The contribution of hematological parameters to prediction of the phase in stage 2 and stage 3 colon cancers Текст научной статьи по специальности «Клиническая медицина»

Х1Ж) JOURNAL OF CLINICAL MEDICINE OF KAZAKHSTAN

Озын, Макала / Оригинальная Статья / Original Article

DOI: 10.23950/1812-2892-JCMK-00771

The contribution of hematological parameters to prediction of the phase in stage 2 and stage 3 colon cancers

Erkan Karacan1, Eyup Murat Yilmaz2, Buse Yildiz2, Ahmet Ender Demirkiran2

Abstract

Purpose: Colorectal cancers are a significant cause of cancer-related deaths around the world. In the preoperative staging of colon cancers, radiological images and various blood tests are used. However, it is both difficult and expensive to apply radiological examinations. In our study, we aimed at predicting the stage of colon cancers by preoperatively viewing the hematological parameters, which are simple, cheap and easy to apply.

Material and methods: The patients, who had been operated due to colon cancer by a single surgeon in the General Surgery Clinic between January 2015 and January 2020, were divided into two groups as stage 2 and stage 3 according to the tumor-nodule-metastases classification. In these groups, preoperative mean platelet volume, carcinoembryonic antigen, platelet/lymphocyte count ratio and neutrophil/lymphocyte count ratios were checked and evaluated in terms of staging and significance according to postoperative pathology results. According to the tumor-nodule-metastases classification, Stage 1-4 patients, emergency cases, patients with an inflammatory disease and rectal cancer were excluded from the study.

Results: In the study, 38 of 59 patients who had been operated between January 2015 and January 2020 were found to be at stage 2 (group 1), and 21 patients at stage 3 (group 2). While no significant difference was found between carcinoembryonic antigen and neutrophil/lymphocyte levels between group 1 and group 2, a proportional increase was observed between the increase in platelet/lymphocyte ratio and staging (p=0.041). Mean platelet volume was seen to be proportional to stage progression (p=0.03).

Conclusion: We think that platelet/lymphocyte ratio and mean platelet volume levels can easily be applied as a cheap and simple test in the prediction of the preoperative stage in stage 2-3 colon cancers.

Key words: colon cancer, neutrophil lymphocyte ratio, platelet lymphocyte ratio, mean platelet volume

2-Ш1 ЖЭНЕ 3-Ш1 КЕЗЕНДЕРЩДЕГ1 ТО»; 1ШЕК ОБЫРЫНЬЩ ФАЗАЛАРЫН БОЛЖАУДАГЫ ГЕМАТОЛОГИЯЛЬЩ ПАРАМЕТРЛЕРДЩ Р0Л1

Э. Карачан1, Э.М. Йылмаз2, Б. Йылдыз2, А.Э. Демиркиран2

'Жалпы хирургия бeлiмшесi, Айдын мемлекеттш ауруханасы, Айдын, ТYркия

2Жалпы хирургия бeлiмшесi, Медицина факультету Аднан Мендерес атындагы университет, Айдын, ТYркия

Т¥ЖЫРЫМДАМА

Максаты: Ток шек пен тк шек обыры - бYкiл элемде катерл1 iсiк ауруларыныц елЫнщ мацызды себебк 1шектщ катерл1 ¡апнщ опе-рацияга дешнп кезецЫде рентген жэне TYрлi кан анализдерi колданылады. Алайда, рентгендк зерттеулердi колдану киын жэне кымбат. Бул зерттеудщ максаты гематологиялык параметрлердi алдын-ала карастыратын шек катерлi iсiгiнiц сатысын болжау болды, оны колдану карапайым.

Материалы жэне эдютерк Жалпы хирургиялык клиникада бiр хирургке ток ¡шектщ катерлi iсiгiне байланысты ота жасаткан наукастар катерлi iсiк сатыларыныц жiктелуiне сэйкес 2-шi жэне 3-шл кезендерге белiндi. Бул топтарда операциядан кейшп патологияныц нэтижелерi бойынша тромбоциттердщ орташа келемшщ, карциноимбрионды антигеннщ, тромбоциттер / лимфоциттер жэне нейтрофилдер / лимфо-циттер саныныц аракатынасы мен кезецге катынасы тексерiлдi жэне багаланды. K¡атерлi iсiк сатыларыныц жктелуше сэйкес 1-4 сатысы бар наукастар, тетенше жагдайлар, кабыну аурулары жэне тк шектщ катерлi iсiк ауруы бар наукастар зерттеуден шыгарылды.

