Clinical and Medical Economic Value of Screening Colonoscopy before Laparoscopic Cholecystectomy

The mortality of colorectal carcinoma (CRC) has increased and has been the second-highest cause of cancer death following lung carcinoma in the world [1‒3]. To reduce the mortality resulting from CRC, a simple screening procedure to detect CRC is quite important, and the fecal occult blood test (FOBT) has been previously accepted worldwide [4, 5]. Additionally, screening colonoscopy (SC) has also been recognized as a useful procedure to reduce the mortality of CRC and as the first choice procedure to detect colorectal adenoma instead of FOBT [5‒7].

SC before surgery for abdominal malignant tumors has been recognized as a useful procedure to detect malignant tumors, including CRC, at the same time [8‒10]. In the first half of the 1990s, introduction of laparoscopic cholecystectomy (LC), laparoscopic visual examination to find CRC was recognized as an alternative procedure to tactile examination during open cholecystectomy. However, it was reported that visual examination under laparoscopy could find only advanced CRC [11‒14]. Accordingly, the SC prior to LC has been considered an alternative procedure for visual examination under laparoscopy to find the CRC during LC [13, 14]. However, its clinical value is still controversial [14].

Additionally, the articles regarding analysis of the cost-effectiveness of SC has been reported and SC is recognized as the best choice for the healthy persons for screening adenoma and/or CRC in spite of economic conditions in different countries [15‒19]. In the literature, there are no reports, which evaluated appropriate patient population for SC before the LC. In this study, we have evaluated the clinical/medical and economic value of SC prior to the LC.

We performed LC in 509 patients at Nagoya University Hospital between July 2010 and August 2023. They were initially diagnosed with gallbladder disease, including gallstones, polyps, and/or cholecystitis, by ultrasonography and/or computed tomography, and had no colonic symptoms. Of them, 335 patients underwent SC before LC, and the remaining 174 did not. The electronic medical records of these patients were retrospectively reviewed, focusing on preoperative clinical data, reports of colonoscopy, and pathological findings of colorectal neoplasia (CRN). As an assessment of medical economy, the technical fees of SC and endoscopic and/or surgical resection for CRN were analyzed. This study was approved by the Human Research Review Committee of Nagoya University Hospital (approval number 2023–0260).

In this study, SC before LC was defined as when the patients underwent colonoscopy in our hospital or other hospital within 12 months before LC. The selection of SC was based on the patients’ preference after informed consent regarding the risk and benefits of SC. The pathological findings of all of the colorectal lesions were reviewed. Of multiple lesions in 1 patient, the highest malignant lesion was adopted in the results. According to the previous reports [20‒22], advanced adenoma (Adv-Ad) included an adenoma with a maximum diameter of ≥1 cm, villous histology, and/or high-grade dysplasia because of the risk of malignant transformation, and advanced neoplasia (Adv-Neo) included Adv-Ad and adenocarcinoma (ADR), respectively.

The clinical factors, recognized as the risk factors for CRN, were investigated and their details were shown as follows: age (≦59 vs. ≧60 years), sex, body mass index (BMI), smoking habit (current smoker who had smoked at the time of scheduling LC, ex-smoker who had stopped smoking more than 12 months before scheduling LC, and nonsmoker who had never smoked), drinking habit (daily drinker who had drunk alcohol every day at the time of scheduling LC, weekly drinker who had drunk 1 to 6 days in a week at the time of scheduling LC, occasional drinker who had drunk occasionally, and nondrinker who had stopped drinking more than 12 months before scheduling LC and had never drunk), comorbidity of diabetes mellitus, comorbidity of hyperlipidemia, previous history of malignant disease, and family history of malignant disease.

Terminology of staging TNM classification of CRC and hepatectomy were described according to the 8th edition of the cancer staging manual by the American Joint Committee on Cancer (AJCC) [23] and the New World Terminology [24], respectively.

