)
.418*
Yes
29 (38.2)
38 (32.5)
DM
3 (33.3)
6 (66.7)
.721†
HT
13 (48.1)
14 (51.9)
.223*
CHF
9 (42.9)
12 (57.1)
.193*
COPD
2 (25.0)
6 (75.0)
.450†
CRF
2 (100)
0 (0)
.184†
Additional organ resection
No
55 (72.4)
99 (84.6)
.172*
Yes
21 (27.6)
18 (15.4)
Spleen
9 (69.2)
4 (30.8)
.702†
Liver
3 (60.0)
2 (40.0)
1.000†
Colon
3 (50.0)
3 (50.0)
.638†
Pancreas
3 (42.9)
4 (57.1)
.392†
Gallbladder
2 (33.3)
4 (66.7)
.198†
Small intestine
1 (50.0)
1 (50.0)
1.000†
CHF = chronic heart failure, COPD = chronic obstructive pulmonary disease, CRF = chronic renal failure, DM = diabetes mellitus, HT = hypertension.
* Pearson-chi square test.
† Fisher exact test.
Preoperative N staging differs significantly among survey outcomes (P = .012; P < .05). It was reported that preoperative N0 patients have higher survival rates than N2 patients. Postoperative N scoring was reported to have a significant impact on survey outcomes (P = .001; P < .01). Postoperative N0 cases have higher survival rates than N2 and N3 cases.
Preoperative T staging do not reveal a statistically significant impact on survey outcomes while postoperative T stage has significant impact on survey outcomes (P > .05) (Table 5 ). The number of positive lymph nodes in dead cases following the survey, was found to be significantly higher in comparison to the ones who were still alive (P = .001; P < .01) (Table 6 ).
Table 5 -
Preoperative and postoperative staging and survey outcomes.
Survey
P
Dead (n = 76)
Alive (n = 117)
Clinical tumor stage
T1
2 (2.6)
13 (11.1)
.052†
T2
8 (10.5)
21 (17.9)
T3
42 (55.3)
56 (47.9)
T4
24 (31.6)
27 (23.1)
Pathological tumor stage
T1
3 (3.9)
17 (14.5)
.048*
†
T2
8 (10.5)
18 (15.4)
T3
33 (43.5)
47 (40.2)
T4
32 (42.1)
35 (29.9)
Clinical lymph node stage
N0
13 (17.1)
31 (26.5)
.004*
†
N1
11 (14.5)
36 (30.8)
N2
27 (35.5)
29 (24.8)
N3
25 (32.9)
21 (17.9)
Pathological lymph node stage
N0
13 (17.1)
47 (40.2)
<.001**
†
N1
8 (10.5)
28 (23.9)
N2
17 (22.4)
20 (17.1)
N3
38 (50.0)
22 (18.8)
Clinical metastasis stage
M0
48 (63.2)
95 (81.2)
.005*
†
M1
28 (36.8)
22 (18.8)
Pathological metastasis stage
M0
41 (53.9)
104 (88.8)
<.001**
†
M1
35 (46.1)
13 (11.2)
* P < .05.
** P < .01.
† Pearson chi-square test.
Table 6 -
Measures and ratios and their implications on survey outcomes.
Survey
P
Dead (n = 76)
Alive (n = 117)
Total lymph node
Median (Min–Max)
24 (1–73)
24 (1–93)
.690†
Positive lymph node
Median (Min–Max)
7 (0–42)
1 (0–43)
.001**
†
Positive lymph node/total lymph node
Median (Min–Max)
0.3 (0–1.1)
0 (0–0.9)
.001**
†
Preoperative albumin
Median (Min–Max)
3.6 (2.3–4.8)
3.8 (2.3–4.9)
.022*,
†
Preop HGB
Median (Min–Max)
10.8 (7–15.8)
11,4 (8.3–16.1)
.285†
CEA
Median (Min–Max)
3.1 (0.8–571.4)
2.1 (0.4–278)
.013*,
†
Ca19.9
Median (Min–Max)
12.4 (0.6–390.9)
10.5 (0.6–7835)
.311†
CEA = carcinoembryonic antigen, HGB = hemoglobin.
