The prevalence of negative fecal occult blood test (FOBT) among colorectal cancer patients in a tertiary care center

Abstract

Objectives:

Colorectal cancer (CRC) is the third most common cancer worldwide and a leading cause of death. The fecal occult blood test (FOBT) is a widely used initial screening test; however, its results can be influenced by multiple factors. This study aimed to evaluate the prevalence of negative FOBT among patients with CRC and possible etiologies.

Methodology:

This case-control study included patients aged 50 years and older who were diagnosed with CRC and underwent FOBT. Risk factors and comorbidities were recorded. FOBT results, Colonoscopy findings, tumor location, and type were investigated.

Results:

A total of 118 patients diagnosed with CRC, who underwent FOBT were included in this study. Of the 118 patients, 63 were males, and 55 were females, with a mean age of 61.3 years and a mean body mass index of 28.87. The most common comorbidity was hypertension (44.9%). Furthermore, 47.5% of the participants had positive FOBT, and 52.5% had negative FOBT. The most common colonoscopy finding was a mass lesion (49%), which was in the rectum (42.4%). Adenocarcinoma was the most common histopathological diagnosis (81.4%). No significant relationship was observed between FOBT results and other variables.

Conclusion:

More than half of the CRC cases had negative FOBT despite the distal location and type of the tumor. Screening options should be discussed with patients, and further studies are needed to evaluate noninvasive stool-based tests.

Introduction

Colorectal cancer (CRC) is the third most common cancer globally in men, and the second most common cancer in women, according to the World Health Organization GLOBOCAN database.[1] In Saudi Arabia, CRC is the most common cancer in men and the third most common cancer in women, making it the fourth leading cause of death, with over one million cases diagnosed annually.[2] The major risk factors for CRC include obesity, diabetes, long-term smoking, and unhealthy alcohol use.[3,4,5,6]

The United States Preventive Services Task Force (USPSTF) recommends screening patients without risk factors for CRC at the age of 45 years, which is different from the previous recommendations of starting screening at the age of 50 years, highlighting the importance of early screening and detection of CRC for better outcomes.[7] Furthermore, the USPSTF recommends annual screening for CRC with fecal occult blood test (FOBT) or fecal immunochemical test (FIT). However, a randomized trial in the Netherlands showed that screening once a year or every 2 or 3 years had comparable positivity rates.[8]

Colonoscopy is the gold standard screening method for CRC. However, proper referral of patients presenting with risk factors should be considered due to its invasiveness and high cost. Therefore, the FOBT is widely used as an initial screening test for CRC. The FOBT detects hemoglobin through a peroxidase reaction by turning guaiac reagent-impregnated paper blue. It is a highly sensitive screening tool for CRC, with a sensitivity of 31%–79% and a specificity of 87%–98%.[9,10] FOBT results may be influenced by the medications used before the test (nonsteroidal anti-inflammatory drugs (NSAIDs) and high-dose vitamin C), the nature of the tumor (nonbleeding colorectal tumors such as lymphoma), and the location of the tumor (cecal or right-sided tumors).[11]

This study aimed to evaluate the prevalence of negative FOBT among patients with CRC and to identify potential factors contributing to false-negative results. It also seeks to enhance understanding of non-invasive stool-based testing, particularly FOBT, in comparison with colonoscopy, thereby supporting more informed patient counseling and screening decisions. Ultimately, this study aims to contribute to the improvement of screening strategies for the early and accurate detection of CRC, with the goal of improving patient prognosis and survival.

Materials and Methods

Study design and setting

This was a case-control study including patients with CRC, who had previously undergone FOBT. The study was conducted at the Family Medicine and Polyclinic Department in a tertiary healthcare center.

Participants

The inclusion criteria were patients who were diagnosed with CRC and underwent FOBT, and those aged 50 years and older. Patients with nonmalignant anorectal disease or upper gastrointestinal bleeding were excluded.

