Comparison of non-schistosomal colorectal cancer and schistosomal colorectal cancer

doi:10.21203/rs.3.rs-16007/v1

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Comparison of non-schistosomal colorectal cancer and schistosomal colorectal cancer

https://doi.org/10.21203/rs.3.rs-16007/v1

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published 01 Jul, 2020

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Aim The purpose of this study was to compare clinicopathological features of patients with non-schistosomal and schistosomal colorectal cancer to explore the prognostic role of schistosoma infection in colorectal cancer(CRC). Methods 354 cases of CRC were retrospectively analyzed in a tissue microarray format. Survival curves were constructed by using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazard regression models were performed to identify associations with outcome variables. Results Patients with schistosomiasis (CRC-S) were significantly older ( P <0.001) and were mostly in stage III and IV tumors ( P <0.001) than patients without schistosomiasis (CRC-NS). However, there were no significant difference between CRC-S and CRC-NS patients in other clinicopathological features. Overall, CRC-S patients were associated with adverse overall survival upon K-M analysis ( P =0.0239). By univariate and multivariate analysis, CRC-S patients were significantly correlated with OS ( P =0.041), but it was not an independent prognostic factor. In addition, age( P =0.013), gender ( P =0.008), tumor differentiation ( P =0.018) and invasive depth ( P =0.013) were all independent predictors. When patients were stratified according to clinical stage and lymph node metastasis state, the prognostic role was not consistent. In patients with stage III-IV tumors and with lymph node metastasis, schistosomiasis, gender and invasive depth were independent predictors, but not in patients with stage I-II tumors and in patients without lymph node metastasis. Conclusion Schistosomiasis is an unfavorable factor for OS and could be considered to refine risk stratification and provide better risk-oriented treatment for CRC patients with different clinical stage or lymph node metastasis state.

Oncology

colorectal cancer

S. japonicum

schistosomiasis

prognosis.

Growing evidences have emerged in recent decades that inflammation is the root of many malignant tumors^1,2. As the fourth most common cancer and the second leading cause of cancer deaths in the world³, colorectal cancer(CRC) represents a growing number of cancers that correlated with inflammation^1,4,5. Schistosoma japonicum (S. japonicum) which is common in Southeast Asia⁶, is regarded as a risk factor of CRC development. Schistosomal infestation has been implicated in the aetiology of several human malignancies including bladder, liver, and colorectal cancer (CRC)⁷. The prevalent view is that the sequestered eggs in the mucosa and submucosa incite a severe inflammatory reaction with cellular infiltration and consequent granuloma formation. This in turn leads to mucosal ulceration, microabscess formation, polyposis, and neoplastic transformation⁸. But the causal relationship between S. japonicum and CRC still remained controversial⁹. Some case reports and descriptive studies from Africa and the Middle East raised the possibility of an association between S. japonicum infestation and induction of CRC^10-12. Nonetheless, the pathological evidence supporting this conclusion is rather weak. While some research demonstrated that S. japonicum infestation was unrelated with CRC¹³.

In the 1950s, schistosomiasis was epidemic at a large scale in regions along the Yangtze River and in more than 400 counties in South China¹⁴ . Because of the effective prevention and cure measures taken in China in recent years, schistosomiasis has been eliminated in most epidemic regions. However, its spread is not yet completely controlled and schistosomiasis occurs every year in a small number of people in the epidemic regions of China¹⁵. Qingpu District of Shanghai used to be one of the 10 areas with serious schistosomiasis epidemic in China¹⁶, and problems of treatment and outcome of a large number of late schistosomiasis patients left over from history are still remaining. Therefore, detailed knowledge about schistosomiasis is necessary to improve the accuracy of clinical prognosis prediction and will shed light on improving our ability to prevention and control of schistosomiasis.

In the present study, we made a retrospective analysis of schistosomiasis and clinicopathologic characteristics in 138 schistosomiasis CRC patients (CRC-S) and 216 patients without schistosomiasis (CRC-NS) using tissue microarrays to investigate the probable prognosis role of chronic schistosomal infestation in CRC.

