RISK FACTORS OF LYMPHOMA AT DR.

SOEBANDI HOSPITAL IN JEMBER DISTRICT EAST JAVA Annisa Reykaningrum1

1

Department of Epidemiology, Biostatistics and Population, Public Health Faculty, Jember University, Jember Correspondence: Jl. Kalimantan I/93 Jember. Telp (0331-337878). Fax (0331-322995). Mobile phone 085730607719. email : annisa_reykaningrum@yahoo.com

ABSTRACT Background: In the world, the incidence of malignant lymphoma was rising but the exact cause of this disease is unknown. Indonesia had not accurate data about malignant lymphoma, but its predicted ranked 6th highest cancer incidence. Objective: This research aims to analyze the risks factors of malignant lymphoma in Jember District Hospital. Methods: This research is an analytical study with cross sectional approach. The study population was 97 patients in General Surgery Clinic in dr. Soebandi Jember District Hospital. This research was analyzed using Chi-square test and multivariable analysis using logistic regression technique. Results: The relationship between age and race with lymphoma were not significant. Risks Factors for lymphoma that significant were gender (male) (p-value=0,019; OR=5,7; 95% CI=1,16-27,8), familial predisposition (p-value=0,012; OR=5,4; 95% CI=1,44-20,34), history of illness (p-value=0,001, OR=10,8; 95% CI=2,59-45,19), and exposure to pesticides (p-value=0,021, OR=9,1; 95% CI=1,12-74,31). Conclusion: The factors that have the stronger relationship with lymphoma are familial predisposition, history of illness and exposure to chemicals (pesticides). Base on this research, developing multi sector approach between hospital, official health, department of agriculture and Organization of Cancer in Indonesia must be built, to prevent and decrease the incidence of lymphoma. Keywords: Pesticides, Familial Predisposition, History of Illness, Lymphoma

Introduction Lymphoma is a malignancy that occurs due to activation of the abnormal gene (mutated lymph cells or lymphocytes) specific to the lymphatic system (lymph nodes, spleen, spinal marrow, and the thymus gland in the neck) which leads to the uncontrolled growth of lymph node cells
(1)

. Lymphoma is one rapidly increased cancer

incidence over the last 30 years, which increased 80% from 1973 to 1999. World Health Organization (WHO) estimates that approximately 1.5 million people worldwide currently live with lymphoma and 300 thousand people die from this disease each year
(2)

In 2007, the incidence of lymphoma in the United States was as many as 71,380 people and it was included five major cancers in men and women. In 2010, there were 65,540 people (35,380 men and 30,160 women) to be diagnosed with lymphoma. Of the overall population suffering from lymphoma, 20,210 people died from this cancer (10,710 men and 9,500 women) (2). Data on lymphoma incidence in Indonesia is still not accurate. It is estimated that this cancer is ranked the sixth highest cancer incidence
(3)

The results of preliminary study on the medical record at Poly Chemotherapy of dr. Soebandi Hospital, Jember, stated that lymphoma was included in one of 2 major cancers in the poly. Each year the number of lymph nodes of cancer patients has increased. In the year 2008 it was recorded 124 patient visits to the hospital and in 2009 it reached 151 visits. The exact cause of this disease remains unknown. Several previous epidemiological studies stated that age, gender, exposure to chemicals, and a history of infectious disease or other types of cancer may increase the risk of lymphoma
(2)

Increased incidence of lymphoma was associated with age, especially in the age group > 55 years. As for gender, lymphoma was more in men than women, which was equal to 2:1. Race also may increase the risk of this cancer. The results of research in the United States stated that lymphoma was found in 40-70% whites compared to blacks. As for the continent of Asia, the race that had a high risk of this cancer was Chinese (4). History of non-communicable diseases such as Diabetes Mellitus proved to have a significant relationship to the incidence of lymphoma (5). History of infections and diseases associated with immune system, such as congenital immunodeficiency, AIDS, use of immunosuppressive drugs after organ transplants, Sicca syndrome, Rheumatoid arthritis, Celiac disease, EBV, HTLV-1, Helicobacter pylori and Campylobacter, hepatitis C virus, Chlamydia psittaci and exposure to chemicals such as pesticides, especially those containing 2,4dichlorophenoxyacetic acid, hexachlorocyclo hexane and benzene could also increase the risk of developing lymphoma
(4)

. The results of a study in California stated that

smoking had an influence on some incidence of lymphoma. Genetic factors or family history of lymphoma or other types of cancer might also increase the risk of developing lymphoma, but the increased risk was also influenced by exposure to carcinogenic chemicals or ingredients (6-7).

