|Year : 2021 | Volume
| Issue : 1 | Page : 8-12
The utility of screening ultrasound in early diagnosis of gall bladder cancer among high-risk population
Amit Sreen1, Ravi K Anadure1, HP Singh2, Anuj K Sharma3, Rohit Sharma4, Aneesh Mohimen5, Simmi Gupta6
1 Department of Medicine, Army Hospital Research and Referral, New Delhi, India
2 Department of Oncology, Army Hospital Research and Referral, New Delhi, India
3 Department of GI Surgery, Army Hospital Research and Referral, New Delhi, India
4 Department of Oncosurgery, Army Hospital Research and Referral, New Delhi, India
5 Department of Radiodiagnosis, Army Command Hospital, Lucknow, Uttar Pradesh, India
6 Department of Psychology, Christ College, Bangalore, India
|Date of Submission||02-Dec-2020|
|Date of Decision||06-Dec-2020|
|Date of Acceptance||04-Feb-2021|
|Date of Web Publication||14-Apr-2021|
Ravi K Anadure
Department of Medicine, Army Hospital Research and Referral, New Delhi - 110 010
Source of Support: None, Conflict of Interest: None
Background: Screening has led to reduction in mortality for cancers of the cervix, prostate, and colon. Advanced gall bladder carcinoma (GBC) have a poor prognosis, compared to early-stage GBC. The aim of this study was early detection of GBC by ultrasound screening, in a high-risk population. Data were analyzed to look at the impact of screening on staging, operability, and survival. Materials and Methods: In this prospective study spanning 4 years, 978 high-risk individuals as per defined criteria, were screened by ultrasound of the abdomen. The clinical profile of patients with screened GBC (S-GBC) and clinically evident GBC (C-GBC) was studied in terms of stage of detection, operability, and median overall survival (mOS). Results: Six cases of GBC were detected as S-GBC. These were compared with a control population of 119 GBC cases presenting to the cancer outpatient department (C-GBC) in the same period. It was found that S-GBC patients compared to C-GBC, had early stages of diagnosis (P = 0.001) and all underwent curative radical cholecystectomy compared to only 18.8% in C-GBC cases (P = 0.004). At 2 years follow-up, mOS was not reached for S-GBC patients as all patients were alive, compared to 9 months mOS in C-GBC cases (P < 0.05). Conclusions: Screening for GBC leads to the detection of GBC in early stages, ensures surgical resection, and significantly improves mOS. Ultrasound screening in high-risk population is recommended to improve the poor prognosis of GBC.
Keywords: Gall bladder carcinoma, overall survival, screening, ultrasound
|How to cite this article:|
Sreen A, Anadure RK, Singh H P, Sharma AK, Sharma R, Mohimen A, Gupta S. The utility of screening ultrasound in early diagnosis of gall bladder cancer among high-risk population. Oncol J India 2021;5:8-12
|How to cite this URL:|
Sreen A, Anadure RK, Singh H P, Sharma AK, Sharma R, Mohimen A, Gupta S. The utility of screening ultrasound in early diagnosis of gall bladder cancer among high-risk population. Oncol J India [serial online] 2021 [cited 2021 Sep 17];5:8-12. Available from: https://www.ojionline.org/text.asp?2021/5/1/8/313671
| Introduction|| |
Screening helps to detect and treat cancer early, and in turn, improves long-term outcomes. In general, cancer treatment is more effective when the disease is found early. Screening tests are used widely to check for cancers of the breast and cervix. However, not all cancers have screening tests. Screening gives lead time by diagnosing the malignancy at an early stage and increasing the chance of treatment with curative intent. Gall bladder carcinoma (GBC) is a common and aggressive malignancy, seen in the Indo Gangectic belt. The female gender is more commonly effected than males. Risk factors of carcinoma gall bladder are both inflammatory and noninflammatory. Gallstones, porcelain gallbladder, primary sclerosing cholangitis, the anomalous pancreaticobiliary junction (APBJ), and chronic GB infection are possible inflammatory risk factors for GBC. Noninflammatory risk factors for GBC are age, gender, socioeconomic status, genetics, and Aflatoxin.
Gallstone disease or gallbladder lithiasis is present in 70%–90% of patients with GBC.,, A history of gallstones appears to be one of the strongest risk factors for the development of GBC.,, A case-control study from Shanghai showed a 34-fold increase in the risk of GBC in patients with gallbladder lithiasis. The overall incidence of GBC in patients with gallstone disease is only 0.5%–4%. The risk increases with the duration of lithiasis and the size of gallstones.,, Indeed, the relative risk of GBC in patients with gallstones is 2.4 if the diameter is 2.0–2.9 cm, but increases to 10.1 if larger than 3.0 cm.