Patients and samples

354 colorectal cancer patients who underwent surgical resection from Qingpu Branch of Zhongshan Hospital affiliated to Fudan University, from January 2008 to August 2016 were included in this study: 138 schistosomal CRC (CRC-S) patients and 216 patients without schistosomiasis (CRC-NS) . None of them received preoperative chemotherapy or radiation therapy. Clinical follow-up data and clinicopathological characteristics such as age, gender, tumor site, clinical stage (TNM stage) were included. Two expert pathologists reviewed HE-stained slides to determine the diagnosis and to restage the tumors according to the eighth edition of American Joint Committee on Cancer (AJCC).

Ethics statement

This study was approved by the medical ethics committee of Fudan University (Ethical approval number 2019-017), in accordance with the Helsinki Declaration of 1975. Prior written informed consent was obtained from all patients.

Tissue microarrays (TMAs)

The TMA blocks were manufactured from the most representative areas of individual paraffin blocks, as previously described¹⁷. Briefly, reviewed HE-stained slides and marked the represented areas in tumor tissues, and the single core (2 mm wide and 6 mm long) for each case was precisely arrayed in to a new recipient paraffin block. The cores containing more than 20% tumor cells were considered as valid cores.

Detection of schistosome ova

Schistosome ova were observed in HE-stained formalin fixed paraffin-embedded (FFPE) sections, which were examined at ×10 and ×40 magnification fields using a conventional light microscope by two pathologists who were blind to clinic data. The diagnosis of schistosomiasis was done by finding schistosome eggs in HE-stained slides.

Statistical analysis

The association between schistosomiasis and clinicopathological characteristics was evaluated by using the Chi square and Fisher’s exact tests. Overall survival (OS) was defined as the time of surgery to death. Kaplan-Meier curves with log-rank tests were used to determine the prognostic significance for OS. Univariate and multivariate regression analyses were used to identify independent prognostic factors, and P < 0.05 was defined as the criterion for variable deletion when performing backward stepwise selection. Statistical analyses were performed using SPSS 22.0 (SPSS Inc, Chicago, IL).

Clinical characteristics in full cohort

A total of 354 surgically resected FFPE primary CRC sampled in TMAs could be assessed. The clinical and pathologic features of the study cohort are summarized in Table 1. Briefly, age of patients at diagnosis ranged from 33 to 91 years (median, 69 years) and were predominantly male (60.2%, 213 out of 354). By anatomic site, 27% tumors were in the rectum, 73% in colon. Lymph node metastasis were observed in 41% of patients and 94% of them were at late stage disease. While patients without lymph node metastasis were mostly (91%) at early stage tumor. On the basis of the AJCC Staging Manual (seventh edition), 76% cases were histologically graded as well to moderately differentiated, and 24% were poorly differentiated. Among these patients, 68 (19%) patients had AJCC pathologic stage Ⅰ disease, and 36% stage Ⅱ disease, and 39% stage Ⅲ disease, and 6% stage Ⅳ disease.

Survival analyses

The median follow-up times was 62.4 (0.4-134.4) months. During the follow up, there was 41.8% (148 out of 354) patients died. Mean and median times to overall survival were 62.63 and 62.49, respectively.

To investigate the prognostic value between schistosomiasis and clinical outcomes, we conducted Kaplan-Meier analysis according to schistosoma infection status. Log-rank test was used to compare survival between subgroups. Result demonstrated that schistosoma infection was significantly associated with poor survival in total colorectal cancer patients (median survival time: 89.98 for CRC-NS set; 75.28 for CRC-S set. P=0.0239) (Figure 1B).

Further analysis was conducted to explore the prognostic significance of schistosoma infection status in patients with similar stage tumors. In stage Ⅰ-Ⅱ set (N=193), a Kaplan-Meier (K-M) curve was plotted and found that schistosoma infection was uncorrelated with survival (P=0.4029) (Figure 2A). Nevertheless, in stage Ⅲ-Ⅳ set (N=161), K-M analysis showed significant correlation between schistosoma infection and OS (P=0.0135) (Figure 2B).

