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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 2  |  Page : 39-42

Role of D-dimer in patients of operable breast cancer with lymph node metastases: A matched cross-sectional study


1 Department of Lab Medicine, IMS and SUM Hospital, Bhubaneswar, Odisha; Department of Lab Medicine AIIMS, New Delhi, India
2 Department of Community and Family Medicine, AIIMS, Bathinda, Punjab, India
3 Department of Pathology and Lab Medicine, AIIMS, Bhubaneswar, Odisha, India
4 Department of Lab Medicine AIIMS, New Delhi, India

Date of Submission20-Mar-2020
Date of Decision05-Apr-2020
Date of Acceptance23-Apr-2020
Date of Web Publication17-Aug-2020

Correspondence Address:
Samanyoya Gochhait
Quarter No 127, Doctors Enclave, Sum Hospital, Bhubaneswar, Odisha
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/oji.oji_16_20

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  Abstract 


Introduction: Breast cancer is the most common malignancy amongst women worldwide. Presence of axillary lymph nodes metastases is an important predictor of survival in patients with infiltrative breast cancer. D-dimer levels are elevated in the plasma of various solid tumor patients. There still exists a gap in our knowledge regarding the relationship between quantitative D-dimer levels and extent of disease in primary breast cancer. Aim: To study the fibrinolytic pathway by assaying D-dimer in breast cancer cases and to calculate a suggestive cutoff value for D-dimer for its use a specific marker of lymph node metastasis preoperatively in the cases of breast cancer. Materials and Methods: In this matched cross-sectional hospital-based study, 50 diagnosed cases of operable breast carcinoma not taking any treatment for the cancer and 50 healthy women both in the 25–65 years age group were selected as cases and controls, respectively. Peripheral venous blood was collected and analyzed for prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time (TT), D-dimer, platelet count, and mean platelet volume. Results: D-dimer was significantly increased in cases compared to healthy controls. It was markedly increased in patients with lymph node involvement irrespective with the number of nodes involved, while PT, aPTT, and TT did not show significant difference. Receiver operating characteristic curve gave a sensitivity of 56% and specificity of 91%, for cutoff value of 0.765 for D-dimer, in order to predict the chances of lymph node metastases preoperatively. Conclusions: D-dimer is a simple, noninvasive, quick, and nonexpensive laboratory investigation which can be used as a predictor of depicting lymph node metastasis.

Keywords: Breast cancer, coagulation, D-dimer, lymph node metastasis


How to cite this article:
Gochhait S, Sahoo SS, Chhabra G, Mukhopahay AK, Sharma S. Role of D-dimer in patients of operable breast cancer with lymph node metastases: A matched cross-sectional study. Oncol J India 2020;4:39-42

How to cite this URL:
Gochhait S, Sahoo SS, Chhabra G, Mukhopahay AK, Sharma S. Role of D-dimer in patients of operable breast cancer with lymph node metastases: A matched cross-sectional study. Oncol J India [serial online] 2020 [cited 2020 Sep 26];4:39-42. Available from: http://www.ojionline.org/text.asp?2020/4/2/39/291900




  Introduction Top


The recent years have witnessed a steep rise of cancer cases globally and in India. Globally, it is the second leading cause of death after cardiovascular diseases.[1] The increase in cancer cases all over the world in recent times has been due to epidemiological transition, aided by growing elderly population and along with more prevalent unhealthy lifestyles.[2] In India, more often than not, cancer patients present at an advanced stage of the disease. Financial constraints, low level of health literacy, and lack of adequate access to health-care facilities and treatment options are the major factors leading to delayed presentation and care seeking.[3],[4]

As per the latest global cancer incidence, mortality, and prevalence 2018 data, there will be an estimated 18.1 million new cancer cases and 9.6 million cancer deaths in 2018. Overall, lung cancer is the most commonly diagnosed cancer (11.6% of cases) and the leading cause of cancer death (18.4% of deaths), followed by females with breast cancer (11.6%).[5]

Breast cancer is the most common cancer in Indian females, accounting for the largest crude incidence rate and prevalence of any cancer type.[6] They represent a heterogeneous group of tumors with varied presentation as well as variable response to therapy. Previous studies have shown independent prognostic significance of the histological grades, hence providing evidence for routine assessment of histological grades in invasive ductal carcinoma.[7],[8],[9],[10] Development of distant metastases is still the primary cause of death in patients with breast cancer. The presence of axillary lymph nodes metastases is an important predictor of survival in patients with infiltrative breast cancer.[11],[12] In many cancerous conditions, there is development of various coagulation disorders. These may be due to the pathogenesis of cancer itself or due to its treatment (nonsurgical/preoperative irradiation).

