Prognostic Analysis of Schistosomal Rectal Cancer

Colorectal cancer (CRC) is the fourth most common carcinoma in China, and the morbidity was increasing rapidly (Gu et al., 2013). Similar situation also appeared in other countries (Greene, 2007). No single risk factor accounted for most cases of colorectal cancer. Many risk factors had been identified and established in epidemiological studies: family history of colorectal cancer, inflammatory bowel disease, smoking, excessive alcohol consumption, high consumption of red and processed meat (Brenner, 2014). And some evidence suggested that infection with Helicobacter pylori, Fusobacterium, and other potential infectious agents might be associated with an increased risk of colorectal cancer (McCoy et al., 2013; Inoue et al., 2014). Schistosomiasis was an infectious disease that affected more than 230 million people worldwide, according to conservative estimates (Vos et al., 2012). Three main species of schistosomes infected human beings, Schistosoma haematobium, Schistosoma mansoni, and Schistosoma japonicum. S japonicum was located to Asia, primarily the China and Philippines (Colley et al., 2014). By the end of 2010, approximately 65 million individuals in China were at risk of infection and 325, 824 cases were diagnosed as schistosomiasis (Liao et al., 2013). Schistosomiasis was considered closely related with the development of malignancy in the bladder (Zaghloul,


Prognostic Analysis of Schistosomal Rectal Cancer
Meng Wang, Yuan-Chuan Zhang, Xu-Yang Yang, Zi-Qiang Wang* 2012), rectum (Matsuda et al., 1999). Some studies published from China (Xu and Su, 1984) and Japan (Ishii et al., 1994) reported that schistosomiasis was a risk factor for colorectal cancer in Asia where the infective species was S. japonicum. One study had reported that there were more substitution mutations at CpG dinucleotides in schistosomal rectal cancer than in non-schistosomal rectal cancer (Zhang et al., 1998). But few studies reported the prognosis of patients with schistosomal rectal cancer.
Total mesorectal excision operation technology (TME) had significantly improved disease-free survival (DFS) and overall survival (OS) for patients with rectal cancer (How et al., 2011). Chemotherapy which was primarily based on 5-fluoruracil had decreased the recurrence of tumour on American Joint Cancer Committee (AJCC) Stage III patients (Cihan et al., 2011). This study aimed to analyze the difference of prognosis between schistosomal rectal cancer (SRC) and non-schistosomal rectal cancer (NSRC) in current treatment.

Patients and pretreatment evaluation
In 2009, a total of 33 consecutive schistosomal rectal cancer patients underwent curative surgery. Among them, 3 patients were lost to follow-up and were excluded from this study. A retrospective review of 30 patients with schistosomal rectal cancer who underwent laparoscopic TME was performed. Clinical information was collected from the database of the West China Hospital of Sichuan University, Chengdu, China. This project was registered with the Institutional Ethics Committee of West China Hospital, Sichuan University.
For each patient with schistosomal rectal cancer, a control group of 30 patients with non-schistosomal rectal cancer who underwent laparoscopic TME was matched for age, gender and tumor stage, resulting in 60 cases and controls.
To establish the diagnosis and determine staging, patients underwent digital rectal examination, complete blood cell count, liver function analysis, serum carcinoembryonic antigen, colonoscopy with biopsy, magnetic resonance imaging of the pelvis, computed tomography (CT) of the abdomen and chest. Bone scan, and F-18 deoxyfluoroglucose positron emission tomography were performed when required.

Treatment
All patients underwent laparoscopic TME by one colorectal surgeon who was experienced in colorectal and laparoscopic advanced surgery. All of operations followed the principle: adequate resection margins, en bloc high ligation of the inferior mesenteric artery (IMA) and lymphadenectomy. All circumferential margins were cleared. The number of positive lymph nodes and total number of retrieved lymph nodes were recorded. The pathologic stage was determined according to the seventh edition of the American Joint Committee on Cancer (AJCC) staging manual.