In patients with lymph node metastasis (N=146), schistosoma infection was observed in 38% (56 out of 146) CRC patients and associated with poor survival (P=0.0234) (Figure 2C). In contrast, there was no statistically significant difference observed in OS between CRC-S and CRC-NS patients without lymph node metastasis (P=0.3202) (Figure 2D).

Univariate and multivariate analysis

The Cox proportional hazards model was used to determine factors that may influence OS. In the whole cohort, by univariate analysis and multivariate analysis (Table 2), age (P=0.013), gender (P=0.008), invasive depth (P=0.013), TNM stage (P＜0.001) and tumor differentiation (P=0.018) were significantly independent predictors. Schistosomiasis was statistically significant for OS in the univariate analysis but it was not statistically significant in multivariate analysis (Table 2).

In late-stage (Ⅲ-Ⅳ) CRC patients(Table 2), schistosoma infection (P=0.010) , gender (P=0.029), invasive depth (P=0.07) and differentiation (P=0.008) were significantly independent prognostic factor for OS. While in early-stage (Ⅰ-Ⅱ), age (P=0.005) and invasive depth (P=0.011) were significantly independent predictors.

In patients with lymph node metastasis (Table 2), gender (P=0.024), invasive depth (P=0.012) and schistosoma infection (P =0.025) were independently prognostic factors. However, schistosoma infection was not associated with OS in patients without lymph node metastasis (Table 2 and Figure 2D). These results further proved that schistosoma infection may have different prognostic implications in colorectal cancer, especially for patients with stage Ⅲ-Ⅳ tumor and patients with lymph node metastasis.

Association of schistosomiasis with clinicopathological features

In the whole cohort, 39.0% (138 out of 354) were infected with schistosoma (Figure 1A). The relationship between schistosomiasis and clinicopathological features was shown in Table 3. Patients with schistosomiasis were significantly older than the patients without schistosomiasis (median age: 74.0 years vs 64.5 years, p＜0.001). CRC-S patients were more frequently at stage Ⅲ or Ⅳ (p＜0.001). The male/female ratio was also higher in CRC-S set (1.65 vs 1.42). There were no significant differences of other clinicopathological characteristics such as tumor location, tumor size, tumor differentiation, invasive depth and lymph node metastasis between CRC-NS and CRC-S set.

In order to further investigate the effect of schistosomiasis on particular CRC population, we divided the whole cohort into different groups according to their clinical stage or the state of lymph node metastasis and further subgrouped into CRC-S and CRC-NS set based on schistosomiasis. Except age and clinical stage, there were no correlation between other clinicopathological features and schistosomiasis when compared between CRC-NS and CRC-S sets in different subgroups(Table 3).

Schistosomiasis results from the host’s immune response to schistosome eggs and the granulomatous reaction evoked by the antigens they secrete¹⁸, and the process of granulomas formation will be accompanied by chronic inflammation^19,20, which may induces the development of tumor. At present, there are sufficient evidence to conclude that S. haematobium has a role in causing some types of bladder cancer^21,22 and hepatocellular carcinoma^6,8. There is limited evidence suggesting that S. japonicum is possibly carcinogenic to humans leading to colorectal cancer.

In this study, results demonstrated that schistosomiasis was an unfavorable factor for OS (p=0.0239, Fig.1B; p=0.041,Table 2). These results indicate that schistosomiasis play an important role in CRC progression and metastases. Shindo²³ reviewed 276 cases of large intestine cancer with schistosomiasis and found significant differences between carcinoma with schistosomiasis and ordinary carcinoma in symptoms, age, sex and histological findings, suggesting that schistosomiasis could induces the carcinoma. Ye et al.²⁴ reported that intestinal schistosomiasis was a risk factor for colorectal cancer and that the lesions caused by the disease might be considered precancerous. Liu et al.²⁵ reported that the history of colon schistosomiasis was a probable risk factor for the development of colorectal neoplasia, but only a few studies reported the clinicopathological characteristics and prognosis of patients with schistosomal colorectal cancer. This may be explained by reasons as follow. Firstly, there is little relevant clinical data in the medical literature, mostly limited to case reports, physicians know little about it²⁶^,²⁷. Secondly, since samples of schistosomiasis patients is too difficult to obtain, leading to small sample size and bias in data analysis.

