|Year : 2019 | Volume
| Issue : 4 | Page : 1452-1458
Diagnostic value of platelet indices, carbohydrate antigen 19-9 and carcinoembryonic antigen in differentiating malignant from benign gastric ulcers
Ayman M El Lehleh1, Naglaa S El-Abd1, Suzy F Gohar2, Mohammad O Zarad3
1 Department of Tropical Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Clinical Oncology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Medical Physiology Department, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
|Date of Submission||25-May-2019|
|Date of Decision||15-Jun-2019|
|Date of Acceptance||23-Jun-2019|
|Date of Web Publication||31-Dec-2019|
Mohammad O Zarad
Medical Physiology Department, Faculty of Medicine, Al-Azhar University, Cairo
Source of Support: None, Conflict of Interest: None
To elucidate the value of platelet indices, carbohydrate antigen 19-9 (CA 19-9) and carcinoembryonic antigen (CEA) in differentiating malignant from benign gastric ulcers.
Gastric cancer is one of the most common malignant diseases and benign gastric ulcer is a worldwide disease, responsible for substantial premature mortality. Clinical symptoms of early gastric cancer could not be used to distinguish gastric cancer from ulcers. Platelet indices: mean platelet volume (MPV) and platelet distribution width (PDW) are a group of platelet parameters investigated as platelet activation indicators.
Patients and methods
This prospective study included 150 patients: 30 patients with malignant gastric ulcer, 60 patients with benign gastric ulcer, and 60 healthy control participants. Upper endoscope with tissue biopsy and pathological evaluation, Helicobacter pylori stool antigen, platelet count, PDW, MPV, CEA, CA 19-9, computed tomography scan of the chest, abdomen, and the pelvis were assessed.
Platelet count, MPV, PDW, CEA, and CA 19-9 were significantly higher in malignant gastric ulcer patients than benign ulcer patients and controls. MPV and PDW showed sensitivity, specificity, and area under the curve (93.3, 70 and 0.934% and 96.7, 86.7 and 0.966%, respectively) in predicting malignancy in gastric ulcer patients with improved diagnostic accuracy when combined with CEA and CA 19-9. Higher platelet count and PDW were significantly associated with advanced clinicopathological parameters of gastric cancer.
Changes in platelet indices are valuable markers in predicting malignancy in gastric ulcer patients. Significant increase in platelet count and PDW correlate and could be reliable markers, together with other markers of gastric cancer (CEA and CA 19-9), for clinicopathological features of malignant gastric ulcer.
Keywords: benign gastric ulcer, gastric cancer, platelet indices, tumor markers
|How to cite this article:|
El Lehleh AM, El-Abd NS, Gohar SF, Zarad MO. Diagnostic value of platelet indices, carbohydrate antigen 19-9 and carcinoembryonic antigen in differentiating malignant from benign gastric ulcers. Menoufia Med J 2019;32:1452-8
|How to cite this URL:|
El Lehleh AM, El-Abd NS, Gohar SF, Zarad MO. Diagnostic value of platelet indices, carbohydrate antigen 19-9 and carcinoembryonic antigen in differentiating malignant from benign gastric ulcers. Menoufia Med J [serial online] 2019 [cited 2020 Feb 24];32:1452-8. Available from: http://www.mmj.eg.net/text.asp?2019/32/4/1452/274227
| Introduction|| |
Gastric cancer is one of the most common malignant diseases in the world. It is the fifth most common cause of cancer death after lung, breast, colorectal, and prostate cancer. It is associated with a 5-year overall survival rate of less than 30% .
Gastric cancer is known to reside in some gastric ulcers, but prediction of this association is still unclear. As a result, biopsies from the edge and base of all gastric ulcers are recommended by most gastroenterological societies . Although endoscopy offers high diagnostic accuracy, it is inconvenient and could cause additional complications. Therefore, additional markers to distinguish early gastric cancer from ulcers are necessary .
Moreover, clinical symptoms of early gastric cancer could not be used to distinguish gastric cancer from ulcers . Gastric ulcer is a global disease, responsible for considerable untimely mortality, with extreme burden in countries . It is a common finding during gastroscopy for patients presenting with symptoms such as dyspepsia, iron-deficiency anemia, and gastrointestinal bleeding .
Carcinoembryonic antigen (CEA) has been widely used as a diagnostic, screening, and monitoring marker in clinical practice. However, CEA lacks high sensitivity and specificity .