Follow-up and response evaluation
Patients were followed up every 3 months for first 2 years, every 6 months for the next 3 years. The examinations included complete blood cell count, liver function analysis, CEA levels, abdominal ultrasound, interval imaging and colonoscopic examinations. CT of chest, CT or MRI of abdominal and pelvic part, were performed annually.
We defined the local recurrence as the recurrent disease in the pelvis. The distant recurrence was defined as the recurrence outside the pelvis. The enteroscope was performed for biopsy when it was required. Disease-free survival (DFS) was the time from the surgery to the local or distant failure. Overall survival (OS) was calculated from surgery to death induced by all causes or end of follow up.

Statistical analysis
Present study was a retrospective case-control study and the case-to-control ratio was 1:1. The chi-square test or t-test was used for comparison of two groups. Kaplan-Meier method was used to draw the survival curves. Survival of all patients was analyzed by each variable: age, gender, smoking, drinking, obesity, pathologic TNM stage, pathologic T stage, pathologic N stage, tumor with/ without schistosome, CEA, tumor location (Distance from anal verge), tumor size, lymphovascular invasion. The comparison of the survival curves was performed by log-rank test. A multivariable Cox regression analysis was performed to identify predictive factors of DFS and OS. Every variable was analyzed by univariate analysis, in order to cover all potentially important predictors, then variables with P≤0.10 in univariate analysis were included in multivariable analysis. Statistical analysis was performed by SPSS version 21. Statistical significance was stated as two tailed P<0.05.

Demographic data
The study included 60 patients including 36 males and 24 females. The mean age at diagnosis was 63.67 (41-85) years for all patients, 63.87 (45-85) years for the SRC group, and 63.47 (41-81) years for the NSRC group. Males constituted 57% of the patients in both groups. Some risk factors accounts for most cases of colorectal cancer such as smoking, drinking and obesity were also analyzed (Brenner, 2014). In this analysis, we defined obesity as BMI greater than or equal to 25. And they were summarized in Table 1.

Clinical characteristics of the tumor
The mean size of tumor was 4.27cm for SRC versus There were no significant difference of the pT and pN classification between two groups (P=0.933&0.624). The two groups were same in terms of the TNM stage: 3 patients were classified Ⅰ, 9ⅡB, 1 ⅢA, 15 ⅢB and 2 ⅢC, respectively. The details were showed in Table 1.

Survival analysis
Median follow-up duration was 49.8 months (range 10 to 66 months). The 4-year DFS rate in SRC and NSRC group were 46.7±9.1% and 70.0±8.4% (P=0.057). The 4-year OS rate in SRC and NSRC group were 63.3±8.8%   and 86.7±6.2% (P=0.026). The DFS and OS curves according two groups were showed in Figure 1 and 2, respectively. Univariate analysis was performed in the whole 60 patients. It showed pathologic N stage (P=0.006) and pathologic TNM stage (P=0.024) were statistically significantly correlated with DFS. Pathologic N stage (P=0.014), pathologic TNM stage (P=0.002), and with/ without schistosomiasis (P=0.026) were statistically significantly correlated with OS. The details were showed in Table 2.
Then, multivariate analysis was performed to assess the prognostic value of factors with P<0.10 in univariate analysis for DFS and OS. Smoking, drinking, obesity and other factors were not included in multivariate analysis. The results were showed in Table 3. Factors of schistosomiasis, pathologic N stage and pathologic TNM stage were included in multivariate analysis for both DFS and OS. Pathologic T stage was also included in OS for P<0.10 in univariate analysis. Multivariate analysis showed schistosomiasis was only independent prognostic factor for both DFS (P=0.007) and OS (P=0.006)