Based on the high number of patients with lymphoma in dr. Soebandi Hospital, Jember, which was included in the 2nd highest cancer incidence after breast cancer at chemotherapy Poly, it was necessary to do research to find out more about the factors associated with the incidence of lymphoma in Jember District, especially at Dr. Soebandi Hospital of Jember. This was needed so that preventive action could be done in the community to expect to reduce the prevalence and risk factors in susceptible people suffering from lymphoma.

Method This study was an observational and analytical study with a cross-sectional approach. The research was conducted at the General Surgery Outpatient Poly of dr. Soebandi Hospital, Jember, because the poly is referral poly to identify the type of lymphadenopathy. As for the research time, it was conducted during the months of March to June 2011. The population in this study was all patients who performed examinations or outpatients at General Surgery Outpatient Poly of Dr. Soebandi diagnosed with lymphoma or other types of disease, in order to obtain a sample size of 97 patients. Patients diagnosed with other types of cancer were excluded. Sampling in this study used systematic random sampling technique. The dependent variable in this study was the status of lymphoma and the independent variables were the age at diagnosis, gender, race, family history of the respondents that had cancer, history of illnesses suffered by respondents (diabetes mellitus, HIV / AIDS, Hepatitis C, Rheumatoid arthritis, another type of cancer) prior to suffering lymphoma as well as other diseases, and exposure to chemicals (pesticides). The needed data in this study were collected with a structured interview method directly to the respondent with the help of a questionnaire to investigate the characteristics of respondents consisting of age, gender, race, family history of cancer, history of other diseases (diabetes mellitus, HIV / AIDS, Hepatitis C, Rheumatoid arthritis, other types of cancer), and exposure to chemicals (pesticides). In addition, the method of review of documents in this case medical records was also conducted to obtain data on the results of laboratory examinations that included the staging of

respondents lymphoma and respondents age when diagnosed with lymphoma, and the status of HIV / AIDS. The collected data were analyzed with univariable, bivariable and multivariable analysis with the help of SPSS data processing program and then presented in the form of frequency distribution tables and contingency tables with narrative interpretation. The univariable analysis was performed to describe the frequency distribution and the proportion of each variable studied, both independent variables and the dependent variable. The bivariable analysis was conducted to determine the relationship between each independent variable with the dependent variable by using the Chi square test at 95% confidence interval ( = 0.05). The multivariable analysis was performed to determine the variables most closely associated with the incidence of lymphoma by using Logistic Regression test 95% confidence interval ( = 0.05).

Results and Discussion Univariable Analysis Table 1 explains that the majority of respondents did not suffer from lymphoma. The majority of respondents who had cancer (81.8%) were diagnosed at stage III or IV (advanced stage) and 18.2% were diagnosed at stage I or II (early stage). In the respondents who suffered from cancer and non cancer, most chose to do self-medication with drugs bought at pharmacies and traditional medicine, as well as alternative treatments. Most respondents were aged 55 years (52.6%) and female (51.5%). In this study, racial/ethnic categorization was also examined by Chinese and non-Chinese (Java or Madura). The majority of respondents (94.8%) were classified as non-Chinese Race (Java or Madura), while the Chinese respondents were only 5.1%. In the group of nonChinese race there were 39 Javanese and 53 Maduranese.
Table 1. Description of research variables
Respondents characteristics Status Cancer non Cancer Age >55 years 55 years Gender Male Female Race N 11 86 46 51 47 50 Percentage (%) 11. 3 88. 7 47. 4 52. 6 48. 5 51. 5

Chinese Non Chinese Family history of cancer Yes No History of illness Yes No Exposure to pesticides Yes No Source: Processed Primary Data (2011)