Previous reports revealed that the development of CRC-S occurs in younger age group^28,29. It was opposite with our results. This might be explained by the reasons as follow. First, since effective prevention and control measures taken in China in 1983, the infection rate has decreased magnificently, which result in CRC-NS patients was in large quantity and relatively younger. Second, this disparity may be related to differences in hereditary factors, environmental carcinogens and so on. Our results showed that there is also a male predominance(about 60%, Table 1) in the cohort, although there was no significant difference between CRC-NS and CRC-S patients. This is because more males engage in farm work, and they may be at greater risk for exposure.

Patients with schistosomiasis were predominantly in late stage, which is in accordance with earlier studies^22,30. This could highlight the potential worse effect on the development of CRC. Schistosomiasis was statistically significant for OS in the univariate analysis in the present study but it was not statistically significant in multivariate analysis. However, when patients were stratified based on clinical stage or state of lymph node metastasis, schistosomiasis was a significantly independent predictor in patients with stage Ⅲ-Ⅳ tumor or with lymph node metastasis, but not in patients with Ⅰ-Ⅱ stage tumors or without lymph node metastasis. This suggested schistosomal infestation may exert effect on the invasion and metastasis of CRC after excluding interference factors. This hypothesis is supported by our observation that schistosomiasis is significantly associated with TNM stage(Table 3). Namely, the prognostic significance of schistosoma infection status was conditioned, only limited in specific CRC population, not in all CRC patients. Furthermore, our observation indicated that schistosomiasis maybe a considerable risk of in different CRC patients, which may bright up the debate that schistosomiasis is a weak risk of colorectal cancer^5,31,32.

Our study had several limitations. First, because it was performed at a single institution, the university of the results may be low. Further work will be needed to validate present results. Second, patient selection bias was a possibility due to the nature of the retrospective study. Third, although we found a negative correlation between schistosomiasis and colorectal cancer outcomes, the precise functional roles of schistosomiasis in colorectal cancer progression and its underlying molecular mechanisms remain obscure. Chen et al. observed variable degree of colonic epithelial dysplasia in 60% of cases with S. japonicum colitis and regarded these changes as the transition on the way towards cancer development in schistosomal colonic disease³³. A similar conclusion was drawn by Yu et al. from their studies on different types of schistosomal egg polyps³¹. All these results suggested the pro-tumor mechanisms of S. japonicum in tumor tissues. Therefore, further analysis about the functional roles of schistosoma infection and underlying molecular mechanisms need to be investigated.

In conclusion, our observations support the prognostic roles of schistosomiasis and in particular, CRC patients with stage Ⅲ-Ⅳ tumors and with lymph node metastasis in predicting patients` overall survival.

colorectal cancer=CRC; colorectal cancer patients with schistosomiasis =CRC-S; patients without schistosomiasis=CRC-NS; Schistosoma japonicum=S. japonicum; American Joint Committee on Cancer =AJCC; Tissue microarrays =TMAs; formalin fixed paraffin-embedded (FFPE); Overall survival =OS;

Conflict of interest: The authors declare that they have no competing interests.

Financial support:

This work is supported by China Shanghai Municipal Commission of Health and Family Planning(Grant No. 20194Y0162).

Authors’ contributions

Kui Lu, Limei Wang and Hongyan Jing contributed to the research design, data analysis, and manuscript writing. Weiyu Pan, Sinian Huang, Yanchao Xu, Dacheng Bu, Meihong Cheng, Jing Liu, Jican Liu, Weidong Shen, Yingyi Zhang and Junxia Yao contributed to the data collection and perform experiments. Ting Zhu and Weixia Wang contributed to the data analysis and manuscript editing. All authors read and approved the final manuscript.