Since 10%–30% of GBC cases do not have gallstone disease and only a small proportion (0.5%–4%) of patients with gallbladder lithiasis develop GBC, other factors may be important in the development of GBC.,,, For example, some ethnic and racial groups show an incidence of GBC higher than expected for their frequency of gallstone disease, suggesting that other environmental or genetic factors may also play a role in the course of carcinogenesis. Carcinoma gall bladder also has a typical geographical distribution like the Indo-Gangetic plane in India, with very less cases seen in other parts of the country.
The symptoms at presentation are vague and are most often related to adjacent organ invasion. The majority of patients with GBC in India present as advanced unresectable disease and results in high mortality., The ease by which this tumor invades the liver and surrounding structures contributes to its high mortality. In a recent study of 132 GBC patients who underwent gallbladder surgery the 1-, 3-, and 5-year survival rate reported was 37%, 11%, and 3%, respectively. Several studies from India and the West have also reported GBC as having a dismal prognosis.,, Early-stage GBC is defined as those confined to the mucosa or muscular layers and are cured with a simple cholecystectomy. Patients with stage II disease are treated with radical cholecystectomy and have a 5-year survival rate of 70%–80%. Stage T1b gallbladder cancers are also managed by radical cholecystectomy. Patients with stage III disease, despite surgical intervention, have a reduced 5-year survival of 45%–60%. Stage IV disease is always treated with palliative intent with no role of curative surgical intervention. GBC fulfills most criteria needed for the screening of cancer, such as, a high prevalence in states of UP and Bihar and ease of detection by ultrasound, which is safe and easily available.
The primary aim of this study was to attempt early detection of GBC by screening with ultrasound, in the high-risk population of UP and Bihar, and see the impact screening had on staging, treatment and survival. The secondary aim was to study the prevalence of Gall stone disease in this population.
| Materials and Methods|| |
A total of 978 high-risk population who fulfilled the criteria for screening were evaluated with ultrasonography (USG) abdomen, at a tertiary care hospital in Lucknow, from June 2013 to Aug 2015, with a follow-up period of 2 years till August 2017. The control population included 119 cases of C-GBC who presented to the cancer OPD of the hospital, in the same period (June 2013 to August 2015). This prospective hospital-based study was approved by the Institutional Ethics Committee (IEC/CHCC/46/2013). All participants in the study were recruited from OPD cases of other departments, and screening USG was performed only after written informed consent.
In a previous USG-based study for gall bladder diseases (stones, polyps, GBC), it was suggested that females above 40 years of age living in endemic zones (eastern Uttar Pradesh and western Bihar), should be screened by sonography at least once annually.
We adopted and modified the above criteria to define the population at high-risk for the development of GBC, which included:
- Residents of Uttar Pradesh and Bihar living for >5 years in the states
- Age >50 years.
After an overnight fast, real-time, gray-scale, B-mode ultrasound scanning (Sonoline 250, Siemens) was done with the subject in the supine and the right lateral position, using a sector mechanical transducer (3.5 and 5 MHz), by a radiologist. Patients who had suspicious features during USG (focal wall thickening, loss of interface with liver) were further evaluated with cross-sectional Gadolinium enhanced magnetic resonance imaging and tumor markers. After confirmation of USG findings on cross-sectional imaging, patients were taken up for surgery. Radical cholecystectomy with wedge liver resection and lymph node dissection was done in all patients (after frozen section confirmation). Only the patients who had a final biopsy-proven malignancy were included in screened GBC (S-GBC) group.
GBC patients detected on screening of a high-risk population (S-GBC) were compared with a control of 119 clinically evident GBC (C-GBC) cases who had directly presented to the cancer outpatient department of the hospital during the study period. Four parameters were used for comparison in these two groups which included stage of presentation, surgical resectability, survival rates, and median overall survival (mOS). All patients in the study were followed up every 3 months for 2 years, with emphasis on the above-mentioned parameters. A Pearson's Chi-squared test was used to compare the difference between the two groups.
| Results|| |
A total of 978 high-risk population who fulfilled the criteria for screening were evaluated with a USG abdomen, at a tertiary hospital in Lucknow, from June 2013 to August 2015. The screening detected suspicious GB wall abnormalities in eight patients, of which six had a postoperator HPE confirmation of malignancy (S-GBC cases). The control population included 119 cases of C-GBC who presented to the cancer OPD of the hospital, in the same period. The prevalence of GBC in high-risk populations was reported to be 0.61%.