In Japan, every technical fee is confirmed by the Ministry of Health, Labour and Welfare and is revised biennially. In this study, both technical fees of endoscopic and surgical procedures were calculated based on those applicable in 2023. The details of endoscopic and surgical procedures in the study patients were as follows; total colonoscopy (USD 100), endoscopic mucosal resection for the tumor with a diameter of <2 cm (USD 323), endoscopic mucosal resection for the tumor with a diameter of ≥2 cm (USD 452), laparoscopic colectomy for benign tumor (USD 2,750), laparoscopic colectomy for malignant tumor (USD 3,840), laparoscopic low anterior resection (USD 5,410), and hepatectomy of H4′5678 (USD 4,920).

Continuous variables, expressed as the mean ± standard deviation unless specified otherwise, were compared using the Mann-Whitney U test. Categorical variables were analyzed using the χ² test, Fisher’s exact test, or Bonferroni procedure, as appropriate. Univariate analysis of differences between the two groups were analyzed using Pearson’s chi-square test. By the stepwise logistic regression model (forward selection), the odds ratio with 95% confidence intervals were calculated. Multivariate analysis was performed among all of the possible risk factors. All tests were two sided, and p < 0.05 was considered statistically significant. Statistical calculations were performed using SPSS^® version 29 on an IBM computer.

Of the 335 patients who underwent SC before LC, there were 197 males and 138 females, with a mean age of 63 ± 13 (range 19–90) years and a mean BMI of 23.6 ± 3.9 (range 15.5–41.5) kg/m². Of them, 323 (96.4%) and 12 (3.6%) underwent SC in our hospital and in other hospital, respectively. There were no major adverse events related to the SC. In the 174 patients who did not undergo SC before LC, there were 89 males and 85 females, with a mean age of 59 ± 14 (range 21–92) years and a mean BMI of 23.6 ± 3.7 (range 15.0–35.9) kg/m². The ratio of male to female and the mean BMI were not significantly different between the 2 patient groups (p = 0.110 and p = 0.689). The mean age of the patients who underwent SC before LC was significantly older than that of the patients who did not (p = 0.006).

The pathological findings of CRN and resection procedure are shown in Table 1. In the 335 patients who underwent SC before LC, CRN was identified in 179 patients (53.4%), including 8 (2.4%) with ADRs, 132 (39.4%) with tubular adenomas, 34 (10.1%) with hyperplastic polyp, and 5 (1.5%) with leiomyoma. Regarding the pathological depth of the 8 patients with ADR, carcinoma in situ was observed in 6 patients, and submucosa and muscularis propria were observed in each one. Among the 3 patients who underwent surgical resection, there were no lymph node metastasis. Of the 132 patients with tubular adenomas, 36 (10.7%) and 96 (28.7%) had Adv-Ad and non-advanced adenomas (Non-Adv-Ad), respectively. Regarding the maximum size of tubular adenoma of the 96 patients with Non-Adv-Ad, 58 and 38 patients had tubular adenoma with a varied diameter between 5 and 9 mm and with a diameter of <5 mm, respectively. The detection rate of adenoma including the ADR was 41.8%. In total, 44 patients (13.1%) had Adv-Neo. Among the 88 patients (26.2%) with multiple lesions, excluding hyperplastic polyps and leiomyoma, the average number of CRN in 1 patient and the maximum number of CRN were 2.5 and 13, respectively. Three patients (0.9%) underwent laparoscopic colorectal resection combined with LC without any postoperative complications. Preoperative endoscopic resection was performed in 169 patients without any major adverse events. After SC and endoscopic and/or surgical resection, all patients had undergone the surveillance program in our and/or in other hospitals, according to “Colonoscopy Screening and Surveillance Guidelines” published by the Japanese Gastroenterological Endoscopy Society (JGES) [25].