*P < 0.05.
** P < .01.
† Mann–Whitney U test.
Carcinoembryonic antigen measures of the cases who were Group 1 were found to be significantly higher than the Group 2 (P = .013; P < .05).
The total number of dissected lymph nodes, preoperative CA19-9 and preoperative Hemoglobin measures were not reported to have a significant impact on the survey outcomes (P > .05).
4. Discussion
Gastric cancers still possess very high mortality rates. The amount of particularly the newly diagnosed gastric cancer cases are higher in Asia and Southern America.[ 18 ] Gastric cancers deteriorate the quality of life and have high health care expenses, causing various morbidities and has a high rate of mortality.[ 19 ] Overall survival rate of gastric cancers in United States of America was reported to be 31%, whereas it is 25% worldwide.[ 20 ] One of the most important factors that affect the mortality is the stage at the diagnosis.[ 2 ] Gastric cancers are yet most commonly diagnosed in an advanced stage and therefore have a poor prognostic expectancy.[ 21 ] The management largely depend on the stage of the disease, the positivity of given biomarkers and the expert opinion of the clinicians. In order to contribute to the efforts of deciding for the right management strategies. There is an effort to define the most important prognostic parameters of gastric cancer . Current literature attributes prognostic value to various markers. Albumin to Fibrinogen Ratio, The hemoglobin, albumin, lymphocyte, and platelet score, multiple tumor markers, increased expression of Histone Deacetylase 5 appear to be useful parameters in predicting orignostic expectancy in gastric tumors.[ 22–25 ] In 2017, the American Joint Committee on Cancer made revisions on cTNM staging system in their 8th Edition.[ 11 ] The staging system of American Joint Committee on Cancer only takes the number of positive lymph nodes into consideration but not the positive to total lymph node ratio.[ 26 , 27 ] Solely considering the number of positive lymph nodes as a predictive parameter does not appear to be efficient to makes statements about prognostic expectance. This is particularly pronounced in case of an insufficient dissection of the lymph nodes, which in turn may lead to errorous staging and treatment.[ 12 , 28 ] A number of studies conclude that the increased number of lymph nodes indicates a better survival outcome, in that it refers to a more radical and extended surgery.[ 29 , 30 ] The improvements in surgical techniques and the increasing surgical experience in the field, the amount of dissected lymph nodes increase but the need of a better prognostic marker to address a more accurate staging still exist. Positive to total of dissected lymph nodes ratio is a useful, readily accessible and reproducible marker that might also be used to better define subgroups in a particular malignancy.[ 15 ] LNR is a measure of number of positive lymph nodes in the total of dissected lymph nodes.[ 31 , 32 ] LNR ratio is increasingly being experimented in thyroid cancers, colon and gastric cancers and other kinds of malignancy, showing a promising prognostic value.[ 15 , 33–35 ] Recent studies indicate the accuracy of LNR in staging is superior than the total amount of the dissected lymph nodes.[ 36 , 37 ] When divided into the groups with regards to the duration of life using the cutoff values of LNR, the lower LNR indicated a longer duration of life.[ 14 ] In our survey, it is stated that the positive lymph node ratio , as well as the number of positive lymph nodes are correlated with prognosis . Different results in various series might imply the diversity of the statistical methods used in the studies.
4.1. ROC curve analysis of the survey outcomes
In this survey, it is concluded that the number of positive lymph nodes, as well as the positive to total number of lymph nodes ratio have been significantly and negatively correlated with the life expectancy. In other words, patients with high numbers of positive lymph nodes or higher LNR tend to live shorter (P = .001; P < .01).