'Department of General Surgery, Aydin State Hospital, Aydin, Turkey

department of General Surgery, Faculty of Medicine, Adnan Menderes University, Aydin, Turkey

© ®

This work is licensed under a Creative Commons Attribution 4.0 International License

Received: 2020-05-01 Accepted: 2020-05-15 UDC: 618.1

J Clin Med Kaz 2020; 3(57):35-38

Corresponding Author: Erkan Karacan, Department of General Surgery, Aydin State Hospital, Aydin, Turkey. Tel.: +905075657221, E-mail: erkan8806@gmail.com

Нэтижелерк Зерттеу нэтижелерi бойынша 2015 жылдыц кацтарынан бастап 2020 жылдыц кацтарына дейiн операция жасалынган 59 наукастыц 38-i 2-шi сатыга (1-топ), 21ч 3-кезецге (2-топ) ие болды. 1-шл жэне 2-шi топ арасында канциноэмбрионды антиген мен нейтрофил-дердщ лимфоциттердщ децгейлерi арасында айтарлыктай айырмашылык болмаганмен, тромбоциттер/лимфоциттердщ аракатынасы мен сатысы арасындагы пропорционалды есу байкалады (р = 0.041). Ортацгы тромбоциттер децгей сатыныц всуiне пропорционалды болды (р = 0.03).

Корытынды: Бiз тромбоциттер мен лимфоциттердщ катынасы мен тромбоциттердщ орташа мвлшерiн 2-3 сатылардагы операция алдындагы кезендi болжау Yшiн арзан эрi карапайым тест ретiнде оцай колдануга болады деп санаймыз.

Негiзгi сездер: ток iшек катерлi iсiгi, нейтрофил/лимфоциттердiц катынасы, тромбоциттер/лимфоциттердiц катынасы, тромбоциттердщ орташа мвлшерi

РОЛЬ ГЕМАТОЛОГИЧЕСКИХ ПАРАМЕТРОВ В ПРОГНОЗИРОВАНИИ ФАЗЫ ПРИ РАКЕ ТОЛСТОЙ КИШКИ 2 И 3 СТАДИИ

Э. Карачан1, Э.М. Йылмаз2, Б. Йылдыз2, А.Э. Демиркиран2

'Отделение общей хирургии, Государственная больница Айдын, Айдын, Турция

2Отделение общей хирургии, Факультет медицины, Университет имени Аднана Мендереса, Айдын, Турция

РЕЗЮМЕ

Цель: Рак ободочной и прямой кишки является важной причиной смертности от рака во всем мире. В предоперационной стадии рака толстой кишки используются рентгенологические снимки и различные анализы крови. Однако применять рентгенологические исследования сложно и дорого. Целью настоящего исследования стало прогнозирование стадии рака толстой кишки, предварительно просматривая гематологические параметры, применение которых является простым дешевым.

Материал и методы: Пациенты, которые были прооперированы в связи с раком толстой кишки одним хирургом в клинике общей хирургии в период с января 2015 года по январь 2020 года, были разделены на две группы: стадия 2 и стадия 3, в соответствии с классификацией стадий злокачественных новообразований. В этих группах проверены и оценены предоперационные значения среднего объема тромбоцитов, карциноэмбрионального антигена, соотношение количества тромбоцитов/лимфоцитов и нейтрофилов/лимфоцитов с точки зрения стадии и значимости, согласно результатам послеоперационной патологии. Согласно классификации стадий злокачественных новообразований, пациенты с 1-4 стадиями, неотложные случаи, пациенты с воспалительным заболеванием и раком прямой кишки были исключены из исследования.