The baseline demographic, clinical, and imaging characteristics of both the study populations were shown in [Table 1]. The median age at diagnosis of S-GBC was 58 years and that of C-GBC was 60 years (P = 0.282). There was a female predominance for both S-GBC and C-GBC groups with a male-to-female ratio of 1:2 and 1:2.7, respectively [Table 2].
|Table 1: Staging, resectability, and survival in screened gall bladder cancer versus clinically evident gall bladder cancer|
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The stage at diagnosis, treatment, and outcome comparisons between the S-GBC and C-GBC groups is mentioned in [Table 1]. Majority of patients in the S-GBC group had the earlier stage at diagnosis, i.e., stage II disease (5 out of 6 cases) as compared to C-GBC group, where the majority were in Stage III or IV and the difference was statistically significant (P = 0.001). S-GBC patients at diagnosis had no distant metastasis on positron emission tomography-computed tomography imaging. Curative radical cholecystectomy followed by adjuvant chemotherapy was performed in all 6 cases of S-GBC, whereas only 32 out of 119 (26.9%) C-GBC patients were able to undergo the same (P = 0.004). All S-GBC patients were alive at 2-years follow-up as compared to 70 out of 119 (58.8%) patients in the C-GBC group (P = 0.01). There was no recurrence found among S-GBC patients at 2-year follow-up. The mOS for S-GBC patients was not reached as all patients were alive at 2-year follow-up, whereas, mOS of C-GBC group was only 9 months (P < 0.05) [Figure 1].
|Figure 1: Survival of S-GBC (screened) versus C-GBC cases (nonscreened). (Legend: Cum Survival-Cumulative Survival, OSMONTH-Median overall survival in months)|
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| Discussion|| |
Gallbladder cancer in India is mainly seen along the Gangetic plains of northern India, in states of UP and Bihar. It has an incidence of 4.5 cases per 100,000 population in men and 10.1 cases per 100,000 in women. The mean age of patients is 51 ± 11 years. Several studies highlight the poor prognosis of this disease with mOS being <1 year, and the reported 5-year OS being <10%.,, Screening is known to detect and treat some types of cancer early. Generally, cancer treatment is more effective when the disease is detected early. It has been found that screening leads to a reduction in cancer-specific mortality for different cancers such as breast, prostate, colon and cervix. There is presently no recommended screening guideline for GBC, because the incidence of GBC is low in the developed world. Ultrasound has been used as a tool for screening for Gall bladder diseases in earlier studies where Pandey et al. detected 03 cases of GBC out of 515 cases screened. No data on treatment, stage of detection, or survival of these patients is available. Okamoto et al. detected 19 GBC cases out of 194,767 screened cases. All of them underwent radical surgery, though no data on the impact of screening on cure rates or survival is reported.
Out of the 6 cases of S-GBC, detected by the USG screening method in the present study, five (83.3%) belonged to Stage II and one patient (16.7%) had a stage IIIB tumor, compared to C-GBC patients who has 23 cases (19.3%) in Stage III and 74 (62.2%) cases in advanced Stage IV disease. This was comparable to other studies from this part of the world on Clinically evident GBC, which showed 18% of patients having stage 3 tumor and 78% in stage 4 tumors at presentation.
It was found in this study that S-GBC patients had their disease detected in early stages compared to C-GBC, which directly translates into improved survival. It was also found in this study that all the six S-GBC patients were able to undergo curative radical cholecystectomy followed by adjuvant chemotherapy. In contrast, only 32 (26.9%) patients of C-GBC patients were able to undergo this definite curative treatment. All S-GBC patients were alive at 2 years follow-up, compared to only 70 (58.8%) in C-GBC, suggesting that screening is an effective tool to overcome the dismal prognosis of GBC. The mOS for S-GBC patients had not been reached as all patients were alive at the last follow-up of 2 years, in contrast, mOS of C-GBC patients is only 9 months. This directly implies that screening improves detection of GBC in early stages and allows surgical treatment with curative intent, which results in better survival in these patients.
