Elevated Risk for Sessile Serrated Polyps in African Americans with Endometrial Polyps

Abstract

Background

Colorectal and endometrial lesions increase with age. It is not known if these two precursor lesions in sporadic cases associate with each other

Aim

To determine the association between colorectal polyps and endometrial polyps (EP) in African Americans (AA).

Methods

We reviewed records of patients referred to gynecology clinics and had colonoscopy at Howard University Hospital from January 2004 to December 2015. We defined cases as all patients who had EP and underwent colonoscopy. For controls, we used EP-free patients who underwent colonoscopy. Logistic regression analysis was used to assess the association between colon polyps and EP.

Results

The median age was 60 years in 118 Cases and 57 years in 664 Controls. The overall colorectal polyps prevalence in the two groups was not statistically different (54% in controls vs. 52% in cases, P=0.60). Sessile serrated adenoma/polyps (SSPs) were more frequent in cases (8% vs. 2% in controls, P=0.003). Sigmoid and rectal locations were more prevalent in controls than cases. In multivariate analysis and after adjusting for age, diabetes mellitus (DM) and BMI, SSPs associated with EP occurrence with an Odds Ratio of 4.6 (CI 1.2–16.7, P=0.022).

Conclusion

Colorectal polyp prevalence was similar in EP patients compared to EP-free controls. However, we observed a significant association between higher-risk SSPs in patients with EP. The prevalence of smoking and DM was higher in these patients. Females with EP might benefit from a screening for colonic lesions in an age-independent manner.

Introduction

Endometrial polyps (EP) are pathologically benign entities originating as localized overgrowths of the basal endometrium. The exact cause for endometrial polyp growth is unknown, but factors such as endogenous and exogenous estrogen excess, tamoxifen (TAM) exposure, overexpression of endometrial aromatase, and hypertension and obesity are known risk factors for EP[1,2].

Although most EP are benign, some polyps can be cancerous or precancerous. Studies showed risk of cancer is higher in benign-looking polyps in patients with increase in endometrial thickness and body mass index [3]. Based on data from observational studies, both symptomatic vaginal bleeding and postmenopausal status in women with endometrial polyps are associated with an increased risk of endometrial malignancy [4]. Endometrial polyps may coexist with other pathologies like colon polyp. A prospective study showed a five-fold higher association between colon polyps in patients with EP compared to patients without EP [5]. EP risk increases with age of the patient.

Colonic polyps may be neoplastic or non-neoplastic and are initially characterized endoscopically by their size and morphology which are two important features that predicts high potential for malignancy (an advanced adenoma) [6]. Morphologically, colon polyps can be broadly classified as either pedunculated or sessile. Pedunculated polyps are those attached to the colonic mucosa by a stalk of variable length, while sessile polyps grow in a more flattened pattern over the mucosa with less separation of the adenomatous epithelium from the underlying layers of the bowel wall. Sessile polyps are more difficult to distinguish visually endoscopically [7]. In addition to size and morphology, advanced histology is predictive for malignant potential but the transformation from adenomatous polyp to colorectal cancer depends on both environmental and genetic factors [8,9]. Colorectal polyps, particularly adenomatous polyps, increase with age of the patient. There is variability in risk for adenoma-to-carcinoma transformation depending on the genetic pathway taken. For instance, serrated adenomatous polyps often acquire hypermethylation of the DNA mismatch repair gene MLH1 that generates a hypermutated serrated adenocarcinoma, moving relatively rapidly through the polyp-to-cancer transition [9].

There are some inherited genetic diseases in which both endometrial and colorectal cancers are of high risk and evolve from the common genetic event. The two most prominent are Lynch syndrome due to germline defects in DNA mismatch repair genes and Polymerase Proofreading Polyposis due to defects in polymerase E epsilon or delta genes. Both conditions will have tumors that are hypermutated, and Lynch tumors but not Polymerase Proofreading Polyposis will demonstrate microsatellite instability [10]. Both conditions are transmitted as autosomal dominant diseases, with a second somatic inactivation of the affected gene’s allele occurring within the tumor. In both conditions, screening for endometrial and colorectal cancer is performed at frequent intervals due to the nature of the two conditions [10,11].

