Prophylactic cholecystectomy for asymptomatic gallstone disease: Two case reports and review of literature

Abstract

BACKGROUND

Whether the gallbladder should be removed prophylactically for asymptomatic gallstone disease (AGD) is still debated. Gallbladder stone is a risk factor for gallbladder cancer (GBC), although the cancerization incidence associated with silent gallbladder stones is low. We herein describe two cases of AGD that resulted in xanthogranulomatous cholecystitis and GBC, aiming to investigate the debated issue and the risk factors.

CASE SUMMARY

The first case was a 62-year-old male with a history of cholecystolithiasis for > 20 years, which became symptomatic in the past 16 months. Enhanced computed tomography showed diffuse inhomogeneous thickening of the gallbladder wall, and cholecystitis with abscess was considered first. However, magnetic resonance imaging unexpectedly suggested GBC with liver involvement. After a negative biopsy pathology for tumor, surgery was still suggested. During the operation, frozen section biopsy revealed no cancer cells, and routine postoperative pathology suggested xanthogranulomatous cholecystitis. Ultimately, the patient recovered uneventfully. The second case was a 65-year-old male farmer with a history of cholecystolithiasis for > 30 years. He had experienced right upper quadrant and periumbilical pain for 2 months and yellow skin for 1 month. Imaging suggested GBC or hilar cholangiocarcinoma, with multiple intrahepatic metastases. Biopsy revealed poorly differentiated carcinoma; therefore, palliative chemotherapy was suggested.

CONCLUSION

Although prophylactic cholecystectomy is not indicated for the general population with AGD, timely operation is suggested when there are signs of abnormality or risk factors.

Key Words: Case report; Asymptomatic gallstone disease; Silent gallbladder stones; Prophylactic cholecystectomy; Xanthogranulomatous cholecystitis; Gallbladder cancer

Core Tip: Whether the gallbladder should be removed prophylactically for asymptomatic gallstone disease (AGD) is still debated. We herein describe two cases with a long history of AGD. In the first case, magnetic resonance imaging suggested gallbladder cancer with liver involvement, but postoperative pathology demonstrated xanthogranulomatous cholecystitis. In the second case, imaging suggested metastatic gallbladder cancer, and biopsy confirmed the diagnosis. Although prophylactic cholecystectomy is not indicated for all AGDs to avoid future risk, annual follow-up is urgently needed. If signs of abnormality or risk factors are present, timely surgery is suggested.

INTRODUCTION

Cholelithiasis (gallstones), especially cholecystolithiasis (gallbladder stones), is very common worldwide. The incidence is 10%-20% in Western populations[1-3] and 2.3%-6.5% in China[4]. Symptomatic cholecystolithiasis usually induces right upper quadrant and mid-back pain, prompting cholecystectomy, especially in patients who have experienced several episodes. However, 50%-70% of cholecystolithiasis patients are asymptomatic at the time of diagnosis[3]. For this subgroup with silent gallbladder stones, whether or not the gallbladder should be removed prophylactically remains a topic of debate.

Characterized by a benign natural course, asymptomatic gallstone disease (AGD) progresses from asymptomatic to symptomatic with a relatively low rate of 10%-25%[3] and about 2%-4% annually[5]. Most patients cannot accept the concept of “organ incompleteness”. Doctors are increasingly realizing that the short- and long-term surgical complications, and the postoperative absence of gallbladder function, cannot be totally ignored. Therefore, caution is needed in determining the treatment for AGD. However, gallbladder stone is a risk factor for gallbladder cancer (GBC)[6], and the risk is not lower for silent gallbladder stones as they still grow over time. In AGD, gallbladder stones are not truly silent, with a long-term possibility of acute episodes and serious diffuse destructive inflammation [e.g., xanthogranulomatous cholecystitis (XGC)] or even GBC[7-9]. Although GBC is less likely than post-cholecystectomy complications[10,11], the consequences of a long history of silent gallbladder stones are more severe than the operation-related complications. Here we report two cases of silent gallbladder stones with negative consequences, aiming to investigate the debated issue and identify the risk factors.

CASE PRESENTATION

Chief complaints

Case 1: A 62-year-old male teacher experienced abdominal distension with distending pain in his back, a poor appetite, and constipation for the past 16 months.

Case 2: A 65-year-old male farmer started to experience debilitating right upper quadrant and periumbilical pain, with poor appetite, 2 months ago. He also experienced abdominal distention and yellow skin, sclera, and urine in the past month.