Data collection

Data were collected retrospectively from the electronic record system from December 2015 to December 2022. All cases that fit the inclusion criteria during the time were included. A chart review was conducted to minimize recall bias, and the date of collection was recorded. The last FOBT result was recorded, and among multiple varying results, the latest positive result was counted despite previous negative results. Additionally, sociodemographic variables, colonoscopy findings, and histopathological findings were collected.

Incomplete and missing data were revisited and corrected.

Data analysis

All analyses were performed using the SPSS software package, version 20. Descriptive statistics for the continuous variables were presented as means and standard deviations (SD), whereas categorical variables were presented as frequencies and percentages. Continuous variables were compared using Student’s t-test and ANOVA, whereas categorical variables were compared using the Chi-square test. A P value <0.05 indicated statistical significance.

Ethical consideration

This study was conducted in accordance with the ethical principles contained in the Declaration of Helsinki (2000), the WHO Operational Guidelines for Ethical Committees that Review Biomedical Research (2000), and the International Ethical Guidelines for Biomedical Research Involving Human Subjects (2002). IRB approval was obtained and attached to the cover letter.

Results

A total of 118 patients diagnosed with CRC with previous FOBT were included in this study. The mean age of the patients was 61.3 years (SD: 12.56). Additionally, 53.4% of the patients were males, and 46.6% were females. Most patients were Saudis (94.9%), whereas only 5.1% were non-Saudis. The mean body mass index (BMI) was 28.87 (SD: 5.6). The most common comorbidities were hypertension (44.9%), type 2 diabetes (37.3%), and dyslipidemia (28.8%). The most used drugs were multivitamins (39.8%), followed by aspirin (11.9), NSAIDs (10.2), and vitamin C (0.8).

Of the 118 patients, 56 (47.5%) had positive FOBT, and 62 (52.5%) had negative FOBT. Furthermore, 82.2% of the patients underwent colonoscopy, mostly with indications of per rectal bleeding (45.8%) and chronic constipation (17.8%). The most common colonoscopy finding was mass lesions (49%), and lesions were mostly located in the rectum (42.4%) and sigmoid colon (19.5%).

Histopathological diagnosis was performed in 97.5% of the patients. The most common histopathological finding was adenocarcinoma (81.4%), followed by high-grade dysplasia (11.9%). No cases of colorectal lymphoma or sarcoma were recorded.

The comparative data analysis revealed no significant relationship between FOBT results and variables such as age, gender, risk factors, tumor location, and histopathological diagnoses. The descriptive and comparative data are presented in Tables 1-3.

Table 1.

Socio demographic variables

Variables		n (%)		FOBT results				P
				Negative		Positive
Age (mean±SD)		61.3±12.56		61.68±12.00		60.95±13.26		0.755
BMI (mean±SD)		28.87±5.6		27.79±4.60		30.07±6.39		0.047
Number of risk factors		1.24±1.21		1.37±1.24		1.10±1.17		0.239
Total number of FOBT done		2.42±2.27		2.65±2.457		2.16±2.052		0.250
Gender
Male		63 (53.4)		36 (57.1)		27 (42.9)		0.284
Female		55 (46.6)		26 (47.3)		29 (52.7)
Nationality
Saudi		112 (94.9)
Non-Saudi		6 (5.1)
FOBT results
Positive		56 (47.5)
Negative		62 (52.5)
Diabetes		44 (37.3)
No				37 (50.0)		37 (50.0)		0.473
Yes				25 (56.8)		19 (43.2)
Smoking		5 (4.2)
No				59 (52.2)		54 (47.8)		0.999
Yes				3 (60)		2 (40)
Hypertension		53 (44.9)
No				31 (47.7)		34 (52.3)		0.243
Yes				31 (58.5)		22 (41.5)
Dyslipidemia		34 (28.8)
No				41 (48.8)		43 (51.2)		0.202
Yes				21 (61.8)		13 (38.2)
Positive family history of CRC		7 (5.9)
No				57 (51.4)		54 (48.6)		0.443
Yes				5 (71.4)		2 (28.6)
Inflammatory bowel disease		4 (3.4)
No				62 (54.4)		52 (45.6)		0.048
Yes				0 (0)		4 (100)
NSAIDs		12 (10.2)
No				54 (50.9)		52 (49.1)		0.370
Yes				8 (66.7)		4 (33.3)
Aspirin		14 (11.9)
No				52 (50)		52 (50)		0.161
Yes				10 (71.4)		4 (28.6)
Vitamin C		1 (0.8)
No				61 (52.1)		56 (47.9)		0.999
Yes				1 (100)		0 (0)
Multivitamins		47 (39.8)
No				41 (57.7)		30 (42.3)		0.164
Yes				21 (44.7)		26 (55.3)

