The authors have declared that no competing interests exist.
Gallbladder (GB) cancer is a highly fatal malignancy and approx. 10% new cases are diagnosed every year in India. The GB cancer has poor prognosis due to progressive nature. Understanding of risk factors that lead to GB development is urgently required for better management of the disease. Presence of stones in gall bladder generates varied mucosal reactions, which leads to different types of histopathological changes in mucosa. Here, our aim is to study the correlation between various types of mucosal responses e. g. inflammation, hyperplasia, metaplasia and carcinoma with different characteristics e. g. number and morphology of gallstones both in males and females.
A retrospective study of gallstones was performed on 438 cases of cholecystectomies operated laparoscopically based on the histological changes. Out of 438 cases, 394 (89.95%) were associated with gallstones and the rest 44 (10.05%) belonged to acalculous cholecystitis. The mucosal changes in calculous gall bladder were studied in 394 cases and its correlation with number and types of observed gallstones were evaluated. Tissue sections were taken from the fundus, body, neck and abnormal area of gallbladder for histopathological studies.
Our study has revealed the higher incidence of inflammatory changes in males, while gall bladder hyperplasia, intestinal metaplasia and cancer cases were found mostly in females.
Our study showed that changes in the number and morphology of gallstones are directly associated with the mucosal changes in gallbladder e.g. inflammation, hyperplasia, metaplasia and gall bladder carcinoma.
Cholelithiasis induces diverse histopathological changes in the gallbladder mucosa e.g. acute & chronic inflammation, hyperplasia, granulomatous inflammation, cholesterosis, dysplasia, and carcinoma
In a recent paper
Etiology and pathogenesis of GB cancer is not well known. The main difficulty in studying the precursor lesions of this disease is the fact that it is impossible to perform follow-up, because the diagnosis is established during surgery or after the cholecystectomy.
Therefore, the evidence relating these lesions to the cancer is determined indirectly. A better understanding of the risk factors for gall bladder cancer and premalignant lesions of the gall bladder could help in selection of prophylactic cholecystectomies and thus reduction in mortality
A retrospective study was conducted on 438 patients from a rural medical college between Jan 2018-Dec 2019, who underwent laparoscopic cholecystectomies. Out of 438 patients, 394 (89.95%) had gallstones and remaining 44 patients (10%) had acalculous cholecystitis. We examined the changes in the mucosa of calculous gall bladder for 394 patients (90%). Various parameters, (i) single or multiple (ii) type of morphology e.g. cholesterol/ pigmented/ combined/ mixed were used for evaluation of the gallstones. The histopathological examination was performed in four sections, (i) in two sections, tissue was taken from fundus and neck of the gall bladder and (ii) in other sections, tissue was taken from abnormal appearing mucosa. All sections were stained with hematoxylin and eosin.
Abdominal ultrasound was performed to diagnose the cholecystolithiasis in all patients aged from 12-89 years old. In ultrasound, the gallbladder changes did not indicate the presence of GB cancer in any patient before preoperative stage. The surgeon conducted the macroscopic examination and laparoscopically removed the gallbladder. All tissues were subjected to histopathological analysis to examine the response e.g. inflammation, acute cholecystitis, chronic cholecystitis, empyema, xanthogranulomatous cholecystitis, hyperplasia, intestinal metaplasia, dysplasia, and malignant changes in gallbladder mucosa and its correlation with number and morphological type of stones.
