*2.2.5. Histological type and grade (G)*

et al. [18]. No differences in N distribution by NLR were found by Kim et al. who analysed a large group of 601 patients [48] and Yu et al. who assessed another significant cohort of 291 patients. In the same study, association with T and TNM stage was significant [20]. There was no correlation between NLR and N in a reasonable group of 262 surgically treated patients affected by T2–T4 gastric cancer while correlation with T in the same study was meaningful.

Some reports have re-evaluated the meaning of NLR in predicting N status, arriving to less positive conclusions. In early gastric cancer (T1a–T1b), NLR was significantly associated with presence of lymph node metastases. The mean NLR was 2.07 in N0 group while it increased to 2.60 in N+ group. However, by multivariate analysis NLR was not an independent prognostic factor. Complex score not including NLR was more informative for preoperative estimation

Presence of distant metastasis has also been associated with higher NLR [38, 77]. Metastatic tumours were significantly more frequent in patients who had high NLR (exceeding 3.44) assessing 1030 patients with resectable gastric cancer [22]. Significant difference in M0 vs. M1 frequencies by NLR groups was reported by Deng et al. In addition, the mean NLR was 5.00

In a large study of 491 gastric cancer patients, NLR was significantly associated with peritoneal metastasis. However, it was not an independent predictive factor for peritoneal spread, while tumour morphology, serum level of carbohydrate antigen CA19-9 and lymphocyte count retained independent predictive value [78]. In contrast, evaluating CRP, activated partial thromboplastin time, NLR and hypoalbuminemia, NLR was identified as an independent risk factor of the presence of peritoneal metastasis. The cut-off level was set at 2.37 [79].

Considering the previously discussed links between NLR and TNM parameters, correlation with TNM stage could be expected as well. Indeed, advanced TNM stage was significantly associated with high NLR [9, 20, 44, 47, 65, 77]. High NLR (exceeding the ROC-set cut-off value of 1.59) was associated with high TNM stage [55]. The mean NLR was 4.73 in stage I–II and 7.07 in stage III–IV [47]. In advanced gastric cancer (stage III–IV) patients, there still was

Statistically significant correlation between cancer stage and high NLR was confirmed also by multicentre [61] and prospective study design [54]. In a prospective study of 1131 surgically treated patients, high NLR (exceeding the median 3.5) was associated with higher TNM stage. The mean NLR was 2.13 in stage I, 2.40 in stage II, 2.53 in stage III and 2.60 in stage IV [54].

Regarding negative reports, no NLR differences by TNM stage were found by Kim et al. who

The cut-off in this study was detected by ROC and was 3.2 [73].

of lymph node metastases [72].

162 Gastric Cancer

*2.2.3. Presence of distant metastases: M*

in M0 cases and 7.82 in M1 cases [47].

difference between stage III and IV [53].

analysed a large group of 601 patients [48].

*2.2.4. TNM stage*

The association between NLR and cancer grade is more controversial. The cancer grade was not different between high and low NLR groups in a cohort of 143 metastatic gastric cancer cases as well as in 389 patients who underwent gastrectomy or in 293 gastric cancer patients diagnosed in stage III–IV [22, 25, 47, 53]. No difference by differentiation degree (G1–2 vs. G3) was found by Yu et al. [20].

In contrast, high NLR was associated with differentiated (vs. undifferentiated) gastric cancer [9]. High differentiation degree (vs. moderate and poorly differentiated cases) was associated with low NLR. In the same study, no differences were observed regarding proliferation fraction by Ki-67 [38]. High NLR (exceeding the ROC-set cut-off value of 1.59) was associated with high grade [55]. In a prospective study of 1131 surgically treated patients, high NLR (exceeding the median 3.5) was associated with poor differentiation or undifferentiated tumours while low NLR—with high and moderate differentiation. The relevant mean NLR values were 2.46 in G3–G4 vs. 2.31 in G1–G2 cancers [54].

There was no correlation between NLR and histological differentiation in a large group of 262 surgically treated patients affected by T2–T4 gastric cancer while correlation with T in the same study was meaningful. The cut-off in this study was detected by ROC and was 3.2 [73]. No correlation between histological type of cancer and NLR was observed in a prospective study of 1131 surgically treated patients [54]. No differences in histology distribution by NLR were found by Kim et al. who analysed a large group of 601 patients [48]. Histological types (papillary, tubular, poorly differentiated, mucinous, signet ring cell carcinoma) were scrutinized by Deng et al., also finding no association with NLR level [47].

No NLR differences were observed between Lauren types: intestinal vs. diffuse [38, 53, 65] that might explain the lack of association with HER-2 protein expression [38].

Low NLR shows significant correlations with mismatch repair deficiency [34]. In cancer tissues, the density of CD4-positive lymphocytes was significantly decreased in high NLR group while the density of CD3 and CD8-positive lymphocytes was not associated with NLR [49]. Although NLR correlated with survival, it did not correlate with tumourinfiltrating lymphocytes [62]. Regarding cytokines and angiogenic factors, serum levels of osteopontin and interleukin 6 were significantly associated with NLR in gastric cancer patients [80]. NLR is significantly associated with helper T lymphocyte Th1/Th2 ratio in blood [65].

#### *2.2.6. Manifestations of invasive growth*

Only few scientists have assessed the relations between NLR and such manifestations of invasive growth as perineural, lymphatic and vascular invasion. Theoretically, such association could be hypothesised on the basis of prognostic value of NLR and the correlations between NLR and metastatic cancer spread. However, at present, negative reports predominate although are not unequivocal.

The frequency of perineural growth was not different between high and low NLR groups [22]. The frequency of lymphovascular invasion also was not different between high and low NLR groups in a cohort of 143 metastatic gastric cancer cases [25]. In contrast, vascular or lymphatic invasion was significantly more frequent in patients who had high NLR (exceeding 3.44) assessing 1030 cases of resectable gastric cancer. Hypothetically, the higher capacity for invasive growth could be the reason of more frequent occurrence of R1 in patients presenting with high NLR. However, association between NLR and resection line status (R0 vs. R1 vs. R2) was found by Jung et al., who observed no differences in the frequency of lymphatic, vascular and perineural growth regarding NLR level [53].