Acknowledgements: None

Availability of data and materials:

The datasets used and/or analyzed during the current study are available from the corresponding authors on reasonable request.

Consent for publication:

Written informed consent was obtained from each participant

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Table 1: Clinicopathological characteristics of the CRC cohort
Characteristics	All patients (N=354)		Patients with stageⅠ-Ⅱ disease (N=193)		Patients with stage Ⅲ-Ⅳ disease(N=161)		Patients with LNM (N=145)		Patients without LNM (N=209)
	N	%	N	%	N	%	N	%	N	%
Age(＜60ys)	127	36	46	24	37	23	34	23	49	23
Gender(Male)	213	60	118	61	95	59	90	62	123	57
Tumor location
Rectum	95	27	50	26	45	28	38	26	57	27
Colon	259	73	143	74	116	72	107	74	152	73
Tumor size(＜5cm)	174	49	94	49	80	49.7	71	49	103	48
Differentiation
Well diff.	270	76	166	86	104	65	94	65	173	82
Poor diff.	84	24	27	14	57	35	51	35	36	18
Invasive depth
I+ II	80	23	65	34	15	9	14	10	63	31
III	274	77	128	66	146	91	131	90	146	69
LNM
No	209	59	190	98	19	12	----	----	----	----
Yes	145	41	3	2	142	88	----	----	----	----
TNM stage
I	68	19	----	----	----	----	2	1	66	31
II	126	36	----	----	----	----	7	5	126	60
III	138	39	----	----	----	----	122	84	9	5
IV	22	6	----	----	----	----	14	10	8	4
schistosomiasis	138	39	77	40	61	38	56	39	82	39
----:Data is not applicable; Abbreviation: N=Number ; LNM=Lymph node metastasis.

	Table2. Univariate and multivariate Cox regression of clinicopathological for overall survival
Variable		All patients		Patients with stage I-II disease		Patients with stage III-IV disease		Patients with LNM		Patients without LNM
Variable		P	HR(95%CI)	P	HR(95%CI)	P	HR(95%CI)	P	HR(95%CI)	P	HR(95%CI)
Univariate analysis
Age		0.008	1.784(1.159-2.746)	0.008	3.516(1.397-8.847)	0.167	1.419(0.864-2.328)	0.074	1.624(0.953-2.765)	0.021	2.397(1.138-5.047)
Gender		0.010	1.581(1.118-2.235)	0.071	1.761(0.954-3.252)	0.011	1.735(1.136-2.649)	0.012	1.787(1.137-2.809)	0.142	1.501(0.873-2.581)
Tumor site		0.931	1.019(0.674-1.540)	0.553	0.834(0.457-1.519)	0.455	0.845(0.542-1.316)	0.359	0.804(0.504-1.282)	0.915	1.031(0.583-1.825)
Tumor size		0.045	1.108(0.792-1.549)	0.954	1.017(0.573-1.804)	0.389	1.199(0.793-1.813)	0.165	1.359(0.881-2.098)	0.627	0.876(0.515-1.492)
Invasive depth		＜0.001	2.628(1.585-4.357)	0.648	1.150(0.631-2.097)	0.005	7.496(1.846-30.445)	0.007	6.922(1.702-28.156)	0.276	1.383(0.772-2.478)
Lymph node metastasis		＜0.001	2.777(1.999-3.858)	0.048	4.184(1.010-17.335)	0.562	0.830(0.442-1.558)	—	—	—	—
TNM stage		＜0.001	3.154(2.247-4.428)	—	—	—	—	0.828	0.856(0.210-3.484)	＜0.001	4.110(2.121-7.967)
Differentiation		0.001	1.846(1.305-2.611)	0.897	1.051(0.495-2.233)	0.012	1.690(1.123-2.541)	0.128	1.402(0.907-2.167)	0.086	1.687(0.929-3.066)
Schistosomiasis		0.041	1.402(1.013-1.939)	0.405	1.262(0.730-2.182)	0.020	1.627(1.080-2.452)	0.020	1.663(1.083-2.555)	0.345	1.276(0.770-2.115)
Multivariate analysis
Age		0.013	1.696 (1.100-2.617)	0.005	3.874(1.519-9.883)	—	—	—	—	0.022	2.390(1.133-5.041)
Gender		0.008	1.610(1.135-2.284)	—	—	0.029	1.603(1.049-2.449)	0.024	1.686(1.072-2.652)	—	—
Invasive depth		0.013	1.921(1.147-3.216)	—	—	0.007	6.971(1.712-28.392)	0.012	6.059(1.489-24.661)	—	—
Lymph node metastasis		—	—	0.011	6.607(1.541-28.326)	—	—	—	—	—	—
TNM stage		＜0.001	2.930(2.070-4.149)	—	—	—	—	—	—	＜0.001	4.105(2.111-7.982)
Differentiation		0.018	1.529(1.074-2.178)	—	—	0.008	1.752(1.157-2.653)	—	—	—	—
Schistosomiasis		—	—	—	—	0.010	1.719(1.140-2.593)	0.025	1.634(1.064-2.510)	—	—
—:Data is nonsignificant ; Abbreviation: CI=confidence interval; HR=Hazard ratio; P < 0.05 was defined as the criterion for variable deletion when performing backward stepwise selection.