Discussion
Schistosomiasis was an ancient human disease with effects worldwide, particularly in the poorest communities. Research on schistosomal rectal cancer had progressed very fast in recent years. Mariana et al. reported the first case of signet ring cell carcinoma of the rectum occurring in the context of chronic infection by S japonicum (Canepa et al., 2012). Wei Liu et al. reported that history of colonic schistosomiasis was a probable independent risk factor for the development of colorectal neoplasias. Renli Zhang et al. reported that there were more substitution mutations at CpG dinucleotides in schistosomal rectal cancer than in non-schistosomal rectal cancer (Zhang et al., 1998). However, few studies reported the prognosis of patients with schistosomal rectal cancer.
In this report, we matched SRC and NSRC patients for age, gender, and pTNM stage of disease. Moreover, we also found that patients in two groups were similar in terms of tumor location (distance from anal verge), pathologic T stage, pathologic N stage and CEA level. However, we noted that the tumor size of SRC was larger than NSRC. In this analysis, there were no patients with signet-ring adenocarcinoma or mucinous adenocarcinoma. All tumors were adenocarcinoma. One article reported the first case of signet ring cell carcinoma of the rectum occurring in the context of chronic infection by S japonicum (Canepa et al., 2012). Abe and co-workers reported a patient with a sessile polyp in the rectum, further histological evaluation revealed a hyperplastic polyp and calcified Schistosoma eggs in the submucosa (Abe et al., 2006). Liu et al. reported one mucinous adenocarcinoma caused by colonic schistosomiasis (Liu et al., 2013).
To evaluate the prognosis of the patients with SRC, univariate and multivariate analysis were applied in this study. Schistosomiasis was the only independent prognostic factor for both DFS and OS in multivariate analysis. Zhang et al. tested patterns of p53 mutations in SRC on the assumption that schistosomiasis japonica might affect carcinogenesis in the colon and rectum. They found that there were more substitution mutations at CpG dinucleotides in SRC than in NSRC (Zhang et al., 1998).
It was probably the cause of poor prognosis in patients with SRC.
Unlike other cancers, such as lung cancer, no single risk factor accounted for most cases of rectal cancer. Apart from age and male sex, the following risk factors had been identified and established in epidemiological studies: Smoking, drinking, obesity and so on. But they were not statistically significantly correlated with DFS and OS in this study. Maybe the reason was the sample size was too small.
There were some effective drugs against Schistosoma. Praziquantel was one of choices for schistosomiasis (Colley et al., 2014). But it was uncertain that patients could benefit from the use of drugs against Schistosoma before or after the operation. There were no specific treatment programs for patient with schistosomal rectal cancer. In this study, TNM stage was a most important indicator for making treatment plan.
This study was different from previous ones. Firstly, previous studies had focused on the epidemiological and clinicopathological characteristics of patients with SRC. Xu et al. reported an epidemiological study about schistosoma japonicum and colorectal cancer in China (Xu et al., 1984). Liu et al. described clinicopathological characteristics of colonic schistosomiasis based on endoscopic findings (Liu et al., 2013). This study reported the poor prognosis of patients with SRC in current treatment. Secondly, multivariate analysis was performed in this study. So this conclusion was more persuasive. In addition, we matched patients for age, gender, and TNM stage of disease at presentation. Moreover, patients in two groups were similar in clinicopathological characteristics (tumor location, pathologic T stage, pathologic N stage and CEA level), which added the consistency of the baseline and comparability between groups. It made the survival analysis result more meaningful.
Soliman et al. reported that intestinal schistosomiasis should be considered as a precancerous condition for development of colonic dysplasia and cancer as a consequence of chronic inflammation that altered inflammatory, antioxidant and fucosylation status associated schistosomiasis (Soliman et al., 2014). Liu et al. described clinicopathological characteristics of colonic schistosomiasis based on endoscopic findings (Liu et al., 2013). This study concluded that the prognosis of patients with SRC was poorer than NSRC. The present study had shortcomings of a retrospective analysis with small sample size, further studies were required to confirm the conclusion by larger sample size and make specific therapeutic program for patients with Schistosomiasisrelated rectal carcinoma.
In conclusion, the prognosis of patients with SRC was poorer than NSRC. Larger studies in patients with SRC with matching for stage and grade were warranted to examine the impact of schistosomiasis on survival.