5 92 28 69 25 72 55 42

5. 2 94. 8 28. 9 71. 1 25. 8 74. 2 56. 7 43. 3

Family cancer history was derived from the fathers parents, mothers parents, both father and mother. Only 28.9% of respondents had a family history of cancer. The disease of cancer included breast cancer, uterine cancer, colon cancer and liver cancer. History of illnesses associated with a decrease in the immune system affected only a minority of respondents (25.8%). The illnesses were Rheumatoid arthritis (60%), Diabetes Mellitus (40%), Hepatitis C (8%), and breast cancer and colon cancer (8%). In this study the status of the respondents on pesticide exposure was viewed through participation in agricultural or plantation activities; the level of exposure risk to pesticides which was classified as moderate or high, the use of self equipment protection which was not complete, 5 working hours in a day, and period of employment in agricultural or plantation activity 5 years (made at least 3 of them). In this research, it was noted that more respondents were exposed to pesticides (56.7%) than those not exposed (43.3%). Bivariable analysis The bivariable analysis was conducted to determine the relationship between each independent variable with the dependent variable. The independent variables consisted of age, gender, race, family illness history, history of illness and exposure to pesticides. In detail they can be observed in Table 2.
Table 2. Percentage, Odds Ratio and 95% Confidence Interval to the incidence of lymphoma by age, gender, family history of cancer, history of illness and exposure to pesticides
Lymphoma Variabel n Age >55 years 55 years Gender Male Female Race 7 4 9 2 Yes % 7. 2 4. 1 9. 2 2. 1 n 39 47 38 48 No % 40. 2 48. 5 39. 2 49. 5 p-value Odds Ratio 95% CI

0. 253 0. 019

2. 1 1 5. 7 1

0. 58-7. 74 1. 16-27. 88

Chinese 1 1. 0 4 4. 1 Non Chinese 10 10. 3 82 84. 6 Family history of cancer Yes 7 7. 2 21 21. 7 No 4 4. 1 65 67. 0 History of illness Yes 8 8. 2 17 17. 6 No 3 3. 1 69 71. 1 Exposure to pesticides Yes 10 10. 3 45 46. 4 No 1 1. 0 41 42. 3 Source: Processed primary data of dr. Soebandi Hospital, Jember (2011)

0. 460

2. 1 1

0. 21-20. 19

0. 012

5. 4 1 10. 8 1 9. 1 1

1. 44-20. 34

0. 001

2. 59-45. 19

0. 021

1. 12-74. 31

Based on Table 2, more respondents who suffered from lymphoma were aged > 55 years (7.2%) and those who did not suffer were aged 55 years (48.5%). The bivariable analysis results using Chi-square test showed p-value = 0.253 with OR 95% CI (2.1; 0.58-7.74). This suggested that the age group > 55 years had a risk 2.1 times more likely to have lymphoma than those aged 55 years. The results of this analysis showed that the relationship of age with the incidence of lymphoma was insignificant statistically. Age is one major characteristic of an individual. Age has an influence to the level of exposure, magnitude of risk and resistance. Different experiences of health problems/diseases and decision-making are also influenced by the individual's age (8). In general, the risk of non-Hodgkin's lymphoma increases with advancing age while Hodgkin's lymphoma in the elderly is associated with a poorer prognosis than that observed in younger patients. Increased incidence of lymphoma age, especially in the age group> 55 years (4, 9-10). Gender is a grouping of respondents based on genital traits, ie males and females. Some diseases sometimes tend to infect a specific gender. That is because of differences in physiological function, hormonal activity, and the need for certain nutrients between men and women. Table 2 describes the respondents who suffered from lymphoma that were more in male sex group (9.2%), while those not suffering from lymphoma were more in female sex group (49.5%). Chi-square test results was associated with

showed that the sex variable had a p-value = 0.019 with OR, 95% CI (5.7; 1.16-27.88). This suggests that men had a 5.7 time greater risk of suffering from lymphoma than women. Thus, gender was significantly related to the incidence of lymphoma. The results of this study were in line with previous research which stated that most patients with lymphoma were male with a comparison between men and women

by 2:1. Risk difference was probably caused by other factors such as exposure to carcinogenic materials received between men and women, including the exposure to chemicals (pesticides), the lifestyle associated with consumption patterns, as well as susceptibility to certain infectious diseases. Other causes of these differences were caused by different physiological functions between men and women who led in a particular gender which was more prone to suffer from a disease
(4)