Table 3.

Histopathological features

Variables		n (%)		FOBT results				P
				Negative		Positive
Histopathological findings
Normal		1 (0.8)
No				62 (53)		55 (47)		0.475
Yes				0 (0)		1 (100)
Hyperplasia		2 (1.7)
No				60 (51.7)		56 (48.3)		0.497
Yes				2 (100)		0 (0)
High-grade dysplasia		9 (7.6)
No				58 (53.2)		51 (46.8)		0.734
Yes				4 (44.4)		5 (55.6)
Low-grade dysplasia		14 (11.9)
No				55 (52.9)		49 (47.1)		0.839
Yes				7 (50)		7 (50)
Adenocarcinoma		96 (81.4)
No				13 (59.1)		9 (40.9)		0.495
Yes				49 (51)		47 (49)
Lymphoma		0 (0)
Sarcoma		0 (0)

Table 2.

Colonoscopy features

Variables		n (%)		FOBT results				P
				Negative		Positive
Was a colonoscopy done?		97 (82.2)
No				13 (61.9)		8 (38.1)		0.343
Yes				49 (50.5)		48 (49.5)
Colonoscopy results
Normal		26 (22)
No				47 (51.1)		45 (48.9)		0.551
Yes				15 (57.7)		11 (42.3)
Polyp		19 (16.1)
No				53 (53.5)		46 (46.5)		0.622
Yes				9 (47.4)		10 (52.6)
Mass		58 (49.2)
No				34 (56.7)		26 (43.3)		0.361
Yes				28 (48.3)		30 (51.7)
Ulceration		6 (5.1)
No				60 (53.6)		52 (46.4)		0.421
Yes				2 (33.3)		4 (66.7)
Inconclusive or poor preparation		1 (0.8)
No				62 (53)		55 (47)		0.475
Yes				0 (0)		1 (100)
Lesion location on colonoscopy
Anal canal		8 (6.8)
No				59 (53.6)		51 (46.4)		0.475
Yes				3 (37.5)		5 (62.5)
Rectum		50 (42.4)
No				36 (52.9)		32 (47.1)		0.919
Yes				26 (52)		24 (48)
Sigmoid colon		23 (19.5)
No				52 (54.7)		43 (45.3)		0.332
Yes				10 (43.5)		13 (56.5)
Descending colon		5 (4.2)
No				59 (52.2)		54 (47.8)		0.999
Yes				3 (60)		2 (40)
Transverse colon		4 (3.4)
No				61 (53.5)		53 (46.5)		0.345
Yes				1 (25)		3 (75)
Ascending colon		7 (5.9)
No				60 (54.1)		51 (45.9)		0.254
Yes				2 (28.6)		5 (71.4)
Cecum		6 (5.1)
No				59 (52.7)		53 (47.3)		0.999
Yes				3 (50)		3 (50)
Multiple locations		4 (3.4)
No				60 (52.6)		54 (47.4)		0.999
Yes				2 (50)		2 (50)

Discussion

CRC is the third most common malignancy worldwide, with approximately 1.9 million new cases and 930,000 deaths in 2020.[12] The USPSTF recommends screening for CRC in adults aged 45–75 years. The guaiac-based FOBT (gFOBT) is one of the stool-based tests that is recommended to be performed annually. Alternatively, FIT and stool DNA test with FIT are superior to gFOBT and do not require dietary restrictions or multiple stool samples.[13] However, both are commonly used locally as noninvasive screening tools, with gFOBT being more available in resource-limited institutions.

