Fikry Ali Abushofa1, Azab Elsayed Azab*2, and Hajar Musa Al Ghawi3
1Department of Zoology, Faculty of Science, University of Zawia, Libya
2Department of Physiology, Faculty of Medicine, Sabratha University, Libya
3Department of Zoology, Faculty of Science, Sabratha University, Libya
Abstract: Background: Cervix cancer is one of the common cancers among women and an important global health problem. As the cervical cancer progresses, changes appear in haematological parameters which have been of relevant consideration in context of cancer patients. Blood group antigens may influence the systemic inflammatory response, that has been associated with the malignancies. Objectives: This review highlight on the haematological alterations among cervical cancer patients and the association between blood groups and cervical cancer disease. The symptoms of cervix cancer in premenopausal women are irregular vaginal bleeding, vaginal bleeding after intercourse, and watery vaginal discharge, and severe pelvic pain caused by tumor metastasis in bone. The incidence and mortality rate of cervical cancer are more prevalent in Africa, Southeast Asia, Latin America, Central and Eastern Europe. There are a significant decreases in the RBCs count, hemoglobin content, and Hct value among cervical cancer patients when compared with the healthy individuals. The incidence of anaemia and thrombocytopaenia were significantly higher among cervical cancer subjects compared to controls. Leukocytosis, lymphopenia, neutrophilia, NLR, and PLR were higher in patients with cancer when compared with the controls and were consistently elevated during tumor progression. In addition to age of patients, and determination of neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios may help in decision making precancerous pathologies of the cervix. Blood group antigens may influence the systemic inflammatory response, that has been associated with the malignancies The ABO antigen expressed on the surface of malignant cells appears to be different from the antigen expressed on normal tissue. The different expression of antigens on the surface of cancer cells might alter motility, apoptosis and immune escape. ABO blood group phenotype is different among different region hence distribution among cervical carcinoma is also different for particular region and also heterogeneity in result largely depends on study design, sample size, races, socioeconomic status, and other associated factors like sexual partners, number of biological fathers, number of children and the use of contraceptive. Association between gynecological cancers and ABO blood groups were significantly found higher in blood type A, followed by B, O and minimum association of gynecological cancers were found in blood type AB. A strong association between incident of carcinoma of cervix and blood group A and weaker association with blood group B and individuals with blood group O appear to be more resistant to the development of cancers. Women of blood group A might be at higher risk of cancers involves diminished immunological surveillance. Conclusion: The current review showed a significant alterations in haematological parameters among cervical cancer patients and a strong association between incident of cervical cancer and blood groups.
Keywords: Cervical Cancer, Haematological altrations, NLR, PLR, inflammatory markers, Blood groups, Rhesus factor.
Cervical carcinoma originates in the transformation zone from the ecto- or endocervical mucosa. The transformation zone is the area of the cervix between the old and new squamocolumnar junction. The most cases of cervical cancer occur as a result of HPV- 16 and HPV- 18. High-risk types, especially HPV 16, are found to be highly prevalent in human populations (Bruni, L. et al., 2010; Bruni, L. et al., 2013), whereas infection by others causes warts and benign lesions and is considered low risk (types HPV- 6 and HPV- 11) (Muñoz, N. et al., 2003). The symptoms of cervix in premenopausal women are irregular vaginal bleeding, vaginal bleeding after intercourse, and watery vaginal discharge, and severe pelvic pain caused by tumor metastasis in bone (Peel, K. R., 1995).
Cervical cancer has the highest incidence rate in young adults (Bruni, L. et al., 2010). (Ferlay, J., et al., 2015) reported that 528,000 new cases and 266,000 cases of death from cervical cancer worldwide were recorded in 2012 and approximately 570 000 cases of cervical cancer and 311 000 deaths from the disease were recorded in 2018. Cervical cancer was the leading cause of cancer-related death in women in eastern, western, middle, and southern Africa (Arbyn, M. et al., 2020).