Результаты: В ходе исследования было установлено, что у 38 из 59 пациентов, которые были прооперированы в период с января 2015 года по январь 2020 года, была стадия 2 (группа 1), и у 21 пациента стадия 3 (группа 2). Хотя не было обнаружено существенного различия между уровнями карциноэмбрионального антигена и уровня нейтрофилов/лимфоцитов между группой 1 и группой 2, наблюдается пропорциональное увеличение между увеличением соотношения тромбоцитов/лимфоцитов и стадированием (р=0.041). Средний объем тромбоцитов был пропорционален прогрессированию стадии (р=0.03).

Заключение: Мы полагаем, что значения соотношения тромбоцитов/лимфоцитов и уровня среднего объема тромбоцитов можно легко применять в качестве дешевого и простого теста для прогнозирования предоперационной стадии при раке толстой кишки 2-3 стадии.

Ключевые слова: рак толстой кишки, соотношение нейтрофилов/лимфоцитов, соотношение тромбоцитов/лимфоцитов, средний объем тромбоцитов

Introduction

Colorectal cancers are a significant cause of cancer-related deaths around the world [1]. In addition to imaging methods such as computed tomography (CT), colonoscopy, Positron emission tomography (PET-CT), Magnetic resonance (MR), transrectal ultrasound, markers such as carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (Ca 19-9) and fecal occult blood test are checked in staging colon cancers [2,3].

More efficient markers are needed for early diagnostic staging in colon cancers. Biomarkers such as neutrophil/ lymphocyte (N/L) ratio, mean platelet volume (MPV) and platelet/lymphocyte (P/L) ratio may have properties to predict preop staging [4,5]. In our study, we aimed at checking whether there was a significant relationship between the patients with stage 2 and stage 3 colon cancer by looking at the N/L ratio, P/L ratio and MPV, which might be low-cost and easy-to-apply predictors to help us predict the preoperative staging.

Material and methods

Patients who had been operated by a single surgeon for colon cancer at the General Surgery Clinic between January 2015 and January 2020 were included in the study. Patients operated for colon cancer were divided into two groups as stage 2 and stage 3 according to the tumor-nodule-metastases (TNM) classification. In these groups, the preoperative mean platelet volume (MPV), carcinoembryonic antigen (CEA), platelet/lymphocyte ratio (P/L), and neutrophil/lymphocyte (N/L) ratios were checked. The distribution between the groups was assessed. These results were compared to the stage that emerged from the postoperative pathology results and evaluated for correlation. According to the TNM classification, Stage 1-4

patients, emergency cases, patients with an inflammatory disease and rectal cancer were excluded from the study.

Statistical analysis

The statistical packaged software SPPS 25 (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.) was used for the evaluation of the data. For the variables, mean±standard deviation, percentage and frequency values were used. The variables were evaluated after the prerequisites for normality and homogeneity of variances were checked (Shapiro-Wilk and Levene's Test). In data analysis, the Independent two-group t-test (Student's t-test) was used for the comparison of two groups, and the Mann-Whitney U test was carried out when the prerequisites were not met. The relationship between the two continuous variables was evaluated with the Pearson Correlation Coefficient, and the Spearman Correlation Coefficient when the prerequisites for parametric testing were not met. Categorical data were analyzed with Fisher's Exact Test and Chi-Square test. When the expected frequency was less than 20%, evaluation was made via the "Monte Carlo Simulation Method" to include these frequencies in the analysis. For the significance level of the tests, p<0.05 was accepted.

Results

In the study, 38 (64%) of 59 patients who had been operated between January 2015 and January 2020 were found to be at stage 2 (group 1), and 21 (36%) patients at stage 3 (group 2). 23 (60%) of 38 patients in Group 1 were operated laparoscopically, and 15 (40%) patients had open operation. 13 (61%) of 21 patients in Group 2 were operated laparoscopically, and 8 (39%) patients had open operation. While the mean P/L ratio of group 1 was 36.03±13.02, the mean P/L ratio of group 2

