Can the parameters of the haemogram of patients with brain tumours be evaluated to obtain information on the stage of the tumour and its prognosis? a preliminary study

Authors

Abstract

Aim We aimed to determine the predictive value of the grade of glial tumors using some cheap, easily available haemogram parameters and their ratios. In our study, we believe some results may be useful for future studies in terms of establishing parameters that may help establish the diagnosis, especially in patients who can’t be diagnosed histopathologically or have insufficient samples for reasons such as biopsy. In addition, we believe that this is a study that can be evaluated in terms of turning it into a simple and useful method that can be useful in terms of prediction in the decision-making process of surgical or non-surgical treatment with algorithms that can be created in the future.
Materials and Methods This study retrospectively evaluated preoperative blood cell ratios of patients who underwent surgery for intracranial tumors at our center between 2007 and 2020. The lack of medical records made forming an optimal control group difficult. The control group was excluded as the aim was to investigate differences in haemogram parameters across glial tumors. Blood samples were analyzed one week before surgery. 3ml of blood was collected and processed within 30 minutes. Data were analysed using SPSS 24. Normally distributed data were analyzed using ANOVA, while non-normally distributed data were analyzed using Kruskal-Wallis. Age correlated with all measures, so it was incorporated as a covariate in ANCOVA. Qualitative data were subjected to a chi-squared analysis.
This study was approved by the Ethics Committee of Karadeniz Technical University (Date: 2021-06-17, No: 147).
Results Data were statistically analyzed, lower hemoglobin and higher lymphocyte values favored grade I; higher neutrophil values and NLR favored grade IV. When the age variable was statistically refined, the increase in platelet count favored grade IV over grade III, and the higher lymphocyte count favored grade I over the other three groups. In the PLR, which was not significant in the first analysis, there was a significant difference between Grade I, Grade II, and Grade IV when age was statistically refined.
Discussion The study shows that haemogram parameters can provide valuable supplementary insights into the grading of glial brain tumors. We believe that by standardizing case selection and increasing sample size in a multicentre setting, we can obtain more objective results on this promising topic.

Keywords

Introduction

Brain tumors are broadly divided into four groups as grades I, II, III, and IV according to the World Health Organization 2007 and 2016 classifications and are studied in major groups based on histopathology. Although the incidence of CNS tumors appears to be lower than that of other neoplasms, they account for a significant proportion of cancer-related morbidity and mortality. It is estimated to account for 1.4% of new cancer diagnoses and 2.6% of cancer-related deaths in 2015. Between 1998 and 2002, the annual incidence of primary brain tumors in the USA was reported to be 14.4 per 100,000. Recent studies have found that the incidence of brain tumors is increasing and that the incidence may vary by sex, age, race, and region. Age at diagnosis can vary significantly between different types . The most common tumors in the pediatric age group are pilocytic astrocytomas, embryonal tumors, and malignant gliomas, while meningiomas, pituitary tumors, and malignant gliomas are the leading types in adults.
Increased access to healthcare and the development of diagnostic tools, combined with longer life expectancy worldwide, are leading to an increase in incidence. As with all malignancies, early diagnosis of brain tumors is crucial. Early diagnosis allows patients to be started on treatment at an early stage, thereby reducing morbidity and mortality.
The prognosis for brain tumors varies. It is crucial for medical practitioners, patients, and their families to be able to anticipate the prognosis prior to the diagnosis. Researchers have been developing alternative modalities that may have diagnostic value, including PET, MRS, and biomarkers. . However, as none of these non-invasive diagnostic tools can replace tissue histopathology, which is the gold standard in diagnosis, there is still a need for non-invasive methods that can be used in the differential diagnosis before biopsy.
Recently, many studies have focused on the relationship between the tumor and the systemic immune response. The main hypothesis is based on obtaining predictive and/or monitoring information through the relationship between inflammation and tumor. In this context, research has focused on platelet indices neutrophil and lymphocyte levels. Some haemogram parameters have been studied in neoplasms affecting different systems, and significant results have been obtained in diagnosis and differential diagnosis. Another study compared patients with and without brain metastases and found that some parameters (decreased MPV, increased RDW) were associated with the presence of brain metastases. . In non-small cell lung cancer patients, those with and without brain metastases were studied in two groups; low MPV was evaluated in favor of brain metastases. Another study evaluated the neutrophil- lymphocyte ratio (NLR) in primary pediatric patients and found that a high NLR was associated with a higher grade of cancer. However, there is no other study in the literature that includes as many parameters as we evaluated in our study and includes primary brain tumors with many histopathological diagnoses in different age groups.