It is not known if sporadic polyps have any common pathway between colorectal polyps and EP. There is some evidence for patients with sporadic endometrial cancer that the risk of having colon cancer is higher. A population-based study found a fourfold increase in the risk of CRC for women diagnosed with endometrial cancer at age 50 years or younger [12]. Moreover, a study by Haraldsdottir et al. has shown that colorectal and endometrial cancers can arise from somatic rather than germline mutation. indeed, in their study, about 70% of potentially Lynch cases turned out to be of a somatic nature [13]. This finding further supports the rationale of this study looking for these the association of these two sets of polyps, outside the lynch syndrome context.

Development of colorectal polyps, particularly advanced adenomas, as well as the incidence and mortality from colorectal cancer is highest among African Americans compared to all racial and ethnic groups in the United States[14]. Due to this, some professional groups such as the U.S. Multi-Society Task Force on Colorectal Cancer Screening and the American Cancer Society now advocate for earlier than the standard age 50 years to commence screening [15][13]. There is no published data regarding African American race and the risk of endometrial polyps. However, African American women have the highest incidence and highest mortality from uterince cancer [16]. There has been no prior correlative studies regarding colorectal polyps and EP in regards to race.

In this study we want to assess the association between endometrial polyps and colon polyps in African Americans and establish factors that define this association.

Methods

This study was retrospectively performed at Howard University Hospital and included cases between January 2004 and September 2015. We reviewed the records of colonoscopies (N=14,888) that were performed after our institutional review board approved (09-MED-79) this study. We linked the colonoscopy records to medical records of patients who were referred to the gynecology clinic with the diagnosis of endometrial polyps. Out of 3,600 women with endometrial polyps, we identified 118 patients with EP who had colonoscopy within the study period. Also, among 5,171 women without EP, we identified 774 women who had colonoscopy during 2010 as potential controls. After a detailed review of patients’ charts, we excluded 76 patients who had previous hysterectomy, other gynecological symptoms or other known lesions (endometrial cancer, endometriosis, leiomyoma). Ultimately, our control group consisted of 664 patients without EP and other gynecological lesions. We assessed risk factors of endometrial cancer (BMI, diabetes mellitus, hypertension, Tamoxifen intake, age, and smoking) in both case and control groups and collected pathological features (histology, location, type of lesions) of colon polyps from both groups. Patients with known family history of colon cancer were excluded from both cases and controls cohorts.

Statistical analysis

Distribution of continuous and categorical variables were analyzed in subjects with and without EP by median (IQR) and frequencies, respectively. We used the Student’s t-test and Chi-squared test to assess the relationship between each variable and study group. We used logistic regression analysis to assess the relationship between colon polyps, location and histology with EP. In all analyses, we adjusted for the effect of age, BMI and diabetes mellitus. P-values <0.05 were considered statistically significant.

Results

Smoking and diabetes are risk factors for endometrial polyps

We had a total of 118 cases defined as patients with EP and 664 patients as controls defined as patients without EP (Table 1). The median age in controls was 57 years in comparison to 60 years for cases. Cases had higher BMI (median BMI of 34.0 vs. 30.7, P = 0.0005) and had higher prevalence of diabetes mellitus (27% vs. 19.8% in controls, P = 0.016). The frequency of smoking was significantly higher in the case group (38.4 % vs. 19.4 in controls, P = 0.001). Differences in the frequency of hypertension and tamoxifen use were not statistically significant between cases and controls.

Table 1:

Distribution of demographics and risk factors in cases and controls

	Controls		Cases		P-value
	N	Result	N	Result
Age year, median (IQR)	664	57 (51–64)	118	60 (53–65)	0.30
Hypertension, n (%)	521	319 (61.2)	102	67 (65.7)	0.40
Tamoxifen history, n (%)	515	6 (1.17)	102	0	0.27
Diabetes mellitus, n (%)	516	102 (19.8)	100	27 (27.0)	0.016
BMI, median (IQR)	510	30.7 (26.4–36.3)	103	34.0 (29.7–39.0)	0.0005

HTN=Hypertension; DM=Diabetes; BMI=Body mass index

Frequency, location, and pathology characteristics of colon polyps in cases and controls

In cases and controls the frequency of colorectal polyps was 52% vs. 54% (P = NS). Number and polyp size was not significantly different between the two groups (Table 2).