Activated platelets are involved in cancer progression and metastases . Platelet indices like platecrit, mean platelet volume (MPV), and platelet distribution width (PDW) are a group of platelet parameters obtained as a part of complete blood count using automated hematology analyzers. They have been investigated as prospective platelet activation indicators . MPV is associated with lung and breast cancer ,. PDW, another platelet index, indicates variation in platelet size .
The aim of this study was to elucidate the value of platelet indices, carbohydrate antigen 19-9 (CA 19-9) and CEA in differentiating malignant from benign gastric ulcers.
| Patients and Methods|| |
One hundred and fifty participants were enrolled in this prospective cross-sectional study. They were selected from the Tropical Medicine and Clinical Oncology Departments of Menoufia University Hospital between December 2017 and December 2018. Laboratory investigations were completed in the Clinical Pathology Department, Faculty of Medicine, Menoufia University. On the basis of clinical, endoscopic, and pathological findings, the patients were classified into one of the three groups: group I: included 30 patients with malignant gastric ulcer; there were 19 (63.3%) men and 11 (36.7%) women with a mean age of 61.1 ± 8.5. Group II: 60 patients with benign gastric ulcer: there were 36 (60%) men and 24 (40%) women with a mean age of 60.6 ± 6.2 years. In addition, 60 apparently healthy patients of matched age and sex were included as controls, group III.
For all the participants, history and clinical evaluation were done. Patients with malignancies elsewhere in the body, hematological, autoimmune and thyroid diseases, systemic inflammatory conditions, renal and hepatic diseases, as well as patients under treatment with anticoagulant, statins, and acetylic salicylic acid were excluded. All participants provided informed consent affirmed by the Faculty of Medicine, Menoufia University Ethics Committee, and as directed as per the Declaration of Helsinki.
Investigations included complete blood count and liver and kidney function tests. For platelet indices, venous blood samples were collected, directly into vacutainer tubes with potassium EDTA as an anticoagulant. All samples were gently mixed by inversion and were kept at room temperature to be examined within half to 3 h after blood collection. Samples were analyzed by two hematology analyzers (Cell Dyn 1700 and Cell Dyn 3200; Abbott Diagnostics, Abbott Park, Illinois, U.S.A.). Impedance resistance was used to measure platelet indices in all blood samples. The unit used is femtoliter (fl) .
Serum CEA and CA 19-9 were assessed by enzyme-linked fluorescence assay (reading at the Mini VIDAS; BioMerieux, Marcy-l'Étoile, France). Helicobacter pylori Ag in stool was done (ELISA Assay kit; Eagle Biosciences, Amherst, New Hampshire, USA). Upper endoscopy was performed for all patients with biopsy taking for pathological evaluation. Radiological assessment was done by abdominal ultrasonography and computed tomography of the chest, abdomen, and the pelvis and bone scan for the assessment of distant metastases. TNM-staging was done for all patients with malignant gastric ulcer .
Statistical analysis: consult a statistician
Data were analyzed using IBM SPSS software program version 20.0. (IBM Corp., Armonk, New York, USA). Comparisons between different groups for categorical variables included χ2-test (Monte Carlo). Analysis of variance was used to compare the studied groups and was followed by the post-hoc test (Tukey's) for making pairwise comparisons. For comparing different groups with abnormally distributed quantitative variables, Kruskal–Wallis test was utilized and was followed by post-hoc test. P values equal to or less than 0.05 were considered statistically significant.