Univariate and multivariate analyses are shown in Table 2. Univariate analysis revealed that age (≥60 years), gender, comorbidity of diabetes mellitus, and previous history of malignant disease were significant risk factors for Adv-Neo. Multivariate analysis identified age (≥60 years) and the presence of previous history of malignant disease as independent risk factors for Adv-Neo. The mean age of the patients with Adv-Neo was 69 ± 11 (range 39–85) years and these were older than the patients with other types of CRN and without any type of CRN (62 ± 13 years) (p = 0.001). Among the patients with Adv-Neo, the rates of patients aged ≥40 years, ≥50 years, and ≥60 years were 97.7%, 93.2%, and 84.1%, respectively.

Among the 335 patients who underwent SC before LC, the details of their previous history of malignant disease, including duplicate malignancies, were as follows: CRC (n = 8), gastric carcinoma (n = 10), hypopharyngeal carcinoma (n = 1), tongue carcinoma (n = 2), hepatocellular carcinoma (n = 3), gastrointestinal stromal tumor of the stomach (n = 1), and malignant non-digestive disease (n = 41). Among the patients with Adv-Neo, the rates of patients with previous history of malignant disease were 36.3% (n = 16), and the details were as follows: CRC (n = 3), gastric carcinoma (n = 4), tongue carcinoma (n = 1), and malignant non-digestive disease (n = 8). The rate of patients with Adv-Neo was significantly different between the patients with or without a previous history of malignant digestive disease (18.2% vs. 5.8%) (p = 0.009) but was not significantly different between the patients with or without a previous history of CRC (6.8% vs. 1.7%) (p = 0.074).

The relationship between the age-groups and the detected rate of CRN is shown in Table 3. The detected rates of CRN in the age-groups of <45, 45–55, 55–65, 65–75, and ≥75 years were 28.9%, 35.8%, 50.0%, 62.0%, and 72.9%, respectively. The detected rates of CRN in the age-groups of <45, 45–55, 55–65, and 65–75 years had no significant differences compared to those of 45–55, 55–65, 65–75, and ≥75 years, respectively, but there were significant differences among the other age-groups.

ADR in the age-groups of <45, 45–55, 55–65, 65–75, and ≥75 years were 18.4%, 24.5%, 34.1%, 50.0%, and 65.7%, respectively. ADR had no significant differences among the age-groups of <45, 45–55, and 55–65 years and between the age-groups of 65–75 and ≥75 years, but there were significant differences among the other age-groups.

The detected rate of CRN requiring resection in the age-groups of <45, 45–55, 55–65, 65–75, and ≥75 years were 5.3%, 3.8%, 9.8%, 17.4%, and 22.9%, respectively. The detected rate of CRN requiring resection had no significant differences among the age-groups of <45, 45–55, and 55–65 years, between the age-groups of 55–65 and 65–75 years, and between the age-groups of 65–75 and ≥75 years, respectively, but there were significant differences among the other age-groups.

Of the 174 patients who did not undergo SC before LC, 6 (3.4%) patients were diagnosed with CRC after LC (Table 4). The mean age when these 6 patients underwent LC was 64 ± 7 (range 57–75) years without any previous history of malignant disease. The mean interval time between LC and the diagnosis of CRC was 48.2 ± 3.0 (range 21.9–84.4) months. Of the 4 patients who underwent laparoscopic colorectal resection, 3 patients have been alive without any recurrence, and 1 patient underwent H4′5678 due to multiple liver metastases 6 months later and died 39.0 months after the diagnosis of CRC. The remaining 2 patients had unresectable tumors due to distant metastases, including multiple liver metastases, and died 5.2 months and 1.4 months after the diagnosis of CRC.

Technical fees for the patients with SC before LC are shown in Table 5. Regarding the technical fee of endoscopic procedures for the diagnosis and treatment of CRCs, the total technical fee of the endoscopic procedure in the 335 patients who underwent SC before LC was USD 72,400. Regarding the technical fee of surgical procedures for the treatment of CRNs that were diagnosed before LC, the total technical fee of the surgical procedure in the 3 patients who underwent laparoscopic colectomy combined with LC was USD 12,900. Accordingly, the total technical fee of SC and treatment of CRNs that were diagnosed before LC was USD 85,300.