Table 2:

Frequency and characteristics of colon polyps in the case and control groups

	Controls		Cases		P- value
	N	Polyp results	N	Polyp results
Polyp detection rate, n (%)	664	358 (53.9)	118	61 (51.7)	0.60
Polyps size cm, median (IQR)	361	0.5 (0.4–0.7)	61	0.5 (0.4–0.7)	0.30
Polyps number, mean (SD)	358	1.8 (1.0)	61	1.7 (1.0)	0.48

Within both groups of patients, left-sided colon polyps were the most frequent (56% in control vs. 59% in cases, P = NS; Table 3). In analyzing the total polyp burden in cases and controls for specific colon location, controls had more sigmoid (58.9% vs 42.6%, P = 0.017) and rectal polyps (36.3% vs 23.0%, P = 0.042) than cases, but when combined as descending/sigmoid and rectum/rectosigmoid, there was no significant difference between both groups for any site within the colon (Table 3).

Table 3:

Polyps location in cases and controls who have colon polyps

	Controls (N=358)	Cases (N=61)	P-value
Location, n (%)
Right colon	83 (23.2)	15 (24.6)	0.81
Left colon	199 (55.6)	36 (59.0)	0.62
Bilateral	76 (21.2)	10 (16.4)	0.39
Specific polyps’ location, n(%)	N=523*	N=92*
Cecum	46 (12.9)	9 (14.8)	0.68
Ascending	79 (22.1)	13 (21.1)	0.90
Transverse	57(15.9)	12 (19.7)	0.47
Descending	0	10 (16.4)	<0.001
Sigmoid	211 (58.9)	26 (42.6)	0.017
Rectosigmoid	0	8 (13.11)	<0.001
Rectum	130 (36.3)	14 (23.0)	0.042

^*In many patients, there was more than 1 polyp, as such the number of polyps does not match the number of patients.

Hyperplastic polyps were the most common and were seen in 46% of control group patients and in 53% of cases (P = NS). There was no difference in tubular adenomas between the two groups. However, sessile serrated polyps were significantly higher in cases as compared to controls (8.2% vs. 1.7%, P = 0.003) (Table 4).

Table 4:

Colon polyps pathology characteristics in cases and controls. Results are in n (%).

	Controls (N=358)	Cases (N=61)	P-value
Hyperplastic	164 (45.8)	32 (52.5)	0.34
Tubular adenoma	144 (40.2)	30 (49.2)	0.19
Inflammatory	11(3.1)	1(1.6)	0.54
Sessile serrated polyp	6 (1.7)	5 (8.2)	0.003
Lymphoid	14 (3.9)	0 (0)	0.12
Tubulovillous	4 (1.1)	0 (0)	0.41

Multivariate analysis

In our study, we evaluated the association between colon polyps and EP. After adjusting for age, BMI and diabetes mellitus, there was no statistically significant association between colon polyps and endometrial polyps (OR = 1.3, 95%CI = 0.8–2.0, P = 0.33). Analysis restricted to women over 50 years did not change the association between colon polyps and EP.

Sessile serrated polyps more prevalent with endometrial lesions

Sessile serrated polyps (those polyps containing a serrated pattern and dysplasia but were not hyperplastic polyps) were more prevalent in patients with endometrial polyps, (OR:4.6, 95% CI: 1.2–16.7). Colorectal polyps located in sigmoid and rectum were less likely to be associated with endometrial polyps (OR = 0.5, Table 5). In a sensitivity analysis, we limited the multivariate analysis of location to non-HPs polyps. Both rectum (OR = 0.09, P = 0.026) and sigmoid (OR = 0.35, P = 0.030) were associated to lower risk of endometrial polyps.