History of present illness

Cases 1 and 2 had AGD for > 20 and > 30 years, respectively.

History of past illness

Both cases denied any history of past illness.

Personal and family history

Case 1’s father died of gastric cancer, whereas case 2’s history was unremarkable.

Physical examination

General and abdominal examinations revealed mild tenderness in the right upper abdomen in both cases.

Laboratory examinations

Case 1: Carbohydrate antigen 125 (CA125) had increased to 35.3 U/mL (reference range: 0.0-35.0 U/mL), carcinoembryonic antigen and CA199 were in the normal range, while liver function was almost in the normal range.

Case 2: Carcinoembryonic antigen had increased to 16.3 ng/mL (reference range: 0.0-5.0 ng/mL), CA125 elevated to 559.8 U/mL (reference range: 0.0-35.0 U/mL), and CA199 to > 12000 U/mL (reference range: 0.0-37.0 U/mL). Liver function test showed slight abnormalities.

Imaging examinations

Case 1: Ultrasonography (US) showed disappearance of the normal gallbladder wall, with multiple hypoechoic masses suspected as occupying lesions. Contrast-enhanced computed tomography showed diffused inhomogeneous thickening of the gallbladder wall (Figure 1A), and cholecystitis with abscess was considered initially. However, magnetic resonance imaging suggested GBC with liver invasion (Figure 1B).

Figure 1 Preoperative imaging examinations of the first case. The imaging examinations did not exclude gallbladder cancer. A: Contrast-enhanced computed tomography showed diffused inhomogeneous thickening of the gallbladder wall. Cholecystitis with abscess was considered initially; B: Magnetic resonance imaging suggested gallbladder cancer with liver involvement. DWI: Diffusion weighted imaging; T1WI: T1 Weighted imaging; T2WI: T2 Weighted imaging.

Case 2: Local hospital US examination found multiple hypoechoic lesions, and liver cancer was considered. Cholecystolithiasis, cholestasis, a rough and thickened gallbladder wall, common bile duct and intrahepatic bile duct dilation, enlarged post-peritoneal lymph nodes, and massive ascites were also found. Contrast-enhanced computed tomography and magnetic resonance imaging suggested GBC or hilar cholangiocarcinoma (Figure 2), with involvement of all extrahepatic bile ducts, the portal vein, and its branches, multiple intrahepatic metastases, multiple portal and retroperitoneal lymph node metastases, and cholecystolithiasis.

Figure 2 Preoperative imaging examinations of the second case. A: Contrast-enhanced computed tomography; B: Magnetic resonance imaging of the second case suggested gallbladder cancer or hilar cholangiocarcinoma, with involvement of all extrahepatic bile ducts and the portal vein and its branches. Multiple intrahepatic metastases, multiple portal and retroperitoneal lymph node metastases, and cholecystolithiasis were observed. DWI: Diffusion weighted imaging; T1WI: T1 Weighted imaging; T2WI: T2 Weighted imaging.

MULTIDISCIPLINARY EXPERT CONSULTATION

Case 1

After careful discussion of multidisciplinary treatment, biopsy was suggested because malignancy could not be excluded. However, biopsy pathology was negative for tumor (Figure 3). Therefore, aggressive surgery was suggested.

Figure 3 Biopsy pathology of the first case showing no evidence of tumor. Hematoxylin and eosin staining showed necrosis of liver tissue, with chronic inflammatory cell infiltration and proliferation of fibrous tissue, in accordance with the positive cluster of differentiation 3 (CD3) and CD20 staining. Other immunohistochemistry assays suggested positive cytokeratin 7 and CD56 staining, and negative staining for hepatitis B surface antigen, cytomegalovirus type 2, and Epstein-Barr virus-encoded small RNAs. HE: Hematoxylin and eosin; HBS: Hepatitis B surface antigen; CMV2: Cytomegalovirus type 2; EBER: Epstein-Barr virus-encoded small RNAs; CK: Cytokeratin; CD: Cluster of differentiation.

Case 2

After multidisciplinary treatment consultation, GBC was considered initially. Biopsy and subsequent chemotherapy were recommended since there was no indication for operation.

FINAL DIAGNOSIS

Case 1

During the operation, an extremely firm cancer-like mass with involvement of the surrounding tissues and the hepatic flexure of the colon was noticed. Rapid frozen-section biopsy was negative for malignancy, leading to a diagnosis of XGC, and postoperative routine pathology unexpectedly revealed focal gallbladder wall mucosal shedding, infiltration by a large number of acute and chronic inflammatory cells, hemorrhage and necrosis, and a multinucleated giant cell reaction. All of these findings are in accordance with XGC (Figure 4), a rare inflammatory disease.