The technical fee of surgical procedures for the treatment of CRCs, which were diagnosed as resectable tumors after LC, in the 4 patients is shown in Table 6. The total technical fee of surgical procedures was USD 32,000 and included the technical fee of H4′5678 in which 1 patient had synchronous multiple liver metastases. Of the 4 patients with resectable CRC, 1 patient, who underwent H4′5678, underwent five regimens of chemotherapy for recurrent disease and died 39.0 months after the diagnosis of CRC. Of the 174 patients who did not undergo SC before LC, 1 patient underwent five courses of FOLFOX + bevacizumab and died 5.2 months after the diagnosis of CRC, and another patient underwent only best supportive care and died 1.4 months after the diagnosis of CRC.

The technical fee per person in the 335 patients who underwent SC (USD 255) had a considerable economic advantage compared to that in the 4 patients who underwent surgery for CRCs after LC (USD 8,000). All patients paid according to the self-pay ratio of medical expenses. Regarding this analysis of medical economy, any fees for chemotherapy and/or expenses for hospitalization were never included.

According to our results, the detected rate of CRN by SC before LC (53.4%) has been determined. In the case of ADR, which is recognized as a quality indicator of SC [26, 27], ADR among the 335 patients who underwent SC before LC (41.8%) was at a high quality compared to the recommended quality with a minimum target for overall ADR (≥25%), according to the American Society for Gastrointestinal Endoscopy (ASGE)/American College of Gastroenterology (ACG) Task Force on Quality in Endoscopy [27]. When the ADR was compared by gender, both our ADRs for male patients (45.7%, 90/197 patients) and for female patients (36.2%, 50/138 patients) were higher than the recommended levels for male patients (≥30%) and for female patients (≥20%) [27]. Therefore, quality level of SC before LC in our study was adequate. For the advanced ADR, the quality level (13.1%) in our study was clinically adequate compared to the previously reported levels (5.6% in Poland and 6.4% in Germany) [20, 27].

As regards the age of patients, among the countries, which introduced total colonoscopy for screening of CRC, SC was recommended in patients aged ≥40 years in Poland, ≥50 years in some states of the USA, and ≥55 years in Germany [6, 20, 27]. In our study, an age of ≥60 years was found to be one of the independent risk factors for Adv-Neo. The adenoma detection rate in the age-groups of <45, 45–55, 55–65, 65–75, ≥75 years were 18.4%, 24.5%, 34.1%, 50.0%, 65.7%, respectively. Similarly, the detection rate of CRN requiring resection in the age-groups of <45, 44–55, 55–65, 65–75, ≥75 years were 5.3%, 3.8%, 9.8%, 17.4%, and 22.9%, respectively. Additionally, among the patients who were diagnosed with CRC without SC before LC, the range of age when the patients underwent LC was 57–75 years. Accordingly, for the patients aged ≥55 years, colonoscopy may not only be a screening option but a clinical necessity due to the high detected rates of adenoma and/or CRN requiring resection.

Among the 174 patients without SC before LC, the rate of the patients who were diagnosed with CRC and that of the patients who died due to CRC was 3.4% and 1.7%, respectively. These rates were detected among the patients who had visited our hospital after LC; therefore, it is easily assumed that actual rates may be higher. Generally, it is recognized that the patients who underwent SC without any lesions under a full visible observation of the total colon are allowed 10 years to undergo next SC [25, 27, 28]; however, all 6 patients were diagnosed with CRC within 10 years after the LC. Additionally, some reports have suggested that cholecystectomy may be considered as a risk factor for CRC because change of enterohepatic cycling after cholecystectomy can influence intestinal flora and can also affect the colorectal mucosa [29, 30]. When the patients had undergone SC before LC and they had been diagnosed with CRN, they could undergo endoscopic and/or surgical resection and might never die due to the CRC.