We examined the 438 cholecystectomy specimens, in which 394 cases (90%) belonged to gallstones and the rest 44 cases (10%) belonged to acalculous cholecystitis. We examined the mucosal changes in gallbladder for 394 cases to identify the correlation between mucosal changes and number and type of observed gallbladder stone. Out of 394 patients, 78 were males and 316 were females with M/F ratio 1:4. The observed mucosal changes in male and female patients are shown in
Type of lesion | Male | Female | Total |
|
Chronic Cholecystitis | 57 | 284 | 341 | 0.004 |
Acute cholecystitis | 4 | 1 | 5 | 0.004 |
Cholesterosis | 3 | 6 | 9 | 0.004 |
Follicular Cholecystitis | 0 | 0 | 0 | 0.004 |
Xanthogranulomatous Cholecystitis | 7 | 9 | 16 | 0.004 |
Papillary Hyperplasia | 1 | 3 | 4 | 0.004 |
Adenomatoid Hyperplasia | 0 | 2 | 2 | 0.004 |
Gastric Metaplasia | 0 | 2 | 2 | 0.004 |
Intestinal Metaplasia | 6 | 8 | 14 | 0.004 |
Carcinoma | 0 | 1 | 1 | 0.004 |
(
No. Of Stones | |||
Type of Stone | Single | Multiple | Total |
Cholesterol | 23 | 18 | 41 |
Mixed | 49 | 227 | 276 |
Pigmented | 37 | 40 | 77 |
(
Number of Stones |
|
|||
Type of lesion | Single | Multiple | Total cases | |
Chronic Cholecystitis | 92 | 249 | 341 | 2.6x10-12 |
Acute cholecystitis | 0 | 5 | 5 | 2.6x10-12 |
Cholesterosis | 4 | 5 | 9 | 2.6x10-12 |
Follicular Cholecystitis | 0 | 0 | 0 | 2.6x10-12 |
Xanthogranulomatous Cholecystitis | 5 | 11 | 16 | 2.6x10-12 |
Papillary Hyperplasia | 2 | 2 | 4 | 2.6x10-12 |
Adenomatoid Hyperplasia | 0 | 2 | 2 | 2.6x10-12 |
Gastric Metaplasia | 1 | 1 | 2 | 2.6x10-12 |
Intestinal Metaplasia | 5 | 9 | 14 | 2.6x10-12 |
Carcinoma | 0 | 1 | 1 | 2.6x10-12 |
(
Type of Stone | ||||
Type of lesion | Cholesterol | Mixed | Pigmented | Total |
Chronic Cholecystitis | 39 | 249 | 53 | 341 |
Acute cholecystitis | 1 | 2 | 2 | 5 |
Cholesterosis | 1 | 2 | 6 | 9 |
Follicular Cholecystitis | 0 | 0 | 0 | 0 |
Xanthogranulomatous Cholecystitis | 0 | 9 | 7 | 16 |
Papillary Hyperplasia | 0 | 1 | 3 | 4 |
Adenomatoid Hyperplasia | 0 | 2 | 0 | 2 |
Gastric Metaplasia | 0 | 1 | 1 | 2 |
Intestinal Metaplasia | 0 | 9 | 5 | 14 |
Carcinoma | 0 | 1 | 0 | 1 |
In the current work, a retrospective study on 394 patients was carried out to find the correlation between gallstones (number and morphology) with mucosal changes that occur in the gall bladder. It is already known that cholecystolithiasis is associated with GB cancer, as cholecystolithiasis is observed in 80% of all GB cancer cases
Mixed stones incidence (70.05%) was most commonly observed gallstone in North India and also observed in our study
Precancerous gall bladder mucosal changes are important clinically as well as pathologically, however not studied carefully by pathologist earlier
Higher incidence of cholecystolithiasis was observed in females compared to males, which causes increased risk of gall bladder cancer. This may be due to decrease in activity of cholesterol reductase and increase in activity of HMG-CoA reductase with age, resulting in increased cholesterol secretion and saturation of bile. The female sex hormones may also expose them to factors that possibly promote the formation of gallstones. Early menarche, early first pregnancy, multiple pregnancies, and delayed menopause may increase the risk of gall bladder carcinoma
An earlier study
In our study, the incidence of acute cholecystitis was higher in males as observed in other study
Adenomatoid hyperplasia, a non-inflammatory benign gall bladder alteration, mostly occurred in middle aged patients and increased with age. It is presently identified as a precancerous lesion, and cancer cases associated with adenomyomatosis have been reported in literature
In our study, we observed that metaplasia and dysplasia increased with age and the metaplastic alterations and dysplasia are taken as precancerous lesions. The gall bladder cancer is an extremely slow progressive disease and prolonged follow up may be needed
Whether prophylactic cholecystectomy should be performed in asymptomatic gallstones is a matter of debate. However, an Indian study recommends prophylactic cholecystectomies for asymptomatic gallstones in young patients with thickened GB wall (greater than 3 mm), with large gallstones (greater than 3 cm), patients with porcelain GB, sessile polyps (greater than 1 cm) and in people from areas with high incidence rates of GB cancer
Our study advocates that there is correlation between gall bladder stones and gall bladder histological changes. Nonetheless, further work is needed to understand about various risk factors of gall bladder cancer. Our data is crucial to establish the surgical treatment for various pathological gall bladder conditions e.g. symptomatic or asymptomatic calculous cholecystitis.
Our study showed that patients with multiple gallstones were more symptomatic (cholecystitis) than with single stone. The mucosal changes like hyperplasia, metaplasia, and carcinoma were also more common in cases with multiple mixed type of stones. Etiology or pathogenesis of multiple stones were more symptomatic (cholecystitis) than with single stone and mucosal changes like hyperplasia, metaplasia, and carcinoma were also more common in cases with multiple mixed type of stone. Still, we require further studies to understand gall bladder stones leading to carcinogenesis and risk factors.