Table 1

Mean values of hematological parameters

Table 2

Comparison of parameters between groups

N Minimum Maximum Mean Std. Deviation

P/L 59 14.58 83.44 38.20 13.15

N/L 59 0.51 0.93 0.67 0.10

MPV 59 7.4 12.5 9.87 0.99

CEA 59 0.71 73.82 7.52 12.01

Stage 2 Stage 3 p

n=38 n=21

P/L 36.03±13.02 39.77±13.9 0.041*

N/L 0.66±0.1 0.67±0.1 0.740

MPV 9.83±1.03 10.89±0.95 0.030*

CEA 8.62±14.55 5.8±5.14 0.290

*p<0.05

was calculated as 39.77±13.9 (p<0.05). While the mean N/L ratio of group 1 was 0.66±0.1, the mean ratio of group 2 was found to be 0.67±0.1 (p=0.741) (Table 1). No significant correlation was detected between the N/L ratio and staging. The mean MPV was determined as 9.83±1.03 in group 1 and 9.83±1.03 in group 2 (p<0.05). A significant correlation was discovered between the MPV values and staging. The mean CEA was 8.62±14.55 in group 1, and 5.8±5.14 in group 2 (p=0.29) (Table 2). No significant correlation was observed between CEA and staging.

Discussion

Previously, systemic inflammation was reported in many studies as one of the important parts of the carcinogenesis process [6,7]. Inflammatory processes play a significant role in the development of colon cancer [8]. One of the important factors that affect survival in colon cancers is the stage of the tumor [9]. Today, the usage of simple, easy-to-apply, cheap and non-invasive tests has become desirable in preop staging of colorectal cancers [10]. The fact that hematological parameters are simple, cheap and easily accessible methods increase their applicability. For this reason, hematological parameters are becoming more and more popular today.

In the literature, there is a low number of studies comparing the N/L ratio to the TNM staging of colon cancers, however, in a study conducted by Roxburgh et al., it was revealed that high N/L ratios are not only an indicator in cancer types, but also an independent factors in short survival [11]. In the study by Absenger et al., the increased N/L ratio was shown to be correlated with an advanced TNM stage, early recurrence and bad survival [12]. However, no statistically significant correlation could be found between the N/L ratio and staging in our study. We assume that this may result from the low number of patients in our study.

In a study, Szkandera et al. reported that the P/L ratio was detected higher in patients with increased stage 3 colon cancer compared to stage 2 patients, and the cancer recurrence was observed earlier in patients with high P/L ratios [13]. In a study conducted by You et al. on patients with colorectal cancer, it was stated that the P/R ratio was an independent factor in terms of advanced tumor stage (III, IV), however, the increased preoperative P/L ratio was correlated with decreased survival, and the P/L ratio could be used as a prognostic marker [14]. There are meta-analysis studies in which the P/L ratio is also attributed to survival in cancer types other than colorectal cancers [15]. In a study involving 376 cases, Jia et al. observed a correlation between the increase in the P/L ratio and the increase in T staging in colorectal cancers, but could not find any correlation with the TNM stage of the tumor. However, they stated that these ratios were promising that they could be used to predict the prognosis in colorectal cancers [16]. In our study, the P/L ratios were found in correlation with the increase in stage, and a statistically and significantly higher P/L ratio was found in stage 3 patients compared to stage 2 patients.

MPV is the value that refers to the average volume of the platelets in the blood, and routinely checked in blood

parameters. In the literature, there are few studies directly comparing the relationship between MPV and TNM. MPV has emerged as an early diagnostic parameter in the detection of colon, pancreas, stomach and hepatocellular cancers [17]. In another study by Kilincalp et al., no significant correlation was discovered between the N/L, P/L, MPV values and TNM stage, however, it was stated that these values were higher in patients with colorectal cancer, and these values dropped back to normal values after curative resection [18]. In their study, Ying Li et al. expressed that a positive correlation was detected between the preoperative MPV value and TNM in patients with colon cancer, and the MPV values dropped back to the normal level after curative resection [19]. In their study, Zhu et al. could not establish a correlation between MPV and TNM stage, but a positive correlation was found between the increased MPV value and perivascular invasion [20]. Therefore, they stated that MPV could be used as a biomarker with potential to predict the prognosis. In our study, advanced stage correlated with increased MPV, i.e. poorer prognosis was encountered in patients with colon cancer.