. Risk differences of

developing lymphoma in men and women were also caused by hormonal functions in the body. In his research, Nelson found that most women suffering from lymphoma took oral contraceptives or hormone replacement therapy (11). Race is a category for a group of individuals / human hereditary with similar physical features and biological characteristics. Table 2 shows that the majority of respondents who suffered from lymphoma (10.3%) were non-Chinese Race (Java or Madura). Similarly, the respondents who did not suffer from lymphoma were also the majority of non-Chinese race (84.6%). Chi-square test results prevailed that the race variable had a p-value = 0.460 with OR, 95% CI (2.1; 0.21-20.19). The results of the analysis indicated that the Chinese race had 2.1 times greater risk of developing lymphoma than non-Chinese race, but race was not significantly associated with incidence of lymphoma statistically. The results of this research were in line with the previous research which stated that in the continent of Asia, the race that had a high risk of cancer was the Chinese race. That is because in Chinese patients it is found that many of them were infected with Epstein-Barr virus and Human T-cell leukemia / lymphoma virus type 1 (HTLV-1) which are one of the infectious causes of lymphoma
(4)

Table 2 shows that most respondents who suffered from lymphoma (7.4%) had a family history of cancer, whereas the respondents who did not have lymphoma (67.0%) did not have a family history of cancer. Chi-square test results prevailed that the family cancer history variable had a p-value = 0.012 with OR, 95% CI (5.4; 1.44-20.34). The analysis results showed that people who had a history of family cancer risk were 5.4 times more likely to have lymphoma than those not having a family history of cancer. Statistically, a family history of cancer was also significantly associated with incidence of lymphoma.

Genetic factors or family history of cancer may increase the risk of developing lymphoma, but the increased risk is also influenced by exposure to chemicals or materials that are carcinogenic. That is because there is a gene (DNA) derived by certain parents who can be a cancer trigger in the offspring
(7)

. People who have an

inherited immune disorder from their parents are at risk of suffering from lymphoma. This risk will increase if the person is also exposed to carcinogenic materials on a continuous basis, either through work, lifestyle, and diet which are a predisposing factor in people who have a genetic abnormality in the immune system. But until now there have still been no studies that examine what genes are found in patients with lymphoma
(12)

. History of previous illness has an influence on the occurrence of lymphoma,

especially diseases associated with decreased immunity or disruption of the immune system in acute and chronic. Based on Table 2, the majority of respondents who suffered from lymphoma (8.2%) had a history of illness, whereas the respondents who did not suffer from lymphoma were known mostly (71.1%) without history of illness. Chi-square test results prevailed that the variable of the history of the disease had a pvalue = 0.001 with OR, 95% CI (10.8; 2.59-45.19). The analysis results showed that people who had a history of illness (Diabetes Mellitus, HIV / AIDS, Hepatitis C and Rheumatoid arthritis, as well as other types of cancer) had a risk 10.8 times likely to suffer from lymphoma than those with no history of illness. Statistically, the history of illness was also related significantly to the incidence of lymphoma. Diabetes Mellitus Patients who routinely take insulin are at increased risk of developing lymphoma. The risk is also influenced by genetic (family history of cancer), environmental, and infectious agent factors. Diabetes Mellitus Patients also often experience complications resulting in physiology function that they cannot work optimally which often causes to be infected with multiple diseases
(5).