The gFOBT has a sensitivity for CRC of 0.50–0.75 (95% confidence interval (95% CI, 0.09–1.0) and specificity of 0.96–0.98 (95% CI, 0.95–0.99). However, it has a lower sensitivity for advanced adenomas, ranging from 0.06 to 0.17 (95% CI, 0.02–0.23), and a comparable specificity, ranging from 0.96 to 0.99 (95% CI, 0.96–0.99).[13]

In this study, we evaluated the prevalence of CRC among patients with previous negative FOBT and explored their characteristics. We concluded that 62 (52.5%) out of A total of 118 patients with CRC had negative FOBT.

The mean age of the study participants was 61.3 years, and they had a mean BMI of 28.87, although a higher BMI has been reported to be associated with CRC.[14] Hypertension (44.9%) and type 2 diabetes (37.3%) were the most common comorbidities among our study population.

Notably, multivitamins were the most used drugs/supplements (39.8%), followed by aspirin, NSAIDs, and vitamin C. Although certain medications and supplementation were observed in the literature to affect gFOBT and FIT test such as Aspirin, clopidogril, NSAIDs, and vitamin C;[15,16,17] No significant association was found among patient’s receiving these medication in our study population; as time of medication administration to FOBT sample collection cannot be accurately measured in this retrospective study; this lack of correlation cannot be certin.

Although (45.8%) of the participants presented with per rectal bleeding. With (49%) of the total participants showing mass lesions on their colonscopy, where (42.4%) were in the rectum and (81.4%) were found to be Adenocarcinoma; none were found to be significantly correlated to FOBT results.

Hirai et al. elaborated that gFOBT and immunochemical FOBT (iFOBT) had significantly lower sensitivity for proximal CRC than distal CRC and comparable specificity.[19]

Similarly, Saraceni et al.[18] showed that the FOBT sensitivity for adenocarcinomas was 100% (95% CI, 39.8%–100%), specificity was 60.2% (95% CI 49.2%–70.5%), positive predictive value was 0.5% (95% CI 0.4%–0.6%), and negative predictive value was 100% (95% CI 100%–100%). Additionally, they showed that 34% of patients with negative FOBT showed abnormal colonoscopy findings, of which 27.8% were adenomas, and 72.2% were other lesions.[19]

Lesion morphology can also affect stool-based testing, where Flat and small lesions are less detectable.[20]

Other factors associated with false-negative results include the early stages of the tumor. Chen et al.[21] showed negative FOBT results for a 3-year follow-up of all new target masses. Delayed sample return is another factor associated with false-negative results, as hemoglobin degradation can significantly affect sample quality.[22]

Although newer stool-based tests like immunochemical tests and multitarget DNA tests have been shown to be superior to older tests, false negatives persist as a limitation compared to colonoscopy.[23] Alternatively, a previous study comparing annual iFOBT with 10-year colonoscopy showed no difference in life years.[24]

Limitations

This study was conducted in a tertiary care hospital with an oncology center, which included many cases due to the inclusion of primary and referred oncology cases for treatment. Therefore, a few cases lacked complete screening data captured in a different facility but had surveillance FOBT results recorded; The date of both FOBT testing and colonoscopy was documented and collected during the data collection process.

In October 2022, the FIT was first introduced into our hospital, and the gFOBT was the primary stool-based test. As FIT data were limited at the start of the study, we opted to measure colorectal cancer cases with prior gFOBT only for reliable results.

Conclusion

Stool-based tests, such as gFOBT and FIT, are recommended as screening tools for CRC. The results showed a higher number of FOBT-negative CRC cases. Additionally, no significant relationship was observed between variables, such as tumor location and type, and FOBT results. Shared decisions can help patients select appropriate screening methods. Further studies on more sensitive stool-based tests, such as FIT are needed for cost effective, less invasive and sensitive screening tools.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.