Even though CEA is generally used in the postoperative follow-up of patients with colon cancer in terms of recurrence, there are studies suggesting that it may contribute to staging preoperatively [21]. Lalosevic et al. stated that the levels of Ca 19-9 and CEA were found higher in patients with colorectal cancer and in patients with lymph node metastasis and distant metastasis, and the preoperative CEA levels could predict the stage [22]. Another study suggested that increased CEA levels did not have any significant contribution in terms of lymph-node metastasis in preoperative staging, apart from detecting the cases with colorectal cancer with liver metastasis and indicating a poor prognosis [23]. In our study, no significant correlation was discovered between CEA antigen levels and staging. We think that the sensitivity of CEA levels is low in preoperative staging. However, its preoperative high level can be considered as an indicator of a poor prognosis since it may point at liver metastasis.

Limitations in the study

Because the number of patients in the study was low, we could not classify the patients according to the localization area of colorectal cancers.

Conclusion

The preoperative usage of P/L and MPV in colon cancers can be possible with prospective studies on larger patient groups. Even though the N/L ratio does not predict staging in patients with colon cancer, it may be useful for predicting the prognosis and survival. Prospective studies with larger groups are needed to increase the usability of these markers. CEA is preoperatively found high while its effectiveness is low in preoperative staging, which can be considered as an indicator of a poor prognosis since it is highly associated with liver metastasis.

Disclosures: There is no conflict of interest for all authors.

References

1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011; 61:69-90. https://doi. org/10.3322/caac.20107

2. Swiderska M, Choromanska B, Dqbrowska E, Konarzewska- Duchnowska E, Choromanska K, Szczurko G, et al. The diagnostics of colorectal cancer. Contemp Oncol (Pozn). 2014; 18:1-6. https://doi.org/10.5114/wo.2013.39995

3. Barone C; Astone A; Cassano A; et al. Advanced colon cancer: Staging and prognosis by CEA Test. Oncology. 1990; 47:128-132. https://doi.org/10.1159/000226804

4. Ong SL, Garcea G, Thomasset SC, Mann CD, Neal CP, Abu Amara M, et al. Surrogate markers of resectability in patients undergoing exploration of potentially resectable pancreatic adenocarcinoma. J Gastrointest Surg. 2008; 12:1068-73. https://doi.org/10.1007/ s11605-007-0422-6

5. Ong SL, Garcea G, Thomasset SC, Mann CD, Neal CP, Abu Amara M, et al. Surrogate markers of resectability in patients undergoing exploration of potentially resectable pancreatic adenocarcinoma. J Gastrointest Surg. 2008; 12:1068-73. https://doi.org/10.1007/ s11605-007-0422-6

6. H.-C. Kwon, S. H. Kim, S. Y. Oh et al. Clinical significance of preoperative neutrophil-lymphocyte versus platelet-lymphocyte ratio in patients with operable colorectal cancer. Biomarkers. 2012; 17(3):216-222. https://doi.org/10.3109/1354750X.2012.656705

7. J.-F. Feng, Y. Huang, Q. Zhao, and Q.-X. Chen. Clinical significance of preoperative neutrophil lymphocyte ratio versus platelet lymphocyte ratio in patients with small cell carcinoma of the esophagus. Scientific World Journal. 2013; 2013(504365):7. https://doi. org/10.1155/2013/504365

8. R. D'Incà, R. Cardin, L. Benazzato, I. Angriman, D. Martines, and G. C. Sturniolo. Oxidative DNA damage in the mucosa of ulcerative colitis increases with disease duration and dysplasia. Inflammatory Bowel Diseases. 2004; 10 (1):23-27. https://doi. org/10.1097/00054725-200401000-00003

9. Roxburgh CS, McMillan DC. Role of systemic inflammatory response in predicting survival in patients with primary operable cancer. Future Oncol. 2010; 6:149-63. https://doi.org/10.2217/fon.09.136

10. O. Andronic, Alexandra Bolocan, Georgiana Radu, D.N. Päduraru, D. Ion, S.M. Hematologicial parameters and tumor size in rectal cancer. Journal of Surg Scienc. 2019; 6(2). https://doi.org/10.33695/jss.v6i2.269

11. Roxburgh CS, Salmond JM, Horgan PG, Oien KA, McMillan DC. Comparison of the prognostic value of inflammation-based pathologic and biochemical criteria in patients undergoing potentially curative resection for colorectal cancer. Ann Surg. 2009; 249:788-93. https:// doi.org/10.1097/SLA.0b013e3181a3e738