Figure 4 Postoperative routine pathology of the first case. Routine pathology revealed focal gallbladder wall mucosal shedding, infiltration by a large number of acute and chronic inflammatory cells, hemorrhage and necrosis, and a multinucleated giant cell reaction. All of these findings are in accordance with xanthogranulomatous cholecystitis.

Case 2

Biopsy pathology revealed poorly differentiated carcinoma (Figure 5), which further confirmed the diagnosis of GBC.

Figure 5 Biopsy pathology of the second case. The biopsy pathology of the second case revealed poorly differentiated carcinoma, and immunohistochemistry staining suggested positive cytokeratin 7, cytokeratin 19, caudal-type homeobox transcription factor 2 and human epidermal growth factor receptor 2. HE: Hematoxylin and eosin; CK: Cytokeratin; CDX2: Caudal-type homeobox transcription factor 2; Her-2 (4B5): Human epidermal growth factor receptor 2; AR: Androgen receptor; Arg-1: Arginase-1; CD: Cluster of differentiation; CPC: Chorionic papillary carcinoma; PAX: Paired box gene; PSA: Prostate-specific antigen; TFE: Transcription factor E.

TREATMENT

Case 1

Open cholecystectomy was performed successfully.

Case 2

Chemotherapy after biopsy was suggested. However, the patient and his family refused the treatment plan due to the poor prognosis.

OUTCOME AND FOLLOW-UP

Case 1

The patient recovered uneventfully, and discharged one week after operation, and achieved long-term survival.

Case 2

The patient refused chemotherapy and was discharged from hospital, and died 1.5 months later because of liver failure.

DISCUSSION

Whether AGD should be prophylactically treated has long been a topic of debate. Currently, despite some controversies, most experts believe prophylactic removal of the gallbladder is not beneficial. Several guidelines recommend expectant observation after careful evaluation of the gallbladder wall and excluding some high risks[1,5,12,13], given the lack of evidence from randomized controlled trials supporting prophylactical cholecystectomy for AGD[14], the relatively low incidence of future silent gallbladder stone-related symptoms and complications, and the possibility of operation induced complications. Prophylactical cholecystectomy is not recommended[5,15], although the evidence is of low or very low quality. Conservative surveillance management for the vast majority of gallstone patients was supported by most investigators, while elective cholecystectomy is only recommended for specific patient populations[8], such as hemolytic anemia patients[16] or native Americans[17,18], at increased risk of developing gallbladder stone-related symptoms and complications.

It is considered to be an overly aggressive management for all patients with silent gallbladder stones to receive routine prophylactic cholecystectomy, which is not indicated in most AGD patients[3]. However, some recommend “aggressive treatment” because silent gallbladder stones are not truly silent. Wacha and Ungeheuer[19] reported relatively high rates of conversion from an asymptomatic to symptomatic state, with up to 50% of patients with AGD operated on or developing symptoms within 10 years to 20 years after the initial diagnosis[3].

Both of our patients delayed their treatments, which resulted in XGC and even GBC. Both patients had some risk factors, especially a long history of cholecystolithiasis and lack of regular observation, such as US every 6 months, which has noninvasive nature, high sensitivity and specificity, universal accessibility and affordability. Emerging cholecystectomy-related complications can be treated, and postoperative discomfort, such as fatty diarrhea, can be resolved.

It still remains elusive with the exact pathogenesis of XGC, but gallbladder stones and cholestasis are usually considered to be implicated in it. Pathologically, XGC is defined by focal or diffuse inflammatory destruction, alongside the accumulation of lipid-laden macrophages and foamy histiocytes associated with significant fibroplasia. Radiologically, key manifestations include diffuse thickening of the gallbladder wall, homogeneous mucosal enhancement, intramural hypodense bands resulting from foamy histiocytes, pericholecystic fluid, and the presence of gallstones. These features occasionally pose challenges in distinguishing XGC from GBC. Although XGC has a relatively low incidence of 1%-6%[20], curative operation (colectomy, choledochectomy, choledochojejunostomy, and certain other complicated procedures) is not easy, and often requires open approach due to the extensive fibrotic and inflammatory nature of the disease, operation is still recommended[21]. As XGC is benign, if the patient recovers well, the prognosis is good.