Cervical cancer has been found that it is the second most common tumor among females in Algeria and Morocco and the third most common tumor in Tunisia (Parkin, D. M. 2006). It is one of the main problems in Libya (El Mistiri, M. et al., 2007). Due to the lack of cancer screening and prevention programs in Libya, only a few cases have been reported in the eastern region of Libya. Almost 100% of all cervical cancer cases are caused by human papillomavirus which ranks as the most sexually transmitted infection worldwide (Parkin, D. M. 2006). The incidence and mortality rate of cervical cancer are more prevalent in sub-Saharan Africa, Southeast Asia, Latin America, the Caribbean, Central and Eastern Europe, Zimbabwe, Malawi, and Uganda Whereas, it is less prevalent in Western Asia (Torre, L. A. et al., 2016). It is estimated that the highest rate of incidence of cervical cancer: in Five countries including India, China, Indonesia, Brazil, and the Russian Federation (Momenimovahed, Z., & Salehiniya, H. 2017).
As the cervical cancer progresses, changes appear in haematological parameters which have been of relevant consideration in context of cancer patients (Nath, A. et al., 2014; Nath, A. et al., 2015). Leukocytosis has been evaluated in many studies in colorectal cancer and lung cancers (Walsh, S. R. et al., 2005; Sprague, B. L. et al., 2008; & Tavares-Murta, B. M. et al., 2010).
This review highlight on the haematological alterations among cervical cancer patients and the association between blood groups and cervical cancer disease.
3.HAEMATOLOGICAL ALTERATIONS IN CERVICAL CANCER PATIENTS
(El Mistiri, M. et al., 2010) reported that among all types of cancers that have been reported in Libya, cervical carcinoma occupies an incidence rate of 4.9 per 100 000 females and the mortality rate of 2.0 per 100 000 females. The median age of incidence of cervix cancer in eastern Libya was 50 years. In addition, (Gascon, P., & Barrett-Lee, P. J. 2006) reported that 70% of cervical cancer in Nigeria was seen between 26-50 years with peak age range of 34-45 years.
A study has been carried out by (Al-Araji, S. M., & Hamad, N. J. 2005) showed that an increase in the number of leukocytes ranges from (11600-25000 cell/mm3) as compared with healthy individuals (4000-11000/mm3), respectively and a decrease in hemoglobin (7.1-9.2 mg/dI) as compared with healthy individuals (11.5-16.5), respectively and decrease in hematocrit (21.8%-30%) as compared with healthy individuals (35%-47%) respectively.
(Tavares-Murta, B. M. et al., 2010) evaluated that the blood leukocyte counts in cervical cancer patients. Patients at a university hospital were reviewed retrospectively. Disease progression was monitored, beginning in 1990 to 2002, for at least 5 years. Blood count parameters included absolute leukocyte, lymphocyte, and neutrophil counts, and the neutrophil-lymphocyte ratio (NLR). The results showed that a total of 315 patients were enrolled: 182 (57.8%) with preinvasive neoplasia, 95 (30.1%) with stages I to II (early group), and 38 patients (12.1%) with stages III to IV neoplasia (advanced group). Neutrophil count was increased and lymphocyte count was decreased, at advanced stages compared with the preinvasive neoplasia group. Leukocytosis, lymphopenia, neutrophilia, and NLR were more frequent at advanced stages compared with the preinvasive neoplasia and early-stage groups. Moreover, neutrophilia was also significantly more frequent at early stage compared with the preinvasive neoplasia group. Authors concluded that patients with advanced cervical cancer had significantly higher frequency of leukocyte alterations, although they may occur apart from the preinvasive stages. Overall, neutrophilia was the best indicator of cancer invasiveness.
(Kose, M. et al., 2015) demonstrated that whether the preoperative platelet to lymphocyte ratio (PLR) could predict invasiveness of cervical pathologies. Patients with preinvasive and invasive diseases were reviewed retrospectively, over a nine-year period, 2005-2014. The complete blood counts of the patients were collected and analyzed by the SPSS program. The median PLR was significantly (p=0.03) higher in the invasive group than in the preinvasive group. There was a correlation between invasion of cervical cancer and white blood cell count, neutrophil-lymphocyte ratio (NLR), and PLR. This study showed that patients with uterine cervical cancer may present with leukocytosis, increased NLR, and PLR.