Materials and Methods

This study retrospectively evaluated preoperative blood cell ratios of patients who underwent surgery for intracranial tumors at our center between 2007 and 2020. The specimens were not re-examined, so the evaluations were performed in accordance with the 2007 and 2016 WHO classifications of central nervous system tumors. The study included complete data sets. Incomplete data excluded patients from the study. The study included patients with different diseases and taking different anticoagulants. The lack of sufficient medical records makes it challenging to establish an ideal control group for each patient in this retrospective study. The control group was not included in the study as the aim was to investigate differences in haemogram parameters across glial tumors. Blood samples were analyzed one week before surgery. 3ml of blood was collected in EDTA vacuum tubes and processed on a Sysmex XN- 1000 automated hematology analyzer within 30 minutes. The data were analyzed using SPSS 24. The Kolmogorov-Smirnov test was used to check if the data in each of the grades 1-4 followed a normal distribution. Normally distributed data were analyzed using ANOVA, while non-normally distributed data were analyzed using Kruskal-Wallis. The results showed that age correlated with all measures. Age was incorporated as a covariate, and all measures were reanalyzed using ANCOVA. The qualitative data were subjected to a chi-squared analysis. The level of statistical significance was set at p < 0.05. The participants in this study gave informed consent for their medical information to be used for scientific purposes on the condition that their identity remained anonymous.
Ethical Approval
This study was approved by the Ethics Committee of Karadeniz Technical University (Date: 2021-06-17, No: 147).

Results

A total of 462 patients were enrolled and divided into four groups. According to the 2007 (for patients between 2007- 2016) and 2016 (for patients between 2016-2020) WHO classifications. As our study was retrospective, the nuances between the two classifications were not taken into account. The first group is the group of grade I patients (n1=31), the second group is the group of grade II patients (n2=99), the third group is the group of grade III patients (n3=50), and the fourth group is the group of grade IV patients (n4=292). As expected, there was a significant difference in age at diagnosis between the groups. Only between Grade II and Grade III, there is no significant difference in age at diagnosis (p>0.05). (p>0.05) The rates and gender distribution of the different groups in the study are shown in Table 1.
This study examined ten hematological parameters and their interrelationships. The grade I group had significantly lower hemoglobin levels than all others. No significant difference between grades II, III, and IV. Grade IV differed from all other groups for neutrophil count and NLR. No significant difference was noted between the other three groups. Although a significant difference was observed in lymphocyte count between Grade I and all other groups, no significant difference was evident between the remaining three groups. No significant difference was identified between the groups using the Kruskal- Wallis pairwise comparison test. Table 2
As there was a significant difference in age at diagnosis in all groups except grades II and III, all measured parameters were reanalyzed using the ANCOVA test, considering that these haemogram parameters may vary with age. As a result, there was a significant difference in platelet count between grades III and IV (p=0.029). There was a significant difference in lymphocyte count between grade I and the other three groups (p<0.005). In the ratio of platelets to MPV, there was a significant difference between Grade I and Grade II and between Grade I and Grade IV when the age variable was refined, but there was no significant difference between Grade I and Grade III. Table 3