Table 5:

Relationship of colon polyps’ characteristics and location with endometrial polyps in patients with colon polyps^*

	Odds ratio	P-value	95% CI
Polyp type
Sessile serrated polyp	4.6	0.022	1.2–16.7
Location
Sigmoid	0.5	0.015	0.3–0.9
Rectum	0.5	0.061	0.3–1.03

^*Adjusted for BMI, Age, DM in the logistic regression model

Discussion

In this study, we evaluated the association between EP and colorectal polyps in an African American population. Overall, our study reports (i) there is no overall increased risk of colorectal polyps in patients with EP, (ii) one specific type of polyp, sessile serrated polyps, associates with a higher odds ratio for the presence of endometrial polyps, and (iii) rectosigmoid polyps have least association with endometrial polyps.

There are limited studies which have evaluated the relationship between colorectal polyps and EP, with none specifically in African Americans. Unler et al. have reported such an association, particularly in post-menopausal women, with a significant increase in colorectal polyps when endometrial polyps are present [5]. However, EP are observed more often in pre-menopausal patients. Prior studies confirmed that EP are more prevalent in the premenopausal age group and chiefly observed in patients 46–55 years old [17] [18]. Because of colon cancer screening age guidelines recommending screening age starting at 50, the association between EP and colorectal polyps in the pre-menopausal population thus remains understudied.

Diabetes and high BMIs were common risk factors in patients with EP in this African American study population. Diabetes is considered a consistent risk factor for malignancy in patients with EP and it has been suggested to screen patients with EP and diabetes at shorter intervals than EP patients without diabetes [19]. Metabolic syndrome including diabetes and obesity is also a strong risk factor for colorectal neoplasia. Previous studies demonstrated that increase in BMI is associated with an increase in risk for colon adenoma and cancer [20]. It is very likely that these clinical associations share a common pathway for both sporadic EP and colorectal polyps, much in the way germline mutations seen in Lynch and Polymerase Proofreading Polyposis push common risk for both endometrial and colorectal cancer. Tobacco smoking is an additional risk factor for colorectal polyps and cancer [21]. In this study, we also find that smoking frequency is higher in patients with EP.

We found that rectal and sigmoid polyps are less frequent in patients with EP. As such, rectosigmoid colonic polyps within the left side are less likely to co-occur with endometrial lesions. Right-sided lesions, particularly the sessile serrated type, have high likelihood of progressing to cancer due to being harder to detect at endoscopy, the difficulty to distinguish them from hyperplastic benign lesions and longer asymptomatic dwell times [22]. Furthermore, these lesions progress faster to cancer than conventional adenomas and polyps. These factors together, make SSPs potentially highly malignant.

In our study, we found that sessile serrated polyps were associated with a higher prevalence of EP with a high odds ratio (> 4) whether the analysis was performed in the overall study population or just in those with colon polyps only. Indeed, the prevalence of sessile serrated polyps was 8.2% in patients with endometrial polyps in comparison to 2.1% in patients without endometrial polyps (P=0.003). As many as 15–20% of sporadic colorectal cancers arise via the serrated pathway, and sessile serrated adenomas have the highest likelihood of transitioning to cancer. Within the colon, several studies have shown that SSPs associate with synchronous lesions [23–25]. Our study suggests the need to explore synchronous lesions within and beyond the colon, namely in the endometrium. More important, the detection of endometrial polyps, regardless of patients’ age, should be an indicator to recommend colorectal screening to detect SSPs at early stages, especially in young pre-menopausal women who might not yet have qualified for such screening as per the current guidelines. One of the limitations of this study might be the small size of cases population, this mandates that our findings be validated in larger populations of female patients with EP.

In conclusion, we observed no higher risk for colorectal polyps in patients with EP within African American females. The association of sessile serrated polyps in African American patients with EP suggests that patients with EP would benefit from colonoscopy screening to detect potentially malignant lesions of the SSPs type at early stages and reduce future risks of colorectal cancer development.