The study of (Nath, A. et al., 2015) investigated that the haematological changes at the first clinical presentation among 30 cervical cancer patients in India-Banta. For haematological changes, haemato-cytometer and Sahli’s method was followed. The results revealed that there is a significant decrease in the RBCs count (3.30±0.49×106/mm3), hemoglobin content (10.61±1.32g/dl) as compared with the healthy volunteers (4.36±0.32x106/mm3, 14.28±2.29g/dl, respectively). On the other hand, WBCs count was increased in cervical cancer patients (10.65± 1.85×103/mm3) as compared with the healthy volunteers (7.25±1.0x106/mm3).
(Okwesili, A.Y. et al., 2017) investigated that some of the haematological parameters among cervical cancer patients in Sokoto, North Western Nigeria. Twenty-two women with cervical cancer aged 40 to 60 years and a mean age of 50 ± 7.0 years, visiting the Gynaecology/Oncology unit of Usmanu Danfodiyo University Teaching Hospital Sokoto, Nigeria were studied. A total of twenty-six (26) apparently healthy women aged 32-62 years with mean age of 49 ± 9.0 years were monitored as controls. The haematological parameters were determined. The mean Hct and lymphocyte count was significantly (p<0.05) lower among cervical cancer subjects compared to controls. The mean of WBC, MCH, MCV, and MCHC were showed a none statistically significant difference between cervical cancer patients and the control subjects. The mean platelet count in the cervical cancer patients was a none significantly increased compared to normal controls. The incidence of anaemia (Hb<11g/dl) and thrombocytopaenia (platelet count<140× 109/l) were significantly (p<0.05) higher among cervical cancer subjects compared to controls.
(Wang, L. et al., 2017) carried out a retrospectively analyzed 515 patients with cancer to investigate the predictive significance of pretreatment values of PLR, and NLR in cervical cancer. The results of the study showed that the median age of the cervix cancer patients was 51 years (range, 25- 79 years). The hemoglobin concentration was significantly decreased as compared with the controls. Leukocytes, neutrophils, lymphocytes, and platelets count were significantly increased compared with the controls. The median values of PLR and NLR were higher in patients with cancer when compared with the controls and were consistently elevated during tumor progression. The pretreatment NLR or PLR value was a significant predictor of lymph node metastasis, which enhanced when NLR and PLR values were combined. However, no prognostic significance of NLR or PLR was found in the patients with early cancer stages. Author suggested that pretreatment values of NLR and PLR might be helpful to predict the presence of distant and LN metastasis in patients with cervical carcinoma, but not adequate prognostic factors for early stage patients.
(Tas, M. et al., 2019) studied that the predictive value of some of the hematological markers of inflammation on the presence/absence of cervical cancer. Patients who presented to Acıbadem Kayseri Hospital between May 2010 and June 2018 were evaluated. 30 patients with cervical cancer and 70 healthy volunteers with normal cervical cytology were included in this study. The results were showed that the neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios were significantly higher in patients with cervix cancer than in controls. Authors concluded that, in addition to age of patients, and determination of neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios, that are simple, low-cost, and readily available markers of systemic inflammation, may help in decision making precancerous pathologies of the cervix.
4. ASSOCIATION BETWEEN BLOOD GROUPS AND CERVICAL CANCER
Blood group antigens are expressed in many other tissues, including breast lobular cells, ductal cells, and even some malignant cells (Yazer, M. H. 2005; Saxsena, S., & Gupta, K. 2016). The ABO antigen expressed on the surface of malignant cells appears to be different from the antigen expressed on normal tissue (Strauchen, J. A. et al., 1980; Vowden, P. et al., 1986). The different expression of antigens on the surface of cancer cells might alter motility, apoptosis and immune escape (Le Pendu, J. et al., 2001). Blood group antigens may influence the systemic inflammatory response, that has been associated with the malignancies (Saxsena, S., & Gupta, K. 2016; Melzer, D. et al., 2008; Paterson, A. D. et al., 2009; Barbalic, M. et al., 2010; & Qi, L. et al., 2010). There may be some association between cervical carcinoma and blood group, but there is no clear explanation about its role in pathogenesis. However, it is reported that the ABO type antigens are expressed at low levels in normal cervical tissue but are expressed at higher frequency in cervical carcinoma tissues (Tailor, H. J. et al., 2020).