D-dimer is a degradation product (plasmin mediated) of the fibrin polymers. It has been previously shown to have positive correlation with operable breast cancer,[13] tumor volume and survival in metastatic breast cancer,[14] lymph node metastasis in esophageal cancer,[15] prognostic significance in lungs cancer,[16] and pancreatic carcinoma[17] as well.

At the time of diagnosis of carcinoma breast, 50% of the patients present with involvement of axillary lymph nodes which are cured with primary locoregional treatment. However, 20%–30% of the patients will experience distant relapses within 5–10 years, indicating an outgrowth of disseminated tumor cells present at the time of diagnosis yet undetectable by the current diagnostic tools.[18] There still exists a gap in our knowledge regarding the relationship between quantitative D-dimer levels and extent of disease involvement in primary breast cancer. In this context, this study was undertaken with an objective of studying the fibrinolytic pathway by assaying D-dimer in operable breast cancer cases and to calculate a cutoff value for D-dimer for its use a specific marker of lymph node metastasis preoperatively in the cases of breast cancer.


  Materials and Methods Top


The present matched cross-sectional study was conducted in the department of laboratory medicine of a tertiary care institute of North India over a period of 1 year (from January to December 2014). The test group comprised fifty patients visiting surgical oncology outpatient department and diagnosed to have carcinoma breast were recruited consecutively. Patients in the age group of 25 to 65 years who had fine-needle aspiration cytology/biopsy-proven infiltrative breast cancer, with or without lymph node metastasis, and no surgical or medical treatment taken for the carcinoma were included in the study. Patients on chemotherapy, anticoagulants, antiplatelet drugs, history of deep vein thrombosis, cardiac valve replacement, or any other malignancies were excluded. The control group comprised 50 age-matched healthy women (25–65 years age) who were nondiseased and not under any regular medications. The study purpose was explained and informed written consent was taken for clinical and laboratory investigations. Ethical clearance was taken from the ethical subcommittee of the institute prior to the commencement of the study.

Laboratory procedure

A total of 5.7 ml of peripheral venous blood was collected for the assay of the selected parameters of the coagulation profile. Out of it, 3 ml was collected in a K2-Ethylene diamine tetra acetic acid -containing Vacutainer for platelet count and mean platelet volume (MPV) assay, while 2.7 ml collected in a 3.2% citrate-containing Vacutainer for prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time (TT), and D-dimer assay. The samples were taken prior to surgery in case of the test group. In the laboratory, platelet-poor plasma was separated by centrifuging the blood sample at 1000g (approximately 3500–4000 rpm) in a standard table top centrifuge for 15 min. The plasma was analyzed within 30–45 min of the sample collection for PT/international normalized ratio, aPTT, and D-dimer. These tests were done in the Sysmex CA 1500 automated coagulation analyzer. 200 μl each of thromboplastin and calcium chloride incubated at 37°C were added to 200 μL of plasma, and the time taken for clot formation was measured automatically by the analyzer as PT. Plasma sample was incubated with contact activator kaolin to activate intrinsic coagulation pathway, and on addition of calcium chloride, intrinsic pathway was triggered. The time taken for clotting was measured by the analyzer as aPTT.

D-dimer was measured by the amount of D-dimer (fibrinolytic product) molecule present in the plasma by aggregation of polystyrene coated with monoclonal antibody, detected turbid metrically. Platelet count and MPV were measured on Beckman Coulter LH-750 automated hematology analyzer using electrical impedance.

Statistical analysis

Data regarding age, mode of presentation, parameters of coagulation, clinical stage of tumor, and lymph node metastasis were obtained and tabulated on a structured pro forma; parametric (Student's unpaired t-test) was used for continuous variables, while in case of categorical variables, differences between the groups were calculated using Chi-square test/Fisher's exact test. P < 0.05 was regarded as statistically significant. Receiver operating characteristic (ROC) curve was used for the determination of a cutoff value for D-dimer to calculate the cutoff with the best (required) sensitivity and specificity.