Discussion

Terminologically, a brain tumor is a neoplasm that arises from different cells by metastasis or primary brain tissue.
Primary brain tumors are a group of tumors that include many histological types. According to the Central Brain Tumor Registry of the United States (CBTRUS), brain tumors account for approximately 2% of all cancers, with an average annual incidence rate of 21.42 per 100,000. CNS tumors are the most common tumors in the pediatric age group.
Brain metastases occur in 10-15% of all cancer patients and are 10 times more common than primary brain tumors. The most common cancers in adults are carcinomas (lung, breast, kidney, colorectal, melanoma); sarcomas are more common in children (neuroblastoma, germ cell tumors).
While there are many studies that show an increased incidence of brain tumors, there are also studies that suggest that this may be due to many different factors. These include more accurate and widespread diagnostic tools, improved access to health care, increased life expectancy, and better health care for older patients.
The incidence of brain tumors is influenced by variables related to age, sex, and race. In terms of age, pilocytic astrocytoma, choroid plexus tumors, neuronal tumors, pineal gland tumors, and germ cell tumors are seen at younger ages, while the median age for meningiomas and glioblastomas is 65 years. In terms of gender, the incidence of brain tumors is slightly higher in men (1.3 times higher); meningiomas are more common in women (2 times higher).). Regarding race, the incidence of primary brain tumors is statistically significantly lower in Native Americans than in whites, blacks, and Asians. Meningiomas, pituitary tumors, and craniopharyngiomas are more common in blacks than in other races. Astrocytomas and oligodendrogliomas are at least 2 times more common in whites than in blacks.
Although brain tumors are thought to be mostly sporadic, the etiology is multifactorial. The main risk factors are exposure to radiation (especially meningioma). Exposure to electromagnetic fields (such as mobile phones), genetics (NF-1,2, hereditary genetic syndromes such as von Hippel-Lindau syndrome, Li-Fraumeni syndrome, Turcot syndrome, basal cell nevus syndrome, etc.), head trauma, some environmental factors (such as diet, smoking, alcohol), allergies and the immune system. . Considering the area of interest of our study, the immune system is considered a risk factor because it can directly influence the parameters we studied. The relationship between infections and brain tumors is controversial in current studies. The relationship between etiologically specific infectious agents and brain tumors has not been convincingly demonstrated. In theory, viruses, in particular, can cause tumors by inducing genetic changes in cells, and the brain tumor study showed that the risk of developing a brain tumor was increased in people who had received polio vaccines contaminated with simian virus 40 (SV40). However, this claim has not been supported by other studies.
Although viral antigens of HSV-6 and JC virus have been detected in brain tumor subtypes, their possible aetiological role is unclear. Nucleic acids and proteins of human CMV have been detected in glioblastoma cases. There are also studies showing that VZV infection reduces the risk of glioma formation. It has also been shown that there is an inverse relationship between allergic diseases and the risk of brain tumors. .
Diagnosis of brain tumors, neurological signs that occur as a result of clinical suspicion, and radiological evaluation are generally made. Neurological signs and symptoms occur as a result of the tumor mass and associated cerebral edema.
If a brain tumor is clinically suspected, radiological investigations such as contrast and non-contrast CT and MRI are performed. MRI is preferred to CT because of its higher resolution and more precise guidance for surgical resection. MRI, using different sequences, can be useful in making a histological diagnosis of tumor tissue (dural tail favors meningioma, hypointensity on T1, and heterogeneous contrast favors high-grade glioma). MR spectroscopy, functional MRI, perfusion MRI, and diffusion MRI (DWI) are available in clinical practice. Some experimental radiological investigations, such as positron emission tomography (PET), can also contribute to histological diagnosis. However, despite all these advantages, the definitive diagnosis can be made as a result of histopathological examination, and the contribution of radiological examination to the definitive diagnosis is often insufficient.
Histopathological examination of the tumor, performed by stereotactic biopsy or open craniotomy. Although histopathological examination provides the definitive diagnosis of the tumor, modalities such as molecular genetics and biomarkers are being intensively studied in addition to radiological examination. Molecular genetics and biomarkers are not available in routine clinical practice for reasons such as lack of availability, cost, and limited significance in the differential diagnosis.
The inflammatory response is known to play a critical role in the initiation, progression, and metastasis of neoplastic disease. In addition, inflammatory molecules are over-expressed in tumor cells. In this context, some parameters found in the routine haemogram panel are considered markers of inflammation. Recently, many studies have focused on the relationship between the tumor and the systemic immune response. Here, the main hypothesis is based on obtaining predictive and/ or monitoring information through the relationship between inflammation and tumor. The studies focus on platelet indices neutrophil and lymphocyte levels. Some haemogram parameters have been studied in neoplasms affecting different systems, and significant results have been obtained in diagnosis and differential diagnosis.. Another study compared patients with and without brain metastases and found that some parameters (decreased MPV, increased RDW) were associated with the presence of brain metastases. Non-small cell lung cancer patients with and without brain metastases were studied in two groups; low MPV was evaluated in favor of brain metastases. Another study evaluated NLR in primary pediatric patients and found that NLR elevation was associated with higher grades. However, there is no other study in the literature that includes as many parameters as we evaluated in our study and includes primary brain tumors with many histopathological diagnoses in different age groups.

Limitations

As the old World Health Organisation tumor classification was used in the years included in the study, the pathology results of the patients were detailed according to the classification used in those years so that future studies with the new classification and subgroups can be dealt with in more detail.

Conclusion

Based on the 10 different haemogram parameters and ratios associated with systemic inflammation, lower hemoglobin, and higher lymphocyte counts favor grade I; higher neutrophil count and neutrophil to lymphocyte ratio may favor grade IV. The mean age at diagnosis was significantly different in all groups, except for Grade II and Grade III when the age variable was statistically refined. A higher platelet count favored grade IV compared to grade III, and a higher lymphocyte count favored grade I compared to the other three groups. For the platelet- lymphocyte ratio, which did not show significant results in the first analysis independent of the age variable, a significant difference was observed between Grade I and Grade II or Grade IV after age was refined.
This shows that some haemogram parameters can guide the histological diagnosis of brain tumors by standardizing case selection and increasing the number of samples in a multicentre setting. We believe that the results of this study may provide clinical benefit in differential diagnosis prior to the histopathological evaluation, as well as a better understanding of the pathophysiology of brain tumors of glial origin.
In our study, we believe that there are results that may be useful for future studies in terms of establishing parameters that may help to establish the diagnosis, especially in patients who cannot be clearly diagnosed histopathologically or where there is insufficient sampling for reasons such as biopsy.
Our study provides results that may be useful for future studies in terms of establishing parameters that may help to establish the diagnosis, especially in patients in whom the histopathological diagnosis is not clear or in whom an adequate sample is not available, e.g., for biopsy. In addition, we believe that this is a study that can be evaluated in terms of turning it into a simple and useful method that can be useful in terms of prediction in the decision-making process of surgical or non- surgical treatment with algorithms that can be created in the future.

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