(D'Adamo, Peter. 1996) reported that cancers in general tend to be associated with blood group A and slightly less strongly with blood group B. Other studies also suggest that ovarian cancer have also strong association with blood group A (Metoki, R. et al., 1989). Carriers of A and AB blood groups had a significantly increased risk of laryngeal carcinoma (Pyd, M. et al., 1995). The carriage of A and AB groups significantly correlated with an increased risk of gallbladder cancer (Pandey, M. et al., 1995). Presence of an A-like antigen (MRG-1) in cervical tissues and persons with blood group A and AB are more susceptible to tumor since they do not have anti A antibodies which can eliminate tumor cells by killing (Cui, Y. et al., 1993; Vaillant, A. J. et al., 2013).
The studies of (Flavarjani, A. H. M. et al., 2014) was found that a correlation between blood group A and breast cancer. Also, (Stamatakos, M. et al., 2009) reported that blood group A was associated with ductal breast cancer (49.6%), in contrast to the other blood groups and particularly to blood group AB (3.6%). In addition, it has been demonstrated that subjects possessing the blood group O have a lower risk of pancreatic cancer compared to those with groups A or B (Wolpin, B. M. et al., 2010).
(Marinaccio, M. et al., 1995) that reported gynecological tumors including, endometrial and cervical cancer are more in women with the blood type A, but it is not statistically significant.
Observational study of (Saxsena, S., & Gupta, K. 2016) was conducted in the Medical College, Jodhpur (Rajasthan), on 256 clinically diagnosed gynaecological cancer patients. Study period was from September 2006 to March 2008. The standard agglutination test was used to determine the blood groups. Results were showed the association between gynecological cancers and ABO blood groups were significantly found higher in blood type A, followed by B, O and minimum association of gynecological cancers were found in blood type AB. Women of blood group A might be at higher risk of cancers involves diminished immunological surveillance. Some tumors, notably of the colon and stomach, express the Forssmann antigen which is structurally similar to the A antigen determinant. People with blood groups other than A produce anti-A antibodies. Because of structural similarity, these antibodies might also attack precancerous or cancerous cells expressing the Forssmann antigen. Thus, some people of blood group A may have a diminished immune response to the tumor (Bisht. D. et al.,1998).
It has been reported in a study carried out by (Lee, J. K. et al., 2013) on the Indian population that the blood group B and age of marriage between 11 to 20 years old are the strongest factors associated with in incidence of cervical carcinoma. Authors recorded that a higher significant incidence of carcinoma cervix among blood group B (55%) patients in 100 cases of cervical cancer patients in semi urban population in India.
(Akhtar. K. et al., 2018) found that a predominance of blood group B (37.9%) in 406 cancer patients in Northern India.
Individuals with blood group O appear to be more resistant to the development of cancers (Gupta, S. et al., 1981). (Kaur, I. et al., 1992) observed that a strong association between incident of carcinoma of cervix and blood group A and weaker association with blood group B.
(Yuzhalin, A. E., & Kutikhin, A. G. 2012) found that a non statistically significant correlations between ABO blood groups and cervical cancer in South East Siberia. But, predominance of blood group A (36.0%) and group O (36.01%). (Su, M. et al., 2001) reported that the frequency of the blood group B was significantly higher in Chinese patients with cardiac cancer and esophageal carcinoma. (Sharma, G. et al., 2007) reported that the frequency of blood group B (36.11%) and O (35.99%) followed by A (19.44%) but revealed a lack of association between ABO blood groups with cancer of the cervix in 108 cases in Bhopal. Also, (Lee, J. K. et al., 2013; Akhtar. K. et al., 2018) found that a higher significant incidence of carcinoma cervix among blood group B (55%) and (37.9%) in Indian cervical cancer patients, respectively.