In addition, the technical fee per person in the 335 patients who underwent SC before LC was USD 255; therefore, when the 6 patients who were diagnosed with CRC after LC had undergone SC before LC, such a technical fee to contain the disease might be more economical (USD 1,520) compared to the technical fee in the 4 patients who underwent surgical resection for resectable CRC (USD 32,000). In Japan, the self-pay ratio of medical expenses is confirmed by public medical insurance system and the details were as follows: the patients with age of <70 years (30%), the patients with age of 70–74 years and with income of USD <24,000 (20%), the patients with age of ≥75 years and with income of USD <24,000 (10%), and the patients with age of ≥70 years and with income of USD ≥24,000 (30%). The medical expenses other than the self-pay ratio are paid to the hospital by the insurer and is approved by the public medical insurance system. Accordingly, of the abovementioned technical fee, the individual patient is only responsible for a smaller amount. If all 174 patients without SC had undergone SC before LC, the total technical fee of SC was USD 43,980. In addition, any fee for chemotherapy and/or expenses for hospitalization were not included in this study. Thus, SC before LC is recognized as an effective and economical procedure to prevent patients who are scheduled for LC from dying due to CRC.

According to the previous report regarding cost-effectiveness analysis of SC in Japan, it was described that SC was less costly and more effective than no screening and the incremental cost per quality-adjusted life year gained for SC against FOBT-based screening [15]. Because SC depends on total colonoscopy capacity, patients’ selection of indication of SC is quite important for an effective and economical use of SC. According to our results, SC before LC should be performed in the patients aged ≥55 years.

This study had a major limitation, which is its small sample size (n = 509) and not having any controls. Despite the small number series, both the sufficient ADR among the 335 patients with SC before LC and the regrettable mortality of CRC among the 174 patients without SC before LC have been reported; therefore, the clinical value of SC before LC can be considered as reliable. In addition, the low technical fee per person, SC before LC had a significant advantage in terms of medical economy compared to surgical resection for CRC after LC.

As another big limitation, this study does not include a cost-effectiveness analysis of SC before LC. There are no cohort data regarding the incident rate of adenoma and/or CRC after the LC; therefore, we cannot decide any model parameters in a state-transition Malkov model that simulate the natural history of CRC development after LC and analyze the actual cost-effectiveness according to Monte Carlo simulation. In future, a cost-effectiveness analysis of SC before LC will be required based on the accumulation of large-scale cohort data on the incidence of CRN after LC in the patients.

Among the patients who are scheduled for LC, SC has clinical and medical economic value to potentially reduce death from CRC; therefore, scheduling LC may be a great motivator for SC. For the patients aged ≥55 years, colonoscopy is not only a screening option but can be considered as a clinical necessity due to the high detected rates of adenoma and/or CRN requiring resection.

This study was approved by the Human Research Review Committee of Nagoya University Hospital (Approval No. 2023-0260). Because of this being a retrospective study, instead of individual informed consent, all patients were guaranteed the opportunity of refusal according to information disclosure of this study on the Webpage (https://nagoya.bvtis.com/rinri/publish.aspx).

All authors have no conflict of interest or financial ties to disclose.

There is no funding support.

Study design and draft writing: Dr. Tsuyoshi Igami; data collection: Drs. Tsuyoshi Igami, Masanao Nakamura, Takuya Ishikawa, Takeshi Yamamura, Kentaro Yamao, Keiko Maeda, Yasuyuki Mizutani, Tsunaki Sawada, Takashi Mizuno, Junpei Yamaguchi, Shunsuke Onoe, Masaki Sunagawa, Nobuyuki Watanabe, and Shoji Kawakatsu; statistical analysis: Drs. Tsuyoshi Igami, Yukihiro Yokoyama, and Taisuke Baba; and draft revising: Drs. Tsuyoshi Igami, Hiroki Kawashima, and Tomoki Ebata.

The data that support the findings of this study are available on request from the corresponding author.