GBC is a more malignant biliary tract cancer. Even for patients who undergo R0 resection, the 5-year survival rate is only 16%[22]. Adjuvant chemotherapy is required, which seriously affects quality of life, and a large proportion (75%) of patients have no chance of an operation when the malignancy is discovered[22].

Although rare, in selected areas with a higher incidence, such as India, Chile, and Japan, GBC is a significant source of mortality[23,24], possibly as a result of early-onset gallbladder stones[25,26]. Other risk factors include large gallbladder polyps[27,28] and a calcified or porcelain gallbladder[29], although this has been questioned recently[30,31]. Epidemiological study consistently demonstrates a close association between gallbladder stones and GBC across different populations. Patients affected by gallbladder stones bear nearly a four-fold increased likelihood of developing GBC. Gallbladder stones can be identified in around 80% of individuals diagnosed with gallbladder malignancy, and this association is more prominent for these with giant stones ≥ 3 cm in diameter[32].

The decision-making for incidentally detected gallbladder stones remains a challenging dilemma for clinicians as well as the patients. Solid clinical evidence regarding the therapeutic advantages of cholecystectomy has not yet been established, and most studies report that AGD progresses from asymptomatic to symptomatic with a relatively low rate of 10%-25%[33]. When evaluating the natural course of AGD, clinicians are primarily concerned about the onset of critical, life-threatening adverse events, including severe necrotizing pancreatitis, acute pyogenic cholangitis, XGC, and GBC. Although gallbladder stones are closely linked to GBC, the annual malignant transformation risk among AGD patients is below 0.01%, lower than the mortality associated with cholecystectomy[34], although the risk increases over time.

However, some researchers advocate surgical intervention for each AGD patient. Operation can be delivered with markedly improved safety prior to the development of severe or lethal complications, which usually tend to emerge in elderly populations and might necessitate emergency operation in older patients, who carry substantially elevated perioperative morbidity and mortality[35], which is the main argument. Laparoscopic cholecystectomy is also easier in asymptomatic patients[3]. Specifically, prophylactic gallbladder removal for GBC prevention is highly recommended for specific high-risk populations with silent gallstones, such as certain ethnic groups living in high GBC incidence areas[25,26,36,37] and patients with large gallstones (> 3 cm)[27,28].

Although prophylactic cholecystectomy is not indicated for AGD to prevent future risk, and even XGC and GBC, it demands attention[12]. Although progression from asymptomatic to symptomatic disease is relatively rare and slow, the risk increases over time. Annual follow-up including physical examination, abdominal US, and other modalities is appropriate[5] and urgently needed. For patients who have experienced at least one episode of biliary colic, examination at least every 6 months is suggested.

Age is also a risk factor; fatal complications usually occur at elderly populations, and surgery is more necessary in patients with a more advanced age, who carry substantially elevated perioperative morbidity and mortality. For patients who have risk factors or are worried about severe complications, prophylactic cholecystectomy is indicated. In view of the poor prognosis, if signs of abnormality are found, such as radiological findings of a thickened gallbladder wall (> 4 mm), or if XGC or GBC is highly suspected or biliary tract malignancy-related tumor markers are elevated, surgery is the first-line therapy. Surgery should be performed as soon as possible on the basis of consultation with the patient, even if no symptoms are observed. Actually, in recent years, a growing body of evidence has favored elective prophylactic cholecystectomy for AGD in the defined conditions[38-40].

Although cholecystectomy is a relatively simple operation associated with only minor injury and even without any complications, most patients refuse it. Many patients in China fear severe diarrhea, cholangiolithiasis relapse, compromised dietary habits, and even colon tumor after cholecystectomy based on the inaccurate information from the Internet or other sources. All these issues need to be discussed and addressed by surgeons. Although only two cases of AGD were presented in this report, there are likely many undiscovered ones given the universality of this disease. Using detailed and vivid cases, this paper reminds surgeons of the value of professional learning, helping them more effectively educate and guide patients to accept therapy suggestions on the basis of science.

CONCLUSION

Although prophylactic cholecystectomy is not indicated for AGD to prevent future risk, annual follow-up is urgently needed. Selection of cholecystectomy should be discussed with all AGD patients to make an informed decision. If signs of abnormality are found, including but not limited to certain ethnic groups, large gallstones (> 3 cm), thickened gallbladder wall (> 4 mm), large gallbladder polyps (> 1 cm), calcified or porcelain gallbladder, stone-filled gallbladders, timely surgery is suggested.