  Results Top


A total of 50 cases of breast cancer and 50 healthy controls were recruited as per the inclusion and the exclusion criteria. The cases and controls were recruited within an age group of 25–65 years. The mean age of the study participants in the case group was 49.14 ± 9.76 years and in the control group was 47.98 ± 8.85 years. The age-wise distribution is shown in [Table 1].
Table 1: Age-wise distribution of cases and controls

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In order to find out the role of activation of the extrinsic/intrinsic coagulation pathways, fibrinolytic pathways, and the platelets, the selected parameters were compared between the breast cancer cases and controls. The values of D-dimer and platelet count were higher in breast cancer cases as compared to control and this difference was statistically significant with the P < 0.001 and P = 0.003, respectively, while aPTT and TT values, though higher in cases, did not show significant difference [Table 2].
Table 2: Comparison of coagulation parameters between cases and controls

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The cases were categorized into those with and without lymph node metastases diagnosed postoperatively to gain an insight into pathogenesis of metastases by comparing both the groups. D-dimer values were found to be significantly elevated in group having lymph node metastasis as compared to those without metastasis [Table 3].
Table 3: Comparison of groups based on postoperative lymph node status in breast cancer cases

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A ROCs curve was plotted to establish a cutoff value for D-dimer (with appropriate sensitivity and specificity using the Youden's index) for use as a marker of lymph node metastases preoperatively [Figure 1]. The ROC curve provided us a cutoff value of 0.765; we have a sensitivity of 55.6% and a specificity of 90.9% with an area under the curve of 0.640 (P = 0.045).
Figure 1: Receiver operating characteristic curve of D-dimer values in cases of breast cancer with metastases

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  Discussion Top


Many studies in the last three decades have shown that the fibrinolytic pathway has a definite role to play in tumor angiogenesis, hence a definite role in carcinogenesis and metastasis as well. Indicators of fibrinolytic pathway such as D-dimer, uPA, and plasminogen activator inhibitors have been found to be elevated in patients with breast cancer.[19]

Kuenen et al. and Kurt et al. showed that platelets and their MPV (signifying the quantitative and quantitative function of platelets) were found to be altered significantly in patients with breast cancer. This outlines the involvement of platelets along with the fibrinolytic pathways in the process of carcinogenesis. Findings of our study showed that an increase in platelet count (2.25 ± 0.83 vs. 1.86 ± 0.51) was also in concurrence with the study by Kuenen et al. However, the decrease in MPV values in our study does not comply with the study made by Kurt et al.[20],[21]

D-dimer was significantly raised (P < 0.001), thus making it evident that the fibrinolytic pathway plays a vital role in the process of carcinogenesis of breast cancer. The same has been put forward by studies done on other solid tumors such as esophageal cancer and pancreatic cancer.[13],[14],[15],[16],[17]

From previous studies[13],[14] and the findings of the present study, we know that the malignant tumors have increased D-dimer values, so we can conclude that the fibrinolytic pathway is definitely involved in carcinogenesis as well as metastases (sign of malignancy) of breast cancer.

Our study revealed that out of all the parameters, only the D-dimer levels were significantly raised in the group of patients with breast cancer having lymph node metastases. This is in coherence with a previous study done by Blackwell et al., where D-dimer raised in metastatic breast cancer.[13]

There are some limitations in our study. The sample size is comparatively small due to time constraints. Multicentric studies with larger sample size need to be undertaken to evaluate the definitive role of various coagulation parameters in patients with operable breast cancer for prediction of lymph node metastases preoperatively, supplemented by comparing its predictive value with sentinel lymph node sampling. Furthermore, the most significant parameter, i.e., D-dimer, is not a very specific marker of malignancy, so other coagulation and fibrinolytic markers should be evaluated hand in hand. However, this study definitely adds to the evidence of work carried out in the field of breast cancer regarding the involvement of coagulation and fibrinolytic pathways in its pathogenesis.


  Conclusions Top


D-dimer is a simple, noninvasive, quick, and less expensive laboratory investigation that can be used as a predictor of depicting lymph node metastasis preoperatively and thus a guide for proceeding with axillary lymph node dissection following tumor removal in cases of breast cancer posted for surgery.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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