| Results|| |
The results of this study demonstrated matched age and sex distributions between the three studied groups, as there was no significant difference (P = 0.126 and 0.387, respectively). Regarding hemoglobin concentration, there was significant decrease between the three studied groups (P < 0.001). Hemoglobin concentration was significantly lower in group I and group II compared with controls with significant difference between malignant and benign gastric ulcer patients (P < 0.033). There was no difference between the studied groups as regards total leukocyte count (P = 0.173). MPV, PDW, CEA, and CA 19-9 were significantly higher in malignant cases compared with patients with benign ulcer and controls (P < 0.001) as well as platelet count with P 0.009. There was no statistically significant difference between the patients groups regarding the presence or absence of H. pylori Ag in stool (P < 0.071; [Table 1]). History of weight loss and presence of pallor were more frequent with statistically significant difference in malignant gastric ulcer patients than benign cases (P < 0.001), while history of smoking and the use of NSAID were statistically nonsignificant between the two groups (P = 0.112 and 0.343, respectively). Regarding the presenting symptom, there was statistically significant difference between malignant and benign gastric ulcer patients (P < 0.001). Clinical manifestations of anemia (including dyspnea on exertion, dizziness, intermittent claudication, and easy fatigability) are the most common presenting symptoms in malignant gastric ulcer patients, while pain related to meal in benign cases [Table 2]. Pathological evaluation of patients with gastric cancer showed that well-differentiated tumor was seen in six (20.0%) patients; moderately differentiated tumor in eight (26.7%) patients; low differentiated tumor in 13 (43.3) patients; and undifferentiated tumor in three (10%) patients. Platelet count at a cutoff point more than 199 × 103 showed a sensitivity of 96.67%, specificity of 40.0% with an area under the curve (AUC) of 0.604 and P 0.109, while the MPV level at a cutoff point more than 11.2 fl has a sensitivity of 93.3%, specificity of 70% with an AUC of 0.934 with P less than 0.001. In addition, higher sensitivity and specificity (96.7 and 86.7%, respectively) were observed with PDW which showed an AUC of 0.966 and P less than 0.001 at a cutoff point more than 12.7 fl in predicting malignancy in gastric ulcer patients. CEA at a cutoff point of 9.3 ng/ml has a sensitivity of 66.67%, specificity of 73.3% with an AUC of 0.873 while CA 19-9 showed a sensitivity of 93.33%, specificity of 90.0% with an AUC of 0.969 at a cutoff point of 31 U/ml [Table 3] and [Figure 1]. When CEA is combined with one of these indices: platelet count, MPV, and PDW its diagnostic accuracy (sensitivity and specificity) has improved in differentiating malignant from benign gastric ulcers. In addition, higher specificity resulted when one of them combined with CA 19-9 than when it is utilized alone. The highest sensitivity and specificity were obtained when the three indices collected together with CA 19-9 or CEA at related cutoff points [Table 4] and [Figure 1].
|Table 1: Comparison between the three studied groups according to demographic data and laboratory investigations|
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|Table 3: Agreement (sensitivity and specificity) for different parameters to predict malignant gastric ulcer versus benign gastric ulcer|
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|Figure 1: Receiver operating characteristic curve curve for different parameters to predict malignant gastric ulcer versus benign gastric ulcer: (a) without combination, (b) combined with carcinoembryonic antigen (CEA), (c) combined with carbohydrate antigen 19-9 (CA 19-9), (d) combined with all parameters. CA 19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; MPV, mean platelet volume; PDW, platelet distribution width.|
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|Table 4: Agreement (sensitivity and specificity) for combined parameters to predict malignant gastric ulcer versus benign gastric ulcer|
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Platelet count was significantly associated with the degree of differentiation and the size of the tumor. PDW showed significant association with the degree of differentiation and tumor invasion of gastric cancer. However, none of them showed significant relation with lymph node metastasis. CA 19-9 was significantly linked to all clinicopathological features of the tumor (tumor size, stage, degree of pathological differentiation, tumor invasion, and lymph node metastasis), while MPV and CEA showed no significant linkage with these features in gastric cancer patients [Table 5].
|Table 5: Relation between mean platelet volume, platelet distribution width, platelet count, carcinoembryonic antigen, carbohydrate antigen 19-9, and different parameters in gastric cancer patients (n=30)|
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| Discussion|| |
Despite an improvement in survival over recent years due to the development of better endoscopic and imaging techniques, surgical skills, and medical treatments, gastric cancer continues to be a major cause of morbidity and mortality worldwide and its prognosis remains unfavorable, especially in developing countries . In spite of scientific efforts, there are few convenient serum biomarkers of gastric cancer, which obtain high sensitivity and specificity for screening or surveillance for this malignancy  and gastric ulcer is still positively associated with the risk of developing cancer stomach .
In agreement with the study done by Xinting et al.  and Gunaldi et al. , this study showed significant increase of platelet count in the gastric cancer group when compared with the other two groups; however Kilincalp et al.  reported nonsignificant decrease in platelet count in patients with gastric cancer.
The mechanism of platelet increase in gastric cancer is still indefinite and not very clear, although explanations as it is possibly related to the bone marrow stimulus released from the inflammatory part of the tumor and that stimulus possibly generates thrombopoietin-like hormone and the tumor cells at the same time can directly or indirectly induce the clotting system and lead to platelet activation . Additionally, many reports documented the role of cytokines, in particular, interleukin-6 in the pathogenesis of thrombocytosis in cancer specifically in gastrointestinal carcinomas, as interleukin-6 is reported to be higher in patients with gastric and colorectal carcinoma compared with controls .