We calculated cutoff value of 0.09 with, sensitivity is 76.32% for positive to total number of lymph nodes ratio, whereas specivity applies for 64.10%, positive predictive value for 58% and negative predictive value for 80.6% (Table 7 ). The area under the ROC curve occupies 72.6%, whereas 3.7% was reported to be the standard deviation. In predicting the mortality, positive to total lymph node ratio (with the cutoff ratio of 0.09%) is found to be significantly correlated (P = .001; P < .01) (Fig. 1 ).
Table 7 -
Diagnostic tests and results of ROC curve for positive LN/total number of LN.
Diagnostic scan
ROC curve
P
Cut off
Sensitivity
Specificity
Positive predictive value
Negative predictive value
Area
95% confidence interval
Positive Ln/Total LN
≥0.09
76.32
64.10
58.00
80.60
0.726
0.653–0.800
.001**
Figure 1.: ROC curve analysis of the survey outcomes.
Aside from the number of the positive lymph nodes or the positive to total number of lymph nodes ratio, another predictive factor is the postoperative metastatic status of the patient, significantly being correlated to life expectancy. Postoperatively metastatic gastric cancer cases have significantly lower expectancy of life. Pre- or postoperative T staging does not appear to have a significant impact on this manner. Other parameters like comorbidities or dissection of the other involved organs were not reported to have a significant correlation to life expectancy. Tumor markers, as well as the preoperative albumin measures do not significantly affect the overall survival rates.
Various studies reported the positive lymph node ratio corresponding to an independent risk factor.[ 38–40 ] cutoff values vary among studies, according to the statistical method, the number of cases and the duration of the follow-up period. Optimally defining the cutoff value might serve to better predict the prognosis of the gastric cancer cases. In our survey, we utilized a cutoff value of 0.09 following statistical calculations. Liu et al used a cutoff value of 0.1 in their studies in which Seer database was utilized.[ 41 ]
Despite the high numbers of the studies focusing on the prognostic measures, there are limited studies which cutoff value was determined. A consensus on the cutoff value might contribute to a more accurate estimation of prognosis following a surgical treatment and thereby in decision making processes regarding the adjuvant therapy. A good example to this is the cutoff value determined by Yalkin et al[ 17 ] as 0.18 and therefore median duration of survival was reported as 22 months. With the help of prospective randomized studies focusing on this challenge, addressing a cutoff value, which the experts agree on, might help clinicians to plan more individualized and in some cases more aggressive management strategies.
Despite the statements and their applicable value, this study has some limitations. The number of cases included in this survey might be inadequate. The retrospective design of the survey is also a methodological limitation. The scarcity of the information regarding whether or not the patients concluded the whole course of adjuvant treatment or the kind of adjuvant treatment they were assigned to limits the study in that these parameters might possibly have an impact on the life expectancy. We speculate that these parameters on the other hand, might have a more prominent impact, if any, for the studies in which the long term survival rates are higher.
5. Conclusions
In this survey, it is concluded that the N ratio is a significant parameter in predicting the prognosis in cases with gastric adenocarcinoma, following a curative gastrectomy . In cases, where sufficient amount of lymph nodes were dissected, it is possible to determine a cutoff value. In order to obtain a consensus on a cutoff value, multicentered, prospective studies with a larger sample size, longer and follow-up duration are needed. NR might also be integrated into the current staging system and thereby contribute to a better estimation of the prognosis .
Acknowledgments
We would like to thank Bilgesu Ergezen for English language editing.
Author contributions
Conceptualization: Emir Capkinoglu.
Formal analysis: Emir Capkinoglu, Aydin Eray Tufan.
Investigation: Sinan Ömeroğlu.
Methodology: Sinan Ömeroğlu.
Project administration: Onur Güven.
Software: Mert Tanal.
Writing – original draft: Sinan Ömeroğlu, Emir Çapkinoğlu.
Writing – review & editing: Uygar Demir.
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