12. G Absenger, J Szkandera, M Pichler, M Stotz, F Arminger, M Weissmueller et al. A derived neutrophil to lymphocyte ratio predicts clinical outcome in stage II and III colon cancer patients. Br J Cancer. 2013; 109(2):395-400. https://doi.org/10.1038/bjc.2013.346

13. Joanna Szkandera, Martin Pichler, Gudrun Absenger, Michael Stotz, Franziska Arminger, Melanie Weissmueller et al. The elevated preoperative platelet to lymphocyte ratio predicts decreased time to recurrence in colon cancer patients. The American Journal of Surgery. 2014; 208:210-214 https://doi.org/10.1016/j.amjsurg.2013.10.030

14. You J, Zhu GQ, Xie L, Liu WY, Shi L, Wang OC et al. Preoperative platelet to lymphocyte ratio is a valuable prognostic biomarker in patients with colorectal cancer. Oncotarget. 2016; 7(18): 25516-25527. https://doi.org/10.18632/oncotarget.8334

15. Zhou X, Du Y, Huang Z, Xu J, Qiu T, Wang J et al. Prognostic Value of PLR in Various Cancers: A Meta-Analysis. PloS one. 2014; 9(6). https://doi.org/10.1371/journal.pone.0101119

16. Jing Jia, Xiongwei Zheng, Ying Chen, Lin Wang, Lu Lin, Xingming Ye et al. Stage-dependent changes of preoperative neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in colorectal cancer. Tumor Biology. 2015; 36(12):9319-9325. https://doi.org/10.1007/ s13277-015-3667-9

17. H. A. Goubran, J. Stakiw, M. Radosevic, and T. Burnouf. Platelets effects on tumor growth. Seminars in Oncology. 2014; 41(3):359-369. https://doi.org/10.1053/j.seminoncol.2014.04.006

18. Serta Kilincalp, Çahin Çoban, Hakan Akinci, Mevlüt Hamamci, Fatih Karaahmet, Yusuf Coçkun et al. Neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, and mean platelet volume as potential biomarkers for early detection and monitoring of colorectal adenocarcinoma. European Journal of Cancer Prevention. 2015; 24(4):328-333. https://doi.org/10.1097/CEJ.0000000000000092

19. Jia-Ying Li, Ying Li, Zheng Jiang, Rui-Tao Wang, Xi-Shan Wang. Elevated mean platelet volume is associated with presence of colon cancer. Asian Pac J Cancer Prev. 2014; 15(23):10501-10504. https://doi.org/10.7314/APJCP.2014.15.23.10501

20. Xianjin Zhu, Yingping Cao, Pingxia Lu, Yanli Kang, Zhen Lin, Taisen Hao et al. Evaluation of platelet indices as diagnostic biomarkers for colorectal cancer. Scientific reports. 8(1):1-7. https://doi.org/10.1038/s41598-018-29293-x

21. Chen CC, Yang SH, Lin JK, Lin TC, Chen WS, Jiang JK et al. Is it reasonable to add preoperative serum level of CEA and CA19-9 to staging for colorectal cancer? Journal of surgical research. 2005; 124(2):169-174. https://doi.org/10.1016/j.jss.2004.08.013

22. Stojkovic Lalosevic M, Stankovic S, Stojkovic M, Markovic V, Dimitrijevic I, Lalosevic J et al. Can preoperative CEA and CA19-9 serum concentrations suggest metastatic disease in colorectal cancer patients? Hell JNuclMed. 2017; 20(1):41-45.

23. Duffy, M. J. (2001). Carcinoembryonic antigen as a marker for colorectal cancer: is it clinically useful? Clinical chemistry. 47(4):624-630. https://doi.org/10.1093/clinchem/47.4.624

How to cite this article: Erkan Karacan, Eyüp Murat Yilmaz, Buse Yildiz, Ahmet Ender Demirkiran. The contribution of hematological parameters to prediction of the phase in stage 2 and stage 3 colon cancers. J Clin Med Kaz. 2020; 3(57):35-38