Table3. The association between clinicopathological characteristics and schistosomiasis in CRC cohort
Characteristic	All patients		P	Stage Ⅰ-Ⅱ disease patients		P	Stage Ⅲ-Ⅳ disease patients		P	With lymph node metastasis patients		P	Without lymph node metastasis patients		P
Characteristic	CRC-NS (N=216)	CRC-S (N=138)	P	CRC-NS (N=116)	CRC-S (N=77)	P	CRC-NS (N=100)	CRC-S (N=61)	P	CRC-NS (N=127)	CRC-S (N=82)	P	CRC-NS (N=89)	CRC-S (N=56)	P
Age(ys)			＜0.001			＜0.001			＜0.001			＜0.001			＜0.001
＜60	79	5		41	5		37	0		44	5		34	0
≥60	137	133		125	72		63	61		83	77		55	56
Gender			0.509			0.781			0.508			0.009			0.663
Male	127	86		70	48		57	38		73	32		54	36
Female	89	52		46	29		43	23		54	50		35	20
Tumor site			0.917			0.750			0.731			0.908			0.900
Rectum	59	37		31	19		27	18		35	22		23	15
Colon	157	101		85	58		73	43		92	60		66	41
Tumor size			0.648			0.660			0.670			0.463			0.409
＜5cm	106	68		55	39		51	29		60	43		46	25
≥5cm	110	70		61	38		49	32		67	39		43	31
Differentiation			0.564			0.603			0.633			0.425			0.941
Well diff.	167	103		101	65		66	38		109	67		58	36
Poor diff.	49	35		15	12		34	23		18	15		31	20
Invasive depth			0.463			0.362			0.633			0.378			0.732
I+ II	56	29		42	23		9	6		43	23		8	6
III	160	109		74	54		91	55		84	59		81	50
LNM			0.839			0.815			0.546						----
No	126	82		114	76		13	6		----	----		----	----
Yes	90	56		2	1		87	55		----	----		----	----
TNM stage			＜0.001			----			----			0.554			＜0.001
I	1	23		----	----		----	----		43	23		1	0
II	168	54		----	----		----	----		70	53		1	1
III	47	52		----	----		----	----		8	3		78	48
IV	0	9		----	----		----	----		6	3		9	7
----:Data is not applicable; Abbreviation: N=Number. The association between schistosomiasis and clinicopathological characteristics was evaluated by using the Chi square and Fisher’s exact tests.

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published 01 Jul, 2020

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Comparison of non-schistosomal colorectal cancer and schistosomal colorectal cancer

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