(Tyagi, S. P. et al., 1967) found that AB blood group has a higher significant risk compared to the stable blood group O in relation of carcinoma cervix.
(Lee, J. K. et al., 2013) reported that a relatively increased risk of cervical carcinoma for those residing in rural area, compared to that of urban area. Rural residency was suggested to have low income, lower education, which in turn leads to low awareness towards hygiene, knowledge of cervical carcinoma, its screening programmes, difficult in persuading women for screening, leading to a delayed diagnosis and increased mortality (Lee, J. K. et al., 2013; Kaku, M. et al., 2008; Damiani, G. et al., 2012).
ABO blood group phenotype is different among different region hence distribution among cervical carcinoma is also different for particular region and also heterogeneity in result largely depends on study design, sample size, races, socioeconomic status, and other associated factors like sexual partners, number of biological fathers, number of children and the use of contraceptive (Vaillant, A. J. et al., 2013).
(Parikh, S. et al., 2003) reported that women in the lower social class were at approximately a 80% increased risk of cervical disease than women in the middle social class group that were at 26% as compared to women in the upper social class group. Lifestyle factors being the primary cause of the social class differences which emphasize the future cervical cancer prevention programmes to includes vaccination and screening especially for women from low socioeconomic groups so that they benefit best.
(Lee, J. K. et al., 2013) observed that women with more number of children (multipara) have a relatively higher odds ratio than that of unipara, although not statistically significant. The odds ratio showed an alarming increased odds ratio of 4.07 for multipara women. One study showed that women with 3 or more births showed 1.51 increased odds ratio to carcinoma cervix (Satija, A. 2012). Again, this reinforced the conventional claim that multipara women are more prone for carcinoma cervix.
(Dixit R. et al., 2020) reported that the distribution of A+, A-, B+, B-, AB+, O+, and O- blood groups showed a non-significant (P<0.068) difference between healthy individuals and cervix cancer patients that, were 13.9%, 1%, 37.3%, 1.9%, 0%, 39.2% & 1.9%, and 21.4%, 1.1%, 40.1%, 1.6%, 6.4%, 26.7%& 2.7% among healthy individuals and breast cancer patients, respectively.
(Kelala, A. A. S., 2020) reported that the distribution of A+, A-, B+, B-, AB+, O+, and O- blood groups showed a significant difference between most of breast cancer patients and healthy individuals that, were 57.1%, 2.4%, 4.7%, 1.6%, 1.7%, 31.2%& 2.9%, and 28.82%, 8.24%, 4.11%, 1.9%, 20%, 23.53% & 15.29%, among healthy individuals and breast cancer patients, respectively.
(Meo, S. A. et al., 2017) suggested that the risk of breast cancer is high for the Rh+. Also, (Kelala, A. A. S., 2020) recorded that a significant difference (P<0.01) between the distribution of Rh+ and Rh- blood groups in breast cancer patients (94.7%, 5.3%) and healthy individuals (75.88%, 24.12%), respectively. Many of previous studies showed that the breast cancer patients with Rh+ were 97.1% ) Flavarjani, A. H. M. et al., 2014(, 93.4% (Stamatakos, M. et al., 2009; Shiryazdi, S. M. et al., 2015; & Payandeh, M. et al., 2015), 88% (Urun, Y. et al., 2012), and 82% (Cihan, Y. B. 2014). In contast, (Yuzhalin, A. E., & Kutikhin, A. G. 2012) found that a non statistically significant correlations between ABO blood groups and Rhesus factor and cervical cancer in South East Siberia. (Yu, J. et al., 2012) failed to demonstrate an association between ABO blood type and Rh factor. Similarly, (Stamatakos, M. et al., 2009) reported inconsistent results between Rh factor and breast cancer risk.
It can be concluded that a significant alterations in haematological parameters among cervical cancer patients and a strong association between incident of cervical cancer and blood groups.
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