In this study, the mean value of MPV in group I was significantly higher than group II and group III and these findings were supported by Matowicka-Karna et al. , Kilincalp et al. , and Shen et al. , but Yun et al.  found significant decrease in MPV levels in patients with gastric cancer compared with benign gastric ulcer and control participants and they documented that the reduced MPV value in gastric cancer was regarded as an increased consumption of large platelets and this can be explained by the degree of bone marrow activity .
The Kilincalp et al.  findings pointed out that newly diagnosed gastric cancer patients have significantly higher MPV values than healthy controls and they found that surgical tumor resection resulted in a significant decrease in MPV values. The possible mechanism of changes in MPV is interaction between cancer and regular host cells, leading to platelet activation which is induced both by direct contact between a cancer cell with a platelet through adhesive molecules, and production and release of its own proinflammatory, prothrombotic, and proangiogenic factors: ADP, thromboxane, thrombin, tumor necrosis factor-α, vascular endothelial growth factor, and tissue factor .
In this study, we observed a significant increase in the mean value of PDW in gastric cancer than benign gastric ulcer patients and controls and this result agreed with those obtained by Yun et al.  and Gunaldi et al.  and was in contrast with Zhang et al. , who reported that significant lower PDW was detected in patients with gastric cancer and early gastric cancer compared with healthy controls and lower PDW correlated with a shorter overall survival in gastric cancer.
Platelet size determines platelet activity and is measured by platelet volume indicators which are MPV that mirrors the average size of the platelets in a blood sample and PDW that reflects the size uniformity of platelets . PDW appears to be a more specific indicator for the activation of platelet than MPV, as it was not elevated throughout single platelet distention brought out by platelet swelling . However, the particular mechanism by which PDW affects cancer progression is still ambiguous  and may be accompanied by abnormal thrombosis, but the relationship between PDW and solid malignancies has hardly been explored .
The results of this study explored the role of different markers in distinguishing gastric cancer from benign gastric ulcer as the MPV level at a cutoff point more than 11.2 fl has sensitivity, specificity, and AUC of 93.3, 70, and 0.934%, respectively; in addition higher values (96.7, 86.7 and 0.966%, respectively) were observed with PDW at a cutoff point more than 12.7 fl in predicting malignancy in gastric ulcer patients, while CEA at a cutoff point of 9.3 ng/ml showed the lowest diagnostic accuracy, whereas CA 19-9 offered AUC 0.969 at a cutoff point of 31 U/ml.
Ulutas et al.  reported that PDW has very similar diagnostic values such as sensitivity and specificity to CA 19-9 and Cheng et al.  found that PDW seems to be a more specific indicator of gastric cancer than MPV.
In this study, we noticed that when CEA or CA 19-9 combined with one or all of the platelet indices the diagnostic accuracy of gastric cancer was improved with higher specificity resulted when one of them combined with CA 19-9. Yun et al.  reported that sensitivity, specificity, and AUC of CEA for differentiating gastric cancer from ulcer were 65.5, 71.2, and 0.692%, respectively, which get better when combined with MPV (85.1, 77, and 0.876%, respectively) and with PDW 99, 97.9, 97.9, and 0.996%, respectively. To our knowledge, no previous studies highlighted the diagnostic accuracy of a combination of platelet indices with CA 19-9.
In this study, we noted that increased platelet count was significantly associated with the degree of differentiation and the size of gastric cancer and increased PDW is associated with the degree of differentiation and tumor invasion. The associations between platelets and their indices with the clinicopathologic features of the tumor were different between authors such as Cheng et al. , who recorded that PDW was significantly associated with tumor size, deeper serosal invasion, and no significant association with lymph node metastasis, histological grade, or cancer stage, while Gunaldi et al.  reported that PDW increased significantly with disease stage and lymph node metastasis, but Yun et al.  found no relation between PDW and clinicopathological parameters.
Thrombocytosis is associated with reduced survival in patients with various tumor types, including cancer of the lung, ovary, endometrium, rectum, kidney, stomach, pancreas, brain, and the breast .
Xinting et al.  reported that in clinical practice, we should have a try to preclude the possibility of the occurrence of malignancy such as gastric cancer when the patients' platelet counts are found to be increasing; moreover, the more elevated platelet count occurs frequently in advanced gastric cancers, demonstrating the course of the disease is rather later and badly prognostic.
| Conclusion|| |
Changes in platelet indices (platelet count, MPV, and PDW) are valuable, simple, costly, effective, easily performed, and noninvasive markers in predicting malignancy in gastric ulcer patients. Higher PDW and platelet count [with other markers of gastric cancer (CEA and CA 19-9)] could be reliable markers for clinicopathological features in gastric cancer patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]