Other methods of screening for GBC have also been reported in the literature. Serum levels of carcino-embryonic antigen (CEA) and CA 19-9 has been used for screening GBC patients. The authors feel that serum CA 19-9 and CEA are good tests for discriminating patients with GBC from patients with gallstones and nonmalignant conditions. However, they are not cost-effective as screening tools for GBC. Some authors from Chile and UK have advised prophylactic cholecystectomy in patients with cholelithiasis,,, to bring down the incidence of GBC. In India also, prophylactic cholecystectomy has been recommended as a strategy to deal with the high incidence of gallbladder cancer in the north of the country. However, at the same time, it has been appreciated that cholecystectomies are not without the risk of complications. Hence, a more noninvasive and feasible approach in the form of ultrasound screening is cost-effective with no complications, and can easily detect GBC in early stages. Given the 0.51% prevalence of GBC in the high risk population in previous studies and the 0.61% prevalence noted in this study, it is estimated that approximately 1.5 lakh people in the state of Uttar Pradesh and Bihar are presently harboring an undiagnosed GBC. Thus a State level or a National level policy on GBC screening among high-risk populations could save many valuable lives. The study has its limitations in that, it was a Hospital-based study and not population-based, which may have introduced a selection bias. Furthermore, the sample size was small, with a short follow-up period of 2 years.
| Conclusions|| |
GBC fulfills all criteria for screening in the high prevalence zones such as Uttar Pradesh and Bihar. USG screening detects GBC in early stages and enables curative Radical surgery, which significantly improves survival in this cancer. The estimated high burden of GBC in the States of Uttar Pradesh and Bihar along the Indo-Gangetic planes is sufficient reason to have a screening policy in place for high-risk populations, which will save innumerable lives at stake.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Dutta U, Bush N, Kalsi D, Popli P, Kapoor VK. Epidemiology of gallbladder cancer in India. Chin Clin Oncol 2019;8:33.
Hsing AW, Gao YT, Han TQ, Rashid A, Sakoda LC, Wang BS, et al
. Gallstones and the risk of biliary tract cancer: A population-based study in China. Br J Cancer 2007;97:1577-82.
Maringhini A, Moreau JA, Melton LJ 3rd
, Hench VS, Zinsmeister AR, DiMagno EP. Gallstones, gallbladder cancer, and other gastrointestinal malignancies. An epidemiologic study in Rochester, Minnesota. Ann Intern Med 1987;107:30-5.
Paraskevopoulos JA, Dennison AR, Ross B, Johnson AG. Primary carcinoma of the gallbladder: A 10-year experience. Ann R Coll Surg Engl 1992;74:222-4.
Zatonski WA, Lowenfels AB, Boyle P, Maisonneuve P, Bueno de Mesquita HB, Ghadirian P, et al
. Epidemiologic aspects of gallbladder cancer: A case-control study of the search program of the International Agency for Research on Cancer. J Natl Cancer Inst 1997;89:1132-8.
Chow WH, Johansen C, Gridley G, Mellemkjaer L, Olsen JH, Fraumeni JF Jr. Gallstones, cholecystectomy and risk of cancers of the liver, biliary tract and pancreas. Br J Cancer 1999;79:640-4.
Diehl AK. Gallstone size and the risk of gallbladder cancer. JAMA 1983;250:2323-6.
Serra I, Yamamoto M, Calvo A, Cavada G, Báez S, Endoh K, et al
. Association of chili pepper consumption, low socioeconomic status and longstanding gallstones with gallbladder cancer in a Chilean population. Int J Cancer 2002;102:407-11.
Koppatz H, Nordin A, Scheinin T, Sallinen V. The risk of incidental gallbladder cancer is negligible in macroscopically normal cholecystectomy specimens. HPB (Oxford) 2018;20:456-61.
Muszynska C, Lundgren L, Lindell G, Andersson R, Nilsson J, Sandström P, et al
. Predictors of incidental gallbladder cancer in patients undergoing cholecystectomy for benign gallbladder disease: Results from a population-based gallstone surgery registry. Surgery 2017;162:256-63.
Ghimire P, Yogi N, Shrestha BB. Kathmandu incidence of incidental carcinoma gall bladder in cases of routine cholecystectomy. Kathmandu Univ Med J 2011;9:3-6.
Andia M, Gederlini A, Ferreccio C. Gallbladder cancer: Trend and risk distribution in Chile. Rev Med Chi 2006;134:565-74.
Duggan MA, Anderson WF, Altekruse S, Penberthy L, Sherman ME. The Surveillance, Epidemiology and End Results (SEER) Program and Pathology: Towards strengthening the critical relationship. Am J Surg Pathol 2016;40:94-102.