Patients with

Hepatitis C virus has the risk of suffering from this disease due to chronic infection caused by a virus that can cause changes in B cells, causing mutations and B cells become malignant and proliferate uncontrollably (13-16). Rheumatoid arthritis is a disease associated with the incidence of lymphoma. It is linked to the impact or side effects of Methoxtrexate (MTX) and Anti-Tumor Necrosis Factor (Anti-TNF) therapy often given to patients with Rheumatoid arthritis

(Wolfe and Michaud, 2004). In congenital immunodeficiency, it is known that the immune system of patients with the disease is not able to fight viral and bacterial pathogens in the respiratory and digestions that cause the immune system disorders continuously which can cause mutations in B cells
(12)

. In people with HIV/AIDS, the

immune system has a significant reduction. Eighty-two percent of HIV / AIDS patients suffer from lymphoma . Therefore, the diagnosis in patients with lymphoma should also be conducted along with tests to determine HIV infection
(17)

. Chronic diseases

associated with immune system can reduce lymphokine and lower natural killer cell activity (NK). It triggers B cells mutation to become malignant and proliferate uncontrollably (18-19). Table 2 describes the respondents who suffered from lymphoma who were exposed more to chemicals (pesticides), as well as those who were not suffering from lymphoma. Chi-square test results prevailed that the variable of exposure to chemicals (pesticides) had a p-value = 0.021 with OR, 95% CI (9.1; 1.12-74.31). The analysis results showed that people exposed to chemicals (pesticides) had a 9.1 times greater risk of suffering from lymphoma than those not exposed to chemicals (pesticides). Statistically, exposure to chemicals (pesticides) was significantly associated with the incidence of lymphoma. Exposure to chemicals such as pesticides, especially those containing 2.4dichlorophenoxyacetic acid, hexachlorocyclohexane and benzene can increase the risk of lymphoma
(20-22)

. Pesticides can enter the human body through various routes,

including through the skin, respiratory system and digestive system. Pesticide residues pose an indirect effect on humans, but in the long run lead to health problems including neurological disorders and metabolic enzymes (23). Chemicals from the content of pesticides can poison the body cells or affect specific organs that may be related to the nature of the chemical or chemicals associated with a place to enter the body or also known as target organs
(24)

. Pesticides contain

carcinogenic; the carcinogenic substances can cause or increase the risk of cancer because exposure to chemicals continuously for long periods can lead to mutations (changes) of genes (DNA) from cells of the body so that it continues to develop into abnormal proliferation uncontrollably. The mechanism of the effect of pesticides on the body is through two stages, namely the pharmacokinetics and pharmacodynamics. Thus,

10

in work or activities with the use of pesticides, preferably one uses Self Protective Equipment (PPE) which consists of work clothes, mask (goggles or face shield), hat, gloves, and boots (25). Multivariable Analysis The independent variables included to logistic regression test were those that had a p-value <0.25. The results of the bivariable analysis using chi-square test included gender, family cancer history, history of illness and exposure to chemicals (pesticides). Selection of the best logistic regression model was performed with backward LR method. The results of logistic regression test analysis with backward LR method produced some value at each stage, namely: a. Value for goodness of fit test 0.128 means that logistic regression model was proper to be used for further analysis, since there was no real difference between the predicted classification and the observed classifications. b. The coefficient value of Negelkerke determination indicated that 4 predictors in step 1 were able to explain 45.3% of the total diversity of the response variable. In step 2 they could explain 44.4%. This means that the regression model for the coefficient determination was good enough to predict the incidence of lymphoma. c. Assessment of the feasibility of regression model in predicting performed used Chisquare test of Hosmer and Lameshow. Hosmer and Lameshow value presented a significance value of 0.01 in step 1 and of 0.214 in step 2. Hosmer and Lameshow value in step 2 was greater than the p-value of 0.05, so that Ho was accepted, or in other words, the estimated model was in accordance with the actual data used. d. Percentage of the overall value of each step was in the range of 91.8%. The high overall percentage value indicated that the accuracy of prediction had been very good to use to predict the incidence of lymphoma at Dr. Soebandi Hospital, Jember. e. Significance value of the multivariable analysis results (regression test with LR backward method) revealed that there were 3 variables related significantly to the incidence of lymphoma at Dr. Soebandi Hospital, Jember, namely family history of cancer, history of illness, and exposure to chemicals (pesticides). Based on the results of multivariable analysis (logistic regression test with LR backward method), there were three variables that had a significant relationship

11

(statistically significant) on the incidence of lymphoma, namely family history of cancer, history of illness, and exposure to chemicals (pesticides). It was based on the pvalue of the 3 variables that was less than = 0.05. The variable having the most powerful relationship to the incidence of lymphoma was a history of illnesses suffered by the respondents. Here were alternative models generated from multivariable analysis:

In logistic regression, the value of E(Y/X) would always be between zero and one (0 E (Y / X) 1). Constant value of 0.962 stated that if there was no family history of cancer, no history of illness and no exposure to chemicals (pesticides), the incidence of lymphoma was 0.32%. It can be seen from the following calculation:

The logistic regression model alternative could be used to predict the likelihood of a person or a respondent to suffer from lymphoma based on the most influential factors, namely family history of cancer, history of illness, and exposure to chemicals (pesticides) by entering a code categorization of each variable to in the logistic regression model as follows:

Some respondents probably had lymphoma: a. Likelihood of the respondents to suffer from lymphoma occurred if there were a family history of cancer, a history of illness, but no exposure to pesticides. Family history of cancer = 1, illness history = 1, and exposure to pesticides = 0

The possibility or chance of suffering from lymphoma that occurred if they had a family history of cancer, a history of illness, but no exposure to pesticides was 4.3%. b. Likelihood of the respondents to suffer from lymphoma occurred if there were no family history of cancer, a history of illness, and no exposure to pesticides. Family history of cancer = 0, illness history = 1, and exposure to pesticides = 0

12

The possibility or chance of suffering from lymphoma that occurred if the respondents did not have a family history of cancer, a history of illness, and no exposure to pesticides was 28%. c. Likelihood of respondents to suffer from lymphoma occurred if there were a family history of cancer, no history of illness, and exposure to pesticides. Family history of cancer = 1, illness history = 0, and exposure to pesticides = 1

The possibility or chance of suffering from lymphoma that occurred if the respondents had a family history of cancer, no history of illness, and exposure to pesticides was 2.1%. d. Likelihood of the respondents to suffer from lymphoma occurred if there were no family history of cancer, a history of illness, and exposure to pesticides. Family history of cancer = 0, illness history = 1, and exposure to pesticides = 1

The possibility or chance of suffering from lymphoma

that occurred if the

respondents did not have a family history of cancer, had a history of the disease, and had exposure to pesticides was 2.6%. e. Likelihood of the respondents to suffer from lymphoma occurred if there were no family history of cancer, no history of illness, and exposure to pesticides. Family history of cancer = 0, illness history = 0, and exposure to pesticides = 1

The possibility or chance of suffering from lymphoma

that occurred if the

respondents did not have a family history of cancer, history of illness, and had exposure to pesticides was 15.5%. f. Likelihood of the respondents to suffer from lymphoma occurred if there were a family history of cancer, no history of illness, and no exposure to pesticides. Family history of cancer = 1, illness history = 0, and exposure to pesticides = 0

13

The possibility or chance of suffering from lymphoma that occurred if the respondents had a family history of cancer, no history of illness, and no exposure to pesticides was 23.6%. g. Likelihood of the respondents to suffer from lymphoma occurred if there were a family history of cancer, a history of illness, and exposure to pesticides. Family history of cancer = 1, illness history = 1, and exposure to pesticides = 1

The possibility or chance of suffering from lymphoma that occurred if the respondents had a family history of cancer, a history of illness, and exposure to pesticides was 72.4%. The logistic regression model alternative could be used to predict the likelihood of a person or a respondent to suffer from lymphoma based on the factors having the most powerful relationship, namely family history of cancer, history of previous illness, and exposure to chemicals (pesticides). Conclusion Based on the results of data analysis and discussion, it can be concluded as follows: 1) There was a significant relationship between gender, family history of cancer, illness history, and exposure to pesticide and the incidence of lymphoma, but it did not happen for the variables of age and race, 2) Factors that could predict the incidence of lymphoma were a family history of cancer, history of illness, and exposure to chemicals (pesticides). Recommendation There is a need for increasing cooperation across sectors including hospitals, Indonesia Cancer Foundation, health office, Ministry of Agriculture and the business industry in developing prevention programs and reducing cancer incidence through increased use of personal protective equipment from exposure to chemicals primarily in people who have a history of cancer in their family and have a history of illness in their immune system.

14

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