Engineer R, Wadasadawala T, Mehta S, Mahantshetty U, Purandare N, Rangarajan V, et al
. Chemoradiation for unresectable gall bladder cancer: Time to review historic nihilism? J Gastrointest Cancer 2011;42:222-7.
Wang RT, Xu XS, Liu J, Liu C. Gallbladder carcinoma: analysis of prognostic factors in 132 cases. Asian Pac J Cancer Prev 2012;13:2511-4.
Fong Y, Jarnagin W, Blumgart LH. Gallbladder cancer: Comparison of patients presenting initially for definitive operation with those presenting after prior noncurative intervention. Ann Surg 2000;232:557-69.
Piehler JM, Crichlow RW. Primary carcinoma of the gallbladder. Surg Gynecol Obstet 1978;147:929-42.
Cubertafond P, Gainant A, Cucchiaro G. Surgical treatment of 724 carcinomas of the gallbladder. Results of the French Surgical Association Survey. Ann Surg 1994;219:275-80.
Pandey M, Pathak AK, Gautam A, Aryya NC, Shukla VK. Carcinoma of the gallbladder: A retrospective review of 99 cases. Dig Dis Sci 2001;46:1145-51.
Liu XF, Zhou LY, Wei ZH, Liu JX, Li A, Wang XZ, et al
. The diagnostic role of circulating inflammation-based biomarker in gallbladder carcinoma. Biomark Med 2018;12:1095-103.
Obuchowski NA, Graham RJ, Baker ME, Powell KA. Ten criteria for effective screening: Their application to multislice CT screening for pulmonary and colorectal cancers. AJR Am J Roentgenol 2001;176:1357-62.
Harris R, Yeatts J, Kinsinger L. Breast cancer screening for women ages 50 to 69 years a systematic review of observational evidence. Prev Med 2011;53:108-14.
Schröder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V, et al
. Prostate-cancer mortality at 11 years of follow-up. N Engl J Med 2012;366:981-90.
Baxter NN, Warren JL, Barrett MJ, Stukel TA, Doria-Rose VP. Association between colonoscopy and colorectal cancer mortality in a US cohort according to site of cancer and colonoscopist specialty. J Clin Oncol 2012;30:2664-9.
Sasieni P, Castanon A, Cuzick J. Effectiveness of cervical screening with age: Population based case-control study of prospectively recorded data. BMJ 2009;339:b2968.
Pandey M, Khatri AK, Sood BP, Shukla RC, Shukla VK. Cholecystosonographic evaluation of the prevalence of gallbladder diseases. A university hospital experience. Clin Imaging 1996;20:269-72.
Okamoto M, Okamoto H, Kitahara F, Kobayashi K, Karikome K, Miura K, et al
. Ultrasonographic evidence of association of polyps and stones with gallbladder cancer. Am J Gastroenterol 1999;94:446-50.
Singh SK, Talwar R, Kannan N, Tyagi AK, Jaiswal P, Kumar A. Patterns of presentation, treatment, and survival rates of gallbladder cancer: A prospective study at a tertiary care centre. J Gastrointest Cancer 2018;49:268-74.
Strom BL, Maislin G, West SL, Atkinson B, Herlyn M, Saul S, et al
. Serum CEA and CA 19-9: Potential future diagnostic or screening tests for gallbladder cancer? Int J Cancer 1990;45:821-4.
Serra I, Calvo A, Maturana M, Medina E, Sharp A. Changing trends of gall-bladder cancer in Chile, a high-risk area. Int J Cancer 1990;45:376-7.
Chianale J, del Pino G, Nervi F. Increasing gall-bladder cancer mortality rates during the last decade in Chile, a high-risk area. Int J Cancer 1990;46:1131-3.
Diehl AK, Beral V. Cholecystectomy and changing mortality from gallbladder cancer. Lancet 1981;2:187-9.
Mohandas KM, Patil PS. Cholecystectomy for asymptomatic gallstones can reduce gall bladder cancer mortality in northern Indian women. Indian J Gastroenterol 2006;25:147-51.
] [Full text]
Shamiyeh A, Wayand W. Laparoscopic cholecystectomy: Early and late complications and their treatment. Langenbecks Arch Surg 2004;389:164-71.
Kapoor VK. Cholecystectomy in patients with asymptomatic gallstones to prevent gall bladder cancer – The case against. Indian J Gastroenterol 2006;25:152-4.
] [Full text]
[Table 1], [Table 2]